Organic chemistry
ORGANIC
CHEMISTRY
methane to macromolecules
JOHN D. ROBERTS
California Institute of Technology
ROSS STEWART
University of British Columbia
MARJORIE C. CASERIO
University of California, Irvine
$%
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W. A. BENJAMIN, INC.
New York 1971
Organic chemistry: Methane to macromolecules
Copyright © 1971 by W. A. Benjamin, Inc.
All rights reserved
Standard Book Number 8053-8332-8
Library of Congress Catalog Card Number 71-130356
Manufactured in the United States of America
12345K54321
Portions of this book appeared previously in
Modern Organic Chemistry
by John D. Roberts and Marjorie C. Caserio,
published by W. A. Benjamin, Inc.
1967, New York
W. A. BENJAMIN, INC.
New York, New York 10016
preface
The success achieved by this book's forerunners, Basic Principles of Organic
Chemistry and Modern Organic Chemistry, was to a considerable extent due
to the rigor with which the subject of organic chemistry was presented. In the
present work we have tried to paint an interesting, relevant, and up-to-date
picture of organic chemistry while retaining the rigorous approach of the
earlier books.
Organic chemistry sometimes appears to be enormously complex to the
beginning student, particularly if he must immediately grapple with the
subjects of structural isomerism and nomenclature. We have attempted to
avoid this difficulty in the following way. Chapter 1 briefly relates carbon to
its neighbors in the Periodic Table and reviews some fundamental concepts.
Chapter 2 deals with the four C t and C 2 hydrocarbons — methane, ethane,
ethene, and ethyne — and discusses their conformational and configurational
properties and some of their chemical reactions. The reader thus makes an
acquaintance with the properties of some important organic compounds before
dealing in an open-ended way with families of compounds — alkanes, alcohols,
etc.
A heavy emphasis on spectroscopy is retained but the subject is introduced
somewhat later than in the earlier books. Important additions are chapters
dealing with enzymic processes and metabolism and with cyclization reac-
tions. Many of the exercises of the earlier books have been retained and have
been supplemented with drill-type problems.
It seems a shame to burden the mind of the beginning student with trivial
names, some of them quite illogical, and throughout we have stressed IUPAC
nomenclature, which is both logical and easy to learn. The instructor, who
may well carry lightly the excess baggage of redundant names, may occasion-
ally find this irritating but we ask him to consider the larger good. As a further
aid to the student, each chapter concludes with a summary of important
points.
The simple introduction to the subject and the emphasis on relevance,
particularly to living systems, should make the book appealing to the general
student. At the same time we hope that the up-to-date and more advanced
topics that are included — the effect of orbital symmetry on cyclization reac-
tions, for example — will also appeal to the chemistry specialist.
We should like to acknowledge the help of many persons who read all or
parts of the manuscript and offered sound advice. Professor George E. Hall
read the manuscript at several stages of revision and we are particularly
preface vi
grateful to him. Others who helped us were Drs. E. Caress, L. D. Hall, D. N.
Harpp, J. P. Kutney, T. Money, M. Smith, T. Spencer, and L. S. Weiler.
We conclude this preface on a mildly philosophical note. The world of to-
morrow will result from the interplay of powerful forces — some social, some
technological. Responsible public action requires public knowledge and there
are few areas of science that impinge more on the life around us than does
organic chemistry. We hope that those who study this book will utilize their
knowledge responsibly for the benefit of all who come after.
JOHN D. ROBERTS
ROSS STEWART
MARJORIE C. CASERIO
Pasadena, California
Vancouver, British Columbia
Irvine, California
contents
Chapter i Introduction I
1-1 Bonding in Organic Compounds 5
1-2 Methane, Ammonia, Water, and Hydrogen Fluoride 6
Summary 13
Exercises ^
Chapter 2 The C t and C 2 hydrocarbons 17
2-1 Molecular Shape of CH 4 , C 2 H 6 , C 2 H 4 , and C 2 H 2 20
2-2 Rotational Conformations of Ethane 21
2-3 Space-Filling Models 22
Chemical Reactions of the C t and C 2 Hydrocarbons 23
2-4 Combustion 23
2-5 Substitution Reactions of Saturated Hydrocarbons 26
2-6 Addition Reactions of Unsaturated Hydrocarbons 34
Summary 40
Exercises 41
Chapter 3 Alkanes 45
3-1 Nomenclature 47
3-2 Physical Properties of Alkanes— Concept of Homology 53
3-3 Alkanes and Their Chemical Reactions 56
3-4 Cycloalkanes 62
Summary ^2
Exercises ^4
Chapter 4 Alkenes 79
4-1 Nomenclature 81
4-2 Isomerism in C 4 H 8 Compounds 83
4-3 Cis and Trans Isomers 84
4-4 Chemical Reactions of Alkenes 86
Summary 103
Exercises 105
Chapter 5 Alkynes 109
5-1 Nomenclature HI
5-2 Physical Properties of Alkynes 112
contents viii
5-3 Ethyne 2J2
5-4 Addition Reactions of Alkynes 113
5-5 Alkynes as Acids U6
5-6 Synthesis of Organic Compounds 117
Summary 120
Exercises 121
Chapter 6 Bonding in conjugated unsaturated
systems 1 25
6-1 Bonding in Benzene 129
6-2 Conjugate Addition 133
6-3 Stabilization of Conjugated Dienes 135
6-4 Stabilization of Cations and Anions 137
6-5 Vinyl Halides and Ethers 139
6-6 Rules for the Resonance Method 140
6-7 Molecular Orbital Method of Htickel 140
Summary 145
Exercises 147
Chapter 7 Isolation and identification of
organic compounds 151
7-1 Isolation and Purification 153
7-2 Identification of Organic Compounds 156
Spectroscopy 159
7-3 Absorption of Electromagnetic Radiation 159
7-4 Infrared Spectroscopy 161
7-5 Ultraviolet and Visible Spectroscopy (Electronic Spectroscopy) 165
7-6 Nuclear Magnetic Resonance Spectroscopy 168
Summary 179
Exercises 180
Chapter 8 Nucleophilic displacement and
elimination reactions 185
8-1 Organic Derivatives of Inorganic Compounds 187
8-2 Alcohol Nomenclature 187
8-3 Ether Nomenclature 190
8-4 Carboxylic Acid Nomenclature 190
8-5 The Use of Greek Letters to Denote Substituent Positions 191
8-6 Single- or Multiple-Word Names 191
Nucleophilic Displacement Reactions 192
8-7 General Considerations 192
8-8 Mechanisms of S N Displacements 195
8-9 Energetics of S N 1 and S N 2 Reactions 197
8-10 Stereochemistry of S N 2 Displacements 200
8-11 Structural and Solvent Effects in S N Reactions 201
contents ix
Elimination Reactions 205
8-12 The E2 Reaction 206
8-13 The El Reaction 207
Summary 209
Exercises 210
Chapter 9 Alkyl halides and organometallic
compounds 215
9T Physical Properties 217
9-2 Spectra 217
9-3 Preparation of Alkyl Halides 218
9-4 Reaction of Alkyl Halides 219
9-5 Vinyl Halides 219
9-6 Allyl Halides ^ 220
9-7 Polyhalogen Compounds 222
9-8 Fluorinated Alkanes 224
9-9 Organometallic Compounds 226
Summary 236
Exercises 237
Chapter 10 Alcohols and ethers 243
10T Physical Properties of Alcohols 245
10-2 Spectroscopic Properties of Alcohols — Hydrogen Bonding 247
10-3 Preparation of Alcohols 249
Chemical Reactions of Alcohols 251
10-4 Reactions Involving the O— H Bond 251
10-5 Reactions Involving the C—O Bond of Alcohols 255
10-6 Oxidation of Alcohols 259
10-7 Polyhydroxy Alcohols 260
10-8 Unsaturated Alcohols 262
Ethers 262
10-9 Preparation of Ethers 263
10-10 Reactions of Ethers 264
10-11 Cyclic Ethers 265
Summary 266
Exercises 267
Chapter 11 Aldehydes and ketones I.
Reactions at the carbonyl group 273
11-1 Nomenclature of Aldehydes and Ketones 275
1 1 -2 Carbonyl Groups of Aldehydes and Ketones 275
11-3 Preparation of Aldehydes and Ketones 278
11-4 Reactions of Aldehydes and Ketones 281
Summary 294
Exercises 296
Chapter 12 Aldehydes and ketones II.
Reactions involving substituent
groups. Polycarbonyl compounds 301
12-1 Halogenation of Aldehydes and Ketones 303
12-2 Reactions of Enolate Anions 306
Unsaturated Carbonyl Compounds 310
12-3 a,j6-Unsaturated Aldehydes and Ketones 311
12-4 Ketenes 312
Polycarbonyl Compounds 313
12-5 1 ,2-Dicarbonyl Compounds 313
12-6 1,3-Dicarbonyl Compounds 314
Summary 316
Exercises 318
Chapter 13 Carboxylic acids and derivatives 327
13-1 Physical Properties of Carboxylic Acids 330
13-2 Spectra of Carboxylic Acids 334
13-3 Preparation of Carboxylic Acids 336
13-4 Dissociation of Carboxylic Acids 336
13-5 Reactions at the Carbonyl Carbon of Carboxylic Acids 339
13-6 Decarboxylation of Carboxylic Acids 341
13-7 Reactions at the 2 Position* of Carboxylic Acids 342
Functional Derivatives of Carboxylic Acids 344
13-8 Displacement Reactions of Acid Derivatives 344
13-9 Reactions at the 2 Position (oc position) of Carboxylic Acid
Derivatives 350
13-10 Reactions of Unsaturated Carboxylic Acids and Their
Derivatives 355
13-11 Dicarboxylic Acids 356
Summary 359
Exercises 361
Chapter 14 Optical isomerism. Enantiomers
and diastereomers 367
14-1 Plane-Polarized Light and the Origin of Optical Rotation 369
14-2 Specific Rotation 371
14-3 Optically Active Compounds with Asymmetric Carbon Atoms 372
14-4 Optically Active Compounds Having No Asymmetric Carbon
Atoms 379
14-5 Absolute and Relative Configuration 381
14-6 Separation or Resolution of Enantiomers 384
14-7 Asymmetric Synthesis and Asymmetric Induction 386
contents xi
14-8 Racemization 388
14-9 Inversion of Configuration 389
14-10 Optical Rotatory Dispersion 389
Summary 391
Exercises 393
Chapter 15 Carbohydrates 397
15-1 Classification of Carbohydrates 400
15-2 Glucose 402
15-3 Cyclic Structures 405
15-4 Mutarotation 4° 6
15-5 Glycosides 407
15-6 Disaccharides 408
15-7 Polysaccharides 410
15-8 Vitamin C 413
15-9 Immunologically Important Carbohydrates 413
Summary 4 ^ 4
Exercises 4 *°
Chapter 16 Organic nitrogen compounds 419
16-1 Amines 421
16-2 Amides 434
16-3 Nitriles 440
16-4 Nitroso Compounds 440
16-5 Nitro Compounds 441
16-6 Some Compounds with Nitrogen-Nitrogen Bonds 442
Summary
Exercises
Chapter 17 Amino acids, proteins, and nucleic
acids 455
17-1 Amino Acids 457
17-2 Lactams 467
17-3 Peptides 468
17-4 Protein Structures 474
17-5 Biosynthesis of Proteins 477
17-6 The Structure of DNA 477
17-7 Genetic Control and the Replication of DNA 483
17-8 Chemical Evolution 486
Summary 487
Exercises 489
Chapter 18 Enzymic processes and metabolism 493
18-1 Catalysis in Organic Systems 495
18-2 Enzymes and Coenzymes 503
18-3 Hydrolytic Enzymes 504
444
446
contents xii
18-4 Oxidative Enzymes 506
18-5 The Energetics of Metabolic Processes 509
Summary 511
Exercises 513
Chapter 19 Organic compounds of sulfur,
phosphorus, silicon and boron 515
19-1 d Orbitals and Chemical Bonds 517
19-2 Types and Nomenclature of Organic Compounds of Sulfur 520
19-3 Phosphorus Compounds 528
19-4 Organosilicon Compounds 531
19-5 Organoboron Compounds 536
Summary 540
Exercises 542
Chapter 20 Arenes. Electrophilic aromatic
substitution 547
20 T Nomenclature of Arenes 549
20-2 Physical Properties of Arenes 553
20-3 Spectroscopic Properties of Arenes 554
20-4 Reactions of Aromatic Hydrocarbons 559
20-5 Effect of Substituents on Reactivity and Orientation
in Electrophilic Aromatic Substitution 567
20-6 Substitution Reactions of Polynuclear Aromatic
Hydrocarbons 574
20-7 Nonbenzenoid Conjugated Cyclic Compounds 578
Summary 579
Exercises - 580
Chapter 21 Aryl halogen compounds. Nucleo-
philic aromatic substitution 587
21 T Physical Properties of Aryl Halogen Compounds 590
21-2 Preparation of Aryl Halides 590
21-3 Reactions of Aryl Halides 592
21-4 Organochlorine Pesticides 596
Summary 598
Exercises 599
Chapter 22 Aryl nitrogen compounds 603
Aromatic Nitro Compounds 606
22-1 Synthesis of Nitro Compounds 606
22-2 Reduction of Aromatic Nitro Compounds 608
22-3 Polynitro Compounds 611
22-4 Charge-Transfer and n Complexes 612
Aromatic Amines $14
22-5 General Properties 614
contents xiii
22-6 Aromatic Amines with Nitrous Acid 616
Diazonium Salts 617
22-7 Preparation and General Properties 617
22-8 Replacement Reactions of Diazonium Salts 618
22-9 Reactions of Diazonium Compounds that Occur Without
Loss of Nitrogen 619
Summary 620
Exercises 621
Chapter 23 Aryl oxygen compounds 625
23-1 Synthesis and Physical Properties of Phenols 627
23-2 Some Chemical Properties of Phenols 630
23-3 Polyhydric Phenols 635
23-4 Quinones 637
23-5 Tropolones and Related Compounds 641
Summary 642
Exercises 644
Chapter 24 Aromatic side-chain derivatives 647
Preparation of Aromatic Side-Chain Compounds 649
24- 1 Aromatic Carboxylic Acids 649
24-2 Preparation of Side-Chain Aromatic Halogen Compounds 650
24-3 Side-Chain Compounds Derived from Arylmethyl Halides 650
24-4 Preparation of Aromatic Side-Chain Compounds by Ring
Substitution 651
Properties of Aromatic Side-Chain Derivatives 653
24-5 Arylmethyl Halides. Stable Carbonium Ions, Carbanions,
and Radicals 653
24-6 Aromatic Aldehydes 656
24-7 Natural Occurrence and Uses of Aromatic Side-Chain
Derivatives 657
24-8 Electron Paramagnetic Resonance (epr) Spectroscopy 659
24-9 Linear Free-Energy Relations 661
Summary 665
Exercises 666
Chapter 25 Heterocyclic compounds 669
25-1 Aromatic Character of Pyrrole, Furan, and Thiophene 672
25-2 Chemical Properties of Pyrrole, Furan, Thiophene, and
Pyridine 673
25-3 Polycyclic and Polyhetero Systems 679
Heterocyclic Natural Products 680
25-4 Natural Products Related to Pyrrole 680
25-5 Natural Products Related to Indole 682
25-6 Natural Products Related to Pyridine, Quinoline, and
Isoquinoline 684
25-7 Natural Products Related to Pyrimidine 685
contents xiv
25-8 Natural Products Related to Purine and Pteridine 686
25-9 Natural Products Related to Pyran 686
25-10 Polyhetero Natural Products 688
Summary 688
Exercises 689
Chapter 26 Photochemistry 693
26-1 Light Absorption, Fluorescence, and Phosphorescence 696
26-2 Light Absorption and Structure 699
26-3 Photodissociation Reactions 703
26-4 Photochemical Reduction 704
26-5 Photochemical Oxidation 705
26-6 Photochemical Isomerization of Cis- and Trans-
Unsaturated Compounds 707
26-7 Photochemical Cycloadditions 707
Summary 708
Exercises 709
Chapter 27 Cyclization reactions 713
27-1 Cyclization Reactions of Carbonyl Compounds 715
27-2 Cycloaddition Reactions of Carbon-Carbon Multiple Bonds 718
27-3 Fluxional Systems 723
27-4 Annulenes 725
27-5 Orbital Symmetry and Cycloaddition 726
Chapter 28 Polymers 735
28-1 Types of Polymers 737
Physical Properties of Polymers 739
28-2 Forces Between Polymer Chains 739
28-3 Correlation of Polymer Properties with Structure 743
Preparation of Synthetic Polymers 748
28-4 Condensation Polymers 748
28-5 Addition Polymers 753
28-6 Naturally Occurring Polymers 756
28-7 Dyeing of Fibrous Polymers 758
Chapter 29 Some aspects of the chemistry
of natural products 767
29-1 Civetone 769
29-2 Spectroscopic Methods in the Determination of the
Structures of Natural Products 772
29-3 Terpenes 778
29-4 Steroids 782
29-5 Biogenesis of Terpenes and Steroids 789
Index 801
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chap 1 introduction 3
Twenty-two centuries ago the Greek mathematician Euclid wrote a textbook
on geometry that is still in use today. Some 300 years ago Isaac Newton
discovered the principles of mechanics that can still be applied with great
precision to most macroscopic systems. By contrast, chemistry, and in
particular organic chemistry, is in its infancy as a precise science. The study of
molecular science — because this is what chemistry essentially is — depends on
inferences about submicroscopic bodies drawn from observations of macro-
scopic behavior. The speculations of the early chemists are best described as
"haywire " rather than as " incorrect " and it was only in the last century that
the foundations of chemical theory became firmly established. Since that time
enormous strides have been made in extending chemical knowledge. And
today, some 1,100,000 organic compounds alone (compounds containing
carbon) have been prepared, their structures elucidated, and their properties
examined.
The flowering of organic chemistry in the past hundred years followed two
events during the last century. The first occurred in 1828, when the German
chemist Wohler discovered that ammonium cyanate (NH 4 ®CNO e ) could be
O
II
converted to the compound urea (NH 2 CNH 2 ). The former was a typical salt
and is considered part of the mineral world, whereas urea was a product of
animal metabolism and therefore part of the living or organic world. The
realization gradually followed that the boundary between living and nonliving
systems could be crossed, and this provided the impetus for intensive investi-
gation of the substances found in nature: the term " organic " was thus applied
to all compounds of carbon whether they were found in nature or were pre-
pared in the laboratory.
The second important occurrence in the last century as far as organic
chemistry was concerned was the recognition, achieved between 1858 and
1872, that unique, three-dimensional structures could be drawn for the mole-
cules of every known compound of carbon. This realization followed essenti-
ally the work of six men : Avogadro, Cannizzaro, Kekule, Couper, LeBel, and
van't Hoff. Avogadro and Cannizzaro distinguished between what we would
now call empirical and molecular formulas. Avogadro's hypothesis that equal
volumes of gases contained equal numbers of molecules was actually made in
1811 but it was not until 1860 that the Italian chemist Cannizzaro made use of
this idea to distinguish between different compounds having the same
composition. Thus, the distinction between the molecules C 2 H 4 and C 4 H 8
became clear, and it was realized that neither had the molecular formula
CH 2 , though both had this empirical formula. At about the same time Kekule,
a German, and Couper, a Scot, suggested that carbon was tetravalent, always
forming four bonds. Two young chemists, LeBel and van't Hoff, then in-
dependently provided convincing proof that these four bonds are tetrahedrally
arranged around the carbon atom (Section 14-6).
Part of the fascination of organic chemistry comes from the knowledge that
the whole complex edifice has been built up from indirect study of molecular
behavior, that is, microscopic understanding from macroscopic observation.
The advent in recent years of sophisticated instrumental techniques for ex-
chap 1 introduction 4
amining structure has confirmed the vast majority of the structures assigned
to organic compounds in the late nineteenth century. Spectroscopy and X-ray
crystallography, in particular, have become powerful tools for checking
previously assigned structures and for elucidating structures of compounds
newly prepared in the laboratory or found in nature.
Considerable use will be made in this book of spectroscopy — the study of
how "light" (to be more exact, electromagnetic radiation) is absorbed by
matter. The infrared, ultraviolet, and nuclear magnetic resonance spectra may
permit the correct structure of a fairly complex compound to be assigned in a
matter of hours. If, at this point, a search of the chemical literature reveals
that the compound with the suspected structure has been previously prepared,
it is only necessary to compare the reported physical or spectroscopic pro-
perties with those of the substance being examined. However, if the compound
has not been previously reported, it must be synthesized from starting materials
of known structure before its structure is really considered to be proven.
Organic chemistry occupies a central position in the undergraduate science
curriculum. It is, of course, an important branch of knowledge in its own
right, but in addition it is the foundation for basic studies in botany, zoology,
microbiology, nutrition, forestry, agricultural sciences, dentistry, and medicine.
Antibiotics, vitamins, hormones, sugars, and proteins are only a few of the
important classes of chemical substances that are organic. In addition, many
industrially important products are organic — plastics, rubber, petroleum
products, most explosives, perfumes, flavors, and synthetic fibers. It is little
wonder that there are more organic chemists than chemists of any other kind.
Of the 2000 or so Ph.D.'s awarded each year in chemistry in North America,
about half go to those whose research has been in organic chemistry. The
research may have involved the synthesis of a new compound of unusual
structure, the elucidation of the structure of a new compound extracted from
a plant, or the discovery of the reaction path that is followed when one
compound is converted to another.
Only a few years ago most people regarded the effects of chemical tech-
nology as being wholly beneficial. Pesticides, herbicides, plastics, and synthetic
drugs all seemed to contribute in large or small measure to human welfare.
Recently we have come to realize, however, that our environment cannot
indefinitely accommodate all the products that are being added to it without
being damaged. A pesticide may be extremely effective at eradicating some
of man's enemies but may seriously endanger some of man's friends. A
cogent example is the way the potent insecticide DDT (Section 24-7) causes
bird egg shells to become thin. Further, a synthetic plastic may be immune to
sunlight, rain, and bacterial decay but this is a doubtful benefit after the object
made from it has been discarded in a park.
Many of the substances that have been added in large amounts to our
environment in recent years are synthetic organic chemicals. Some are harmful
to man and to life in general; some are not. An understanding of the proper-
ties and reactions of organic compounds will help us assess the possible perils
associated with new processes or products and will help us develop suitable
control procedures. The grave consequences of a polluted environment can
only be avoided by the wise application of chemical knowledge.
sec 1.1 bonding in organic compounds 5
1 • 1 bonding in organic compounds
Why is carbon unique ? What accounts for the apparently limitless number of
carbon compounds that can be prepared? The answer is that bonds between
carbon atoms are stable, allowing chains of carbon atoms to be formed, with
each carbon atom of a chain being capable of joining to other atoms such as
hydrogen, oxygen, sulfur, nitrogen, and the halogens. Neighboring atoms in
the periodic table, such as boron, silicon, sulfur, and phosphorus, can also
bond to themselves to form chains in the elemental state, but the resulting
compounds are generally quite unstable and highly reactive when atoms of
hydrogen or halogen, for example, are attached to them. The elements at the
right or left of the periodic table do not form chains at all — their electron-
attracting or electron-repelling properties are too great.
The forces that hold atoms and groups of atoms together are the electrostatic
forces of attraction between positively charged nuclei and negatively charged
electrons on different atoms. We usually recognize two kinds of binding.
The first is the familiar ionic bond that holds a crystal of sodium chloride
together. Each Na® in the crystal feels a force of attraction to each Cl e , the
force decreasing as the distance increases. (Repulsion between ions of the same
sign of charge is also present, of course, but the stable crystal arrangement has
more attraction than repulsion.) Thus, you cannot identify a sodium chloride
pair as being a molecule of sodium chloride. Similarly, in an aqueous solution
of sodium chloride, each sodium ion and chloride ion move in the resultant
electric field of all the other ions in the solution. Sodium chloride, like other
salts, can be vaporized at high temperatures. The boiling point of sodium
chloride is 1400 . 1 For sodium chloride vapor, you can at last speak of sodium
chloride molecules which, in fact, are pairs of ions, Na e Cl e . Enormous energy
is required to vaporize the salt because in the vapor state each ion interacts
with just one partner instead of many.
The second kind of bonding referred to above results from the simul-
taneous interaction of a pair of electrons (or, less frequently, just one
electron) with two nuclei, and is called the covalent bond. Whereas metallic
sodium reacts with chlorine by completely transferring an electron to it to
form Na® and Cl e , the elements toward the middle of the rows of the periodic
table tend to react with each other by sharing electrons.
Transfer of an electron from a sodium atom to a chlorine atom produces
two ions, each of which now possesses an octet of electrons. This means of
achieving an octet of electrons is not open to an element such as carbon, which
has two electrons in a filled inner K shell and four valence electrons in the
outer L shell. A quadrinegative ion C 4e with an octet of electrons in the
valence shell would have an enormous concentration of charge and be of
very high energy. Similarly, the quadripositive ion C 4 ®, which would have a
filled K shell like helium, would be equally unstable. Carbon (and to a great
extent boron, nitrogen, oxygen, and the halogens) completes its valence-shell
octet by sharing electrons with other atoms.
"In this book all temperatures are given in degrees centigrade unless otherwise noted.
chap 1 introduction 6
In compounds with shared electron bonds (or covalent bonds) such as
methane (CH 4 ) or tetrafluoromethane (CF 4 ), carbon has its valence shell
filled, as shown in these Lewis structures :
H :F:
H:CH :F:C:F:
H :F:"
methane tetrafluoromethane
(carbon tetrafluoride)
For convenience, these molecules are usually written with each bonding
pair of electrons represented by a dash:
H F
I I
H— C-H F-C-F
I I
H F
1-2 methane, ammonia, water, and hydrogen fluoride
The elements in the first main row of the periodic table are
Li
Be
B
C N
F Ne
Atomic number
3
4
5
6 7
8
9 10
Number of valence
electrons
1
2
3
4 5
6
7 (8)
Lithium and beryllium are able to form positive ions by loss of one or two
electrons, respectively. Boron is in an intermediate position and its somewhat
unusual bonding properties are considered later in the book (Section 19-5).
Carbon, nitrogen, oxygen, and fluorine all have the ability to form covalent
bonds because each can complete its octet by sharing electrons with other
atoms. (Fluorine or oxygen can also exist as stable anions in compounds such
as Na e F e or Na ffi OH e .)
The degree of sharing of electrons in a covalent bond will not be exactly
equal if the elements being linked are different. The relative attractive power
exerted by an element on the electrons in a covalent bond can be expressed
by its electronegativity. In one quantitative definition of electronegativity we
have an increase in electronegativity along the series toward fluorine as
follows :
C N O F
2.5 3.0 3.5 4.0
The electronegativity of hydrogen is 2.0, close to that for carbon. Each
covalent bond between elements with different electronegativities will have
the bonding electrons unequally shared between them, which leads to what is
called polar character. In a carbon-fluorine bond the pair of electrons are
sec 1.2 methane, ammonia, water, and hydrogen fluoride 7
attracted more to the fluorine nucleus than to the carbon nucleus. The regions
of space occupied by electrons are called orbitals and, in a molecule such as
CF 4 , the pair of electrons in the orbital that represents each covalent bond
will not be divided equally between the carbon and fluorine but will be polar-
ised towards fluorine.
We say that such a bond is dipolar and it can be represented, when necessary,
by the symbols
\S© Se
\
-C-F
or
— C-
-»F
/
/
28©
Se 28© Se
F— — F
e / \ So
F F
The electronegativity of oxygen is less than that of fluorine and closer to that
of carbon; therefore the polarity of a C — O bond will be less than that of a
C— F bond. Clearly the polarity of a C — N bond will be smaller still.
Even though a molecule contains polar bonds, the molecule itself may be
nonpolar, that is, not possess a dipole moment. This will occur when the
molecule has a shape (or symmetry) such that the dipoles of the individual
bonds cancel each other. Thus, molecules such as F— O— F and H— O— H
will have dipole moments (as they do) if the angle between the two F— O (or
H— O) bonds is different from 180°, and zero dipole moment if the angle is
180°. To predict whether a molecule has a dipole moment, it is therefore
28e S© 28e S©
A ~ H-O-H
B / \ 8©
H H
necessary to know its shape, and in the next section the principles governing
the shapes of covalently bound molecules are considered, with special refer-
ence to the series CH 4 , NH 3 , H 2 0, and HF.
If a substance is a liquid, it is an easy matter to show experimentally
whether its molecules are polar and have a dipole moment. All you have to do
is to hold an object carrying an electrostatic charge near a fine stream of the
falling liquid and note whether the stream is deflected. The charged object
can be as simple as a glass rod rubbed on silk or an amber rod rubbed on
cat's fur, the charge being positive in the first case and negative in the second.
A fine stream of water is sharply deflected by such an object and this shows
that the individual molecules in the liquid have positive and negative ends.
The molecules tend to orient themselves so that the appropriately charged
end is directed towards the charged object (for example, the negative end,
oxygen, toward the positively charged rod) and then the electrostatic attrac-
tion draws the molecules toward the rod. A fine stream of carbon tetra-
chap 1 introduction 8
chloride (tetrachloromethane), CC1 4 , cannot be deflected at all. This shows
that the CC1 4 molecule is sufficiently symmetrical in its arrangement of the
four carbon-chlorine bonds so that the polarities of these bonds cancel each
other.
A. MOLECULAR SHAPES
It is important to recognize that an understanding of the shapes of organic
compounds is absolutely vital to understanding the physical, chemical, and
biochemical properties of organic compounds. We present in this section a
few simple concepts which will turn out later to be of great utility in predicting
and correlating the shapes of complex organic molecules.
The compounds CH 4 , NH 3 , H 2 0, and HF are all isoelectronic : they have
the same number of electrons, 10. Two are in the inner K shell of the central
atom and eight are in the valence, or bonding, shell. The bonding arrange-
ments can be indicated by Lewis structures :
H
H:C=H H:N:H H:6:H H=F:
H H
Carbon, nitrogen, oxygen, and fluorine have, respectively, contributed four,
five, six, and seven of the electrons that make up the octet. Because no more
than two electrons can occupy an orbital, we will expect that the electrons in
the octet can be treated as four distinct pairs. The electron pairs repel one
another and, if the four pairs are to get as far away from each other as
possible, we will expect to find the four orbitals directed toward the corners
of a tetrahedron, because this provides the maximum separation between the
^T
tetrahedral tetrahedral angle
arrangement of
electron pairs
electrons. Methane, CH 4 , is in fact tetrahedral, as is tetrafluoromethane,
CF 4 . The three bonds in ammonia and the two bonds in water are directed at
slightly different angles, 106.6° and 104.5°, respectively. This is reasonable
because the repulsions between the four pairs of electrons in each of these
ft
H H
bond angle 106.6° bond angle 104.5°
molecules will not be the same. Thus, for water, two of the four orbitals
H
H
1
\
c—
.C
1
H'7
H
H
sec 1.2 methane, ammonia, water, and hydrogen fluoride 9
contain protons and two do not. We expect somewhat greater repulsions
between the nonbonding pairs than between bonding pairs, and this results
in the angle of the bonding pairs being somewhat less than the tetrahedral
value.
Replacement of any of the hydrogen atoms in the three molecules CH 4 ,
NH 3 , and H 2 with another kind of group will alter the bond angles to some
extent. Replacement of one or more such hydrogens by the methyl group
(methane minus a hydrogen atom), CH 3 — , gives the structures shown in Table
1-1. The methyl group is an especially important substituent group and can be
conveniently represented in three ways, the last being a three-dimensional
representation.
CH,
The four derivatives of methane shown in Table IT are all hydrocarbons —
that is, they contain only carbon and hydrogen. Hence their physical and
chemical properties will resemble those of methane itself. (The molecular
shapes are not well represented by the structures in the table because each of
the carbon atoms in these molecules will have a tetrahedral arrangement of
bonds connected to it. The three-dimensional shapes of such hydrocarbons
are considered in more detail in Chapter 3.) The three derivatives of ammonia
are called amines and share many of the properties of ammonia; for example,
like ammonia, they have dipole moments and are weak bases. A different
situation exists with the derivatives of water; each of them is representative
of a class of compounds The structure CH 3 — OH is an alcohol while CH 3 —
O— CH 3 is an ether. The reason that water is considered to give two classes
of compounds on methyl substitution can be traced to the great importance
of the hydroxyl (OH) group in chemistry. Alcohols, like water, contain a
Table 1-1 Some simple derivatives of methane, ammonia, and water
CH 4
NH 3
H 2
CH 3 CH 3
CH 3 -NH 2
CH 3 -OH
CH 3 -CH 2 -CH 3
CH 3 -NH
1
CH 3
CH 3 -0-CH 3
CH3-CH-CH3
CH 3 -N-CH 3
1
CH 3
CH 3
CH 3
1
CH 3 -C-CH 3
1
CH 3
chap 1 introduction 10
hydroxyl group whereas ethers do not. Hydroxyl groups have a great in-
fluence on molecular properties (see next section), and the properties of
alcohols (ROH) and ethers (R— O— R) are quite different. (The symbol R is
usually used in organic chemistry for an alkyl group, a connected group of
atoms formed by removing a hydrogen atom from a hydrocarbon ; a methyl
group is one kind of R group.)
The bond angles at oxygen in the two compounds CH 3 — O— H and
CH 3 — O— CH 3 are somewhat greater than those found in water. This is
expected because the CH 3 group is larger than hydrogen, and interference
between the CH 3 groups in CH 3 — O— CH 3 is lessened by opening the
C— O— C bond angle in the ether. A compromise angle is allowed in which
the interference between the CH 3 groups is reduced at the expense of moving
the pairs of electrons on oxygen to less favorable arrangements with respect
to one another. A common description of the overall change is " relief of
steric hindrance between the CH 3 groups by opening the C — O— C bond
angle."
A A A
H H CH 3 H CH 3 CH 3
bond angle i04.5° bond angle 106° bond angle 1 12°
B. PHYSICAL PROPERTIES
The four compounds methane, ammonia, water, and hydrogen fluoride
have the physical constants shown in Table 1 -2. In each of these compounds
the atoms are held together to form molecules by strong covalent bonds. The
melting and boiling points are governed not by these powerful forces but
rather by the weaker interactions that exist between molecules — intermolec-
ular forces. Everything else being the same, the weaker such intermolecular
interactions, the lower the temperature which will usually be required, first
to break down the crystal lattice of the solid by melting, and then to separate
the molecules to relatively large distances by boiling.
What is the origin of these weak, secondary forces that exist between
neutral molecules? We shall consider two here: van der Waals forces and
hydrogen bonding. Van der Waals forces, sometimes called London forces,
depend in an important way on the numbers of electrons in a molecule. This
means that, in general, the bigger the molecule the greater will be the various
Table t-Z Physical properties of methane, ammonia, water, and hydrogen
fluoride
CH, NH, H,0 HF
boiling point
-161.5°
-33°
100°
20°
melting point
-183°
-78°
0°
-84°
solubility in water
very low
high
00
00
solubility in CC1 4
high
very low
very low
very low
sec 1.2 methane, ammonia, water, and hydrogen fluoride 11
Table 1-3 Boiling and melting points of some methane derivatives
CH 3
I
CH^ CH3 — CH3 CH3 — CH 2 — CH3 Co 3 — CH — CH3 CM 3 — C — CM 3
CHa CM*
boiling point -161.5° -88.6° -42.1° -10.2° 9.5°
melting point -183° -172° -188° -145° -20°
possible intermolecular attractions and the higher the melting and boiling
points will tend to be. Boiling points tend to increase regularly within a series
of compounds as the molecular weight increases. Melting points, however,
usually show much less regularity. This is because the stability of a crystal
lattice depends so much on molecular symmetry, which largely determines the
ability of the molecules to pack well in the lattice. Thus, the five hydrocarbons
shown in Table IT have the boiling and melting points shown in Table 1-3.
In addition to experiencing van der Waals forces (dispersion forces),
molecules containing certain groups are attracted to one another by hydrogen
bonding. To be effective, hydrogen bonding requires the presence of an
—OH, — N— H, or F— H group; in other words, a hydrogen atom joined to a
I
small electronegative atom. The covalent bonds to such hydrogen atoms are
8e se
strongly polarized toward the electronegative atom, for example, R— O— H,
and the partially positive hydrogen will be attracted toward the partially
negative oxygen atom in a neighboring molecule. In the liquid state a number
/
H
I
ae
he/
aeO-
-H-
--<>
/
\
R
R
of molecules may be linked together this way at any given time. These liaisons
are not permanent because thermal energies of the molecules are sufficient
to cause these bonds to break very rapidly (usually within milliseconds or
less). Such bonds are continually being formed and broken and this leads to
the description of such temporary aggregates in a hydrogen-bonded liquid as
" flickering clusters."
By far the most important of the groups responsible for hydrogen bonding
is the hydroxyl group, —OH. The strength of O— H • • • O hydrogen bonds
may be as much as one-tenth that of an ordinary carbon-carbon covalent
bond. 2 (See Section 2-4 on bond strengths.) The highest boiling point in the
2 Recently, minute quantities of what is claimed to be a new form of water, sometimes
called "polywater," have been isolated, in which very strong hydrogen bonds are believed
to exist, indeed stable to temperatures above 400°. It is not yet known to what degree one
should expect to find a multiplicity of bond strengths for hydrogen bonds to a specific
molecule or indeed whether " polywater " is in fact even a compound of formula (H 2 0)„ .
chap 1 introduction 12
Table 1 -4 Boiling and melting points of some oxygen compounds
H,0 CH,OH CH,OCH,
boiling point 100° 65° -24°
melting point 0° -89° -139°
series CH 4 , NH 3 , H 2 0, HF belongs to water and the lowest to methane, in
which hydrogen bonding is completely absent (Table 1-2).
The three oxygen compounds shown in Table 1-1 have melting and boiling
points as shown in Table 1 -4.
The trends are exactly opposite to those expected on the basis of molecular
weight alone and are the result of having two hydrogens bonded to oxygen in
each molecule of water, one in the alcohol, CH 3 OH, and none in the ether,
CH 3 OCH 3 .
The hydroxyl group also has an important influence on solubility character-
istics. The alcohol CH 3 OH is completely miscible with water because the two
kinds of molecule can form hydrogen bonds to one another. On the other
hand, the ether CH 3 OCH 3 is only partly soluble in water. Its oxygen atom
can interact with the protons of water but it has no OH protons itself to
continue the operation. Hydrocarbons have extremely low solubilities in
water. Hydrocarbon molecules would tend to interfere with the hydrogen
bonding between water molecules and could offer in exchange only the much
weaker van der Waals forces.
The nitrogen compounds shown in Table IT have boiling and melting
points as shown in Table 1 -5. There is not a great deal of difference between
the values for the three amines. Hydrogen bonding N— H---N is not as
effective as O— H* • • O and the reduction in hydrogen bonding in going from
CH 3 — NH 2 to CH 3 — N— CH 3 is roughly compensated by the increase in
CH 3
van der Waals forces caused by increasing molecular size.
C. ACIDITY AND BASICITY
The acidity of the four compounds methane, ammonia, water, and hydrogen
fluoride increases regularly as the central atom becomes more electronegative.
Table 1-5 Boiling and melting points of some nitrogen compounds
NH 3
CH 3 NH 2
CH,— NH
1
CH 3
CH 3 -
-N— CH 3
1
CH 3
boiling point
melting point
-33°
-78°
-6.5°
-93°
7°
-96°
4°
-124°
summary 13
Thus the acid dissociation constants for these compounds in water solution
are:
CH 4 NH 3 H 2 HF
A"ha,25° ~1(T 55 ~10~ 35 . 5.5 x 1(T 15 3.5 x 1(T 4
The ionization constant used here for water is the customary value of 10" 14
divided by the concentration of water in pure water (55 M). The symbol
K HA denotes the equilibrium constant for dissociation of a neutral acid HA,
that is, HA?±H® + A e and K HA = [H e ][A e ]/[HA]. The values refer to
water solution whether actually measurable in water or not and the symbol
H® represents the oxonium ion H 3 0®.
Methane, like most other hydrocarbons, has a negligible acidity in water.
Amines resemble ammonia in being very feeble acids. Alcohols are somewhat
stronger and have acidities similar to that of water.
The basicities of these four compounds follow a different pattern which is
not simply the reverse of that for acidity :
CH 4 NH 3 H 2 HF
K B 25° <1(T 30 1.8 x 10~ 5 5.5 x 1(T 15 ~1(T 25
The symbol K B denotes the equilibrium constant for ionization of a neutral
base B, that is, B + H 2 0?±BH® + OH® and K B = [BH®][OH®]/[B]. Base
strengths are sometimes taken to be indicated by the acid strengths of the
corresponding conjugate acids. When this is done the symbol K BH o should be
used to denote the process being referred to; that is, K BH ® = [H®][B]/[BH®]
represents the acid dissociation BH® ?± H® + B. Ordinary basic ionization
constants, K B , will be used in this book.
The increase in basicity from HF to H 2 to NH 3 is readily understandable
in terms of the decreasing electronegativity of the central atom along the
series. Why then is the basicity of methane so low ? The reason is that this
molecule has no unshared pairs of electrons available for bonding to a proton
as do ammonia and the other compounds with which we have compared it.
H 3 N: + H 2 . NH 4 e + OH e
If methane is to accept a proton to form the ion CH 5 ® the carbon atom must
hold five hydrogen atoms with four pairs of electrons. (There is evidence that
CH 5 ® can be generated and detected in the gas phase in a mass spectro-
meter. It may also be a transient intermediate in solutions of methane in the
so-called " super acids." Examples of the latter are mixtures of FS0 3 H and
SbF 5 ; their protonating power far exceeds that of concentrated sulfuric acid.)
summary
Carbon is unique among the elements: it is able to form an enormous
number of compounds by bonding to itself and to the atoms of other elements,
principally hydrogen, oxygen, nitrogen, sulfur, and the halogens. Such
chap 1 introduction 14
bonding is almost always covalent, with each carbon atom having four bonds,
each bond resulting from a pair of electrons in an orbital which encloses both
the bonded nuclei. Repulsions between the four electron pairs in CH 4 , NH 3 ,
and H 2 determine the shapes of these molecules; CH 4 is tetrahedral with
bond angles of 109.5° and NH 3 and H 2 have slightly smaller bond angles.
Of these compounds only methane, CH 4 , because of its symmetry, has no
dipole moment.
The hydrogen atoms in CH 4 , NH 3 , and H 2 can be replaced by alkyl
groups such as methyl, CH 3 — . Compounds formed from CH 4 this way are
hydrocarbons like CH 4 itself. Those from NH 3 are called amines, CH 3 NH 2
or CH3NHCH3 . Those from H 2 are alcohols if only one hydrogen is
replaced, CH 3 OH; and ethers if both hydrogens are replaced, CH 3 OCH 3 .
The physical properties of such compounds are determined chiefly by
iVrtermolecular forces, van der Waals forces and hydrogen bonds, which are
normally much weaker than those involved in covalent bond formation. In
general, the larger the molecule, the greater the van der Waals forces and the
higher the boiling point. The presence of one or more hydroxyl groups (or
other good hydrogen-bonding groups) will raise the boiling point consider-
ably and will tend to make the compound soluble in water.
Acidity increases in the order CH 4 < NH 3 <H 2 < HF; basicity in the
order CH 4 < HF <H 2 < NH 3 .
exercises
1 • 1 Write Lewis structures for each of the following compounds using dots for the
electrons. Mark any atoms which are not neutral with charges of the ap-
propriate sign.
a. ammonia e. ozone (Z0-O-0 = 120°)
b. ammonium bromide / hydroxylamine, H 2 NOH
c. carbon dioxide g. hydrogen cyanide
d. hydrogen peroxide h. boron trifluoride
1-2 Tetramethyllead, Pb(CH 3 )4, is a volatile liquid, bp 106°, while lead fluoride,
PbF 2 , is a high-melting solid, mp 824°. What kinds of bonding forces are
present in the two compounds ?
1-3 Which of the following substances are expected to possess a dipole moment?
Why?
(CH 3 ) 3 N, 3 , C0 2) BF 3 , CH 2 F 2 , CF 4 , CH3OCH3, CH3CH3
1-4 Do you expect the compound hydrazine, NH 2 NH 2 , to be more or less basic
than ammonia? Explain your answer.
1 • 5 Which of the compounds in the following list are expected to be more soluble
in water than in carbon tetrachloride?
D 2 0, CH 3 NH 2 , CH 3 CH 3 , CH 3 C0 2 e Na e , HC1, CCU
exercises IS
1-6 Why is hydrogen peroxide a stronger acid than water?
1-7 Arrange the following compounds in the order of increasing acidity in water
solution.
NH 3 -NH 3 S0 4 2e , CH 3 OH, CH 4 , NH 4 ®Cl e , CH3OCH3
1-8 The term autoprotolysis means self- ionization by proton transfer, that is,
2 H 2 *± H 3 O ffl + OH e . Write autoprotolysis reactions for the following
liquids: NH 3 , CH 3 OH, H 2 S0 4 , HOOH, CH 3 NH 2 .
1-9 Addition of 17.9 g of water to 100 g of pure liquid perchloric acid, HC10 4 ,
produces a crystalline solid. What is its formula ?
1-10 There is evidence to suggest that the form of the solvated proton in water
solution is better represented by the formula H 9 O 4 than H 3 O e . Draw a
structural formula for H 9 4 ® and identify the kinds of bonds that might
hold it together.
1-11 On pp. 8-9 it is suggested that the repulsions between the bonded pairs of
electrons in water will be less than between the nonbonded pairs, thus
making the H— O— H angle less than 109.5°. Explain why this should be so.
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chap 2 the C x and C 2 hydrocarbons 19
Hydrocarbons are compounds that contain only carbon and hydrogen.
We shall consider in this chapter the four simplest known hydrocarbons —
those with the lowest molecular weights — and we shall see that they represent
three classes of compounds: the alkanes, in which each carbon atom has four
single bonds ; the alkenes, in which two carbon atoms are joined by a double
bond (two electron pairs); and the alkynes, in which two carbon atoms are
joined by a triple bond (three electron pairs). We shall also see that these
classes of compounds are physically similar but chemically rather different.
There are four stable hydrocarbons of molecular weight 30 or less. They are
all gases at room temperature, and analyses for carbon and hydrogen content
coupled with determinations of their molecular weights show them to have
the formulas CH 4 , C 2 H 6 , C 2 H 4 , and C 2 H 2 . The first of these is methane,
CH 4 , whose physical properties and molecular shape were discussed in Chap-
ter 1. The other three are all C 2 compounds and are called, respectively,
ethane, ethene, and ethyne (ethyne rhymes with brine). These are the syste-
matic names approved by the International Union of Pure and Applied
Chemistry, IUPAC. 1 However, ethene is often called ethylene and ethyne
called acetylene. It is to be hoped that both of these older names will pass out
of use in time.
If the carbon atoms in each of the three C 2 compounds are tetravalent,
then there is only one possible way to bond the atoms together in each case :
H H
H H ||
ethane H:C:CH or H— C— C-H
H " It li
ethene H. .H \ /
(ethylene) H : - C::C .-' H or / C = C \
H H
ethyne
(acetylene) H:C:::CH or H-C=C-H
The tendency of carbon to form bonds at the tetrahedral angle results in
compounds such as methane and ethane being nonplanar. The two-dimen-
sional representation of ethane, above, is thus misleading and it is just as
informative (and quicker) to write the formula as CH 3 — CH 3 . (Or, indeed,
as C 2 H 6 , since there is only one stable compound known with this formula.
We shall see that with some C 3 hydrocarbons and with all hydrocarbons
having four or more carbons, some indication of structure is necessary because
a designation such as C 4 H 8 is ambiguous, there being five known compounds
with this formula.)
1 IUPAC, with headquarters at Zurich, Switzerland, is an international organization
concerned with creating worldwide standards in nomenclature, analytical procedures,
purity, atomic weights, and so on. It is governed by a Congress of delegates from many
countries, the number of delegates depending partly on a country's financial resources and
partly on its scientific maturity. The following countries have the maximum number of
delegates (six): Australia, Belgium, Canada, Denmark, France, Germany, Italy, Japan,
Netherlands, Sweden, Switzerland, United Kingdom, United States, U.S.S.R. IUPAC was
founded in 1918 at the famous Coq d'Or restaurant in London.
chap 2 the C x and C 2 hydrocarbons 20
#
Figure 2- 1 Ball-and-stick model of CH 4 .
Because of the importance of molecular structure in organic chemistry, we
shall consider the three-dimensional shapes of these compounds in the next
section.
2-1 molecular shape of CH 4 , C 2 H 6 , C 2 H 4 ,
and C 2 H 2
You can illustrate the shape of a tetrahedral molecule such as methane with
ball-and-stick models (Figure 2-1).
With ethene and ethyne, the model's carbon-to-carbon bonds are con-
structed from stiff metal springs or flexible or curved plastic connectors be-
cause more than one bond exists between the carbon atoms (Figure 2-2).
These simple mechanical models are surprisingly good for predicting the
shapes of molecules and, indeed, their reactivity. Ethene is known from
spectroscopic measurements to be planar, and this is the shape the model
naturally takes. The electronic analogy here is that the orbitals for each pair
of electrons extend as far away from one another as possible. Ethyne, likewise,
is known to be linear. The strain involved in making " bent bonds " for these
models is reflected in a higher degree of chemical reactivity for these com-
pounds than for ethane.
Figure 2-2 Ball-and-stick models of ethene and ethyne.
sec 2.2 rotational conformations of ethane 21
Figure 2-3 Two rotational conformations of ethane.
The arrangement of the linkages in the ethene model suggests that one CH 2
group cannot twist with respect to the other CH 2 group without gross dis-
tortion from the favored geometry. We shall see that this conclusion, too, is
borne out by chemical evidence (Section 2-6B). By contrast, the model of the
saturated compound, ethane, suggests that free rotation should be possible
about the single bond joining the two carbon atoms if the sticks representing
the bonds are allowed to rotate in the holes of the balls representing the
atoms. Such rotation is considered in more detail in the next section.
2-2 rotational conformations of ethane
In organic chemistry, the word structure has a specific meaning; It designates
the order in which the atoms are joined to each other. A structure does not
necessarily specify the exact shape of a molecule because rotation about single
bonds could lead, even for a molecule as simple as ethane, to an infinite
number of different arrangements of the atoms in space. These are called
conformations and depend on the angular relationship between the hydrogens
on each carbon. Two extreme arrangements are shown in Figure 2-3.
In end-on views of the models, the eclipsed conformation is seen to have the
hydrogens on the forward carbon directly in front of those on the back carbon.
The staggered conformation has each of the hydrogens on the forward carbon
set between each of the hydrogens on the back carbon. It has not been possible
to obtain separate samples of ethane which correspond to these or intermediate
arrangements because actual ethane molecules appear to have essentially
"free rotation" about the single bond joining the carbons.
Free, or at least rapid, rotation is possible around all single bonds, except
under special circumstances, as when the groups attached are so large that
they cannot pass by one another, or when the attached groups are connected
together by chemical bonds (e.g., in ring compounds). For ethane and its
derivatives, the staggered conformation is always more stable than the eclip-
chap 2 the C 1 and C 2 hydrocarbons 22
H
H
jj
X
H
HH
H-y^H
Hi rN
H^
^ H
r
\
H^H
H^H
A
^
"J<
y%
H
staggered eclipsed
"sawhorse"
staggered eclipsed
"Newman"
Figure 2-4 Conventions for showing the staggered and eclipsed conformations
of ethane. In " sawhorse " drawings the lower left-hand carbon is always
taken to be towards the front. In " Newman " drawings the view is along the
C — C bond axis with the most exposed bonds being towards the front.
sed conformation because in the staggered conformation the atoms are as
far away from one another as possible and offer the least interaction.
Many problems in organic chemistry require consideration of structures in
three dimensions, and it is very helpful to be able to use ball-and-stick models
for visualizing the relative positions of the atoms in space. Unfortunately,
we are very often forced to communicate three-dimensional concepts with
drawings in two dimensions, and not all of us are equally gifted in making
or visualizing such drawings. Obviously, communication by means of draw-
ings such as the ones shown in Figure 2-3 would be impractically difficult and
time consuming — some form of abbreviation is necessary.
Two styles of abbreviating the eclipsed and staggered conformations of
ethane are shown in Figure 2-4. Of these, we strongly favor the " sawhorse "
convention because, although it is perhaps the hardest to visualize and the
hardest to master, it is the only three-dimensional convention which is suitable
for complex compounds, particularly natural products. With the sawhorse
drawings, we always consider that we are viewing the molecule slightly from
above and from the right, just as we have shown in Figure 2-4.
2-3 space-filling models
Ball-and-stick models of molecules are very useful for visualizing the relative
positions of the atoms in space but are unsatisfactory whenever we also want
to show how large the atoms are. Actually, atomic radii are so large relative
to the lengths of chemical bonds that when a model of a molecule such as
chloromethane is constructed with atomic radii and bond lengths, both to
scale, the bonds connecting the atoms are not clearly evident. Nonetheless,
this type of "space-filling" model, made with truncated balls held together
with snap fasteners, is widely used to determine the possible closeness of
approach of groups to each other and the degree of crowding of atoms in
various arrangements (see Figure 2-5).
A defect of both the ball-and-stick and space-filling models is their motion-
less character. The atoms in molecules are in constant motion, even at absolute
sec 2.4 combustion 23
zero, and the frequencies of these vibrations give valuable information about
molecular structure and shape. This subject is considered in greater detail in
the section on infrared spectroscopy (Section 7-4).
chemical reactions of the d and C 2 hydrocarbons
Two of the four simple hydrocarbons we have been considering are saturated
(contain only single bonds) and two are unsaturated (contain multiple bonds).
All four are rather similar physically, being low-boiling, colorless gases that
are insoluble in water, Chemically, however, they are rather different, the
unsaturated compounds being much the more reactive. The three kinds of
reactions we shall consider in the following sections are combustion (shared
by all hydrocarbons), substitution reactions (more important for saturated
compounds), and addition reactions (confined to the unsaturated compounds).
2-4 combustion
The rapid reaction of a chemical substance with oxygen to give an oxide,
usually carbon dioxide, is called combustion. The burning of a candle, the
explosion of a gasoline-air mixture in the cylinder of an automobile engine,
and the oxidation of glucose in a living cell are all examples bf this process.
In all of these cases, the result is liberation of energy.
Water and carbon dioxide, the products of complete combustion of organic
compounds, are very stable substances, relative to oxygen and hydrocarbons.
This means that large amounts of energy are given out when combustion
occurs. Most of the energy of combustion shows up as heat, and the heat
liberated in a reaction occurring at constant pressure is called the enthalpy
change, AH, or simply heat of reaction. By convention, AH is given a negative
sign when heat is evolved (exothermic reaction) and a positive sign when heat
is absorbed (endothermic reaction). Some examples are given below, with the
state of the reactants and products being indicated by subscripts (g) for gas
and (s) for solid.
For each of these examples, AH can be visualized as the total heat given off
when a mixture of gaseous hydrocarbon and excess oxygen at 1 atm pressure
is exploded in a bomb at 25°, the contents allowed to expand or contract by
Figure 2-5 Space-filling models of organic compounds.
#*^>Ss^''
methane
ethane (staggered conformation)
-M^
ethane
chap 2 the C x and C 2 hydrocarbons 24
means of a piston to maintain the pressure at 1 atm, and allowed to cool to
25°.
CH 4 (g) + 2 2 (g) -> C0 2 (g) + 2 H 2 0(g) AH= - 1 92 kcal per mole of
methane (—11.95 kcal per
gram)
CH 3 — CH 3 (g) + f 2 (g)^2 CO z (g) + 3 H 2 0(g) MU= -341.3 kcal per mole of
ethane (—11.35 kcal per gram)
H— C=C— H(g)+ 4 2 (g)->2 C0 2 (g) + H 2 0(g) &H= -300.1 kcal per mole of
ethyne (— 1 1 . 50 kcal per gram)
C s H ls (g)+ ^ 5 -0 2 (g)^ 8 C0 2 (g) + 9 H 2 0(g) AH= -1222 kcal per mole of
octane (— 10.71 kcal per gram)
C 6 Hj 2 6 (s) + 6 2 (g)-+6 C0 2 (g) + 6 H 2 0(g) AH= -610 kcal per mole of glucose
(—3.39 kcal per gram)
You can see that the amount of heat liberated per gram of fuel is not greatly
different in the case of the four hydrocarbons, but is much lower for the com-
pound C 6 H 12 6 (glucose), which is already in a partly oxidized state. In the
next section, we shall consider how you can estimate heats of reaction, with
particular reference to combustion.
A. ESTIMATION OF HEAT OF COMBUSTION OF METHANE
The experimental value for the heat of combustion of methane obtained as
described above does not depend on speed of the reaction. Slow oxidation of
methane over many years would liberate as much heat as that obtained in an
explosion, provided the reaction were complete in both cases, and the initial
and final temperatures and pressures are the same. At 25°, combustion of each
mole of methane to carbon dioxide and water vapor produces 192 kcal of heat.
We can estimate the heat of this and many other reactions by making use
of the bond energies given in Table 2- 1 . Bond energies for diatomic molecules
represent the energy required to dissociate completely the gaseous substances
to gaseous atoms at 25° or, alternatively, the heat evolved when the bonds are
formed from such atoms. For polyatomic molecules the bond energies are
average values. They are selected to work with a variety of molecules and re-
flect the fact that the bond energy of any particular bond is likely to be
influenced to some extent by other groups in the molecule.
It turns out that what is called conjugation (alternation of double and single
bonds) can have a relatively large effect on bond strengths. We will see in
Chapter 6 that this effect normally operates to increase bond energies ; that is,
the bonds are harder to break and the molecule is made more stable. However,
the effects of conjugation are so special that they are not normally averaged
into bond energies, but are treated separately instead.
To calculate Af/for the combustion of methane, first we calculate the energy
to break the four C— H bonds as follows (using the average value of 99 kcal
for the energy of a C— H bond):
H
H:CH(s) ► -C- (g) + 4 H-(g) A«=+4x99kcal
H ' = + 396 kcal
sec 2.4 combustion 25
Table 2-1 Bond energies (kcal/mole at 25°)"
diatomic
molecules
H-H
104.2
F-F
36.6
H-F
134.5
o=o
119.1
CI- CI
58.0
H-Cl
103.2
N^N
225.8
Br— Br
46.1
H-Br
87.5
c=o
255.8
I-I
36.1
H-I
71.4
bonds in polyat
omic molycules 6
C— H
99
c-c
83
C-F
116
N-H
93
C=C
146
C-Cl
81
O-H
111
C=C
200
C-Br
68
S— H
83
C-N
73
C-I
51
P— H
76
C=N
147
C-S
65
N— N
39
C-N
213
C=S
128
N=N
100
c-o
86
N-F
65
o-o
35
c=o c
192
N— CI
46
s-s
54
c=(y
176
O-F
45.
N— O
53
c=o e
179
O-Cl
52
N=0
145
O-Br
48
intermolecular forces
hydrogen
bonds
3-10
" The bond energies in this table are derived from those of T. C. Cottrell, The Strengths of
Chemical Bonds, 2nd Ed., Butterworths, London, 1958, and L. Pauling, The Nature of the Chem-
ical Bond, 3rd Ed., Cornell Univ. Press, Ithaca, N.Y., 1960.
b Average values.
c For carbon dioxide.
d Aldehydes.
e Ketones.
Then 119 kcal is used for the energy required to cleave a molecule of oxygen
(rounded off from the exact value of 119.1):
2 0,(g) -♦ 4-6- (g) A//= +2 x 119 kcal
= + 238 kcal
Then we make bonds, using 192 kcal for each C=0 bond in carbon dioxide.
■6 (g) + 2-6-(g) :6::C::6:(g) AH = - 2 x 192 kcal
= -384 kcal
We use 111 kcal for each of the H— O bonds of water:
2-6-(g) + 4 H- (g) > 2 H:6:H(g) A//= -4 x 111 kcal
= - 444 kcal
The net of these AH changes is 396 + 238 - 384 - 444 = - 194 kcal, which
is reasonably close to the value of 191.8 kcal for the heat of combustion of
methane determined experimentally.
The same type of procedure can be used to estimate AH values for many
other kinds of reactions of organic compounds in the vapor phase at 25°.
chap 2 the C x and C 2 hydrocarbons 26
Moreover, if appropriate heats of vaporization or solution are available, it is
straightforward to compute AH for liquid, solid, or dissolved substances.
The steps shown above are not intended to depict the actual mechanism
of methane combustion. The overall heat of reaction is independent of the way
that combustion occurs and so the above calculations are just as reliable as
(and more convenient than) those based on the actual reaction path. Some of
the general questions posed by the reaction mechanism are taken up in Section
2-5B.
2-5 substitution reactions oj saturated hydrocarbons
Of the four simple hydrocarbons we are considering in this chapter, only
ethene and ethyne are unsaturated, meaning they have a multiple bond to
which reagents may add. The other two compounds, methane and ethane,
have their atoms joined together by the minimum number of electrons and
can react only by substitution — replacement of a hydrogen by some other
atom or group.
There are only a few reagents which are able to effect the substitution of a
hydrogen atom in a saturated hydrocarbon (an aikane). The most important
of these are easily the halogens, and the mechanism and energetics of halogen
substitution will be discussed in detail later. (Although the hydrogen atoms in
alkenes such as ethene and alkynes such as ethyne are also subject to substi-
tution, these reactions under normal conditions tend to be much slower than
addition to the multiple bond and are therefore usually not important when
compared to addition.)
A complete description of a chemical reaction would include the structures
of the reactants and products, the position of equilibrium of the reaction, its
rate, and its mechanism. These four characteristics fall nicely into two groups.
The equilibrium constant for a reaction depends only on the energies of the
reactants and products, not on the rate of reaction nor on the mechanism. The
rate of the reaction, on the other hand, is intimately related to the reaction
mechanism and, in particular, to the energy of the least stable state along the
reaction path. The subjects of equilibrium constants and reaction rates are
treated in the next two sections.
A. EQUILIBRIUM CONSTANTS
In Section 2-4A we considered bond energies and showed how heats of reac-
tion could be calculated. Reactions which give out large amounts of heat
(highly exothermic processes) usually proceed to completion. Consequently
it is reasonable to ask if the equilibrium constant, K, for a reaction is deter-
mined only by the heat of reaction, AH. The study of thermodynamics tells
us that the answer to this question is no. The equilibrium constant is, in fact,
a function of the quantity free energy (AG), which is made up of AH and
a second quantity called entropy (AS). These relations are
AG = -RTlnK
AG = AH -T AS
sec 2.S substitution reactions of saturated hydrocarbons 27
where
AG = Free energy change for the reaction
R = The gas constant (1.986 cal/deg mole)
T = Temperature in degrees Kelvin
K = Equilibrium constant
AH = Heat of reaction
AS = Entropy of reaction
The heat of reaction term, AH, is readily understood but the meaning of
the entropy term, AS, is more elusive. It is related to the difference in the num-
bers of vibrational, rotational, and translational states available to reactants
and products (see Sections 7-3 and 7-4). As we have seen, molecules are not
lifeless objects but are in constant motion, each undergoing vibrational,
rotational, and translational motions. Thes6 states of motion are quantized —
that is, they can have certain energies only. The more of these states or degrees
of freedom available to a molecule, the higher its entropy and the more favor-
able the equilibrium constant for its formation. Thus, a positive entropy
change in a reaction tends to make the free energy change more negative and
increase the equilibrium constant, hence moving the reaction toward comple-
tion.
In simple terms, a negative entropy change (a AS" that is unfavorable for the
reaction as written) means that the freedom of the atoms in the products
(including the environment) is restricted more than in the reactants. A posi-
tive entropy change (favorable for the reaction as written) means a greater
freedom in the products.
In practice, reactions which are fairly exothermic ( — AH> 15 kcal/mole)
almost always proceed far to the right ; that is, K is large. An unfavorable
entropy term will seldom overcome such a AH value at ordinary temperatures
because a AG that is negative by only a few kilocalories per mole will still
have a large K, This follows from the logarithmic relation between AG and K.
The thermodynamic values for the chlorination of methane are
CH 4 + C1 2 — > CH3GI + HCI
AH= -27 kcal/mole
(measurable experimentally or calculable from the data in Table 2-1);
AS — — 6 cal/deg mole
(estimated from the spectroscopic properties of reactants and products) ;
AG= -25 kcal/mole
(calculated from above values of AH and AS and the equation AG = AH — T
AS);
(calculated from above value of AG and the equation AG = — RT In K).
In some cases, you can experimentally check an equilibrium constant
calculated as above by measuring the concentrations of reactants and pro-
chap 2 the Cj and C 2 hydrocarbons 28
ducts when the system has come to equilibrium. Here, however, K is so large
that no trace of the reactants can be detected at equilibrium, a situation often
encountered in organic chemistry.
Suppose bond energy calculations for a certain reaction indicate that the
equilibrium strongly favors the desired products. Can we be assured that the
reaction is a practical one to perform in the laboratory ? Unfortunately, no,
because first, side reactions may occur (other reactions which also have
favorable equilibrium constants); and second, the rate of the desired reaction
may be far too low for the reaction to be a practical one.
In the chlorination of methane, whose equilibrium constant we have seen
overwhelmingly favors the products, the first of these two matters of concern
is whether the substitution process may proceed further to give dichloro-
methane, CH 2 C1 2 .
CHjCl + Cl 2 ► CH 2 C1 2 + HC1
In fact, given sufficient chlorine, complete substitution may occur to give
tetrachloromethane (carbon tetrachloride), CC1 4 . Indeed, if the rate of chlori-
nation of chloromethane greatly exceeds that of the first step, methane
chlorination, there will be only traces of the mono substituted product in the
mixture at any time. Using an excess of methane will help encourage mono-
substitution only if the rates of the first two chlorination steps are comparable.
With compounds and reagents that are more complex than methane and
chlorine, you can imagine side reactions taking other forms. When devising
synthetic schemes you must always consider possible side reactions that may
make the proposed route an impractical one.
The second question about the chlorination of methane that is left un-
answered by the calculation of the equilibrium constant is whether or not the
reaction will proceed at a reasonable rate. The subject of reaction rates is bound
up intimately with the question of reaction mechanism and this subject is ex-
plored in the next section.
B. REACTION RATES AND MECHANISM
Despite the enormously favorable equilibrium constant for the formation of
chloromethane and hydrogen chloride from methane and chlorine, this
reaction does not occur at a measurable rate at room temperature in the dark.
An explosive reaction may occur, however, if such a mixture is irradiated with
strong violet or ultraviolet light. Evidently, light makes possible a very
effective reaction path by which chlorine may react with methane.
Any kind of a theoretical prediction or rationalization of the rate of this or
other reactions must inevitably take into account the details of how the
reactants are converted to the products — in other words, the reaction mech-
anism. One possible path for methane to react with chlorine would have a
chlorine molecule collide with a methane molecule in such a way that hydro-
gen chloride and chloromethane are formed directly (see Figure 2-6). The
failure of methane to react with chlorine in the dark at moderate temperatures
is strong evidence against this path, and indeed four-center reactions of this
type are rather rare.
sec 2.5 substitution reactions of saturated hydrocarbons 29
*
Figure 2*6 Possible four-center collision of chlorine with methane, as
visualized with ball-and-stick models.
If concerted four-center mechanisms for formation of chloromethane and
hydrogen chloride from chlorine and methane are discarded, the remaining
possibilities are all stepwise mechanisms. A slow stepwise reaction is dynami-
cally analogous to the flow of sand through a succession of funnels with
different stem diameters. The funnel with the smallest stem will be the most
important bottleneck, and if its stem diameter is much smaller than the others,
it alone will determine the flow rate. Generally, a multistep chemical reaction
will have a slow rate-determining step (analogous to the funnel with the small
stem) and other, relatively fast steps which may occur either before or after
the slow step. The prediction of the rate of a reaction proceeding by a step-
wise mechanism then involves, as the central problem, a decision as to which
step is rate determining and an analysis of the factors which determine the
rate of that step.
A possible set of steps for the chlorination of methane follows :
slow
(1) Cl 2 > 2:CI-
slow
(2) CH 4 ► CH 3 - + H-
fist
(3) :CI- + CH 3 - ^—> CH 3 C1
fast
(4) :C1- + H- ► HCI
chap 2 the C x and C 2 hydrocarbons 30
Reactions (1) and (2) involve dissociation of chlorine into chlorine atoms,
and the breaking of a C— H bond of methane to give a methyl radical and a
hydrogen atom. The methyl radical, like chlorine and hydrogen atoms, has
one odd electron not involved in bond formation. Atoms and free radicals
are usually highly reactive, so that formation of chloromethane and
hydrogen chloride should proceed readily by (3) and (4). The crux then will
be whether steps (1) and (2) are reasonable under the reaction conditions.
Our plan in evaluating the reasonableness of these steps is to determine how
much energy is required to break the bonds. This will be helpful because, in
the absence of some external stimulus, only collisions due to the usual thermal
motions of the molecules can provide the energy needed to break the bonds.
Below 100°C, it is very rare indeed that thermal agitation alone can supply
sufficient energy to break any significant number of bonds stronger than 30
to 35 kcal/mole. Therefore, we can discard as unreasonable any step, such as
the dissociation reactions (1) and (2), if the A//'s for breaking the bonds are
greater than 30 to 35 kcal.
In most reactions, new bonds form as old bonds break and it is usually in-
correct to consider bond strengths alone in evaluating reaction rates. (The
appropriate parameters, the heat of activation, AH 1 , and the entropy of
activation, AS*, are discussed in Section 8-9.) However, the above rule of
thumb of 30 to 35 kcal is a useful one for thermal dissociation reactions such
as (1) and (2), and we can discard these as unreasonable if their heats of
dissociation are greater than this amount.
For reaction (1) we can reach a decision on the basis of the CI— CI bond
energy from Table 2-1, which is 58.0 kcal and clearly too large to lead to
bond breaking as the result of thermal agitation at or below 100°. The C— H
bonds of methane are also too strong to break at 100° or less.
The promotion of the chlorination reaction by light must be due to light
being absorbed by one or the other of the reacting molecules to produce a
highly reactive species. Since a CI— CI bond is much weaker than a C— H
bond, it is reasonable to suppose that the former is split by light to give two
chlorine atoms. We shall see in Section 7-3 that the energy which can be
supplied by ultraviolet light is high enough to do this ; photolytic rupture of
the more stable C— H bonds requires radiation with much higher energy. It
should now be clear why a mixture of methane and chlorine does not react in
the dark at moderate temperatures.
Cl 2 -^- 2:C1-
Once produced, a chlorine atom can remove a hydrogen atom from a meth-
ane molecule and form a methyl radical and a hydrogen chloride molecule
(as will be seen from Table 2T, the strengths of C— H and CI— H bonds are
quite close) :
CH 4 + -'CI- ► CH 3 - + HCI
The methyl radical resulting from the attack of atomic chlorine on a hydrogen
sec 2.5 substitution reactions of saturated hydrocarbons 3 1
of methane can then remove a chlorine atom from molecular chlorine and
form chloromethane and a new chlorine atom:
CH 3 - + Cl 2 ► CH3CI + :CI-
An important feature of the mechanistic sequence postulated for the chlori-
nation of methane is that the chlorine atom consumed in the first step is
replaced by another chlorine atom in the second step. This type of process is
CH 4 + :g- ► CH 3 - + HCI
CH 3 - + Cl 2 ► CH3CI + :C1-
CH 4 + Cl 2 ► CH3CI + HCI
called a chain reaction since, in principle, one chlorine atom can induce the
chlorination of an infinite number of methane molecules through operation
of a "chain" or cycle of reactions. In practice, chain reactions are limited
by so-called termination processes, where chlorine atoms or methyl radicals
are destroyed by reacting with one another, as shown in these equations:
CH 3 - + :C1- ► CH3CI
2 CH 3 - > CH3CH3
Chain reactions may be considered to involve three phases. First, chain
initiation must occur, which for chlorination of methane is activation and
conversion of chlorine molecules to chlorine atoms by light. In the second
phase, the chain-propagation steps convert reactants to products with no
net consumption of atoms or radicals. The propagation reactions occur in
competition with chain-terminating steps, which result in destruction of atoms
or radicals.
light ••
CI, ► 2:C1- chain initiation
CH 4 + :Cl- ► CH 3 - + HCI
CH3-+ Cl 2 ► CH3CI +:cV chai »P r <W ti0 »
► CH3CI
CHj- + CHj- ► CHjCH 3
chain termination
The two chain-termination reactions for methane chlorination as shown
might be expected to be exceedingly fast, because they involve combination
of unstable atoms or radicals to give stable molecules. Actually, combination
of chlorine atoms does not occur readily in the gas phase because there is
almost no way for the resulting molecule to lose the energy of reaction except
by redissociating or colliding with some third body, including the container
chap 2 the C± and C 2 hydrocarbons 32
wall. The products in the other termination steps shown above, by contrast,
can take care of this energy by redistributing it as vibrational excitation of
their C— H bonds. Collisions with other molecules then disperse the excess
vibrational energy throughout the system in the form of heat.
If much chain propagation is to occur before the termination steps destroy
the active intermediates the propagation steps must themselves be very
fast. However, propagation is favored over termination when the concen-
trations of radicals (or atoms) are low because then the chance of two radicals
meeting (termination) is much less likely than encounters of radicals with
molecules which are present at relatively high concentrations (propagation).
The overall rates of chain reactions are usually slowed significantly by
substances which can combine with atoms or radicals and convert then into
species incapable of participating in the chain-propagation steps. Such
substances are often called radical traps, or inhibitors. Oxygen acts as an
inhibitor in the chlorination of methane by rapidly combining with a methyl
radical to form the comparatively stable (less reactive) peroxymethyl radical,
CH 3 00 • . This effectively terminates the chain. Under favorable conditions,
the methane-chlorination chain may go through 100 to 10,000 cycles before
termination occurs by free-radical or atom combination. The efficiency (or
quantum yield) of the reaction is thus very high in terms of the amount of
chlorination that occurs relative to the amount of the light absorbed.
C. REACTIVE INTERMEDIATES
We have seen that the chlorination of methane proceeds stepwise via highly
unstable intermediate species such as chlorine atoms (CI • ) and methyl radicals
(CH 3 • ). Are there other molecules or ions which are too unstable for isolation
but which might exist as transient intermediates in organic reactions ? If we
examine simple Q species we find the possibilities :
H H H
H:6 or CH 3 - H:C e or CH® H:C: e or CH 3 : e H:CH or:CH 2
H H H
methyl cation methyl anion methylene
(a carbonium ion) (a carbanion) (a carbene)
Each of these C L entities possesses some serious structural defect that makes
it much less stable than methane itself. The methyl radical is unstable because
it has only seven electrons in its valence shell. It exists for only brief periods of
time at low concentrations before dimerizing to ethane :
CH 3 - + CH 3 - ► CH 3 — CH 3
The methyl cation, CH 3 ®, is an example of a carbonium ion. This species
has only six valence electrons ; moreover, it carries a positive charge. Methyl
cations react with most species that contain an unshared pair of electrons —
for example, a chloride ion, CH 3 ® + Cl e -»■ CH 3 — CI. We shall see later,
however, that the replacement of the hydrogens of the methyl with other
sec 2.5 substitution reactions of saturated hydrocarbons 33
groups, such as CH 3 — or C 6 H 5 — , can' provide sufficient stability to make
carbonium ions important reaction intermediates. In fact, they can sometimes
be isolated as stable salts (Section 24-5). Having only three pairs of electrons
about the central carbon atom, carbonium ions tend toward planarity with
bond angles of 120°. This gives the maximum separation of the three pairs
of electrons.
H
k 120°
methyl cation (a carbonium ion)
The methyl anion, CH 3 e , does possess an octet of electrons but bears a
negative charge, for which it is ill suited by virtue of carbon's low electronega-
tivity. Such carbanions react rapidly with any species that will accept a share
in an electron pair — any proton donor, CH 3 e -5^. CH 4 , for example. We shall
see later that carbanions can be stabilized and rendered less reactive by having
strongly electron- withdrawing groups, such as nitro ( — N0 2 ), attached to
them, and we shall encounter such carbanions as reaction intermediates in
subsequent chapters. Carbanions have four pairs of electrons about the cen-
tral carbon atom. The mutual repulsion of the electrons gives the ion a pyra-
midal shape. The methyl anion, for example, is isoelectronic with ammonia
and is believed to have a similar shape :
c
N
H-7 ^H
h"/
H
H
The nonbonding electron pairs in each of the above molecules are expected
to repel the bonding pairs more than the bonding pairs repel each other
(see pp. 8-9 and Exercise 1-11). This accounts for the fact that the H— N— H
bond angles in ammonia (Section 1-2A) are slightly less than the tetrahedral
value.
Methylene, :CH 2 , like a carbonium ion, possesses only a sextet of electrons
in its valence shell and tends to react rapidly with electron donors (Section 9-7).
It is important to be able to deduce the overall charge of a species from its
H
electronic arrangement and vice versa. A carbonium ion, such as H: C®, is
a
positively charged because, although the hydrogens are formally neutral, the
carbon atom has a half-share of six valence electrons. It thus has, effectively,
only three electrons in its own outer shell instead of the four electrons that a
H
neutral carbon atom possesses. By contrast, a carbanion such as H:C: e is
H
negatively charged because the carbon has an unshared electron pair in addi-
chap 2 the C x and C 2 hydrocarbons 34
H^
r^^n^
H
H
JA
^c cC
or
- C v
,cC
H"
"^fiXjS^
~"H
H"
— 'St
^H
Figure 2-7 Bent bonds in ethene.
tion to its half-share of the six bonding electrons, giving it effective possession
of five valence electrons, one more than that of a neutral carbon atom.
2-6 addition reactions of unsaturated hydrocarbons
The two simplest unsaturated compounds (those containing a multiple bond)
are ethene (CH 2 =CH 2 ) and ethyne (HC=CH). The generally lower stability
of multiply bonded compounds arises from the restriction that only one
electron pair can occupy a given orbital. Because the most effective region for
interaction between an electron pair and the two nuclei it links is along the
bond axis, we expect to find this to be the region of highest electron density
in a single bond. Bonds that run symmetrically along the bond axis are called
sigma bonds (a bonds).
In a molecule such as ethene, though, the two carbon atoms are linked by
two electron pairs and it is quite clear that only one pair can occupy the prime
space along the bond axis. There are two ways of looking at the electronic
arrangement of ethene. The first, and simplest, is to consider the two orbitals
used to link the carbons together as being identical, both being bent, somewhat
like the arrangement taken up by springs in the ball-and-stick model of ethene
(Figure 2-7). This simple view of the bonding of ethene accounts for its mole-
cular geometry (repulsion between the electron pairs produces a planar
molecule) and its chemical reactivity (the electron pairs are not bound as
tightly to the nuclei as in the case of ethane where space along the bond axes
can be used).
The alternative way of looking at the bonding of ethene is to consider the
double bond as being made up of an ordinary single-type bond along the bond
axis, a a bond, and a second bond occupying the regions of space above and
below the plane of the molecule, a it bond (pi bond). (A % bond is not cylin-
drically symmetrical along the bond axis.) The shaded regions above and below
the plane of the molecule (see Figure 2-8) represent just one bonding orbital :
Figure 2-8 a and n bonding in ethene.
7T
W
H^
^%k
H
(
l> cC
H"
^ttn
a
^H
sec 2.6 addition reactions of unsaturated hydrocarbons 35
that which corresponds to the % bond. This model also accounts for the geo-
metry of ethene and for its high chemical reactivity. Despite being less simple
than the bent-bond model, it is extensively used by chemists to describe the
bonding in unsaturated systems. In the case of ethyne, two n bonds and one
a bond can be said to link the two carbons together.
Neither model can be called correct or incorrect. And, indeed, refined theory
suggests that they represent equivalent approximations. Each is useful accord-
ing to the degree of clarity it gives the user and according to its ability to
predict molecular behavior. The language of chemistry (particularly the
theory of spectroscopy and bonding) is based to a great extent on the a, n
model, and it must be considered by anyone wishing to explore organic
chemistry in depth. Paradoxically, it is only recently that the simple bent-
bond model has received much attention from theorists.
Both models account for the shortening of the carbon-carbon bond
distance as the number of bonds between the carbons increases — the greater
the forces, the shorter the bond distance. We shall see that the analogy of
springs and bonds also accounts for the vibrational energies of these com-
pounds. A greater amount of energy is required to increase the vibration in
the strong triple bond of ethyne than in the double bond in ethene or the single
bond in ethane.
/1.54 A
/ 1.34 A
.1.20A
H / H
\ / /
-C-C-H
/ \
H H
H / H
\ i /
C = C
/ \
H H
/
H-C^C-H
ethane ethene ethyne
A. HYDROGENATION OF MULTIPLE BONDS
The reaction of hydrogen with ethyne is highly exothermic:
H-C=C-H + H 2 ► CH,=CH, A//„ p = - 42.2 kcal
Alcaic = — 40 kcal (from bond
energies in Table 2-1)
Likewise, the further reduction of ethene to ethane is highly exothermic :
CH 2 =CH 2 + H 2 ► CH3-CH3 A// cxp = - 32.8 kcal
AH C1 | C = - 30 kcal (from bond
energies in Table 2- 1)
However, mixtures of either compound with hydrogen are indefinitely stable
under ordinary conditions, and this again reminds us that reaction rates
cannot be deduced from heats of reaction. Both ethyne and ethene, however,
react rapidly and completely with hydrogen at low temperatures and pressures
in the presence of metals such as nickel, platinum, and palladium. For
maximum catalytic effect, the metal is usually obtained in a finely divided
state. This is achieved for platinum and palladium by reducing the metal
oxides with hydrogen before hydrogenating the alkene or alkyne. A specially
chap 2 the C t and C 2 hydrocarbons 36
active form of nickel (" Raney nickel ") is prepared from a nickel-aluminum
alloy; sodium hydroxide is added to dissolve the aluminum, and the nickel
remains as a black, pyrophoric powder.
2N1-A1 + 2 0H e + 2H 2
-» 2Ni + 2A10, B + 3H,
Highly active platinum, palladium, and nickel catalysts can also be prepared
by reducing metal salts with sodium borohydride.
Besides having synthetic applications, catalytic hydrogenation is useful
for analytical and thermochemical purposes. The analysis of a compound
for the number of double bonds is carried out by measuring the uptake of
hydrogen for a given amount of sample.
The reaction occurs on the surface of the catalyst to which the reacting
substances may be held loosely by van der Waals forces or, more tightly, by
chemical bonds. The relatively loosely held electrons in a double or triple
bond participate in forming carbon-metal bonds to the surface while hydrogen
combines with the surface to give metal-to-hydrogen bonds (see Figure 2-9).
The new bonds are much more reactive than the old ones and allow combina-
tion to occur readily. The hydrogenated compound is then replaced on the
surface by a fresh molecule of unsaturated compound, which has a stronger
attraction for the surface.
This is an example of heterogeneous catalysis — a type of reaction which
involves adsorption on a surface of a solid or liquid and is often hard to
describe in precise terms because the chemical nature of a surface is hard to
define in precise terms. Homogeneous catalysis occurs in solution or in the
vapor state. For such reactions, it is usually easier to trace the path from
reactants to products in terms of intermediates with discrete structures. The
light-induced chlorination of methane is an example of a homogeneous
reaction.
Ethene will add one mole of hydrogen while ethyne can add either one or
Figure 2-9 Schematic representation of the hydrogenation of ethene on the
surface of a nickel crystal.
H
H
CH,
CH 2
yy\y y
y\A ./
y y y '/
y
nickel crystal
sec 2.6 addition reactions of unsaturated hydrocarbons 37
two. Special catalysts are available which will convert ethyne to ethene much
faster than they convert ethene to ethane.
B. ADDITION OF BROMINE TO MULTIPLE BONDS
When ethene is treated with bromine (or with chlorine), a rapid addition occurs
to give the 1 ,2-dihaloethane. The name given to the reaction product can be
Br 2 + CH 2 =CH 2 ► BrCH 2 -CH 2 Br
1 ,2-dibromoethane
understood as follows. First, it is saturated (no double or triple bonds) and
contains two carbon atoms and therefore is a derivative of ethane. The posi-
tions of two of the hydrogen atoms of ethane have been taken by two bromine
atoms ; hence it is a dibromoetham. The two bromines are located on different
carbon atoms. We call one of the carbon atoms number 1 and the other num-
ber 2, hence the name 1,2-dibromoethane. This naming system can be used to
name the vast majority of organic compounds. In using it one should remem-
ber these points .
1. Pick out the parent hydrocarbon. Here it is ethane, not ethene, because
we are interested in designating the structure, not the way the compound is
formed in any particular reaction.
2. Pick out those groups or atoms that replace any of the hydrogens of the
parent compound and join their names to the front of the name of the parent
hydrocarbon. If there are two such groups, as in the case we are working with,
designate them with the prefix di; three such groups, tri; and so on. The name
at this stage should be all one word — for example, dibromoethane.
3. Locate the substituent groups by counting the carbon atoms from the
end of the carbon chain. One can start numbering at either end in the example
above, but this will not be generally true. The numbers designating the carbon
atoms that bear substituents are separated from one another by commas and
from the rest of the name by a hyphen — for example, 1,2-dibromoethane.
Remember that the number of substituents is designated by the prefixes
di, tri, and so on, but that their locations are designated by the numerals that
identify particular carbon atoms.
We shall examine nomenclature further in the next chapter, which deals with
alkanes.
The rapidity of the reaction of ethene with bromine illustrates the high
reactivity of carbon-carbon double bonds. It would be natural to suppose
that this reaction occurs by a simple simultaneous addition of both atoms of
bromine to the double bond :
Br- Br
It will be recalled from the discussion of the methane-chlorine reaction, how-
chap 2 the C x and C 2 hydrocarbons 38
ever, that four-center reactions are rare, and in fact the addition of bromine to
alkenes is known to occur in a stepwise manner, usually (but not always) to
involve ionic intermediates, and usually to proceed by addition of the two
bromines from opposite sides of the double bond. The evidence for this course
of reaction is described in detail in Chapter 4 on alkenes. Suffice it to say here
that an examination of the product of the ethene-bromine addition reaction
will not tell us whether addition occurred from the same or the opposite
side of the double bond, since rotation about the C— C bond converts one
product into the other and thus obliterates the distinction between the
two possible products (Equation 2-1). Both products are different confor-
mations of the same compound, 1,2-dibromoethane.
Br
H
J
H
Br
-H
H
Addition of bromine to ethyne also occurs readily to give the compound
1,2-dibromoethene. (Note that the parent compound is now ethene, not
ethyne.) The product of this reaction is a liquid, bp 108°, mp —6.5°. It is
Br 2 + H-CsC-H ► BrCH=CHBr
1,2-dibromoethene
immiscible with water and easily can be shown to possess no dipole moment.
However, there is another known compound that has the same structure
— that is, possesses two carbon atoms joined by a double bond and has a
bromine and hydrogen atom on each carbon. This second compound is a
liquid, bp 110°, mp —53°. It is also immiscible with water but has a large
dipole moment. The two isomers arise because of a lack of rotation about the
double bond. The molecule with the bromine atoms on the opposite side is
called the trans isomer, and the other the cis isomer.
Br H Br Br
w
/ \ / \
H Br H H
trans- 1,2-dibromoethene cis- 1,2-dibromoethene
These two compounds are said to have different configurations. It is worth
reviewing here the meanings of the terms structure, conformation, and
configuration. Structure designates the atoms that are linked together and the
bonds that do this. Compounds with the same formula, C 2 H 4 Br 2 for example,
but different structures, such as Br 2 CH— CH 3 and BrCH 2 —CH 2 Br, are
called structural isomers. If the compound contains one or more carbon-
sec 2.6 addition reactions of unsaturated hydrocarbons 39
carbon single bonds, rotation can usually occur freely about these and give
rise to different conformations. If the compound contains double bonds (or a
ring of atoms), rotation is prevented and different configurations may then
be possible. Compounds with different configurations are called stereoisomers
— for example, cis- and ?ranj-l,2-dibromoethene — and they can only be
interconverted by the rupture of chemical bonds. We shall encounter later in
the book (Chapter 14) a more subtle form of stereoisomerism. The form of
stereoisomerism we are discussing here is called either cis-trans isomerism or
geometrical isomerism and, harking back to our ball-and-stick models, it is
easy to rationalize why interconversion between geometrical isomers does
not take place readily (Equation 2-2). For rotation to occur, one of the C— C
Br H Br Br Br
\ / A. A . H \ /
/ C=C \ ' / C & C -Br ' r\ (2-2)
H Br H H H
trans cis
bonds of the double bond must be broken. For this, the necessary energy
input would be roughly equal to the difference in energy between a double
and a single bond — 63 kcal/mole (see Table 2-1). Such an amount of energy
is not available from molecular collision at ordinary temperatures.
It is a simple matter to assign configurations to the two geometrical isomers
of BrCH=CHBr. The one formed by the addition of bromine to ethyne has
no dipole moment and hence must be the trans isomer. The boiling points of
these compounds are nearly the same, but the melting points are vastly
Br
r<< Vv
H BA H H
trans isomer cis isomer
dipoles cancel, fi = dipoles do not cancel, (i=1.3D
bp 108°, mp - 6.5° bp 110°, mp - 53°
different. Trans compounds often have somewhat higher melting points than
the corresponding cis isomers, reflecting greater ease of crystal packing of
their somewhat more symmetrical molecules. Dihaloethenes are exceptional
in that the cis isomers tend to be slightly more stable than the trans. This is
because the distances between the halogens in these compounds (but not
usually between other substituents) are just right for operation of favorable
van der Waals attractive forces. With most other substituents, particularly
if they are bulky, the trans arrangement is preferred. Where three or four
different groups are attached to the double bond, you must define what you
mean by the terms cis and trans, and the generalizations given here about
melting points and stabilities do not apply.
Will 1,1-dibromoethene (CH 2 =CBr 2 ), which is a structural isomer of the
above compounds, also exist in cis and trans forms? Clearly not, because
chap 2 the C t and C 2 hydrocarbons 40
interchange of the two bromines on one carbon or interchange of the two hyd-
rogens on the other produces the same molecule. The requirement for the
existence of geometrical isomers of an alkene is that the two groups on one
end of the double bond be different from each other and the two groups on the
other end be different from each other.
Geometrical isomerism does not arise with triply bonded compounds,
because the — C=C— bonds in these molecules are linear.
summary
There are four Q and C 2 hydrocarbons: methane (CH 4 ) and ethane (CH 3 —
CH 3 ) are alkanes, ethene (CH 2 =CH 2 ) is an alkene, and ethyne (HC=CH) is
an alkyne. Ethene is a planar molecule, ethyne is linear, and ethane nonplanar.
Rotation around the single bond in ethane can be seen to give rise to an in-
finite number of arrangements called conformations, two extreme forms of
which are designated eclipsed and staggered.
All hydrocarbons undergo combustion — complete oxidation to carbon
dioxide and water. Heats of combustion and of other reactions can be cal-
culated from bond energy data.
The hydrogens in alkanes can be replaced by halogen atoms via a substi-
tution process — for instance, CH 4 + Cl 2 -> CH 3 C1 + HC1. The position of
equilibrium of this reaction is far to the right, the equilibrium constant K
being determined by the free energy of reaction, AG, which in turn is related
to the heat of reaction, the entropy factor, and the absolute temperature:
AG = -RTln K = AH - T AS. Reactions that are fairly exothermic (-AH >
15 kcal) usually have large K values. The rate of a reaction cannot be re-
lated in a simple way to its overall AH or K. It depends on the reaction path.
For the chlorination of methane, this involves a chain reaction with the follow-
ing steps : Cl 2 is cleaved by light to give CI • atoms (initiation) ; a hydrogen
atom is abstracted from CH 4 by CI- to give CH 3 -, a methyl radical; the
radical, in turn, abstracts a chlorine atom from Cl 2 .
CH 4 + CI- ► CH 3 - + HC1
CH 3 - + Cl 2 ► CHjCI + CI-
These two steps are the propagation steps in the chain reaction, CI • being con-
sumed in the first step and regenerated in the second ; the chain is terminated
when radicals or atoms combine.
Some important intermediate species that will be encountered in other
reactions, in addition to radicals such as CH 3 -, are carbonium ions, such as
CH 3 ®; carbanions, such as CH 3 e ; and carbenes, such as :CH 2 .
The double bonds in alkenes can be considered as two identical bent bonds,
or as one bond along the bond axis (a a bond) and a second bond above and
below the plane of the molecule (a % bond).
Unsaturated hydrocarbons undergo addition reactions, as with hydrogen or
exercises 41
halogens. Addition of bromine is often very fast while the addition of hydro-
gen requires the presence of a heterogeneous catalyst such as finely divided
nickel :
HC = CH __ ^ h 2 C=CH 2 — ^-* CH3-CH3
Ni Ni 3 j
HC = CH tj -* BrCH=CHBr Br2 > Br 2 CH — CHBr,
Compounds such as 1,2-dibromoethene (BrCH=CHBr) can exist as two
geometrical isomers, designated cis and trans. These two compounds have
Br Br Br H
\ / \ /
c=c c=c
/ \ / \
H H H Br
cis- 1,2-dibromoethene /ranj-l,2-dibromoethene
different physical properties and, because of the restricted rotation about the
double bond, are quite stable to interconversion. The requirements for geo-
metrical isomerism at a double bond are that two different groups be attached
to one carbon atom and two different groups be attached to the other. Cis and
trans isomers (geometrical isomers) have the same structure but different
configurations. (The many arrangements that arise because of rotation about
a single bond, as in ethane, are called conformations.)
exercises
2-1 Show how the two conventions of Figure 2-4 can be used to represent the
possible staggered conformations of the following substances :
a. CH 3 CH 2 C1 (chloroethane)
b. CH 2 C1CH 2 C1 (1,2-dichloroethane)
c. CH3CH2CH2CH3 (butane); consider rotation about the middle two
carbon atoms in this compound.
2-2 Use the bond-energy table to calculate A/7 for the following reactions in the
vapor phase at 25° :
4 H 2
a.
CH 3 CH 2 CH 3 + 5 2 ->3CO
b.
CH 4 + f 2 ->CO + 2H 2
c.
CO + 3H 2 -CH 4 + H 2
d.
CHU + 4 Cl 2 -»■ CCU + 4 HC1
e.
CH 4 + I 2 ->CH 3 I+HI
2-3 Calculate AH for C(s)-+C(g) from the heat of combustion of 1 gram-atom
of solid carbon (94.05 kcal) and the bond energies in Table 2- 1 .
2-4 Write balanced equations for the complete and incomplete combustion of
ethane to give, respectively, carbon dioxide and carbon monoxide. Use the
chap 2 the C x and C 2 hydrocarbons 42
table of bond energies to calculate the heats evolved in the two cases from 10 g
of ethane.
2-5 A possible mechanism for the reaction of chlorine with methane would be to
have collisions where a chlorine molecule removes a hydrogen according to
the following scheme:
.. .. slow
CH 3 :H + :Cl:Cl: «• CH 3 - + H:C1: + :C1-
. , " ' fact ..
(?' CH 3 - + :C1- ►■CH 3 :Cl:
Use appropriate bond energies to assess the likelihood of this reaction mech-
anism. What about the possibility of a similar mechanism with elemental
fluorine and methane?
2-6 Write the steps of a chain reaction for the light-catalyzed chlorination of
ethane.
2-7 Calculate A/f for each of the propagation steps of methane chlorination by
a mechanism of the type
(IV
Cl 2 »• 2 CI- initiation
C1+CH 4 ► CH 3 C1 + H-
H- + C1, > HCl + Cl- ' P r °P a g ation
Discuss the relative energetic feasibilities of these chain-propagation steps in
comparison with those of other possible mechanisms.
2-8 How many dichloro substitution (not addition) products are possible with
(a) methane, (b) ethane, (c) ethene, (d) ethyne?
29 Show that the methyl radical, CH 3 , has no charge. Show that the carbons of
the neutral molecules CH and CH 2 are electron deficient, that is, they do not
possess an octet of valence electrons.
2-10 Which of the following molecules or ions contain a carbon atom that lack
an octet of electrons: CH 3 CH 2 -, CH 3 ®, CH 3 e , CH 3 CH 3 , HC^CH, CH 2 :?
2-11 Consider the feasibility of a free-radical chain mechanism for hydrogenation
of ethene in the vapor state at 25° by the following propagation steps :
CH 3 — CH 2 +H 2 ► CH 3 — CH 3 + H-
CH 2 =CH 2 + H- ► CH 3 -CH 2 -
2-12 Name the following compounds:
a. C1CH 2 CC1 3 d , ClCsCCl
b. C1 2 CHCHC1 2 e . Br 2 C=CBr 2
c. BrCH=CH 2
exercises 43
2-13 Provide structures for the following compounds:
a. 1,1,1-tribromoethane
b. 1,1,2-tribromoethane
c. l-chloro-2-fiuoroethene
d. bromoethyne
2-14 Is geometrical isomerism possible in the following cases? Draw formulas to
show the configurations of the cis and trans isomers where appropriate.
a. Br 2 C=CHCl d. C1C=CC1
b. BrClC=CHBr e. CHF=CHF
c. C1 2 CH— CHC1 2 t
2-15 How many grams of bromine will react with (a) 20 g of ethene, (b) 20 g of
ethyne? /
2-16 What volume of carbon dioxide (dry, at 20° and 1 atm) will be obtained by the
complete combustion of (a) 20 g of ethene, (b) 20 g of ethyne?
2-17 The reaction HC=CH(<?) + H 2 (g)-> CH 2 =CH 2 (#) has the following
thermodynamic parameters at 25 °C.
AG = -33.7 kcal
A#= -41.7 kcal
^S = -26:8 eal
a. Does the position of equilibrium favor reactants or product?
b. Does the entropy term favor formation of reactants or product ? Explain
the significance of your answer about the entropy in terms of the
relative freedom of the atoms in the reactants and product.
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chap 3 alkanes 47
In the previous two chapters we have studied in some detail the properties
of the two simplest saturated hydrocarbons, methane and ethane, and have
shown how their simple derivatives are named using the rules of the Inter-
national Union of Pure and Applied Chemistry (IUPAC rules). In this
chapter we shall examine the larger alkanes, including those that are cyclic
(cycloalkanes). Open-chain, or acyclic, alkanes have the general formula
C„H 2 „+ 2 , whereas cycloalkanes have the formula C„H 2 „ . It is essential that
one be able to name compounds correctly and we will begin our discussion .
of alkanes with a survey of nomenclature.
3 ' 1 nomenclature
The IUPAC rules for naming alkanes are simple and easy to apply. -However,
few people adhere strictly to these rules and it is necessary to be familiar with
some other commonly used naming terms; these are often simple and con-
venient when applied to simple compounds but become cumbersome or
ambiguous with more complex compounds. The IUPAC name for a compound
is always acceptable; hence, when asked to supply a name to a compound
whose structure is given, it is best to follow the IUPAC rules. You should
become familiar enough with other common terms, however, so you can
supply the correct structure to a compound whose name is given in non-
IUPAC terminology.
The alkanes are classified as "continuous chain" (i.e., unbranched) if all
the carbon atoms in the chain are linked to no more than two other carbons,
or " branched chain " with one or more carbon atoms linked to three or four
other carbons. Branching is only possible with alkanes C 4 and up. 1
HiC CH* CHi
II I
CH 3 -CH 2 -CH 2 -CH 2 -CH 2 -CH 3 CH 3 — C-C-CH 3 CH 3 -C-CH 2 -CH 3
H H CH 3
continuous-chain hydrocarbon branched-chain hydrocarbons
The first four continuous-chain hydrocarbons have nonsystematic names :
CH 4 CH 3 -CH 3 CH 3 -CH 2 -CH 3 CH 3 -CH 2 -CH 2 -CH 3
methane ethane propane butane
The higher members, beginning with pentane, are named systematically with
a numerical prefix (pent-, hex-, hept-, etc., to denote the number of car-
bon atoms) and with the ending -ane to classify the compound as a saturated
hydrocarbon. Examples are listed in Table 3T. These names are generic of
1 The notation C 4 means a compound containing four carbon atoms whereas C-4 means
the fourth carbon atom in a chain.
chap 3 alkanes 48
Table 3-1 Continuous-chain alkanes (C„H 2 „ +2 )
no. branched-chain
no. of carbons, n
name
of isomers
1
methane
2
ethane
3
propane
4
butane
1
5
pentane
2
6
hexane
4
7
heptane
8
8
octane
17
9
nonane
34
10
decane
74
20
eicosane
366,318
30
triacontane
4.11 X 10"
both branched and unbranched hydrocarbons and, to specify a continuous-
chain hydrocarbon, the prefix n- (for normal) is often attached. In the absence
of any qualifying prefix the hydrocarbon is considered to be "normal" or
unbranched.
CH 3 -CH 2 - CH 2 - CH 2 - CH 3
pentane
(//-pentane)
The possibility of branched-chain hydrocarbons isomeric with the con-
tinuous-chain hydrocarbons begins with butane (n = 4). The total number of
theoretically possible isomers for each alkane up to n = 10 is given in Table
3-1, and is seen to increase very rapidly with n. All 75 possible alkanes from
n = 1 to n = 9 inclusive have now been synthesized.
There are two structural isomers of C 4 H 10 , one the continuous-chain
compound called butane (or w-butane to emphasize its lack of branching)
and the other called 2-methylpropane (or, in common terminology, isobutane).
CH 3 -CH — CH 3
CH 3 -CH 2 -CH 2 -CH 3 I
CH 3
butane 2-methylpropane
( //-butane) (isobutane)
The name 2-methylpropane is appropriate because the longest continuous
chain in the molecule is made up of three carbons ; it is thus a derivative of
propane. The second carbon (from either end) has one of its hydrogens
replaced by a methyl group, hence the prefix 2-methyl. It should be re-
membered that the shape of this molecule is not as depicted in the formula
shown. The tetrahedral arrangement about the central carbon atom makes
all three methyl groups equivalent (Figure 3-1).
sec 3.1 nomenclature 49
Figure 3-1 Shape of 2-methylpropane.
There are three known compounds with the formula C 5 H 12 , and this is
the number of isomers expected on the basis of carbon being tetravalent and
hydrogen monovalent:
CH 3 CH 3
CH 3 -CH 2 -CH 2 -CH 2 -CH 3 CH 3 -CH-CH 2 -CH 3 CH 3 -C-CH 3
CH 3
pentane 2-methylbutane 2,2-dimethylpropane
(;?-pentane) (isopentane) (neopentane)
The prefix iso denotes a compound with two methyl groups at the end of a
chain, and neo means three methyl groups at the end of a chain.
When we come to the C 6 alkanes we find that there are five isomeric
compounds, C 6 H 14 . Clearly, trivial prefixes become less and less useful as the
length of the chain grows and the number of possible isomers increases.
Accordingly, hexane and its four branched-chain isomers are here only given
IUPAC names. (The second compound in the list might be called isohexane
and the fourth neohexane.)
CH 3
I
CH 3 — CH 2 — CH 2 -CH 2 — CH 2 — CH 3 CH 3 — CH-CH 2 — CH 2 — CH 3
hexane 2-methylpentane
CH 3 CH 3 CH 3 CH 3
CH 3 -CH 2 -CH-CH 2 -CH 3 CH 3 -C-CH 2 -CH 3 CH 3 -CH-CH-CH 3
CH 3
3-methylpentane 2,2-dimethylbutane 2,3-dimethylbutane
The branched-chain compounds considered so far all contain the simplest
group, methyl, as substituent. Alkyl groups such as methyl are obtained by
writing the alkane minus one of its hydrogens. Thus, we have methyl (CH 3 — )
and ethyl (CH 3 — CH 2 — ). A problem arises when we come to the alkyl
groups of propane, CH 3 — CH 2 — CH 3 . The hydrogen atoms in this molecule
are not all equivalent. Removing one of the six terminal hydrogens produces
the n-propyl group, CH 3 — CH 2 — CH 2 — ; removing one of the two central
chap 3 alkanes SO
hydrogens produces the isopropyl group, CH 3 — CH— CH 3 (usually written
V
/
CH— or(CH 3 ) 2 CH— ).
H 3 C
Additional examples are listed in Table 3-2. These have been further classi-
Table 3-2 Typical alkyl groups (C„H 2 „ + 1 )
primary (RCH 2 — )
CH 3 -
CH3CH2
CH3CH2CH2 — •
methyl
ethyl
«-propyl
CH3CH2CH2CH2
CH 3
\
CH-CH 2 -
CH 3
n-butyl
isobutyl
CH3CH2CH2CH2CH2
CH 3
CH— CH 2 -CH 2 -
CH 3
1
CH3 — C CH 2
1
*
CH 3
CH 3
pentyl
isopentyl
neopentyl
(«-amyl)
(isoamyl)
CH3CH2CH2CH2CH2CH2
CH 3
V
CH— CH 2 — CH 2 — CH
CH 3
CH 3
1
2 CH3 — C Cri2Cri2
CH 3
K-hexyl
isohexyl
neohexyl
secondary (R 2 CH — )
CH 3
\ 3
CH 3 CH 2
/C H
CH 3
-
CH 3
isopropyl s-butyl
tertiary (R 3 C— )
CH 3
1
ch 3
1
CH 3 -C-
1
CH 3 CH 2 -
c—
1
CH 3
CH 3
r-butyl
r-pentyl
(/-amyl)
sec 3.1 nomenclature SI
fied according to whether they are primary, secondary, or tertiary. An alkyl
group is described as primary if the carbon at the point of attachment is
bonded to only one other carbon, as secondary if bonded to two other carbons,
and tertiary if bonded to three other carbons. The methyl group is a special
case and is regarded as a primary group.
In a few cases, where there is a high degree of symmetry, hydrocarbons are
conveniently named as derivatives of methane or ethane.
H 3 C v CH 3
H >\ 7 -ii
CH-C-H CH3-C-C-CH3
/I II
H 3 C CH H 3 C CH 3
/ \
H 3 C CH 3
triisopropyltnethane hexamethylethane
In naming complex compounds, you must pick out the longest consecutive
chain of carbon atoms. The longest chain may not be obvious from the way
in which the structure has been drawn on paper. Thus the hydrocarbon [1]
is a pentane rather than a butane derivative, since the longest chain is one
with five carbons.
H 3 C
CH 3
CH 2
CH 3 -CH-CH-
CH,
[1]
(dotted lines enclose
longest chain of suc-
cessive carbon atoms)
The parent hydrocarbon is numbered starting from the end of the chain,
and the substituent groups are assigned numbers corresponding to their
positions on the chain. The direction of numbering is chosen to give the
lowest sum for the numbers of the side-chain substituents. Thus, hydrocarbon
[1] is 2,3-dimethylpentane rather than 3,4-dimethylpentane. Although the
latter name would enable one to write the correct structure for this com-
pound, it would not be found in any dictionary or compendium of organic
compounds.
5CH 3 'CH 3
I I
H 3 C *CH 2 H 3 C 2CH 2
II II
CH 3 — CH — CH— CHj not CH 3 -CH-CH-CH 3
54 3
2,3-dimethylpentane 3,4-dimethylpentane
chap 3 alkanes 52
Where there are two identical substituents at one position, as in [2],
numbers are supplied for each. Remember that the numerals represent posi-
tions and the prefixes di-, tri-, and so on represent the number of substituents.
Note that there should always be as many numerals as there are substituents,
that is, 2,2,3 (three numerals) and trimethyl (three substituents).
H 3 C CH 3
I I
CH3-C-CH-CH3
I
CH 3
2,2,3-trimethylbutane
[2]
Branched-chain substituent groups are given appropriate names by a simple
extension of the system used for branched-chain hydrocarbons. The longest
chain of the substituent is numbered starting with the carbon attached directly
to the parent hydrocarbon chain. Parentheses are used to separate the number-
ing of the substituent and the main hydrocarbon chain. The IUPAC rules
23
rliC CHi CHi
CH
CH 3 -CH 2 -CH 2 -CH 2 — CH-CH 2 — CH 2 -CH 2 -CH 2 -CH 3
1 2 3 4 56 7 8 910
5-(l-methy!propyl)decane
(5-.s-butyldecanc)
permit use of the substituent group names in Table 3-2, so that s-butyl can
be used in place of (1-methylpropyl) for this example.
When there are two or more different substituents present, the question
arises as to what order they should be cited in naming the compound. Two
systems are commonly used which cite the alkyl substituents (1) in order of
increasing complexity or (2) in alphabetical order. We shall adhere to the
latter system mainly because it is the practice of Chemical Abstracts. 2 Examples
are given below.
CH 3 CH 2 CH 3
CH 3 -CH 2 — CH 2 — CH-CH-CH 2 — CH 3
7 3 6 5 4 3 2 1
4-ethyl-3-methyl heptane
(i.e.. ethyl is cited before methyl)
CH 3 -C-CH 3
CH 3 -CH 2 -CH 2 — C-CH 2 -CH 2 -CH 2 — CH 2 — CH 2 -CH 3
1 3 2 3 4| i Z b i lit9 i iQ
CH 3 -CH
CH 3
4-/-butyl-4-isopropyldecane
2 Biweekly publication of the American Chemical Society: an index to, and a digest of,
recent chemical publications throughout the world.
sec 3.2 physical properties of alkanes — concept of homology 53
Derivatives of alkanes, such as haloalkanes (R— CI) and nitroalkanes
(R— N0 2 ), where R denotes an alkyl group, are named similarly by the
IUPAC system. Definite orders of precedence are assigned substituents of
different types when two or more are attached to a hydrocarbon chain. Thus,
alkanes with halogen and alkyl substituents are generally named as halo-
alkylalkanes (not as alkylhaloalkanes) ; alkanes with halogen and nitro
substituents are named as halonitroalkanes (not as nitrohaloalkanes).
CH 3
I
CH 3 -CH 2 -CH,-CH,-CI CH 3 — CH,-CH-CH-CH 3
N0 2
l-chlorobutane 3-nitro-2-metliylpentane
(n-bulyl ehloride)
H 3 C CH 3
\ I
CH-CH 2 -Br CI-CH-CH 2 -CH 2 — N0 2
H 3 C
l-bromo-2-melhylpropane 3-chloro-l-nitrobutane
(isobutyl bromide)
Note that l-chlorobutane is written as one word whereas the alternate
name «-butyl chloride is written as two words. In the former the chloro group
is substituted for one of the hydrogens of butane and the position of sub-
stitution is indicated by the numeral. The latter name is formed by simply
combining names for the two parts of the compound just as one would do
for NaCl, sodium chloride.
3 ' 2 physical properties of alkanes — concept of homology
The series of continuous-chain alkanes, CH 3 (CH 2 )„_ 2 CH 3 , shows a remark-
ably smooth gradation of physical properties (see Table 3-3 and Figure 3-2).
As you go up the series, each additional CH 2 group contributes a fairly
constant increment to the boiling point and density and, to a lesser extent,
to the melting point. This makes it possible to estimate the properties of an
unknown member of the series from those of its neighbors. For example, the
boiling points of hexane and heptane are 69° and 98°, respectively; a difference
in structure of one CH 2 group therefore makes a difference in boiling point
of 29°. This places the boiling point of the next higher member, octane, at
98° + 29°, or 127°, which is close to the actual boiling point of 126°.
Members of a group of compounds with similar chemical structures and
graded physical properties and which differ from one another by the number
of atoms in the structural backbone, such as the «-alkanes, are said to con-
stitute a homologous series. The concept of homology, when used to forecast
the properties of unknown members of the series, works most satisfactorily
for the higher-molecular-weight members. For these members, the intro-
duction of additional CH 2 groups makes a smaller relative change in the
overall composition of the molecule. This is better seen from Figure 3-2,
chap 3 alkanes 54
200
100
-100
-200
^•""'^
^^^
boiling
point ^
yS&i
nsity
^ *~
/
,
1
melt in« point
1 ^S
*^«
ijllSIt
/
0.75
0.65 dl°
10
11 12
0.55
Figure 3 • 2 Dependence on n of melting points, and densities (c^ ) of straight-
chain alkanes, CH 3 (CH 2 )„_ 2 CH 3 .
which shows how the boiling points and melting points of the homologous
series of normal alkanes change with the number of carbons, n. See also
Figure 3-3.
Branched-chain alkanes do not exhibit the same smooth gradation of
physical properties as the «-alkanes. Usually, there is too great a variation in
Figure 3-3 Dependence of A T (difference in boiling and melting points
between consecutive members of the series of normal alkanes) on n (number
of carbon atoms).
80 i
60
, bo
ling f
>oinl
V
,
w
— mei
tinu p
oint
AT 40
/
r
/
\
^„ /
\^
20
\
/
\
\
\f
10
11 12
sec 3.2 physical properties of alkanes — concept of homology 55
Table 3-3 Physical properties of rc-alkanes, CH 3 (CH 2 )„ _ 2 CH 3
refractive
bp,°C
mp,
density,
index,
n
name
(760 mm)
°C
dl°
n 20 D
1
methane
-161.5
-183
0.424"
2
ethane
-88.6
-172
0.546"
3
propane
-42.1
-188
0.501"
4
butane
-0.5
-135
0.579"
1.3326"
5
pentane
36.1
-130
0.626
1.3575
6
hexane
68.7
-95
0.659
1.3749
7
heptane
98.4
-91
0.684
1.3876
8
octane
125.7
-57
0.703
1.3974
9
nonane
150.8
-54
0.718
1.4054
10
decane
174.1
-30
0.730
1.4119
11
undecane
195.9
-26
0.740
1.4176
12
dodecane
216.3
-10
0.749
1.4216
15
pentadecane
270.6
10
0.769
1.4319
20
eicosane
342.7
37
0.786*
1.4409 c
30
triacontane
446.4
66
0.810 c
1.4536 c
At the boiling point.
* Under pressure.
c For the supercooled liquid.
molecular structure for regularities to be apparent. Nevertheless, in any one
set of isomeric hydrocarbons, volatility increases with increased branching.
This can be seen from the data in Table 3-4, in which are listed the physical
Table 3-4 Physical properties of hexane isomers
isomer
structure
bp,
°C
mp,
°C
density
at 20°, dl°
hexane
CH 3 (CH 2 ) 4 CH 3
CH 3
1
68.7
-94
0.659
3-methylpentane
CH 3 CH 2 CHCH 2 CH 3
CH 3
1
63.3
-118
0.664
2-methylpentane
(isohexane)
CH 3 CHCH 2 CH 2 CH 3
CH 3 CH 3
1 1
60.3
-154
0.653
2,3-dimethylbutane
CH 3 CH-CHCH 3
CH 3
|
58.0
-129
0.661
2,2-dimethylbutane
(neohexane)
CH 3 CCH 2 CH 3
1
CH 3
49.7
-98
0.649
chap 3 alkanes 56
properties of the five hexane isomers; the most striking feature is the 19°
difference between the boiling points of hexane and neohexane.
33 alkanes and their chemical reactions
As a class, alkanes are singularly unreactive. The name saturated hydrocarbon
(or "paraffin," which literally means "little affinity" [L. par{um), little,
+ affins, affinity]) arises because their chemical affinity for most common
reagents may be regarded as saturated or satisfied. Thus none of the C— H
or C— C bonds in a typical saturated hydrocarbon such as ethane are attacked
at ordinary temperatures by a strong acid such as sulfuric, or by powerful
oxidizing agents such as potassium permanganate, or by vigorous reducing
agents such as lithium aluminum hydride (LiAlH 4 ).
We have seen that methane and other hydrocarbons are attacked by oxygen
at elevated temperatures and, if oxygen is in excess, complete combustion
occurs to give carbon dioxide and water with the evolution of large amounts
of heat. Vast quantities of hydrocarbons from petroleum are utilized as fuels
for the production of heat and power, as will be described in the next section.
A. PETROLEUM AND COMBUSTION OF ALKANES
The liquid mixture of hydrocarbons delivered by oil wells is called petroleum.
Its composition varies according to the location of the field but the major
components are invariably alkanes. Natural gas is found in association with
petroleum and also alone as trapped pockets of underground gas. Natural
gas is chiefly methane, while crude petroleum is an astonishing mixture of
hydrocarbons up to C 50 in size. This dark, viscous oil is present in interstices
in porous rock and is usually under great pressure.
Petroleum is believed to arise from the decomposition of the remains of
marine organisms over the ages and new fields are continually sought to satisfy
the enormous world demand. The effect of advanced technology on our
environment is shown by the fact that combustion of fossil fuels, chiefly
petroleum, has increased the carbon dioxide content of the atmosphere by
10% in the past century and an increase of 25% has been predicted by the
year 2000. These increases would be even more marked were it not for the
fact that the rate of photosynthesis by plants becomes more efficient at
utilizing carbon dioxide as the concentration increases.
In addition to serving as a source of power — and being the only natural
sources of suitable fuel for the internal combustion engine — petroleum and
natural gas are extremely useful as starting materials for the synthesis of
other organic compounds. These are often called petrochemicals to indicate
their source but they are, of course, identical with compounds prepared in
other ways or found in nature.
Petroleum refining involves separation into fractions by distillation. Each
of these fractions with the exception of the first, which contains only a few
components, is still a complex mixture of hydrocarbons. The main petroleum
fractions are given below in order of decreasing volatility.
sec 3.3 alkanes and their chemical reactions 57
1 . Natural Gas. Natural gas varies considerably in composition depending
on the source but methane is always the major component, mixed with smaller
amounts of ethane, propane, butane, and 2-methylpropane (isobutane). These
are the only alkanes with boiling points below 0°C. Methane and ethane
cannot be liquefied by pressure at room temperature (their critical tempera-
tures are too low) but propane, butane, and isobutane can. Liquid propane
(containing some of the C 4 compounds) can be easily stored in cylinders and
is a convenient source of gaseous fuel. It is possible to separate natural gas
into its pure components for sale as pure chemicals although the mixture is,
of course, perfectly adequate as a fuel.
2. Gasoline. Gasoline is a complex liquid mixture of hydrocarbons
composed mainly of C 5 to C 10 compounds. Accordingly, the boiling range of
gasoline is usually very wide, from approximately 40° to 180°. Because of the
large number of isomers possible with alkanes of this size, it is much more
difficult to separate gasoline into its pure components by fractional distillation
than is the case with natural gas. Using a technique known as gas chromatog-
raphy (Section 7-1), this separation can be done on an analytical scale. It has
been shown that well over 100 compounds are present in appreciable amounts
in ordinary gasoline. These include, besides the open-chain alkanes, cyclic
alkanes (cycloalkanes, Section 3-4) and alkylbenzenes (arenes, Section 20T).
The efficiency of gasoline as a fuel in modern high-compression internal
combustion engines varies greatly with composition. Gasolines containing
large amounts of branched-chain alkanes such as 2,2,4-trimethylpentane
have high octane ratings and are in great demand, while those containing
large amounts of continuous-chain alkanes such as octane or heptane have
low octane ratings and perform poorly in a modern high-compression auto-
mobile engine. The much greater efficiency of branched-chain alkanes is not
the result of greater heat of combustion but of the smoothness with which
they burn. The heats of combustion of octane and 2,2,4-trimethylpentane
can be calculated from the data in Table 2T and, since each contains the
same number of carbon-carbon bonds (seven) and carbon-hydrogen bonds
(18), we would expect their heats of combustion to be identical. The calculated
value is —1218 kcal/mole, and the experimental values are close to this.
25.
2
CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 + — 2 ► 8 C0 2 + 9 H 2 AH = -1222.8 kcal
25.
2
CH,
CH 3 -C-CH 2 -CH-CH 3 + — 2 ► 8C0 2 + 9H 2 AH= -1220.6kcal
The combustion of vaporized branched-chain alkanes is slower and less
explosive than that of continuous-chain compounds. In an automobile
engine, too rapid combustion leads to dissipation of the combustion energy
as heat to the engine block, rather than as movement of the piston. You can
clearly hear the "knock" in an engine that is undergoing too rapid com-
bustion of the fuel vapor in the cylinders. The problem is aggravated in high-
compression engines. These will often continue to run (though inefficiently)
chap 3 alkanes 58
on low-octane gasoline even when the ignition switch has been turned off,
the heat of compression in the cylinder being sufficient to ignite the fuel
mixture.
Combustion of hydrocarbons occurs by a complex chain reaction (Section
2-5B). It is possible to slow the propagation of the chain by adding volatile
compounds such as tetraethyllead, (CH 3 CH 2 ) 4 Pb, to gasoline. The fine
particles of solid lead oxide formed by oxidation of tetraethyllead moderate
the chain-carrying reactions and reduce the tendency for knock to occur. 3
The octane rating of a gasoline is measured by comparing its knock with that
of blends of 2,2,4-trimethylpentane whose octane rating is set at 100, and
heptane whose octane rating is set at zero. Octane itself has a rating of — 20.
The higher the octane rating, the smoother the ignition and, with high-com-
pression engines, the more efficient the gasoline. With low-compression engines
the effect is negligible and it is wasteful or worse (see footnote) to use gasoline
of higher rating than is needed to eliminate knocking.
The steadily increasing use of hydrocarbons in internal combustion engines
has led to increasingly serious pollution problems. Some of these are associated
with waste products from the refining operations used to produce suitable
fuels from crude petroleum, others with spillage of petroleum in transit to the
refineiies, but possibly the worst is atmospheric pollution from carbon mon-
oxide and of the type known as "smog." The chemical processes in the
production of smog are complex but appear to involve hydrocarbons (espe-
cially branched-chain hydrocarbons), sunlight, and oxides of nitrogen. The
products of the reactions are ozone, which produces rubber cracking and
plant damage, particulate matter, which produces haze, oxides of nitrogen,
which color the atmosphere, and virulent eye irritants (one being acetyl
O
II
pernitrite, CH 3 — C— O— O— N=0). The hydrocarbons in the atmosphere
which produce smog come principally from incomplete combustion in
gasoline engines, although sizable amounts arise from evaporation and spill-
age. Whether smog can be eliminated without eliminating the internal com-
bustion engine is not yet known, but the prognosis is rather unfavorable.
Pollution of the atmosphere from carbon monoxide is already so severe in
heavy downtown traffic in large cities as to pose immediate health problems.
The main reason for high concentrations of carbon monoxide in automobile
exhaust is that the modern gasoline engine runs most efficiently on a slight
deficiency in the ratio of oxygen to hydrocarbon which would produce
complete combustion. A current solution to this problem is to introduce air
and complete the combustion process in the exhaust manifold.
3 Accumulation of lead oxide in a motor would rapidly damage the cylinder walls and
valves. Tetraethyllead is normally used in conjunction with 1 ,2-dibromoethane in gasoline
and this combination forms volatile lead bromide which is swept out with the exhaust
gases. An unfortunate consequence of this means of improving octane rating is the addition
of toxic lead compounds to the atmosphere. Isomerizing normal alkanes or cracking
kerosene to produce branched-chain compounds would seem to be better solutions to the
problem. The manufacture of engines capable of running on nonleaded gasoline is also
being considered.
sec 3.3 alkanes and their chemical reactions 59
3. Kerosene. Kerosene consists chiefly of C u and C 12 hydrocarbons,
compounds that do not vaporize well in automobile engines. It now finds
considerable use as fuel for jet engines. It is also used in small heating units
and can, if necessary, be converted to gasoline by a process known as cracking.
This involves catalytic decomposition to smaller molecules, one of which is an
alkene :
heat
CuH24 catalyst* C9H20 + CH 2 =CH 2
4. Diesel Oil. The petroleum fraction which boils between about 250° and
400° (C 13 to C 25 ) is known as diesel oil or fuel oil. Large amounts are used in
oil-burning furnaces, some is cracked to gasoline, and much is used as fuel
for diesel engines. These engines operate with a very high compression ratio
and no spark system, so that they depend on compression to supply the
heat for ignition of the fine spray of liquid fuel that is injected into the
cylinder near the top of the compression stroke. Branched-chain compounds
turn out to be too unreactive to ignite and for this reason diesel and auto-
mobile engines have quite different fuel requirements.
5. Lubricating Oils and Waxes. The high-molecular- weight hydrocarbons
(C 26 to C 28 ) in petroleum have very high boiling points and can only be
obtained in a reasonably pure state by distillation at reduced pressure.
Thermal decomposition (pyrolysis) occurs if distillation is attempted at
atmospheric pressure because the thermal energy acquired by collision of
these compounds at their boiling points (400°) is sufficient to rupture carbon-
carbon bonds. Almost all alkanes higher than C 20 are solids at room temper-
ature, and you might be wondering why lubricating oil is liquid. This is
because it is a complex mixture whose melting point is much below that of its
pure components. Indeed, as the temperature is lowered, its viscosity simply
increases although this undesirable property can often be corrected by special
additives such as chlorinated hydrocarbons.
Paraffin wax used in candles is a mixture of very high-molecular-weight
hydrocarbons similar enough in structure to pack together to give a semi-
crystalline solid. Vaseline is a mixture of paraffin wax and low-melting oils.
6. Residue. After removal of all volatile components from petroleum, a
black, tarry material remains which is a mixture of minerals and complex
high-molecular- weight organic compounds; it is known as asphalt.
B. SUBSTITUTION OF HALO AND NITRO GROUPS IN ALKANES
The chlorination of methane was discussed in considerable detail in the
previous chapter. This reaction actually occurs with all alkanes and can also
be performed satisfactorily with bromine (but not with fluorine or iodine).
I I
For the general reaction — C— H + X, -» — C— X + H— X, where X = F,
II
CI, Br, or I, the calculated AH value is negative and very large for fluorine,
chap 3 alkanes 60
Table 3.5 Calculated heats of reaction for halogenation of hydrocarbons
I I
— C— H + X 2 ► — C— X + HX
I I
X
A/f, kcal/mole
F
-115
CI
-27
Br
-10
I
12
negative and moderate for chlorine and bromine, and positive for iodine (see
Table 3-5). With fluorine, the reaction evolves so much heat that it is difficult
to control, and products from cleavage of carbon-carbon as well as of carbon-
hydrogen bonds are obtained. Indirect methods for preparation of fluorine-
substituted hydrocarbons will be discussed later. Bromine is generally much
less reactive toward hydrocarbons than chlorine, both at high temperatures
and with activation by light. Nonetheless, it is usually possible to brominate
saturated hydrocarbons successfully. Iodine is unreactive.
As we have seen, the chlorination of methane does not have to stop with the
formation of chloromethane, and it is possible to obtain the higher chlorin-
ation products: dichloromethane (methylene chloride), trichloromethane
(chloroform), and tetrachloromethane (carbon tetrachloride). In practice,
all the substitution products are formed to some extent, depending on the
CH 4
► CHjCI
chloro-
methane
— ► CH,CI 2 —
dichloro-
methane
> CHCl.,
trichloro-
methane
► CCI 4
tetrachloro
methane
chlorine-to-methane ratio employed. If monochlorination is desired, a large
excess of hydrocarbon is advantageous.
For propane and higher hydrocarbons, where more than one monosub-
stitution product is generally possible, difficult separation problems may arise
when a particular product is desired. For example, the chlorination of
2-methylbutane at 300° gives all four possible monosubstitution products,
[3], [4], [5], and [6]. On a purely statistical basis, we might expect the ratio of
products to correlate with the number of available hydrogens at the various
positions of substitution; that is, [3], [4], [5], and [6] would be formed in the
ratio 6:3:2:1. However, in practice, the product composition is substanti-
ally different, because the different kinds of hydrogens are not attacked at
equal rates. Actually, the approximate ratios of the rates of attack of chlorine
atoms on hydrogens located at primary, secondary, and tertiary positions are
1.0:3.3:4.4 at 300°. These results indicate that dissociation energies of
C— H bonds are not exactly the same but decrease in the order primary >
secondary > tertiary.
CH,
I
H
CH,
I
sec 3.3 alkanes and their chemical reactions 61
CH 3 CH 3
Cl 2 I I
— —> C1CH 2 -C-CH 2 -CH 3 + CH 3 -C-CH 2 -CH 2 C1
300° 2 | 2 J ■* | i*
H H
l-chloro-2-methylbutane l-chloro-3-methylbutane
[3] _ [4]
CH,
+ CH 3 -C— CHC1-CH, + CH 3 -C-CH 2 -CH 3
H CI
3-chloro-2-methylbutane 2-chIoro-2-methylbutane
[5] [6]
Bromine atoms are far more selective than chlorine atoms, and bromine
attacks only tertiary hydrogens, and these not very efficiently. Thus, photo-
chemical (light-induced) monobromination of 2-methylbutane proceeds
slowly and gives quite pure 2-bromo-2-methylbutane. Bromine atoms might
be expected to be more selective than chlorine atoms, because bond energies
I .. I
indicate that the process — C— H + :Br- ->•— C- + HBr is distinctly en-
I •• I
dothermic while the corresponding reaction with a chlorine atom is exothermic.
In such circumstances it is not surprising to find that bromine only removes
those hydrogens which are less strongly bonded to a carbon chain.
Another reaction of commercial importance is the nitration of alkanes to
give nitroalkanes. Reaction is usually carried out in the vapor phase at
elevated temperatures using nitric acid or nitrogen tetroxide as the nitrating
agent. All available evidence points to a radical-type mechanism for nitration
RH + HNO,
-425°
RNO,
H,0
but many aspects of the reaction are not fully understood. Mixtures are
obtained — nitration of propane gives not only 1- and 2-nitropropanes but
nitroethane and nitromethane.
CH 3 CH 2 CH 3 + HN0 3
CH 3 CH 2 CH 2 N0 2
1-nitropropane (25%)
CH 3 CH 2 N0 2
nitroethane (10%)
I
N0 2
2-nitropropane (40%)
CH 3 N0 2
nitromethane (25%)
In commercial practice, the yield and product distribution in nitration of
alkanes are controlled as far as possible by the judicious addition of catalysts
(e.g., oxygen and halogens) which are claimed to raise the concentration of
alkyl radicals. The product mixtures are separated by fractional distillation.
chap 3 alkanes 62
3-4 cycloalkanes
An important and interesting group of hydrocarbons, known as cycloalkanes,
contain rings of carbon atoms linked together by single bonds. The simple
unsubstituted cycloalkanes of the formula (CH 2 )„ make up a particularly
important homologous series in which the chemical properties change in a
much more striking way than do the properties of the open-chain hydro-
carbons, CH 3 (CH 2 ) n _2CH 3 . The reasons for this will be developed with the
aid of two concepts, steric hindrance and angle strain, each of which is simple
and easy to understand, being essentially mechanical in nature.
The conformations of the cycloalkanes, particularly cyclohexane, will be
discussed in some detail, because of their importance to the chemistry of many
kinds of naturally occurring organic compounds.
Cyclohexane is a typical cycloalkane and has six methylene (CH 2 ) groups
joined together to form a six-membered ring. Cycloalkanes with one ring
have the general formula C„H 2 „ and are named by adding the prefix cyclo to
H 2 C^ ^CH 2
I I
H 2 C \ C / CH 2
H 2
cyclohexane
the name of the corresponding n-alkane having the same number of carbon
atoms as in the ring. Substituents are assigned numbers consistent with their
positions in such a way as to keep the sum of the numbers to a minimum.
CH I
2 C" ^CH 2 ..^ CH V
II H 2 C CH 2
^ **> h 2 V c— c'h
\
C,H,
CH
I
CH,
1,4-dimethylcyclohexane l-ethyl-3-methylcyclopentane
(not 3,6-dimethylcyclohexane) (not l-methyI-4-ethylcyclopentane)
The substituent groups derived from cycloalkanes by removing one hydro-
gen are named by replacing the ending -ane of the hydrocarbon with -yl to
give cycloalkyl. Thus cyclohexane becomes cyclohexyl; cyclopentane,
cyclopentyl; and so on.
H 2 cA H2
I CHCI
h » c Vh,
cyclopentyl chloride
(or chlorocyclopentane)
sec 3.4 cycloalkanes 63
Frequently it is convenient to write the structure of a cyclic compound in an
abbreviated form as in the following examples. Each line junction represents
a carbon atom and the normal number of hydrogens on each carbon atom is
understood.
cyclobutane 2-methylcyclohexyl bromide cyclooctane
( 1 -bromo-2-methylcyclohexane)
A. PHYSICAL PROPERTIES OF CYCLOALKANES
The melting and boiling points of cycloalkanes (Table 3-6) are somewhat
higher than for the corresponding alkanes. The general "floppiness" of
open-chain hydrocarbons makes them harder to fit into a crystal lattice
(hence lower melting points) and less hospitable to neighboring molecules of
the same type (hence lower boiling points) than the more rigid cyclic com-
pounds.
B. CONFORMATIONS OF CYCLOHEXANE
If cyclohexane existed as a regular planar hexagon with carbon atoms at the
corners, the C—C—C bond angles would be 120° instead of the normal
Table 3*6 Physical properties of alkanes and cycloalkanes
compounds
bp,°C
mp, °C
di°
propane
-42
-187
0.580°
cyclopropane
-33
-127
0.689°
«-butane
- 0.5
-135
0.579"
cyclobutane
13
- 90
0.689"
«-pentane
36
-130
0.626
cyclopentane
49
- 94
0.746
«-hexane
69
- 95
0.659
cyclohexane
81
7
0.778
H-heptane
98
- 91
0.684
cycloheptane
119
- 8
0.810
«-octane
126
- 57
0.703
cyclooctane
151
15
0.830
«-nonane
151
- 54
0.718
cyclononane
178
11
0.845
" At -40°.
* Under pressure.
chap 3 alkanes 64
«*
A
#
4 HjI
ti ft.
Figure 3-4 Two conformations of cyclohexane with 109.5° bond angles
(hydrogens omitted).
valence angle of carbon, 109.5°. Thus, a cyclohexane molecule with a planar
structure could be said to have an angle strain of 10.5° at each of the carbon
atoms. Puckering of the ring, however, allows the molecule to adopt confor-
mations that are free of angle strain.
Inspection of molecular models reveals that there are actually two extreme
conformations of the cyclohexane molecule that may be constructed if the
Figure 3-5 Boat form of cyclohexane showing interfering and eclipsed
hydrogens. Top, scale model; center, ball-and-stick models ; bottom, sawhorse
representations.
— ♦
-ortydwscni
r»>-aa>Mi!s
side view
end view
sec 3.4 cycloalkanes 65
carbon valence angles are held at 109.5°. These are known as the "chair"
and "boat" conformations (Figure 3-4). These two forms are so rapidly
interconverted at ordinary temperatures that they cannot be separated. It is
known, however, that the chair conformation is considerably more stable
and comprises more than 99 % of the equilibrium mixture at room tempera-
ture.
The higher energy of the boat form is not due to angle strain because all
the carbon atoms in both forms have their bond angles near the tetrahedral
angle of 109.5°. It is caused, instead, by relatively unfavorable interactions
between the hydrogen atoms around the ring. If we make all the bond angles
normal and orient the carbons in the ring to give the extreme boat con-
formation shown in Figure 3-5, we see that a pair of 1,4 hydrogens (the
so-called flagpole hydrogens) have to be so close together (1.83 A) that they
repel one another. This is an example of steric hindrance.
There is still another factor which makes the extreme boat form unfavorable ;
namely, that the eight hydrogens around the "sides" of the boat are eclipsed,
which brings them substantially closer together than they would be in a stag-
gered arrangement (about 2.27 A compared with 2.50 A). This is in striking
contrast with the chair form (Figure 3-6) for which adjacent hydrogens are
seen to be in staggered positions with respect to one another all the way
around the ring. The chair form is therefore expected to be the more stable of
the two. Even so, its equilibrium with the boat form produces inversion about
10 6 times per second at room temperature. If you make a molecular model of
less stable
cyclohexane you will find that the chair form has a considerable rigidity and the
carbon-carbon bonds have to be slightly bent in going to the boat form. You
will find that the boat form is extremely flexible and even if the bond angles
are held exactly at 109.5°, simultaneous rotation around all the carbon-
carbon bonds at once permits the ring to twist one way or the other to reduce
the repulsions between the flagpole hydrogens and between the eight hydro-
gens around the sides of the ring. These arrangements are called twist-boat
(sometimes skew-boat) conformations (Figure 3-7) and are believed to be only
about 5 kcal less stable than the chair form.
It will be seen that there are two distinct kinds of hydrogens in the chair
form of cyclohexane. Six are almost contained by the "average" plane of the
ring (called equatorial hydrogens) and three are above and three below this
average plane (called axial hydrogens). This raises an interesting question in
connection with substituted cyclohexanes : For example, is the methyl group
in methylcyclohexane equatorial or axial ?
a CH 3
^ T^ fast . t ,
£^J - \ ^CH 3
(axial) (equatorial)
chap 3 alkanes 66
Figure 3-6 Chair form of cyclohexane showing equatorial and axial hydro-
gens. Top left, scale model; bottom, ball-and-stick model; top right, sawhorse
representations. Note that all the axial positions are equivalent and all the
equatorial positions are equivalent.
There is considerable evidence which shows that the equatorial form of
methylcyclohexane predominates in the equilibrium mixture (K~15), and
the same is generally true of all monosubstituted cyclohexane derivatives.
The reason can be seen from scale models which show that a substituent
group has more room in an equatorial conformation than in an axial con-
formation (see Figure 3-8). The bigger the substituent, the greater the tendency
for it to occupy an equatorial position.
The forms with axial and equatorial methyl are interconverted about 10 6
Figure 3-7 Drawings of the twist-boat conformations of cyclohexane.
sec 3.4 cycloalkanes 67
Figure 3-8 Scale models of equatorial and axial forms of the chair form of
bromocyclohexane.
times/second at room temperature. The rate decreases as the temperature is
lowered. If one cools the normal mixture of chlorocyclohexane conform-
ations dissolved in a suitable solvent to very low temperatures (—150°), the
pure equatorial conformation crystallizes out. This conformation can then be
dissolved in solvents at — 1 50° and, when warmed to — 60°, is converted to the
equilibrium mixture in a few tenths of a second. However, the calculated
half-time of the conversion of the equatorial to the axial form is 22 years at
-160°.
C. OTHER CYCLOALKANE RINGS
The three cycloalkanes with smaller rings than cyclohexane are cyclopentane,
cyclobutane, and cyclopropane, each with bond angles less than the tetrahedral
value of 109.5°. If you consider a carbon-carbon double bond as a two-
membered ring, then ethene, C 2 H 4 , is the simplest cycloalkane ("cyclo-
ethane") and, as such, has carbon bond angles of 0° and, therefore, a very
large degree of angle strain.
H 2 C CH 2
\ /
H 2 C-CH 2
H 2 C — CH 2
1 1
H 2 C — CH 2
CH 2
/ \
H 2 C— CH 2
CH 2 =C
cyclopentane
cyclobutane
cyclopropane
ethene
bond angle if planar: 108°
90°
60°
0°
angle strain 1 5°
(109.5° -bond angle):
19.5°
49.5°
109.5°
Table 37 shows how strain decreases stability and causes the heat of com-
bustion per methylene group (or per gram) to rise.
The idea that cyclopropane and cyclobutane should be strained because
their C—C—C bond angles cannot have the normal tetrahedral value of
109.5° was advanced by Baeyer in 1885. It was also suggested that the diffi-
chap 3 alkanes
Table 3-7 Strain and heats of combustion of cycloalkanes
angle strain
heat of
at each CH 2
heat of
combustion
total
cycloalkane,
for planar
combustion,"
per CH 2 , AH/n,
strain, 6
(CH 2 )„
n
molecules, deg
AH, kcal/mole
kcal
kcal/mole
ethene
2
109.5
337.23
168.6
22.4
cyclopropane
3
49.5
499.83
166.6
27.6
cyclobutane
4
19.5
655.86
164.0
26.4
cyclopentane
5
1.5
793.52
158.7
6.5
cyclohexane
6
(10.5) c
944.48
157.4
0.0
cycloheptane
7
(19.0) c
1108.2
158.3
6.3
cyclooctane
8
(25.5) c
1269.2
158.6
9.6
cyclononane
9
(30.5) c
1429.5
158.8
11.2
cyclodecane
10
(34.5) c
1586.0
158.6
12.0
cyclopentaclecane
15
(46.5)'
2362.5
157.5
1.5
open-chain, «-alkane
00
157.4
" For gaseous hydrocarbons to give liquid water at 25°, datafromS.Kaarsemakerand J. Coops,
Rec. Trav. Chim. 71, 261 (1952), and J. Coops, H. Van Kamp, W. A. Lambgrets, B. J. Visser, and
H. Dekker, Rec. Trav. Chim. 79, 1226 (1960).
b Calculated by subtracting (« X 1 57.4) from the observed heat of combustion.
c Angle strain calculated for planar ring as per the Baeyer theory. The strain that is present in
the C7 to Cio compounds is not the result of angle strain (the molecules are puckered) but of
eclipsing or interfering of hydrogen atoms.
culties encountered up to that time in synthesizing cycloalkane rings from C 7
upward was the direct result of the angle strain which would be expected if
the large rings were regular planar polygons (see again Table 3-7).
We now know that the Baeyer strain theory cannot be applied to large
rings because cyclohexane and the higher cycloalkanes have puckered rings
with normal or nearly normal bond angles. Much of the difficulty in synthe-
sizing large rings from open-chain compounds is due to the low probability
of having reactive groups on the two fairly remote ends of a long hydrocarbon
chain come together to effect cyclization. Usually, coupling of reactive groups
on the ends of different molecules occurs in preference to cyclization, unless
the reactions are carried out in very dilute solutions.
For cyclopentane, a planar structure would give bond angles of 108°,
very close to the natural bond angle of 109.5°. Actually, the angle strain is
believed to be somewhat greater than 1.5° in this molecule; the eclipsing of all
of the hydrogens causes the molecule to distort substantially even though this
increases the angle strain. Cyclobutane is also not completely flat for the
same reason. (It should be remembered that molecules such as these are in
vibrational motion at all times and the shapes that have been described refer
to the mean atomic positions averaged over a period of time corresponding to
several vibrations.)
D. CHEMICAL PROPERTIES OF CYCLOALKANES
We have already observed how strain in the small-ring cycloalkanes affects
their heats of combustion. We can reasonably expect other chemical properties
sec 3.4 cycloalkanes 69
also to be affected by ring strain, and indeed cyclopropane and cyclobutane
are considerably more reactive than saturated, open-chain hydrocarbons. In
fact, they undergo some of the reactions which are typical of compounds with
carbon-carbon double bonds, their reactivity depending on the degree of angle
strain and the vigor of the reagent.
The result of these reactions is always opening of the ring by cleavage of a
C— C bond to give an open-chain compound having normal bond angles.
Relief of angle strain may therefore be considered to be an important part
of the driving force of these reactions. A summary of a number of ring-
opening reactions is given in Table 3-8. Ethene is highly reactive, while cyclo-
propane and cyclobutane are less so (in that order). The C— C bonds of the
larger, relatively strain-free cycloalkanes are inert, so that these substances
resemble the «-alkanes in their chemical behavior. Substitution reactions of
these cycloalkanes are generally less complex than those of the corresponding
alkanes because there are fewer possible isomeric substitution products.
Thus, cyclohexane can give only one monochlorination product while
«-hexane can give three.
E. Cis-Trans ISOMERISM OF SUBSTITUTED CYCLOALKANES
The form of stereoisomerism (isomerism caused by different spatial arrange-
ments) called geometrical isomerism or cis-trans isomerism was discussed in
the preceding chapter. This type of isomerism arises when rotation is prevented
by, for example, the presence of a double bond. A ring prevents rotation
equally well and we find that cis and trans isomers can also exist with ap-
propriately substituted cycloalkanes. Thus, when a cycloalkane is disub-
CH 2
/ \ 2
CH 3 CH-CHCH 3
1,2-dimethylcyclopropane
stituted at different ring positions, as in 1,2-dimethylcyclopropane, two
isomeric structures are possible according to whether the substituents are
both situated above (or both below) the plane of the ring {cis isomer), or one
above and one below (trans isomer), as shown in Figure 3-9.
The cis and trans isomers of 1,2-dimethylcyclopropane cannot be inter-
converted without breaking one or more bonds. One way of doing this is to
break open the ring and then close it again with a substituent on the opposite
side from where it started. Alternatively, the bond to the substituent (or the
hydrogen) can be broken and reformed on the opposite side of the ring.
Examples of both processes will be discussed in later chapters.
Cis and trans isomers of cyclohexane derivatives have the additional
possibility of different conformational forms. For example, 4-?-butylcyclo-
hexyl chloride can theoretically exist in four stereoisomeric chair forms,
chap 3 alkanes 70
Table 3-8 Reactions of cycloalkanes, (CH 2 )„
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sec 3.4 cycloalkanes 71
\ ••■•.-.•.
: :• #^li
.-■.-■?ISS
Figure 3*9 Ball-and-stick models of cis and /raws isomers of 1,2-dimethyl-
cyclopropane.
[7], [8], [9], and [10].
I
H 3 L H c ,
[7] rrani [8]
CI
I
H,C— C-CH,
*> C ^ e y^ T^H ^^- H^~^\ 5 C1
CH
H 3 C y\ H
[9] cis [10]
Structures [7] and [8] have the substituents trans to one another, but in
[7] they are both equatorial while in [8] they are both axial. Structures [9]
and [10] have the cis relationship between the groups, but the /-butyl and
chlorine are equatorial-axial in [9] and axial-equatorial in [10]. 7-Butyl groups
are very large and bulky and much more steric hindrance results when a
?-butyl group is in an axial position than when chlorine is in an axial position
(Figure 3-10). Hence the equilibrium between the two conformational forms
of the trans isomer strongly favors structure [7] over structure [8] because
both ?-butyl and chlorine are equatorial. For the cis isomer, structure [9] is
favored over [10] to accommodate the 7-butyl group in the equatorial position.
When there are two substituents in the cis-1,4 arrangement on a cyclo-
hexane ring, neither of which will go easily into an axial position, then it
chap 3 alkanes 72
X C "•■- "H
Figure 3-10 1,3 Interactions in a cyclohexane ring
with an axial 7-butyl group.
appears that the twist-boat conformation (Section 3-4B) is most favorable
(Figure 3-11).
summary
Alkanes are hydrocarbons possessing only single bonds. The open-chain
alkanes have the formula C„H 2 „ + 2 . The 1UPAC names for alkanes are based
on the longest continuous carbon chain with substituents being indicated by
their position along the chain. The alkane names from C x to C 10 are methane,
ethane, propane, butane, pentane, hexane, heptane, octane, nonane, and
decane. Structural isomerism appears at C 4 , there being two compounds of
formula C 4 H 10 — the continuous-chain compound CH 3 CH 2 CH,CH 3 (butane)
CH 3
and the branched-chain compound I (2-methylpropane or
CH 3 — CH — CH 3
isobutane). The larger the number of carbon atoms in a continuous-chain
alkane, the larger the number of branched-chain isomers of it that will exist.
Alkyl groups are obtained by removing a hydrogen atom from an alkane,
and structural isomerism appears here at the C 3 level. The group CH 3 —
CH 2 — CH 2 — is called the «-propyl group and CH 3 — CH— CH 3 the isopropyl
group. '
The physical properties of the alkanes show a smooth gradation. At room
temperature the C t to C 4 compounds are gases, the C 5 to C 18 continuous-
chain (normal) alkanes are liquids, and higher-molecular-weight compounds
are solids. The normal alkanes which are liquids often have branched-chain
isomers which are solids. All alkanes are less dense than water and all are
immiscible with water.
Petroleum is a complex mixture of hydrocarbons which can be separated
into fractions, according to volatility: natural gas, gasoline, kerosene, diesel
Figure 3-11 Twist-boat conformation of c/,s-l,4-di-?-butylcyclohexane.
summary 73
oil, lubricating oils and waxes, and residual material (asphalt). The heats of
combustion of the alkanes with the same molecular weights in the gasoline
fraction are all very close but their efficiencies in producing power in high-
compression internal combustion engines vary widely with structure. The
normal alkanes, which knock in the cylinder, have low octane ratings; the
branched alkanes, which burn less rapidly, have high octane ratings.
In addition to combustion, alkanes undergo substitution reactions with
halogens or nitric acid. These three reactions are illustrated using propane
as the alkane:
°' 2 > CH3CHCICH3 + CH 3 CH 2 CH 2 C1 (+HCI)
N0 2
HNO3 I
* CH3CHCH3 + CH 3 CH 2 CH 2 N0 2 (+H 2 0)
With higher alkanes, more complex mixtures of substitution products result,
although the major products are usually those in which a tertiary hydrogen has
been replaced.
The cycloalkanes have similar physical and chemical properties to those of
the open-chain alkanes except that the small-ring compounds such as cyclo-
CH 2
propane, / \ are more reactive because of bond-angle strain.
H 2 C — CH 2
Cyclohexane exists in two principal conformations that are rapidly inter-
converted, the more stable and rather rigid chair form and the less stable
and flexible twist-boat form. The twelve carbon-hydrogen bonds in the chair
^=7 -= b^
chair form twist-boat form
of cyclohexane of cyclohexane
form are of two types, six axial bonds parallel to the vertical axis of the ring
and six equatorial bonds pointing out from the equator of the ring. Of the
two kinds of positions, the equatorial provides more room for bulky substi-
tuent groups and, therefore, a substituent group will normally prefer to take
an equatorial position. Some of the principal conformational forms of
methylcyclohexane are shown here (all are in rapid equilibrium, with the form
on the far right being the most stable).
H
a twist-boat form chair form chair form
methyl group axial methyl group equatorial
chap 3 alkanes 74
Geometrical isomers can exist with appropriately substituted cycloalkanes
since rotation about the C— C bonds in the ring is prevented by the ring itself.
Cis isomers have the substituent groups on the same side of the ring and trans
isomers on the opposite side. A number of forms are possible in cycloalkanes
because of the combination of geometrical isomerism and conformational
equilibria.
exercises
3-1 Name each of the foDowing hydrocarbons by the IUPAC system and in
example e as an alkyl-substituted methane.
CH 3 CH 3
\ /
a. CH-CH 2 -CH 2 -CH
/ 2 \
CH 3 CH 3
CH, CH,
I I
b. CH 3 -C-CH 2 -CH-CH 3
CH 3 CH 2 .CH 3
c. CH-CH 2 -CH
/ \
CH 3 CH 3
CH 3 — CH 2
\
d. CH-CH,
/
CH 3 — CH 2
e. (CH 3 — CH 2 -CH 2 ^C
H 3 C CH 3
CH
CH 2 CH 3
I /
CH 3 — CH 2 — CH 2 -CH 2 -CH— CH 2 -CH 2 -CH
CH 3
3-2 Write the structures of the eight branched-chain isomers of heptane
CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 . Name each by the IUPAC system.
3-3 What is the IUPAC name for (a) triethylmethane, (b) hexamethylethane ?
3-4 Each of the names given below violates the rules of organic nomenclature.
Supply the correct name in each case.
a. 2,3-diethylbutane
b. 2,4,4-trichlorohexane
c. 1,4-diisopropylbutane
d. 2,4,5-trimethyl-3-«-propylheptane
exercises 75
3-5 Fill in the appropriate prefix in the names given below and draw the structural
formula in each case.
a
2,3-
_ methylpentane
h.
1,1,1-
chloroethane
c.
1,2,3,4,5,6-
iodohexane
3-6 Write structures for all seventeen possible monochlorohexanes and name them
by the IUPAC system.
3-7 Use the data of Tables 3-3 and 3-4 to estimate the boiling points of tetra-
decane, heptadecane, 2-methylhexane, and 2,2-dimethylpentane.
3-8 Is "neoheptane" an unambiguous name? Explain.
3-9 Write structural formulas for each of the following and name each by the
IUPAC system:
a. ?-butyl-isobutyl-,s-butyl-M-butylmethane
b. isononane
c. the monochloropentane isomers ; also name each as best as you can as
an alkyl chloride.
3-10 Calculate AH for the following reactions in the vapor state at 25°:
a. 2 CH 4 + 7 Cl 2 > CCh-C0 3 + 8 HC1
b. CH 3 CH 3 + 5 2 * 2C0 2 + 3H 2
c. CH 3 CH 3 + H 2 > 2CH 4
d. CH 3 CH 3 + Br 2 > 2CH 3 Br
e. CH 4 + 2C1 2 ► C(g) + 4HCl
3-11 a. Would the calculated AHin Exercise 3-10e be greater or less if C (solid)
were the reaction product ? Explain.
b. What are the implications of the heats of reaction determined in Exercise
3-10c and d to the "saturated" character of ethane?
3-12 The C— F bond energy in Table 2-1 was computed from recent thermo-
chemical studies of the vapor-phase reaction,
CHU + 4 F 2 — ► CF 4 + 4 HF AH = -460 kcal
Show how the AH value for this reaction may be used to calculate the energy
of the C— F bond if all the other required bond energies are known.
3-13 Investigate the energetics (AH) of possible chain mechanisms for the light-
induced monobromination of methane and make a comparison with those
for chlorination. What are the prospects for iodination of methane?
3-14 The heat of combustion of cyclopropane (CH 2 ) 3 to give carbon dioxide and
water vapor is 468.6 kcal. Show how this value can be used to calculate the
average C— C bond energies of cyclopropane.
chap 3 alkanes 76
3-15 Combustion of a pure sample of a gaseous alkane produced a quantity of
carbon dioxide whose weight and volume (under the same conditions) were
exactly three times that of the gaseous alkane. What is the latter's formula ?
3.16 Combustion of natural gas is generally a "cleaner" process (in terms of
atmospheric pollution) than combustion of either gasoline or fuel oil. Explain
why this is so.
3-17 Write a mechanism in harmony with that usually written for hydrocarbon
chlorination which would lead to production of hexachloroethane as in
Exercise 3- 10a. (This reaction is used for commercial production of hexa-
chloroethane.)
3-18 Show the configurations of all of the possible cis-trans isomers of the following
compounds :
a. 1,2,3-trimethylcyclopropane
b. 1,3-dichlorocyclopentane
c. 1,1,3-trimethylcyclohexane
3-19 Would you expect cis- or ?ra««-l,2-dimethylcyclopropane to be the more
stable ? Explain.
3-20 Write expanded structures showing the C— C bonds for each of the following
condensed formulas. Name each substance by an accepted system.
a. (CH 2 ) 10
b. (CH 2 ) 5 CHCH 3
c. (CH 3 ) 2 C(CH 2 ) 6 CHC 2 H 5
d. The isomers of trimethylcyclobutane
e. (CH 2 ) 6 CHCH 2 C(CH 3 ) 2 CH 2 C1
/. [(CH 2 ) 2 CH] 2 C(CH 3 )C 2 H 5
3-21 Draw structural formulas for all C 4 H 8 and all C 5 Hi compounds that con-
tain a ring. Designate those that exist in cis and trans forms.
3'22 The energy barrier for rotation about the C— C bond in ethane is about 3
kcal, which suggests that the energy required to bring one pair of hydrogens
into an eclipsed arrangement is 1 kcal. Calculate how many kilocalories the
planar form and extreme boat form of cyclohexane would be unstable rela-
tive to the chair form on account of H— H eclipsing interactions alone.
3-23 Use the sawhorse convention and draw all the possible conformations of
cyclohexyl chloride with the ring in the chair and in the boat forms. Arrange
these in order of expected stability. Show your reasoning.
3-24 Formation of a cycloalkane (CH 2 )„ by reactions such as Br-fCH 2 -KZnBr
-» (CH 2 )„ + ZnBr 2 occurs in competition with other reactions such as
, exercises 77
2 Br-f(CH 2 ^-„ZnBr -> Br-eCH 2 )„(CH 2 >„ ZnBr + ZnBr 2 . Explain why
cyclization reactions of this kind carried out in dilute solutions are likely to
give better yields of (CH 2 )„ than in concentrated solutions.
3-25 Use the data of Table 3-7 and other needed bond energies to calculate AH
for the following reaction in the vapor state at 25° with n = 3, 4, and 5.
(CH 2 )„ > CH 3 (CH 2 )„- 3 CH=CH 2
3-26 What can you conclude about the stability of the cycloalkanes with n = 3, 4,
and 5 with respect to corresponding open-chain compounds with double
bonds ?
3-27 Use the heats of combustion (to liquid water) given in Table 3-7 and appro-
priate bond energies to calculate AH (vapor) for ring opening of the cyclo-
alkanes with bromine over the range n =2 to n — 6:
(CH 2 )„ + Br 2 * (CH 2 )„_ 2 (CH 2 Br) 2
3-28 Show how the reactions described in Table 3-8 could be used to tell whether
a hydrocarbon of formula C 4 H 8 is methylcyclopropane, cyclobutane, or
1-butene (CH 3 CH 2 CH=CH 2 ). Write equations for the reactions used.
3-29 Draw the possible chair conformations of trans- and cw-l,3-dimethylcyclo-
hexane. Is the cis or the trans isomer likely to be the more stable? Explain.
3-30 An empirical rule known as the von Auwers-Skita rule was used to assign
configurations of pairs of cis and trans isomers in cyclic systems at a time
when cis isomers were thought to be always less stable than trans isomers.
The rule states that the cis isomer will have the higher boiling point, density,
and refractive index. However, the rule fails for 1,3-disubstituted cyclohexanes,
where the trans isomer has the higher boiling point, density, and refractive
index. Explain how the von Auwers-Skita rule might be restated to include
such 1,3-systems.
3-31 Would you expect cyclohexene oxide to be more stable in the cis or trans
configuration ? Give your reasons.
.O cyclohexene oxide
3-32 Write structural formulas for substances (one for each part) which fit the
following descriptions. Make sawhorse drawings of the substances where
conformational problems are involved.
a. a compound of formula C 4 H 8 which reacts slowly with bromine and
sulfuric acid but not with potassium permanganate solution
b. the most highly strained isomer of C 5 Hi
c. the possible products from treatment of l-ethyl-2-methylcyclopropane
with bromine
chap 3 alkan.es 78
d. the least stable chair and the least stable boat conformations of trans-
1 ,4-dichlorocyclohexane
e, the most stable geometrical isomer of l,3-di-?-butylcyclobutane
/. a compound with a six-membered ring which is most stable with the
ring in a boat form
g. the most stable possible conformation of fra«i , -l,3-di-Nbutylcyclo-
hexane
! •*.*"-. r-V*- ' V' ,
'^■l!l''---.-''l'm
tiic'M
chap 4 alkenes 81
In the early days of organic chemistry, when it was found that the alkenes,
but not the alkanes, readily undergo addition reactions with substances such
as halogens, hydrogen halides, sulfuric acid, and oxidizing agents, the chemi-
cal affinity of alkanes was said to be " saturated " while that of the alkenes
was said to be " unsaturated." Now, even though we recognize that no chemi-
cal entity (even the noble gases such as helium and xenon) can surely be
classified as saturated, the description of alkanes and alkenes as saturated and
unsaturated is still commonly used. However, in place of a nebulous chemical
affinity, we ascribe the unsaturation of alkenes to the ease of cleaving half
of a carbon-carbon double bond in an addition reaction. Additions occur with
alkenes much more easily than with alkanes because (1) the carbon-carbon
bonds of a double bond are individually weaker (more strained) than a normal
carbon-carbon single bond and (2) the double-bond electrons are generally
more accessible than single-bond electrons to an attacking reagent (see
Section 2-6).
The great variety and specificity of the addition reactions that compounds
with double bonds undergo make these substances extremely important as
intermediates in organic syntheses. We have already examined two of these
reactions (addition of halogens and hydrogen) in connection with our study
of ethene, the simplest alkene, in Chapter 2.
4-1 nomenclature
Open-chain alkenes containing one double bond have the general formula
C„H 2 „ and are sometimes called olefins. According to the IUPAC system for
naming alkenes, the longest continuous chain containing the double bond is
given the name of the corresponding alkane with the ending -one changed
to -ene. This chain is then numbered so that the position of the first carbon
of the double bond is indicated by the lowest possible number.
CH,CH,CH=CH, CH,-CH,-CH,
2CH
1-butene 3-propyl-l-heptene
(not 3-butene) (the dotted lines indicate longest continuous
chain containing the double bond)
Other, less systematic names are often used for the simpler alkenes. By
one method, alkenes are named as substituted ethylenes. This nomenclature,
(CH 3 ) 2 C = C(CH 3 ) 2 C1 2 C = CHC1
ethylene tetramethylethylene trichloroethylene
based on the older name " ethylene," is given here because, even though not
in accord with modern practices, it has been widely used in the literature. A
chap 4 alkenes 82
little reflection will show that attempts to name alkenes as derivatives of pro-
pylene (propene) or butylene (as will be seen, there are four open-chain C 4 H 8
isomers) will require special rules or be hopelessly ambiguous.
The hydrocarbon groups derived from alkenes carry the suffix -enyl, as in
alkenyl, and numbering of the group starts with the carbon atom with the
free bond :
CH 3 ~CH = CH— CH 2 -
2-bntenyl 3-butenyl
However, there are a few alkenyl groups for which trivial names are commonly
used in place of systematic names. These are vinyl, allyl, and isopropenyl
groups :
CH 3
I
CH 2 =CH- CH 2 =CH— CH 2 — CH 2 =C —
vinyl allyl isopropenyl
(ethenyl) (2-propenyl) (1-methylethenyl)
Cycloalkenes with double bonds in the ring (endocyclic double bonds) are
named by the system used for the open- chain alkenes, except that the num-
bering is always started at one of the carbons of the double bond and con-
tinued on around the ring through the double bond so as to keep the sum of the
index numbers as small as possible.
More complex nomenclature systems are required when the double bond
is exocyclic to the ring, especially if a ring carbon is one terminus of the
double bond. Usually the parent compounds of this type are called methylene-
cycloalkanes.
H 2 C6 s iCH 2 H 2 C-C
I. J II
CUJCH
H CH 3
H 3 cr "c/ \
1 ,3-dimethylcyclohexene methylenecyclobutane
(not 1,5-dimethylcydohexene)
Many compounds contain two or more double bonds and are known as
alkadienes, alkatrienes, alkatetraenes, and so on, the suffix denoting the num-
ber of double bonds. The location of each double bond is specified by appro-
priate numbers.
CH 2 =C=CH-CH 3 CH 2 =CH-CH=CH 2 CH 2 =C = C = CH 2
1.2-butadiene 1 ,3-buladiene 1,2.3-butatriene
sec 4.2 isomerism in C 4 H 8 compounds 83
A further classification is used according to the relationships of the double
bonds, one to the other. Thus, 1,2-alkadienes and similar substances are
said to have cumulated double bonds. 1,3-Alkadienes and other compounds
\ /
CH 2 =C=CH 2 C = C = C
/ \
allene cumulated double bonds
(propadiene)
with alternating double and single bonds are said to have conjugated double
bonds, and this arrangement leads, as we shall see in Chapter 6, to com-
pounds having rather special properties.
CH 3
\ I I / I
C = C — C — C CH,= CH— C=CH 2
/ \
1,3-pentadiene conjugated 2-methyl-l,3-butadiene
double bonds (isoprene)
Compounds with double bonds that are neither cumulated nor conjugated
are classified as having isolated double-bond systems.
\ I I I /
CH,=CH — CH 2 — CH=CH, C = C-eC^rC = C
/ | \
1.4-penladiene isolated double bond system (n £ 1)
4-2 isomerism in C + H 8 compounds
In the homologous series of alkanes, isomerism first appears at the C 4 level,
two compounds of formula C 4 H 10 being known. These are structural
isomers:
CH,
I
CH 3 — CH 2 — CH 2 — CH 3 CH 3 — CH-CH 3
butane, bp —0.5 2-methylpropane, bp —12°
There are in all six isomers of C 4 H 8 . Some are structural isomers and some
stereoisomers (see Section 2-6B). Their boiling points and general physical
properties are similar to those of butane and 2-methylpropane. Four of these
compounds react quickly with bromine; one reacts slowly, and one not at all.
The latter two compounds must be methylcyclopropane and cyclobutane,
respectively (Section 3-4D), and these compounds are cycloalkanes, not
chap 4 alkenes 84
alkenes. Note that the 2-butene structure is the only one that can exist in
/CH 2
CHj-HC |
^CH 2
H 2 C-CH 2
1 1
H 2 C — CH 2
methylcyclopropane. bp 4°
cyclobutane. bp 1 1
CH 3 — CH 2 — CH=CH 2
CH 3 CH 3
\ /
c=c
/ \
H H
l-butenc. bp —6.3°
ra-2-butene, bp 3.7°
CH 3 H
\ /
c=c
/ \
H CH 3
CH 3
1
CH 3 -CH = CH 2
trans-2-butene, bp 0.9° 2-methylpropene, bp - 6°
two different configurational arrangements. The other two isomers, 1-butene
and 2-methylpropene, have at least one carbon atom of the double bond with
identical groups attached to it. Thus, a rotation about the double bond, even
if it could occur, would produce an identical arrangement.
It is worth reviewing once again the meanings of the terms structure,
configuration, and conformation (Sections 2-2 and 2-6B). Of the six known com-
pounds of formula C 4 H 8 , there are five different structures. These are cyclo-
butane, methylcyclopropane, 1-butene, 2-butene, and 2-methylpropene. One
of these structures, 2-butene, has two different stable configurations or spatial
arrangements. All of these substances have many different possible conforma-
tions because rotation can occur to at least some degree about their single
bonds. Putting it another way, the C 4 H 8 compounds illustrate structural
isomerism, geometrical isomerism, and conformational variation. Structural
and geometrical isomers (but not conformational isomers), because of their
stability to interconversion and their somewhat different physical constants,
can be separated by physical techniques such as fractional distillation or,
better, by chromatography (Section 7T).
4- 3 cis and trans isomers
By convention, the configuration of complex alkenes is taken to correspond to
the configuration of the longest continuous chain as it passes through the
double bond. Thus the following compound is 4-ethyl-3-methyl-/ran,s'-3-
heptene, despite the fact that two identical groups are cis with respect to each
CH3 CH 2 CH 2 CH3
;-CH 2
CH 2
\
/
c=
= C
/
\
H 3 C
CH 2
CH 2 -CH 3
4-ethyl-3-methyl-/ra«5-3-heptene
sec 4.3 cis and trans isomers 85
repulsions between
methyl groups
.)(".
/C c'
CH * c c CHs
/ \
H H
Figure 4-1 Repulsive interactions between the methyl groups of cis-sym-
di-/-butylethylene (2,2,S,S-tetramethyl-m-3-hexene).
other, because the longest continuous chain is trans as it passes through the
double bond.
The trans isomers of the simple alkenes are usually more stable than the
corresponding cis isomers. The methyl groups in trans-2-butene are far
apart; in cz's-2-butene, they are much closer to one another. Scale models,
which reflect the sizes of the methyl groups, indicate some interference be-
tween the methyl groups of the cis isomer. The cis alkenes with large groups
have very considerable repulsive interactions (steric hindrance) between the
substituents, and are much less stable than the corresponding trans isomers
(see Figure 4-1).
The generally greater stability of trans over cis isomers (see, however,
Section 2-6B) is reflected in their lower heats of combustion. Table 4-1 com-
pares the heats of combustion and the boiling and melting points of some cis
and trans isomers. The data also reveal that trans isomers tend to have higher
melting points and lower boiling points than cis isomers. Although the
differences are not large, they may be of some help in assigning configurations.
When electron-withdrawing groups such as halogens are attached to the
Table 4-1 Comparison of properties of cis and trans isomers
heat of
bp,
mp,
combustion,
alkene
formula
°C
°C
AH, kcal
cw-2-butene
CH 3 -CH=CH-CH 3
3.7
-139
-606.4
/ra/z.s-2-butene
CH 3 -CH=CH-CH 3
0.9
-106
-605.4
c«-2-pentene
CH 3 -CH 2 -CH=CH-
-CH 3
37.9
-151
-752.6
trans-2-pentene
CH 3 — CH 2 -CH=CH-
-CH 3
36.4
-140
-751.7
cw-3-hexene
CH 3 -CH 2 -CH=CH-
-CH 2 -
-CH 3
66.4
-138
-899.7
rran.s-3-hexene
CH 3 -CH 2 -CH=CH-
-CH 2 -
-CH 3
67.1
-113
-898.1
chap 4 alkenes 86
double bond, the dipole moments of cis and trans isomers are different
(Section 2-6B), allowing an assignment of configuration to be made. Infrared
spectroscopy (Section 7-4) is also useful for distinguishing cis and trans
isomers.
Occasionally, a chemical method, ring closure, can be used to determine the
configuration of cis-trans isomers. In general, cis isomers can undergo ring
closure much more readily than the corresponding trans isomers because it
is not possible to prepare a five- or six-membered ring compound with a
trans double bond in the ring. The kind of difference which is observed is well
illustrated by maleic acid, which has a cis double bond and, on heating to
1 50°, loses water to give maleic anhydride. The corresponding trans isomer,
fumaric acid, does not give an anhydride at 150°. In fact, fumaric anhydride,
which would have a trans double bond in a five-membered ring, has never
been prepared. Clearly, of this pair, maleic acid has the cis configuration and
o
II
c
II
o
OH
OH
150°
- H 2
maleic
acid
O
II o
c^ /
H-" C
w
o
maleic
anhydride
O
Y ^OH 150°
HO. X.
^C^ ^H
II
O
fumaric
acid
*o
• rk°
o"
fumaric
anhydride
(unknown)
fumaric acid the trans configuration.
4-4 chemical reactions of alkenes
We have previously examined briefly two addition reactions of ethene, the
first member of the homologous series of alkenes. These were addition of
hydrogen, catalyzed by surfaces of finely divided metals such as nickel, and the
addition of bromine. These reactions also occur with the higher homologs.
For example, the colorless, volatile liquid 4-methyl-2-hexene reacts as follows :
CH 3
CH 3 -CH 2 -CH-CH=CH-CH 3
4-methyl-2-hexene Br
CH 3
I
CH 3 - CH 2 - CH- CH 2 - CH 2 - CH 3
3-methylhexane
CH 3 Br Br
II I
CH 3 -CH 2 -CH-CH-CH-CH 3
2,3-dibromo-4-methylhexane
Note that in the names of the three compounds shown, the number 1 carbon
sec 4.4 chemical reactions of alkenes 87
atom in one case is at the opposite end of the chain to that for the other two
compounds. This is necessary to make the names conform to systematic
usage (Sections 3-1 and 4-1).
The ease with which addition reactions to alkenes occur is the result of
the repulsions between the two pairs of electrons that make up the double
bond. Cleavage of one half of a carbon-carbon double bond requires 63
kcal, while cleavage of a carbon-carbon single bond requires 83 kcal (Table
2-1). Furthermore, because the repulsions push the electrons to average
positions further from the bond axis than the electron positions of a single
bond, the alkenes will be more readily attacked by electrophiles, that is,
reagents that act to acquire electrons. On the other hand, nucleophiles
("nucleus-loving" reagents) are rather poor at reacting with carbon-carbon
double bonds, unless one or more groups with a high degree of electron-
withdrawing power are attached to one of the carbon atoms.
Of the two reagents so far considered, H 2 and Br 2 , the latter, like all the
halogens, is electrophilic, as we shall see when the mechanism of the reaction
is considered in the next section. We have already noted that the addition of
hydrogen to alkenes occurs on activated surfaces, and the availability of the
electrons in the double bond is here reflected in part in the ease of adsorption
of the alkene on the metallic surface.
A. ELECTROPHILIC ADDITION TO ALKENES. THE STEPWISE POLAR
MECHANISM
Reagents such as the halogens (Cl 2 , Br 2 , and, to a lesser extent, I 2 ), hydrogen
halides (HC1, HBr, and HI), hypohalous acids (HOC1 and HOBr), water,
and sulfuric acid commonly add to the double bonds of alkenes to give
H OSO,H
chap 4 alkenes 88
saturated compounds. These reactions have much in common in their mech-
anisms and have been much studied from this point of view. They are also of
considerable synthetic and analytical utility. The addition of water to alkenes
(hydration) is particularly important for the preparation of a number of com-
mercially important alcohols. Thus ethyl alcohol and ?-butyl alcohol are made
on a very large scale by hydrating the corresponding alkenes (ethene and 2-
methylpropene), using sulfuric or phosphoric acids as catalysts.
H 2 0, 10% H 2 S0 4
CH 2 =CH 2 —
► CH 3 CH 2 OH
240° 3 2
ethene
ethyl alcohol
H 3 C
C=CH 2
H 3 C
H 2 0, 10% H 2 SO, H 3 C X ^/ CH 3
25° / \
H 3 C OH
!-methylpropene
/-butyl alcohol
We shall pay particular attention here to addition of bromine to alkenes.
This reaction is conveniently carried out in the laboratory and illustrates a
number of important points about addition reactions. The characteristics of
bromine addition are best understood through consideration of the reaction
mechanism. A particularly significant observation concerning the mechanism
is that bromine addition (and the other additions listed above) proceeds in the
dark and in the presence of radical traps (reagents such as oxygen that react
rapidly with radicals to produce reasonably stable compounds). This is evi-
dence against a radical chain mechanism analogous to the chain mechanism
involved in the halogenation of alkanes (Section 2-5B). It does not, however,
preclude operation of radical addition reactions under other conditions. In
fact, there are light-induced radical-trap inhibited reactions of bromine and
hydrogen bromide with alkenes which we shall describe later.
The alternative to a radical-type chain reaction is an ionic, or polar, reaction
in which electron-pair bonds are regarded as being broken in a heterolytic
manner in contrast to the radical, or homolytic, processes discussed pre-
viously.
XJ:Y ► X ffl + :Y° heterolytic bond-breaking
X r H Y * X- + -Y homolytic bond-breaking
Most polar addition reactions do not seem to be simple four-center, one-
step processes for two important reasons. First, it should be noted that such
mechanisms require the formation of the new bonds to be on the same side
of the double bond and hence produce cis addition (Figure 4-2). However,
there is ample evidence to show that bromine and many other reagents give
trans addition. For example, cyclohexene adds bromine and hypochlorous
acid to give ?ra«.s'-l,2-dibromocyclohexane and /ran.y-2-chlorocyclohexanol.
Such trans additions can hardly involve simple four-center reactions between
sec 4.4 chemical reactions of alkenes 89
plane of the
ethene molecule
X— Y
H */
Figure 4-2 Schematic representation of cis addition of a reagent X-
ethene by a four-center mechanism. (Most reagents do not add ii
manner.)
•Y to
this
one molecule of alkene and one molecule of an addend X— Y, because the
X— Y bond would have to be stretched impossibly far to permit the formation
of trans C— X and C— Y bonds at the same time.
CH
Br, + H,C
2-CH, x
CH,
TH==CH'
H 2 H 2
c — c
/ \
H,C Br H CH,
c— c
I I
H Br
HOC1 + H,C
N
,CH,-CH
2\
CH=CH
/
CH,
H 2 H 2
/ C - C \
H 2 C OH H CH 2
^C— c
I I
H CI
The second piece of evidence against the four-center mechanism is that
mixtures of products are often formed when addition reactions are carried
out in the presence of reagents able to react by donation of a pair of electrons
(nucleophilic reagents). Thus, the addition of bromine to an alkene in methyl
alcohol solution containing lithium chloride leads not only to the expected
dibromoalkane, but also to products resulting from attack by chloride ions
and by the solvent. This intervention of extraneous nucleophilic agents in the
reaction mixture is evidence against a one-step mechanism.
Br 2
-► BrCH,CH,Br
CH 2 =CH, + Br,
Br,
Cl e
Br,
-+ ClCH,CH 2 Br + Br e
CH,-0-H
♦ CH 3 OCH 2 CH 2 Br + HBr
chap 4 alkenes 90
A somewhat oversimplified two-step mechanism that accounts for most of
the facts is illustrated for the addition of bromine toethene. (The curved arrows
are not considered to have real mechanistic significance but are used primarily
to show which atoms can be regarded as nucleophilic — donating electrons —
and which as electrophilic — accepting electrons. The arrowheads point to the
atoms that accept electrons.)
electrophilic
attack (4-1)
-> BrCH 2 CH,Br nucleophilic
. ... " attack (4-2)
1,2-dibromoetnanc
(ethylene dibromidc)
The first step (which involves electrophilic attack on the double bond and
heterolytic breaking of both a carbon-carbon and a bromine-bromine bond)
as shown in Equation 4T) produces a bromide ion and carbonium ion. The
latter is electron deficient (Section 2-5C) and, in the second step of the pos-
tulated mechanism shown in Equation 4-2, it combines rapidly with an
available nucleophile (:Br: e ) to give the reaction product.
Clearly, if other nucleophiles (e.g., : CI : e , CH 3 OH) are present in solution,
they may compete with the bromide ion for the carbonium ion, as in Equa-
tions 4-3 and 4-4, and mixtures of products will result.
:C1. +^ 6 CH 2 — CH 2 Br ► CICH,CH 2 Br (4-3)
.. ,. — x .. lie
CH 3 :0: + ffi CH,-CH,Br > CH 3 :0:CH,-CH,Br > CH 3 OCH 2 CH,Br
H H (4-4)
In short, we must conclude that the reagents mentioned add across the double
bond in a trans and stepwise manner and that the two steps take place from
opposite ends of the double bond.
B. WHY TRANS ADDITION?
The simple carbonium-ion intermediate of Equation 4T does not account
for formation of the ^ra/M-addition product. For one thing, there is no obvious
reason why free rotation should not occur about the C— C bond of the cation
I I m
— C— C® derived from an open-chain alkene; if such occurs, all stereospeci-
I I
ficity is lost. In the case of cyclic alkenes, addition of Br° might be expected
to occur from either side of the ring.
sec 4.4 chemical reactions of alkenes 91
H 2 H 2
C — C
/ \
H 2 C CH 2
C=C
/ \
H H
To account for the stereospecificity of bromine addition to alkenes, it has
been suggested that a cyclic intermediate is formed in which bromine is
bonded to both carbons of the double bond. This "bridged" ion is called
a bromonium ion because the bromine formally carries the positive charge.
H 2
H 2
C-
-c\
/
\
H 2 C Br
Br CH,
V
i y
C-
-c
1
I CIS
H
H
H 2
H 2
c-
-c s
/
\
H,C Br
H CH 2
V
] y
C-
-c
i
| trans
H
Br
I
,Br w + :Br:
.9
-c
bromonium ion
Attack of a bromide ion, or other nucleophile, at the carbon on the side
opposite the bridging group results in formation of the 7ra/M-addition
product. 1
I
Br— C —
► I
— C — Br
By analogy, a hydrogen-bridged intermediate can be used to account for
trans addition of acids such as HBr, HC1, H 3 O ffi , and H 2 S0 4 , to alkenes.
These intermediates are sometimes called protonium ions and might appear
to violate the usual generalization that hydrogen can form only one stable
^ -C.
II + HA ► I: ® ; H + A e
c — c'
protonium ion
1 It is clear that the cis and trans addition routes can be distinguished in the case of
addition to cycloalkenes on the basis of the stereochemistry of the product. You might
wonder, however, how this can possibly be done for open-chain alkenes because free
rotation can occur about the C— C bond of the product. This will be made clear when we
examine optical isomerism in Chapter 14.
chap 4 alkenes 92
bond. It should be emphasized, however, that the bonding between the
bridging hydrogen and the two carbon atoms is not considered to be normal
electron-pair covalent bonding. It is different in that one electron pair effects
the bonding of three atomic centers rather than the usual two. Protonium
ions of this structure may be regarded as examples of " electron-deficient
bonding," there being insufficient electrons with which to form all normal
electron-pair bonds.
During the past few years, a number of species having electron-deficient
bonds to hydrogen have been carefully investigated. The simplest example is
the H 2 ® ion, which may be regarded as a combination of a proton and a
hydrogen atom. This ion has been detected and studied spectroscopically in
the gaseous state. Another and very striking example is afforded by the stable
compound diborane (B 2 H 6 ), which has been shown to have a hydrogen-
bridged structure. The bonds to each of the bridge hydrogens in diborane,
like those postulated to the bridge hydrogen of an alkene-protonium ion, are
examples of three-center electron-pair bonds. Spectroscopic evidence is also
H x / H x / H
B; ;B
H X V X H
diborane
available for the stable existence of alkylhalonium ions, (CH 3 ) 2 X®, in solu-
tions containing extremely weak nucleophiles.
Whether the intermediates in alkene-addition reactions are correctly
formulated with bridged bromonium, chloronium, or protonium structures
is still a controversial matter. Certainly, there are many other reactions of
carbonium ions that are known to be far from being stereospecific, and
therefore carbonium ions are not to be considered as necessarily, or generally,
having bridged structures. It should also be remembered that all ions in
solution, even those with only transitory existence, are strongly solvated, and
this in itself may have important stereochemical consequences. In subsequent
discussion, we shall most frequently write carbonium ions with the charge
fully localized on one carbon atom, but it should be understood that this may
not always be either the most accurate or the most desirable representation.
C. ORIENTATION IN ADDITION TO ALKENES; MARKOWNIKOFF'S
RULE
Addition of an unsymmetrical substance such as HX to an unsymmetrical
alkene can theoretically give two products :
(CH 3 ) 2 C = CH 2 + HX ► (CH 3 ) 2 C — CH 2 and/or (CH 3 ) 2 C — CH 2
X H H X
One of the most important early generalizations in organic chemistry was
Markownikoff's rule (1870), which may be stated as follows: During the
addition of HX to an unsymmetrical carbon-carbon double bond, the hydrogen
sec 4.4 chemical reactions of alkenes 93
of HX goes to that carbon of the double bond that carries the greater number
of hydrogens. Thus, Markownikoff' s rule predicts that hydrogen chloride will
add to propene to give 2-chloropropane (isopropyl chloride) and to 2-methyl-
propene to give 2-chloro-2-methylp'ropane (?-butyl chloride). These are, in
fact, the products that are formed. The rule by no means has universal
CH,-CH = CH,
HC1
-> CH3-CH-CH3
I
CI
(CH 3 ) 2 C = CH 2 + HC1
— (CH 3 ) 2 C-CH 3
CI
additions in accord with MarkownikofT's rule
application, but it is of considerable utility for polar additions to hydrocarbons
with only one double bond.
D. A THEORETICAL BASIS FOR MARKOWNIKOFF'S RULE
To understand the reason for MarkownikofT's rule, it will be desirable to
discuss further some of the principles that are important to intelligent pre-
diction of the course of an organic reaction. Consider the addition of hydro-
gen bromide to 2-methylpropene. Two different carbonium-ion intermediates
could be formed by attachment of a proton to one or the other of the double-
bond carbons. Subsequent reaction of the cations so formed with bromide
\ r^
C-CH 2
/
H 3 C
C-CH,
/
r-butyl cation
H,C CH 3
X
H,C Br
/-butyl bromide
H,C
C-CH 2 + H s
/
H 3 C v H
H,C CH, 9
isobutyl cation
Br e
H 3 C x /H
H,C CH,Br
isobutyl bromide
ion gives ?-butyl bromide and isobutyl bromide. In the usual way of running
these additions, the product is, in fact, quite pure 7-butyl bromide.
How could we have predicted which product would be favored ? The first
step is to decide whether the prediction is to be based on which of the two
products is the more stable, or which of the two products is formed more
rapidly. If we make a decision on the basis of product stabilities, we take into
account AH and AS values to estimate an equilibrium constant K between the
reactants and each product. When the ratio of the products is determined by
the ratio of their equilibrium constants, we say the overall reaction is subject
to equilibrium (or thermodynamic) control. This will be the case when the
reaction is carried out under conditions that make it readily reversible.
When a reaction is carried out under conditions in which it is not reversible,
chap 4 alkenes 94
the ratio of the products is determined by the relative rates of formation of the
products. Such reactions are said to be under kinetic control. To predict rela-
tive reaction rates, we take into account steric hindrance, stabilities of possible
intermediates, and so on.
Addition of hydrogen bromide to 2-methylpropene is predicted by Mark-
ownikoff's rule to give /-butyl bromide. It turns out that the equilibrium
constant connecting /-butyl bromide and isobutyl bromide is 4.5 at 25°,
meaning that 82% of an equilibrium mixture is /-butyl bromide and 18% is
isobutyl bromide.
[/-butyl bromide]
[isobutyl bromide]
Addition of hydrogen bromide to 2-methylpropene actually gives 99 + %
/-butyl bromide in accord with Markownikoff's rule. This means that the
rule is a kinetic-control rule and may very well be invalid under conditions
where addition is reversible.
If Markownikoff's rule depends on kinetic control of the product ratio in
the polar addition of hydrogen bromide to 2-methylpropene, then it is proper
to try to explain the direction of addition in terms of the ease of formation
of the two possible carbonium-ion intermediates. There is abundant evidence
that tertiary carbonium ions are more easily formed than secondary car-
bonium ions and these, in turn, are more easily formed than primary carbo-
nium ions. A number of carbonium salts have been prepared, and the tertiary
ones are by far the most stable. Thus, the theoretical problem presented by
Markownikoff's rule is reduced to predicting which of the two possible
carbonium-ion intermediates will be most readily formed. With the simple
alkenes, formation of the carbonium ion accords with the order of preference
tertiary > secondary > primary.
E. ADDITIONS OF UNSYMMETRICAL REAGENTS OPPOSITE
TO MARKOWNIKOFF'S RULE
The early chemical literature concerning the addition of hydrogen bromide to
unsymmetrical alkenes is rather confused, and sometimes the same alkene was
reported to give addition both according to and in opposition to Markow-
nikoff's rule under very similar conditions. Much of the uncertainty about the
addition of hydrogen bromide was removed by the classical researches of
Kharasch and Mayo (1933), who showed that there must be two reaction
mechanisms, each giving a different product. Under polar conditions,
Kharasch and Mayo found that hydrogen bromide adds to propene in a rather
slow reaction to give pure 2-bromopropane (isopropyl bromide):
CH 3 CH=CH 2 + HBr ■ ► CH 3 CHCH 3
polar J I *
conditions
slow
polar
Br
With light or peroxides (radical initiators) and in the absence of radical
sec 4.4 chemical reactions of alkenes 95
traps, a rapid radical chain addition of hydrogen bromide occurs to yield
80% or more of 1-bromopropane (n-propyl bromide):
HBr ^!— ► CH 3 CH,CH 2 Br
peroxides
Similar effects have been occasionally noted with hydrogen chloride but
never with hydrogen iodide or fluoride. A few substances apparently add to
alkenes only by radical mechanisms and always give addition opposite to
Markownikoff 's rule.
The polar addition of hydrogen bromide was discussed in the previous
section and will not be further considered now. Two questions with regard to
the so-called abnormal addition will be given special attention: why the
radical mechanism should give a product of different structure from the polar
addition, and why the radical addition occurs readily with hydrogen bromide
but rarely with the other hydrogen halides (see Exercise 4-17).
The abnormal addition of hydrogen bromide is strongly catalyzed by
peroxides, which have the structure R— O— O— R and decompose thermally
to give radicals :
R — 6:5 — R ► 2 R— O- Atf=+35kcal
The RO • radicals can react with hydrogen bromide in two ways :
^ ROH + Br- A//=~23kcal
RO- + HBr ^^
^"^ ROBr + H- AH= +39kcal
Clearly, the formation of ROH and a bromine atom is energetically more
favorable. The overall process of decomposition of peroxide and attack on
hydrogen bromide, which results in the formation of a bromine atom, can
initiate a radical chain addition of hydrogen bromide to an alkene :
Chain
CH 3 CH=CH 2 + Br- >
CH 3 CH-CH 2 Br
AH =
- 5 kcal
propa-
t^Ttr j"irr /in n i tin
fc PU pit ptr 13 1 t> .
Atf =
- 1 1 kcal
gation:
LH3CH Crl 2 or + HBr
* Cri3^rl2^rl2Dr ^ or
Chain
rt 1 I r> ' » P ' T> '
R' • = atom or radical
termi-
nation:
K ' t K ' K K.
The chain-propagating steps, taken together, are exothermic by 16 kcal
and have a fairly reasonable energy balance between the separate steps,
which means that one is not highly exothermic and the other highly endother-
mic. Both steps are, in fact, comparably exothermic. The reaction chains
appear to be rather long, since only traces of peroxide catalyst are needed and
the addition is strongly inhibited by radical traps.
The direction of addition of hydrogen bromide to propene clearly depends
chap 4 alkenes 96
on which end of the double bond the bromine attacks. The choice will depend
on which of the two possible carbon radicals that may be formed is the
CH 3 -CH— CH 2 -Br CH 3 — CH-CH 2 -
Br
[1] [2]
more stable, the l-brom'o-2-propyl radical [1] or the 2-bromo-l -propyl
radical [2]. As with carbonium ions, the ease of formation and stabilities of
carbon radicals follow the sequence tertiary > secondary > primary. There-
fore, the secondary l-bromo-2-propyl radical [1] is expected to be more
stable and more easily formed than the primary 2-bromo-l -propyl radical [2].
The product of radical addition should be, and indeed is, 1-bromopropane.
It may seem strange to refer to certain radicals or ions as being stable and
therefore more likely to be reaction intermediates than other less stable
radicals or ions. Would not the unstable radicals or ions actually be more
likely as intermediates because they would react more rapidly to give products ?
"Stable" is used here only in a relative sense. All of the radicals and ions
which we are invoking as intermediates react very quickly to give products
and never attain high concentrations in the reaction mixture. This means that
the reactions will go more readily by way of the relatively more stable in-
termediates because these are formed most easily and react rapidly to give
products. The less stable intermediates are not formed as readily and the fact
that they would react more rapidly does not increase the overall reaction rate
in processes which would involve them. This point will be considered in other
connections later. The important thing to recognize is that there may be
large differences in the ease of formation of different kinds of reaction in-
termediates — so much so that mechanisms which imply that primary car-
bonium ions or radicals (RCH 2 ffi or RCH 2 *) are formed in preference to
secondary or tertiary carbonium ions and radicals should be regarded as
suspect.
F. ADDITION OF BORON HYDRIDES TO ALKENES
A recently developed and widely used reaction is that of diborane (B 2 H 6 )
with alkenes. Diborane (Section 19-5) is the dimer of the electron-deficient
species BH 3 , and it is as BH 3 that it adds to the double bond to give tri-
alkylboron compounds (organoboranes). With ethene, triethylborane
results :
6 CH 2 =CH 2 + B 2 H 6 — ^-» 2(CH 3 CH 2 ) 3 B
This reaction is called hydroboration ; it proceeds in three stages, but the
intermediate mono- and dialkylboranes are not generally isolated, as they
react rapidly by adding further to the alkene.
CH 2 =CH 2 + CH 3 CH 2 BH 2 ► (CH 3 CH 2 ) 2 BH
CH 2 =CH 2 + (CH 3 CH 2 ) 2 BH ► (CH 3 CH 2 ) 3 B
sec 4.4 chemical reactions of alkenes 97
With an unsymmetrical alkene such as propene, hydroboration occurs so
that boron becomes attached to the less substituted end of the double bond —
with propene forming tri-«-propylborane.
6 CH 3 CH=CH 2 + B 2 H 6 2 (CH 3 CH 2 CH 2 ) 3 B
Hydroborations have to be carried out with some care, since diborane and
alkylboranes are highly reactive substances ; in fact, they are spontaneously
inflammable in air. For most synthetic purposes it is not necessary to isolate
the addition products, and diborane can be generated either in situ or exter-
nally through the reaction of boron trifluoride with sodium borohydride.
3 NaBH 4 + 4 BF 3 ► 2 B 2 H 6 + 3 NaBF 4
Boron trifluoride is conveniently used in the form of its stable complex
with diethyl ether, (C 2 H 5 ) 2 0:BF 3 , the reactions usually being carried out in
ether solvents such as diethyl ether, (C 2 H 5 ) 2 0; diglyme, (CH 3 OCH 2 CH 2 ) 2 0;
or tetrahydrofuran, (CH 2 ) 4 0.
The most common synthetic reactions of the resulting alkylboranes are
oxidation with alkaline hydrogen peroxide to the corresponding primary
alcohol, and cleavage with aqueous acid (or, better, anhydrous propanoic
acid, CH 3 CH 2 C0 2 H) to give alkanes. Thus, for tri-n-propylborane :
(CH 3 CH 2 CH 2 ) 3 B + 3H 2 2 -^^ 3 CH 3 CH 2 CH 2 OH + B(OH) 3
n -propyl alchohol
(a primary alcohol)
(CH 3 CH 2 CH 2 ) 3 B + 3H 2 "^ > 3 CH 3 CH 2 CH 3 + B(OH) 3
The first of these processes achieves " anti-Markownikoff " addition of water
to a carbon-carbon double bond as the overall result of the two steps. The
second reaction provides a method of reducing carbon-carbon double bonds
without using hydrogen and a metal catalyst. Both of these conversions are
difficult to do any other way and this accounts for the extensive use that
organic chemists have made of diborane in recent years.
G. OXIDATION OF ALKENES
Most alkenes react readily with ozone, even at low temperatures, to cleave
the double bond and yield cyclic peroxide derivatives known as ozonides.
O
3 -> H.CHC^ X CHCH,
-80° \ I
o-o
2-butene ozonide
Considerable evidence exists to indicate that the overall reaction occurs in
chap 4 alkenes 98
three main steps, the first of which involves a cz's-cycloaddition reaction that
produces an unstable addition product called a molozonide.
H 3 C CH 3
3 \ / 3
CH,-HC=CH-CH, HC-CH
/ \
<x o e o. o
2 °
molozonide (unstable)
HjC \ // CHj H 3 C rH,
HQfCH CH HC /O
/^'C.\ > II + IL " CH 3 HCT X CHCH 3
°< /° o o! _ \ /
fro' ^o e o-o
€
ozonide
Ozonides, like most substances with peroxide (O— O) bonds, may explode
violently and unpredictably. Ozonizations must therefore be carried out with
due caution. The ozonides are not usually isolated but are destroyed by
hydrolysis with water and reduction with zinc to yield carbonyl compounds
that are generally quite easy to isolate and identify. (In the absence of zinc,
hydrogen peroxide is formed which may degrade the carbonyl products by
oxidation). The overall reaction sequence provides an excellent means for
° O
/O x h 2 // \
H 3 CHC CHCH 3 ► CH 3 C + CCH 3 + ZnO
\ / Zn \ /
O-O H H
locating the positions of double bonds in alkenes. The potentialities of the
method may be illustrated by the difference in reaction products between the
1- and 2-butenes:
O
i.o 3 /
CH 3 CH=CHCH 3 ► 2CH 3 C
3 2. Zn,H 2 3 \
H
O H
1.O3 // \
CH 3 CH,CH=CH, ► CH 3 CH 2 C + C =
32 2 2. Zn,H 2 \ /
H H
Natural rubber (polyisoprene, Section 28-2) is a substance with many
double bonds, and ozone formed in the atmosphere by sunlight or by smog-
producing reactions (Section 3-3A) combines with the double bonds of the
rubber and causes the rubber to crack. This destructive action can be re-
duced by antioxidants mixed with the rubber, or by use of rubberlike materials
without double bonds (see Section 4-4H).
Several other oxidizing reagents react with alkenes under mild conditions
to give, overall, addition of hydrogen peroxide as HO— OH. Of particular
sec 4.4 chemical reactions of alkenes 99
importance are permanganate ion and osmium tetroxide, both of which
react in an initial step by a cw-cycloaddition mechanism like that postulated
for ozone:
°s P
Mn
o o
r \
/ 1
'f-
-s-
o
\
/
Mn
//
V
L o
J
unstable
O O
stable osmate
ester
H 2 o
OH e
mild
reduction
(Na 2 S0 3 ) '
— C-
I
HO
I
-C —
I
OH
— C-
I
HO
I
-C-
MnO^
L
MnO, + MnO<
+ Os
OH
Each of these reagents produces m-dihydroxy compounds (diols) with
cycloalkenes :
l,OsO*,25°
2.Na 2 S0 3
(or KMnO, , OH e , H 2 0)
OH
OH
cis- 1 ,2-cyclopentanediol
An alternate scheme for oxidation of alkenes with hydrogen peroxide in
formic acid follows a different course in that trans addition occurs. (The
mechanism of this reaction is analogous to the addition of bromine to a
carbon-carbon double bond, which also takes place by trans addition.)
<CJ
35%H 2 Q 2
HC0 2 H, 25°
OH
OH
trans-\ ,2-cyclopentanediol
H. POLYMERIZATION OF ALKENES
One of the most important industrial reactions of alkenes is their conversion
to higher-molecular-weight compounds (polymers). A polymer is here de-
fined as a long-chain molecule with recurring structural units. Polymerization
of propene, for example, gives a long-chain hydrocarbon with recurring
CH 3 units. Most industrially important polymerizations of alkenes
-CH-CH 2 -
chap 4 alkenes 100
CH 3
CH 3 CH=CH 2 ► -j-CH— CH 2 - AH= -n ■ 20kcal
propene polypropene
(polypropylene)
occur by chain mechanisms and may be classed as anion, cation, or radical-
type reactions, depending upon the character of the chain-carrying species.
In each case, the key steps involve successive additions to molecules of the
alkene. The differences are in the number of electrons that are supplied by
the attacking agent for formation of the new carbon-carbon bond. For
simplicity, these steps will be illustrated by using ethene, even though it does
not polymerize very easily by any of them :
R— CH 2 -CH? + ch 2 =Q:h 2
R-CH 2 — CH 2 + CH 2 =CH 2 > R-CH 2 -CH 2 -CH 2 -CH 2 , etc.
R-CH 2 -CH 2 + CH 2 -CH 2 > R-CH 2 -CH 2 -CH 2 -CH 2
Anionic Polymerization. Initiation of alkene polymerization by the anion-
chain mechanism may be formulated as involving an attack by a nucleo-
philic reagent Y: e on one end of the double bond and formation of a carban-
ion. Attack by the carbanion on another alkene molecule gives a four-
Y: + CH,^CH
2 — v~n 2 ^ i«^n 2
carbanion
carbon carbanion, and subsequent additions to further alkene molecules
lead to a high-molecular-weight anion. The growing chain can be terminated
► Y:CH 2 -CH 2 -CH 2 -CH 2
n (CH 2 =CH 2 ) n
> Y:CH 2 -CH 2 -fCH 2 -CH 2 ^rCH 2 -CH 2 e
by any reaction (such as the addition of a proton) that would destroy the
carbanion on the end of the chain :
Y:CH 2 -CH 2 -eCH 2 -CH 2 ^-CH 2 -CH 2 e ► YiCHj-CHj-fCHj-CH^CHj-CHj
Anionic polymerization of alkenes is quite difficult to achieve, since few
anions (or nucleophiles) are able to add readily to alkene double bonds
(see p. 87). Anionic polymerization occurs readily only with ethenes
substituted with sufficiently powerful electron-attracting groups to expedite
nucleophilic attack.
sec 4.4 chemical reactions of alkenes 101
Cationic Polymerization. Polymerization of an alkene by acidic reagents
can be formulated by a mechanism similar to the addition of hydrogen
halides to alkene linkages. First, a proton from a suitable acid adds to an
alkene to yield a carbonium ion. Then, in the absence of any other reasonably
strong nucleophilic reagent, another alkene molecule donates an electron
pair and forms a longer chain cation. Continuation of this process can lead
to a high-molecular-weight cation. Termination can occur by loss of a proton.
CH, = CH,
CH 3 -CH 2 -CH 2 — CH
-H®
CH3 CH2 ~t~ CH 2 — CH 2
n(CH 2 =CH 2 )
* CH 3 -CH 2 -fCH 2 -CH 2 ^CH 2 -CH 2 tt
CH 3 -CH 2 -eCH 2 -CH 2 -^-CH=CH 2
Ethene does not polymerize by the cationic mechanism, because it does
not have groups that are sufficiently electron donating to permit ready
formation of the intermediate growing-chain cation. 2-Methylpropene has
electron-donating alkyl groups and polymerizes much more easily than ethene
by this type of mechanism.
The usual catalysts for cationic polymerization of 2-methylpropene are
sulfuric acid, hydrogen fluoride, or boron trifluoride plus small amounts of
water. Under nearly anhydrous conditions, a very long-chain polymer is
formed called " polyisobutylene." Polyisobutylene fractions of particular
CH,
CH,
CH,
tr. h 2 o
CH,
CH,
-C-
I
CH,
CH 2
CH,
I
C —
I
CH,
CH 3
polyisobutylene
CH,
CH,
molecular weights are very tacky and are used as adhesives for pressure-
sealing tapes.
In the presence of 60 % sulfuric acid, 2-methylpropene is not converted to
a long-chain polymer, but is dimerized to a mixture of C 8 alkenes. The mech-
anism is like the polymerization reaction described for polyisobutylene,
except that chain termination occurs after only one alkene molecule has been
added. The short chain length is due to the high water concentration; the
intermediate carbonium ion loses a proton to water before it can react with
CH,
CH,
60%H 2 SO,
>
70°
CH,
CH,
I
-c-c
I
CH,
/H 2
C
\
CH,
+ CH 3 -
CH 3
I
-C-
I
CH,
CH 3
/ 3
CH = C
\
CH,
20%
"diisobutylene"
chap 4 alkenes 102
another alkene molecule. Because the proton can be lost two different ways,
a mixture of alkene isomers is obtained. The alkene mixture is known as
" diisobutylene " and has a number of commercial uses. Hydrogenation gives
2,2,4-trimethylpentane (often erroneously called " isooctane "), which is used
as the standard "100 antiknock rating" fuel for internal-combustion gasoline
engines (Section 3-3A).
CH,
CH, = C
CH,
CH,
CH 2 =C
CH 3
/
- CH,-C S
\
CH,
CH,
\ CH 3
CH 3 I /
► CH 3 -C-CH 2 -C ffi
I \
CH 3 CH 3
CH,
CH,
CH,
CH,
CH 3
I
+ CH,-C-CH=C
CH,
CH,
CH,
CH 3 CH 3
H 2 (Ni) I I
diisobutylene isomers ► CH 3 — C— CH, — CH — CH,
50° J j 2 3
CH 3
2,2,4-trimethylpentane
Radical Polymerization. Ethene may be polymerized with peroxide cata-
lysts under high pressure (1000 atmospheres or more, literally in a cannon
barrel) at temperatures in excess of 100°. The initiation step involves forma-
tion of RO radicals, and chain propagation entails stepwise addition of radi-
cals to ethene molecules.
Initiation: R:Q:0:R
-> 2R=0-
Propa-
gation:
R:0- + CH 2 = CH 2 -
R:p:CH 2 -CH 2 + «(CH 2 =CH 2 )
♦ R:0:CH,-CH,
-» RO-r-CH 2 -CH 2 ^-CH 2 -CH 2
Termi-
nation:
2ROfCH 2 — CH 2 ^;CH 2 — CH 2
- [RO-eCH.-CH^CH.-CH^
combination
RO-(-CH 2 -CH 2 i-„CH=CH 2 + ROf CH 2 CH 2 )„-
disproportionation
-CH,-CH,
Chain termination may occur by any reaction resulting in combination or
disproportionation of two radicals. (Disproportionation means that two
identical molecules react with one another to give two different product
molecules.) The polymer produced this way has from 100 to 1000 ethene
units in the hydrocarbon chain. The polymer, called Polythene (or sometimes
polyethylene), possesses a number of desirable properties as a plastic and is
summary 103
widely used for electrical insulation, packaging films, piping, and a variety
of molded particles. The very low cost of ethene (a few cents a pound) makes
Polythene a commercially competitive material despite the practical diffi-
culties involved in the polymerization process. Propene and 2-methylpropene
do not polymerize satisfactorily by radical mechanisms.
Coordination Polymerization. A relatively low-pressure low-temperature
ethene polymerization has been achieved with an aluminum-molybdenum
oxide catalyst, which requires occasional activation with hydrogen (Phillips
Petroleum). Ethene also polymerizes quite rapidly at atmospheric pressure
and room temperature in an alkane solvent containing a suspension of the
insoluble reaction product from triethylaluminum and titanium tetrachloride
(Ziegler). Both the Phillips and Ziegler processes produce a very high-
molecular-weight polymer with exceptional physical properties. The unusual
characteristics of these reactions indicate that no simple anion, cation, or
radical mechanism can be involved. It is believed that the catalysts act by
coordinating with the alkene molecules in somewhat the way hydrogenation
catalysts combine with alkenes.
Polymerization of propene by catalysts of the Ziegler type gives a most
useful plastic material. It can be made into durable fibers or molded into a
variety of shapes. Copolymers (polymers with more than one kind of monomer
unit in the polymer chains) of ethene and propene made with Ziegler cata-
lysts have highly desirable rubberlike properties and are potentially the cheap-
est useful elastomers (elastic polymers). A Nobel Prize was shared in 1963 by
K. Ziegler and G. Natta for their work on alkene polymerization.
summary
Alkenes are hydrocarbons possessing a carbon-carbon double bond. Simple
open-chain alkenes have the formula C„H 2 „ . The IUPAC names for alkenes
are obtained by finding the longest continuous carbon chain containing the
double bond and giving it the name of the corresponding alkane with the
ending changed from -ane to -ene. The numbering of the carbon chain is
started at the end that will provide the lowest number for the position of the
first carbon of the double bond. Thus,
I
CH 3 - CH- CH 2 - CH=CH- CH 3
is 5-methyl-2-hexene. Some common alkenyl groups (an alkene minus a
hydrogen atom) are vinyl (CH 2 =CH-), allyl (CH 2 =CH-CH 2 -), and
isopropenyl (CH 2 =C— CH 3 ). Compounds with two carbon-carbon double
bonds are named as alkadienes; if the double bonds are adjacent they are
called cumulated ; if they are separated by a single bond they are conjugated ;
and if they are separated by more than one single bond they are isolated.
chap 4 alkenes 104
Both structural and geometrical isomerism appear at the C 4 level in the
alkene series, there being three structural isomers. One of these (2-butene)
exists in cis and trans forms. Trans isomers have the substituents on the
H 3 C CH 3 H 3 C^ H
c=c c-c
/ \ / \
H H H CH 3
cu-2-butene trans-2-buiene
opposite side of the double bond and usually are of lower energy (more stable)
than their cis isomers. Trans isomers usually have the higher melting points,
lower boiling points, lower dipole moments (often zero) and, because their
substituent groups are far apart, they do not undergo ring closure reactions
which may occur with some cis compounds.
The physical properties of alkenes are similar to those of the corresponding
alkanes, but alkenes are much more reactive chemically. Because of the
concentration of electrons in the double bond, alkenes are subject to attack
by electrophiles (reagents that seek electrons). These addition reactions can
be illustrated with a typical alkene such as propene :
CH 3 CH=CH 2 " 2 > CH,CH 2 CH
3 i Nl J z
3^112^113
Br 2
(other halogens
behave similarly)
HOC1
H 2 so 4 OS0 3 H
► I
CH 3 CHCH 3
HC1
-♦ CH3CHCICH3
■> CH 3 CHBrCH,Br
(HI behaves
similarly)
HRr
-> CHXHBrCH,
(peroxide-free, in dark)
HBr
(peroxides)
H 2
H 8>
-♦ CH 3 CHOHCH,
H2O2
B a H 6 _ /OH e
-* (CH 3 CH 2 CH 2 ) 3 B
\H 2
CH 3 CH 2 CH 3
/°v.
-^— CH 3<\ H CH 2 Jh^ C H 3 CHO + CH 2
O-O Zn
Mn0 4 e 9
> I (cis addition)
CH 3 CHCH 2 OH
exercises 10S
HC0 2 H OH
., _ ' I (trans addition)
H *°> CH 3 CHCH 2 OH
R e
RO-
^y
CH 3
CH, CH,
(polymer; none of
1
1 1
these reactions works
CH-CH 2 -
-CH-CH 2 -CH-
very well for ethene
or propene)
The reactions shown involve attack by electrophilic reagents at the double
bond with the following four exceptions: the metal-induced reaction with
H 2 ; hydrogen bromide with peroxides; and polymerization initiated by
radicals, R-, or anions, Y e , both of which are difficult to achieve.
Addition of most electrophiles occurs stepwise by way of ionic intermediates
(heterolytic bond breaking), with the groups being connected to the carbons
in the trans manner.
When unsymmetrical electrophilic reagents add to unsymmetrical alkenes,
Markownikoff's rule can be used to predict the principal product. Thus,
during the addition of HX, the hydrogen goes to that carbon of the double
bond that carries the greater number of hydrogens — for example, CH 3 CH=
CH 2 + HX -> CH3CHXCH3 . The basis for this rule is the tendency for that
part of the electrophile that initiates the reaction (H® from HX) to add in
such a way as to produce the lowest-energy carbonium ion. (Tertiary carbon-
ium ions are of lowest energy and primary carbonium ions are of highest ener-
gy.) For this reason, the first step of the HX addition is CH 3 CH=CH 2 +
9
H® -» CH 3 CHCH 3 , to give the secondary carbonium ion (not CH 3 CH—
CH 2 + H® -> CH 3 CH 2 CH 2 ffi to give the primary carbonium ion); the final
©
step involves addition of X e , CH 3 CHCH 3 + X e -* CH 3 CHXCH 3 .
The ratios of products in such reactions show that they are governed by
the rates of the two possible reaction paths, not by the stabilities of the final
products. This is called kinetic control of the reaction as opposed to equilib-
rium (or thermodynamic) control.
exercises
4-1 Name each of the following substances by the IUPAC system and, if straight-
forward to do so, as in examples a and e, as a derivative of ethylene :
a. (CH 3 ) 2 C=CHCH 3 / ^"^^h
CH
b. C1 2 C=C(CH 3 ) 2
c. (CH 3 ) 3 CCH 2 C(CH 3 )=CH 2 ,
d. (CH 3 ) 2 C=C=CHBr H 2 C /CH ^CH
e. [(CH 3 ) 2 CH] 2 C=C[CH(CH 3 ) 2 ] 2 g- j| H
XHT CH 3
chap 4 alkenes 106
4-2 Write structural formulas for each of the following substances:
a. trifiuorochloroethylene d. l,l-di-(l-cyclohexenyl)-ethene
b. 1,1-dineopentylethylene e. trivinylallene
c. 1 ,4-hexadiene
4-3 The trans alkenes are generally more stable than the cis alkenes. Give one or
more examples of unsaturated systems where you would expect the cis form to
be more stable and explain the reason for your choice.
4-4 Write structural formulas for each of the following:
a. The thirteen hexene structural isomers; name each by the IUPAC
system. Show by suitable formulas which isomers can exist in cis
and trans forms and correctly designate each.
b. All trans- 1 , 1 8-di-(2,6,6-trimethyl-l -cyclohexenyl)-3,7, 11,1 5-tetramethyl
1,3,5,7,9,11, 13,15,17-octadecanonaene(C 4 oH 56 ).
4-5 Calculate, from the data in Table 3-7 and any necessary bond energies, the
minimum thermal energy that would be required to break one of the ring
carbon-carbon bonds and interconvert cis- and frays'- 1,2-dimethylcyclo-
butanes (see pp. 67-69).
4-6 What volume of hydrogen gas (STP) is required to hydrogenate 100 g of a
mixture of 1 -hexene and 2-hexene?
4-7 Supply the structure and a suitable name for the products of the reaction of
2-methyl-2-pentene with each of the following reagents :
a. H 2 , Ni d. HBr (plus peroxide)
b. Cl 2 e. B 2 H 6 followed by aqueous acid
c. Cl 2 in presence of NH 4 F
4-8 How could bromoethane be prepared starting with ethyne?
4-9 Show how each of the following compounds could be prepared starting with
1,5-hexadiene.
a. 1,2,5,6-tetrabromohexane
b. 2,5-diiodohexane
c. 2-iodohexane
4-10 Write the structures of the products of the reaction of 3,4-dimefhyl-2-octene
with each of the following reagents.
a. diborane followed by hydrogen peroxide and base
b. dilute aqueous sulfuric acid
c. hypobromous acid
d. aqueous potassium permanganate
e. ozone followed by zinc and steam
4-11 Calculate AH (vapor) for addition of fluorine, chlorine, bromine, and iodine
to an alkene. What can you conclude from these figures about the kind of
problems that might attend practical use of each of the halogens as a reagent
to synthesize a 1,2-dihalide?
exercises 107
4-12 a. Write as detailed a mechanism as you can for the trans addition of hypo-
chlorous acid (HOC1) to cyclopentene.
b. How does the fact that HOC1 is a weak acid (K HA in water = 7 x 10~'°)
make formation of CH 3 CH 2 OCl from ethene unlikely?
4-13 Calculate AH for the addition of water to ethene in the vapor state at 25°.
Why are alkenes not hydrated in aqueous sodium hydroxide solutions ?
4-14 When r-butyl bromide is allowed to stand at room temperature for long
periods, the material becomes contaminated with isobutyl bromide. Write a
reasonable mechanism for the formation of isobutyl bromide under the
influence of traces of water and/or oxygen from the atmosphere.
4-15 Arrange ethene, propene, and 2-methylpropene in order of expected ease of
hydration with aqueous acid. Show your reasoning.
4-16 Write two different radical chain mechanisms for addition of hydrogen
chloride to alkenes and consider the energetic feasibility for each.
4-17 Calculate the A// values for initiation and chain propagation steps of radical
addition of hydrogen fluoride, hydrogen chloride, and hydrogen iodide to an
alkene. Would you expect these reagents to add easily to double bonds by
such a mechanism ?
4-18 Bromotrichloromethane, CBrCl 3 , adds to 1-octene by a radical chain
mechanism on heating in the presence of a peroxide catalyst. Use bond
energies (Table 2-1) to devise a feasible mechanism for this reaction and work
out the most likely structure for the product. Show your reasoning.
4-19 Determine from the general characteristics of additions to double bonds
whether the direction of addition of B 2 H 6 to propene is consistent with a
polar mechanism.
4-20 The following physical properties and analytical data pertain to two isomeric
hydrocarbons, A and B, isolated from a gasoline:
Both A and B readily decolorize bromine and permanganate solutions and
give the same products on ozonization. Suggest possible structures and
configurations for A and B. What experiments would you consider necessary
to further establish the structure and configuration of A and B?
4-21 a. Write a mechanism for the sulfuric acid-induced dimerization of trimethyl-
ethylene, indicating the products you expect to be formed.
b. Ozonization of the mixture that is actually formed gives, among
chap 4 alkenes 108
o
II
other carbonyl products(— C— ), substantial amounts of 2-butanone
( ' )
\CH 3 — C— CH 2 — CH 3 / Write a structure and reaction mechanism for
formation of a Cio alkene that might reasonably be formed in the dimer-
ization reaction and that, on ozonization, would yield 2-butanone and a
C 6 carbonyl compound. (Consider how sulfuric acid might cause the
double bond in trimethylethylene to shift its position.)
4-22 A pure hydrocarbon of formula C 6 Hi 2 does not decolorize bromine water.
Draw structures for at least six possible compounds that fit this description
(including geometrical isomers, if any).
4-23 Calculate the heats ( — A/7) of the following reactions in the gas phase at 25° :
H 2 2 + (CH 2 ) 2 > HO-CH 2 -CH 2 -OH
H 2 2 + (CH 2 ) 6 ► HO-(CH 2 ) 6 -OH
a. What conclusion as to the rates of the above reactions can be made on
the basis of the A// values? Explain.
b. What change in the heats of the reactions would be expected if they were
carried out in the liquid phase ? Why ?
c. What agents might be effective in inducing the reactions in the liquid
phase? Explain.
4-24 Evaluate (show your reasoning) the possibility that the following reaction
will give the indicated product:
D 2
If you do not think the indicated product would be important, write the
structure(s) of the product(s) you think most likely to be found.
4-25 Investigate the energetic feasibility of adding ammonia (NH 3 ) to an alkene
by a radical chain mechanism with the aid of a peroxide (ROOR) catalyst.
Would such a mechanism give addition in accord with Markownikoff's rule?
Why? What practical difficulties might be encountered in attempts to add
ammonia to 2-methylpropene with a sulfuric acid catalyst ?
4-26 It has been found possible to synthesize two isomeric cycloalkenes of formula
C 8 H 14 . Both of these compounds react with hydrogen in the presence of
platinum to give cyclooctane, and each, on ozonization followed by reduction,
gives
ii ii
H-C-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -C-H
a. What are the structures and configurations of the two compounds ?
b. Would the two substances give the same compound on hydroxylation
with potassium permanganate?
itlti
lap,
gin;
MsgfS Saw
Kg
'MJs&s* *kSs* ,5-Jfeii
lis'ssEsr VSSSSf RJ»
S3
• v- '::■/■*•■>
■. •'.■'■''
"t">* \$'A' >V^G
liii
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•v.i^i*" 1
i /y*\4y?*:- :
: '■Hi..* 1 3i
k ■;."-■-: r.;\,i:';V .'**%)
chap 5 alkynes 111
Alkynes are hydrocarbons with carbon-carbon triple bonds. The simplest
alkyne is ethyne, H— C=C — H, usually called acetylene, an important
starting material for organic syntheses, especially on an industrial scale. We
have previously discussed the geometry of ethyne and its addition reactions
with hydrogen and bromine (Section 2-6).
5-1 nomenclature
The IUPAC system for naming alkynes employs the ending -yne in place of the
-ane used for the name of the corresponding, completely saturated, hydro-
carbon. Many alkynes are conveniently named as substitution products of
acetylene, as shown in parentheses in these examples.
H-C = C-H CH 3 -C = C-CH 3
ethyne 2-butyne
(acetylene) (dimethylacetylene)
The numbering system for location of the triple bond and substituent
groups is analogous to that used for the corresponding alkenes.
CH 3 CH 3
I I
CH,-C-C=C — C-CH 3
I I
CH 3 H
2,2,5-trimethyl-3-hexyne
(isopropyl-(-butylacetylene)
Open-chain hydrocarbons with more than one triple bond are called
alkadiynes, alkatriynes, and so on, according to the number of triple bonds.
Hydrocarbons with both double and triple bonds are called alkenynes,
alkadienynes, alkendiynes, and so on, also according to the number of double
and triple bonds. The order enyne (not ynene) is used when both double and
triple bonds are present:
HC = C-Cs=CH H 2 C = CH-C = CH
butadiyne butenyne
HC = C — CH=CH— CH=CH 2 HC=C — C = C — CH=CH 2
1 ,3-hexadien-5-yne 1 -hexen-3,5-diyne
The hydrocarbon substituents derived from alkynes are called alkynyl
groups :
HC = C— HC=C-CH 2 —
ethynyl 2-propynyI
(propargyl)
chap 5 alkynes 112
5-2 physical properties of alkynes
Alkynes generally have physical properties rather similar to the alkenes and
alkanes, as can be seen by comparing the boiling points of C 2 and C 6 repre-
sentatives of these three classes of hydrocarbon :
bp 68.7°
Alkynes, like other hydrocarbons, are almost completely insoluble in water.
CH3-CH3 CH 2 = CH 2
HC^CH C
bp -88.6° bp-105°
bp -84°
CH 3 CH 2 CH 2 CH 2 CH=CH 2
CH 3 CH 2 CH 2 CH 2 C = CH
bp 63.5°
bp71.5°
5-3 ethyne
The simplest alkyne, HC^CH, is of considerable industrial importance and
usually goes by the trivial name acetylene, rather than by the systematic
name ethyne, which will be used here. Ethyne is customarily obtained on a
commercial scale by hydrolysis of calcium carbide (CaC 2 ) or, in low yield, by
high-temperature cracking (or partial combustion) of petroleum gases,
particularly methane. Calcium carbide is obtained from the reaction of
calcium oxide with carbon at about 2000° :
2000°
CaO + 3 C ► CaC 2 + CO
It is cleaved by water (acting as an acid) to give ethyne and calcium hydroxide :
CaC 2 + 2H 2 ► HC-CH + Ca(OH) 2
Ethyne is much less stable with respect to the elements than ethene or ethane :
HC=CH (g) —
H 2 C=CH 2 (<?)
H 3 C-CH 3 (<7)
2 C (s) + H 2 (g)
AH =
-54.2kcal
2C(s) + 2H 2 (g)
AH =
-12.5kcal
2C(s) + 3H 2 (g)
AH =
+ 20.2 kcal
An explosive decomposition of ethyne to carbon and hydrogen may occur
if the gas is compressed to several hundred pounds per square inch (psi). Even
liquid ethyne (bp — 83°) must be handled with care. Ethyne is not used com-
mercially under substantial pressures unless it is mixed with an inert gas and
handled in rugged equipment with the minimum amount of free volumes
Large-diameter pipes for transmission of compressed ethyne are often packed
with metal rods to cut the free volume. Ethyne for welding is dissolved under
O
II
200 psi in acetone (CH 3 — C— CH 3 , bp 56.5°) and contained in cylinders
packed with diatomaceous earth.
Flame temperatures of about 2800° can be obtained by combustion of
ethyne with pure oxygen. It is interesting that ethyne gives higher flame temp-
eratures than ethene or ethane even though ethyne has a substantially lower
heat of combustion than these hydrocarbons. The higher temperature of
sec 5.4 addition reactions of alkynes 113
ethyne flames, compared with those of ethene or ethane, is possible despite
the smaller molar heat of combustion :
C 2 H 2 (g) + i 2 (g) ► 2 C0 2 (g) + H 2 (I) AH = -31 1 kcal
C 2 H 4 (<?) + 3 2 (g) ► 2 C0 2 (g) + 2H 2 (/) AH = -337 kcal
C 2 H 6 (g) + 1 2 (g) ► 2 C0 2 (g) + 3H 2 (/) A//= -373 kcal
This is because the heat capacity of the products is less. Less water is formed
and less of the reaction heat is used to bring the combustion products up to
the flame temperatures. Alternatively, what this means is more heat liberated
per unit volume of stoichiometric hydrocarbon-oxygen mixture. The com-
parative figures are ethyne, 3.97; ethene, 3.76; and ethane, 3.70 kcal/liter of
gas mixture at standard temperature and pressure.
5-4 addition reactions of alkynes
That ethyne (acetylene) undergoes addition reactions with one or two moles of
hydrogen or with halogens such as bromine was discussed in Chapter 2. The
higher alkynes react similarly as can be illustrated with 4,4-dimethyl-l-
pentyne :
CH 3 CH 3
I H, I
CH,-C-CH 2 -C = CH ^— ♦ CH 3 -C-CH 2 -CH = CH 2
\ Ni I
CH 3 CH 3
4,4-dimet hyl- 1 -pentyne 4,4-dimethyI- 1 -pentene
I
CH 3 -C-CH 2 -CH 2 -CH 3
CH 3
2,2-dimethylpentane
CH 3 CH 3
_ C = CH -Jfi^ CH 3 -C-CH 2 -CBr = CHBr
I
CH 3
4,4-dimethyl- 1 ,2-dibromo- 1 -pentene
(trans isomer formed predominantly)
Br 2
CH 3
I
— C— CH 2 — CBr 2 - CHBr 2
CH 3
1 , 1 ,2,2-tetrabromo-4,4-
dimethylpentane
chap 5 alkynes 114
Alkynes undergo addition reactions with many other reagents which add to
alkenes, particularly those which are electrophilic. The susceptibility of alkenes
to electrophilic reagents was explained earlier on the basis of repulsions
between the electrons in the double bond (Section 4-4), and you might rea-
sonably expect alkynes, with triple bonds, to be even more susceptible to
electrophilic attack. Actually, however, the reaction rates of alkynes with elec-
trophilic reagents are rather less than those of alkenes. Whereas the deep
color of liquid bromine is almost instantly discharged when it is added to an
alkene, the bromine color persists for a few minutes with most alkynes.
Similarly, the addition of water (hydration) to alkynes not only requires the
catalytic assistance of acids (as do alkenes), but also mercuric ions:
HC = CH
H,0
H 2 S0 4
HgS0 4 '
OH
vinyl alcohol
(unstable)
/
H
acetaldehyde
Mercuric, cuprous, and nickel ions are often specific catalysts for reactions
of alkynes, perhaps because of their ability to form complexes with' triple
bonds.
Hg 2
R-C=C-R + He
± R — CssC— R
The product of addition of one molecule of water to ethyne is unstable and
rearranges to a carbonyl compound, acetaldehyde. With an alkyl-substituted
ethyne, addition of water always occurs in accord with Markownikoff's rule:
CH 3 -C=CH + H 2
propyne
H 2 S0 4
HgSoT
OH
I
CH 3 — C = CH 2
O
II
CH 3 -C— CH 3
acetone
Alkynes react with potassium permanganate with formation of man-
ganese dioxide and discharge of the purple color of the permanganate ion just
as do alkenes but, again, the reaction is generally not quite as fast with alkynes.
Hydrogen halides also add to the triple bond. These additions, like the ones to
alkenes, occur in accord with Markownikoff's rule:
HC=CH
HF
H 2 C = CHF
fluoroethene
(vinyl fluoride)
♦ CH 3 -CHF 2
1,1-difluoroethane
Ethyne dimerizes under the influence of aqueous cuprous ammonium
chloride. This reaction is formally analogous to the dimerization of 2-methyl-
propene under the influence of sulfuric acid (see Section 4-4H), but the details
sec 5.4 addition reactions of alkynes 115
of the reaction mechanism are not known :
H H
Cu(NH 3 ) 2 ®Cl e \ I
2HC=CH ► C=C— C = CH
/
H
butenyne
(vinylacetylene)
Alkynes, like alkenes, react with boron hydrides by addition of B— H
across the carbon-carbon triple bond (Section 4-4F) and give vinylboranes :
CH,CH, H
\ /
CH,CH 2 — C = C — H + BH 3 ► C = C
/ \
H BH 2
(a vinylborane)
Vinylboranes react readily with acetic acid under mild conditions to give
alkenes. The overall process is quite stereospecific, for a disubstituted alkyne
gives only a cis alkene. Evidently the boron hydride adds in a cis manner to
the triple bond, and the vinylborane produced then reacts with acid to give the
corresponding cis alkene.
CH 3 CH 2 H H
I \/
C B
III + I
C H
I
CH 3 CH 2
3-hexyne
Whereas nucleophilic reagents do not generally add to alkenes, they add
readily to alkynes, particularly to conjugated diynes and triynes. For example,
1,3-butadiyne adds methanol in the presence of a basic catalyst such as
sodium hydroxide. The mechanism of this type of reaction resembles the
NaOH
HC=C— C=CH + CH3OH > CH 3 OCH=CH— C^CH
1,3-butadiyne l-methoxy-l-buten-3-yne
ionic addition reactions discussed previously (Section 4- 4A) except that the
initial step involves attack of the nucleophile (CH 3 O e ) on a terminal carbon
to form a carbanion intermediate. The nucleophile is initially formed by the
reaction of methanol with the basic catalyst. The carbanion intermediate is a
H
CH 3 CH 2 ^
II
CH 3 CH 2 H
H
CH 3 CH 2 H
CH 3 C0 2 H C
— ~ II
c
CH 3 CH 2 ^H
90 % c/.s-3-hexene
CH 3 OH+NaOH r
CH 3 O e + HC^C-C=CH •■ CH 3 0-CH=C-C=CH
very strong base and reacts rapidly with methanol to remove a proton and
reform the nucleophile, CH 3 O e , and generate the product, 1-methoxy-l-
buten-3-yne.
x a
CH 3 0— CH=C— C=CH + CH 3 OH ► CH 3 OCH=CH-C=CH+ CH 3 O e
chap S alkynes 116
5-5 alkynes as acids
A characteristic and synthetically important reaction of 1 -alkynes is salt (or
"alkynide") formation with very strong bases. Calcium carbide, CaC 2 ,
can be regarded as the calcium salt of ethyne with both hydrogens removed,
/e e\
Ca 2 ®\C=C/. Thus, the alkynes behave as acids in the sense that they give up
protons to suitably strong bases:
liquid
ffi e NH-, e ffi
R-C = C:H +K:NH 2 ^_ ' R— C = C:K + :NH 3
R = H or alky] a potassium. alkynide
Alkynes are much less acidic than water. In other words, water is much
too weakly basic to accept protons from 1 -alkynes; consequently, even if
alkynes were soluble in water, no measurable hydrogen-ion concentration
would be expected from the ionization of 1 -alkynes in dilute aqueous solu-
tions. However, 1-alkynes are roughly 10 13 times more acidic than ammonia,
and alkynide salts are readily formed from 1-alkynes and metal amides in
liquid ammonia.
Alkynes are at least 10 18 times more acidic than ethene or ethane. The
high acidity of ethyne and 1-alkynes relative to other hydrocarbons can
be simply explained in terms of lower repulsion between the electron pair
of the C — H bond of 1-alkynes and the other carbon electrons. In the triple
bond, three pairs of bonding electrons are constrained to orbitals between
the two carbon nuclei. As a result, they are, on the average, farther away
from the C — H electron pair than are the C — C electrons from the C — H
electron pairs in alkenes or alkanes.
Consequently, less electron repulsion is expected for the C — H electron pair
of a 1-alkyne: the less the electron repulsion, the more closely the C — H
electrons will be held to the carbon nucleus ; and the more strongly they are
held to carbon, the more easily the hydrogen can be removed as a proton by a
base. By this reasoning, 1-alkynes are expected to be stronger acids than
alkenes or alkanes. It should be clear from this discussion that the ability of
an atom to attract bonding electrons — its electronegativity (Section 1 • 2) —
will depend on whether it is singly, doubly, or triply bonded. For carbon, a
triply bonded atom will have the highest electronegativity, and a saturated
carbon the lowest.
In terms of degree, the very much larger acidity of alkynes, compared with
alkanes, is easily understood if you remember that electrostatic forces depend
upon the inverse square of the distance. A small displacement of electrons will
cause a very large electrostatic effect at the short distances which correspond
to atomic diameters.
A simple and useful chemical test for a 1-alkyne is provided by its reaction
sec 5.6 synthesis of organic compounds 117
with silver ammonia solution. Alkynes with a terminal triple bond give
solid silver salts, while disubstituted alkynes do not react :
R-C = C-H + Ag(NH 3 ) 2 ► R-C = C-Ag(j) + NH 3 + NH 4
(R = H or alkyl) silver alkynide
The silver alkynides appear to have substantially covalent carbon-metal bonds
and are not true salts like calcium, sodium, and potassium alkynides. Silver
ammonia solutions may be used to precipitate terminal alkynes from mixtures
with disubstituted alkynes. The monosubstituted alkynes are easily regener-
ated from the silver precipitates by treatment with mineral acids or sodium
cyanide :
R— C=C— Ag + NaCN + H 2 > R-C=C-H + NaOH + AgCN(s)
It should be noted that dry silver alkynides may be quite shock sensitive and
can decompose explosively.
5-6 synthesis of organic compounds
In this chapter we have described the chemistry of one of the important
reactive groups (or "functional groups") in organic chemistry, the carbon-
carbon triple bond. The previous chapter covered another important func-
tional group, the carbon-carbon double bond. The numerous reactions of
these groups are part of the complex web of reactions that allows us to convert
one compound to another, often to one which has a quite different structure,
by utilizing a number of reactions in sequence. Choosing the best route to
convert compound A to compound Z is the forte of the synthetic organic
chemist and, when he combines a high degree of intellectual skill in sifting
through the many possible reactions with a high degree of skill in the labor-
atory, his work can fairly be described as both elegant and creative.
The purposes of syntheses are widely divergent: Thus one might desire to
confirm by synthesis the structure of a naturally occurring substance, and at
the same time, develop routes whereby analogs of it could be prepared for
comparisons of chemical and physiological properties. Another aim might be
to make available previously unreported substances that would be expected
on theoretical grounds to have unusual characteristics because of abnormal
steric or electronic effects, for example, the following compounds:
H
C(CH 3 ) 3
1
C
(CH 3 ) 3 C-C-C(CH 3 ) 3
C=C
\ /
C(CN) 4
H"Cd 7 C-
C(CH 3 ) 3
CH 2
c
cyclopropyne
tetracyanomethane
H
tetra-/-butylmethane
tetrahedrane
chap 5 alkynes 118
Much research is also done to develop or improve processes for synthesizing
commercially important compounds : in such work, economic considerations
are obviously paramount.
Regardless of why a compound is synthesized, the goal is to make it from
available starting materials as efficiently and economically as possible.
Naturally, what is efficient and economical in a laboratory-scale synthesis
may be wholly impractical in industrial production; and, while we shall
emphasize laboratory methods, we shall also indicate industrial practices in
connection with the preparation of many commercially important substances.
An essential difference between industrial and laboratory methods is that
the most efficient industrial process is frequently a completely continuous
process, in which starting materials flow continuously into a reactor and
products flow continuously out. By contrast, research in a laboratory is
usually unconcerned with sustained production of any single substance, and
laboratory preparations are therefore normally carried out in batches.
Another difference concerns by-products. In laboratory syntheses, a by-
product such as the sulfuric acid used to hydrate an alkene is easily disposed
of. But, on an industrial scale, the problem of disposal or recovery of millions
of pounds per year of spent impure acid might well preclude use of an other-
wise satisfactory synthesis.
We believe that it is important in writing out projected syntheses to specify
reagents and reaction conditions as closely as possible because different sets
of products are sometimes formed from the same mixture of reagents, de-
pending upon the solvent, temperature, and so on. The addition of hydrogen
bromide to alkenes (Section 4-4E) provides a cogent example of how a change
in conditions can change the course of a reaction.
Most syntheses involve more than one step — indeed, in the preparation of
complex natural products, it is not uncommon to have 30 or more separate
steps. The planning of such syntheses can be a real exercise in logistics. The
reason is that the overall yield is the product of the yields in the separate
steps ; thus, if each of any three steps in a 30-step synthesis gives only 20 % of
the desired product, the overall yield is limited to (0.20) 3 x 100 = 0.8% even
if all the other yields are 100 %. If 90 % yields could be achieved in each step,
the overall yield would still be only (0.90) 30 x 100 = 4%. Obviously in a
situation of this kind, one should plan to encounter the reactions that have
the least likelihood of succeeding in the earliest possible stages of the syntheses.
In planning multistep syntheses, you must have a knowledge of how
compounds are formed and how they react. For example, if asked to convert
compound A to compound C, one would quickly check the reactions of
compounds of type A and the preparations of the compounds of type C to
see if any of them coincide. If they do not, the next step is to see if there is a
compound B that can be prepared from A which could itself give C. In this,
one is guided by the changes, if any, that are required in the carbon skeleton.
Some simple examples are shown.
Possible starting materials:
CH 3
HC^CH CH 3 — CH— C = C— H any inorganic reagents
sec 5.6 synthesis of organic compounds 119
Desired products :
CH 3
CH 3 Br
1 1
CH-CH 2 -
CH 2 Br
CH 3 -
-CH-C = CH 2
CH 3
A quick glance at the carbon skeletons of the starting materials and the de-
sired products shows that the product listed first, butane, has a different
carbon skeleton than that of either of the possible organic starting materials
but that the other two, l-bromo-3-methylbutane and 2-bromo-3-methyl-l-
butene, have the same skeleton as one of the possible starting materials,
-3-methyl-l-butyne. Let us then begin with an example where no change in
carbon skeleton is necessary and try to think of reactions which will in one
step convert 3-methyl-l-butyne to the desired products.
In going back over the previously discussed addition reactions, we note that
addition of hydrogen bromide to a triple bond gives a bromoalkene (Section
4-4). Furthermore, if this addition occurs in the Markownikoff manner, the
third product would be obtained in one step :
CH 3 CH 3 Br
I II
CH 3 — CH-C = CH + HBr — — — » CH 3 — CH-C = CH 2
dark
With regard to the second desired product, the bromoalkane, there is no
reaction that we have thus far encountered (nor does one exist) that will
convert a triple bond to this arrangement in one step. Alkenes, however, can
be made by the catalytic hydrogenation of alkynes and one could thus convert
the alkyne to the desired product by the following route :
CH 3 CH 3 CH 3
I H 2 I HBr I
CH 3 -CH-C = CH > CH 3 -CH-CH = CH 2 — ->■ CH 3 -CH-CH 2 -CH 2 -Br
Ni peroxides
The other desired product, butane, requires a change in the carbon skeleton.
The only such synthetic reaction that we have thus far encountered is the
dimerization of ethyne under the influence of cuprous ion. Thus, butenyne
can be made from ethyne and this, when hydrogenated, gives butane:
Cu(NH 3 ) 2 e 3H 2
2HC=CH >
Ni
Each of the reactions used in the above syntheses gives reasonably high
yields of products so that troublesome separation of isomers is not necessary.
We have met one reaction thus far which is not specific and which usually
leads to the production of isomeric mixtures — the halogenation of alkanes. If
we had included 2-methylbutane in the list of available starting materials for
the above syntheses one might have been tempted to try to prepare 1-bromo-
3-methylbutane by light-catalyzed bromination because the carbon skeletons
of these two compounds are the same :
CH 3 CH 3
CH,-CH-CH,-CH 3 + Br 2 > CH 3 — CH-CH 2 -CH 2 Br + HBr
chap 5 alkynes 120
Unfortunately, there is no way to ensure that substitution will occur at the de-
sired place in the alkane. Indeed, you can be sure that a mixture of bromoalkanes
CH 3
I
will be produced with the principal product being CH 3 — C— CH 2 — CH 3 ,
Br
resulting from substitution at the tertiary carbon atom. Thus, it is
important to consider the "practicality of synthetic schemes that you devise.
The extremely important matters of identification and purification of products
are considered in Chapter 7.
It should be clear that a reaction of one type of compound may well be a
method of preparation of another. So far, we have considered the reactions
of alkanes, alkenes, and alkynes and have not listed separately their methods
of preparation. There are two reasons for this. First, some of these compounds,
particularly alkanes, can be obtained quite pure by careful fractionation of
petroleum and we would seldom need to prepare them in the laboratory.
Second, and more important, we have as yet encountered only a few of the
many functional groups which can efficiently be converted to alkanes, alkenes,
and alkynes. However, when we discuss a new functional group we shall list
for purposes of convenience the common preparative methods that lead to it
even though they may involve reactions or types of compounds to be described
later in the book.
In the interest of completeness, some useful methods of forming carbon-
carbon single, double, and triple bonds are summarized below.
C-C bonds:
Addition, as of hydrogen to C=Cor C=C bonds (Sections 4-4, 5-4)
C=C bonds:
a. Dehydration of alcohols (Section 10-5B)
b. Elimination of hydrogen halides from haloalkanes and related
compounds (Sections 8-12, 8-13)
c. Partial additions, such as catalytic hydrogenation, to C=C bonds
(Section 5-4)
C^C bonds:
a. Elimination of two moles of hydrogen halide from 1,2-dihaloalkanes
(Section 9-5)
b. Elimination of one mole of hydrogen halide from haloalkenes (Section
9-5)
summary
Alkynes possess carbon-carbon triple bonds. Simple open-chain alkynes have
the formula C„H 2 „_ 2 and, in the IUPAC system, are named the same way as
alkenes except that the -ene ending becomes -yne. Ethyne, HC=CH, is usually
called acetylene. The physical properties of alkynes, alkenes, and alkanes are
similar. Chemically, alkynes resemble alkenes in undergoing addition reactions
with electrophilic reagents although they do not usually react as rapidly as
exercises 12 1
alkenes. However, they will undergo additions with nucleophilic reagents
more readily than alkenes. Several typical addition reactions of alkynes are
illustrated with propyne as an example. The final reaction produces cis
alkenes when nonterminal triple bonds are reduced.
CH 3 C=CH " 2 > CH 3 CH=CH 2
H 3 C Br
Br 2 \ /
> c = c
(other halogens / \
behave similarly) Br H
— ► CH 3 CC1=CH 2
(other hydrogen halides
behave similarly)
H 2 _ CH3 _^_ CH3
H®, Hg 2
H 3 C H
B 2 H 6 \ / acid
> C = C > CH 3 CH=CH 2
/ \
H BH 2
Ethyne can be dimerized to butenyne (vinylacetylene) by the action
of ammoniacal cuprous ion :
2 HC3C H Cu(NH3)2a > CH 2 = CH-C^CH
1 -Alkynes are feebly acidic and can be converted to anions (alkynide ions)
by the action of powerful bases.
-»• RC = C e + NH,
Insoluble silver salts are produced by the action of ammoniacal silver ion on
1 -alkynes and this is a useful means of detecting terminal triple bonds.
Some of the principles of organic synthesis have been discussed with the aid
of several specific examples.
exercises
5-1 Name each of the following substances by the IUPAC system and as a
substituted acetylene.
a. CH 3 C=CC1 HX-CH HC-CH 2
b. (CH 3 )3CC=CCH 2 C(CH3) 3 e. H 2 C^ C-C = C-C^ CH 2
c. CH 2 =CHCH 2 C=CCH=CH 2 H 2 C-CH 2 H 2 C-CH 2
d. HC=CCH 2 C=C-C(CH 3 )=CH 2 /^^c
/• (CH 2 ) 8 III
V c
chap 5 alkynes 122
5-2 Write structural formulas for each of the following, showing possible geo-
metrical isomers :
a. 1 ,2-dibromocyclopropane
b. 2,4-hexadiene
c. cyclooctyne
d. dibromoethyne
e. l,5-hexadien-3-yne
5-3 Calculate AH values from the bond-energy table in Chapter 2 for the follow-
ing reactions in the vapor state at 25° :
a. HO=CH + Br 2 > CHBr=CHBr
b. CHBr=CHBr+Br 2 > CHBr 2 -CHBr 2
c.
HC=CH + H 2 ► CH 2 =CHOH
P
d. CH 2 = CHOH ► CH 3 C
H
e. 2HC=CH ► H 2 C=CH-C=CH
/ CH 3 -C=C-H ► CH 2 =C=CH 2
g. Calculate also a AH for reaction f from the experimental AH values for
the following reactions :
CH 3 C=CH + 2H 2 ► CH 3 CH 2 CH 3 AH = -69.7 kcal
CH 2 =C=CH 2 + 2H 2 * CH3CH2CH3 A J ff=-71.3kcal
Explain why the value of AH calculated from bond energies might be un-
reliable for the last reaction.
5-4 Ethyne has an acid ionization constant (K U a) of ~ 10~ 20 in water.
a. Calculate the concentration of ethynide ion expected to be present
in 1 M solution of aqueous potassium hydroxide that is 10 " 4 M in
ethyne (assuming ideal solutions).
b. Outline a practical method (or methods) that you think might be
suitable to determine an approximate experimental value of K H a for
ethynes, remembering that water has a K H a of about 10 ~ 16 .
c. Would you expect H — C=N to be a stronger acid than H — C= C — H ?
Why?
5-5 Suppose you were given four unlabeled bottles, each of which is known to
contain one of the following compounds: «-pentane, 1-pentene, 2-pentyne,
and 1-pentyne. Explain how you could use simple chemical tests (preferably
test tube reactions that produce visible effects) to identify the contents of
each bottle. (Note that all four compounds are low-boiling liquids.)
5-6 How would you distinguish between the compounds in each of the following
pairs using chemical methods (preferably test tube reactions).
a. CH 3 CH 2 C=CH and CH 3 C=CCH 3
b. CH 3 CH 2 C=CH and CH 2 =CH-CH=CH 2
c. C 6 H 5 C=CC 6 H S and C 6 H 5 CH 2 CH 2 C 6 H 5
5-7 Write balanced equations for the reaction of 3,3-dimethyl-l-butyne with each
exercises 123
of the following reagents and, in the first three cases, name the product.
a. H 2 (two moles), Ni c. Cl 2 (one mole)
b. HC1 (two moles) d. H 2 0, H e , Hg 2 ®
5-8 Show how each of the following compounds could be synthesized from the
indicated starting material and appropriate inorganic reagents. Specify the
reaction conditions, mention important side reactions, and justify the practi-
cality of any isomer separations.
CI
I
a. CH 2 =CH— C=CH 2 from ethyne (the product is an intermediate in
the synthesis of the artificial rubber, neoprene)
b. CH 3 CHFCH 2 Br from propyne
c. CH 3 CH 2 COCH 3 from 1-butyne
CH 3 CH 3
\ 3 / 3
d. C=Q from 2-butyne
H H
CH 3 CH 2 H from ,. but y ne and
e. C=C deuteroacetic acid
H / \ D (CH 3 C0 2 D)
5-9 Starting with ethyne, 3-methyl-l-butyne, and any inorganic reagents (the
same starting materials used in the examples on pp. 118-119) show how you
could prepare the following compounds.
CH 3
I
a. CH 3 -CH-CHBr-CH 3
CH 3
I
b. CH 3 -CH-CC1 2 -CH 2 C1
CH 3 O
I I!
c. CH 3 -CH-C-CH 3
d. CH 3 CH 2 CHOHCH 3
5-10 When 0.100 g of an unsaturated hydrocarbon was treated with an excess of
hydrogen in the presence of a platinum catalyst, 90.6 ml of hydrogen was
absorbed at atmospheric pressure and 25°. Furthermore, the compound gave
a precipitate with ammoniacal silver nitrate. What is its structural formula ?
5-11 Indicate how you would synthesize each of the following compounds from
any one of the given organic starting materials and inorganic reagents.
Specify reagents and the reaction conditions, and justify the practicality of
any isomer separations. If separations are not readily possible, estimate the
proportion of the desired compound in the final product. Starting materials :
ethene, propene, isobutane, 2-methylpropene.
CH,
OH
CH,
b. CH 3 — C-CH 3
CH 3 CH-CH 2
c I I
OH Br
CH, CH 3
I I
d. CH 3 -C — CH 2 -C— CH,
I I
CH, I
chap 5 alkynes 124
CH 3
I
e. CH 3 -C-CH 2 Br
I
H
CH 3 CH 3
I I
/. C1CH 2 -C-CH 2 -CH-CH 3
CH 3
g. CH 3 — CH 2 — CH 2 OH
* o t
u :::: mm-'
. £* <S i
chap 6 bonding in conjugated unsaturated systems 127
The nomenclature of alkenes, including those with more than one carbon-
carbon double bond, was discussed in Chapter 4. The compounds with two
double bonds separated by just one single bond were categorized as con-
jugated dienes; those with double bonds separated by more than one single
bond, as isolated dienes. Dienes with isolated double bonds have properties
similar to those of simple alkenes except that there are two reactive groups
instead of one. Thus, 1,5-hexadiene reacts with one mole of bromine to form
5,6-dibromo-l-hexene and with two moles to give 1 ,2,5,6-tetrabromohexane.
CH 2 = CH-CH 2 -CH 2 -CH=CH 2 ^ > CH 2 = CH-CH,-CH 2 - CHBr-CH 2 Br
'^—> BrCH 2 — CHBr — CH 2 — CH 2 — CHBr — CH 2 Br
Furthermore, the heat of hydrogenation of 1,5-hexadiene is almost exactly
double that of the heat of hydrogenation of 1-hexene, indicating the normalcy
of each of the double bonds.
On the other hand, 2,4-hexadiene, the conjugated isomer, has properties
which indicate that two double bonds are not wholly independent of one
another. Addition of one mole of bromine produces a mixture of products.
Br Br
I I
CH 3 — CH — CH=CH— CH — CH 3
2.5-dibromo-3-hexene (major product)
Br Br
I I
CH 3 — CH = CH — CH — CH — CH 3
4.5-dibromo-2-hexene (minor product)
The major product results from addition not to adjacent positions (1,2
addition) but to positions separated by two intervening carbon atoms (1,4
addition, or conjugate addition). Furthermore, hydrogenation of one mole of
2,4-hexadiene liberates about 6 kcal less heat than hydrogenation of one
mole of 1,5-hexadiene.
A more striking anomaly is the case of benzene. This compound is a liquid
hydrocarbon of formula C 6 H 6 . It is now known from a variety of experi-
mental studies to be a cyclic molecule in the shape of a flat hexagon. The only
way that carbon can preserve a tetravalent bonding arrangement here is by
having three double bonds in the ring; for example,
H
I
H C H
^C^ ^C^ (T^*! (where a carbon and hydrogen atom
|| I or I I are understood to be at each corner
,<X ^>C \^ of the hexagon)
H C H
I
H
This structure for benzene was advanced in 1865 by August Kekule, only a
few years after his postulate of tetravalent carbon. Those were the years in
CH 3 — CH = CH— CH = CH — CH 3 + Br 2
chap 6 bonding in conjugated unsaturated systems 128
which enormous strides were made in establishing structural organic chem-
istry as a sound branch of science. The objections to Kekule's structure that
were soon put forward centered on the lack of reactivity of benzene toward
reagents such as bromine. A number of alternative proposals were made
in the following five years, of which the structures proposed by Ladenburg,
Claus, and Dewar received the most attention. The Ladenburg and Dewar
Ladenburg (1869) Claus (1867)
Dewar (1867)
formulas will be met again later in the book. The Claus structure is difficult
to formulate in modern electronic theory and must be regarded as an attempt
to formulate a substance with formula C 6 H 6 (no carbon is implied at the
center of the ring) with all saturated tetravalent carbons. Actually, another
40 years were to pass before the electron was discovered and an additional 20
before the need would be recognized to identify bonds with pairs of electrons.
Over this period, Kekule's structure for benzene was generally accepted,
despite the dissimilarity between the reactivities of benzene and the alkenes.
It was thought that the conjugated arrangement of the bonds must somehow
be responsible for its inertness. Whereas the orange color of bromine vanishes
instantly when cyclohexene and bromine are mixed, a benzene-bromine
mixture remains colored for hours. When the mixture eventually becomes
colorless, an examination of the reaction product shows it to be not the addi-
tion compound, but a substitution compound. * Clearly benzene is much more
+ Br,
fast
Br
Br
cyclohexene
(C ( ,H 10 )
1 ,2-dibromocyclohexanc
(C 6 H 10 Br,)
+ Br,
benzene
(QH 6 )
slow
Br
+ HBr
bromobenzene
(C„H 5 Br)
resistant to addition than cyclohexene, which means that its three conjugated
double bonds constitute an unusually stable system for a triene. The stabiliza-
tion of benzene is further indicated by a 37 kcal/mole lower heat of combus-
tion than calculated for a molecule containing three ordinary double bonds.
The heat of combustion of cyclohexene, on the other hand, is quite close to
1 The general formula for a monosubstituted benzene is C 6 H 5 X. The group C 6 H 5 — is
known as the phenyl group and the hydrocarbon C 6 H 5 CH=CH 2 is by the IUPAC system
phenylethene, although commonly called styrene.
sec 6.1 bonding in benzene 129
that calculated using the standard table of bond energies (Table 2-1). The
15
+ _ o, ► 6 C0 2 + 3 H 2 A// e = —759.1 kcal 37 kcal
%/* AW calc = -796.5 kcal difference
17
-» 6 C0 2 + 5 H 2 A W exp = -849.6 kcal 2 kcal
AW cak = -851.5 kcal difference
degree of stabilization of benzene compared to what might be expected for
cyclohexene, about 35 kcal/mole, is a large quantity of energy. This is, of
course, much larger than the 6 kcal/mole stabilization of 2,4-hexadiene; but
even 6 kcal/mole can give rise to important chemical effects because energies
are related to equilibrium constants (and, in a crude way, to rate constants)
logarithmically (Sections 2- 5 A and 8-9).
What is the origin of the stabilization associated with these conjugated
systems and how does 1,4 addition occur? A qualitative answer to these
questions is given in the next two sections.
6-1 bonding in benzene
Formation of an ordinary covalent bond between atoms A and B results in
release of energy (stabilization) because the electrons that were localized on
A and B can now interact with two nuclei instead of one :
A- + B- * A:B
The atomic orbitals on A* and B- occupied by the single electrons are de-
signated by symbols (s, p, d, f) that are relics of the early days of atomic
spectroscopy and serve now to indicate energy levels and orbital shapes. For
example, s orbitals are spherical and an electron in an s orbital is of lower
energy than an electron in a p orbital, which is dumbbell shaped (Figure 6T).
Quantum theory tells us that only certain total energies are allowed of a
system made up of a nucleus and an electron. The diffuse regions of space in
which the electrons move are called orbitals, and the system has a specific
energy when an orbital is occupied by one electron. An orbital can be des-
cribed qualitatively by its approximate shape and quantitatively by rather
Figure 6-1 Shapes of s and p orbitals.
s atomic orbital p atomic orbital
chap 6 bonding in conjugated unsaturated systems 130
complex mathematical expressions that give the exact energies when the
orbital is occupied by electrons. Because electrons have some of the character-
istics of waves, the equations which define the electron distributions and their
energies are called wave equations. While the equations describing one electron
and one nucleus are not unduly complex, no rigorous solutions have so far
been possible for molecules as simple as methane.
Chemistry is almost entirely devoted to the study of molecules and, except
for the noble gases, it is difficult to obtain a stable system for study of isolated
atoms. Thus, elemental carbon exists not as an assemblage of isolated atoms
but in the form of diamond or graphite, the atoms of which are covalently
bonded together just as tightly as are the carbons in ethane and benzene. It is
therefore preferable to direct attention not to orbitals for electrons in atoms
but orbitals for electrons in molecules, molecular orbitals. There is a stable
molecular orbital for each C— H bond in methane; they are all equivalent and
point to the corners of a regular tetrahedron. 2 The eight valence electrons
of these atoms assume the configuration of lowest energy regardless of the
shape of the orbitals occupied by electrons on the isolated atoms. Only two
electrons can occupy the same orbital 3 and there will then be two electrons
in each of the C— H molecular orbitals. The repulsion between the four pairs
of electrons makes the tetrahedral arrangement the one of lowest energy or
greatest stability. The resulting bonds are equivalent and those like them in
other saturated compounds are often called sp 3 bonds, on the basis of a
mathematical analysis of the relations of the molecular orbitals to the orbitals
occupied by electrons on atomic carbon.
With carbon-carbon double bonds, a dilemma arises. Should we regard
the two bonds as equivalent with both being bent or should we imagine that
one of them — the a (sigma) bond — occupies the prime space along the bond
axis and the other — the n (pi) bond — the space above and below the plane
defined by the other bonds to the double-bonded carbons? We saw earlier
(Section 2-6) that either of these models accounts for the geometry of ethene
although the second of these is less straightforward and harder to visualize
than the first. However, most theoretical treatments of conjugated systems
make use of the idea of clouds of % electrons above and below the a bond.
The popularity of this approach stems to a great extent from the fact that if
we ascribe the unusual properties of benzene exclusively to the % electrons, we
2 Strictly speaking, a molecular orbital describes the interaction of an electron with every
nucleus in the molecule. In the case of molecules such as alkanes, however, the pair of
electrons in a C— H bond appears to interact almost entirely with the carbon and hydrogen
nuclei that make up the bond. To put it in other terms, the electrons in the orbitals of the
C— H bonds of methane can be called " localized " bonding electrons.
3 Why only two electrons to an orbital ? The reasons are not simple or very intuitively
reasonable. That only two electrons can occupy a given orbital is a statement of the Pauli
exclusion principle. The basic idea is that only two nonidentical electrons can occupy an
orbital. How can electrons be nonidentical? By having different spins. For electrons there
are only two different possibilities, corresponding to right handed or left handed. Two
right-handed electrons or two left-handed electrons cannot occupy the same orbital — only
a right-handed and left-handed pair, like the nonidentical pairs of animals allowed on
Noah's ark.
sec 6.1 bonding in benzene 131
Figure 6-2 Diagram of the diradical -CHj — CH 2 - with the planes of the CH 2
groups set at right angles to one another. Each carbon atom has a p orbital
containing one electron.
greatly reduce the number of electrons we have to deal with. We shall make
use of this approach (which should be regarded as a matter of convenience
and not as revealed truth) in the subsequent discussion. The three a bonds to
carbon in an alkene, often designated sp 2 bonds, are taken to be spread at
angles of 120° to one another.
The n bonding in ethene can be thought to arise as follows. Imagine the
diradical -Cr^ - CH 2 - with the carbon atoms joined only by a single bond.
A reasonable electronic formulation would be the one in which the carbons
are trigonal, that is to say, the three covalent bonds to each carbon lie in a
plane at angles of 120° to one another (the maximum bond angle). The two
extra electrons are considered to be placed in dumbbell-shaped p orbitals,
one on each carbon atom. If the planes of the two CH 2 (methylene) groups are
set at right angles to one another, the interaction between the electrons in the
p orbitals is minimized (Figure 6-2) because the electrons are as far away from
one another as they can be. If the methylene groups are now rotated with
respect to one another until the carbons and hydrogens all lie in the same
plane, the p orbitals will became parallel to one another (indeed, overlap with
each other) and interaction between the electrons will be at a maximum. If
the electrons have the same spin they cannot occupy a molecular orbital made
up of the two p atomic orbitals; they repel each other and give an arrangement
less stable than the one with the CH 2 groups at right angles. The setup with
unpaired electrons does not give a stable 7r bond. On the other hand, if the
spins are paired, they form a n bond — both electrons have the same energy,
occupy the same region of space (n molecular orbital), and interact with both
nuclei (see Figure 6-3).
Benzene can be described by a similar orbital arrangement. Imagine a
hexagon of carbon atoms joined by single bonds (<r bonds, localized along
each bond axis) with a singly occupied p orbital on each. 7r-Bond formation
between adjacent pairs of p orbitals as in ethene would give a triene (Figure
6-4). The high degree of symmetry in this molecule, however, allows 7r-bond
formation between each carbon and both its neighbors. The result is a system
where the n electrons are associated with more than two nuclei and can be
fairly called delocalized. Association of a pair of electrons with two nuclei
results in stabilization with formation of a localized bond; association with
more than two nuclei leads to still greater stabilization and delocalized bonds.
The extra degree of stabilization that can be ascribed to delocalized n bonds is
chap 6 bonding in conjugated unsaturated systems 132
a
CD
H .*•*«&
\ »-
"LI WS^*
,H
H^v
i H
- - ;S S| , H
/
/
/
/
/
H
"H
s
\
fr '
...;\, H
Figure 6-3 The energy levels that result from rotating the CH 2 groups of
•CH 2 — CH 2 - into the same plane. The lowest energy form, above, is CH 2 =CH 2 ,
ethene, with a n bond.
reflected in benzene's inertness to bromine addition and in its low heat of
combustion. The stabilization energy, often called derealization or resonance
energy, amounts to more than 30 kcal/mole (the difference between the heat of
combustion calculated on the basis of "normal" localized bonds and the
experimental heat of combustion).
How should we draw the bonding arrangement in benzene ? The following
notations are often used to indicate the symmetry of the molecule and the
delocalized character of some of the bonds :
It is difficult, however, to determine the number of % electrons by inspection
of such structures. Indeed, with some derivatives of benzene one can be
seriously misled by such notation (Section 20TB). A more revealing repre-
sentation of the structure of benzene is achieved by drawing the following
resonance structures:
Figure 6-4 Electron-pairing arrangements for benzene.
sec 6.2 conjugate addition 133
The double-headed arrow bears no relation to the symbol <± used to describe
chemical equilibrium. Rather, it indicates the two directions in which % bonds
can be formed by showing the separate structures we would write if derealiza-
tion were not considered and each pair of electrons was restricted to binding
only two nuclei (see Figure 6-4). Because the orbital arrangement permits
extensive derealization, we know that benzene is not the structure represented
by either formula but is actually a hybrid which embodies some of the character
expected of each and is more stable than either of the structures would be, if
each were to correspond to a real substance. For convenience, we draw just
one of these structures
to indicate benzene whenever there is no need to represent the bonding more
precisely.
There are many advantages to writing the various possible structures of a
delocalized molecule or ion. You can account for all the electrons in a system
at a glance and determine whether a given structure is that of a cation, an
anion, or a neutral molecule, and whether or not it is a radical. Furthermore,
the description is in terms of structures usually with ordinary valences of
carbon, oxygen, nitrogen, and so on. This way of describing molecules with
delocalized electrons, the resonance method, as it is usually called, has been
extraordinarily successful at predicting molecular geometries and behavior,
notwithstanding its apparent artificiality in using more than one structural
formula to describe a single compound and its occasional failures (Section
6-7).
6-2 conjugate addition
How does conjugate addition (1,4 addition; seep. 127) occur? 1,3-Butadiene,
a typical conjugated diene, exists in two important planar conformations, the
H H
\ /
C-C
// \
H 2 C CH 2
H CH
\ //
c-c
// \
H 2 C H
s- cis
s-trans
s-cis and the s-trans forms. Although rotation occurs rather rapidly about the
central bond, these are the two favored conformations because they permit
some degree of 7r-bond formation across what is normally written as a single
carbon-carbon bond.
We have seen that addition of bromine to double bonds can occur by way
of ionic intermediates (Section 4-4B). If we examine the bonding in the ion
produced by the attack of bromine on a conjugated diene, we can see how
chap 6 bonding in conjugated unsaturated systems 134
conjugate addition takes place with 1,3-butadiene, and that an intermediate
bromonium cation can be produced as follows:
► CH 2 = CH-CH-CH 2 Br + Br e
(In the earlier discussion, the possibility was raised that bridged bromonium
ions are intermediates in addition of bromine to alkenes. Such species may
also be formed here but do not vitiate the following argument.) Neither the
double-bond n electrons nor the cationic charge will be localized as shown
above. There will be n bonding between three carbons as indicated by the
resonance structures [1]. In accord with these structures, the positive charge
will be divided between the 2 and the 4 carbon. The charge will not be expected
to be significant on the third carbon from the bromine because any resonance
structure which puts the charge there will preclude ft-bond formation between
adjacent carbons. We sometimes speak of the spreading of the charge as
" derealization of the charge." It should, however, be clear from what we
have said that derealization of charge is a consequence of the derealization
of the electrons by 7r-bond formation between two different pairs of carbons ;
CH 2 =CH-CH-CH 2 Br < ► CH,-CH=CH-CH 2 Br
4 3 2 1 [|]
that is, derealization of positive charge and electron derealization are two
sides of the same coin.
Addition of bromide ion can occur at either of the two partially positively
charged carbon atoms in ion [l], 4 which accounts for the mixture of products
that is, in fact, formed. If initial addition of the Br® ion were to take place at
BrCH,-CH=CH-CH,Br
[CH 2 =CH-CH-CH 2 Br < ► CH 2 -CH=CH-CH 2 Br] + Br e
CH 2 = CH— CHBr — CH 2 Br
the 2 position of the diene, the charge would be localized at the 1 position and
the n electrons between atoms 3 and 4 so that no resonance stabilization
of the carbonium ion intermediate (CH 2 =CH— CHBr— CH 2 ®) would be
expected. On the other hand, the carbonium ion formed by addition of a Br®
ion to a terminal position of the diene has a substantial degree of resonance
stabilization.
If we could prepare separate ions corresponding to the two localized
structures that we have written to represent the hybrid, we would expect them
to have similar bond energies and similar arrangements of the atoms in space.
4 Note the singular form ion, not ions. In the resonance hybrid shown above we have used
two structures, each with localized bonding, to represent as nearly as we can the true struc-
ture of the single ion which is the reaction intermediate.
sec 6.3 stabilization of conjugated dienes 135
The reason for the similar geometries is that the cationic carbons of carbonium
ions tend to have their three bonds planar (Section 2-5C), as do alkenic carbon
atoms. Thus, delocalized 7r-bond formation in the hybrid ion [2] can be seen
to occur in ar completely natural way for the two structures. This is an espe-
cially important point to which we will return later. (The ion formed from the
■y-cwjEonformation of the diene is shown here.)
H
t
H
CH,Br
<
CKUBr
H
CH,Br
[2]
A cationic carbon atom, such as those depicted in each of the structures
making up the hybrid, possesses only a sextet of electrons (the six in the three
a bonds) and hence has an empty p orbital available to interact with the
adjacent pair of n electrons. These electrons thus spread over three atoms
instead of two, providing a delocalized u bond. The consequence is a more
stable system than would be represented by either resonance structure alone.
In the next section we shall see that the electron system of 1,3-butadiene, al-
though conjugated, is delocalized to a much smaller extent.
6-3 stabilization of conjugated dienes
The special character of conjugated dienes is manifest in their tendency to
undergo 1,4 addition and in their lower heats of combustion. Conjugate
addition has been accounted for on the basis of resonance stabilization (and
preferential formation) of an intermediate cation which gives rise to the
1,4 product. This reaction does not tell us whether or not resonance stabiliza-
tion is important in the diene. However, its low heat of combustion can be
attributed to resonance in the diene because here we are dealing with the over-
all stabilization of the diene itself, not of a product to which it may be convert-
ed. The stabilization of 1,3-butadiene, as determined by the difference between
calculated and experimental heats of combustion, is only about 6 kcal as
compared to more than 30 kcal for benzene. Why should this be so ? Cannot %
electrons of the two adjacent double bonds bind together all of the carbons
in the same way as in benzene? Such an orbital arrangement for the s-cis
conformation is shown in [3].
■•y-^tfr
chap 6 bonding in conjugated unsaturated systems 136
The reason for the resonance stabilization being small is readily apparent
when you compare the possible ways of getting n bonding in butadiene with
those for benzene. First, we write the basic structure with four singly occupied
p orbitals:
H H
\ . ./
c-c
./ \.
H — C C — H
\ /
H H
Now we consider % bonds to be made by pairing the electrons two different
H H H H
.c-
(■■•'■c^i? — H h — Al-
ways [4]. The first way corresponds to normal double bonds between the
1,2 and 3,4 carbons while the second corresponds to a double bond between
the 2,3 carbons but essentially no binding between the 1,4 carbons, which are
impossibly far apart to participate in effective binding, even though the 1,4
electrons are paired. Any attempt to increase the stabilization of s-cis-
butadiene by bringing the 1,4 atoms closer together, thus increasing the 1,4
interaction, would run afoul of increasing angle strain and increasing inter-
action between the inside 1,4 hydrogens. The 2,3 % bonding does seem to
increase the stability of butadiene to some extent. That it does not do more
can be ascribed to the fact that 2,3 % bonding is associated with 1,4 "non-
bonding."
The above discussion can be rephrased in terms of resonance structures as
follows :
H H H H
V / \ /
c— c c=c
// \ / \
H— C C— H < ► H-C C— H
\ / \ /
H H H H
The " 1 ,4 7t bonding " is represented in the second structure by a dotted line
(sometimes called a formal bond) to emphasize that the structure does not
represent cyclobutene, which is a stable isomer of butadiene and differs from
H H H
HC = CH >=/=c /
H 2 C-CH 2 \/_ j/
/ \
cyclobutene H H
sec 6.4 stabilization of cations and anions 137
butadiene in chemical behavior and in the arrangement of its atoms in space.
Unlike s-cis or ,y-/ra«.s-butadiene, cyclobutene does not have all its carbons
and hydrogens in a single plane. Also unlike butadiene, the bonding between
the two methylene (CH 2 ) carbons results from a cr-type C— C bond of
essentially normal length.
We can summarize the above discussion by noting that the resonance
method considers the binding which might be produced by pairing electrons
in different ways for a given geometrical arrangement of the atoms. The
predictive power of the resonance method is derived from the fact that for a
given arrangement of the atoms, important contributions will be made to the
hybrid structure only by those ways of pairing the electrons which correspond
to reasonably feasible ball-and-stick models.
The % bonds in the hybrid structure for butadiene can be represented by a
combination of heavy and light dotted lines.
weak n binding
- strong 7t binding
No 1,4 bonding is shown because of the large distance between the atoms.
It is important to recognize that each of the resonance structures for
1,3-butadiene (or benzene) has the same number of pairs of electrons. No
structures need be considered which have a different number of paired
electrons, such as CH 2 — CH=CH— CH 2 , where now the 1,4 electrons are
taken to be unpaired (both right handed or both left handed ; see Section 6-1).
Such structures correspond to a diradical form of butadiene which is known
to exist but has entirely different properties and is grossly less stable. It
has a n bond only between two adjacent carbons.
— ► CH,-CH-CH=CH, < ► CH, = CH-CH-CH 2
no 7t bonds because the
electrons are unpaired
6-4 stabilization of cations and anions
You might well ask why we do not consider ionic-type resonance structures
for 1,3-butadiene similar to those written for the conjugate addition inter-
mediate in the previous section.
CH, = CH-CH-CH 2 < ► CH, = CH— CH-CH,
etc.
chap 6 bonding in conjugated unsaturated systems 138
The answer is that in the ionic structures we have substituted ionic bonding
© f.
for n bonding; and just as CH 2 — CH 2 is far from the best structure for CH 2 =
CH 2 , so the above ionic structures are less important than the wholly 71-bonded
CH 2 =CH— CH=CH 2 structure for butadiene. To put it in another way,
carbon is intermediate in electronegativity and has little tendency to attract
electrons and become negative or give up electrons and become positive.
Thus, the ionic (or dipolar) structures are less favorable than the shared
©
electron structures. The cationic intermediate CH 2 =CH— CH— CH 2 Br
e
<h>CH 2 — CH=CH 2 — CH 2 Br is different in that there is no way that the
charge can disappear by changing the 71-bond arrangements. This cation is
in fact just one representative of the important class of allyl cations, the
parent of which is
CH 2 -CH=CH 2 < > CH 2 = CH-CH 2 = [CH 2 ^CH=-CH 2 ]®
The allyl cation is a relatively stable carbonium ion as carbonium ions go
and we shall meet it again as a reaction intermediate in Chapter 8.
The bicarbonate ion is an example of an anion stabilized by resonance.
Sodium bicarbonate, NaHCO s , is a salt whose ionic components are sodium
ion (Na ffi ) and bicarbonate ion (HC0 3 e ). If you draw a structural formula
for bicarbonate ion so that the carbon and oxygen atoms have octets of elec-
trons, you obtain
O
H-O-Cf Na 9
V
Each of the two oxygens on the right-hand side of this formula for the bi-
carbonate ion is bonded only to the carbon atom. Their electronic environ-
ments appear to be different : one oxygen bears a full negative charge and the
other no charge at all. There is, however, another way to arrange the electrons
which reverses the roles of the two oxygens and gives additional n bonding.
The actual structure is therefore that of a resonance hybrid with half of the
negative charge on each of the oxygens.
O O e p+ e
HOC < ► HOC or HOC
O e O O*
Since neither of these formulations is convenient to write, we usually indicate
bicarbonate ion with the ambiguous formula H— O — C0 2 e or, more simply,
HC0 3 e . Note, however, that only two of the three oxygen atoms in the ion
can bear the negative charge. The third is bonded to hydrogen and cannot
participate in n bonding to carbon without giving an unfavorable dipolar type
of structure :
9 /
HO = C
sec 6.5 vinyl halides and ethers 139
The anion of a carboxylic acid as acetic acid CH / | is usually written
K )
\ OH/
CH3CO2 to avoid the necessity of indicating the dispersal of the negative
charge to both oxygen atoms, and the same is done with many inorganic ions
such as N0 3 e , S0 4 2e , and N 3 e . It is important, however, to be aware that in
any detailed consideration of the properties of these anions, more than one
resonance structure must be taken into account.
6-5 vinyl halides and ethers
An anion that falls in the same classification as those mentioned in the pre-
vious section is the allyl anion, which can be seen to be structurally analogous
to the allyl cation and involves two energetically equivalent resonance struc-
tures :
e e
CH 2 = CH-CH 2 < » CH 2 -CH = CH 2 == [CH 2 -CH-CH 2 ] e
allyl anion
For many stable compounds, such as unsaturated ethers and halides, we may
write electronic structures formally similar to those of the allyl anion except
that there is no net charge :
CH 2 = CH— O— R CH 2 = CH — F:
The problem is whether we should draw resonance structures corresponding
to 71 bonding between carbon and the attached oxygen or halogen :
f. ®
CH 2 = CH — O— R < ► CH 2 — CH=0— R
CH 2 = CH-F: <-
This is a matter of controversy. Such structures lead to an increase of %
bonding but with an associated separation of charge wherein electron-attract-
ing nuclei such as oxygen and fluorine become positive, and weakly electron-
attracting atoms become negative. There may be some degree of stabilization
connected with resonance of this type but it is small at best. However, what is
more certain is that attack of a positive reagent such as Br® on CH 2 =CH—
OR will occur at the 2 carbon, not at the 1 carbon, because more v. bonding is
possible in the resulting cationic intermediate :
Br-CH 2 — CH — 6— R < > Br — CH 2 — CH=0— R
CH 2 = CH — OR + Br® n bonding
CH 2 -CH — 6— R
I
Br
chap 6 bonding in conjugated unsaturated systems 140
Generally speaking, we should expect that importance of resonance of the
type CH 2 =CH— Z<-+CH 2 — CH=Z will increase as Z becomes less electro-
negative and will, therefore, be much more important in CH 2 =CH—
N(CH 3 ) 2 than in CH 2 =CH— F:, and all evidence indicates that this is indeed
the case.
6-6 rules Jor the resonance method
The principles outlined in the previous sections can be reduced to a fairly
precise prescription which is generally applicable for evaluating the properties
of conjugated systems :
1. All resonance structures must have identical locations of the atoms in
space and the same number of paired electrons. Ionic structures should be
considered if atoms are present that carry unshared pairs of electrons or
unfilled octets, or are substantially different in electronegativity.
2. Relative energies of the various structures are estimated by considering:
(a) bond energies; (b) the degree of distortion from the geometrically favorable
atomic positions (if the geometry of the actual molecule is known, then the
spatial arrangements of all the resonance structures can be taken to conform
with it) ; (c) the maximum number of valence electrons which each atom can
accommodate in its outer shell — two for hydrogen and eight for first-row
elements (this is particularly important).
3. Electron stabilization is expected to be greatest when structures of
lowest energy are equivalent.
4. If there is only a single contributing structure of low energy, then, to a
first approximation, the resonance hybrid may be expected to have properties
like those predicted for the particular structure.
6-7 molecular orbital method of H'uckel
We have seen that the resonance method is a very useful way of describing
the behavior of delocalized systems (in which an electron may interact with
three or more nuclei) in terms of localized structures (in which each electron
interacts with only two nuclei). The success of the resonance method in
describing the chemistry of benzene, conjugated dienes, and so on has been
indicated in earlier sections of this chapter. For benzene and the intermediate
cation formed in the bromine-butadiene reaction, it was shown that bonding
involving delocalized electrons could be conceived as arising from electron
pairing in three or more p orbitals on adjacent atoms overlapping in the n
manner. These representations were designed to try to overcome the principal
esthetic defect of the resonance method in that it describes conjugated mole-
cules or ions in terms of two or more structures.
It should be recognized that the resonance method is by no means a unique
approach to rationalizing the properties of conjugated molecules, and we now
sec 6.7 molecular orbital method of Hiickel 141
will consider briefly an alternative procedure, molecular orbital (MO)
theory. Although this theory has many advantages it is less useful in purely
qualitative structure analysis. MO theory was introduced in 1933 by the
German chemist E. Hiickel as a method to calculate mathematically the
relative energies of unsaturated molecules. In the original Hiickel treatment,
the a bonds were ignored and only the energies of the n electrons considered.
To do this, ethene and 1,3-butadiene were considered to be made up of
CH 2 — CH 2 and CH 2 — CH— CH— CH 2 frameworks with singly occupied
parallel p orbitals on each carbon atom,
'(f 2 c
Combination of these p atomic orbitals with due regard for sign (positive or
negative) gives rise to two molecular orbitals for ethene and four molecular
orbitals for the diene. (The number of molecular orbitals is always equal to
the number of atomic orbitals in the combinations.) The energy of an electron
in each of the molecular orbitals can be calculated, giving us a set of energy
levels for the n electrons.
The Hiickel MO method can be applied to a wide variety of unsaturated
systems. 5 It permits rather simple (though lengthy) calculations to be made
of the re-electron energies of localized and delocalized conjugated systems
such as benzene. Furthermore, it allows us to see which energy levels con-
tribute to bonding and which do not. If an electron in a molecular orbital has
an energy higher than that of an electron in an isolated p orbital, the orbital
will, in fact, be antibonding. We will see later that antibonding orbitals are
especially important in formulating the excited states resulting from ab-
sorption of visible or ultraviolet light (Section 26T).
Huckel-type calculations of molecular orbital energies for the % electrons in
ethene and in 1,3-butadiene reveal that they are arranged as in Figure 6-5.
The "nonbonding level" is the energy of an electron in an isolated p orbital.
In both these molecules, the low-lying levels are fully occupied with electrons
having paired spins, as indicated by the symbol \\.
A disadvantage of using Hiickel MO theory in an introductory study of
organic chemistry is that both mathematical and artistic skills are required.
Furthermore, while drawings in which p orbitals are shown combining toge-
ther to form n molecular orbitals are useful in many cases (we have already
used them for illustration earlier in the chapter), in others they can lead to
false conclusions. The following example illustrates this point.
Consider the 71-electron systems of 1,3-butadiene and trimethylenemethyl,
(CH 2 ) 3 C, each of which is C 4 H 6 (Figure 6-6). If we arrange each system to
give four molecular orbitals into which the four unsaturation electrons are
placed, and draw dotted lines between the adjacent p-orbitals, we can see no
5 J. D. Roberts, Notes on Molecular Orbital Calculations, Benjamin, New York, 1961.
chap 6 bonding in conjugated unsaturated systems 142
o
u
antibonding orbitals
o
increasing
ene
rgy
©
bonding orbitals
©
©
ethane
1,3-butadiene
Figure 6-5 Schematic representation of MO energies of ethene and 1,3-
butadiene.
reason for any pronounced difference between the two possible arrangements.
But inspection of possible electron-pairing schemes (as in the resonance
method) leads immediately to the conclusion that butadiene is likely to be
very different from trimethylene methyl. The latter will be a diradical if there
is to be an average of one electron per carbon as can be seen from the possible
forms that contribute to the resonance hybrid :
CH,
CH, = C
\
CH,
•CH,
,CH 2
CH,
■CH,
CH,
CH,
It should be emphasized that the detailed Hiickel MO calculation of energy
levels leads to the same conclusion. The four energy levels (there are four p
orbitals with which to construct molecular orbitals) are arranged as in Figure
6-7. The two electrons at the nonbonding energy level occupy different orbitals
and have unpaired spins because this arrangement minimizes the repulsion
between them (Hund's rule). Trimethylenemethyl has been characterized
Figure 6-6 Atomic orbital models of 1,3-butadiene and trimethylenemethyl.
CH,
CH 2 CH CH CH,
CH, C *•
\ CH,
sec 6.7 molecular orbital method of Huckel 143
increasing energy —
o
©
antibonding
- nonbonding
bonding
Figure 6-7 Molecular orbitals (energy levels) for trimethylenemethyl,
(CH 2 ) 3 C.
as a reaction intermediate and found to have the diradical character expected
on the basis of the above treatments.
The greatest triumph of the Huckel MO method is in its treatment of
conjugated cyclic systems. We can show diagrammatically the result of a
calculation of the energy levels in any regular, planar, cyclic conjugated system
made up of trigonally bonded carbon atoms such as benzene by simply
inscribing a polygon of the appropriate shape within a circle such that one
apex of the polygon is directly downward. The center of the circle then
represents the nonbonding level and the apexes represent molecular orbital
energy levels (Figure 6-8). Note that in the odd-numbered cases, such as the
three-, five-, and seven-membered rings, there is a trivalent carbon atom. If
you consider the p orbital on this atom, neglecting for the moment any
interaction with the neighboring n orbitals, you can see that it may contain
0, 1 , or 2 electrons. If the orbital is empty, the species will be a carbonium
ion; if it has one electron, the species will be a neutral radical; if it has two
electrons, the species will be a carbanion. Using the five-membered ring as an
example, the three entities are
Figure 6-8 Energy levels of n molecular orbitals in various conjugated cyclic
systems.
3-membered
ring
V
I
H
4-membered
ring
c— C
5-membered
ring
6-membered
ring
,c-c s
c-
//
-c
w
^r
c^-%
7-membered
ring
H
H
-H
c=c x
H-c C
\\ //
r C
i
H
chap 6 bonding in conjugated unsaturated systems 144
H H
H H
carbonium ion
H
rati ical
'The resonance method, discussed earlier, suggests that all of these species
should be substantially stabilized. Thus, we can write five equivalent structures
for the carbonium ion.
H H
H H
H
H
hA^h ~ hAAh
I
H H
H
H H
H^C7-H < ' H-O-H
There are five similarly equivalent resonance structures for the radical and
for the carbanion and, from what has been said so far, there would seem to be
little to choose between them as far as stability is concerned. In the same way,
we should expect the radical and the ions of the seven-membered ring system
to be highly stabilized. Again, we show the resonance forms of the carbonium
ion only, although analogous structures can be written for the radical and
carbanion :
H
/ \
H H
y
H
H
H
»w»
H A H ■
H
tf-
H A/ H
H~
/ \
H H
H H
/ \
H H
summary 145
____2_2_Q__o_
© © © © © ©
© © ©
nonbonding level
C„H 6 C 7 H 7
Figure 6-9 Filling of the orbitals for five-, six-, and seven-membered rings.
It turns out that there is a considerable variation in the stabilities of these
six systems — the cation, radical, and anion forms of the five- and seven-
membered rings. The anion of the five-membered ring and the cation of the
seven-membered ring are by far the most stable and we shall encounter these
later (Section 20-7). It is sufficient to point out at this stage that the Huckel
MO calculations correctly predicted (in advance) that these in fact were
the more stable entities. The energy levels shown in Figure 6-8 might appear
to have been obtained empirically but are, in fact, the consequence of the
calculations. It will be seen that there are three bonding orbitals (orbitals of
lower energy than a nonbonding arrangement in which the p orbitals do not
interact at all) for the five-, six-, and seven-membered rings. The six-membered
ring with six % electrons filling the three bonding orbitals is the very stable
compound benzene. The five- and seven-membered rings can also accommo-
date six % electrons by filling their bonding orbitals. The resulting electronic
configurations give the anion of the five-membered ring and the cation of the
seven-membered ring. Because the bonding in these species is maximized,
they are expected to be particularly stable. The filling of the orbitals is shown
in Figure 6-9.
A similar analysis of rings of other sizes shows that the number of electrons
which suffice to fill the bonding molecular orbitals is given by the formula
An + 2, where n is an integer or zero. Thus, we expect planar cyclic systems
containing 2, 6, 10, 14, . . . % electrons to be particularly stable. This has be-
come known as the "Huckel An + 2 rule" and can be stated thus: "Regular
monocyclic planar systems made up of trigonal carbon atoms will be most
stable when they contain {An + 2) n electrons."
summary
Compounds with conjugated double bonds are normally more stable than
their unconjugated isomers, and often undergo conjugate addition reactions.
Benzene, C 6 H 6 , is an extreme example of stabilization by conjugation. The
heat of combustion of benzene is more than 30 kcal per mole less than that
calculated for a compound containing three double bonds, and it does not
add bromine. The unusual degree of binding in a benzene molecule can be
expressed in terms of two structural formulas, each with localized bonding
chap 6 bonding in conjugated unsaturated systems 146
(electrons interacting with only two nuclei). These correspond to the two
important ways of pairing the electrons in the p orbitals perpendicular to the
ring. Benzene is well represented as a resonance hybrid of these structures with
delocalized bonding (electrons interacting with more than two nuclei).
1,4-Addition to 1 ,3-butadiene occurs by way of a carbonium ion intermedi-
ate which can be formulated as a resonance hybrid having the positive charge
divided between two different carbon atoms :
CH 2 = CH-CH=CH 2 + Br 2 > Br e + [CH 2 — CH=CH — CH 2 -Br
< ► CH 2 =CH — CH— CH 2 — Br]
The n bonding in this ion can be pictured as involving pairing of the electrons
in three overlapping p orbitals — two from the double bond and one from the
adjacent atom:
CH,Br
1,3-Butadiene, CH 2 =CH— CH=CH 2 , is only slightly stabilized by
resonance because there is but one favorable low-energy structure. Other
possible structures are less important because they correspond to much less
efficient binding. In writing resonance structures, all those to be considered for
a specific molecule must have the same number of unpaired electrons. Thus, for
1,3-butadiene, we do not include structures such as • CH 2 — CH=CH— CH 2 • ,
where this structure is meant to be the one with the 1,4 electrons unpaired.
Such a structure represents a different chemical entity from butadiene.
Cations such as the allyl carbonium ion, the BrCH 2 derivative of which is
the intermediate in the 1,4 addition of bromine to butadiene, and anions such
o o e
CH 2 =CH-CH 2 < > CH 2 -CH=CH 2 H — O-C < > H-O— C
O e O
allyl carbonium ion bicarbonate ion
as the bicarbonate ion, are stabilized by resonance which, in these cases,
leads to dispersal of charge.
Vinyl halides and others have minor contributions to their hybrid structures
from ionic electron-pairing schemes :
exercises 147
e 9
CH 2 = CH— X < ► CH 2 -CH = X
CH 2 = CH-0-R < ► CH 2 -CH=0-R
The most important of the rules for application of the resonance method
(Section 6-6) are that all of the resonance structures must have the same
locations of the atoms and the same number of paired electrons.
Although the resonance method generally gives very satisfactory qualitative
predictions of the behavior of delocalized systems, the Hiickel molecular
orbital (MO) procedure for calculating molecular orbital energy levels has
found many important applications, particularly in cyclic systems.
In the MO procedure, the p orbitals on each carbon atom in an unsaturated
system are combined to give molecular orbitals for the n electrons. The molec-
ular orbitals with energies less than the nonbonding level (which corresponds
to isolated noninteracting p orbitals) are bonding orbitals, and those of higher
energy are antibonding orbitals. In regular, planar, cyclic systems made up
of trigonal carbon atoms, the number of n electrons which exactly fill the
bonding orbitals is given by the expression An + 2 (where n is an integer or
zero).
exercises
6-1 Discuss the meaning and merit of a statement such as "compound X res-
onates between forms A and B " in terms of a specific example.
6-2 Evaluate the relative stabilities of actual molecules of butadiene in each of
the three forms shown below from the standpoint of steric effects and the
resonance method. Give your reasoning.
6-3 Evaluate the importance of resonance of the following types (it may be helpful
to use ball-and-stick models) :
H H
H-_/V_H H^As_.H
* — • iT < — - xX —
b.
H
HC^ CH
I II
^
H H
HCT CH
HC^ CH
% CH
HC
III
HC
H H
HC
HC
#
CH
CH
etc.
chap 6 bonding in conjugated unsaturated systems 148
c CH 2 = CH-O e < > CH 2 -CH = C)
HC=CH HC CH
A / \ \
d. HC X® < ► HC ^C
^CH 2 7 ^CH 2 7
H 2 C CH 2 H 2 C "CH 2
CH ®CH
e. // \ © < > / \
H 2 C CH 2
H 2 C.
I
I 2 C n 2 v
/ |>-CH 2 < ► | CH=CH 2
H 2 C H 2 C
6-4 Do you expect conjugate addition of bromine to occur with
a. 1,3-cyclohexadiene c. 1,5-hexadiene
b. l-penten-3-yne d. vinylbenzene
6-5 Write the structure of the intermediate cation formed by the addition of
Br® to each of the compounds in Exercise 6-4.
6-6 Write resonance structures for the ions N 3 e and N0 2 e .
6-7 Consider the importance of the following resonance for cyclobutene (give your
reasoning in detail) :
H 2 C CH
> II III
H 2 C-CH H 2 C CH
Explain what differences in geometry one would expect for a hybrid of such
structures as compared with conventional cyclobutene geometry.
6-8 Write three structures for C 4 H 2 with tetravalent carbon and univalent
hydrogen. Decide on the most favorable geometrical configuration and
evaluate the resonance energy for this configuration.
6-9 Propene reacts with chlorine at 300° to yield allyl chloride (3-chloropropene).
a. Write two chain mechanisms for this chlorination, one involving attack
of a chlorine atom on the hydrogen of the — CH 3 group and the other
an attack of a chlorine atom at the double bond.
b. Consider the relative feasibilities of the two different mechanisms on
the basis either of bond energies or the stabilities of intermediate
species.
6-10 Use the heats of combustion of cyclooctatetraene (1095 kcal/mole) and of
cyclooctane (1269 kcal/mole), and any required bond energies (Table 2-1),
to calculate the heat of hydrogenation of cyclooctatetraene to cyclooctane in
the vapor phase at 25°.
6-11 Write the five Kekule-type resonance structures of phenanthrene, and show
how these can account for the fact that phenanthrene, unlike benzene, adds
bromine, but only across the 9,10 positions.
exercises 149
^ phenanthrene
6-12 The compound trichlorocyclopropenium tetrachloroaluminate, C 3 C1 3 ®,
AlCl 4 e exists as a stable salt at room temperature. Use the Huckel rule to
account for the unusual stability of this carbonium salt.
6-13 An ionic derivative of cyclooctatetraene, C 8 H 8 , has recently been prepared.
On the basis of the Huckel rule, which of the following formulas do you
expect it to have: C 8 H 8 ®, C s H 8 e , or C 8 H 8 2e ?
6-14 In 1825, a yellow crystalline compound, named croconic acid, was prepared
by the action of hot potassium hydroxide on carbon powder followed by
acidification. This compound, whose formula was later shown to be H 2 C 5 5
and to contain a five-membered carbon ring, is quite a strong acid and gives
the ion C 5 5 2e on ionization. Suggest a structure for this acid and the ion
and show how resonance stabilization of the ion accounts for the acid being
strong.
0; IB tl ft: "' ^ V -tW^ ' : ^&ipl^ij^ i
isolation an<J identification
•"■'■'? of organic compounds
sec 7.1 isolation and purification 1S3
A characteristic of chemistry that is not always shared with the other sciences
is a concern for purity (in the sense of molecular homogeneity) in the materials
under study. Much of the time of some organic chemists working in the lab-
oratory is devoted to isolating compounds in pure form, and the culmination
of a synthetic scheme is always the purification and confirmation of the iden-
tity of the product. In this chapter we consider, first, some modern means of
separating and purifying organic compounds and, second, instrumental
methods which can be used to elucidate structures. There have been enormous
advances in these regards over the past 20 years through introduction of new
techniques. Structural or purification problems which once may have required
years for solution, if they could be solved at all, can often now be solved in
hours or days, but very frequently with complex and costly apparatus.
7-1 isolation and purification
Fractional distillation and crystallization are the time-honored methods for
separating and purifying liquids and solids, respectively. Obviously, knowledge
of the relationship between structure and boiling point will be helpful in
conducting a distillation. Crystallization of solid compounds calls more for
an understanding of solubilities as a function of temperature in the common
solvents such as water, ethyl alcohol, benzene, and tetrachloromethane
(carbon tetrachloride). The most suitable solvent for crystallizing or recrystal-
lizing an impure compound is usually one in which the compound is slightly
soluble at room temperature, for if the solubility is too high the recovery will
be poor because too much of the compound will be left in solution. On the
other hand, if the solubility at room temperature is too low, you can expect
difficulty in trying to dissolve the compound completely in the solvent at
higher temperatures.
Liquid-liquid extraction techniques, using a separatory funnel, can some-
times provide clean separations, particularly with compounds possessing
a basic group such as amino ( — NH 2 ) or an acidic group such as carboxyl
The most widely used technique for separating and purifying compounds
on a small scale is chromatography. Chromatography can be defined as the
separation of components of a mixture by differences in the way they be-
come distributed (partitioned) between two phases. By this definition, chroma-
tography includes the simple techniques described above, such as extraction in
a separatory funnel (a liquid-liquid two-phase system), fractional distillation
(a gas-liquid two-phase system), and crystallization (a solid-liquid two-phase
system). These techniques require fairly large amounts of material and they
may give unsatisfactory separations, which may be attributed to the small
degree of separation possible in any given one-stage, or even several-stage,
partitioning process. We now have available what might be called super-
separation chromatographic methods, which involve multistage partitioning of
chap 7 isolation and identification of organic compounds 154
very small amounts of sample, a few milligrams or less, wherein extraordin-
ary separations can often be achieved. To this end, the most frequently
employed combinations of phases are gas-liquid and liquid-solid.
Liquid-solid chromatography was originally developed for the separation
of colored substances, hence the name chromatography (which stems from
the Greek word chroma meaning color). In a typical examination, a colored
substance suspected of containing colored impurities is dissolved in a suitable
solvent and the solution allowed to pass through a column packed with some
solid adsorbent (e.g., alumina), as shown in Figure 7-1. The " chromatogram "
is then "developed" by adding a suitable solvent that washes the adsorbate
down through the column. Hopefully, and this is the crux of the entire
separation, the components are adsorbed unequally by the solid phase, and
distinct bands or zones of color appear. The bands at the top of the column
contain the most strongly adsorbed components; the bands at the bottom
contain the least strongly held components. The zones may be separated me-
chanically, or solvent can be added to wash, or elute, the zones separately from
the column for further analysis. If all attempts to resolve a given substance
chromatographically are unsuccessful, evidence (albeit negative) is thus pro-
vided for the presence of a single pure chemical entity. Although the various
zones can be observed by eye only if the substances are colored, a variety of
other techniques can be used to detect the bands on the chromatogram and
the method is by no means limited to colored substances.
Figure 7-1 A simple chromatographic column for liquid-solid chromatog-
raphy.
im
. solvent
lUSlilMil I s °lid adsorbent with
> bands of separated
sample components
eluate
sec 7.1 isolation and purification 1SS
pressure -regulated exit vapors i— detector , — packed column
carrier gas supply i / /
in/ 1
( \ l_ll_J ))
■ i oven
\— sample injection port
Figure 7-2 Schematic diagram of a vapor-phase chromatography apparatus.
The detector is arranged to measure the difference in some property of the
carrier gas alone versus the carrier gas plus effluent sample at the exit. Differ-
ences in thermal conductivity are particularly easy to measure and give high
detection sensitivities.
More recently, gas-liquid phase chromatography, glpc (also called vapor-
phase chromatography, vpc, or gas chromatography, gc) has added a new
dimension for the analysis of volatile substances. In the usual form of vpc,
a few microliters of a liquid to be analyzed are injected into a vaporizer
and carried with a stream of gas (most frequently helium) into a long heated
column, packed with some porous solid (such as crushed firebrick) impreg-
nated with a nonvolatile liquid or oil. Gas-liquid partitioning occurs, and small
differences between partitioning of the components can be magnified by the
large number of repetitive partitions possible in a long column. Detection is
usually achieved by measuring changes in thermal conductivity of the effluent
gases. A schematic diagram of the apparatus and a typical separation are
shown in Figures 7-2 and 7-3. While observation of a single peak in the vpc
Figure 7-3 A vapor-phase chromatogram of a mixture of isomeric butyl
alcohols, C 4 Hc,OH.
;
i
CH,
|
CH,CH,
\
CHj— G— «
til '
^^^^^ft
dete
ctor
CH,
[.
signal
J
^^^^^M
M
time
chap 7 isolation and identification of organic compounds 1 56
analysis of a material is, of course, only negative evidence for purity, the
method is extraordinarily useful for detection of minute amounts of impuri-
ties when these are separated from the main peak. The sensitivity of vpc
makes it the method of choice for analysis of volatile pesticide residues in
food products, automobile exhausts, smokestack effluents, trace components
of alcoholic beverages, flavors, perfumes, and so on.
Vapor-phase chromatography can be used effectively to purify materials
as well as to detect impurities. To do this, the sample size and the size of the
apparatus are generally increased, and the vapor of the pure component is
condensed as it emerges from the column.
Two other chromatographic methods, paper chromatography and thin-
layer chromatography (tic), are described in Chapter 17.
7-2 identification of organic compounds
Distillation, crystallization, or chromatography often tells us something of the
state of purity of a compound. A single chromatographic peak, a sharp boiling
point, or a sharp melting point of a crystallized solid is an indication that a
pure compound has been obtained. (Although melting and boiling points
will be listed in this and other books as single temperatures, in practice one
encounters a melting or boiling range of usually one degree or so.)
If the substance being purified is believed to be a previously known com-
pound, it is usually a simple matter to compare its physical properties (melting
point, boiling point, refractive index) or spectroscopic properties with those
reported in the chemical literature for the known compound. However, if
the structure of the compound is not known, you must adopt a different
approach.
The traditional method, and indeed the only one really available until the
second half of this century, is based on the molecular formula obtained from
the molecular weight and the elemental analysis, in combination with
qualitative chemical tests and degradative reactions which ultimately would
lead to known compounds. The process was to a large extent highly intuitive
but the conclusions drawn about structure usually proved correct. Although
instrumental methods of analysis have revolutionized structure determina-
tion in the past 25 years, it would be a mistake to conclude that a wide knowl-
edge of the transformations of organic compounds that are possible is no
longer necessary for the successful elucidation of molecular structures.
The first step in the process of determining a structure is a quantitative
analysis for the elements it contains.
A. ELEMENTAL ANALYSIS
The vast majority of organic substances are compounds of carbon with hydro-
gen, oxygen, nitrogen, or the halogens. All of these elements can be determined
directly by routine procedures. Carbon and hydrogen in combustible com-
pounds can be measured by combustion of a weighed sample in a stream of
sec 7.2 identification of organic compounds 157
sample in
platinum boal>
furnace
m^-
-CuO pellets
B excess
MgC10 4
soda-lime
2^
Figure 7-4 Schematic representation of a combustion train for determination
of carbon and hydrogen in combustible substances.
oxygen (Figure 7-4) followed by gravimetric determination of the resulting
water and carbon dioxide through absorption in anhydrous magnesium
perchlorate and soda lime, respectively. Routine carbon-hydrogen analyses
by combustion procedures utilize 3- to 5-mg samples and attain an accuracy
of 0.1 to 0.2%. Complete elemental analyses permit computation of empirical
formulas which are equal to, or are submultiples of, the molecular formulas.
A knowledge of the molecular weight is needed to determine which of the
multiples of the empirical formula corresponds to the molecular formula. For
example, the empirical formula of the important sugar, glucose, is CH 2 0,
but the molecular weight defines the molecular formula as (CH 2 0) 6 or
C 6 H 12 6 .
Molecular weights of gaseous organic compounds may be determined
directly by vapor-density experiments. Liquid substances of moderate vola-
tility may be vaporized, and their vapor densities determined. However,
molecular weights of volatile compounds are not often determined in present-
day organic research, because the molecular weight of a given substance
may usually be estimated from the boiling point, to perhaps 25 % accuracy,
by knowledge of the boiling points of related compounds. Molecular weights
of high-boiling liquids and slightly volatile solids are generally determined
by measuring freezing-point depressions or boiling-point elevations of solu-
tions in suitable solvents. Solutions in a substance such as camphor, which
gives a very large freezing-point depression (37.7° per mole of solute dissolved
in 1000 g of camphor), are particularly suitable for small-scale operations and
can, with ordinary equipment, permit reasonably accurate molecular-weight
measurements by determination of melting points.
There are many other more or less specialized techniques available, the
choice depending on the problem at hand and accessibility of equipment.
Thus, molecular weights of even slightly volatile substances may often be
obtained by mass spectrometry, which is the method of choice, particularly
since resolution is routinely achieved for masses as high as 600. The molec-
ular weights of very high-molecular-weight compounds such as proteins and
polymeric materials are frequently determined by end-group analysis,
measurement of osmotic pressure, viscosity, light scattering, and sedimenta-
tion. Some of these methods will be discussed in more detail in later chapters.
chap 7 isolation and identification of organic compounds 158
B. MASS SPECTROMETRY
The application of mass spectrometry to organic molecules involves bom-
bardment of a vaporized sample with a beam of medium-energy electrons in
high vacuum and analysis of the charged particles and fragments produced.
The elements of a mass spectrometer are shown in Figure 7-5. The positive
ions produced by electron bombardment are accelerated by the negatively
charged accelerating plates and are swept down to the curve of the analyzer
tube where they are sorted as to their mass-to-charge (m/e) ratio by the
analyzing magnet. With good resolution, only the ions of a single mass num-
ber will pass through the slit and impinge on the collector, even when the
mass numbers are in the neighborhood of several hundred or a thousand.
The populations of the whole range of mass numbers of interest can be deter-
mined by plotting the rate of ion collection as a function of the magnetic
field of the analyzing magnet.
The intense peak that is highest in mass number is of considerable impor-
tance ; this corresponds to the positive ion formed from the parent molecule
by the loss of just one electron and provides a highly accurate method for
measuring molecular weights.
In recent years, considerable success has been achieved in the correlation
of the relative abundances of various-sized fragmentation products with the
molecular structures of the parent molecules. This use of mass spectrometry
is discussed in more detail in Chapter 29.
Figure 7-5 Schematic diagram of a mass spectrometer.
• electron gun
accelerating plates (negative potential)
sample
ion collector-
sec 7.3 absorption of electromagnetic radiation 159
Super-resolution mass spectrometers are now available which permit
distinction between ions of such molecules as C 43 H 50 N 4 O 6 (mol. wt. 718.373)
and C 42 H 46 N 4 7 (mol. wt. 718.337). Such mass spectrometers can be used
for elemental analysis.
spectroscopy
Virtually all parts of the spectrum of electromagnetic radiation, from X rays
to radio waves, have found some practical application for the study of
organic molecules. Visible light is an extremely narrow band in the spectrum
characterized by the wavelength range 4000 to 7500 A; it occupies a position
between ultraviolet and infrared radiation but, in terms of the way it interacts
with organic molecules, it can be considered part of the ultraviolet region.
The absorption of electromagnetic radiation by molecules results in an
increase in their energy. Very short-wavelength radiation, such as X rays or
gamma rays, supplies so much energy that it causes covalent bonds to rupture
and thus leads to drastic chemical changes. Long-wavelength radiation such
as radio waves, on the other hand, may be able to induce only more rapid
rotation of a molecule.
Most of the spectroscopic methods in use by organic chemists involve
measuring the amount or wavelengths, or both, of radiant energy absorbed
by molecules, and the principles and practice of some of these methods will
be discussed. First, however, mention should be made of X-ray diffraction,
because this technique has proved to be of special value in elucidating
structures of organic molecules.
When a beam of X rays strikes a crystal, the result is a diffraction pattern
which is characteristic of the locations of the atoms in the crystal. The diffrac-
tion pattern can usually be analyzed with the aid of a high-speed digital com-
puter and the molecular structure may often be determined in a matter of
days. (Diffraction does not itself involve absorption of radiation, although
the crystal usually suffers some damage because of bond rupture caused by
absorption of X rays.) Not all compounds can be examined in this way,
because the compound must be crystalline and, preferably, contain at least
one " heavy " atom, such as chlorine or bromine.
7-3 absorption of electromagnetic radiation
The energy, e, of a photon is related to its frequency of vibration, v, by Planck's
constant, h:
e = hx
In general, you can say that a molecule will absorb incident radiation only if
there is some higher energy state (with energy E 2 ) to which the molecule can
be raised from its normal or ground state (with energy E t ) by the energy of
chap 7 isolation and identification of organic compounds 160
the photon. Because not all photons have the proper energy to take a molecule
from the normal to a higher energy state, we say that the energy levels are
quantized, and that a specific quantum of energy separates the two states :
Energy AE l2
! E,
The difference in energy AE 12 (=E 2 — £"i) is related to the frequency (v sec -1 )
or wavelength (A cm) of the absorbed radiation by the equations
he
AE 12 = hv = —
where h is Planck's constant and c is the velocity of light. We generally will
be interested in the energy change in kilocalories (1 kcal = 10 3 cal) which
would result from one mole of substance absorbing light and we can rewrite
the above equation in the form
286,000
A£l2 = ^AT kcal
where X is now in angstrom (A) units (1 A = 10~ 8 cm). As defined here,
AE 12 corresponds to 1 einstein of radiation.
The total energy (E) of a molecule (apart from nuclear and kinetic energy)
can be expressed as the sum of three energy terms :
-^ -'-'electronic ' -^vibrational ~t~ -^rotational
The electronic energy levels correspond to the energies of the various molecular
orbitals (Section 6-7) and are rather widely spaced. Ultraviolet light (and
sometimes visible light) has sufficient energy to cause transitions between
the electronic energy levels. Vibrational energies are also quantized but the
vibrational energy levels are more closely spaced and the differences between
them correspond to photons of infrared radiation. Finally, the energies of
rotational states for a molecule or its parts are very closely spaced and ro-
tational transitions result from absorption of microwaves (radar) or radio
waves.
A molecule that has absorbed a photon of ultraviolet light, for example,
normally remains in the resulting excited electronic state for only a very
brief period. The energy may be reemitted or it may be shuffled into vibration-
al and rotational energy with a resulting increase in thermal energy of the
system. In some cases, the excited molecules undergo chemical reactions and
do not return to the original ground state. The fading of dyes is an example
of this kind of behavior. The types of transition associated with absorption
of radiation from the various regions of the electromagnetic spectrum are
shown in Figure 7-6.
Although microwave spectroscopy can provide valuable information about
bond lengths and bond angles in simple molecules, it has not so far been of
sec 7.4 infrared spectroscopy 161
wavelength, X 1CT 10 1CT 6 10~ 2 10 2 10 6
i 1 m — n 1 r
X-RAYS
7-RAYS
]
cm
UV M IR RADAR RADIO
type of transition (BOND RUPTURE) VIBRATIONAL
ELECTRONIC ROTATIONAL
Figure 7-6 The types of transitions in molecules brought about by absorption
of radiation from various regions of the electromagnetic spectrum.
general use for identification or structure proof of organic compounds. In-
frared and ultraviolet spectroscopy are much more widely and routinely
useful. The radio wave absorptions when used in conjunction with an applied
magnetic field are also of great importance, as we shall see in a later section
of this chapter.
1-4 infrared spectroscopy
Possibly the single most widely used tool for investigating organic structures
and for organic chemical analyses is the infrared spectrometer. Spectra for
infrared radiation over the wavelength region from 2 to 15 microns (1 micron
= n = 10~ 4 cm) are of most interest. Recording infrared spectrophotom-
eters with excellent resolution and reproducibility are commercially
available and are widely used in organic research. The operating parts of a
spectrometer are shown in Figure 7-7. The sample containers (cells) and opti-
cal parts of infrared spectrophotometers are made of rock salt (NaCl) or
similar materials, since glass is opaque to infrared radiation. Gaseous, liquid,
or solid samples can be used. Solids are often run as finely ground suspensions
(mulls) in various kinds of oils, or ground up with potassium bromide and
compressed by a hydraulic press into wafers. Considerable differences are
often observed between the spectra of a solid and its solutions.
In Figures 7-8, 7-9, and 7-10 are shown the infrared spectra of an alkane,
an alkene, and an alkyne. In accord with current practice, the infrared spectra
given here are linear in wave numbers (v cm -1 ) that are related to radiation
frequencies (v sec -1 ) so that v = v/c, where c is the velocity of light in cm/sec.
A supplementary nonlinear wavelength scale in microns is shown, and to
convert wave numbers v to A in microns we use the relation 1 = 10 4 /v.
Considerable confusion exists as to the units used to express wavelength or
frequency for various kinds of spectra. For electronic spectra, A is most
commonly expressed in angstrom units (10~ 8 cm) or millimicrons (10~ 7 cm).
For infrared spectra, absorbed radiation may be defined by its wavelength X
in microns (10 ~ 4 cm) or by its frequency v in units of wave numbers (10 4 /A
cm" 1 ).
The infrared absorption bands between 3600 and 1250 cm -1 can be identi-
fied in most cases with the changes in the vibration of a particular bond.
chap 7 isolation and identification of organic compounds 162
K
iwi.ink-r
i infrared detector
(thermocouple)
cell for solution
of sample
f!L
infrared source
(electrically
heated filament)
beam
chopper
-cell for solvent
Figure 7-7 Schematic representation of a "double-beam" recording infrared
spectrophotometer. The beam chopper permits radiation passing alternately
through sample cell and solvent cell to reach the thermocouple. This
procedure permits the difference in absorption by solute and solvent to be
measured as an alternating electric current from the thermocouple. The
alternating-current output is particularly desirable for electronic amplifica-
tion. The usual commercial instruments operate on a "null" principle with
the recorder pen linked mechanically to a "comb" (not shown here), which
is placed across the solvent-cell beam and moved by a servomechanism to
reduce or increase the solvent-cell-beam intensity. The servomechanism is
actuated by the amplified thermocouple output to make the solvent-beam in-
tensity equal to the solution-beam intensity — that is, to reduce the thermo-
couple output to zero or the null point. The spectrum can be scanned
through the various wavelengths by rotation of the prism in synchronization
with the motion of the recorder drum. The use of a diffraction grating in
place of the prism is becoming increasingly common.
Below 1250 cm" 1 is the so-called fingerprint region, which is associated chiefly
with complex vibrational changes in the molecule as a whole.
The band at highest frequency in all three hydrocarbons is that which
corresponds to changes in the C — H stretching energies. The higher the fre-
quency of the radiation, the higher its energy, and this means that to raise the
vibrational level of a C — H bond requires more energy than that for any
other bond to carbon. We can regard the C— H bond to be like a spring be-
tween the two atoms, with the light hydrogen atom vibrating with respect to
the much heavier carbon atom. Because vibrational energies are strictly
quantized, only certain values of the stretching frequency are allowed.
sec 7.4 infrared spectroscopy 163
Figure 7-8 The infrared spectrum of octane, CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 3 .
Figure 7-9 The infrared spectrum of 1-butene, CH 3 CH 2 CH=CH 2 .
wavelength, IX
3 4 5 5
6 7 8 9 10 12 14
1 ^JU-^. 11 1 1 III II
: II \ i i / %' v\ / I
^^^■HpiWpl lit
■ ,\ (C.ll,) ■. A
.2
oveiB
'1 '
E
s^asw|Ji|lipsM^i^»li- |i%
^ip|%feiillifr€tiiiilllilpps^
•■■V f-II
/ suvu-h
l--l'll 2 M
H W beml ' | !
(CIU. r 1 1 , i
^lllP^P^lll sNftPft^illiP 111!
i i
/ i i i 1
1,1.1,1,1.1.
3600 3200* 2800 2400 2000 2000
J 8O0 1 600 1 400 1 200 1 000 800
frequency, cm -
chap 7 isolation and identification of organic compounds 164
wavelength, jU
3 4
S
5 6 7 8
\ W Y*YV J \/ /
1 " ' " [1. ^
~"N. ' * If It . 11
9
M
10
n V \
l|
12
14
II |
{II i
I 1 ,
fjf
L
G
.2
I
G
1
(.' = ( ';
stretch !|
V
1
1
J.
^
^^^^^^^^^^^^^^^« ^^^^^^^^^^^
h"-^
f . C-H
I^S/1
1
(BC-H S,R ' tdl
» it i
i
i ,
[_
3600 3200 2800 2400
2000
2000 1800 1600 1400 1200
1000
800
frequency, cm"
Figure 7-10 The infrared spectrum of phenylacetylene, C 6 H 5 C=CH, in carbon
tetrachloride solution. The sharp band near 1500 cm -1 is characteristic of a
vibration of the benzene ring.
At room temperature, more than 95 % of the C— H bonds of a sample of
hydrocarbon are vibrating in their lowest (or zero-point) energy level. That is,
the thermal energy of the system is sufficient to raise only a small fraction of
the hydrogens to a higher vibrational level than that which would be found at
absolute zero. The absorption bands near 3000 cm"" 1 , then, correspond to a
change from the lowest vibrational state to the first excited vibrational state
of the C— H bond. The slightly different locations of these bands for different
kinds of C— H bond (compare Figures 7-8, 7-9, and 7-10) are of considerable
use in structure identification.
The bending frequencies for C— H bonds occur at lower wave numbers
showing that a smaller quantum of energy is required for excitation of bending
vibrations :
V
Eq— H > ^C-H •
The absorption of energy by changing the stretching energies of carbon-
carbon bonds occurs at lower frequencies than those of carbon-hydrogen
bonds and are widely separated, depending on whether the atoms are joined
by a single, double, or triple bond. The carbon-carbon single-bond stretching
bands occur in the complex "fingerprint" region and are difficult to identify.
Carbon-carbon double and triple bonds, however, absorb at higher frequen-
cies and can be readily identified in an infrared spectrum. The analogy of
bonds to springs can be usefully applied here. The stronger the forces holding
two atoms together, the greater will be the energy required to raise the system
sec 7.5 ultraviolet and visible spectroscopy (electronic spectroscopy) 16S
to the next vibrational level. The total binding energy of a double bond is less
than that of a triple bond, and this is shown in the infrared spectra by the fact
that the C=C stretching band in 1-butene appears at 1700 cm -1 and the C=C
band in phenylacetylene at 2100 cm -1 .
The most common positions of the easily identified stretching frequencies
in hydrocarbons are
C— H C=C C=C
-3000 cm- 1 -1650 cm- 1 -2200 cm" 1
Table 7-1 lists the characteristic infrared frequencies for many kinds of com-
pounds that we shall subsequently meet.
, The spectrum of 1-butene in Figure 7-9 shows an absorption that can
trap the unwary. Thus the band at 1830 cm -1 falls in the region where
stretching vibrations are usually observed. However, this band actually arises
from an overtone (harmonic) of the =CH 2 out-of-plane bending at 915 cm -1 .
Such overtone absorptions come at just twice the frequency of the funda-
mental frequency and whenever an absorption like this is observed, which
does not seem to fit with the normal fundamental vibrations, the possibility
of its being an overtone should be checked.
7-5 ultraviolet and visible spectroscopy
(electronic spectroscopy)
The photons of visible light (4000-7500 A) are an order of magnitude
higher in energy than infrared photons and the photons of ultraviolet light
are of still higher energy. The type of spectroscopy that embraces these more
energetic kinds of radiation is called electronic spectroscopy because the
excitation that results from absorption of such photons normally involves
the raising of one electron to a higher energy orbital.
We expect that electronic excitation will occur with lower-energy photons
in molecules whose ground-state electrons are only loosely bound to their
nuclei. Such compounds may, in fact, absorb visible light and be colored.
Molecules in which all the electrons are rather tightly bound — alkanes, for
instance — can only be excited electronically by the high-energy ultraviolet
radiation. The valence electrons in alkanes are in C— C and C— H a bonds,
and raising one of these electrons to a higher energy, called a a -+ a* transi-
tion, requires radiation of wavelength 1300 A or less. Such radiation is not
easily accessible for routine analysis because neither air nor quartz (the best
substance available for constructing cells and prisms) is transparent to such
radiation. The practical lower limit for routine ultraviolet absorption spectros-
copy is about 1900 A, and for this reason alkanes are transparent throughout
the whole of the readily accessible ultraviolet and visible region.
The experimental arrangement for determining such spectra is usually
quite similar to that of infrared spectrometers shown in Figure 7-1. The
principal differences lie in the use of a tungsten lamp (3200 to 8000 A) or
hydrogen arc (1800 to 4000 A) as the light source; quartz prism and sample
cells ; and a photoelectric cell, rather than a thermocouple, as the radiation
chap 7 isolation and identification of organic compounds 166
Table 7-1 Some characteristic infrared absorption frequencies
bond
type of compound
frequency,
cm -1
intensity
1
— C-H
1
alkanes
2850-2960
strong
1
— C-D
1
alkanes
-2200
strong
1
=C-H
alkenes and arenes
3010-3100
medium
=C-H
alkyras
3300
strong,
sharp
1 1
— c-c-
1 I
alkanes
600-1500"
weak
w
r \
alkenes
1620-1680
variable
-c=c-
alkynes
2100-2260
variable
— C=N
nitriles
2200-2300
variable
1
— c— o-
i
1 1
alcohols — C— OH, ethers — C— O-
1 i
1
-c— ,
1
J
i i
i
p
— c
\
o-
1000-1300
strong
-C —
I .
' In general, C — C single-bond stretching frequencies are not useful for identification.
detector. In these spectrometers, the prism is placed ahead of the sample.
In simple alkenes and alkynes the n electrons are, of course, less tightly
bonded than are a electrons, but the excitation energy is still too great for
significant absorption to occur in the easily accessible region of the ultraviolet
spectrum. Conjugated dienes, however, absorb strongly at wavelengths above
2000 A. This kind of absorption results from raising an electron from a normal
rc-bonding state to a 71-antibonding state and is called a % -* n* transition.
The more extended the conjugated system becomes, the smaller is the energy
difference between the normal and excited states. Thus, the diphenylpolyenes,
C 6 H 5 — (CH=CH)„— C 6 H 5 , absorb light at progressively longer wave-
lengths as n increases ; this is apparent from the colors of these compounds,
which range from colorless (» = 1) through yellow and orange (n = 2-7) to
red (n = 8) as the wavelength increases from the ultraviolet well into the visible
region of the electromagnetic spectrum. Lycopene, the red pigment in
tomatoes, is a polyene with 11 conjugated double bonds (Section 29-3).
sec 7.S ultraviolet and visible spectroscopy 167
Table 7.1 Some characteristic infrared absorption frequencies (continued)
bond
type of compound
frequency,
cm -1
intensity
\
c=o
/
O
II
aldehydes — C— H
1720-1740
strong
x c=o
/
O
1 II 1
ketones — C— C— C—
1 1
1705-1725
strong
x c=o
/
O O
/ //
acids — C esters — C
O-H O-
-c— '
1
1700-1750
strong
-O-H
1 1
alcohols — C— O— H, phenols =C-
-O-H
3590-3650
variable,
sharp
-O-H
hydrogen-bonded, alcohols and
phenols — O — H-O
3200-3400
strong,
broad
-O-H
hydrogen-bonded, acids — O — H-
/
O
\
2500-3000
variable,
broad
-NH 2
1
amines — C — NH 2
3300-3500
medium
1
(double peak)
1
H
1 1 1
3300-3500
medium
— N— H
amines — C— N — C—
1 1
(single peak)
Electronic absorption bands are usually much broader than infrared bands
for two principal reasons. First, at ordinary temperatures, molecules in
either the ground or excited electronic states exist in a number of vibrational
or rotational states, and the transitions which occur between the electronic
states are brought about by quanta of slightly different energy. The result is
to give an absorption band made up of a large number of lines which are too
closely spaced to be separately distinguishable. The second reason arises from
the fact that electronic spectra are usually taken of solutions, and the range
of solute-solvent interactions gives a spread of energies to both the ground
and excited electronic states.
We have seen that conjugated molecules, such as 1,3-butadiene, have normal
or ground states (Section 6-3) which are slightly more stable than would other-
wise be expected. Because conjugated molecules also have electronic absorp-
tion bands toward longer wavelengths than nonconjugated molecules
(smaller energy differences between ground and excited states), the energies
chap 7 isolation and identification of organic compounds 168
of the excited states of such molecules must have a higher degree of resonance
stabilization than the ground state.
Can you depict excited electronic states by conventional structural for-
mulas? Only in a rather unsatisfactory way, unfortunately. You can formulate
the excited state of 1,3-butadiene associated with absorption of ultraviolet
© e
radiation by a dipolar structure such as CH 2 — CH=CH— CH 2 , which we
have already considered in connection with the ground state of the molecule
(Section 6-4). Thus, you can consider the ground state as being close to [1]
CH 2 =CH-CH=CH 2 < ► CH 2 -CH=CH-CH 2
[1] [2]
[3]
with minor contributions from [2], [3], and other energetically unfavorable
structures. On the other hand, the excited state can be taken to correspond to
[2] with major contributions from other polar forms such as [3], which can
contribute in a major way because they should have comparable energies and
a minor contribution from [I]. The important points are that the excited state
has less total bonding than the ground state and, because it is expected to be
more of a hybrid structure than the ground state, it will have a different geom-
etry, particularly a shorter 2,3 carbon-carbon bond. In general, we will ex-
pect that the greater the degree of conjugation and the more favorable the
polar forms appear, the more the excited state will be stabilized and the
longer will be the wavelength of the maximum absorption, A max .
7-6 nuclear magnetic resonance spectroscopy
Nuclear magnetic resonance (nmr) spectroscopy is very useful for identifi-
cation and analysis of organic compounds. The principles of this form of
spectroscopy are quite simple. The nuclei of some kinds of atoms act like
tiny magnets and become lined up when placed in a magnetic field. In nmr
spectroscopy, we measure the energy required to change the alignment of
magnetic nuclei in a magnetic field.
A schematic diagram of a very simple form of an nmr instrument is shown
in Figure 7-11. When a substance such as ethyl alcohol, CH 3 — CH 2 — OH,
(the hydrogens of which have nuclei that are magnetic) is placed in the center
of the coil between the magnet pole faces, and the magnetic field is increased
gradually, energy is absorbed by the sample at certain field strengths and the
current flow in the coil is increased. The result is a spectrum such as the one
shown in Figure 7-12. This spectrum is detailed enough to serve as a most
useful fingerprint for ethyl alcohol but is also simple enough for the origin of
each line to be accounted for, as we shall see.
sec 7.6 nuclear magnetic resonance spectroscopy 169
A
f
1
W///
m
radiofrequency
oscillator
i
i
o\
W/
w
AA
sensitive
ammeter
magns
ngth/7
-tic field of stre
Figure 7-11 Essential features of a simple nmr spectrometer.
For what kinds of substances can we expect nuclear magnetic resonance
absorption to occur? Magnetic properties are always found with nuclei of
odd-numbered masses, *H, 13 C, 15 N, 17 0, 19 F, 31 P, and so on, and nuclei of
even mass but odd number, 2 H, 10 B, 14 N, and so on. Nuclei such as 12 C,
16 0, 32 S, and so on, with even mass and atomic numbers have no magnetic
properties and do not give nuclear magnetic resonance signals. For various
reasons, routine use of nmr spectra in organic chemistry is confined to 1 H,
Figure 7-12 Nuclear magnetic resonance spectrum of ethyl alcohol (contain-
ing a trace of hydrochloric acid). Chemical shifts are relative to tetramethyl-
silane, (CH 3 ) 4 Si or TMS = 0-Q0 ppm. The stepped line is an integral of the
areas under each of the resonance lines.
chap 7 isolation and identification of organic compounds 170
19 F, and 31 P. We shall be concerned here principally with nmr spectra of
hydrogen ('H), often called pmr spectroscopy (proton magnetic resonance
spectroscopy).
Nuclear magnetic resonance spectra may be so simple as to have only a
single absorption peak but can also be much more complex than the spectrum
of Figure 7-12. On the one hand, complexity is helpful because it makes the
spectra more individualistic and better suited as fingerprints for characteri-
zation of organic molecules. However, complexity can hinder the use of nmr
spectra for qualitative analysis and structure proofs. Fortunately, with the aid
of isotopic substitution and a technique known as " double resonance," it
is now possible to analyze completely spectra that show literally hundreds of
lines. The ways of doing this are beyond the scope of this book. However, it is
important to recognize that no matter how complex an nmr spectrum appears
to be, it can be analyzed in terms of just three elements : chemical shifts,
spin-spin splittings, and kinetic (reaction-rate) processes.
The kind of nmr spectroscopy we shall discuss here is limited in its applica-
tions, because it can only be carried on with liquids or solutions. Fortunately,
the allowable range of solvents is large, from hydrocarbons to concentrated
sulfuric acid, and for most compounds it is possible to find a suitable solvent.
A. THE CHEMICAL SHIFT
Ethyl alcohol, CH 3 — CH 2 — OH, has three kinds of hydrogens: methyl
(CH 3 ), methylene (CH 2 ), and hydroxyl (OH). In a magnetic field, the nuclei
(protons) of each of these kinds of hydrogens have slightly different magnetic
environments as the result of the motions of their valence electrons and those
of neighboring atoms in response to the magnetic field. The magnetic field
strength at a particular nucleus is usually less than the strength of the applied
external magnetic field, because the motions of the electrons result in a shield-
ing effect (the so-called diamagnetic shielding effect). The important point is
that the effects arising from the motions of the electrons will be different for
each kind of hydrogen and, therefore, the resonance signal produced for each
kind of hydrogen will come at different field strengths. A plot of signal against
field strength (Figure 7T2) thus shows three principal groups of lines for ethyl
alcohol. The areas under the curves as measured by the stepped line of the
chart ("the integrals") correspond to the three varieties of hydrogen.
Differences in the field strength at which signals are obtained for nuclei of
the same kind, such as protons or 19 F, but located in different molecular
environments, are called chemical shifts.
Chemical shifts are always measured with reference to a standard. For
protons in organic molecules, the customary standard is tetramethylsilane,
(CH 3 ) 4 Si, which has the advantage of giving a strong, sharp nmr signal in a
region where only a very few other kinds of protons absorb. Chemical shifts
are usually expressed in hertz (Hz, or cycles per second) relative to tetramethyl-
silane (TMS). These may seem like odd units for magnetic field strength but
since resonance occurs at a radio frequency, the use of either frequency units
(hertz, cycles per second) or magnetic field units (gauss) is appropriate.
Most nmr spectrometers for routine use operate with radio frequency (rf)
sec 7.6 nuclear magnetic resonance spectroscopy 171
200
150
CAU
\ l! fi\
yy\~
3.0
CM.
100 Hz
■Mr
L_/
fVV:
2.0
ppm
Figure 7-13 Nuclear magnetic resonance spectrum of iodoethane, CH 3 CH 2 I,
at 60 MHz relative to TMS, 0.00 ppm.
oscillators set at 30, 60, 100, 220, or 300 megahertz (MHz). Since chemical
shifts turn out to be strictly proportional to the spectrometer frequency, we
expect lines 100 Hz apart at 60 MHz to be 167 Hz apart at 100 MHz. To
facilitate comparisons between chemical shifts measured at different frequen-
cies, shifts in hertz are often divided by the oscillator frequency and reported
as ppm (parts per million). Thus, if a proton signal comes at 100 Hz at 60
MHz downfield (toward higher frequencies), relative to tetramethylsilane, it
can be designated as being ( + 100 Hz/60 x 10 6 Hz) x 10 6 = +1.67 ppm
relative to tetramethylsilane. 1 At 100 MHz the line will then be 1.67 x 100 x
10 6 x 10~ 6 = 167 Hz downfield from tetramethylsilane. A table of typical
proton chemical shifts relative to TMS is given in Table 7-2. The values quoted
for each type of proton may, in practice, show variations of 5 to 20 Hz. This is
not unreasonable, because the chemical shift of a given proton is expected to
depend somewhat on the nature of the particular molecule involved and also
on the solvent, temperature, and concentration.
B. SPIN-SPIN SPLITTING
We have noted that organic molecules with protons on contiguous carbon
atoms, such as ethyl derivatives CH 3 CH 2 X (X # H), show principal resonance
signals for protons of different chemical shifts (see Figure 7T2). Each of these
signals is actually a group of lines that results from " spin-spin splitting."
Taking as a typical example the protons of iodoethane (Figure 7T3), the
1 In the past, a ppm scale was more commonly used than at present, based on so-called
"t values." The t scale has the TMS reference at +10, so that most proton signals fall in
the region of to + 10 t. A t value can be converted to ppm, with TMS at 0.0, by subtracting
it from 10.
chap 7 isolation and identification of organic compounds 172
Table 7*2 Typical proton chemical shift values
(dilute chloroform solutions)
type of proton"
chemical shift 6
type of proton"
chemical shift*
ppm
Hz'
ppm
Hz c
R-CH 3
0.9
54
0=C-CH 3
1
R
2.3
126
R-CH 2 -R
1.3
78
R-CH 2 -C1
3.7
220
R 3 CH
2.0
120
R-CH 2 -Br
3.5
210
R 2 C=CH 2
~5.0
300
R-CH 2 -I
3.2
190
R 2 C=CH
1
~5.3
320
i
R
RCH(-Cl) 2 d
5.8
350
HC— CH
/ ^
HC CH
\ /
HC=CH
R-O-CH3
3.8
220
7.3
440
(R-0-) 2 CH 2 d
5.3
320
R-C-H
II
O
9.7
580
R-C=C-H
2.5
150
R 2 C=C-CH 3
|
~1.8
108
R-O-H
~5 e
300"
R
HC-CH
t \
HC C-OH
HC=CH
HC-CH
// \
HC C-CH 3
\ /
HC=CH
~T
420*
2.3
140
R-C-OH
II
O
~ll e
660 e
" The proton undergoing resonance absorption is shown in heavy type. The group R denotes a
saturated hydrocarbon chain.
* Relative to tetramethylsilane as 0.00 ppm.
c Spectrometer frequency, 60 MHz (14,100 gauss magnetic field).
d Note how the shift produced by two chlorines or two RO — groups is greater than, but by
no means double, that produced by one chlorine or RO — group.
e Sensitive to solvent, concentration, and temperature.
chemical-shift difference between the methyl and methylene protons gives
the two main groups of lines. These are split ("first-order" effect) into equally
spaced sets of three and four lines by mutual magnetic interactions that are
called " spin-spin interactions." Several of these lines are further discernibly
split as the result of "second-order" spin-spin splitting.
How do we know what we are dealing with when there are so many lines
present ? First, the chemical shift is easily recognizable as such by the fact that
the spacing between the main groups is directly proportional to the oscillator
sec 7.6 nuclear magnetic resonance spectroscopy 173
frequency v. If we double v, the spacing doubles. In contrast, the line spacings
for the first-order splitting are independent of v, and for this reason the
first-order splitting is easily recognized, also. Finally, the second-order
splitting turns out to depend on v for rather complicated reasons ; it tends to
disappear as v is increased. (See Figure 7-14.)
It can be shown by isotopic substitution with heavy hydrogen (deuterium,
D) that the three-four pattern of lines observed for spin-spin splitting with
compounds having ethyl groups (XCH 2 CH 3 , see Figure 7-13) arises from
magnetic interaction of each group of protons with the other. Deuterons have
much smaller magnetic moments than protons, and substitution of one deu-
teron on the methyl of an ethyl group (XCH 2 CH 2 D) reduces the resonance of
the methylene group to a triplet (actually somewhat broadened because of the
Figure 7-14 Comparison of the pmr spectra of 2-methyl-2-butanol at rf oscil-
lator frequencies of 60, 100, and 220 MHz. The line at 16S Hz in the 60-MHz
spectrum is due to the OH protons, and this is off-scale to the left in the 220-
MHz spectrum. The large single line in the center of the spectra arises from
the resonances of the six methyl hydrogens.
20 MHz
Jl_J
100 MHz
~J
JV\J%
60 MHz
__jlJ^
*_
400
200
Hz
chap 7 isolation and identification of organic compounds 174
small magnetic effect of the deuteron) ; substitution of two deuterons (XCH 2
CHD 2 ) produces a doublet resonance with the splitting caused by the re-
maining proton. Three deuterons (XCH 2 CD 3 ) give a one-line XCH 2 spectrum
(see Figure 7-15). Thus, for this particular simple case, the multiplicity of
lines can be seen to be (n + 1) where n is the number of protons on contiguous
carbons. That the methylene resonance of an ethyl group is not complicated
beyond the observed quartet by interaction of the methylene protons with
each other is, for our purposes here, best condensed into a simple catechism.
Protons with the same chemical shift do not normally split one another's
absorption lines. Thus, only single resonance lines are observed for H 2 ,
CH 4 , C 2 H 6 , (CH 3 ) 4 Si, and so on, and we say that the protons in such com-
pounds are equivalent.
In general, the magnitude of the spin-spin splitting effect of one proton on
another proton (or group of equivalent protons) depends on the number and
kind of intervening chemical bonds, and on the spatial relations between the
groups. For nonequivalent protons on adjacent saturated carbon atoms, the
so-called three-bond splitting is normally about 5-8 Hz.
H-C-C-H
5-8
Hz
For protons separated by more than three bonds, the coupling is usually too
small for observation unless a double or triple bond intervenes.
The ratios of the line intensities in spin-spin splitting patterns usually follow
simple rules when the chemical shifts are large with respect to the splittings.
A symmetrical doublet is produced by a single proton, a 1 : 2 : 1 triplet by
two protons in a group, a 1:3:3:1 quartet by three protons in a group,
1:4:6:4:1 quintet by four protons, and so on. The intensities follow the
binomial coefficients.
The spectrum of (CH 3 0) 2 CHCH 3 (Figure 7-16) provides an excellent
example of how nmr shows the presence of contiguous protons. The symmet-
rical doublet and 1:3:3:1 quartet are typical of interaction between a single
proton and an adjacent group of three. The methyl protons of the CH 3
groups are too far from the others to give demonstrable spin-spin splitting.
C. USE OF NUCLEAR MAGNETIC RESONANCE SPECTROSCOPY
IN QUALITATIVE ANALYSIS
The solution of a typical qualitative analysis problem by nmr can be illustrated
with the aidof the spectrum shown in Figure 7-17. Here, we see three principal
groups of lines at 9.8, 2.4, and 1.0 ppm for a compound of formula C 3 H g O.
The relative heights of the principal steps of the integrated spectrum show these
groups to arise from one, two, and three hydrogens, respectively. The single
sec 7.6 nuclear magnetic resonance spectroscopy 175
X— CH 2 — CH, 1 M I
X— CH 2 — CH 2 D ■
X— CH,— CHD,
X— CH, — CD,
CH 2
i_J_L
i i i
CH 3
Figure 7-15 Schematic spectra of deuteriated ethyl derivatives. The right-hand
set of lines is always a triplet when observable because of the two protons of
the X — CH 2 — group.
Figure 7-16 Nuclear magnetic resonance spectrum of dimethyl acetal,
(CH 3 0) 2 CHCH 3 , at 60 MHz relative to TMS, 0.00 ppm.
250
CM
4.0
200
150
100
50
iGCIl.
CH
f
3.0
2.0
1.0
Hz
TMS
*
ppm
chap 7 isolation and identification of organic compounds 176
~i 1 r
586
150
100
50
Hz
CH,— C-
TMS
J IL
9.77
2.0
1.0
ppm
Figure 7-17 Nuclear magnetic resonance spectrum and integral for compound
of formula C 3 H 6 Q at 60 MHz relative to TMS.
hydrogen at 9.8 ppm is seen from Table 7-2 to have a chemical shift compatible
with either RCHO or RC0 2 H. The latter possibility is, of course, excluded
because the compound has only one oxygen. The only structure that can be
written for C 3 H 6 possessing an RCHO group is CH 3 CH 2 CHO (propion-
aldehyde), and this structure is completely compatible with the other features
of the spectrum. Thus, the CH 3 — resonance comes at 1.0 ppm (0.9 ppm
predicted for CH 3 R) and the — CH 2 — resonance at 2.4 ppm (2.3 ppm pre-
dicted for CH 3 COR).
The spin-spin splitting pattern agrees with the assigned structure, there
being the same 7 Hz spacings as in the characteristic three-four pattern of the
CH 3 CH 2 ~ group shown by iodoethane (Figure 7-13). The doubling up
(somewhat obscured by second-order splitting) of each of the — CH 2 —
resonance lines is due to a small (~2 Hz) coupling between the — CHO and
— CH 2 — protons. This interaction also causes the —CHO resonance to be
split into a 1:2:1 triplet, as expected from the n + 1 rule. Three-bond
couplings between —CHO and adjacent — CH 2 — protons appear to be
generally much smaller than — CH 2 — CH 3 couplings.
D. NUCLEAR MAGNETIC RESONANCE AND RATE PROCESSES
An nmr spectrometer is unusual among instruments used to study molecules
through absorption of electromagnetic radiation in that it acts like a camera
with a relatively slow shutter speed. In fact, its "shutter speed" is quite
commonly about the same as a conventional camera having exposure times
sec 7.6 nuclear magnetic resonance spectroscopy 177
of a 100th of a second or so. When we take an nmr spectrum of a molecule
that is undergoing any rapid motion or reaction, the result is something like
taking a picture of a turning spoked wheel with a box camera. If the wheel
turns only once a minute, a photograph at a 100th of a second will show the
individual spokes without much blurring. On the other hand, if the wheel
turns 100 or more times a second, then a photograph does not show the in-
dividual spokes at all, but only the average outline of the rim and hub as a
border to the gray of the spokes. Pictures showing blurred individual spokes
result only when the wheel is turning neither very rapidly nor very slowly in
relation to the camera shutter speed.
A vivid example of the use of nmr in the study of motions within molecules
is given by the fluorine ( 19 F) resonance spectrum of l-chloro-2-fluoro-l,l,2,2-
tetrabromoethane. This molecule exists in three staggered rotational confor-
mations [4-6]. Of these, [5] and [6] will have identical nmr spectra because for
each the fluorine on one carbon is equivalently located with respect to the
halogens on the other carbon. However, the fluorine of [4] has a different
environment, being located between Br and Br, and should have a different
chemical shift from the fluorines of [5] and [6]. In principle, therefore, one
would expect to observe separate nmr resonances for the isomers ; in fact, at
122°, rotation around the C— C bond occurs so rapidly that only a single
fluorine resonance line is obtained (see Figure 7-18). The observed line position
is an average position, the location of which depends on the lengths of time
the molecules exist separately as [4], [5], and [6]. The rate of rotation about
the C— C bond becomes slower with decreasing temperature, and is so slow
at —40° that you can observe the separate resonances of [4] and the isomers
[5] and [6] as shown in Figure 7-18. Studies of the changes in line shape of the
nmr spectrum of l-chloro-2-fluoro-l,l,2,2-tetrabromoethane with temperature
provide a means of evaluating the amount of energy the molecules must have
to allow rotation to take place. Because the halogens are large and do not
move past each other easily, it takes fully 1 5 kcal/mole of thermal energy to
interconvert [4], [5], and [6]. At 25°, the rate of interconversion is about 100
times per second.
The loss of identity of particular protons by rapid rate processes makes the
nmr spectra of ethyl derivatives much simpler than they would otherwise be.
Inspection of a ball-and-stick model of an ethyl derivative in the staggered
conformation (see Figure 2-3) shows that one of the CH 3 hydrogens (marked
here with *) should not have exactly the same chemical shift as the other two.
chap 7 isolation and identification of organic compounds 178
AiftMfHt'''-
-,«^»JsW<n
^v* i %Vi*,v«>,',\Mv< , /** KV >> rfJ * u * ; >■^Ay^ ,w, '* ,, '
Figure 7-18 The 19 F spectrum at 56.4 MHz of l-chloro-2-fluoro-l,l,2,2-tetra-
bromoethane as a function of temperature.
However, rotation about the single bond in this case is sufficiently fast (10~ 6
sec) to average out the differences between the protons, and an average
resonance line position is observed.
H*
H, /H
The nmr spectra of cyclohexane and substituted cyclohexanes have been
extensively studied in connection with the interconversions of the boat and
chair forms (Section 3-4B). The proton nmr spectrum of cyclohexane itself
is a single line at room temperature because of rapid inversion (~10 6 times
per second) which averages to zero the chemical-shift differences of the equa-
torial and axial protons (Figure 3-6). At — 100°, the pmr spectrum of cyclo-
summary 179
hexane is so complex as to be ilninterpretable because all of the axial protons
have different chemical shifts from the equatorial protons and especially
complex spin-spin interactions occur. The device of substituting deuterium
for hydrogen (Section 7-6B) has particular utility here. Undecadeuteriocyclo-
hexane, C 6 D n H, gives a single proton nmr line at room temperature, while
at — 100° and 60 MHz two equally intense lines are observed separated by
29 Hz. These lines arise from the axial and equatorial protons in [7] and [8],
respectively. The rate of interconversion of [7] and [8] is on the average about
D
[7] [8]
once per 10 seconds at — 100° so that it can be seen why separate resonance
lines are obtained for the hydrogens in [7] and [8].
summary
Organic compounds can be isolated and purified by distillation, crystalliza-
tion, or chromatographic techniques. The latter include (a) multistage liquid-
liquid extractions ; (b) column chromatography, in which a mixture is separated
on a column of alumina or other solid absorbent by passage of appropriate
solvents through the column; (c) vapor-phase chromatography, in which a
gas stream carries the sample through a column packed with a nonvolatile
liquid on a porous solid ; and (d) paper and thin-layer chromatography (which
will be discussed later).
A compound can often be identified by comparison of its physical and spec-
troscopic properties with those of known compounds published in the litera-
ture. If this is unsuccessful, elemental analysis and molecular weight deter-
mination (by freezing-point depression, etc., or by mass spectrometry) can
be used to establish the molecular formula and, following this, the structure
may be deduced by studies of its chemical transformation products, X-ray
analysis, or spectroscopic analysis.
The three most important types of spectral analysis in routine use are
infrared, electronic (ultraviolet and visible), and nuclear magnetic resonance
spectroscopy. In each the absorption of a photon of electromagnetic radiation
produces an excited state.
Absorption of infrared radiation causes changes in the vibrational and
rotational energy levels of molecules. The stretching vibrations of C— H
bonds are characterized by absorptions near 3000 cm" l whereas their bending
vibrations (and both kinds of vibration for other bonds to carbon) occur at
lower frequencies. For carbon-carbon bonds, the greater the bond strength,
the higher the frequency of vibration and the greater the energy required for
excitation to a higher stretching vibrational state. Thus, C=C absorptions
chap 7 isolation and identification of organic compounds 180
occur near 2100 cm -1 , C=Cnear 1700 cm -1 , and C— Cat still lower frequen-
cies. The region below 1250 cm -1 is called the "fingerprint" region because
here occur complex vibrations characteristic of the molecule as a whole
rather than of specific bonds.
Absorption of ultraviolet or visible light causes electronic excitations. The
usual practical short- wavelength limit for the ultraviolet region is about 1900
A. Saturated compounds and those containing isolated C=C or C=C bonds
are usually transparent down to this wavelength, but conjugated polyenes
(and other unsaturated compounds) show strong absorption above 1900 A.
In general, the greater the degree of conjugation, the lower will be the energy
necessary for excitation and the longer will be the wavelength of absorption.
Colored substances are those which absorb visible light and hence require
intermediate energy photons for excitation.
Nuclear magnetic resonance spectroscopy (nmr) involves absorption of
very low-energy radio-frequency photons by atomic nuclei in an applied
magnetic field. The magnetic nuclei characteristic of atoms such as 1 H, 19 F,
and 31 P can be oriented so as to be lined up with or opposed to the applied
field and hence can differ very slightly in energy. This energy difference will
depend, among other things, on the atom's environment in the molecule. In
practice, either the frequency of the radiation or magnetic field can be kept
constant while the other is varied. The chemical shift for protons is given in
hertz (cycles per second) or ppm and is relative to some standard, usually
tetramethylsilane (TMS). In general, the presence of electronegative groups
or multiple bonds can cause large proton shifts from the standard.
When nonequivalent protons are attached to adjacent carbon atoms, there
is a spin-spin splitting of 5-8 Hz. A single proton will cause a split of its
neighbor's absorption into a symmetrical doublet, a pair of protons produces
a 1 : 2 : 1 triplet, and so on.
Rate processes, particularly interconversion of conformational isomers, can
be examined by nmr because the time interval for absorption of the radio-
frequency photons used in nmr is often comparable to the rates of confor-
mational interconversion.
exercises
7-1 Suppose you are asked to purify a compound by recrystallization from one
of these solvents: water, ethanol, benzene, or heptane. The solubilities of the
compound in grams per 100 ml of solvent at 20° and 80°, respectively, in the
four solvents are water (0.15, 0.27), ethanol (0.70, 8.2), benzene (16, 38),
heptane (36, 41). Which solvent would you choose for the purpose?
7-2 A liquid hydrocarbon, which does not decolorize bromine, has prominent
bands near 1500 cm -1 and 3000 cm -1 in its infrared spectrum. Its mass
spectrum shows a parent peak at 92 mass units. Suggest a likely structure
for this compound.
exercises 181
7-3 A compound that is gaseous at room temperature was found on analysis to
contain 88.9% carbon and 11.1 % hydrogen. Its infrared spectrum contained
a rather weak band near 2200 cm^ 1 . There are only two known compounds
that fit this description. What are their names ?
7-4 Explain how a mass spectrometer, capable of distinguishing between ions
with mje values differing by 1 part in 50,000, could be used to tell whether
an ion of mass 29 is C 2 H 5 ffl or CHO®.
7-5 Calculate the energy in kilocalories which corresponds to the absorption of 1
einstein of light of 5893 A (sodium D line) by sodium vapor. Explain how this
absorption of light by sodium vapor might have chemical utility.
7-6 From the discussion in Section 7-5 about the structures of the ground and
excited states of butadiene, see if you can rationalize why it is that the degree
of 7t bonding between the 2,3 carbons is relatively larger in the excited state
than in the ground state.
7-7 Sketch out the nmr spectrum and integral expected at 60 MHz withTMS
as standard for the following substances. Show the line positions in hertz,
neglecting spin-spin couplings smaller than 1 to 2 Hz and all second-order
effects. Note that chlorine, bromine, and iodine (but not fluorine) act as
nonmagnetic nuclei.
a. CH 3 C1 /. CHCl 2 CHBr 2
b. CH 3 CH 2 C1 g. CH 3 (CH 2 ) 6 CH 3
c. (CH 3 ) 2 CHC1 h. C1CH 2 CH 2 CH 2 I
d. CH 3 CD 2 CH 2 C1 i. (C1CH 2 ) 3 CH
e. (CH 3 ) 3 CC1
7-8 Figure 7-19 shows nmr spectra and integrals at 60 MHz for three simple
organic compounds. Write a structure for each substance that is in accord
with both its molecular formula and nmr spectrum. Explain how you
assign each of the lines in the nmr spectrum.
7-9 Figure 7-20 shows the nmr spectrum of a compound, C 5 H S 2 . Which of the
following structures fits the spectrum best? Explain.
CH 3 CH=CHC0 2 CH 3 CH 2 =CHCH 2 C0 2 CH 3
CH 2 =CHC0 2 CH 2 CH 3 HC0 2 CH 2 CH 2 CH =CH 2
CH 2 =C(CH 3 )C0 2 CH 3 1 1
CH 2 =C(OCH 3 )COCH 3 OCH 2 CH 2 CH 2 CH 2 C=0
(CH 2 ) 2 CHC0 2 CH 3
7-10 In reasonably concentrated solutions in water, acetic acid acts as a weak acid
(less than 1 % dissociated). Acetic acid gives two nmr resonance lines at 2
and 1 1 ppm, relative to TMS, while water gives a line at 5 ppm. Nonetheless,
mixtures of acetic acid and water are found to give just two lines. The position
of one of these lines depends on the ratio of acetic acid to water concentration,
while the other one does not. Explain and show how you would expect the
position of the concentration-dependent line to change over the range of
acetic acid concentrations from to 100%.
chap 7 isolation and identification of organic compounds 182
5.0
3.0
1.0 ppm
.1
200
C,H,.Bi
I 1
150 100
>
1
50 1
1
D 11/
f
_^-— '
1 . 1
>~-
„ -,-. ., , ^AAM-u.-, ,,J
l t
1 1
1
1
4.0
3.0
2.0
1.0
ppm
' T"
200
150
-I
100 llz
CH.RiI
-—
' 1 I
,-
—
__
■■ * ^ '
1 i f*
u
in
Sjlljjl
^^^^^^^^M
i ill 1
H:!;li,
II 11 i
A n 1 /
Hi V V
1 1
v— ™
i
, „ wtirn.
\^_j\
4.0 3.0 2.0 ppm
Figure 7-19 Nuclear magnetic resonance spectra and integrated spectra of
some simple organic compounds at 60 MHz relative to TMS, 0.00 ppm. See
Exercise 7-8.
exercises 183
ppm
Figure 7-20 Spectrum of a compound C 5 H 8 2 at 60 MHz relative to TMS as
standard. See Exercise 7-9.
7-11 Sketch out the principal features you would expect for the infrared and nmr
spectra of the following substances. (It will be helpful to review pages 20
and 116 as well as Sections 7-4 and 7-6.)
a. CH3C-CCH3
b. CH 3 C=CH (expect a long-range nmr coupling of 3 Hz)
c. CH 3 CH 2 C=CCH 2 CH 3
d. HC=C-CH=CH-C=CH (cis and trans)
e. (CH 2 ) 8 III
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chap 8 nucleophilic displacement and elimination reactions 187
There are relatively few basic types of organic reactions. Of these, substitution,
addition, and elimination are of the greatest importance. So far, we have
discussed substitution of halogen for hydrogen, addition reactions of alkenes,
and addition reactions of cycloalkanes with strained rings. In this chapter, the
principal topics are the substitution or displacement by nucleophilic reagents
of groups attached to carbon, and the formation of carbon-carbon double
bonds by elimination reactions. These reactions are often profoundly in-
fluenced by seemingly minor variations in structure, reagents, solvent, and
temperature. It is our purpose to show how these variations can be understood
and, as far as possible, predicted in terms of the principles we have already
discussed. Before proceeding, however, it will be helpful to consider the nomen-
clature of many of the organic reactants and products involved. The reader
who is already acquainted with these nomenclature systems, or wishes to
study them at a later time, can pass directly to Section 8-7.
8-1 organic derivatives of inorganic compounds
We have so far classified organic compounds by their functional groups;
alkenes possess double bonds, alkynes triple bonds, and so on. Another useful
classification of organic compound considers them as substitution products
of water, ammonia, hydrogen sulfide, nitrous or nitric acids, and so on,
through replacement of one or more hydrogens with an organic group.
Reference to Table 8- 1 shows how alcohols, ethers, carboxy lie acids, anhydrides,
and esters may be regarded as derivatives of water; mercaptans and sulfides
as hydrogen sulfide derivatives; amines and amides as ammonia derivatives;
alkyl nitrates as derivatives of nitric acid; alkyl nitrites as derivatives of
nitrous acid; and alkyl sulfates as derivatives of sulfuric acid. For the sake
of completeness, we include alkyl halides, which we have already classed as
substituted alkanes, but which may also be considered as derivatives of the
hydrogen halides.
8-2 alcohol nomenclature
In naming an alcohol by the IUPAC system, the ending -ol is appended to
the name of the parent hydrocarbon. The latter corresponds to the longest
straight chain of carbon atoms that includes the carbon carrying the hydroxyl
group; it also includes the double bond when the compound is unsaturated.
Note also that the -ol function normally takes precedence over a double bond,
halogen, and alkyl in determining the suffix of the name. With respect to
numbering, the carbon carrying the hydroxyl group is taken as number one
if it terminates the chain, or the lowest number thereafter if it is attached to
the nonterminal carbon.
OH CH 2 CH 3
I I
CH 3 -OH CH 3 CH 2 -OH C 6 H 5 CH 2 CHCH 2 CH 3 C1CH 2 CH = CCH 2 0H
methanol ethanol 1 -phenyl- 4-chloro-2-ethyl-
2-butanol 2-buten-l-ol
The most commonly used system for naming alcohols (and halides) com-
bines the name of the appropriate alkyl group with the word alcohol (or
chap 8 imcleophilic displacement and elimination reactions 188
Table 8-1 Organic compounds as derivatives of common inorganic compounds
parent
compound
organic derivative
class of compound
example
H-O-H
R— O— H
alcohol
CH 3 OH
methanol
R-0-R<
ether
CH3OCH3
dimethyl ether
O
II
R-C-O-
O
||
-H
carboxylic acid
CH3COH
acetic acid
O
II
R-C-O-
O
||
-R'
carboxylic ester
CH3COCH3
methyl acetate
O
II
R-C-O-
O
II
-C-R
carboxylic
anhydride
O O
II II
CH3COCCH3
acetic anhy-
dride
H-S-H
R-S-H
thiol
(mercaptan)
CH 3 SH
methanethiol
(methyl
mercaptan)
R-S-R'
thioether
(sulfide)
CH3SCH3
methylthio-
methane (di-
methyl
sulfide)
O
II
R-C-S-
H
thio acid
O
II
CH3CSH
thioacetic acid
NH 3
RNH 2
prim, amine
CH 3 NH 2
methylamine
R 2 NH
sec. amine
(CH 3 ) 2 NH
dimethylamine
R 3 N
tert. amine
(CH 3 ) 3 N
trimethylamine
O
II
R-C-NH
[ 2
acylamine (un-
substituted
amide)
O
II
CH 3 -C-NH 2
acetamide
O
II
O
II
R— C— NHR
(monosubsti-
tuted amide)
CH3-C-NHCH3
N-methyl-
acetamide
O
II
R— C— NR
2
(disubstituted
amide)
O
II
CH 3 -C-N(CH 3 ) 2
N,N-dimethyl-
acetamide
H-ON0 2
(nitric acid)
R-ON0 2
alkyl nitrate
CH 3 -ON0 2
methyl nitrate
H— ONO
(nitrous acid)
R-ONO
alkyl nitrite
CH3-ONO
methyl nitrite
H-N0 2
(unknown)
R-N0 2
nitroalkane
CH 3 -N0 2
nitromethane
sec 8.2 alcohol nomenclature 189
Table 8-1 Organic compounds as derivatives of common inorganic
compounds {continued)
parent
compound
organic derivative
class of compound exampl
e
H-NO (hypo-
nitrous acid,
R-NO
nitrosoalkane CH 3 — NO
nitroso-
methane
monomenc
form)
O
II
H— O— S— OH
II
O
(sulfuric acid)
O
II
R-O-S-OH
II
O
o
II
alkyl hydrogen CH 3 — O-S— OH
sulfate II
O
methyl hydrogen
sulfate
O
11
R-O-S-O-R
II
o
O
II
dialkyl sulfate CH 3 -0— S-OCH 3
II
O
dimethyl
sulfate
H-X
(X=F, CI,
Br, I)
R-X
alkyl halide CH 3 — F
(haloalkane)
methyl fluoride
(fluoro-
methane)
halide). The system works well whenever the group name is simple and
easily visualized :
CH 3
I
CH 3 — C— OH
I
CH 3
/-butyl alcohol
CH 3
I
CH 3 — C— CH 2 — OH
I
H
isobutyl alcohol
CH 2 =CH-CH 2 -C1
allyl chloride
A prevalent but unofficial procedure names alcohols as substitution prod-
ucts of carbinol, CH 3 OH, a synonym of methanol. Many alcohols that are
cumbersome to name by the IUPAC system may have structures that are
more easily visualized when named by the carbinol system.
H 3 C H CH 3
III
CH 3 — C— C— C — CH 3
III
H 3 C OH CH 3
di-r-butylcarbinol
(2,2,4,4-tetramethyl-3-
pentanol by
IUPAC system)
C 6 H 5 C CH 2 CH — CH 2
OH
allylphenylcarbinol
( 1 -phenyl-3-buten- 1 -ol
by IUPAC system)
The carbinol system has been extended to include other derivatives. Alkyl
chap 8 nucleophilic displacement and elimination reactions 190
halides and alkylamines, for example, are frequently called carbinyl halides
and carbinylamines.
/ \-CH 2 Cl
cyclohexylcarbinyl chloride
C 6 H 5 CH CH 2 CH 3
NH 2
ethylphenylcarbinylamine
8-3 ether nomenclature
Symmetrical ethers (both R groups in R— O— R being the same) are named
simply dialkyl, dialkenyl, or diaryl ethers, as the case may be. The prefix di-
to denote disubstitution is sometimes omitted as superfluous, but most
current opinion regards this form of redundancy desirable to help prevent
errors. Clearly, when an ether is unsymmetrical, the names of both R groups
must be included:
CH 3 CH 2 -0-CH 2 CH 3
diethyl ether
CH 3 -0-CH = CH 2
methyl vinyl ether
diphenyl ether
8-4 carboxjlic acid nomenclature
According to the IUPAC system, carboxylic acids with saturated alkyl
chains are called alkanoic acids. The suffix -ok is added to the name of the
longest continuous-chain hydrocarbon in the molecule that includes thecarbon
of the carboxyl (— C0 2 H) group. Note that the carboxyl function normally
takes precedence over the hydroxyl function and that the carboxyl carbon
is C-l.
CI
I
2-chloropentanoic acid
CH 3 OH
I I
CH 3 CHCH= CHCHC0 2 H
2-hydroxy-5-methyl-3-hexenoic acid
The simple alkanoic acids have long been known by descriptive but
unsystematic names that correspond variously to their properties, odors, or
natural origin. It seems likely that for the following acids these trivial names
will not be completely superseded by the more systematic names (shown in
parentheses) for some time to come.
HC0 2 H
CH 3 C0 2 H
CH 3 CH 2 C0 2 H
CH 3 CH 2 CH 2 C0 2 H
H 3 C
\
CHC0 2 H
formic acid
acetic acid
propionic acid
butyric acid
(methanoic acid)
(ethanoic acid)
(propanoic acid)
(butanoic acid)
(L. formica, ant)
(L. acetum, vinegar)
(proto + Gr. pion, fat)
(L. butyrum, butter)
isobutyric acid (2-methylpropanoic acid)
H 3 C
sec 8.6 single- or multiple-word names 191
Esters of carboxylic acids carry the suffix -oate in place of -oic (or -ate in
place of -ic for acids with descriptive names).
O O CI o
II II I II
CH 3 CH 2 COCH 3 C 6 H 5 CH 2 COCH 2 CH 3 CH 2 = CHCHCOCH 2 CH 3
methyl propionate ethyl phenylacetate ethyl 2-chloro-3-butenoate
(methyl propanoate)
Alkanoic acids are sometimes called aliphatic acids (or fatty acids) to
distinguish them from those containing a benzene ring and which are called
aromatic acids. The term aliphatic is often used for noncyclic systems in
general.
8-5 the use of greek letters to denote
substituent positions
Considerable use is made of the Greek letters a, fl, y, and so on to designate
successive positions along a hydrocarbon chain. The carbon directly attached
to the principal functional group is denoted as a, the second as /?, and so on.
CH 3 CH 3
I I
CH 2 = CH-C-OH Br 2 CH-C-C0 2 H
I I
CH 3 Br
a.a-dimethylallyl alcohol a,/J,/J-tribromoisobutyric acid
(2-methyl-3-buten-2-ol) (2,3,3-tribromo-2-methyl-
propanoic acid)
Note that the a position of an acid is at the number 2 carbon atom. In general,
the use of these names is to be deplored, but since it is widespread, cognizance
of the system is important.
8-6 single- or multiple-word names
A troublesome point in naming chemical compounds concerns the cir-
cumstances that govern whether a compound is written as a single word (e.g.,
methylamine, trimethylcarbinol) or as two or more words (e.g., methyl
alcohol, methyl ethyl ether). When a compound is named as a derivative of
substances such as methane, ammonia, acetic acid, or carbinol because of the
substitution of hydrogen for some other atom or group, its name is written
(C 6 H 5 ) 3 CH CH 3 -
-N-
H
-C 2 H 5
triphenylmethane methylethylamine
CH 2 = CH-CH 2 -C(CH 3 ) 2
CH 2 = CH-CH 2 Q
OH
dimethylallylcarbinol
vinylacetic acid
CH 3 MgI
C 6 H 5 Li
methylmagnesium iodide
phenyllithium
chap 8 nucleophilic displacement and elimination reactions 192
as a single word. This is correct because we do not speak of" a methane " but
of the compound "methane." It follows that a derivative such as (C 6 H 5 ) 3 CH
is called triphenylmethane and not triphenyl methane. We do speak, however,
of an alcohol, an ether, a halide, acid, ester, sulfide, or ketone, for these words
correspond to types of compounds rather than particular compounds. There-
fore additional words are required to fully identify particular alcohols,
ethers, halides, and so on. Several examples are given.
ethyl iodide
O
II
CH3COH
acetic acid
(CH 3 ) 2 CHOH
isopropyl alcohol
O
II
CH3COCH3
methyl acetate
O
II
C(
methyl ethyl ketone
dimethyl sulfide
CH 3 OCH 2 CH 3
methyl ethyl ether
O
II
(CH 3 C) 2
acetic anhydride
nucleophilic displacement reactions
8-7 general considerations
Broadly defined, a displacement reaction involves the replacement of one
functional group (X) by another (Y) :
RX + Y
RY + X
We are here concerned with nucleophilic displacement reactions of alkyl
derivatives; these are ionic ox polar reactions involving the attack by a nucleo-
phile (i.e., an electron-pair donating reagent) at carbon. A typical example is
the reaction of hydroxide ion with methyl bromide to displace bromide
ion. The electron pair of the C— O bond to be formed can be regarded as
H:0: 9 CH,
:Br:
CH 3 :0:H
donated by the hydroxide ion, whereas the electron pair of the C— Br bond
to be broken departs with the leaving bromide ion. The name for this type
of reaction is abbreviated S N , S for substitution and N for nucleophilic.
A number of nucleophilic reagents commonly encountered in S N reactions
are listed in Table 8-2 along with the names of the products obtained when
they react with methyl chloride. The nucleophile may be an anion, Y: e , or a
sec 8.7 general considerations 193
Table 8'2 Typical S N displacement reactions of alkyl halides, RX
1.
R
:X + Y:e
->■ R:Y + X=e
nucleophilic agent
product
product name, R = CH 3
useful solvents
Cl e
RC1
methyl chloride
acetone, ethanol
Br e
RBr
methyl bromide
acetone, ethanol
I e
RI
methyl iodide
acetone, ethanol
e OH
ROH
methyl alcohol
water, dioxane-water
e OCH 3
ROCH 3
dimethyl ether
methyl alcohol
e SCH 3
RSCH 3
dimethyl sulfide
ethyl alcohol
P P
// //
CH 3 — C RO — C
V CH 3
methyl acetate
acetic acid, ethanol
e :C=N
RCN
acetonitrile
acetone, dimethyl
sulfoxide
HC=C: e
RC^CH
propyne
liquid ammonia
e :CH(C0 2 C 2 H 5 ) 2
RCH(C0 2 C 2 H 5 ) 2
diethyl methylmalonate
ethyl alcohol
e :NH 2
RNH 2
methylamine
liquid ammonia
e © e
:N=N=N:
RN 3
methyl azide
acetone
O
II
O
II
II
o
II
II
)
N-methylphthalimide
N,N-dimethylforma-
mide
N0 2 e
RN0 2
nitromethane
N,N-dimethylforma-
mide
2.
R
:X + Y:
© e
-s- R:Y + X:
nucleophilic agent
product
product name, R = CH 3
useful solvents
(CH 3 ) 3 N:
RN(CH 3 ),
e
X
tetramethylammonium
chloride
ether, benzene
(C 6 H 5 ) 3 P:
RP(C 6 H 5 )
e
3 X
triphenylmethylphos-
phonium chloride
ether, benzene
(CH 3 ) 2 S:
RS(CH 3 ) 2
e
X
trimethylsulfonium
chloride
ether, benzene
chap 8 nucleophilic displacement and elimination reactions 194
Table 8-2 Typical S N displacement reactions of alkyl halides, RX {continued)
3.
R:
:X + H.Y: ~>
e
R.Y
:;H + X:e ->
R
Y: +H
:X
nucleophilic
agent
product
product name,
R =
= CH 3
useful solvents
H 2
ROH,
methyl alcohol
water, dioxane-water
CH 3 OH
ROCH 3
O
II
ROCCH3
dimethyl ether
methyl alcohol
CH 3 C0 2 H
methyl acetate
acetic acid
NH 3
RNH 2
methylamine
ammonia, methanol
neutral molecule, Y: or HY:, and the operation of each is illustrated in the
following general equations for a compound RX :
R— X + Y: e
R— X + Y:
R — X + HY:
R— Y + X: fc
R — Y
X: fc
-+ RYH + X: e
-♦ RY: + HX
The wide range of products listed in Table 8-2 shows the synthetic utility of
S N reactions. Displacement can result in the formation of bonds between
carbon and chlorine, bromine, iodine, oxygen, sulfur, carbon, nitrogen, and
phosphorus.
Nucleophilic displacements are by no means confined to alkyl halides.
Other alkyl derivatives include alcohols, ethers, esters, and "onium ions." 1
Some illustrative reactions of several different alkyl compounds with various
nucleophiles are assembled in Table 8-3.
As we shall see in a later section, the mechanism of an S N reaction and the
reactivity of a given alkyl compound RX toward a nucleophile Y depend
upon the nature of R, X, and Y, and upon the nature of the solvent. For
reaction to occur at a reasonable rate, it is very important to select a solvent
that will dissolve both the alkyl compound and the nucleophilic reagent.
Furthermore, the nucleophile may require considerable assistance from the
solvent in breaking the slightly polar C— X bond. However, the highly polar
Examples of -onium cations follow:
R 4 N®
Tetraalkylammonium
Tetraalkylphosphonium
R 3 0®
Trialkyloxonium
R3C 95
Trialkylcarbonium
R 3 S®
Trialkylsulfonium
R _ N = N :
Alkyldiazonium
R 2 I®
Dialkyliodonium
sec 8.8 mechanisms of S N displacements 195
nucleophilic agents most used (e.g., NaBr, NaCN, H 2 0) are seldom soluble
in the solvents that best dissolve slightly polar organic compounds. In
practice, relatively polar solvents, or solvent mixtures, such as acetone,
aqueous acetone, ethanol, aqueous dioxane, and so on are found to provide
the best compromise for reactions between alkyl compounds and salt-like
nucleophilic reagents. A number of useful solvents for typical S N reactions are
listed in Table 8-2.
8-8 mechanisms of S N displacements
Two mechanisms may be written for the reaction of methyl chloride with
hydroxide ion in aqueous solution that differ in the timing of bond breaking
in relation to bond making. In the ensuing discussion, we are not implying
that these are the only possible mechanisms that one could conceive for this
reaction. They appear to be the most plausible ones and by confining our
attention to two possibilities we can greatly simplify the discussion. In the
first mechanism, A, the reaction is written as taking place in two steps, the
first of which involves a slow and reversible dissociation of methyl chloride
Table 8-3 S N displacement reactions of various types of compounds, RX
type of compound, RX
alkyl chloride
alkyl bromide
alkyl iodide
dialkyl sulfate
benzenesulfonate
ester
acetate ester
alcohol
ether
ammonium ion
iodonium ion
diazonium ion
R-Cl + I e ;
R-Br + I e ;
R-I + CH 3 6
RI + Cl e
RI + Br e
->■ ROCH 3 + 1 €
R-OS0 2 OR + CH3O -
O
R-OShTj> + H 2
o
o
II
R-OCCH3 + H 2
R-OH + HBr —
R-OR' + HBr —
-► ROCH 3 + e OS0 2 OR
O
II /=\
-> ROH + HOS-d J>
O
o
li
-► ROH + HOCCH3
-> RBr + H 2
R-NR 3 + HO e
R-I-R' + OH e
R-N=N + H 2
-* RBr + R'OH
—* ROH + NR 3
— + ROH + R'l
-> ROH + H ffi + N 2
chap 8 nucleophilic displacement and elimination reactions 196
to methyl cation and chloride ion. The second step involves a fast reaction
between methyl cation and hydroxide ion (or water) to yield methanol.
Mechanism A:
slow
CH,-C1
e fast
CH/ + OH e ' CH3OH
© OH 9
(or CH 3 e + H 2 CH 3 OH 2 » CH 3 OH + H 2 0)
In the second mechanism, B, the reaction proceeds in a single step. Attack
of hydroxide ion at carbon occurs simultaneously with the loss of chloride
ion; that is, the carbon-oxygen bond is formed at the same time that the
carbon-chlorine bond is broken.
Mechanism B:
HO: e CH,:Cl:
slow
Of the two mechanisms, A requires that the reaction rate be determined
solely by the rate of the first step (cf. earlier discussion, Section 2-5B). This
means that the rate at which methanol is formed (measured in moles per unit
volume per unit time) will depend on the concentration of methyl chloride,
and not on the hydroxide ion concentration, because hydroxide ion is not
utilized except in a fast secondary reaction. In contrast, mechanism B requires
the rate to depend on the concentrations of both reagents since the slow step
involves collisions between hydroxide ions and methyl chloride molecules.
More precisely, the reaction rate (v) may be expressed in terms of Equation
8-1 for mechanism A and Equation 8-2 for mechanism B.
v = k[CH 3 C\] (8-1)
z; = MCH 3 Cl][OH e ] (8-2)
Customarily, v is expressed in moles of product formed per liter of solution
per unit of time (most frequently in seconds). The concentration terms
[CH 3 C1] and [OH e ] are in units of moles per liter, and the proportionality
constant k (called the specific-rate constant) has the dimensions of sec" 1 for
mechanism A and mole -1 x liters x sec -1 for mechanism B.
It is useful to speak of both the order of a reaction with respect to a specific
reactant and the overall order of a reaction. The order of a reaction with
respect to a given reactant is the power to which the concentration of that
particular reagent must be raised to have direct proportionality between
concentration and reaction rate. According to Equation 8-2 the rate of the
methyl chloride-hydroxide ion reaction is first order with respect to both
reagents. In Equation 8T the rate is first order in methyl chloride; the order
with respect to hydroxide ion may be said to be zero since [OH e ]° = 1.
The overall order of reaction is the sum of the orders of the respective re-
actants. Thus, Equations 8-1 and 8-2 express the rates of first-order and
second-order reactions, respectively.
sec 8.9 energetics of S N 1 and S N 2 reactions 197
We have, then, a kinetic method for distinguishing between the two possible
mechanisms, A and B, that we are considering. Experimentally, the rate of
formation of methyl alcohol is found to be proportional to the concentrations
of both methyl chloride and hydroxide ion. The reaction rate is second order
overall and is expressed correctly by Equation 8-2. From this we infer that the
mechanism of the reaction is the single-step bimolecular process B. Reactions
having this type of mechanism are generally classified as bimolecular nucleo-
philic substitutions, often designated S N 2 (S for substitution, N for nucleo-
philic, and 2 for bimolecular).
On the other hand, the rate of the reaction of ?-butyl chloride with aqueous
base depends only on the concentration of the chloride. The concentration of
the base (and its strength) is irrelevant, as long as there is enough to neutralize
the acid produced in the reaction. (Bicarbonate ion serves just as well as
hydroxide ion for this purpose.)
(CH 3 ) 3 CC1 s '° w > (CH 3 ) 3 C e + Cl e
(CH 3 ) 3 C® + H 2 fast > (CH 3 ) 3 COH 2 B: > (CH 3 ) 3 CQH+ BH ffi
(or (CH 3 ) 3 C ffl + OH e fast > (CH 3 ) 3 COH)
Mechanisms such as this are designated S N 1 reactions because they are
nucleophilic substitutions in which the first-order kinetics suggest that the
rate-controlling step is unimolecular. That is, the rate is proportional to the
concentration of alkyl halide and not to the concentration of the base.
Many S N reactions are carried out using the solvent as the nucleophilic
agent. They are called solvolysis reactions; specific solvents such as water,
ethanol, acetic acid, and formic acid produce hydrolysis, ethanolysis, ace-
tolysis, and formolysis reactions, respectively. The rates of all solvolysis
reactions are necessarily first order since the solvent is in such great excess that
its concentration does not change effectively during reaction, and hence its
contribution to the rate does not change. But this does not mean that reaction
is necessarily proceeding by an S N 1 mechanism, particularly in solvents such
as water, alcohols, or amines, which are expected to be reasonably good
nucleophilic agents.
8-9 energetics of S N 1 and S N 2 reactions
We have seen that the S N 2 reaction of methyl chloride with hydroxide is a
one-step process in which no intermediate compound is formed. As the
hydroxide ion begins to bond to carbon, the carbon-chlorine bond begins to
break and one can formulate the course of the reaction as in Equation 8-3.
u ^e H H H
HCT \ 8e I Se ± /
.-CI > [H-O-C-Cir > HO-C + CI (8-3)
^C-Cl > [H--0~C~CI] + ► HO-C
H "i "I V-H
chap 8 nucleophilic displacement and elimination reactions 198
The transition state in Equation 8-3 which is designated by t is not a
molecule in the ordinary sense. It is simply a stage in the transition from
reactants to products. Its importance derives from the fact that it represents
the point of highest energy along the lowest-energy (most favorable) reaction
path. There are many routes by which one could imagine the atoms of the
reactants being rearranged so as to give the products, but most of them would
involve transition states of exorbitantly high energy. (See mechanism A,
Section 8-8, that involves formation of a primary carbonium ion, for one
such route.) The course of any reaction — its mechanism — is that for which the
highest energy state lying on the reaction path is lower than the lowest energy
state on all other paths. Figure 8-1 shows the energy profile of the methyl
chloride-hydroxide ion reaction.
The transition state is at the top of an energy barrier that must be overcome
for reaction to occur but, in geographical terms, it should be considered as
the highest point along the path for the most favorable pass between
reactants and products. The transition state is not a peak between reactants
and products.
The rate of a reaction will be expected to be determined by the height of the
energy barrier to be overcome — that is, the energy difference between reactants
and transition state. The energy of the final products is not relevant to the rate,
although AG for the overall reaction must be negative for the equilibrium
constant to be greater than unity (Section 2-5A).
In the so-called "theory of absolute reaction rates," the reaction rate is
determined by the free-energy difference between reactants and transition
Figure 8-1 Energy profile for the reaction of a molecule of methyl chloride
and a hydroxide ion. The reaction coordinate indicates the extent of reaction
and might be taken as the difference in the CI to C and C to OH distances,
thus, in principle, covering the range from — oo to + oo.
H
HO c a
>>
so
a
ch 3 ci -
HOH e \
1 CH 3 OH + Cl e
reaction coordinate
sec 8.9 energetics of S N 1 and S N 2 reactions 199
r S® 5e~|
Lf-Bu CI J +0H
f-BuOH + CI '
reaction coordinate
Figure 8-2 Energy profile for reaction of t-butyl chloride, (CH 3 ) 3 C1, with
hydroxide ion.
state (AG*). This quantity, like AG, can be equated to a heat term and an
entropy term:
AG = AH-TAS
AG t = AH t -TAS t
The heat of activation, AH f , is usually the dominant term and can be thought
of as representing the thermal energy a colliding pair of reactants must
possess (in excess of the average) to reach the transition state. As the temper-
ature is raised, more and more collisions will be between reactants having
sufficient thermal energy to attain the transition state and the reaction rate
will increase. Experimental values for AH f are, in fact, determined by mea-
suring the effect of temperature on the reaction rate.
The entropy of activation, AS*, is related to the difference in the degree of
vibrational, rotational, and translational freedom of the reactants and the
transition state. (Compare this with the description given previously for AS,
in Section 2- 5 A.) The more freedom that the transition state possesses relative
to the reactants, the more positive will be AS 1 and the greater the reaction rate.
Conversely, the less freedom in the transition state relative to reactants, the
more negative AS* will be and the slower the reaction rate. In simple terms,
a transition state that is loose, with substantial freedom in the locations for
the constituent atoms, will be favored over one in which a high degree of
organization is required.
The energy profile for the S N 1 reaction of ?-butyl chloride with hydroxide
ion is given in Figure 8-2. This profile shows two transition states. The first
leads to the formation of a discrete intermediate, (CH 3 ) 3 C®; the second, with
a low barrier, corresponds to the very rapid reaction of the intermediate
chap 8 nucleophilic displacement and elimination reactions 200
carbonium ion with hydroxide ion (or water) to form the products. The overall
reaction is believed to be unimolecular because the rate is independent of the
concentration of hydroxide ion. Hydroxide ion is involved only in a fast
following step, not in the initial slow ionization (see Section 8-8). Hydroxide
ion is shown as an ingredient of the first transition state in the diagram only
for the purpose of preserving the correct stoichiometry. It takes no part in the
reaction until the critical ionization stage has been passed.
In Section 4-4E we discussed reaction rates in terms of energies of possible
intermediates that might be formed. A more rigorous procedure is to consider
not AG for formation of the intermediate but AG* for formation of the tran-
sition state. In the case of the ionization of /-butyl chloride, this does not make
much difference because the energy of the /-butyl cation formed as the inter-
mediate is not likely to be greatly different from that of the transition state
that precedes it. How can we expect this ? Largely on the basis of intuition
(tempered by experience) that an alkyl carbonium ion is likely to react very
rapidly with chloride ion to form /-butyl chloride. The reaction between the
more basic OH e and t-Bu® will be expected to have a still smaller AG % , and
this is reflected in Figure 8-2 by the smaller height of the second barrier as
compared to the first. The anion, SbF 6 e , of the super acid, HSbF 6 , (Section
1-2C), has such a small tendency to react with t-Bu® that it is possible to pre-
pare t-Bu® SbF 6 e and determine the nmr spectrum of the cation.
8-10 stereochemistry of S N 2 displacements
If we pause to consider the S N 2 reaction of methyl chloride with hydroxide
ion in more detail, we can think of two simple ways in which the reaction
Figure 8-3 Back-side (inverting) and front-side (noninverting) attack of
hydroxide ion on methyl chloride, as visualized with ball-and-stick models.
[ f
sec 8.1 1 structural and solvent effects in S N reactions 201
could be effected; these differ in the direction of approach of the reagents,
one to the other (see Figure 8-3). The hydroxide ion might attack methyl
chloride directly at the site where the chlorine is attached (i.e., front-side
approach). Alternatively, hydroxide might approach the molecule from the
rear to cause expulsion of chloride ion from the front (i.e., back-side approach).
There is no simple way of proving which of these paths is followed in this
particular case, but the arguments in favor of the back-side approach are
very strong. First, the transition state for this approach will have the oxygen
and chlorine atoms well separated; that is, the charge in the transition state
will be dispersed. The front-side approach would not disperse the negative
charge to nearly the same extent and hence would be a less favorable arrange-
ment. Second, in the case of cyclic compounds, the two types of displacement
predict different products. For example, an S N 2 reaction between cis-3-
chloro-1-methylcyclopentane and hydroxide ion would give the cis alcohol
by front-side attack but the trans alcohol by back-side attack (Figure 8-4).
The actual product is the trans alcohol, from which we infer that reaction
occurs by back-side displacement.
Third, in the case of certain kinds of stereoisomers of open-chain com-
pounds, back-side displacement has been conclusively proven. This is dis-
cussed later in the book (Section 1 4-9).
8-11 structural and solvent effects in S N reactions
We shall consider first the relation between the structures of alkyl derivatives
and their reaction rates toward a given nucleophile. This will be followed by
a discussion of the relative reactivities of various nucleophiles toward a
given alkyl derivative. Finally, we shall comment on the role of the solvent
in S N reactions.
Figure 8-4 Back-side and front-side displacement paths for reaction of
cis- 3-chloro-l-methylcyclopentane with hydroxide ion.
back-side
— 1
displacement
+ OH
front- side
displacement
OH
H
trans alcohol
H,C
OH
cis alcohol
(not formed)
chap 8 nucleophilic displacement and elimination reactions 202
A. STRUCTURE OF THE ALKYL GROUP, R
The rates of S N 2 displacement reactions of simple alkyl derivatives, RX,
follow the order primary R > secondary R > tertiary R. In practical syntheses
involving S N 2 reactions, the primary compounds generally work very well,
secondary isomers are fair, and the tertiary isomers are completely impractical.
Steric hindrance appears to be particularly important in determining S N 2-
reaction rates, and the slowness of tertiary halides is best accounted for by
steric hindrance to the back-side approach of an attacking nucleophile by the
alkyl groups on the a carbon. Neopentyl halides, which are primary halides,
are very unreactive in S N 2 reactions, and scale models indicate this to be
the result of their steric hindrance by the methyl groups on the /? carbon.
CH 3 -C-CH 2 Br
I
CH 3
neopentyl bromide
(slow in S N 2-type reactions)
In complete contrast to S N 2 reactions, the rates of S N 1 reactions of alkyl
derivatives follow the order tertiary R > secondary R > primary R.
Steric hindrance is relatively unimportant in S N 1 reactions because attack
by the nucleophile is not involved in the rate-determining step. In fact, steric
acceleration is possible in the solvolysis of highly branched alkyl halides
through relief of steric compression by formation of a planar cation :
CH 3 |ch 3 CH 3 ch 3
I I _ ve I /
CH 3 — C — C— X > CH 3 -C — C®
lil I \
CH 3 CH 3 CH 3 \^CH 3
■*. . steric relief of
crowding strain
The reactivity sequence tertiary > secondary > primary is to be expected
since we know that electron-deficient centers are stabilized more by alkyl
groups than by hydrogen. The reason for this is that alkyl groups are less
electron attracting than hydrogen.
B. THE LEAVING GROUP, X
The reactivity of a given alkyl derivative, RX, in either S N 1 or S N 2 reactions
is determined in part by the nature of the leaving group, X. In general, there
is a reasonable correlation between the reactivity of RX and the acid strength
of H— X, the X groups that correspond to the strongest acids being the best
leaving groups. Thus, since H— F is a relatively weak acid and H— I is a very
strong acid, the usual order of reactivity of alkyl halides is R— I > R— Br
> R— CI >R— F. Also, the greater ease of breaking a C— OS0 2 C 6 H 5 bond
than a C— CI bond in S N 2 reactions on carbon correlates with the greater
acid strength of HOS0 2 C 6 H 5 in relation to HC1. A further factor influencing
sec 8.11 structural and solvent effects in S N reactions 203
the rate of nucleophilic displacements is the polarizabilities of the attacking
and leaving groups. A highly polarizable atom is one whose electron cloud
can be easily deformed by an electric field, such as will be produced by ions in
solutions. Polarizability increases as one goes down a group in the Periodic
Table, and this means that iodide is not only more easily displaced than the
other halogens but is itself a more reactive nucleophile. In a similar way,
sulfur compounds react faster than the analogous oxygen compounds.
Alcohols are particularly unreactive in S N reactions, unless a strong acid is
present as a catalyst. The reason is that the OH e group is a very poor leaving
group. The acid functions by donating a proton to the oxygen of the alcohol,
transforming the hydroxyl function into a better leaving group (H 2 in
place of OH e ). Reactions of ethers and esters are acid catalyzed for the same
reasons :
ROH + Br e — #—> RBr + q H
H
R:5:H + H* ,. R:0:H ffi
: H
RJ:0:H e + Br e > RBr + H 2 S N 2
H
Ri:6:H > R® + H 2 Br6 > RBr S„l
Heavy-metal salts, particularly those of silver, mercury, and copper, catalyze
S N 1 reactions of alkyl halides in much the same way as acids catalyze the S N
reactions of alcohols. The heavy-metal ion functions by complexing with the
unshared electrons of the halide, making the leaving group a metal halide
rather than a halide ion. This acceleration of the rates of halide reactions is
the basis for a qualitative test for alkyl halides with silver nitrate in ethanor
solution. Silver halide precipitates at a rate that depends upon the structure of
the alkyl group, tertiary > secondary > primary. Tertiary halides usually
react immediately at room temperature, whereas primary halides require
heating.
r:X: t^^ [R:X:-Ag] ffi -^U R® _^_> RY + H®
(-AgX)
There is additional evidence for the formation of complexes between
organic halides and silver ion: where the formation of carbonium ions is
slow enough to permit determination of water solubility, the solubility of the
halide is found to be increased by the presence of silver ion.
C. THE NUCLEOPHILIC REAGENT
The S N 2 reactivity of a particular reagent towards an alkyl derivative can be
defined as its nucleophilicity, which is its ability to donate an electron pair
to carbon. The nucleophilicity of a reagent does not always parallel its basicity,
measured by its ability to donate an electron pair to a proton. The lack of
parallelism can be seen from Table 84, which indicates the range of reactivities
chap 8 nucleophilic displacement and elimination reactions 204
Table 8-4 Reactivities of various nucleophiles toward methyl bromide
in water at 50°
nucleophile
approximate
reaction half-time, hr°
rate relative
to water
Kb
H 2
1,100*
0)
,0-16
CH 3 C0 2 &
2.1
5.2 x 10 2
10-"
Cl e
1
1.1 x 10 3
~io~ 20
Br e
0.17
7.8 x 10 3
<io- 20
N 3 e
0.11
1.0 x 10*
10-"
HO e
0.07
1.6 x 10 4
10°
C 6 H 5 NH 2
0.04
3.1 x 10 4
10 -io
SCN e
0.02
5.9 x 10 4
io- 14
I e
0.01
1.1 x 10 5
<io- 22
" Time in hours required for half of methyl bromide to react at constant (1 M) concentration of
nucleophile.
b Calculated from data for pure water, assuming water to be 55 M,
of various nucleophilic agents (toward methyl bromide in water) and their
corresponding basicities. Clearly, a strong base is a good nucleophile (e.g.,
OH e ), but a very weak base may also be a good nucleophile (e.g., I s ) if it is
highly polarizable.
D. THE NATURE OF THE SOLVENT
The rates of most S N 1 reactions are very sensitive to solvent changes. This is
reasonable because the ionizing power of a solvent is crucial to the ease of
e e
formation of the highly ionic transition state R —X from RX.
Actually, two factors are relevant in regard to the ionizing ability of sol-
vents. First, a high dielectric constant increases ionizing power by making it
easier to separate ions, the force between charged particles depending inversely
upon the dielectric constant of the medium. On this count, water with a
dielectric constant of 80 should be much more effective than a hydrocarbon
with a dielectric constant of 2. A related and probably more important factor
is the ability of the solvent to solvate the separated ions. Cations are most
effectively solvated by compounds of elements in the first row of the periodic
table that have unshared electron pairs. Examples are ammonia, water,
alcohols, carboxylic acids, sulfur dioxide, and dimethyl sulfoxide, (CH 3 ) 2 SO.
Anions are solvated most efficiently by solvents having hydrogen attached to a
strongly electronegative element Y so that the H— Y bond is strongly polarized.
With such solvents, hydrogen bonds between the solvent and the leaving
group assist ionization in much the same way that silver ion catalyzes ioniz-
ation of alkyl halides (Section 8*1 IB):
Se a© ?. se se
Y-H-:Ci:-H-Y
H
H
\
©
/
:<>:-
--Na-
-:<>:
/
H
\
H
solvation of a cation solvation of an anion
by a solvent with unshared by a hydrogen-bonding
electron pairs solvent
sec 8.11 structural and solvent effects in S N reactions 205
Water appears to strike the best compromise with regard to the structural
features that make up ionizing power, that is, dielectric constant and solvating
ability, and we expect f-butyl chloride to hydrolyze more readily in water-
alcohol mixtures than in ether-alcohol mixtures. An ether can only solvate
cations effectively whereas water can solvate both anions and cations.
(However, the water solubility of alkyl halides is too low for pure water to be
a suitable medium for these reactions.)
For S N 2 reactions, effects of changing solvents might be expected to be
smaller because the reactants and the transition state each possess a full unit
s& so
of negative charge: HO e + RX -> (HO— R~ X). No charges have been
created but the charge in the transition state is less concentrated than in
the reactants. Accordingly, a poor solvating solvent should raise the energy
of the reactants more than it raises that of the transition state (a large diffuse
ion is solvated less than a small concentrated one) and hence speed up the reac-
tion. This hypothesis is not easily tested with solvents such as hexane or carbon
tetrachloride because they do not dissolve metal hydroxides. We can, however,
look for solvents with high dielectric constants but which lack hydrogen-
bonding ability to solvate anions well. There are a number of such solvents
and the most important of these, together with their dielectric constants, are
listed here.
H 2 C-CH 2 O
o / \ /
II H 2 C X /CH 2 H-C
CH3-S-CH3 o / %Q N(CH3)2
dimethyl sulfoxide tetramethylene sulfone dimethylformamide
(DMSO) e = 48 (sulfolane) s = 44 (DMF) £ = 38
O
(CH 3 ) 2 N-P-N(CH 3 ) 2
N(CH 3 ) 2
hexamethylphosphoramide
(HMP)e = 30
These solvents, called polar aprotic solvents, have a remarkable effect on
the rates of many S N 2 reactions. For example, the S N 2 reaction of methyl
iodide with chloride ion,
Cl e + CH3I ► [CI-CH3-I] ► CICH3 + 1°
is a million times faster in dimethylformamide than in water. Of the four
solvents listed above, DMSO and HMP are usually the most effective in
accelerating S N 2 reactions.
elimination reactions
The reverse of addition to alkene double bonds is elimination. Generally,
an alkyl derivative will, under appropriate conditions, eliminate HX, where
chap 8 nucleophilic displacement and elimination reactions 206
X is commonly a halide, hydroxyl, ester, or onium function, and a hydrogen
is located on the carbon adjacent to that bearing the X function :
II \ /
— C — C— ► C=C + HX
II / \
H X
O
X = C1, Br, 1, — O-C-CHj, -SR 2> — NR 3 ,— OH 2
Substitution and elimination usually proceed concurrently for alkyl
derivatives and, in synthetic work, it is important to be able to have as much
control as possible over the proportions of the possible products. As we shall
see, substitution and elimination have rather closely related mechanisms, a
fact which makes achievement of control much more difficult than if the
mechanisms were sufficiently diverse to give very different responses to changes
in experimental conditions.
8-12 the E2 reaction
Consider the reaction of ethyl chloride with sodium hydroxide :
CH 3 CH 2 OH + Cl e S N 2
CH 3 CH 2 C1 + OH e
CH 2 = CH 2 + H 2 + Cl e E2
Elimination to give ethene competes with substitution to give ethanol.
Furthermore, the rate of elimination, like the rate of substitution, has been
found to be proportional to both the concentration of ethyl chloride and the
concentration of hydroxide ion; thus, elimination is here a bimolecular process,
appropriately abbreviated as E2. As to its mechanism, the attacking base,
OH e , removes a proton from the ft carbon simultaneously with the formation
of the double bond and the loss of chloride ion from the a carbon :
, . O.
CH 2 j-CH 2 :Cl= ► H 2 + CH 2 = CH 2 + Cl e
H:0:
Structural influences on E2 reactions have been studied extensively. The
ease of elimination follows the order tertiary R > secondary R > primary R.
The contrast with S N 2 reactions is strong here because E2 reactions are only
slightly influenced by steric hindrance and can take place easily with tertiary
sec 8.13 the El reaction 207
CH 3
I
o , , - CH3-C-OH
CH 3 Sn2^/-* 3 I
I e -— -"^ CH 3
-C— CI + OH
I . ^\P CH,
CH, ^---^ ___ /
1 i
CH 2 = C
halides, unlike S N 2 reactions. Rather strong bases are generally required to
bring about the E2 reaction. The effectiveness of bases parallels base strength,
e e e e
and the order NH 2 > OC 2 H 5 > OH > 2 CCH 3 is observed for E2 re-
actions. This fact is important in planning practical syntheses because the
E2 reaction tends to predominate with strongly basic, slightly polarizable
e e
reagents such as amide ion, NH 2 , or ethoxide ion, OC 2 H 5 . On the other
hand, S N 2 reactions tend to be favored with weakly basic reagents such as
iodide ion or acetate ion. Elimination is favored over substitution at elevated
temperatures.
8-13 the El reaction
Many secondary and tertiary halides undergo El type of elimination in com-
petitition with the S N 1 reaction in neutral or acidic solutions. For example,
when /-butyl chloride solvolyzes in 80 % aqueous ethanol at 25°, it gives 83 %
/-butyl alcohol by substitution and 17% 2-methylpropene by elimination:
CH 3
I
CH 3 -C=CH 2 17%
I
CI
El
80%C 2 H 5 OH
" ^S N l CH 3
CH 3 -C-CH 3 83%
I
OH
The ratio of substitution and elimination remains constant throughout the
reaction, which means that each process has the same kinetic order with
respect to the concentration of /-butyl halide. Usually, but not always, the
S N 1 and El reactions have a common rate-determining step — namely, slow
ionization of the halide. The solvent then has the choice of attacking the
intermediate carbonium ion at carbon to effect substitution, or at a jS hydrogen
to effect elimination.
CH 3
I e
CH CH, CH 3 -C=CH 2 + H 3 El
I 3 I 3 H z O -»
CH 3 -C-CH 3 -~^ CH 3 -C-CH 3 -J2!L>^ c „
*3 Y 3 Slow ' ^"3 ^ ^i
CI
2H 2
I
OH
chap 8 nucleophilic displacement and elimination reactions 208
Structural influences on the El reaction are similar to those for the S N 1
reactions and, for RX, the rate orders are X = I > Br > CI > F and tertiary
R > secondary R > primary R. With halides such as f-pentyl chloride, which
can give different alkenes depending upon the direction of elimination, the
El reaction tends to favor the most stable, that is the most highly substituted,
alkene.
CH 3
CI
H 2 1/
./slow
CH,
CH 3 CH 2 = C— CH 2 -CH
^^^ 20% + H ,O e +cf
fast
CH
+ I "
e CH,-C = CH-CH
CI
Another feature of El reactions (and also of S N 1 reactions) is the tendency
of the initially formed carbonium ion to rearrange if by so doing a more stable
ion results. For example, the very slow S N 1 formolysis of neopentyl iodide
leads predominantly to 2-methyl-2-butene. Here, ionization results in
CH 3
CH 3
[
3-C— CH 2 I
1
— ie 1 si
HC0 2 H ' |
CH 3
CH 3
► CH 3
-C=CH-CH 3
CH 3
-* CH 3 -C — CH 2 — CH 3
I
CH,
migration of a methyl group with its bonding pair of electrons from the ft to
the a carbon transforming an unstable primary carbonium ion to a relatively
stable tertiary cation. Elimination of a proton completes the reaction.
Rearrangements involving shifts of hydrogen (as H: e ) occur with compar-
able ease if a more stable carbonium ion can be formed thereby.
H 3 C H CH 3 CH 3
CH 3 -C-C-CH 3 — ^-* CH 3 -C-CH-CH 3 ► CH 3 -C-CH 2 CH 3
|| " |_> e ©
H Br H
CH 3 CH 3
I I
CH 3 — C-CH 2 CH 3 CH 3 -C = CHCH 3
OH
Rearrangements of this type are also discussed in Chapter 10.
summary 209
summary
Many organic compounds can be considered derivatives of the inorganic com-
pounds water (alcohols, ethers, carboxylic acids, anhydrides), hydrogen
sulfide (thiols, thioethers, thioacids), ammonia (amines and amides), nitric
and nitrous acids (alkyl nitrates and nitrites), sulfuric acid (alkyl sulfates), and
hydrogen halide (alkyl halides).
CH 3
I
Three methods of naming alcohols can be illustrated using CH 3 — CH— OH
as an example : 2-propanol (IUPAC name), isopropyl alcohol, and dimethyl-
carbinol. Ethers, ROR, take their names from the two R groups. Carboxylic
acids, RC0 2 H, are named either as alkanoic acids (IUPAC system) in which
the longest chain provides the name and -oic acid is added or, in the case of
the short-chain acids, with the common names formic, acetic, propionic, or
butyric (Q to C 4 ). The carboxyl carbon is taken as C-l in the IUPAC
system and the adjacent carbon is a in the common system. Thus, CH 3 —
CI
I
CH— CH 2 C0 2 H can be named either 3-chlorobutanoic acid or j6-chloro-
butyric acid.
Nucleophilic displacement reactions of the following types occur:
RX + Y 9 ► RY + X s
RX + Y > RY« + X 9
RX + HY > RY + HX ( a ^ vol f h is re f cti °"
if HY is the solvent)
RZ® + Y ► RY® + Z
RZ ffi + Y e ► RY + Z
Common nucleophiles are :
Y e = Cl e , Br e , I s , HO e , RO e , RC0 2 e , CN e , R e , NH 2 e , N 3 e , N0 2 e
Y = R 3 N, R 3 P, R 2 S
HY = H 2 0, ROH, RC0 2 H, NH 3
Easily displaced groups are :
X e = Cl e , Br e , I e , RS0 3 e , RC0 2 e
Z = R 3 N, RI, N 2
Nucleophilic displacements can occur by either S N 1 or S N 2 mechanisms.
o
state
S„l RX ► [R da3 -X de ] ► R®+ X e two-step reaction, rate a [RX]
transition
Y©
♦ RY
fast
S N 2 RX + Y e ► [Y 8e -R-X se ] ► RY + X e one-step reaction,
transition rate a [RX][Y]
state
The course of such reactions can be plotted on an energy-profile diagram with
chap 8 nucleophilic displacement and elimination reactions 210
energy as a function of the reaction coordinate. The activation parameters
AH 1 and AS 1 that govern the rate of the reaction are analogous to the terms
AH and AS that determine the equilibrium position of a system. The S N 2
route is favored for primary and the S N 1 route for tertiary alkyl groups.
In general, strong bases make good nucleophiles and stable molecules or
ions make good leaving groups. Weak bases and less stable leaving groups
may also react rapidly if their polarizabilities are high.
S N 1 reactions are greatly accelerated by highly polar solvents which promote
ionization. S N 2 reactions that involve attack by an anion are greatly accelerated
by polar aprotic solvents, such as dimethyl sulfoxide. The energy of the
nucleophile is raised more than that of the transition state by these solvents,
which solvate anions poorly.
Elimination processes are analogous to nucleophilic displacements except
that the base Y e removes a proton from the adjacent carbon. The same
RCH 2 CH 2 X + Y e ► RCH=CH 2 +
variations in structure and charge of X and Y are possible with elimination
as with displacement and the two kinds of reaction compete with one another.
Furthermore, there are two mechanisms, El and E2, analogous to S N 1 and
S N 2. The E2 reaction is favored over S N 2 by the use of (a) powerful bases of
low polarizability, (b) high temperatures, and (c) tertiary alkyl substrates.
The El and S N 1 reactions usually have a common first step and so the factors
that govern their rates are the same. Rearrangement of the intermediate
cation that is produced in both processes sometimes occurs.
exercises
8-1 Name each of the following by an accepted system:
CH 3
I
a. CH 3 -C-CH 2 -CH 2 OH d. BrCH 2 CH 2 OCH=CH 2
CH 3 CH 3
'■Ch H
OH
CH 3
c.
CH 3 -CH-CH-C0 2 CH 3 /■ <f \-C-CH 3
Br Br NO
8-2 Write structural formulas for each of the following:
a. dimethylvinylamine
b. allyl trimethylacetate
c. N-methyl-N-ethylformamide
d. formic acetic anhydride
e. a-phenylethanol
/. isoamyl nitrite
exercises 211
i-3 Name each of the following alcohols by the IUPAC method:
a. s-butyl alcohol c. trirnethylcarbinol
b. allyl alcohol d. isobutyl alcohol
i-4 Name each of the following carboxylic acids by the IUPAC method:
a. CH 3 CH 2 CHC0 2 H c. (C 6 H 5 ) 2 CHCH 2 C0 2 H
I
CH 3
b. CH 2 =CHCH 2 CH 2 CH 2 C0 2 H d. C1 3 CCH 2 CH 2 CC1 2 C0 2 H
•5 Complete the following equations and provide a suitable name for each of the
organic products. If additional products are likely to be formed, provide
structures and names for them also.
H 2 Q
H 2
►
C 2 H 5 OH
a. (CH 3 ) 2 CHCH 2 Br + KOH
b. C 6 H 5 CH 2 CH 2 Br+NH 4 I
c. (CH 3 ) 2 CHCl+NaOC 2 H 5
d. C 2 H 5 Br + NH 3 H2 ° >
(~"H OH
e. (C 6 H 5 ) 3 CCH 2 I + CH 3 OH — ^ ►
8-6 Write structural formulas for the principal organic products formed by the
action of each of the following reagents on (C 6 H 5 ) 2 CHC1: sodium cyanide,
ammonia, potassium ethoxide, sodium acetate, methanol.
8-7 The numbers 1 and 2 in the symbols S N 1 and S N 2 designate the " molecularity "
of the rate-controlling step; that is, the number of molecular species that are
believed to react to form the transition state. This often corresponds to the
kinetics of the reactions, S N 1 displacements often being first order and S N 2
displacements often being second order. Under what conditions would the
molecularity and the observed kinetics not correspond ?
8-8 How would you expect geometry of the transition state to be related to the
entropy of activation ?
8-9 The reaction of alcohols with hydrobromic acid to give alkyl bromides is an
equilibrium reaction. Alkyl bromides are usually formed from alcohols and
concentrated hydrobromic acid in good yields, whereas alkyl bromides
hydrolyze almost completely in neutral water solution. Estimate the change in
equilibrium ratio of alkyl bromide to alcohol in changing from a solution
with 10 M bromide ion buffered at pH 7 to 10 M hydrobromic acid.
8-10 The S N 1 reactions of many RX derivatives that form moderately stable
carbonium ions are substantially retarded by added X e ions. However, such
retardation is diminished, at given X e concentrations, by adding another
nucleophile such as N 3 e . Explain.
The relative reactivity of water and N 3 e toward methyl bromide is seen from
Table 8-4 to be 1 : 10,000. Would you expect the relative reactivity of these
substances toward the f-butyl cation to be larger, smaller, or about the same?
Why?
chap 8 nucleophilic displacement and elimination reactions 212
8-11 Classify the following solvents according to effectiveness expected for solva-
tion of cations and anions :
a. acetone d. chloroform
b. carbon tetrachloride e. trimethylamine, (CH 3 ) 3 N
c. anhydrous hydrogen fluoride / trimethylamine oxide,
e e
(CH 3 ) 3 N-0
8-12 An alternative mechanism for E2 elimination is the following:
CH 3 CH 2 Cl+OH e ^z± CH 2 CH 2 C1 + H 2 S '° W » CH 2 =CH 2 +Cr
a. Would this mechanism lead to first-order kinetics with respect to the
concentrations of OH e and ethyl chloride? Explain.
b. This mechanism has been excluded for several halides by carrying out
the reaction in deuteriated solvents such as D 2 and C2H5OD. Explain
how such experiments could be relevant to the reaction mechanism.
a e
8-13 a. Why is potassium ?-butoxide, KOC(CH 3 ) 3 , an excellent base for
promoting elimination reactions of alkyl halides, whereas ethylamine,
CH3CH2NH2, is relatively poor for the same purpose?
b. Potassium 7-butoxide is many powers of ten more effective as an elim-
inating agent in dimethyl sulfoxide than in ?-butyl alcohol. Explain.
8-14 The reaction of ?-butyl chloride with water is strongly accelerated by sodium
hydroxide. How would the ratio of elimination to substitution products be
affected thereby?
8-15 Write equations and mechanisms for all the products that might reasonably
be expected from the reaction of s-butyl chloride with a solution of potassium
hydroxide in ethanol.
8-16 Why is apocamphyl chloride practically inert toward hydroxide ion?
H 3 C.
•17 Show how the following conversions may be achieved (specify reagents and
conditions; note that several steps may be needed). Write a mechanism for
each reaction you use. (Note that some of the steps required are described in
earlier chapters.)
CH 3 CH 3
I ■ !
a. CH 3 -C-CH 2 -CH 3 ► CH 3 -C-CH-CH 3
I II
Br HO Br
exercises 213
\
CH 2 CH 3
c. CH3-C-CH3
CH 3 -C = CH-CH 3
CH,
CI I
CH 3 CH 3
d. CH 3 — C— CH 3 —
I 1
CI H
8-18 Explain how (CH 3 ) 2 CDCHBrCH 3 might be used to determine whether
trimethylethylene is formed directly from the bromide in an El reaction, or by
rearrangement and elimination as shown in Section 8-13.
8-19 Predict the products of the following reactions:
a. CH 3 CH 2 CBr(CH 3 )CH 2 CH 3 s " 2 ° t >
b. (CH 3 ) 3 CCH(CH 3 )CI ^f^'
H 2 C
c. H 2 C V X \:H-CH 2 Br " 2 ° »
i \ / 2 S N 1, El
H 2 C
8-20 Write structural formulas for each of the following substances:
a. diisobutyl ether
b. 2-methyl-3-buten-2-ol
c. dineopentylcarbinol
d. <x,/3-dibromopropionic acid
e. ethyl vinyl ether
/ 9-(2,6,6-trimethyl-l-cyclohexenyl)-3,7-dimethyl-2,4,6,8-nonatetraen-
l-ol
8-21 Name each of the following by the IUPAC system and, where applicable , by
the carbinol (or substituted acid) system:
CH 3
a. HC = C-CH 2 OH d. CH 3 -C-CH 2 C0 2 H
CH 3 CH 3
b. CH 3 -C-CH-CH
CH 3
H 3 C OH e. CH 3 -CH-CH-CH-C0 2 H
H 3 C /=\OH CI OH
H 3 C \==/ H
chap 8 nucleophilic displacement and elimination reactions 214
8-22 Indicate how you would synthesize each of the following substances from the
given organic starting materials and any other necessary organic or inorganic
reagents. Specify reagents and conditions.
a. 2-butyne from ethyne
b. 3-chloropropyl acetate from 3-chloro-l-propene
c. methyl ethyl ether from ethanol
d. methyl r-butyl ether from 2-methylpropene
e. l-iodo-2-chloropropane from propene
8-23 Which one of the following pairs of compounds would you expect to react
more readily with (A) potassium iodide in acetone, (B) concentrated sodium
hydroxide in ethanol, and (C) silver nitrate in aqueous ethanol? Write
equations for all the reactions involved and give your reasoning with respect
to the predicted orders of reactivity.
a. methyl chloride and isobutyl chloride with A, B, and C
b. methyl chloride and Nbutyl chloride with A, B, and C
c. 7-butyl chloride and l-fluoro-2-chloro-2-methylpropane with B and C
d. allyl and allylcarbinyl chlorides with A, B, and C
1 chapter 9
[alkyl Jialides and oi^ikh
metallic compounds
chap 9 alkyl halides and organometallic compounds 217
Many simple halogen derivatives of hydrocarbons have been met in earlier
chapters. Their nomenclature was described in Section 3-1, the mechanism
of their formation by substitution in alkanes in Sections 2-5A, 2-5B, and
3-3B, and the details of their reactions with nucleophiles (S N 1, S N 2) and
bases (El, E2) in the previous chapter.
9-1 physical properties
Methyl iodide (iodomethane), CH 3 I, boils at 42° and is the only mono-
halomethane that is not a gas at room temperature and atmospheric pressure.
Ethyl bromide (bromoethane), CH 3 CH 2 Br, bp 38°, is the first monobromo-
alkane in the series tobea liquid and thetwochloropropanes,CH 3 CH 2 CH 2 Cl
(1-chloropropane), bp 47°, and CH 3 CHC1CH 3 (2-chloropropane), bp 37°,
are the first monochloroalkanes in the series to be liquids.
With the exception of the fluoroalkanes, which are discussed in a later sec-
tion, the boiling points of haloalkanes tend to be near those of the alkanes of
the same molecular weight.
All alkyl halides have extremely low water solubilities.
All iodo-, bromo-, and polychloro-substituted alkanes are denser than
water.
9-2 spectra
The infrared spectra of alkyl halides have relatively few bands that are as-
sociated directly with the C— X bond. However, C— F bonds give rise to
very intense absorption bands in the region of 1350 to 1000 cm -1 ; C— CI
bonds absorb strongly in the region of 800 to 600 cm -1 ; whereas C— Br and
C — I bonds absorb at still lower frequencies.
Carbon tetrachloride, CC1 4 , and chloroform, CHC1 3 , are commonly used
solvents for infrared work, and their spectra are shown in Figure 9-1. Carbon
tetrachloride contains only one kind of bond and this makes its spectrum
simpler than that of chloroform. Furthermore, the high degree of symmetry
in carbon tetrachloride contributes to the simplicity of its spectrum. Absorp-
tion of a quantum of radiation can only occur if accompanied by a change in
the polarity of the molecule. In many cases, changes in the vibrational energies
of highly symmetrical molecules may not result in a change in polarity and
thus not correspond to observable absorptions in the infrared spectrum. You
should be able to deduce from this discussion why the absorption correspond-
ing to changes in the C— H vibrational energy but not the C=C vibrational
energy can be observed in the infrared spectrum of ethyne, HC=CH.
The nmr spectra of a number of halogen derivatives of hydrocarbons were
described in Chapter 7.
The ultraviolet spectra of monohaloalkanes are unremarkable. Neither
fluoroalkanes nor chloroalkanes show significant absorption in the accessible
part of the spectrum. Bromo- and iodoalkanes have weak absorption maxima
between 2000 A and 2500 A. Conjugation of a halogen atom with a double
chap 9 alkyl halides and organometallic compounds 218
4 5
wavelength, n
6 7
9 10 12 14
3600 3200
2400 2000 2000
1800 1600 1400
frequency, cm" 1
1200
1000
800
3600 3200 2400 2000 2000 1800 1600 1400 1200 1000 800
frequency, cm -1
Figure 9*1 Infrared spectra of carbon tetrachloride, CC1 4 (upper), and chloro-
form, CHC1 3 (lower); neat liquids, 0.1-mm thickness (look for overtones).
bond, however, causes significant absorption bands to appear, as does an
accumulation of iodine on a single carbon, CHI 3 being yellow and CI 4 red.
9-3 preparation of alkyl halides
A number of ways of forming a carbon-halogen bond have been outlined
previously. These are illustrated for the production of the isomeric compounds
1-bromopropane and 2-bromopropane.
sec 9.5 vinyl halides 219
a. Halogenation of alkanes is not usually a satisfactory preparative
CH 3 CH 2 CH 3 + Br 2 -^ HBr + ^h^ ^ ""Ti
1 CH 3 CH 2 CH 2 Br (minor product)
method for bromides unless a tertiary C— H is to be substituted. With
chlorine, serious mixtures of mono- and polysubstitution products may be
formed.
b. Reaction of alcohols with hydrogen halides is satisfactory for most
CH 3 CH 2 CH 2 OH + HBr ► CH 3 CH 2 CH 2 Br + H 2
CH,CHOHCH, + HBr ► OHLCHBrCH, + H,0
bromides and iodides; primary alcohols (RCH 2 OH) react only slowly with
HC1 unless ZnCl 2 is added (Section 10-5).
c. Addition of hydrogen halides to alkenes proceeds as follows :
CH 3 CH=CH 2 + HX > CH 3 CHXCH 3 (X = F,C1, 1)
CH 3 CH=CH 2 + HBr .
peroxides^. CHCHCHBr
9-4 reactions of alkyl halides
a. Displacement (S N 1 , S N 2). The displacement reactions of alkyl halides with
nucleophiles were listed in Table 8-2. They can be summarized as follows:
R— X + Y s ► R— Y + X e Y e = Cl e , Br e , OH e , RO e , RS e , CH 3 C0 2 e ,
CN e , Re, NH 2 e , N 3 e , N0 2 9
R— X + HY ► R— Y + HX HY = H 2 0, ROH, RC0 2 H, NH 3
b. Elimination (El, E2). If there is a hydrogen atom on the carbon atom
adjacent to the C— X group, elimination of HX will compete with the
displacement reaction :
RCH 2 CH 2 X + Y e ► RCH=CH 2 + HY + X e
c. Formation of organometallic compounds from alkyl halides and
metals is discussed in Section 9-9B.
9-5 vinyl halides
The most readily available vinyl halide is vinyl chloride, which can be prepared
by a number of routes:
chap 9 alkyl halides and organo metallic compounds 220
CI
CH^CH
+ HC1
\
CH 2 =CH 2 + CI
/high
,/ temp.
CH 2 =
= CHC1
ow yii
\0H 9
E2 \
* CH 2 - CH 2
CH 3 -CHC1 2
■h
CI CI
The most feasible commercial preparation (though not convenient on a
laboratory scale) is probably by way of high-temperature chlorination of
ethene.
The outstanding chemical characteristic of vinyl halides is their general
inertness in S N 1 and S N 2 reactions. Thus vinyl chloride, on long heating with
solutions of silver nitrate in ethanol, gives no silver chloride, fails to react
with potassium iodide by the S N 2 mechanism, and with sodium hydroxide
only gives ethene by a slow E2 reaction. The haloalkynes, such as RC=C— CI,
are not very reactive in S N 1 and S N 2 reactions.
The phenyl halides, C 6 H 5 X, are like the vinyl and ethynyl halides in being
unreactive in both S N 1 and S N 2 reactions. The chemistry of these compounds
is discussed in Chapter 21.
9-6 allyl halides
Allyl chloride is made on a commercial scale by the chlorination of propene
at 400° (1 ,2-dichloropropane is a minor product under the reaction conditions,
although at room temperature it is essentially the only product obtained).
CH 2 = CH-CH 3 + Cl 2 400 ° » CH 2 = CH — CH 2 C1 + HC1
Allyl chloride is an intermediate in the commercial synthesis of glycerol
(1,2,3-propanetriol) from propene.
CH 2 =CHCH 3 C ' 2 > CH 2 =CHCH 2 C1 H2 ° > CH 2 =CHCH 2 OH
HOC1 „„ „„ „„ , „„ „„ „„ H 2 CH CH _ CH
I I I I I I II
OH CI OH CI OH OH OH OH OH
glycerol
A general method for preparing allylic halides is by addition of halogen
acids to conjugated dienes, which usually gives a mixture of 1,2 and 1,4
addition products (see Section 6-2).
In contrast to the vinyl halides, which are characteristically inert, the allyl
sec 9.6 allyl halides 221
CI
CH 3 -CH-CH=CH 2 + CH 3 -CH=CH-CH 2 C1
3-chIoro-l-butene l-chloro-2-butene
(a-methylallyl (y-methylallyl chloride)
chloride)
halides are very reactive — in fact, much more reactive than corresponding
saturated compounds, particularly in S N 1 reactions. Other allylic derivatives
besides the halides also tend to be unusually reactive in displacement and
substitution reactions, the double bond providing an activating effect on
breaking the bond to the functional group. A triple bond has a comparable
effect and, for example, it is found that the chlorine of 3-chloro-l-propyne is
quite labile.
HC = C-CH,C1
3-chloro- 1 -propyne
(propargyl chloride)
The considerable S N 1 reactivity of allyl chloride compared with ra-propyl
chloride can be explained by reference to the electronic energies of the
intermediate carbonium ions and starting halides, as shown in Figure 9-2.
As we have seen previously (Section 6-2), two equivalent electron-pairing
schemes may be written for the allyl cation, which suggest a stabilized hybrid
structure with substantially delocalized electrons :
(one low-energy
electron-pairing
scheme)
I© a i & j- © 1
CH 2 = CH-CH 2 < ► CH 2 -CH=CH 2 ~ CH 2 -CH-CH 2 J +Cl e
(two low-energy (hybrid structure)
electron-pairing
schemes)
No such stabilized hybrid structure can be written for the n-propyl cation.
e
+ CI
(one low-energy (one low-energy
electron-pairing electron-pairing
scheme) scheme)
Thus, we see that less energy is required to form the allyl cation from allyl
chloride than to form the «-propyl cation from n-propyl chloride. (The ease
chap 9 alkyl halides and organometallic compounds 222
- CH,CH 2 CH, ffl
-[CH 2 -CH=CH,
AH,
AH.,
CH 2 = CH— CH 2 C1
propyl
-CH 3 CH,CH,C1
Figure 9-2 The high S N 1 reactivity of allyl chloride compared with n-propyl
chloride is here related to the low energy of allyl-cation formation.
of reaction is actually determined by the energy differences between the
starting halides and the transition states. However, the transition states must
be rather close in energy to the carbonium ions, and it is convenient to deal
with the latter species when developing the argument; see Section 8-9.)
Figure 9-2 shows the energetics of the ionization reaction.
9-7 poljhalogen compounds
Polychlorination of methane affords the di-, tri-, and tetrachloromethanes
CH 2 C1 2
dichloromethane
(methylene chloride)
bp40°
CHC1 3
trichioromethane
(chloroform)
bp61°
ecu
tetrachloromethane
carbon tetrachloride)
bp77°
cheaply and efficiently. These substances have excellent solvent properties
for nonpolar and slightly polar substances. Chloroform was once widely
used as an inhalation anesthetic but has a deleterious effect on the heart and
is slowly oxidized by atmospheric oxygen to highly toxic phosgene (COCl 2 ).
Commercial chloroform contains about 1 % ethanol to destroy any phosgene
formed by oxidation.
Carbon tetrachloride is very commonly employed as a cleaning solvent,
although its high toxicity entails some hazard in indiscriminate use. Carbon
tetrachloride was once widely used as a fire extinguishing fluid for petroleum
fires, although its tendency to phosgene formation makes it undesirable for
confined areas. The common laboratory practice of removing traces of water
from solvents with metallic sodium should never be applied to halogenated
compounds. Carbon tetrachloride-sodium mixtures can detonate and are
shock sensitive.
sec 9.7 polyhalogen compounds 223
Trichloroethylene (" Triclene," bp 87°) is a widely used dry-cleaning solvent.
It may be prepared from either ethene or ethyne.
Ca(OH) 2
HC^CH + 2C1 2 ► CHC1 2 -CHC1 2 — et-\ H CI
\ /
c=c
300° y / \
CH 2 = CH 2
3 CI
2 (-3HC1)
CI
CI
Methylene chloride reacts with hydroxide ion by an S N 2 mechanism very
much less readily than does methyl chloride. The chloromethanol formed
then undergoes a rapid E2 elimination to give formaldehyde, a substance that
exists in water largely as dihydroxymethane (formaldehyde hydrate).
CH,C1,
e OH
slow
S N 2
OtH
CH 2
CI
l<c,
OH e
fast
E2
-► H 2 C =
H 2 Q
fast
OH
/
CH 2
\
OH
Carbon tetrachloride is even less reactive than methylene chloride. One might
expect chloroform to be intermediate in reactivity between methylene chloride
and carbon tetrachloride, but chloroform is surprisingly reactive toward
hydroxide ion and ultimately gives carbon monoxide, formate, and chlo-
ride ions. We may then infer that a different reaction mechanism is involved.
Apparently, a strong base, such as hydroxide ion, attacks the chloroform
molecule much more rapidly at hydrogen than at carbon. There is strong
evidence to show that the carbanion so formed, Cl 3 C: e , can eliminate
chloride ion to give a highly reactive intermediate of bivalent carbon, :CC1 2 ,
called dichloromethylene, a carbene (Section 2-5C). This intermediate has
only six valence electrons around carbon (two covalent bonds), and although
it is electrically neutral it is powerfully electrophilic, and rapidly attacks the
solvent to give the final products.
:CC1,
e
H + OH
e
C1,C:
slow
H 2
fast
2 H 2
CUC:
■> :CC1 2 + cr
♦ CO + 2 HCI
?
fast * HC v + 2 HC1
O e
Note the analogy between this mechanism for the hydrolysis of chloroform
and the elimination mechanism of Exercise 8T2. Both reactions involve a
carbanion intermediate, but subsequent elimination from a /? carbon leads to
an alkene, and from an a carbon to a carbene. Carbene formation is the
result of 1,1 or a elimination.
The electrophilic nature of dichloromethylene, :CC1 2 , and other carbenes,
including the simplest carbene (:C^ called methylene), can be profitably
chap 9 alkyl halides and organometallic compounds 224
used in synthetic reactions. Alkene double bonds can provide electrons,
and carbenes react with an alkene by cis addition to the double bond to
give cyclopropane derivatives, by what can be characterized as a cis-\,\
cycloaddition to the double bond. Activated carbenes, such as are formed
/CI
+ :CC1 2 ► [ j6c
from the light-induced decomposition of diazomethane (CH 2 N 2 ), even
react with the electrons of a carbon-hydrogen bond to "insert" the carbon
of the carbene between carbon and hydrogen. This transforms C— H to
C-CH 3 .
I I
— C:H + =CH 2 ► — C— CH 2 -H
The high activity of the carbene formed from diazomethane and light is
because the :CH 2 is formed in an excited electronic state. The absorption
of the photon not only cleaves the carbon-nitrogen bond but leaves the frag-
ments in high-energy states. The :CH 2 generated this way is one of the most
reactive reagents known in organic chemistry. More selective carbene-type
reactions are possible by elimination of zinc iodide from iodomethylzinc
iodide, ICH 2 ZnI, which leads only to cyclopropane formation with simple
alkenes.
+ CH 2 I, + Zn (CU) > I |;CH, + Znl 2
9-8 Jluor incited alkanes
A. FLUOROCHLOROMETHANES
Replacement of either one or two of the chlorines of carbon tetrachloride
by fluorine can be readily achieved with the aid of antimony triftuoride
containing some antimony pentachloride. The reaction stops after two
chlorines have been replaced. The antimony trifluoride may be regenerated
continuously from the antimony chloride by addition of anhydrous hydrogen
fluoride.
3 CC1 4 + SbF 3 SbC ' 5 > 3 CFCI3 + SbCl 3
bp25°
3 CC1 4 + 2 SbF 3 -^-> 3 CF 2 CI 2 + 2 SbCI 3
bp -30°
Both products have considerable utility as refrigerants, particularly for
household refrigerators and air-conditioning units, under the trade name
Freon. Difiuorodichloromethane (Freon 12) is also employed as a propellant
sec 9.8 fluorinated alkanes 225
in aerosol bombs, shaving-cream dispensers, and other such containers. It is
nontoxic, odorless, and noninflammable, and will not react with hot con-
centrated mineral acids or metallic sodium. This lack of reactivity is quite
generally characteristic of the difluoromethylene group, provided the fluorines
are not located on an unsaturated carbon. Attachment of fluorine to a carbon
atom carrying one or more chlorines tends greatly to reduce the reactivity of
the chlorines toward almost all types of reagents.
B. FLUOROCARBONS
Plastics and lubricating compounds of unusual chemical and thermal stability
are required for many applications in the atomic energy and space programs.
As one example, extraordinary chemical resistance is needed for the pumping
apparatus used for separating U 235 from U 238 by diffusion of very corrosive
uranium hexafluoride through porous barriers. The use of substances made
of only carbon and fluorine (fluorocarbons) for lubricants, gaskets, pro-
tective coatings, and so on, for such equipment is suggested by the chemical
resistance of the — CF 2 — group, and considerable effort has been spent on
methods of preparing compounds such as -f-CF 2 -)- n .
Direct fluorination is highly exothermic and exceedingly difficult to control,
but an indirect hydrocarbon-fluorination process, using cobalt trifluoride as
a fluorinating intermediate, works quite well.
The radical-catalyzed polymerization of tetrafluoroethene produces the
polymer called Teflon.
«CF 2 =CF 2 R ' > -fCF 2 -CF 2 ^
Teflon is a solid, very chemically inert substance, which is stable to around
300°. It makes excellent electrical insulation and gasket materials. It also has
self-lubricating properties, which are exploited in the preparation of low-
adhesion surfaces and light-duty bearing surfaces.
Tetrafluoroethene can be made on a commercial scale by the following
route :
3 CHC1, + 2 SbF 3 SbC ' 5 > 3 CHC1F 2 + 2 SbCl 3
2 CHC1F 2 7 °°T 90 J CF 2 =CF 2 + 2 HC1
2 90% yield z l
Radical polymerization of chlorotrifluoroethene gives a useful polymer
(Kel-F) that is similar to polytetrafluoroethene (Teflon).
An excellent elastomer of high chemical resistance (Viton) can be made by
copolymerizing hexafluoropropene with 1,1-difluoroethene. The product is
stable to 300° and is not attacked by red fuming nitric acid.
C. PROPERTIES OF FLUOROCARBONS
The fluorocarbons have extraordinarily low boiling points relative to the
hydrocarbons of comparable molecular weights and, as seen in Figure 9-3,
chap 9 alkyl halides and organometallic compounds 226
7nn
,
100
100
ulkanes^* ■*"* __ „-—
4-*£Z ,000 \)uou\ l \k-jiw>>
•**
*r
//
-200'
Figure 9-3 Boiling points of straight-chain fluorocarbons (C„F 2n+2 ) and
hydrocarbons (C„H 2 „ + 2 ).
the boiling points of fluorocarbons with the same number of carbons and
about 3.5 times the molecular weight are nearly the same or even lower than
those of the corresponding alkanes. Octafluorocyclobutane boils 17° lower
than cyclobutane, despite a molecular weight more than three times as great.
The high chemical stability, nontoxicity, and low boiling point of octafiuoro-
cyclobutane make it of wide potential use as a propellant in the pressure
H 2 C-
I
CH 2
I
bp + 12°
mol. wt. = 56
F 2 C— CF 2
I I
F 2 C-CF 2
bp -5°
mol. wt.=200
packaging of food. Fluorocarbons are very insoluble in most polar solvents
and are only slightly soluble in alkanes in the kerosene range. The higher-
molecular-weight fluorocarbons are not even miscible in all proportions with
their lower-molecular-weight homologs.
The physiological properties of organofluorine compounds vary exception-
ally widely. Dichlorodifluoromethane and the saturated fluorocarbons appear
to be completely nontoxic. On the other hand, perfluoro-2-methylpropene
is exceedingly toxic, more so than phosgene (COCl 2 ), which was used as a
toxicant in World War I. Many phosphorus-containing organic compounds are
highly toxic if they also have a P— F group. The so-called "nerve gases" are
of this type. Sodium fluoroacetate (CH 2 FC0 2 Na) and 2-fluoroethanol are
toxic fluorine derivatives of oxygen-containing organic substances. The
fluoroacetate salt is sold commercially as a rodenticide. Interestingly, sodium
trifluoroacetate is nontoxic.
9-9
oraanome
r 9<
talli
ic compoun
poi
ids
Research on the chemistry of organometallic compounds has progressed
rapidly in recent years. A number of magnesium, aluminum, and lithium
sec 9.9 organometallic compounds 227
organometallics are now commercially available, and are used on a large
scale despite their being extremely reactive to water, oxygen, and almost all
organic solvents other than hydrocarbons or ethers. This high degree of
reactivity is one reason for the interest in organometallic chemistry, because
compounds with high reactivity generally enter into a wide variety of reactions
and are therefore of value in synthetic work.
Organometallic compounds are most simply defined as substances posses-
sing carbon-metal bonds. This definition excludes substances such as sodium
acetate and sodium methoxide, since these are best regarded as having oxygen-
metal bonds. Among the common metallic elements that form important
organic derivatives are lithium, sodium, potassium, magnesium, aluminum,
cadmium, iron, and mercury.
Less typically metallic elements (the metalloids) — boron, silicon, germa-
nium, selenium, arsenic, and so on — also form organic derivatives, some of
which are quite important, but these fall between true metallic and nonmetallic
organic compounds. They are best considered separately and will not be
included in the present discussion.
A. GENERAL PROPERTIES OF ORGANOMETALLIC COMPOUNDS
The physical and chemical properties of organometallic compounds vary over
an extraordinarily wide range and can be well correlated with the degree of
ionic character of the carbon-metal bonds present. This varies from sub-
stantially ionic, in the case of sodium acetylide, CH=C: e Na®, to essentially
covalent as in tetraethyllead, (C 2 H 5 ) 4 Pb. The more electropositive the
metal, the more ionic is the carbon-metal bond, with carbon at the negative
end of the dipole.
Sel se
— C: Metal
I
The reactivity of organometallic compounds increases with the ionic
character of the carbon-metal bond. It is not then surprising that organo-
sodium and organopotassium compounds are among the most reactive
organometallics. They are spontaneously inflammable in air, react violently
with water and carbon dioxide, and, as might be expected from their saltlike
character, are nonvolatile and do not readily dissolve in nonpolar solvents.
In contrast, the more covalent compounds such as organomercurials [e.g.,
(CH 3 ) 2 Hg] are far less reactive; they are relatively stable in air, much more
volatile, and will dissolve in nonpolar solvents.
For many organometallic compounds the metal atom does not formally
have a full shell of valence electrons. Thus, the usual formulation of trimethyl-
aluminum will have the aluminum with six electrons in its outer valence shell.
There is a tendency for such compounds to form relatively loose dimers, or
more complex structures, to give the metal more nearly complete shells in a
manner discussed earlier for BH 3 which forms B 2 H 6 (Section 4-4B).
chap 9 alkyl halides and organometallic compounds 228
H 3
CH 3 H 3 C x ,C. /CH3
.Al. /( ,- A1 x
CH 3 " " CH 3 H,C V CH 3
H 3
(monomer) (dimer)
trimethylaluminum
B. PREPARATION OF ORGANOMETALLIC COMPOUNDS
Metals with Organic Halides. The reaction of a metal with an organic halide
is a convenient method for preparation of organometallics derived from rea-
sonably active metals such as lithium, magnesium, and zinc. Dialkyl ethers,
particularly diethyl ether, provide an inert, slightly polar medium with
unshared electron pairs on oxygen in which organometallic compounds are
usually soluble. Care is necessary to exclude moisture, oxygen, and carbon
dioxide, which would otherwise react with the organometallic compound,
and this is usually done by using an inert atmosphere of nitrogen or helium.
(CH 3 CH 2 ) 2
CH 3 Br + 2 Li ► CH 3 Li + LiBr
methyllithium
CH 3 CH 2 Br + Mg HiiHkM^ CH 3 CH 2 MgBr
ethylmagnesium
bromide
The reactivity order of thevarioushalides is I > Br > CI > > F. Alkyl fluorides
do not react with lithium or magnesium. Concerning the metal, zinc reacts
well with bromides and iodides, whereas mercury is satisfactory only if
amalgamated with sodium.
2 CH 3 I + Hg(Na) >• (CH 3 ) 2 Hg + 2 Nal
Sodium presents a special problem because of the high reactivity of organo-
sodium compounds toward ether and organic halides. Both lithium and
sodium alkyls attack diethyl ether but, whereas the lithium compounds usually
react slowly, the sodium compounds react so rapidly as to make diethyl ether
impractical as a solvent for the preparation of most organosodium com-
pounds. Hydrocarbon solvents are usually necessary. Even so, special pre-
parative techniques are necessary to avoid having organosodium compounds
react with the organic halide as fast as formed to give hydrocarbons by either
S N 2 displacement or E2 elimination, depending on whether the sodium de-
rivative attacks carbon or a fi hydrogen of the halide.
Sn2 displacement:
CH 3 CH 2 :'Na ffi + CH 3 CH,
E2 elimination
•Br ► CH 3 CH 2 CH 2 CH 3 + Na ffi Br 6
CH 3 CH,:Na e + H-CHXH,:Br ► CH 3 CH 3 + CH 2 =CH 2 + Na® Br e
sec 9.9 organometallic compounds 229
Displacement reactions of this kind brought about by sodium and organic
halides (often called Wurtz coupling reactions) are only of limited synthetic
importance.
Organometallic Compounds with Metallic Halides. The less reactive
organometallic compounds are best prepared from organomagnesium halides
(Grignard reagents) and metallic halides.
CH 3 MgCl + HgCl 2 < — > CH 3 HgCl + MgCl 2
2CH 3 MgCl + HgCl 2 < — ' (CH 3 ) 2 Hg + 2 MgCl 2
These reactions, which are reversible, actually go so as to have the most
electropositive metal ending up combined with halogen. On this basis, sodium
chloride can be predicted confidently not to react with dimethylmercury to
yield methylsodium and mercuric chloride.
Organometallic Compounds and Acidic Hydrocarbons. A few organo-
metallics are most conveniently prepared by the reaction of an alkylmetal
derivative with an acidic hydrocarbon such as an alkyne or cyclopentadiene.
CH 3 MgBr + CH 3 C=CH ► CH 4 + CH 3 C = CMgBr
Such reactions may be regarded as reactions of the salt of a weak acid
(methane, K K < 10~ 40 ) with a stronger acid (propyne, K A ~ 10~ 22 ).
The more reactive organometallic compounds are seldom isolated from the
solutions in which they are prepared. These solutions are not themselves
generally stored for any length of time but are used directly in subsequent
reactions. However, ether solutions of certain organomagnesium halides
(phenyl-, methyl-, and ethylmagnesium halides) are obtainable commercially;
also, «-butyllithium is available dissolved in mineral oil and in paraffin wax.
Manipulation of any organometallic compounds should always be carried
out with caution, owing to their extreme reactivity, and, in many cases, their
considerable toxicity (particularly organic compounds of mercury, lead, and
zinc).
C. ORGANOMAGNESIUM COMPOUNDS (GRIGNARD REAGENTS)
The most important organometallic compounds for synthetic purposes are
the organomagnesium halides, or Grignard reagents. They are so named
after Victor Grignard, who discovered them and developed their use as
synthetic reagents, for which he received a Nobel Prize in 1912. As already
mentioned, these substances are customarily prepared in dry ether solution
from magnesium turnings and an organic halide. Chlorides often react
ether _
CH 3 I + Mg > CH 3 MgI
95% yield
sluggishly. In addition, they may give an unwelcome precipitate of magnesium
chap 9 alkyl halides and organometallic compounds 230
chloride which, unlike magnesium bromide and iodide, is only very slightly
soluble in ether. Very few organomagnesium fluorides are known.
Organomagnesium compounds, such as methylmagnesium iodide, are not
e ®>
well expressed by formulas such as CH 3 MgI or CH 3 MgI because they
appear to possess polar rather than purely covalent or ionic carbon-magnesium
bonds. However, the reactions of Grignard reagents may often be conveniently
considered as involving the carbanion, R e .
se 8© ©
R-Mg-X « -* R: e + MgX
The state of the MgX bond has not been specified here because it is not
usually significant to the course of the reaction. The MgX bond may well have
as much or more polar character than the RMg bond but our policy in this
ae s® <5 e s&
book will be to write structures such as R— MgX or RMg— X only when we
feel that this will contribute something to understanding the reaction. Thus,
CH 3 MgI is usually to be understood as the composition of a substance,
rather than a depiction of a structure, in the same way as we use the formulas
NaClandH 2 S0 4 .
Grignard reagents as prepared in ether solution are very highly associated
with the solvent. Not all the ether can be removed, even under reduced
pressure at moderate temperatures, and the solid contains one or more
moles of ether for every mole of organomagnesium compound. The ether
molecules appear to be coordinated through the unshared electron pairs of
oxygen to magnesium.
Reaction with Active Hydrogen Compounds. Grignard reagents react with
acids, even very weak acids such as water, alcohols, alkynes, and primary
and secondary amines. These reactions may be regarded as involving the
neutralization of a strong base (R: e of RMgX). The products are hydro-
carbon, RH, and a magnesium salt :
se §© © ©
CH 3 -MgI + CH 3 CH 2 OH <■ CH 4 + CH 3 CH 2 Mgl
This type of reaction occasionally provides a useful way of replacing a halogen
bound to carbon by hydrogen as in a published synthesis of cyclobutane from
cyclo butyl bromide:
H 2 C-CH-Br _^ H 2 C-CH-MgBr ^
H 2 C-CH 2
Reaction with Oxygen, Sulfur, and Halogens. Grignard reagents react
with oxygen, sulfur, and halogens to form substances containing C— O,
C— S, and C— X bonds, respectively. These reactions are not usually impor-
RMgX + 2 > R-O-O-MgX RMgX > 2ROMgX ^2Jl!t 2 ROH
H 2 0, H ffi
8 RMgX + S 8 > 8 RSMgX ► 8 RSH
RMgX + I 2 ► Rl + MgXI
sec 9.9 organometallic compounds 231
tant for synthetic work since the products ROH, RSH, and RX can usually
be obtained more conveniently and directly from alkyl halides by S N 1 and
S N 2 displacement reactions, as described in Chapter 8. However, when both
S N 1 and S N 2 reactions are slow or otherwise impractical, as for neopentyl
derivatives, the Grignard reactions can be very useful.
CH 3 CH 3 CH 3
' Ma I I, I
CH 3 -C-CH 2 C1 *-> CH 3 -C-CH 2 MgCl —* CH 3 -C-CH 2 I
CH 3 CH 3 CH 3
neopentyl chloride neopentyl iodide
Also, oxygenation of a Grignard reagent at low temperatures provides an
excellent method for the synthesis of hydroperoxides. To prevent formation
RMgX + 2 ~ 7 ° » ROOMgX Hi6 > ROOH
of excessive amounts of the alcohol, inverse addition is desirable (i.e., a solution
of Grignard reagent is added to ether through which oxygen is bubbled rather
than have the oxygen bubble through a solution of the Grignard reagent).
Additions to Carbonyl Groups. The most important synthetic use of
Grignard reagents is for formation of new carbon-carbon bonds by addition
to multiple bonds, particularly carbonyl bonds. (Carbon-carbon double and
triple bonds, being nonpolar, are inert to Grignard reagents.) In each case,
magnesium is transferred from carbon to a more electronegative element. An
example is the addition of methylmagnesium iodide to formaldehyde. The
CH 3 :MgI + H 2 C = O v ► CH 3 :CH 2 -0 Mgl " 2 ° » CH 3 CH 2 OH
new carbon-carbon bond
yields of addition products are generally high in these reactions and, with
suitable variations of the carbonyl compound, a wide range of compounds can
be built up from substances containing fewer carbon atoms per molecule.
The products formed from a number of types of carbonyl compounds with
Grignard reagents are listed in Table 9T. (The nomenclature of carbonyl
compounds is considered in Section 11-1.)
The products are complex magnesium salts from which the desired organic
product is freed by acid hydrolysis :
ROMgX + HOH ► ROH + HOMgX
HC1
■> H 2 + MgXCl
If the product is sensitive to strong acids, the hydrolysis may be conveniently
carried out with a saturated solution of ammonium chloride ; basic magnesium
salts precipitate while the organic product remains in ether solution.
The reaction of carbon dioxide with Grignard reagents gives initially
\
chap 9 alkyi halides and organometallic compounds 232
Table 94 Products from the reaction of Grignard reagents as RMgX
with carbonyl compounds
product
hydrolysis product customary yield
formaldehyde
aldehyde
ketone
carbon dioxide
carboxylic acid
carboxylic ester
acid chloride
,c=o
R'
c=o
>-0
CO,
R'
V
,c=o
HO
R'
\
,c=o
R"0
R'
V
c=o
/
CI
R'
N,N-dimethyJ C =
carboxamide ,„„ -, J
(LH 3 ) 2 in
RCH 2 OMgX prim, alcohol RCH 2 OH
R'
I
R-C-OMgX
1
H
R'
1
R-C-OMgX
I
R"
RCQ 2 MgX
R'
I
sec. alcohol R— CHOH
R'
I
ten. alcohol R— C— OH
I
R"
carboxylic acid RC0 2 H
R'C0 2 MgX + RH carboxylic acid R'CO z H
R'
I
R-C-OMgX
I
R
R'
I
R-C-OMgX
I
R
R'
I
R— C— OMgX ketone
I
N(CH 3 ) 2
R'
\
good
good
good to poor
good
good
R'
I
ten. alcohol R— C— OH good to poor
I
R
R'
I
ten. alcohol R— C— OH good to poor
I
R
r — O good to poor
RC0 2 MgX. This substance is a halomagnesium salt of carboxylic acid and
RMgX + co 2 -
->• R — C
O
//
o
— - — > R-C
\ \
OMgX OH
acidification produces the carboxylic acid itself.
O
Acid chlorides such as acetyl chloride, CH 3 C usually combine with
CI
two moles of Grignard reagent to give a tertiary alcohol. Presumably, the
first step is addition to the carbonyl bond :
sec 9.9 organometallic compounds 233
O OMgX
CH 3 C + RMgX ► CHj-C-Cl
CI
R
C OM g X O
CH 3 -C-^C1 ► CH 3 -C-R + MgXCl
R
O R
II I
CH3-C-R + RMgX ► CH 3 -C— OMgX
The reaction of acid chloride with RMgX is impractical for the synthesis
of ketones because RMgX usually adds rapidly to the ketone as it is formed.
However, the use of the less reactive organocadmium reagent, RCdX, usually
gives good yields of ketone.
Reaction of esters with Grignard reagents is similar to the reaction of acid
chlorides and is very useful for synthesis of tertiary alcohols with two identical
groups attached to the carbonyl carbon:
T
CH 3 -C + 2 RMgX <• CH 3 -C-OMgX + MgX(OCH 3 )
OCH 3 r
Many additions of Grignard reagents to carbonyl compounds proceed in
nearly quantitative yields, while others give no addition product whatsoever.
Trouble is most likely to be encountered in the synthesis of tertiary alcohols
with bulky alkyl groups, because the R group of the Grignard reagent will
be hindered from reaching the carbonyl carbon of the ketone and side re-
actions may compete more effectively.
Addition to Carbon-Nitrogen Triple Bonds. Nitrogen is a more electro-
negative element than carbon and the nitrile group is polarized in the sense
88 se
— C=N. Accordingly, Grignard reagents add to nitrile groups in much the
same way as they add to carbonyl groups :
R'
e a \ e a
R— C=N + R — MgX ► C = N — MgX
R
Hydrolysis of the adducts leads to ketimines, which are unstable under the
reaction conditions and rapidly hydrolyze to ketones:
R'
\ e e H®, H 2
C = N— MgX >
R
R'
\
C=NH
/
R
ketimine
R'
i^2 C = + NH 4
R
chap 9 alkyl halides and organometaliic compounds 234
Small-Ring Cyclic Ethers. Grignard reagents react with most small-ring
cyclic ethers by S N 2 displacement. The angle strain in three- and four-
membered rings facilitates ring opening, whereas the strainless five- and six-
membered cyclic ethers are not attacked by Grignard reagents.
RMgX + H 2 C-CH 2 ► RCH 2 -CH 2 OMgX
O
ethylene oxide
RMgX + H 2 C O ► RCH 2 CH 2 CH 2 OMgX
C
H 2
trimethylene oxide
D. ORGANOSODIUM AND ORGANOLITHIUM COMPOUNDS
Alkylsodium and alkyllithium derivatives behave in much the same way as
organomagnesium compounds, but with increased reactivity. As mentioned
previously, they are particularly sensitive to air and moisture, and react with
ethers, alkyl halides, active hydrogen compounds, and multiple carbon-
carbon, carbon-oxygen, and carbon-nitrogen bonds. In additions to carbonyl
groups they give fewer side reactions than Grignard reagents and permit
syntheses of very highly branched tertiary alcohols. Triisopropylcarbinol,
which has considerable steric hindrance between its methyl groups, can be
made from diisopropyl ketone and isopropyllithium, but not with the cor-
responding Grignard reagent.
H 3 C O C h 3 h 3 C /H 3 C \
\ II / \ / \ \
CH-C-CH + CH-Li > I CH J C-OH
H 3 C CH 3 H 3 C VHjC 7 / 3
triisopropylcarbinol
E. SOME COMMERCIAL APPLICATIONS OF ORGANOMETALLIC
COMPOUNDS
Tetraethyllead, bp 202°, is the most important organometaliic compound in
commercial use. It greatly improves the antiknock rating of gasoline in
concentrations on the order of 1 to 3 ml per gallon (Section 3-3). 1,2-Dibro-
moethane is added to leaded gasoline to convert the lead oxide formed in
combustion to volatile lead bromide and thus diminish deposit formation.
Most tetraethyllead is made by the reaction of a lead-sodium alloy with ethyl
chloride. The excess lead is reconverted to the sodium alloy. Tetramethyllead
shows some advantage over tetraethyllead in high-performance engines.
4C 2 H 5 C1 + 4PbNa >• (C 2 H 5 ) 4 Pb -I- 4 NaCl + 3 Pb
Some alkylmercuric halides, such as ethylmercuric chloride, have fungicidal
properties and are used to preserve seeds and grains. This practice, however,
may be having a deleterious effect on ducks and other kinds of wildlife.
sec 9.9 organometallic compounds 235
F. FERROCENE
An exceptionally stable organometallic compound of unusual structure was
discovered in 1952. An orange solid, mp 174°, containing iron, it was given
the name ferrocene. It can be prepared by converting cyclopentadiene to its
anion and treating this with a ferrous salt.
> Fe + 2 NaCl
Bonding in the ferrocene molecule results from sharing of the n electrons
of the two rings with iron. The carbons are in parallel planes about 3.4 A
apart with the iron between, hence the name " sandwich compound." This
compound is not simply an ionic salt, Fe 2 ®(C 5 H 5 e ) 2 , because it is insoluble
in water, soluble in most organic solvents, and is not affected by boiling with
dilute acid or base. In contrast, the truly ionic sodium salt of cyclopentadiene
reacts rapidly with water or acids and is insoluble in most organic solvents.
Analogous sandwich compounds (metallocenes) can be formed with many
other transition metals, such as nickel, cobalt, and manganese. Other sandwich
compounds are known with different ring sizes — six-, seven-, and eight-
membered rings with metals as diverse as chromium and uranium.
A few metals form more or less stable complexes with alkenes, which have
metal-carbon bonds. Silver ion, as in solutions of silver nitrate, complexes
some alkenes and alkadienes strongly enough to make them soluble in water
and/or form crystalline silver nitrate complexes. Platinum, rhodium, and
palladium, which in the metallic state are good hydrogenation catalysts, form
some quite stable alkene complexes. A specially interesting example is stable
71-cyclopentadienyldiethenerhodium, 1 a "half-sandwich" compound.
£5
c c
H 2 H 2
The organic groups of such compounds do not usually show much nucleo-
philic character. Indeed, some platinum-ethene complexes are stable in strong
hydrochloric acid.
1 The designation 77-cyclopentadienyl means that the C 5 H 5 group is bound to the metal
as in ferrocene.
chap 9 alkyl halides and organometallic compounds 236
summary
Alkyl halides (haloalkanes) have low water solubilities and except for alkyl
fluorides their boiling points are close to those of the alkanes of similar
molecular weight. Other than their nmr spectra, their only striking spectral
characteristics are strong infrared bands at 1350-1000 cm -1 (C— F stretch)
and at 800-600 cm"" 1 (C— CI stretch).
Alkyl halides can be prepared from alkanes, alkenes, and alcohols.
RCH 2 CH 3
ny " HX
-> RCHXCH 3 < RCHOHCH3 (X = C1, Br, I)
RCH 2 CH 2 Br
The reactions of alkyl halides include displacement and elimination reac-
tions. (See summary in Chapter 8.)
Vinyl halides (RCH=CHX) are much less reactive than alkyl halides in
nucleophilic displacement reactions. Allyl halides (RCH=CHCH 2 X) are
much more reactive, because of the ease of forming the resonance-stabilized
cation RCH=CH-CH 2 +-> RCH-CH=CH 2 .
Polyhalogen compounds are useful solvents. Di- and trihalomethanes are
rather unreactive in displacement reactions with strong bases. Chloroform,
however, undergoes a ready elimination with base to give a carbene, :CC1 2 .
This can add to the double bond of alkenes. Activated carbenes (as from
diazomethane photolysis) also undergo insertion reactions at C— H bonds.
^C -c. \ \
II + :CZ 2 ► LCZ 2 „C-H + :CZ 2 * ► ^C-CHZ 2
/C^ -C' / /
Fluoroalkanes have rather different properties than the other haloalkanes;
they are very much more volatile, their polymers have exceptional thermal
and chemical stability (Teflon, Viton), and their toxicities vary widely.
Alkyl halides can be converted to organometallic compounds whose prop-
erties vary from the highly ionic and reactive (R e Na®) to the highly covalent
and unreactive (R 4 Pb, R 2 Hg). Midway are organomagnesium compounds
(Grignard reagents), the most important of the organometallics. Grignard
RX + Mg ► RMgX (in dry ether)
reagents react with virtually all organic compounds except alkanes, alkenes,
and ethers. A summary of important Grignard reactions follows and the final
step (required in all but the first example) is addition of an active hydrogen
compound, such as water, to destroy a halomagnesium salt.
:gx + h 2 o —
► RH + MgOHX
+
o 2 —
—
ROH
+
R'CHO
— ►
— ♦ R'RCHOH
+
O
II
R'-C-
R' -
R
-♦ — ♦ R' 2 COH
+
O
II
RC-OCH3
-—►—»—» R'R 2 COH
+
co 2 — >
-
RC0 2 H
+
RC=N
—
— — » R 2 C =
+
V^
—
RCH 2 CH 2 OH
exercises 237
ROH, RC0 2 H, NH 3 , and deriva-
tives, and RC=CH react similarly
(S g and I 2 react similarly)
(HCHO reacts similarly and
gives a primary alcohol)
(via R'RC=0; RCOC1 reacts
similarly)
(O
reacts similarly )
Organocadmium compounds, RCdX, are less reactive than Grignard
reagents. They react with acid chlorides but not with ketones.
RCdX + R'COCl > R'RC=0 + CdXCl
The stable organoiron compound ferrocene, Fe(C 5 H 5 ) 2 , has a sandwich
structure. Other transition metals form similar compounds.
exercises
9-1 Show how 2-bromoheptane can be prepared starting from (a) 2-heptanol,
(b) 1-heptanol, (c) 1-heptyne.
9-2 When 3-ethyl-3-chloropentane reacts at room temperature with aqueous
sodium carbonate solution a mixture of two compounds, one an alcohol
and one an alkene, is obtained.
a. Write the equations for these two reactions and name each of the
products.
b. Suggest changes in reaction conditions that would favor formation of
the alkene.
(You may wish to review Sections 8-12 and 8-13.)
9-3 a. Write resonance structures for the transition states of S N 2 substitution for
allyl and n-propyl chlorides with hydroxide ion and show how these can
account for the greater reactivity of the allyl compound.
b. Would you expect that electron-donating or electron-withdrawing groups
substituted at the y carbon of allyl chloride would increase the S N 2
reactivity of allyl chloride ?
9-4 The rate of formation of the CH 2 -addition product from iodomethylzinc
iodide and cyclohexene is first order in each participant. Suggest a mechanism
that is in accord with this fact.
chap 9 alkyl halides and organometallic compounds 238
9-5 What products would you expect from the reaction of bromoform, CHBr 3 ,
with potassium /-butoxide in ?-butyl alcohol in the presence of (a) trans-2-
butene, (b) cw-2-butene?
9-6 Would you expect the same products if, instead of addition to the carbonyl
group, the acyl halides were to undergo a simple S N 2 displacement of halogen
with the Grignard reagent acting to furnish R: e ? Explain why simple dis-
placement is unlikely to be the correct mechanism from the fact that acid
fluorides react with Grignard reagents faster than acid chlorides, which in
turn react faster than acid bromides.
9-7 What products would you expect to be formed in an attempt to synthesize
hexamethylethane from ^-butyl chloride and sodium ? Write equations for the
reactions involved.
9 • 8 Write structures for the products of the folio wing reactions involving Grignard
reagents. Show the structures of both the intermediate substances and the
substances obtained after hydrolysis with dilute acid. Unless otherwise
specified, assume that sufficient Grignard reagent is used to cause those reac-
tions to go to completion which occur readily at room temperatures.
a. C 6 H 5 MgBr + C 6 H 5 CHO
b. CH 3 MgI + CH 3 CH 2 C0 2 C 2 H 5
c. (CH 3 ) 3 CMgCl + C0 2
d. CH 3 CH 2 MgBr + C1C0 2 C 2 H 5
e. CH 3 MgI + CH 3 COCH 2 CH 2 C0 2 C 2 H 5
(1 mole) (1 mole)
O
II
/ C 6 H 5 MgBr + CH 3 0-C-OCH 3
o o
II II
g. (CH 3 ) 3 CCH 2 MgBr + CH3C-O-CCH3
9-9 Show how each of the following substances can be prepared by a reaction
involving a Grignard reagent :
H 2 C
a. H 2 C^ \)H— CH 2 OH (two ways)
H 2 C
b. CH 2 =CH-C(CH 3 ) 2 OH
c. CH 3 CH 2 CH(OH)CH 3 (two ways)
d. (CH 3 CH 2 ) 3 COH (three ways)
H,C S
e. | ^CHOH
H 2 C
9-10 Complete the following equations:
a. C 6 H 5 CH 2 CH 2 MgBr + (CH 3 )2S0 4 *
exercises 239
b. C 2 H 5 MgBr + CH 3 C=C-CH 2 Br <
c. CH 2 =CH-CH 2 Li + CH 2 =CH-CH 2 C1
d. CH 3 CH 2 CH 2 MgBr + ClCH 2 OCH 3
9-11 Each of the following equations represents a " possible " Grignard synthesis.
Consider each equation and decide whether or not you think the reaction
will go satisfactorily. Give your reasoning and, for those reactions that are
unsatisfactory, give the expected product or write "No Reaction" where
applicable.
a. methylmagnesium iodide + butyryl chloride ► * n-propyl
methyl ketone
b. methylmagnesium iodide + CH 3 CH=N—CH 3 ► ►
CH 3
I
CH 3 CH 2 -N-CH 3
Mg CH 2 =
c. 2-bromoethyl acetate * Grignard reagent ► ►
ether
3-hydroxypropyl acetate
d. allylmagnesium chloride + ethyl bromide ► 1-pentene
9-12 Predict the products of each of the following Grignard reactions before and
after hydrolysis. Give reasoning or analogies for each.
a. CH 3 MgI + HC0 2 C 2 H 5 ►
b. CH 3 CH 2 MgBr + CS 2 ►
c. CH 3 CH 2 MgBr + NH 3 »■
9-13 Show how each of the following substances can be synthesized from the
indicated starting materials by a route that involves organometallic substances
in at least one step :
a. (CH 3 ) 3 C-D from (CH 3 ) 3 CCI
b. CH 3 C=C-C0 2 H from CH^CH
CH 3
I
c. CH 3 -C-CH 2 I from (CH 3 ) 4 C
I
CH 3
CH 3
I
d. CH 3 -C-CH(CH 3 ) 2
'•(OJt
OH
COH from < ^Br
CH,
*3
I
/ CH 3 -C-CH 2 CH 2 CH 2 CH 2 OH from (CH 3 ) 3 CCH 2 C1
9-14 Explain what inferences about the stereochemistry of the E2 reaction can be
made from the knowledge that the basic dehydrohalogenation of A is
exceedingly slow compared with that of B.
chap 9 alkyl halides and organometallic compounds 240
CI
]_
H
1
Cl
Cl
Ml
p:
c lAr
H
i
Cl
Cl
B
H
9' 15 Classify each of the following reactions by consideration of yield, side reac-
tions, and reaction rate as good, fair, or bad synthetic procedures for prepa-
ration of the indicated products under the given conditions. Show your reason-
ing and designate any important side reactions.
CH,
CH,
CHL-C-C1 + CH 3 -C-ONa
50°
CH,
CH,
CH,
CH 3
I
-C— o-
I
CH 3
CH 3
I
-C-CH, + NaCl
I
CH,
/■
CH 3
CH 3
CH 3 -
1 25°
1
T _ /-< _ r\ 1
1 *r C1I3 v- Uri ' *^H 4 t* ^113 \_, \j 1
CH 3
CH 3
CH 3 CH 3
CH 3 -
1 H <~> 1
-CH-CH-CH 3 ]0 2 0O > CH 3 -CH-CH=CH 2 + HC1
1
Cl
H 3 C
^N H Nai Hi V^4
H K
\ A^St' H\ / H
CH 3 O
CH 3 O
CH 3 -
1 II 50°
-C-CH 2 C1 +CH 3 C-ONa ► CH 3 -
1 II
- C- CH 2 - O- C- CH 3 +NaCl
CH 3
CH 3
CH 3
CH 3
CH 3 -
1 35°
1
-C-0-CH 2 CH 3 +CH 3 CH 2 C1
C U t LnjLn2ULH 2 trl3 ' Ln 3 "
CH 3
CH 3
O
O
CH 2 =
CH 2 =
II 25°
H-0-C-CH 3 + AgCl
-CH 2 F + iSbCl 3
-tntlTLrljL UAg * Cri 2 — C
=CH-CH 2 C| +iSbF 3 5 °° > CH 2 =CH-
9-16 Consider each of the following compounds to be in unlabeled bottles in pairs
as indicated. Give for each pair a chemical test (preferably a test tube reaction)
that will distinguish between the two substances and show what the observa-
tions will be. Write equations for the reactions expected.
Bottle A
Bottle B
a.
(CH 3 ) 3 CCH 2 C1
CH 3 CH 2 CH 2 CH 2 C1
b.
BrCH=CHCH 2 Cl
ClCH=CHCH 2 Br
c.
(CH 3 ) 3 CC1
(CH 3 ) 2 CHCH 2 C1
d.
CH 3 CH=CHC1
CH 2 =CHCH 2 C1
e.
(CH 3 ) 2 C=CHC1
CH 3 CH 2 CH=CHC1
f.
CH 3 CH 2 CH=CHC1
CH 2 =CHCH 2 CH 2 C1
-o
UAh
' —
^-
X
■-.. •■■■ -■=
o
- o
o
- o
— __
— ^
i
o
- o
CO
o
-
s
o
5<a
-§
^-
*Tfc
. ., ... . -^^M
-
o
-o
1
-
' > ' -1
-
CQ
1
o
- o
CO
CJ
•" ' ' 1
•
c
s„
1 3
8*
241
UOISSIUISUBI} %
chap 9 alkyl halides and organometallic compounds 242
9-17 Show how the pairs of compounds listed in Exercise 9-16 could be distin-
guished by spectroscopic means.
9-18 Deduce the structures of the two compounds whose nmr and infrared spectra
are shown in Figure 94. Assign as many of the infrared bands as you can and
analyze the nmr spectra in terms of chemical shifts and spin-spin splittings.
9-19 Write balanced equations for reactions that you expect would occur between
the following substances (1 mole) and 1 mole of pentylsodium. Indicate
your reasoning where you make a choice between several possible alternatives.
a. water /. allyl chloride
b. diethyl ether g. acetic acid (added slowly to the
c. f-butyl chloride pentylsodium)
d. pentyl iodide h. acetic acid (pentylsodium added
e. propene slowly to it)
chapter 10
alcohols and ethers
chap 10 alcohols and ethers 245
Alcohols, ROH, and ethers, ROR, can be regarded as substitution prod-
ucts of water. With alcohols, we shall be interested on the one hand in
reactions that proceed at the O— H bond without involving the C— O bond or
the organic group directly, and on the other hand with processes that result in
cleavage of the C— O bond or changes in the organic group. The reactions
involving the O— H bond are expected to be similar to the corresponding
reactions of water.
The simple ethers do not have O— H bonds, and the few reactions that they
undergo involve the substituent groups.
Alcohols are classed as primary, secondary, or tertiary according to the
number of hydrogen atoms attached to the hydroxylic carbon atom. This
RCH 2 OH R 2 CHOH R 3 COH
primary alcohol secondary alcohol tertiary alcohol
classification is necessary because of the somewhat different reactions the
three kinds of compounds undergo.
The nomenclature of alcohols has been discussed previously (page 187).
The first member of the alcohol series, methanol or methyl alcohol,
CH3OH, is a toxic liquid. In the past it was prepared by the destructive dis-
tillation of wood and acquired the name wood alcohol. Many cases of
blindness and death have resulted from persons drinking it under the impres-
sion that it was ethyl alcohol, CH 3 CH 2 OH (ethanol).
Ethanol is intoxicating in small amounts but toxic in large amounts. The
higher alcohols are unpleasant tasting, moderately toxic compounds which are
produced in small amounts along with ethanol by fermentation of grain. A
mixture of higher alcohols is called fusel oil. (Fusel means bad liquor in
German.) One hundred proof whiskey (or whisky) 1 contains 50% ethanol by
volume and 42.5% ethanol by weight. Pure ethanol (200 proof) is a strong
dehydrating agent and is corrosive to the gullet.
An understanding of the chemistry of alcohols is important to under-
standing the functioning of biological systems which involve a wide variety
of substances with hydroxyl groups. The OH group attached to a carbon
chain often dramatically changes physical properties and provides a locus for
chemical attack.
10-1 physical properties of alcohols
Comparison of the physical properties of alcohols with those of hydrocar-
bons of comparable molecular weight shows several striking differences,
especially for the lower members. Alcohols are substantially less volatile and
have higher melting points and greater water solubility than the corres-
ponding hydrocarbons, although the differences become progressively
smaller as molecular weight increases. x The first member of the alcohol
1 Scotch and Canadian whisky, but Irish and American whiskey.
chap 10 alcohols and ethers 246
series, CH 3 OH (methanol or methyl alcohol), has a boiling point of 65°,
whereas ethane, CH 3 CH 3 , with almost the same molecular weight boils at
-89°.
The profound effect of the hydroxyl group on the physical properties of
alcohols is caused by hydrogen bonding. The way in which the molecules of
hydroxylic compounds interact via hydrogen bonds was described earlier
(Section 1-2B).
The water solubility of the lower-molecular-weight alcohols is high and is
also a result of hydrogen bonding. In methanol, the hydroxyl group accounts
for almost half of the weight of the molecule, and it is thus not surprising that
the substance is miscible with water in all proportions. As the size of the
hydrocarbon group of an alcohol increases, the hydroxyl group accounts for
progressively less of the molecular weight, and hence water solubility decreases
(Figure 10-1). Indeed, the physical properties of higher-molecular-weight
alcohols are very similar to those of the corresponding hydrocarbons.
An interesting effect of chain branching on solubility can be seen in the
four butyl alcohols. «-Butyl alcohol is soluble to the extent of 8 g in 100 g of
water whereas ?-butyl alcohol is completely miscible with water (Table 10-1.)
Branching also affects volatility. The highly branched alcohol, f-butyl
alcohol, has a boiling point 35° lower than that of «-butyl alcohol. The
effect of branching on melting point is in the opposite direction because
crystal packing is improved by branching. The result is that ^-butyl alcohol
has the highest melting point and the lowest boiling point of the four isomeric
C 4 alcohols. (?-Butyl alcohol is liquid over a range of only 58° whereas
«-butyl alcohol is liquid over a range of 208°.) See Table 10-1.
Figure 10-1 Dependence of melting points, boiling points, and water solu-
bilities of continuous-chain primary alcohols (C„H 2 „ + 2 0) on«. (The alcohols
with C 3 or fewer carbons are infinitely soluble in water.)
250
200
150
100
-100
3 3
sec 10.2 spectroscopic properties of alcohols — hydrogen bonding 247
Table 10-1 Physical properties of the butyl alcohols
name
formula
mp,
°C
bp,
°C
solubility,
g/lOOg water
n-butyl alcohol (1-butanol)
CH 3 CH 2 CH 2 CH 2 OH
-90
118
8.0
isobutyl alcohol
(2-methy 1- 1 -propanol)
(CH 3 ) 2 CHCH 2 OH
-108
108
10.0
.s-butyl alcohol (2-butanol)
CH 3 CH 2 CHOHCH 3
-114
100
12.5
/-butyl alcohol (2-methyl-
2-propanol)
(CH 3 ) 3 COH
25
83
00
10-2 spectroscopic properties of alcohols— hydrogen
bonding
The hydrogen-oxygen bond of a hydroxyl group gives a characteristic
absorption band in the infrared and, as we might expect, this absorption is
considerably influenced by hydrogen bonding. For example, in the vapor state
(in which there is essentially no hydrogen bonding because of the large inter-
molecular distances), ethanol gives an infrared spectrum with a fairly sharp
absorption band at 3700 cm -1 owing to a free or unassociated hydroxyl
group (Figure 10-2a). In contrast, this band is barely visible at 3640 cm -1 in
the spectrum of a 10% solution of ethanol in carbon tetrachloride (Figure
10-2b). However, there is a relatively broad band around 3350 cm -1 which is
characteristic of hydrogen-bonded hydroxyl groups. The shift in frequency of
about 300 cm -1 is not surprising, since hydrogen bonding weakens the
O— H bond; its absorption frequency will then be lower. The association
band is broad because the hydroxyl groups are associated in aggregates of
various sizes and shapes, giving rise to a variety of different kinds of hydro-
gen bonds and therefore a spectrum of closely spaced O— H absorption
frequencies.
In very dilute solutions of alcohols in nonpolar solvents, hydrogen bonding
is minimized ; but as the concentration is increased, more and more of the
molecules become associated and the intensity of the infrared absorption
band due to associated hydroxyl groups increases at the expense of the free
hydroxyl band. Furthermore, the frequency of the association band is a
measure of the strength of the hydrogen bond. The lower the frequency
relative to the position of the free hydroxyl group, the stronger is the hydrogen
bond. As we shall see in Chapter 13, the hydroxyl group in carboxylic acids
(RC0 2 H) forms stronger hydrogen bonds than alcohols and, accordingly,
absorbs at lower frequencies (lower by about 400 cm -1 ).
From the foregoing discussion of the influence of hydrogen bonding on the
infrared spectra of alcohols, it should come as no surprise that the nuclear
magnetic resonance spectra of the hydroxyl protons of alcohols are similarly
affected. Thus the chemical shift of a hydroxyl proton is influenced by the
degree of molecular association through hydrogen bonding and on the
chap 10 alcohols and ethers 248
m
wavelength, fJL
4 5 5
9 10 12 14
T— 1 T T
~V
,a,
-I i i i _J i i ■ l_
3600 3200 2800 2400 2000 2000
1 800 1 600 1 400 1 200 1 000 800
frequency, cm -
(b)
J i i i i
wavelength, jJ.
10 12 14
i 1 r
3600 3200 2800 2400 2000 2000
-. 1 i I I L_
1 800 1 600 1 400
frequency, cm -1
J l l 1_
1 200 1 000 800
Figure 10-2 Infrared spectrum of ethanol in the vapor phase (a) and as a 10%
solution in carbon tetrachloride (b).
sec 10.3 preparation of alcohols 249
strengths of the hydrogen bonds. Except for alcohols that form intramolecular
hydrogen bonds, the OH chemical shift varies extensively with temperature,
concentration, and the nature of the solvent. Also, resonance appears at
lower magnetic fields (i.e., the chemical shift is larger relative to TMS) as the
strengths of hydrogen bonds increase. Thus, the chemical shifts of the OH
protons of simple alcohols as pure liquids generally fall between 4 and 5 ppm
downfield with respect to tetramethylsilane, but when the degree of hydrogen
bonding is reduced by dilution with carbon tetrachloride, the OH reso-
nances move upheld. With ethyl alcohol, the shift is found to be 3 ppm between
the pure liquid and very dilute solution in carbon tetrachloride.
One may well question why it is that absorptions are observed in the infra-
red spectrum of alcohols which correspond both to free and hydrogen-
bonded hydroxyl groups, while only one OH resonance is observed in their
nmr spectra. The answer is that the lifetime of any one molecule in the free
or unassociated state is long enough to be detected by infrared absorption but
too short to be detected by nmr. Consequently, one sees only the average OH
resonance for all species present. (For a discussion of nmr and rate processes,
see Section 7-6D.)
10-3 preparation of alcohols
We have already encountered most of the important methods of preparing
alcohols, which are summarized below.
1. Hydration of alkenes (Section 4-4). The direction of addition is governed
RCH=CH 2 + H 2 HS > RCHOHCH3
by Markownikoff 's rule and primary alcohols, therefore, cannot be made this
way (except for CH 3 CH 2 OH).
2. Hydroboration of alkenes (Section 4-4F). The direction of addition is
RCH=CH 2 + B 2 H 6 ► (RCH 2 CH 2 ) 3 B H2 ° 2 . RCH 2 CH 2 OH
" anti-Markownikoff " and primary alcohols, therefore, can be made this way.
3. Addition of hypohalous acids to alkenes (Section 4-4). The HO group
RCH=CH 2 + HOC1 ► RCHOHCH 2 Cl
becomes bonded to the carbon atom bearing the least number of hydrogen
atoms.
4. S N 2 and S N 1 hydrolyses of alkyl halides (Sections 8-7 to 8T0). Primary
RCH 2 CH 2 C1 + OH e ► RCH 2 CH 2 OH + Cl e S N 2
r 3 CC1 H2 ° > R3COH S N 1
and secondary but not tertiary alkyl halides require hydroxide ion. A side
reaction is elimination, which can be especially important with tertiary
halides and strong bases.
chap 10 alcohols and ethers 250
5. Grignard reagents to carbonyl groups (Section 9-9C). Grignard reagents
o
RMgBr + H— C-H ► RCH 2 MgBr H2 ° > RCH 2 OH primary
alcohol
O O MgBr OH
II . | ho I secondary
+ R'— C— H ► R'CH— R — ► R'-CH— R alcohol
e e
O O MgBr OH
II I H.O I
+ R' — C— R" ► R — C — R" ► R'-C-R"
I I
R R
tertiary
alcohol
O O MgBr OH
+ R' — C— OR" ► R' — C-R — ► R' — C-R tertiary
| | alcohol
R R
with ketones can be used to produce tertiary alcohols in which all three R
groups are different; with esters, tertiary alcohols result in which at least
two of the R groups are identical.
6. Reduction of carbonyl compounds (to be described in Section 11-4F):
R— C ► R— CH 2 OH primary alcohol
R— C ► R— CH 2 OH primary alcohol
OR'
° 0H , u ,
|| | secondary alcohol
R— C-R ► R— CH— R
A few of the reactions mentioned have been adapted for large-scale produc-
tion. Ethanol, for example, is made in quantity by the hydration of ethene,
using an excess of steam under pressure at temperatures around 300° in the
presence of phosphoric acid :
300°, H 3 PO„
CH 2 = CH 2 + H 2 , CH 3 CH 2 OH
A dilute solution of ethanol is obtained which can be concentrated by distilla-
tion to a constant boiling point mixture that contains 95.6 % ethanol by weight.
Removal of the remaining few percent of water to give " absolute alcohol " is
usually achieved either by chemical means or by distillation with benzene,
which results in preferential separation of the water. Ethanol is also made in
large quantities by fermentation, but this route is not competitive for indus-
trial uses with the hydration of ethene.
sec 10.4 reactions involving the O — H bond 251
Isopropyl alcohol and /-butyl alcohol are also manufactured by hydration
of the corresponding alkenes. The industrial synthesis of methyl alcohol
involves hydrogenation of carbon monoxide. Although this reaction has a
favorable AH value of —28.4 kcal, it requires high pressures and high tem-
peratures and a suitable catalyst; excellent conversions are achieved using a
zinc oxide-chromic oxide catalyst:
^ ^ „ 4°°°. 200 atm
CO + 2 H 2 -—± » CH 3 OH AH = - 28.4 kcal
ZnO— Cr0 3
chemical reactions of alcohols
10-4 reactions involving the 0~H bond
A. ACIDIC AND BASIC PROPERTIES
Several important reactions of alcohols involve only the oxygen-hydrogen
bond and leave the carbon-oxygen bond intact. An important example is salt
formation with acids and bases.
Alcohols, like water, are amphoteric and are neither strong bases nor
strong acids. The acid ionization constant (K HA ) of ethanol is about 10" 18 —
slightly less than that of water. Ethanol can be converted to a salt by the salt
of a weaker acid such as ammonia (X HA ~ 1CT 35 ), but it is usually more con-
venient to employ sodium or sodium hydride. The reactions are vigorous
but can be more easily controlled than the analogous reactions with water.
C 2 H,O a Na lB +
1 2
sodium amide sodium ethoxide
(sodamide)
C 2 H 5 OH + Na e H e ► C 2 H 5 O e Na® + H 2
The order of acidity of various alcohols is generally primary > secondary >
tertiary; ?-butyl alcohol is therefore considerably less acidic than ethanol.
The anions of alcohols are known as alkoxide ions.
CH 3 Oe C 2 H 5 O e (CH 3 ) 2 CHOe (CH 3 ) 3 CO e
methoxide ethoxide isopropoxide f-butoxide
Alcohols are bases comparable in strength to water and are converted to
their conjugate acids by strong acids. An example is the reaction of methanol
with hydrogen bromide to give methyloxonium bromide.
CH,:0:H + HBr . CH 3 :0:H + Br e
H„
methyloxonium bromide
The reaction of hydrogen bromide with water proceeds in an analogous
manner :
Ha,
H:6:H + HBr , H:0:H + Br e
hydroxonium bromide
chap 10 alcohols and ethers 252
B. ETHER FORMATION
Alkoxide formation is important as a means of generating a powerful
nucleophile that will readily enter into S N 2 reactions. Whereas ethanol reacts
only slowly and incompletely with methyl iodide, sodium ethoxide in ethanol
solution reacts rapidly with methyl iodide and gives a high yield of methyl
ethyl ether.
fast
CH 3 I + C 2 H 5 Oe Na ffl ► CH 3 OC 2 H 5 + Nal
In fact, the reaction of alkoxides with alkyl halides or alkyl sulfates is an
important general method for the preparation of ethers, and is known as the
Williamson synthesis. Complications can occur because the increase of
nucleophilicity associated with the conversion of an alcohol to an alkoxide
ion is always accompanied by an even greater increase in eliminating power
by the E2-type mechanism. The reaction of an alkyl halide with alkoxide may
then be one of elimination rather than substitution, depending on the tem-
perature, the structure of the halide, and the alkoxide (Section 8T2). For
example, if we wish to prepare isopropyl methyl ether, better yields would be
obtained if we were to use methyl iodide and isopropoxide ion rather than
isopropyl iodide and methoxide ion because of the prevalence of E2 elimina-
tion with the latter combination :
CH3I + (CH 3 ) 2 CHO e ^— (CH 3 ) 2 CHOCH 3 + ie
(CH 3 ) 2 CHI + CH 3 O e E ' > CH 3 CH=CH 2 +CH 3 OH + ie
Potassium /-butoxide is often an excellent reagent to achieve E2 elimina-
tion, since it is strongly basic but so bulky as to not undergo S N 2 reactions
readily.
C. ESTER FORMATION
Esters are one of a number of compounds containing the carbonyl group
O
II
(— C— ) that are important to a discussion of alcohols and whose detailed
chemistry will be discussed in subsequent chapters.
OO OOO
II II II II II
R-C— OR R-C— OH R— C — CI R-C— H R-C — R
esters carboxylic acids acyl halides aldehydes ketones
Esters are produced by the reactions of alcohols with either acyl halides or
carboxylic acids. Acyl halides, for example, have a rather positive carbonyl
carbon because of the polarization of the carbon-oxygen and carbon-halogen
sec 10.4 reactions involving the O — H bond 253
bonds. Addition of an electron-pair-donating agent such as the oxygen of an
alcohol occurs rather easily.
ie O> O e
i9 v^ -\.. i .
CH 3 — C — CI + CH 3 :0:H , CH 3 -C-C1
<se <se " |
CH3OH
[1]
The complex [1] contains both an acidic group (CH 3 — O— H) and a basic
O e I
I
group (— C— ), so that one oxygen loses a proton and the other gains a
I
proton to give [2], which then rapidly loses hydrogen chloride by either an
El or E2 elimination to form the ester. The overall process resembles an
O e 6) O
| iv . ||
CH3-C-CI . CH 3 -C^C1 ► CH 3 -C-0-CH 3 + HC1
CH 3 OH CH 3
e
[I] [2]
S N 2 reaction, but the mechanism is different in being an addition-elimination
with three transition states rather than a one-stage displacement reaction with
one transition state.
A similar but less complete reaction occurs between acetic acid and
O O e
II .. I
CH 3 -C-OH + CH 3 :0=H ;=i CH 3 -C-OH ^
CH,— O-H
OH O
I II
CH 3 -C-OH . CH 3 -C-OCH 3 + H 2
CH 3 -0
methanol. This reaction is slow in either direction in the absence of a strong
mineral acid. Strong acids catalyze ester formation from the alcohol provided
they are not present in large amount. The reason for the " too much of a good
thing " behavior of the catalyst is readily apparent from a consideration of
the reaction mechanism. A strong acid such as sulfuric acid may donate a
proton to the unshared oxygen electron pairs of either acetic acid or methanol :
chap 10 alcohols and ethers 254
CH,
//
+ H 2 S0 4
OH
.OH
CH 3
//
-C +
\
OH
[3]
H
HSO,
CH,-
1
-0— H +
e
HSO,
CH,— O— H + H,S0 4 ;=
a
Clearly, formation of methyloxonium bisulfate can only operate to reduce the
reactivity of methanol toward the carbonyl carbon of acetic acid. However,
this anticatalytic effect is more than balanced (at low concentrations of
H 2 S0 4 ) by protonation of the carbonyl oxygen of the carboxylic acid [3],
since this greatly enhances the electron-pair accepting power of the carbonyl
carbon :
eOH
r
CH 3 -C— OH
OH
I
CH,-C-OH
+ CH,-0-H
[3]
CH,
OH
I
-C— OH
CH 3 -0-H
[4]
The resulting intermediate [4] is in equilibrium with its isomer [5], which can
lose a water molecule to give the protonated ester [6] :
OH
CH 3 -C— OH
I
CH3-O-H
e
[4]
c
OH,
CH,-C— OH
[5]
S 0H
II
CH 3 — C— OCH 3 + H 2
[6]
O
II ffi
CH 3 -C-OCH 3 + H 3
methyl acetate
Transfer of a proton from [6] to water gives the reaction product.
At high acid concentrations, essentially all the methanol would be con-
verted to inert methyloxonium ion and the rate of esteriflcation would then be
very slow, even though more of the oxonium ion of acetic acid would be
present.
As mentioned earlier, esteriflcation is reversible and, with ethanol and
acetic acid, has an equilibrium constant of about 4 at room temperature,
which corresponds to 66% conversion to ester with equimolal quantities.
Higher ester conversions can be obtained by using an excess of either the
o
II
CH,C-OH
C,H,OH
O
II
CH 3 C-0-C 2 H 5 + H 2
K =
[CH 3 CQ 2 C 2 H 5 ] [H 2 Q]
[CH 3 C0 2 H][C 2 H 5 OH] '
sec 10.5 reactions involving the C — O bond of alcohols 255
alcohol or the acid. The reaction may be driven to completion by removing
the ester and (or) water as they are formed.
Steric hindrance is very important in determining esteriflcation rates, and
esters with highly branched groups, in either the acid or alcohol parts, are
formed at slower rates and with smaller equilibrium constants than their less
highly branched analogs. In general, the ease of esteriflcation for alcohols is
primary > secondary > tertiary with a given carboxylic acid.
10-5 reactions involving the C~ O bond of alcohols
A. HALIDE FORMATION
Alkyl halide formation from an alcohol and a hydrogen halide offers an
important example of a reaction in which the C— O bond of the alcohol is
R-rOH + HBr . RBr + H,0
broken. The reaction is reversible and the favored direction depends on the
water concentration (see Exercise 8-9). Primary bromides are often best
prepared by passing dry hydrogen bromide into the alcohol heated to just
slightly below its boiling point.
Reaction proceeds at a useful rate only in the presence of strong acid,
which can be furnished by excess hydrogen bromide or, usually and more
economically, by sulfuric acid. The alcohol accepts a proton from the acid to
give an alkyloxonium ion, which is more reactive in subsequent displacement
with bromide ion than the alcohol, since it can more easily lose a neutral
water molecule than the alcohol can lose a hydroxide ion (Section 8-1 IB).
H
Bi^T^R-^p-H > RBr + H 2 S N 2
H
| (-H 2 0) Br e
R-O-H , R e ► RBr S N 1
Hydrogen chloride is less reactive than hydrogen bromide or hydrogen iodide
toward primary alcohols, and application of heat and the addition of a
catalyst (zinc chloride) are usually required for preparation purposes.
A solution of zinc chloride in concentrated hydrochloric acid (Lucas
reagent) is widely used, in fact, to differentiate between the lower primary,
secondary, and tertiary alcohols. Tertiary alcohols react very rapidly to give
an insoluble layer of alkyl chloride at room temperature. Secondary alcohols
react in several minutes, whereas primary alcohols form chlorides only on
heating.
Thionyl chloride, SOCl 2 , is a useful reagent for the preparation of alkyl
chlorides, especially when the use of zinc chloride and hydrochloric acid is
chap 10 alcohols and ethers 256
undesirable. Addition of 1 mole of an alcohol to 1 mole of thionyl chloride
gives an unstable alkyl chlorosulfite, which generally decomposes on mild
heating to yield the alkyl chloride and sulfur dioxide.
o
— HCl "
ROH + SOCl 2 > R-O-S— CI ► RC1 + S0 2
alkyl chlorosulfite
Phosphorus tribromide, PBr 3 , is an excellent reagent for converting
alcohols to bromides. A disadvantage compared to thionyl chloride is the
formation of involatile P(OH) 3 rather than sulfur dioxide.
3 ROH + PBr 3 ► 3 RBr + P(OH) 3
B. ESTERS OF SULFURIC ACID— DEHYDRATION OF ALCOHOLS
Alkyl hydrogen sulfate formation from alcohols and concentrated sulfuric
acid may occur by a reaction rather closely related to alkyl halide formation.
ROH + H 2 S0 4 , ROH 2 + HS0 4 ► ROS0 3 H + H 2
alkyl hydrogen sulfate
On heating, alkyl hydrogen sulfates readily undergo elimination of sulfuric
acid to give alkenes and, in the reaction of an alcohol with hot concentrated
sulfuric acid, which gives overall dehydration of the alcohol, the hydrogen
sulfate may well be a key intermediate. This is the reverse of acid-catalyzed
hydration of alkenes discussed previously (Section 4-4) and goes to comple-
tion if the alkene is allowed to distill out of the reaction mixture as it is
formed.
(- H 2 0) 150°
CH 3 CH 2 OH + H 2 S0 4 ' CH 3 CH 2 0SO 3 H ^ - CH 2 =CH 2 + H 2 S0 4
The mechanism of elimination of sulfuric acid from ethyl hydrogen sulfate
is probably of the E2 type, with water or bisulfate ion acting as the base.
At lower temperatures, alkyl hydrogen sulfate may react by a displacement
mechanism with excess alcohol in the reaction mixture with formation of a
dialkyl ether. Diethyl ether is made commercially by this process. Although
each step in the reaction is reversible, ether formation can be favored by
distilling away the ether as fast as it forms.
H
-^— - CH 3 CH 2 -0— CH 2 CH 3 + HSO?
CH 3 CH 2 OCH 2 CH 3 + H 2 SQ 4
sec 10.S reactions involving the C — O bond of alcohols 257
Most alcohols will also dehydrate at fairly high temperatures to give
alkenes and (or) ethers in the presence of solid catalysts such as silica gel or
aluminum oxide. The behavior of ethanol, which is reasonably typical of
primary alcohols, is summarized in the following equations :
Al 2 Q 3
375°
- CH,= CH, + H,0
CH 3 CH 2 OH
\ AUO3 |
300°
CH 3 CH 2 OCH 2 CH 3 + H 2
Tertiary alcohols react with sulfuric acid at much lower temperatures than
do most primary alcohols. The S N 1 and El reactions in Scheme I may be
written for r-butyl alcohol and sulfuric acid. Di-f-butyl ether is unstable in
I " H 2 S0 4 I
CH3-C-OH . * CH 3 -C-OH 2
CH,
CH,
-H 2
HSO4
H " <-«, CH,
Is
(CH^C-O— C(CH 3 ) 3 CH 3 -C = CH 2 CH 3 -C-OS0 3 H
CH 3
-H®
(CH 3 ) 3 C-0-C(CH 3 ) 3
polymer
SCHEME I
sulfuric acid solution and it has never been detected in reaction mixtures of
this type. Its low stability may be due to steric crowding between the alkyl
groups.
CH,
CH
/*
\/y? H
dH ^ c ^H 3
1
CH,
steric repulsions
2-Methylpropene can be removed from the reaction mixture by distillation
and is easily made the principal product by appropriate adjustment of the
chap 10 alcohols and ethers 258
reaction conditions. If the 2-methylpropene is not removed as it is formed,
polymer is the most important end product. Sulfuric acid is often an unduly
strenuous reagent for dehydration of tertiary alcohols. Potassium hydrogen
sulfate, copper sulfate, iodine, phosphoric acid, or phosphorus pentoxide may
give better results by causing less polymerization and less oxidative degrada-
tion. The oxidizing action of sulfuric acid results in formation of sulfur
dioxide.
Rearrangement of the alkyl group of an alcohol is very common in dehydra-
tion, particularly in the presence of sulfuric acid, which is highly conducive
to carbonium ion formation. Shown are typical examples of both methyl and
hydrogen migration. The key step in each such rearrangement involves an
isomerization of a carbonium ion along lines discussed in Section 8T3.
CH 3
I
CH 3 -C— CH-CH 3
CH 3
I
C-
I
H
CH 3 ,CH 3
H 2 SO* \„ „/
C=C + H 2
CH 3 CH 3
CH,
H 2 SO»
Except in a few circumstances where thermodynamic control dominates and
leads to different results from kinetic control, the final products always cor-
respond to rearrangement of a less stable carbonium ion to a more stable
carbonium ion.
reactants
R
I e
— C—C-
I I
less stable
carbonium ion
R
e I
-C— C—
I I
more stable
carbonium ion
products
For the particular case of the dehydration of methyl-?-butylcarbinol, the
sequence is
CH 3
I H 2 S0 4
CH 3 — C— CH — CH 3 ;=
(-OH e )
H,C OH
CH 3
CH 3 — C-CH-CH 3
I e
CH 3
secondary
carbonium ion
I I
-+ CH 3 — C — C— CH 3
© I
H
tertiary
carbonium ion
-H«
CH 3 CH 3
\ /
c=c
/ \
CH 3 CH 3
sec 10.6 oxidation of alcohols 259
10-6 oxidation of alcohols
Primary alcohols on oxidation first give aldehydes and thence carboxylic
acids, whereas secondary alcohols give ketones.
o ,o
[O] S [O] #
RCH 2 OH > R-C > R-C
H OH
R R
\ [O] \
CHOH ► / C= °
R R
Tertiary alcohols are oxidized with considerable difficulty and then only
with degradation into smaller fragments by cleavage of carbon-carbon bonds.
Similarly, oxidation of secondary alcohols beyond the ketone stage does not
proceed readily and leads to degradation.
Laboratory oxidation of alcohols is most often carried out with chromic
acid (H 2 Cr0 4 ), which is usually prepared as required from chromic oxide
(Cr0 3 ) or from sodium dichromate (Na 2 Cr 2 7 ) in combination with sulfuric
acid. Acetic acid is the most generally useful solvent for such reactions.
3 CH-OH + 2 H 2 Cr0 4 + 6 H® ► 3 C=0 + 2 Cr 3 ® + 8 H 2
/ /
CH 3 CH 3
The mechanism of the chromic acid oxidation of isopropyl alcohol to
acetone has been investigated very thoroughly and is highly interesting in that
it reveals how changes of oxidation level can occur involving a typical inorgan-
ic and a typical organic compound. The initial step is reversible formation of
isopropyl hydrogen chromate [7], which is quite unstable and is not usually
isolated (although it can be isolated by working rapidly at low temperatures).
CH 3 CH 3
X CH-OH + H 2 Cr0 4 . H 2 + \:H—0— Cr0 3 H
CH 3 CH 3
CH 3
X CH-0— CrOjHf
CH 3
The subsequent step is the slowest in the reaction and appears to involve
either (a) a cyclic decomposition of the protonated ester or (b) attack of a
base (water) at the a, hydrogen of the protonated chromate ester concurrent
with elimination of the grouping H 2 Cr0 3 , for which there is an obvious
analogy with an E2 reaction (Section 8T2).
chap 10 alcohols and ethers 260
CH < / H I „ . CH \ / H -9
(a) C CrO z Hf ► C li
CH
CH 3
C— O + H 2 Cr0 3 + H a
H
CH 3 H<-:(/ ^ CH 3
(b) / x ) ^ H ► JZ-0 + H 3 + H 2 Cr0 3
CH 3 O— Cr0 3 H? CH 3
Despite intensive study, the exact mechanism of decomposition of the
chromate ester remains in doubt. The Cr IV shown as the reduction product
(H 2 Cr0 3 ) in both (a) and (b) is a highly reactive oxidant and is rapidly con-
verted to Cr m in subsequent steps.
The Cr VI oxidation of alcohols is acid catalyzed, as shown above. Indeed,
neutral and basic solutions of chromate are without any effect on alcohols.
Permanganate oxidation of alcohols, on the other hand, is subject to both
acid and base catalysis. The acid catalysis is the result of the conversion of
MnOf to HMn0 4 , a more powerful oxidant, and requires a high concentra-
tion of acid. The base catalysis, however, is the result of converting the
neutral alcohol to the more easily oxidized alkoxide ion :
R H R H
X C 7 + OH e < \ + H 2
R y X OH R 7 V
The rate-controlling step of this reaction is transfer of hydrogen, possibly as
hydride ion, to the Mn v ".
R (^rP^M R
X C ^ + MnOe > C=0 + HMn0 4 2e
R X N > * r 7
The ion UMn0 2 4 e (Mn v ) quickly disproportionates to Mn IV and Mn v ".
Presumably Cr VI is ineffective in oxidizing alcohols by such a path because
in basic solution the chromate ion, CrO^ 8 , carries a double negative charge
and the repulsions between the reactants would be too great.
Biological oxidation of alcohols is considered later in the book (Section
18-4).
10 -1 polyhydroxj alcohols
The simplest example of an alcohol with more than one hydroxyl group is
methylene glycol, HOCH 2 OH, the term " glycol " meaning a diol, a substance
sec 10.7 polyhydroxy alcohols 261
with two alcoholic hydroxyl groups. Methylene glycol is reasonably stable in
water solution but attempts to isolate it lead only to its dehydration product,
formaldehyde.
HO-CH,-OH
This behavior is typical of gem-diols (gem = geminal, i.e., with both hydroxyl
groups on the same carbon atom), and the very few gem-diols that are
isolable are those which carry strongly electron-attracting substituents, such
as chloral hydrate and hexafluoroacetone hydrate.
OH OH
I I
CI3C-C-OH CF3-C-CF3
I I
H OH
chloral hydrate hexafluoroacetone hydrate
Polyhydroxy alcohols in which the hydroxyl groups are situated on different
carbons are relatively stable and, as we might expect for substances with a
multiplicity of hydrogen bonding groups, they have high boiling points,
considerable water solubility, and low solubility in nonpolar solvents.
CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 -CH-CH 2
II II III
OH OH OH OH OH OH OH
ethylene glycol tetramethylene glycol glycerol
1 , 2-ethanediol 1 , 4-butanediol 1,2, 3-propanetrioI
bp 197° bp 230° bp 290°
1,2-Diols are usually prepared from alkenes by oxidation with reagents
such as osmium tetroxide, potassium permanganate, or hydrogen peroxide
(Section 4-4G). However, ethylene glycol is made on a large scale commer-
cially from ethylene oxide, which in turn is made by air oxidation of ethene
at high temperatures over a silver catalyst.
CH 2 =CH 2 + 10 2 -^jU CH 2 -CH 2 H2 °' HS ..
O OH OH
ethylene oxide
Ethylene glycol has important commercial uses. It is an excellent per-
manent antifreeze for automotive cooling systems, because it is miscible with
water in all proportions anda 50% solution freezes at -34° ( — 29°F). It is
also used as a solvent and as ah-- intermediate in the production of polymers
(polyesters) and other products, as shown in Section 28-4.
The trihydroxy alcohol, glycerol, is a nontoxic, water-soluble, viscous,
hygroscopic liquid that is widely used as a humectant (moistening agent). It
is an important component of many food, cosmetic, and pharmaceutical
preparations. At one time, glycerol was obtained on a commercial scale only
chap 10 alcohols and ethers 262
as a byproduct of soap manufacture through hydrolysis of fats, which are
glycerol esters of long-chain alkanoic acids (see Chapter 13), but now the
main source is synthesis from propene as described in Section 9-6. The
trinitrate ester of glycerol (nitroglycerin) is an important but shock-sensitive
explosive. Dynamite is a much safer and more controllable explosive, made
by absorbing nitroglycerin in porous material like sawdust or diatomaceous
earth. Smokeless powder is nitroglycerin mixed with partially nitrated
cellulose.
CH 2 ON0 2
I nitroglycerin
CHON0 2 (glyceryl trinitrate)
CH,ONO,
Glycerol plays an important role in animal metabolism as a constituent of
fats and lipids.
10-8 unsaturated alcohols
The simplest unsaturated alcohol, vinyl alcohol, is unstable with respect to
acetaldehyde and has never been isolated. Other simple vinyl alcohols undergo
o
//
CH 2 =CHOH ^_ ' CH 3 -C
H
vinyl alcohol acetaldehyde
similar transformations to carbonyl compounds. However, ether and ester
derivatives of vinyl alcohols are known and the esters are used to make many
commercially important polymers.
Allyl alcohol, CH 2 =CH— CH 2 OH, unlike vinyl alcohol, is a stable com-
pound. It displays the usual double-bond and alcohol reactions but, as expec-
ted from the behavior of allylic halides (Section 9-6), it is much more reactive
than saturated primary alcohols toward reagents such as Lucas reagent that
cleave the C— O bond.
ethers
Substitution of both hydrogens in water by alkyl or similar groups gives
compounds known as ethers, general formula R— O — R. Ethers thus lack the
sec 10.9 preparation of ethers 263
hydroxyl group which determines to such a great extent the physical and
chemical properties of water and alcohols. Ethers are much more volatile than
alcohols of the same molecular weight. Thus, diethyl ether (C 2 H 5 OC 2 H 5 )
boils at 35° (body temperature), which is 48° to 83° below the boiling points
of the isomeric butyl alcohols. Its solubility in water, however, is 7 g per 100 g
of water, about the same as «-butyl alcohol (but much less than that of
(-butyl alcohol which is miscible with water). Diethyl ether is often used to
extract organic substances out of water solution and it should be remembered
that a considerable amount of ether can be retained in the water layer, which
may release enough ether vapor to create a fire hazard.
A number of important ethers are listed here. (Nomenclature of ethers was
discussed in Section 8-3.)
CH 3 CH 2 OCH 2 CH 3 CH 3 OCH=CH 2 H 2 C CH 2 HOCH 2 CH 2 OCH 2 CH 2 OH
O
diethyl ether
bp35°
methyl vinyl ether ethylene oxide
bp 8° bpll"
diethylene glycol
bp 245°
^}-OCH3
H 2 C-CH 2
H 2 C V /CH 2
O
H 2 C^ X CH 2
H 2 C V .CH 2
ethyl phenyl ether
(anisole)
bp 155°
tetrahydrofuran
bp65°
1, 4-dioxane
bp 101.5°
10-9 preparation of ethers
There are only two generally useful ways of preparing ethers and these have
been previously discussed in connection with the reactions of alcohols.
The first is the Williamson synthesis (Section 10-4B), to which the general
rules governing S N 2 displacements and the competing elimination reactions
apply (Sections 8-7, 8-12).
R-X + R'CTNa 95
-► R— O— R + Na*
The second is dehydration of alcohols (Section 10- 5B), which can be accom-
2 ROH
-H 2
-» R— O— R
plished with concentrated H 2 S0 4 , H 3 P0 4 , or at high temperatures with
A1 2 3 catalysis. Only symmetrical ethers can be made efficiently by this
route; intramolecular dehydration to give alkenes is a competing reaction.
chap 10 alcohols and ethers 264
10-10 reactions of ethers
In general, ethers are low on the scale of chemical reactivity, since the
carbon-oxygen bond is not cleaved readily. For this reason, ethers are fre-
quently employed as inert solvents in organic synthesis. Particularly important
in this connection are diethyl ether, diisopropyl ether, tetrahydrofuran, and
1,4-dioxane. The latter two compounds are both miscible with water.
The mono and dialkyl ethers of ethylene glycol and diethylene glycol are
useful high-boiling solvents. Unfortunately, they have acquired irrational
names like " polyglymes," "cellosolves," and "carbitols"; for reference,
cellosolves are monoalkyl ethers of ethylene glycol ; carbitols are monoalkyl
ethers of diethylene glycol; polyglymes are dimethyl ethers of di- or triethyl-
ene glycol, diglyme, and triglyme, respectively.
CH 3 OCH 2 CH 2 OH C 4 H 9 OCH 2 CH 2 OCH 2 CH 2 OH
methyl cellosolve butyl carbitol
bp 124° bp231°
CH 3 OCH 2 CH 2 OCH 2 CH 2 OCH 3
diglyme
bp 161°
Unlike alcohols, ethers are not acidic and do not usually react with bases.
However, exceptionally powerfully basic reagents, particularly certain
alkali-metal alkyls, will react destructively with many ethers (see also Sec-
tion 9-9B).
CHf Na a> + H:CH 2
CH 4 + CH 2 =CH 2 + CH 3 CH 2 ONa
Ethers, like alcohols, are weakly basic and are converted to oxonium ions
by strong acids (e.g., H 2 S0 4 , HC10 4 , and HBr) and to coordination com-
plexes with Lewis acids (e.g., BF 3 and RMgX).
C 2 H 5 6C 2 H 5 + HBr . C 2 H 5 OC 2 H 5 + Br e
diethyloxonium bromide
F F F
\l/
B
C 2 H 5 OC 2 H 5 + BF 3 ► C 2 H 5 OC 2 H 5
boron trifluoride etherate
Dialkyloxonium ions are susceptible to nucleophilic displacement and
elimination reactions just as are the conjugate acids of alcohols (Section
10-5A). Acidic conditions, therefore, are used to cleave ethers, and as appro-
priate to the degree of substitution either S N 2 or S N 1 (El) reactions may
occur.
C,H,-0-C 2 H 5 + H s
H
I
sec 10.11 cyclic ethers 265
Br 9
C 2 H 5 -0— C 2 H 5 „ . > C 2 H s Br + C 2 H 5 OH
H
(CH 3 ) 3 C-0-C(CH 3 ) 3 + H® . (CH 3 ) 3 C-0-C(CH 3 ) 3
HS0 4
El
2(CH 3 ) 2 C=CH 2 «-
(CH 3 ) 3 C-OH + (CH 3 ) 2 C=CH 2 + H 2 S0 4
Ethers are quite susceptible to attack by radicals, and for this reason are not
good solvents for radical-type reactions. In fact, ethers are potentially
hazardous chemicals since, in the presence of atmospheric oxygen, a radical-
chain process can occur, resulting in the formation of peroxides which are
unstable, nonvolatile explosion-prone compounds. This process is called
autoxidation and occurs not only with ethers but with many aldehydes and
hydrocarbons. Commonly used ethers such as diethyl ether, diisopropyl
ether, tetrahydrofuran, and dioxane often become contaminated with perox-
ides formed by autoxidation on prolonged storage and exposure to air and
light. Purification of ethers is frequently necessary before use, and caution
should always be exercised in their distillation as the distillation residues may
contain dangerously high concentrations of explosive peroxides.
10-11 cyclic ethers
Ethylene oxide, the simplest cyclic ether, is an outstanding exception to the
generalization that most ethers resist cleavage. Like that of cyclopropane, the
three-membered ring of ethylene oxide is highly strained and opens readily
under mild conditions. Unlike ordinary ethers it reacts with Grignard
reagents (Section 9-9C), a useful way of extending a chain by two carbon
atoms. For example, conversion of 1-hexanol to 1-octanol can be easily
accomplished this way via the alkyl bromide.
CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 OH + HBr
-> CH 3 CH 2 CH,CH 2 CH 2 CH 2 Br + H,0
CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 Br + Mg dry ethet > CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 MgBr
CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 MgBr + CH 2 -CH 2
O
CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 MgBr
H 2
CH 3 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 CH 2 OH + HOMgBr
' chap 10 alcohols and ethers 266
The commercial importance of ethylene oxide lies in its readiness to form
other important compounds; for example, ethylene glycol, diethylene
glycol, the cellosolves and carbitols, dioxane, ethylene chlorohydrin, and
polymers (Carbowax) (see Scheme II).
H2 ° HOCH 2 CH 2 OH -5— -> (HOCH 2 CH 2 ) 2
\V
o
l>
H,C
H®
ethylene
glycol
methyl
cellosolve
H 2 C— CH 2
H — > O O dioxane
\ /
H 2 C-CH 2
ethylene
* ClCH 2 CH 2 OH chlorohydrin
> H-0-c-CH 2 -CH 2 — 0-);H
SCHEME II
diethylene
glycol
CH 3 (CH 2 ) 2 (CH 2 ) 2 OH
methyl
carbitol
Carbowax
The lesser-known four-membered cyclic ether, trimethylene oxide (CH 2 ) 3 0,
is also cleaved readily, but less so than ethylene oxide. Tetramethylene oxide
(tetrahydrofuran) is relatively stable and is a water-miscible compound with
desirable properties as an organic solvent. It is often used in place of diethyl
ether in Grignard reactions and reductions with lithium aluminum hydride.
summary
Alcohols, whether primary (RCH 2 OH), secondary (R 2 CHOH), or tertiary
(R 3 COH), have higher melting and boiling points and much higher water
solubilities than the corresponding hydrocarbons. The highest melting points
and water solubilities (but not boiling points) belong to tertiary and other
branched-chain alcohols.
The H— O stretching frequencies in the infrared spectra of alcohols occur
near 3700 cm -1 (free OH) and near 3350 cm" 1 (hydrogen-bonded OH).
The nmr peaks of hydrogen-bonded OH protons occur 4-5 ppm downfield
from TMS but shift upheld with dilution.
Alcohols can be prepared in the following ways for a set of typical
primary, secondary, and tertiary alcohols.
exercises 267
RCH,C0 2 R' RCHXHXI
RCHXHO > RCH,CH 2 OH «-
RCH 2 MgBr
RCHCICHj
O
RCH=CH 2 ► RCHOHCH., < RC-CH 3
RMgBr > R 2 COHCH 3
R,C=CH 2
R,CC1CH,
The reactions of alcohols include the following:
ROH
RO e
ROH 2 ®
ROR'
R'C0 2 R
RX
ROSO3H-
(or R®)<
(with powerful bases)
(with strong acids)
(Williamson synthesis; S N 2 mechanism)
(with R'COCl or with R'C0 2 H; addition-elimination
mechanism)
(with HX; S N 1 or S N 2 mechanism)
— > symmetrical ether
, ^alkene - » polymer
rearranged products
On oxidation, primary alcohols give aldehydes and secondary alcohols give
ketones. Tertiary alcohols are oxidized only with degradation. The Cr VI
oxidation of alcohols proceeds via a chromate ester, ROCr0 3 H, while the
Mn™ oxidation involves the anion of the alcohol, RO e .
Important polyhydric or unsaturated alcohols include chloral hydrate,
ethylene glycol, glycerol, and allyl alcohol.
Ethers are less soluble and are more volatile than alcohols of the same
molecular weight. They are prepared from alcohols by dehydration or by the
Williamson synthesis (see above). Ethers are cleaved by strong acids,
ROR + HX ->■ RX + ROH, and are susceptible to attack by radicals and
exceptionally powerful bases (R e ).
Some important cyclic ethers include 1,4-dioxane, tetrahydrofuran, and
ethylene oxide ; the latter is not a typical ether because it reacts with Grignard
reagents.
exercises
10-1 c«-l,2-Cyclopentanediol is appreciably more volatile (bp 124° at 29 mm) than
frww-l,2-cyclopentanediol (bp 136° at 22 mm). Explain.
10-2 Suggest a likely structure for the compound of molecular formula C 4 H e O
whose nmr and infrared spectra are shown in Figure 10-3a. Show your
reasoning. Do the same for the compound of formula C 3 Hs0 2 whose spectra
are shown in Figure 10-3b.
UOISSIUISUBI} %
T
r
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-^---^-h-----^ 1213 *
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o
f
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o
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a.
r
^^^^^i|^^^^^^||
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JS
m °
C
\
till -o >»
J
; c
1
>
f
1 =
S
o a 1
Jo -j
„|i
i
\
d
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o
o
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-*■ b
^
c;
lift o
Jo
'.J
H$s||«
li
C
filo
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r
UOISSIUISUBIJ %
Figure 10-3 Nuclear magnetic resonance spectra and infrared spectra of
C 4 H 6 (a) and C 3 H 8 2 (b); see Exercise 10-2.
268
exercises 269
10-3 What type of infrared absorption bands due to hydroxyl groups would you
expect for ?ra«.y-l,2-cyclobutanediol and 1 ,2-butanediol (a) in very dilute
solution, (b) in moderately concentrated solution, and (c) as pure liquids ?
10-4 Show the reagents and conditions for the reactions used to prepare alcohols
that are summarized on p. 267.
10-5 Show how you can convert 1-phenylethanol to 2-phenylethanol and 2-phenyl-
ethanol to 1-phenylethanol.
10-6 Show how you can prepare 2-methyl-2-butanol starting with (a) 2-butanol,
(b) 2-propanol.
10-7 In the esterification of an acid with an alcohol, how could you distinguish
between C— O and O— H cleavage of the alcohol using heavy oxygen ( ls O)
as a tracer?
O O
i II ! H ® II
CH3O-T-H + RCi-OH ► RCOCH3 + H 2
or
O O
i II ! h« II
CH 3 -rOH + RCO-i-H ► RCOCHj + H 2
What type of alcohols would be most likely to react by C— O cleavage, and
what side reactions would you anticipate for such alcohols?
10-8 Predict the major products of the following reactions :
a. (CH 3 ) 3 CCH 2 1 + C 2 H 5 O e >
b. (CH 3 ) 3 CBr + CH 3 O e ►
c. I Vci + (CH 3 ) 3 CO e ►
d. L V-CH 2 Br + (CH 3 ) 2 CHCH,O e
10-9 Predict the products likely to be formed on cleavage of the following ethers
with hydrobromic acid:
XH 2
a. CH 2 =CH-CH 2 -0-CH 3 H 2 C^ \ 2
d. I O
b. CH 3 CH 2 -0-CH = CH 2 2 ^CH 2
c. (CH 3 ) 3 CCH 2 -0-CH 3 e . ^ r A_ -CH 3
chap 10 alcohols and ethers 270
10-10 What would be the products of the following reactions? Indicate your
reasoning.
a. (CH 3 ) 3 COH + CH 3 OH COnC - H2S °'
H H
I I
b. H-C-C-H .
I I 75%H 2 S0 4
I 1 100°
HO OH
CH 3
I
c. CH,-C— CH,-OH
95%H 2 SO«
>
25°
100% H 2 S0 4
CH, 25°
cone. H 2 S0 4
I I
d. CH 3 — C-O-C-CH3
I I
CH 3 CH 3
0°
10-11 The reaction of methyl acetate with water to give methanol and acetic acid
is catalyzed by strong mineral acids such as sulfuric acid. Furthermore, when
hydrolysis is carried out in ls O water, the following exchange takes place
faster than formation of methanol.
O ,S P
f H® //
CH 3 -C + H 2 ls O 7==t CH 3 -C x + H 2
X OCH 3 O-CH3
No methanol- 1 s O (CH3 1 8 OH) is formed in hydrolysis under these conditions.
a. Write a stepwise mechanism which is in harmony with the acid catalysis
and with the results obtained in ls O water. Mark the steps of the reac-
tion that are indicated to be fast or slow.
b. The reaction depends on methyl acetate having a proton-accepting
ability comparable to that of water. Why? Consider different ways of
adding a proton to methyl acetate and decide which is most favorable
on the basis of structural theory. Give your reasoning.
c. Explain how the reaction could be slowed down in the presence of high
concentrations of sulfuric acid.
10-12 Indicate how you would synthesize each of the following substances from
the given organic starting materials and other necessary organic or inorganic
reagents. Specify reagents and conditions.
a. CH 3 CH 2 CH 2 C(CH 3 ) 2 C1 from CH 3 CH 2 CH 2 OH
b. CH 3 CH 2 CHCH 2 CH 3 from CH 3 CH 2 OH
I
O-C-CH3
II
O
c. (CH 3 ) 2 CH-CH 2 Br from (CH 3 ) 3 COH
exercises 271
d. CH 3 CH 2 CHCH 3 from CH 3 CH 2 CH 2 CH 2 OH
I
OSO3H
e. CH 3 CH 2 C(CH 3 ) 2 CH0 from (CH 3 ) 2 C(OH)CH 2 CH 3
/ CH 3 OCH 2 CH 2 OCH 3 from ethene
from
H 3 C
OH
(cis)
CH,
(trans)
CH 3
h. CH 3 — C— CH 2 — CH 3 from CH 3 — C-OH
CH,
/. (CH 2 =CHCH 2 ) 2
J. rf
,CH 3
OCH 2 CH 3
CH,
CH 3
=Cr
CH 2
from I I
kCH,
OCH,
H
from
AT
10-13 Give for each of the following pairs of compounds a chemical test, preferably
a test tube reaction, which will distinguish between the two substances.
Write an equation for each reaction.
CH,
I
H
and CH 3 CH=CH-CH 2 OH
CH 3
I
and CH 3 -CH-CH 2 CH 2 OH
CH 3
I
a. CH 3 -C-CH 3
I
OH
b. CH 2 =CH-CH 2 CH 2 OH
CH 3
I
c. CH 3 -C-CH 2 OH
I
CH 3
d. CH 3 CH 2 -0-S0 2 -0-CH 2 CH 3 and CH 3 CH 2 CH 2 CH 2 -0-S0 3 H
o o
II II
e. CH 3 -C-CI and C1CH 2 C-0H
18 o o
II II
/. CH 3 -C-0CH 3 and CH 3 -C- 18 0CH 3
CH 3 CH 3
g. CH 3 -C-0-Cr0 3 H
CH,
and CH 3 -C— CH 2 — O— Cr0 3 H
H
chap 10 alcohols and ethers 272
h. CH 2 -CH-CH 3 and CH 2 -CH 2 -CH 2
II I I
OH OH OH OH
H,C O and CH 3 CH-CH 2
\ / \ /
CH 2 V
I 3 ' I J I J T T
CH 3 -C-CH 2 -0-CH 2 -C-CH 3 and CH 3 -C-0-CH 2 -CH 2 -C-CH 3
CH 3 CH, CH 3 CH 3
10-14 Suppose you were given unlabeled bottles, each of which is known to contain
one of the following compounds: 1-pentanol, 2-pentanol, 2-methyl-2-
butanol, 3-penten-l-ol, 4-pentyn-l-ol, di-«-butyl ether, and 1-pentyl
acetate. Explain how you could use simple chemical tests (test tube reactions
with a visible result) to identify the contents of each bottle.
10-15 Predict the principal features with approximate chemical shifts in the nmr
spectra of the following compounds (neat liquid unless otherwise noted) :
a. isobutyl alcohol
b. neopentyl alcohol
c. methyl /3-methylvinyl ether
d. /-butyl alcohol
e. f-butyl alcohol in carbon tetrachloride
10-16 Sketch out the energy profile for the reaction of CH 3 COCl with CH 3 OH as
discussed in Section 10-4C, following the arguments in Section 8-9. It will
help, in this connection, if you calculate Aif for the addition of ROH to a
carbon-oxygen double bond to estimate the energy of [2] in Section 10-4C.
llf
ear uSvs ■fSss
illil
-
ffW.
BOB
i./.; -f|- ..--': ;%..•' &!
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ff ^iiC**'^^
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chap 11 aldehydes and ketones I 275
o
II
The carbonyl group, — C— , is an extremely important functional group, and
indeed the chemistry of carbonyl compounds is virtually the backbone of
synthetic organic chemistry. We shall divide our study of these substances
into three parts. In this chapter we shall consider first methods for the
synthesis of simple aldehydes and ketones and then the reactions of aldehydes
and ketones which involve only their carbonyl groups. In Chapter 12, con-
sideration will be given to the way in which the carbonyl function activates
groups on adjacent carbons. In Chapter 13, we shall discuss the role of the
carbonyl group in reactions of carboxylic acids and their derivatives. Through-
out these discussions attention will be given to the differences in behavior of
various kinds of carbonyl groups — differences that may be correlated with
electrical and steric effects.
11' 1 nomenclature of aldehydes and ketones
o o
Aldehydes have the general formula R— C and ketones R— C— R.
H
Since their nomenclature follows along the lines discussed previously for
other types of compounds, the most widely used naming systems are sum-
marized in Table 11-1.
11 -2 carbonyl groups of aldehydes and ketones
A. COMPARISON WITH CARBON-CARBON DOUBLE BONDS
The carbon-oxygen double bond is both a strong and a reactive bond. Its
bond energy (179 kcal) is rather more than that of two carbon-oxygen single
bonds (2 x 86 kcal) in contrast to the carbon-carbon double bond (146
kcal), which is weaker than two carbon-carbon single bonds (2 x 83 kcal). A
typical difference in reactivity is seen in hydration :
CH 2 = + H 2 , CH 2 -0
I
OH H
CH,=CH, + H,0
I ' I
OH H
Formaldehyde adds water rapidly and reversibly at room temperature
without an added catalyst; but the addition of water to ethene does not occur
in the absence of a very strongly acidic catalyst, even though the equilibrium
constant is considerably larger.
The reactivity of the carbonyl bond is primarily due to the difference in
electronegativity between carbon and oxygen, which leads to a considerable
contribution of the dipolar resonance form with oxygen negative and carbon
positive.
chap 1 1 aldehydes and ketones I 276
Table 11-1 Nomenclature systems for carbonyl compounds
P
Aldehydes, R— C
H
formula
IUPAC name = longest
straight chain" -\- suffix -al
name as derivative of a
carboxylic acid (i.e.,
a carboxaldehyde)
H 2 C=0
methanal
formaldehyde
ClCH 2 CH 2 CHO
3-ohloropropanal
/3-chloropropionaIdehyde
CH 3
|
CH 2 =CCHO
2-methylpropenal
methacrolein
(methacrylaldehyde) 1 '
[^CHO
cyclopropylmethanal
cyclopropanecarboxal-
dehyde c
R
Ketones, p = °
R'
formula
IUPAC name = longest
straight chain" -\- suffix -one
name as ketone 11
(CH 3 ) 2 C=0
propanone
dimethyl ketone
(acetone) 8
O
II
CH 3 CCH 2 CH=CH 2
4-penten-2-one
methyl allyl ketone
O
Q4-CH S
phenylethanone
methyl phenyl ketone
(acetophenone)"
o
cyclohexanone
—
" The longest straight chain which includes the functional group is understood.
b Propenoic acid is commonly called acrylic acid and 2-methylpropenoic acid methacrylic acid.
c The acid (CH 2 ) 2 CHC0 2 H is commonly called cyclopropanecarboxylic acid.
d Ketone is a separate word even though aldehyde is not. Thus (CH 3 CH 2 ) 2 CO is diethyl
ketone but (CH 3 CH 2 ) 2 CHCHO is diethylacetaldehyde (see Section 8-6).
e A few ketones are named as derivatives of carboxylic acids. Names by this system stem
from the synthesis (real or imagined) of the ketone by the reaction RC0 2 H-f R'C0 2 H->
RCOR'+C0 2 + H 2 0.
sec 11.2 carbonyl groups of aldehydes and ketones 277
\ \<b P. \t& se
C=0 < ► -C-O: ~ C=~0
The polarity of the carbonyl bond is expected to facilitate addition of water
0® se ae a®
and other polar reagents such as H— X and R— MgX relative to addition of
the same reagents to alkene double bonds. However, we must always keep in
mind the possibility that, whereas additions to carbonyl groups may be
rapid, their equilibrium constants may be small, because of the strength of
the carbonyl bond.
The polarity of the carbonyl group is manifested in many of the other
properties of aldehydes and ketones. Boiling points for the lower members of
the series are 50° to 80° higher than for hydrocarbons of the same molecular
weight. The water solubility of the lower-molecular-weight aldehydes and
ketones is large.
O
II
Formaldehyde, H— C— H, the first member of the aldehyde series, is a gas,
bp —21°. It is readily soluble in water, forming the hydrate (Section 10-7).
O
//
The second member, acetaldehyde, CH 3 — C , has a boiling point near
H
O
II
room temperature (21°). Acetone, CH 3 — C— CH 3 , the first member of the
ketone series, boils at 56°. It is completely miscible both with water and with
benzene. As might be expected, the higher aldehydes and ketones are insoluble
in water.
B. SPECTROSCOPIC PROPERTIES
The infrared stretching frequencies for the carbonyl groups of aldehydes
and ketones generally fall between 1705 and 1740 cm -1 and the absorption
intensities are much greater than for carbon-carbon double bonds.
All carbonyl compounds have absorption in the accessible part of the
ultraviolet spectrum. This absorption, which is weak for ordinary carbonyl
O
II
groups such as that in methyl ethyl ketone, CH 3 — C— CH 2 CH 3 (Figure 11-1),
is designated as an n -> n* transition, meaning that one of the nonbonding
electrons on oxygen is elevated to an antibonding n* orbital.
Conjugation with a carbon-carbon double bond has a large effect on the
spectrum of the carbonyl group. The spectrum of methyl vinyl ketone,
O
II
CH 3 — C— CH=CH 2 , shown in Figure 11-1 reveals a significant shift
toward the visible. (The tail of the band just reaches the visible part of the
spectrum and imparts a slight yellow cast to the compound.) This means that
less energy is required to excite a nonbonding electron in the conjugated
ketone than in the saturated ketone. We can understand this behavior on the
chap 1 1 aldehydes and ketones I 278
2500 3000
wavelength, A
Figure 11*1 Ultraviolet spectra of methyl ethyl ketone, a, and methyl vinyl
ketone, b, in cyclohexane solution.
basis of differences in the degree of resonance stabilization of the excited states
of the two kinds of compounds.
More significant in practical terms is the appearance in the accessible part
of the spectrum of methyl vinyl ketone of an intense absorption band that is
due to a n -* n* transition. The almost vertical rise of the absorption curve in
Figure 11-1 is caused by this intense absorption, whose peak is at 2190 A. A
comparable band for the carbonyl group of methyl ethyl ketone is not shown
in Figure 11-1 because it occurs at much shorter wavelength, about 1850 A,
which is out of the range of most spectrometers.
The character of the carbonyl bond is such as to give very low-field nmr
absorptions for protons of the aldehyde group (RCHO). As Table 7-2 shows,
these absorptions come some 4 ppm below vinylic hydrogens. Much of this
difference is probably due to the polarity of the carbonyl group. It is carried
over in much smaller degree to hydrogens in the a position and we find that
O
II
protons of the type CH 3 — C— R come at lower fields (0.3 ppm) than those of
R
I
CH,-C=CR, .
11-3 preparation of aldehydes and ketones
Of the six methods listed below for the preparation of aldehydes and
ketones, the first four have already been met. The other two will, therefore, be
described in more detail. There are a number of additional routes to aromatic
aldehydes and ketones, in which the carbonyl group is directly attached to a
benzene ring, and these will be encountered in Chapter 24.
1. Oxidation of alcohols (Section 10-6). The primary alcohols give aide-
sec 11.3 preparation of aldehydes and ketones 279
primary alcohols RCH 2 OH > RCHO
secondary alcohols R 2 CHOH ► R 2 C =
hydes readily with many oxidants but subsequent oxidation of the aldehyde
to a carboxylic acid, RC0 2 H (Section 11-4G), can occur; secondary alcohols
give ketones in good yield; tertiary alcohols are inert unless drastic conditions
are used, in which case carbon-carbon bond rupture occurs to give a mixture
of cleavage products.
2. Oxidative cleavage of alkenes (Section 4-4G). The number of alkyl
R 2 C=CHR' ° 3 > ^" > R 2 C = + R— CHO
groups at the double bond determines whether aldehydes or ketones are
produced ; many oxidants will cleave a carbon-carbon double bond but ozone is
one of the few that will not further oxidize the aldehyde produced; oxidative
cleavage of 1,2-glycols (Section 10-7) by HI0 4 or Pb(OAc) 4 produces the
same products (aldehydes or ketones).
3. Hydration of alkynes (Section 5-4). This method can be used only to
o
RC^CR + H 2 ,"1» RCCH 2 R
prepare ketones (and acetaldehyde, CH 3 CHO).
4. Organocadmium compounds react with acyl chlorides (Section 9-9C).
O O
II II
R— C— CI + R'CdCl ► R— C— R' + CdCl 2
Grignard reagents react the same way but, being more reactive than organo-
cadmium compounds, they usually attack the ketone to give tertiary alcohols.
5. Reduction of carboxylic acids to aldehydes. Conversion of a carboxylic
acid to an aldehyde by direct reduction is not easy to achieve because acids
are generally difficult to reduce, whereas aldehydes are easily reduced. Thus
the problem is to keep the reaction from going too far.
The most useful procedures involve conversion of the acid to a derivative
that either is more easily reduced than an aldehyde, or else is reduced to a
substance from which the aldehyde can be generated. The so-called Rosen-
mund reduction involves the first of these schemes; in this procedure, the acid
is converted to an acyl chloride, which is reduced with hydrogen over a
palladium catalyst to the aldehyde in yields up to 90 %. The rate of reduction
of the aldehyde to the corresponding alcohol is kept at a low level by poison-
ing the catalyst with sulfur.
R-C0 2 H ( S q° C ^ c|) > RCOC1 p " 2 s) ' RCHO + HC1
Reduction of an acid to a substance that can be converted to an aldehyde is
usefully achieved by way of lithium aluminum hydride reduction of the
nitrile corresponding to the acid. The following scheme outlines the sequence
chap 1 1 aldehydes and ketones I 280
of reactions involved starting with the acid :
RCO,H SOC ' 2 > RCOC1 NHa > RCONH,
POCI = > RC.N -t^ R _ C =N-Li
(-H z O)
H H
_2«^ R _(L N H "1"^ R_<L
R
R
1 1
-c-c-
1 |
H® ,
1
— c-c
ii 1
HO OH
II 1
o
The reduction step is usually successful only {{inverse addition is used; that is,
a solution of lithium aluminum hydride is added to a solution of the nitrile in
ether, preferably at low temperatures.
[Vc-N t!A!Hi_^ ^J^ [^cho
l""^^ (C 2 H 5 ) 2 0, - 50° ^
70%
cyclopropanecarbonitrile cyclopropanecarboxaldehyde
If the nitrile is added to the hydride, the reduction product is a primary
amine, RCH 2 NH 2 .
6. Rearrangements of 1,2-glycols. Many carbonyl compounds can be
usefully synthesized by acid-catalyzed rearrangements of 1,2-glycols, the
so-called "pinacol-pinacolone" rearrangement:
+ H,0
R = alkyl, aryl, or hydrogen
The general characteristics of the reaction are similar to those of carbonium
ion rearrangements (see Section 8-13). The acid protonates one of the —OH
groups and makes it a better leaving group. The carbonium ion which results
can then undergo rearrangement by shift of the neighboring group R with its
pair of bonding electrons to give a new, more stable, species with a carbon-
oxygen double bond.
An important example is provided by the rearrangement of pinacol to
pinacolone, as follows :
H 3 C CH 3 H 3 C CH 3 H 3 C CH 3
II H® II -H,0 "->l
CH 3 -C-C-CH 3 . CH 3 -C-C-CH 3 > CH 3 -C-C-CH 3
ii ii Vi •
HO OH HO OH, k :OH
® *
2, 3-dimethyl-2, 3-butanediol
(pinacol)
CH 3 CI
I -H- I
O CH 3 HO CH 3
3, 3-dimethyl-2-butanone
(pinacolone)
sec 11.4 reactions of aldehydes and ketones 281
Alkenes may be converted to carbonyl compounds with the same number of
carbon atoms by hydroxylation, followed by rearrangement. Isobutyralde-
hyde is made on a large scale this way from 2-methylpropene.
CH 3 CH 3 CH 3
CH 3 -C=CH 2 — ^ CH 3 -C-CH 2 -^^-* CH 3 -C-CH 2
CI CI HO OH
CH 3
CH C-CHO
I
H
11-4 reactions of aldehydes and ketones
The important reactions of carbonyl groups characteristically involve
addition at one step or another. We have already discussed additions achieved
by Grignard reagents as part of Chapter 9, It will be recalled that steric
hindrance plays an important role in determining the ratio between addition
and other competing reactions. Similar effects are noted in a wide variety cf
other reactions. We shall expect the reactivity of carbonyl groups in addition
processes to be influenced by the size of the substituents thereon because
when addition occurs, the substituent groups are pushed back closer to one
another. On this basis, we anticipate decreasing reactivity with increasing
bujkiness of substituents, as in the accompanying series.
H. R CH
H 3 C ,CH 3
V
) C =0 > >=0 > )c=0 » gx' \ =
H X CH 3 CH 3 *%/
H 3 C X X CH 3
The term " reactivity " is often used somewhat loosely in connection with
discussions of this type. Although it is probably best confined to considera-
tions of reaction rate it is also rather widely employed in connection with
equilibrium constants — -that is, how far the reaction goes, as well as how fast
it goes. If steric hindrance is high we expect equilibrium reactions to go
neither very fast nor very far. In the case of carbonyl additions, this is gen-
erally true, but there are exceptions which will be noted later.
Cyclic ketones almost always react more rapidly in addition processes than
their open-chain analogs.
O O
H 2 c' N CH 2 > H 2 C' X CH 2
H 2 C-CH 2 H 3 C CH 3
chap 11 aldehydes and ketones I 282
This is because the alkyl groups of the open-chain compounds have consider-
ably more freedom of motion and produce greater steric hindrance in transi-
tion states for addition.
Electrical effects are also important in influencing the ease of addition to
carbonyl groups. Electron-attracting groups facilitate the addition of nucleo-
philic reagents to carbon by increasing its positive character. Thus we find
that compounds such as the following add nucleophilic reagents readily :
O O
II II
CC1 3 — C— H H0 2 C — C— C0 2 H
trichloroacetaldehyde (chloral) oxomalonic acid
Although Grignard reagents, organolithium compounds, and the like gen-
erally add to aldehydes and ketones (Section 9-9C) rapidly and irrevers-
ibly, this is not true of many other reagents. Their addition reactions may
require acidic or basic catalysts and have relatively unfavorable equilibrium
constants. Some of these reactions are discussed in considerable detail in the
following sections.
A. CYANOHYDRIN FORMATION
Hydrogen cyanide adds to many aldehydes and ketones to give a-cyano-
alcohols, usually called cyanohydrins.
o OH
II
CH3-C-CH3 + HCN
The products are useful in synthesis — for example, in the preparation of
cyanoalkenes and hydroxy acids :
( - H 2 0)
CH 3
I
* CH 2 =C — C=N
OH / a-methacrylonitrile
I
CH3-C-CH3
OH
acetone cyanohydrin _ >jh / ^^ 3 — — ^^ 3
C0 2 H
2-hydroxy-2-methylpropanoic acid
(dimethylglycolic acid)
An important feature of cyanohydrin formation is that it requires a basic
catalyst. In the absence of base, the reaction does not proceed, or is at best
very slow. In principle the basic catalyst might activate either the carbonyl
group or the hydrogen cyanide. With hydroxide ion as the base, one reaction
to be expected is a reversible addition of hydroxide to the carbonyl group.
sec 11.4 reactions of aldehydes and ketones 283
5® 8e e H3C X>
(CH 3 ) 2 C=^p +OH ;=± V
H 3 C OH
HI
However, such addition is not likely to facilitate formation of cyanohydrin,
because it represents a competitive saturation of the carbonyl double bond.
Indeed, if the equilibrium constant for this addition were large, an excess of
hydroxide ion could inhibit cyanohydrin formation by tying up acetone as the
adduct [1].
Hydrogen cyanide itself has no unshared electron pair on carbon and is
unable to form a carbon-carbon bond to a carbonyl carbon (indeed, the fact is
that hydrogen cyanide, when it does react as a nucleophilic agent toward
carbon, forms C— N rather than C— C bonds). However, an activating
function of hydroxide ion is clearly possible through conversion of hydrogen
cyanide to cyanide ion, which can function as a nucleophile toward carbon.
A complete reaction sequence for cyanohydrin formation is shown.
H— C=N + OH . :C=N + H 2
CH 3 H 3 C O e
C=0 + :C = N , C
/ IT /-•' \
CH,
C = N
H 3 C O e H 3 C OH
C + H 2 ^z^ r' + OH
H 3 C C^N H 3 C C^N
The last step regenerates the base catalyst. All steps of the overall reaction
are reversible but, with aldehydes and most nonhindered ketones, formation
of the cyanohydrin is reasonably favorable. In practical syntheses of cyano-
hydrins, it is convenient to add a strong acid to a mixture of sodium cyanide
and the carbonyl compound, so that hydrogen cyanide is generated in situ.
The amount of acid added should be insufficient to consume all the cyanide
ion, so that sufficiently alkaline conditions are maintained for rapid addition.
If sodium cyanide alone is used the reaction is rapid but does not go to com-
pletion because of the reversibility of the final step.
Table 1 1 .2 shows the extent of reaction for some simple carbonyl com-
pounds. The effect of introducing an isopropyl group in the 2 position of
cyclohexanone is seen to be considerable and is probably steric in origin.
However, in other cases where steric effects might be expected to be impor-
tant, no evidence for such effects is reported. Thus virtually the same equilib-
rium constant is found for acetone and methyl ?-butyl ketone. This is difficult
to explain and it appears that the factors governing cyanohydrin formation
require further study.
B. HEMIACETAL AND ACETAL FORMATION
Hemiacetals and acetals are products of addition of alcohols to aldehydes
— thus, for acetaldehyde and methanol,
chap 1 1 aldehydes and ketones I 284
Table 11-2 Equilibrium in cyanohydrin formation in 96% ethanol solution
at 20°
carbonyl compound
equilibrium constant,
liters/mole
% cyanohydrin at
equilibrium"
CH 3 COCH 3
32.8
84
CH 3 COCH 2 CH 3
37.7
85
CH 3 COCH(CH 3 ) 2
81.2
90
CH 3 COC(CH 3 ) 3
32.3
84
H 2 C C ^
I c=o
67
89
H * C ^CH 2
H^C CH-»
/ \ 2
H,C C =
\ /
H 2 C-CH 2
11,000
~100
H 2/ C-CH 2
H 3 C— HC C=0
H 2 C-CH CH 3
c
h' x ch 3
15.3
78
(menthone)
" Starting with 1 M concentrations of carbonyl compound and hydrogen cyanide.
CH, H,C OH „ H,C OCH 3
\ 3 CH3OH 3 \ / CH jOH, - H 2 Q 3 \ / 3
c=o ^=t C - A
H 7 H X OCH3 » OCH3
a hemiacetal acetaldehyde dimethyl acetal
(1-methoxyethanol) (1, 1-dimethoxyethane)
First, we shall consider hemiacetal formation, which is catalyzed by both
acids and bases. The base catalysis is similar to that involved in cyanohydrin
formation. The slow step here is the addition of alkoxide ion to the carbonyl
group.
=± CH 3 O e + H 2
CH 3 H 3 C X)CH 3
\ x — -^e slow 3 \ /
C = 0-CH 3 . C.
H ' ^> H y V
H3C X/ OCH3 fast H 3C x/ OCH 3
t + H 2 . C + OH e
H O e W OH
sec 11.4 reactions of aldehydes and ketones 285
Acid catalysis of hemiacetal formation might involve activation of either
the alcohol or the carbonyl compound. However, the only simple reaction
one would expect between various species of alcohols and proton donors is
oxonium ion formation, which hardly seems the proper way to activate an
alcohol for nucleophilic attack at the carbonyl group of an aldehyde.
CH,OH + H a
H
I
CH,-0- H
methyloxonium ion
On the other hand, formation of the oxonium ion (or conjugate acid) 1 of
the carbonyl compound is expected to provide activation for hemiacetal
formation by increasing the positive character of the carbonyl carbon.
CH 3
\
c=o
/
H
CH^-^
C=?=OH +O-CH3
H H
CH 3
\ ©
C = OH
H
CH 3
C— OH
/
H
conjugate acid of acetaldehyde
,CH 3
H,C.
O
/
W y \>H
H,C N /O-CH,
H /C \)H
+ H 9
hemiacetal
In water solution most aldehydes form hydrates. This reaction is analogous
\
C=0 + H,0
R OH
X
H OH
to hemiacetal formation and is catalyzed by both acids and bases. The equilib-
rium constant for hydrate formation depends on steric and electrical factors.
In contrast to hemiacetal formation, acetal formation is catalyzed only by
acids. Addition of a proton to a hemiacetal can occur two ways to give either
[2] or [3].
CH,
h 3 c ;o
X H
H OH
H 3 C x ^OCH,
H OH
+ H tt
[2]
H 3 C x OCH 3
C
/ \©
H O-H
I
H
[3]
1 The conjugate acid of X is XH®, while the conjugate base of HY is Y e .
chap 11 aldehydes and ketones I 286
The first of these [2] can lose CH 3 OH and yield the conjugate acid of acetalde-
hyde. This is the reverse of acid-catalyzed hemiacetal formation.
H 3 C ffi q ch,
V H . C=OH + CH3OH
/ > /
H M)H h
[2]
The second of these [3] can lose H 2 and give a new entity, the methyloxo-
nium cation of the aldehyde [4].
H 3 C /O-CH3 CHj
C , C=0-CH 3 + H 2
/ ,\s> /
H VO-H h
I
H [4]
[3]
The reaction of [4] with water gives back [3], but reaction with alcohol leads
to the conjugate acid of the acetal [5]. Loss of a proton from [5] gives the
acetal.
CH 3
H,C. ffl .O. ,,„ H 3 C, ,OCH,
\ ^© ~^\ "3-^ / x _ H S 3- x /
C=0-CH 3 + 0-CH 3 ■ C H , C
H h H ° _CH 3 H OCH 3
[4] [5]
The fact that acetals are formed only in an acid-catalyzed reaction has the
corollary that acetal groups are stable to base. This can be synthetically very
useful, as illustrated by the following synthesis of glyceraldehyde from
readily available acrolein (CH 2 =CHCHO). Hydrogen chloride in ethanol
adds in the anti-Markownikoff manner to acrolein to give /?-chloropropion-
aldehyde, which then reacts with the ethanol to give the acetal. (Markow-
nikoff 's rule does not apply when a carbon-carbon double bond is conjugated
to groups such as carbonyl.)
CH 2 =CHCHO + HCI -
ClCH 2 CH 2 CHO + 2C 2 H 5 OH ► ClCH 2 CH 2 CH(OC 2 H 5 ) 2
The key step in the synthesis involves E2 dehydrochlorination of the chloro-
acetal without destroying the acetal group, which is stable to base.
ClCH 2 -CH 2 -CH(OC 2 H 5 ) 2 + KOH E2 » CH 2 =CH-CH(OC 2 H 5 ) 2 + KC1 + H 2
Hydroxylation of the double bond with neutral permanganate then gives the
diethyl acetal of glyceraldehyde. This kind of step would not be possible with
acrolein itself because the aldehyde group reacts with permanganate as easily
sec 11.4 reactions of aldehydes and ketones 287
Table 1 1*3 Conversions of aldehydes to acetals with various alcohols
(1 mole of aldehyde to S moles of alcohol)
°/ conversion to acetal
aldehyde
isopropyl J-butyl
ethanol cyclohexanol alcohol alcohol
CH3CH0
78
56
43
(CH 3 ) 2 CHCHO
71
23
(CH 3 ) 3 CCHO
56
16
11
QH5CHO
39
23
13
23
as does the double bond.
CH 2 =CH-CH(OC 2 H 5 ) 2 ^^ CH 2 -CH-CH(OC 2 H 5 ) 2
OH OH
Finally, mild acidic hydrolysis of the acetal function yields glyceraldehyde.
CH 2 -CH-CH(OC 2 H 5 ) 2 + H 2 "" > CH 2 -CH-CHO + 2 C 2 H,OH
II II
OH OH OH OH
glyceraldehyde
The position of equilibrium in acetal and hemiacetal formation is rather
sensitive to steric hindrance. Large groups in either the aldehyde or the alcohol
tend to make the reaction less favorable. Table 11-3 shows some typical
conversions in acetal formation when 1 mole of aldehyde is allowed to come
to equilibrium with 5 moles of alcohol.
Hemiacetal formation occurs readily in an intramolecular manner when a
five- or six-membered ring can be formed from a hydroxyaldehyde. This type
H 2 C-CH 2/ OH
HOCH 2 CH 2 CH,CHO < > 2 | C
H 2 CV \ H
of reaction is especially important for carbohydrates as will be discussed in
Chapter 15.
C. POLYMERIZATION OF ALDEHYDES
A reaction closely related to acetal formation is the polymerization of alde-
hydes. Both linear and cyclic polymers are obtained. For example, formalde-
hyde in water solution polymerizes to a solid long-chain polymer called para-
formaldehyde or "polyoxymethylene." This material, when strongly heated,
n-CH 2 =0 + H 2 ► H— 0-CH 2 ~(-O— CH 2 ^-0-CH 2 — O— H
paraformaldehyde
chap 1 1 aldehydes and ketones I 288
reverts to formaldehyde; it is therefore a convenient source of gaseous
formaldehyde. When heated with dilute acid, paraformaldehyde yields the
solid trimer trioxymethylene (mp 61°). The cyclic tetramer is also known.
CH 2
of ^O
I I trioxymethylene
H 2 C. /CH 2
Long-chain formaldehyde polymers have become very important as plas-
tics in recent years. The low cost of paraformaldehyde (10-15 cents/lb) is
highly favorable in this connection, but the instability of the material to
elevated temperatures and dilute acids precludes its use in plastics. However,
the "end-capping" of polyoxymethylene chains through formation of esters
or acetals produces a remarkable increase in stability, and such modified
polymers have excellent properties as plastics. Delrin (DuPont) and Celcon
(Celanese) are stabilized formaldehyde polymers with exceptional strength
and ease of molding.
D. CONDENSATIONS OF CARBONYL COMPOUNDS WITH
DERIVATIVES OF AMMONIA
Ammonia adds readily to acetaldehyde to give a crystalline compound.
OH
I
H3C-C-NH,
I
H
The corresponding adducts with most other aldehydes are not very stable,
undergoing dehydration and polymerization rapidly. Amines and other
derivatives of ammonia react in a similar way except that the dehydration
products are usually stable compounds that do not polymerize. Reactions of
this sort, in which two molecules combine and then water is split out, are
often called condensation reactions and usually require acid or base catalysis.
In the case of condensations between carbonyl compounds and amines, catal-
ysis is normally brought about by acids.
\ u® \
C=0 + H 2 N-R ► C
/ /
Table 11-4 summarizes a number of important reactions of this type and the
nomenclature of the reactants and products.
E. HYDROGEN HALIDE ADDITION AND REPLACEMENT BY
HALOGEN
Addition of hydrogen halides to carbonyl groups is so easily reversible as to
prevent isolation of the products.
sec 1 1 .4 reactions of aldehydes and ketones 289
Table 1 1*4 Condensation reactions of carbonyl compounds with
derivatives of ammonia
reactant
typical product
class of product
H 2 N-R (R = alkyl, aryl
CH 3 CH=N-CH 3
inline"
or hydrogen)
acetaldehyde methylimine
(Schiff's base)
amine
CH 3
C = N-NH,
NH 2 -NH 2
hydrazone
hydrazine
/
CH 3
acetone hydrazone
CH 3 CH 3
\ / 3
C=N-N=C
/ \
CH 3 CH 3
azine
acetone azine
N0 2
H 2 N-NHR (R =
= alkyl, aryl,
or <X>=N — NH-f \-N0 2
substituted
hydrogen)
hydrazone*
substituted hydrazine
cyclobutanone 2,4-dinitro-
phenylhydrazone
O
H
II
H 2 NNHCNH 2
{ VCH==N— N-C-NH,
semicarbazone 6
semicarbazide
benzaldehyde semicarbazone
HO-NH 2
CH 2 =N-OH
oxime 6
hydroxylamine
formaldoxime
" Most unsubstituted imines, that is, R = H, are unstable and polymerize.
* Usually these derivatives are solids and are excellent for the isolation and characterization of
aldehydes and ketones.
CH 3
\
C=0 + HC1 -
/
H
CH 3 CI
X
H OH
However, many aldehydes react with alcohols in the presence of an excess of
hydrogen chloride to give a-chloro ethers :
CH 3
\
C=0 + HC1 + CH 3 OH
/ 3
H
CH 3 O — CH 3
\ /
/ C N + H 2
H CI
Replacement of the carbonyl function by two chlorines occurs with phos-
chap 1 1 aldehydes and ketones I 290
phorus pentachloride in ether, and by two fluorines with sulfur tetrafluoride :
CI
F. REDUCTION OF CARBONYL COMPOUNDS
Formation of Alcohols. The easiest large-scale reduction method for con-
version of aldehydes and ketones to alcohols is by catalytic hydrogenation.
H >r c >=o ȣ&& h ^ c >hoh
h > c Vh 2 <N0 ' 50 h > c Vh 2
95-100%
The advantage over most chemical reduction schemes is that usually the
product can be obtained simply by filtration from the catalyst followed by
distillation. The usual catalysts are nickel, palladium, copper chromite, or
platinum promoted with ferrous iron. Hydrogenation of aldehyde and ketone
carbonyl groups is much slower than of carbon-carbon double bonds and
rather more strenuous conditions are required. This is not surprising, because
hydrogenation of carbonyl groups is calculated to be less exothermic than
that of double bonds. It follows that it is generally not possible to reduce a
\ / II
C=C + H 2 ' > -C— C- A#=-30kcal
/ \ II
H H
\ I
C=0 + H, ► — C— OH Atf=-12kcal
/ I
H
carbonyl group with hydrogen in the presence of a double bond without also
saturating the double bond.
In recent years inorganic hydrides such as lithium aluminum hydride,
LiAlH 4 , and sodium borohydride, NaBH 4 , have become extremely important
as reducing agents of carbonyl compounds. These reagents have considerable
utility, especially with sensitive and expensive carbonyl compounds. The
reduction of cyclobutanone to cyclobutanol is a good example :
^o^^O"
OH
90%
With the metal hydrides the key step is transfer of a hydride ion to the carbonyl
carbon of the substance being reduced :
sec 11.4 reactions of aldehydes and ketones 291
R H r 0-AlH 3 Li
\ r< |e © \ /
C=0 + H— Al-H Li ► .C
Lithium aluminum hydride is handled very much like a Grignard reagent,
since it is soluble in ether and is sensitive to both oxygen and moisture.
(Lithium hydride is insoluble in organic solvents and is not an effective
reducing agent for organic compounds.) All four hydrogens on aluminum can
be utilized.
H OCH 3
Li® H-A1^H + 4CH 2 = ► Li e CH 3 0-A1-0CH 3 -**sitiU
H OCH 3
4CH 3 OH + Al 3 ® + Li®
The reaction products must be decomposed with water and acid as with the
Grignard complexes. Any excess lithium aluminum hydride is decomposed by
water and acid with evolution of hydrogen.
LiAlH 4 + 4H® ► Li® + AF© + 4 H 2
Lithium aluminum hydride usually reduces carbonyl groups without affec-
ting carbon-carbon double bonds. It is, in addition, a strong reducing agent
for carbonyl groups of carboxylic acids, esters, and other acid derivatives,
as will be described in Chapter 13.
Sodium borohydride is a milder reducing agent than lithium aluminum
hydride and will reduce aldehydes and ketones but not acids or esters. It
reacts sufficiently slowly with water in neutral or alkaline solution so that
reductions which are reasonably rapid can be carried out in water solution
with only slight hydrolysis of the reagent.
NaBH 4 + 4CH 2 =0 + 4H 2 ► 4CH 3 OH + NaB(OH) 4
Reduction of Carbonyl Compounds to Hydrocarbons. There are a number of
methods of transforming
\ \
C = to CH 2
In some cases, the following sequence of conventional reactions may be
useful :
, .0 *f OH H V H
\y \y \ r s \y
<f ^L <f -^ ? -£- i
c c c ' c
1 H ' H ' H
chap 1 1 aldehydes and ketones I 292
This route is long, requires a hydrogen a to the carbonyl function, and may
give rearrangement in the dehydration step (Section 10-5B).
More direct methods may be used depending on the character of the R
groups of the carbonyl compound. If the R groups are stable to a variety of
reagents there is no problem, but with sensitive R groups not all methods are
equally applicable. When the R groups are stable to acid but unstable to base,
the Clemmensen reduction with amalgamated zinc and hydrochloric acid is
often very good. The mechanism of the Clemmensen reduction is not well
o
"^ " ^ ^VcH 2 CH 2 C0 2 C 2 H 5
^ y— <~— <~n 2 <~<-» 2 ^ 2 n 5 HC |
59%
understood. It is clear that in most cases the alcohol is not an intermediate,
because the Clemmensen conditions do not suffice to reduce most alcohols to
hydrocarbons.
When the R groups of the carbonyl compound are stable to base but not
to acid, the Wolff-Kishner reduction is often 1 very convenient. This involves
treating the carbonyl compound with hydrazine and potassium hydroxide
in dimethyl sulfoxide solution.
X CH 2 CH 2
H 2 <\ C-O + NH 2 -NH 2 -&¥* H 2 C^ Vh 2 + N 2 + H 2
CH 2 \rf 2
90%
G. OXIDATION OF CARBONYL COMPOUNDS
Aldehydes are easily oxidized by moist silver oxide or by potassium per-
manganate solution to the corresponding acids.
o o
« [O] //
R-C l J > R-C
\ \
H OH
Ketones are much more difficult to oxidize at the carbonyl group than
aldehydes. Ketones with a hydrogens can be oxidized in acidic or basic solu-
tions because of enol formation, as will be described in Chapter 12. Thus,
O OH
II OH e (or H®) I
CH 3 -C— CH 3 , CH 3 -C=CH 2
ketone enol
Enols, being unsaturated, are easily attacked by reagents which oxidize
unsaturated molecules.
Methyl ketones can be oxidized to carboxylic acids with the loss of a
carbon atom by the haloform reaction (Section 12- 1C).
sec 11.4 reactions of aldehydes and ketones 293
H. THE CANNIZZARO REACTION
A characteristic reaction of aldehydes without a hydrogens is the self
oxidation-reduction that they undergo in the presence of strong base. Using
formaldehyde as an example,
O
heat " ff
2CH 2 =0 + NaOH ™ Q > CH 3 OH + H—C
ONa
If the aldehyde has a hydrogens, other reactions usually occur more rapidly.
The mechanism of the Cannizzaro reaction combines many features of
other processes studied in this chapter. The first step is reversible addition of
hydroxide ion to the carbonyl groups.
H H O e
\ e \ /
C = + OH . C^
H 7 H OH
The hydroxyalkoxide ion so formed can act as a hydride ion donor like lithium
aluminum hydride and reduce a molecule of formaldehyde to methanol.
hVs .
H 2 C=0 + X C^ -^ H3C-O + H-C — ^U CH3OH + HC0 2
H OH OH
I. DISTINGUISHING BETWEEN ALDEHYDES AND KETONES
Most of the reactions described in earlier sections of this chapter take place
with both aldehydes and ketones. There are a number of tests, however, to
distinguish between these classes of compounds, one of which is the use of
ammoniacal silver ion. This is a mild reagent which oxidizes aldehydes but
RCHO _ Ag(NH ^ g ', RCO.H + AgCs)
leaves most ketones untouched. If the reagent and substrate are carefully
mixed in a test tube the metallic silver will deposit on the walls to form a
mirror. A similar test for aldehydes involves the oxidizing action of com-
plexed cupric ion (Fehling's reagent); a red precipitate of cuprous oxide
indicates the oxidation of an aldehyde or other easily oxidized substance.
Another reaction that is characteristic of aldehydes and a few ketones is
addition of sodium bisulfite to the carbonyl group. The resulting ionic
O OH
R-C + Na®HSOf . R-C-S0 3 e Na ffl
\ I
H H
chap 1 1 aldehydes and ketones I 294
compound is a salt of a sulfonic acid (Section 19-2D), although it is usually
called simply the bisulfite addition compound of the particular aldehyde. It
contains a carbon-sulfur bond. The reaction is reversible and addition of acid
regenerates the aldehyde by converting the sodium bisulfite to sulfur dioxide.
Most bisulfite addition compounds are nicely crystalline and aldehydes are
sometimes purified through them. The few ketones that form bisulfite addition
compounds have relatively unhindered carbonyl groups — for example,
acetone and cyclopentanone.
Although the carbonyl stretching frequencies of aldehydes and ketones
lie close together (1705-1740 cm -1 ) the aldehydic C— H stretching frequency
occurs at somewhat lower frequency (near 2700 cm -1 ) than the C— H
absorption in ketones and most other compounds. This band is not always
easy to recognize, however, and a more characteristic absorption is the nmr
peak of the aldehydic proton which occurs at very low field (9.7 ppm from
TMS).
summary
// II
Aldehydes, R— C , and ketones, R— C— R, both contain the carbonyl
H
group. The IUPAC system names aldehydes as alkanals — methanal, for
example — and ketones as alkanones — propanone, for example. In addition,
the simple aldehydes can be named as analogs of carboxylic acids— formalde-
hyde, for example — and ketones can be named by giving the names of the two
groups attached to carbonyl — dimethyl ketone, for example.
The polarity of the carbonyl group accounts for aldehydes and ketones being
part way between alkanes and alcohols in terms of most physical properties.
Aldehydes and ketones have characteristic infrared, ultraviolet, and nmr
spectra. Strong absorption just above 1700 cm -1 in the infrared is due to
C=0 stretching. Rather weak absorption near 2750 A in the ultraviolet is
due to an n -> tc* electronic transition in saturated aldehydes or ketones ;
conjugation of the carbonyl group with a double bond causes an increase in
both A max and e max and the appearance of powerful n -> n* absorption just
above 2000 A. The aldehydic proton absorbs at very low field in the nmr.
The methods of preparing aldehydes and ketones may be summarized as
follows:
RCH,OH ^ z- RCH=CR 2
RCHO q R 2 C=0 «-
RC0 2 H
RC-C1
O OH OH °
II II II
RC=CR > RCCH 2 R R 2 C-CR 2 ► RCCR 3
Most of the reactions of aldehydes and ketones at the carbonyl group
involve addition processes. These usually occur more readily with aldehydes
or with cyclic ketones than with open-chain ketones, especially those with
summary
295
bulky groups attached. In almost all the reactions shown below a nucleophile
attacks the carbon atom of the carbonyl group. In some cases the active
nucleophile is produced by the action of base; in others, the carbonyl group
is activated by protonation.
p
R-C
O
II
-C-+H®
RCHOHR'
-► RCHOHCN
OH
I
-» RCOR
I
H
OR
I
RC-OR
I
H
-> polymers
-» RCH=NZ
-> RCHXOR
-► RCHX,
->■ RCH 2 OH
-> RCH 3
-* RCH 2 OH + RC0 2 H
®OH
II
— C-
R 2 C=0
OH
I
-> -C-
I
N
-> R 2 R'COH (by the Grignard
reaction)
► R 2 COHCN
(cyanohydrms)
OH
* 1
► RC— OR
I
R
(hemiacetals, ace-
tals, hemiketals,
ketals)
OR
I
RC-OR
1
R
*
C=NZ
(Z = -H, -NH 2 ,
O
Jl
-NHCNH 2 ,-OH)
(with HX and ROH)
► R 2 CX 2
(with PX 5 )
-♦ R 2 CHOH (with LiAlH 4 or
cat. H 2 )
-* RCH 2 R
(Clemmensen or
WoJff-Kishner
reductions)
(Cannizzaro
reaction)
Acid catalyzed through prior protonation of the carbonyl group.
Aldehydes can be distinguished from most ketones by their ability to
reduce Ag 1 or Cu 11 , by their ability to form bisulfite addition compounds, and
by the characteristic low-field nmr absorption of the aldehydic proton.
chap 1 1 aldehydes and ketones I 296
exercises
11-1 Draw structural formulas for each of the following substances.
a. hexanal
b. divinyl ketone
c. phenylethanal
d. 3-phenyl-2-butenal
e. cyclohexyl phenyl ketone
11-2 Name the following substances according to the systems developed in
Table 11-1.
a. CH 3 CH=CHCHO
<x
O
d. CF3COCF3
e. CH 3 CH— CHCHO
I I
OH CH 3
/. (CH 3 ) 2 C(CH 2 ) 2 CHCHO
c. C fi H,COCH,COC„H,
11-3 Write structural formulas for each of the following :
a. bromomethyl 1 ,2-dimethylcyclopropyl ketone
b. diallyl ketone
c. 4-bromo-2-methyl-3-butynal
d. diacetylacetylene (and supply the IUPAC name;
O
II
acetyl =CH 3 -C-)
e. 3-acetyl-2-cyclohexenone
11-4 Show how you could prepare 3-hexanone using, in turn, each of the following
compounds as starting material.
a. butanal
b. 3-hexyne
c. 3-ethyl-2-hexene
O
//
d. propanoyl chloride (CH 3 CH 2 C )
CI
11-5 A compound C 6 Hi 2 was treated with ozone and the reaction products
boiled with water and zinc dust.
A single organic product was obtained which had a strong infrared absorp-
tion band near 1725 cm -1 and a low-field absorption in the nmr (almost 10
ppm from TMS). What is the structure and name of the compound C 6 Hi 2 ?
11-6 Identify the reagents A-F in each of the steps below:
2-pentanol
2-pentanone
D C
butanal < < butanoic acid
exercises 297
11-7 Predict the products to be expected from acid-catalyzed rearrangements of
1 ,2-propanediol and 2-methyl-2,3-butanediol.
11-8 Treatment of tetramethylethylene oxide (CH 3 ) 2 C — C(CH 3 ) 2 with acid
produces pinacolone (pp. 280-281). Explain. O
11-9 How might one dehydrate pinacol to 2,3-dimethyl-l,3-butadiene without
forming excessive amounts of pinacolone in the process ?
11-10 Arrange the following pairs of compounds in order of expected reactivity
toward addition of a common nucleophilic agent such as hydroxide ion to
the carbonyl bond. Indicate your reasoning.
O O
II II
a. CH3-C-CH3 and CH 3 -C-CC1 3
O O
II II
b. (CH 3 ) 3 C-C-H and CH 3 -C— CH 3
o o
II II
c. CH 3 — C-OCH 3 and CH 3 — C— CH 3
o o
II II
d. CH 3 -C-C1 and CH 3 -C-CH 3
, ^CH 2 CH 2
e. I C=0 and H 2 C C=0
u r / \ /
11-11 What should be the rate law for the formation of acetone cyanohydrin by the
mechanism given on p. 283 if the first step is slow and the others fast ? If the
second step is slow and the others fast?
a. Calculate A.H for the formation of acetone cyanohydrin from hydro-
gen cyanide and acetone in the vapor phase at 25°. Do the same for
the formation of dimethylethynylcarbinol from ethyne and acetone.
b. What are the prospects for carrying out addition of ethyne to acetone
by the same procedure used for hydrogen cyanide? Explain.
c. What would you expect to happen if one attempted to prepare
acetone cyanohydrin with acetone and a solution of sodium cyanide ?
11-12 The equilibrium constant for hydration is especially large for formaldehyde,
trichloroacetaldehyde, and cyclopropanone. Explain.
11-13 Write equations for the synthesis of the following substances based on the
indicated starting materials. Give the reaction conditions as accurately as
possible.
a. (CH 3 ) 2 CHCHO from (CH 3 ) 2 CHCH 2 CH 2 OH
O
II
CH 2 -CH-C-CH 3 CH— CHC0 2 H
b. I I from I I
CH 2 — CH 2
chap 11 aldehydes and ketones I 298
CH 2 -CHO C H 2
c. CH, from | C=0
\ H 2 CX /
CH 2 — CHO CH 2
CH 2 -CH 2 CH 2 -C=CH 2
d I I from
CH 2 -CH 2
e. | CHC0 2 H from | C=0
HjC ~~c£ 2 H ^CH 2
11-14 Write reasonable mechanisms for each of the following reactions. Support
your formulations with detailed analogies insofar as possible.
O O
II II H 2
a. H-C-C-H + NaOH —+ HOCH 2 C0 2 Na
H H
b. CH3-C-C-CH3 „ g ,! » CH 3 -C-CH 2 CH3
Br OH O
11-15 The following reactions represent "possible" synthetic reactions. Consider
each carefully and decide whether or not the reaction will proceed as written.
Show your reasoning. If you think side reactions would be important, write
equations for each.
excess
a. CH 3 CH(OC 2 H 5 ) 2 + 2 NaOCH 3 CH 5 3 ° H > CH 3 CH(OCH 3 ) 2 +2 NaOC 2 H 5
b. (CH 3 ) 3 CCOCH 2 CH 3 + KMn0 4 ^° > (CH 3 ) 3 COH + CH 3 CH 2 C0 2 K
c. CH 3 CC1(CH 3 )CH 2 C1 + 2 NaOCH 3 CH3 ° H > CH 3 C(CH 3 )(OCH 3 )CH 2 OCH 3 + 2 NaCl
d. 0=CH-C0 2 H + NaBH 4 CH3 ° H > 0=CH-CH 2 OH
e. CH 2 =0 + CH 3 C0 2 CH 3 + NaOH > HC0 2 Na + CH 3 CH 2 OH + CH 3 OH
11-16 Name each of the following substances by an accepted system :
a. CH 3 OCH 2 C(OCH 3 ) 3
b. CH 3 -CH-S0 3 Na
I
OH
c. CH 3 C(OCH 3 ) 3
d. [(CH 3 ) 3 CO] 3 Al
e. CH 3 (CH 3 C0 2 )C(CN)(CH 3 )
/ (CH 3 ) 2 C=N-N(CH 3 ) 2
g. (CH 2 ) 2 CHC(CH 3 )NOH
11-17 Show how structures may be deduced for the two substances with respective
infrared and nmr spectra as shown in Figure 11-2.
■* :
o
o
8
o>
<d
' -' ~^~-
o
o
00
"* g TTT ' ' - - '•
■-^Zpmm . ^
o
o
:
l-l
a.
^hfiH^HI^piHl^BHffiBHH&
'fi
.g
^^^^^^^^^^^^^^^^^^^^
8°.
•o >>
C o
-
a
i
>
td
^^ s :
3
o O"
2 o
2*1
^^^^^^^^^^^^^^^^^^^^^^^^B
8
"sf^^^SM^SiM^^^^ff^^^Mifg^^^s^^^^Si^S^^^S^
o
■*
o
o
W^^fVw^^^B^^^^^s^WwWvfW^i^^M^f^f^-
o
o
-t
S»fcft(lH^WftSi^8Hfc^^(^^^w
£N
«r
8
iS^^^^^^^^^^^^^^^^^^^^^tf^^H
o
o
§
•o
.
-r
= L
J.....
~__
o I
'«==
=_
o pi
.~£
so U
{-p**"'
("v
3.
fi
o
wilt
1
4>
UOKSIUISUBJ} %
chap 1 1 aldehydes and ketones I 300
11-18 The mass spectra (Section 7-2B) of propanal and butanone both show strong
peaks at mass 57. What is the ionic fragment that accounts for these peaks
in the two cases? Propanone (acetone), on the other hand, has almost no
peak at 57 but has a strong peak at mass 43. What does this suggest about
the ease of bond breaking in carbonyl compounds ?
11-19 Both periodic acid and lead tetraacetate are useful reagents for cleaving
1,2-diols to aldehydes or ketones. *ra«.y-9,10-Decalindiol, however, does not
react with periodic acid at all, although it is cleaved slowly by lead tetra-
acetate.
What general conclusions can you draw about the reaction pathways used by
these two reagents?
chap 12 aldehydes and ketones II 303
Carbonyl groups often have a profound effect on the reactivity of their
substituents. This is particularly evident when the substituents have hydrogen
and halogen atoms on the carbon a to the carbonyl group, or when there is a
double bond in the oc,/i position. In this chapter we shall consider first a
number of very important synthetic reactions involving a hydrogens and later
reactions of unsaturated and polycarbonyl compounds.
12-1 halogenation of aldehydes and ketones
Halogenation of saturated aldehydes and ketones usually occurs exclusively
by replacement of hydrogens a to the carbonyl groups. The characteristics of
o o
II II
CH3CCH3 + Cl 2 ► C1CH 2 CCH 3 + HC1
chloroacetone
Br
<^ \=0 + Br 2 «• / \=0 + HBr
2-bromocyclohexano ne
such reactions are very different from those of the halogenation of alkanes
(Chapter 3). Acetone has been particularly well studied and reacts smoothly
with chlorine, bromine, and iodine.
An important feature of the reaction is that acetone reacts at the same rate
with each halogen. Indeed, the rate of formation of halogenated acetone is
independent of the concentration of halogen, even at quite low halogen
concentrations. Furthermore, halogenation of acetone is catalyzed by both
acids and bases. The rate expressions for formation of halogenated acetone in
water solution are
e
v = &[CH 3 COCH 3 ][OH] at moderate concentrations of OH e
v = /t'[CH 3 COCH 3 ][H ffi ] at moderate concentrations of H®
(The ratio of fc to k' is 12,000, which means that hydroxide ion is a much more
effective catalyst than hydrogen ion.)
To account for the role of the catalysts and the lack of effect of halogen
concentration on the rate, the acetone must necessarily be slowly converted
by the catalysts to an intermediate that reacts rapidly with halogen to give the
products. This intermediate is a-methylvinyl alcohol, which is the unstable
enol form of acetone.
O OH e OH
II H®(orOH e ) I Br 2 II e
CH 3 -C-CH 3 — ► CH 3 -C=CH 2 -jt^- CH 3 -C-CH 2 -Br + Br
enol
(a-methylvinyl alcohol)
O
— ^ CH 3 -C-CH 2 Br + H ffi + Br e
chap 12 aldehydes and ketones II 304
As long as the first step is slow compared with the second and third steps, the
rate will be independent of both the concentration of halogen and its nature,
whether chlorine, bromine, or iodine.
We shall now discuss each step in the reaction in more detail. First, there is
the question of how the catalysts function to convert the ketone to its enol
form.
A. BASE-CATALYZED ENOLIZATION
With a basic catalyst, the first step is removal of a proton from the a position
to give the enolate anion [1]. Normally, C— H bonds are highly resistant to
o
II
CH.-C-
•CH, + OH
slow
CH,
II e
-C-CH,:
[1]
I
CH,— C = CH,
+ H,0
attack by basic reagents, but removal of a hydrogen a to a carbonyl group
results in the formation of a considerably stabilized anion with a substantial
proportion of the negative charge on oxygen. As a result, hydrogens a to
carbonyl groups have acidic character and can be removed as protons. In con-
trast to the dissociation of many weak acids (e.g., CH 3 C0 2 H, H 3 B0 3 , HF),
the acidic proton on carbon is removed slowly and equilibrium between the
ketone and its enolate anion [1] is not established rapidly. The reverse reac-
tion is also slow and, as a result, the enolate anion has ample time to add a
proton to oxygen to form the enol (this process is at least 10 10 times faster
than conversion to the ketone).
O
I:
CH,-C— CH,
+ H a
fast
CH
OH
I
-C=CH 2
Both the enol and the enolate anion can combine rapidly with halogen to give
the a-halo ketone.
O
OH
I
+ Br,
fasi
O
ffi OH
fast II
► CH 3 -C-CH 2 Br + Br'
O
a ( - HBr) II
e > CH,-C-CH,Br
The slowest step in the whole sequence is the formation of the enolate anion,
and the overall rate is thus independent of the halogen concentration.
B. ACID-CATALYZED ENOLIZATION
Catalysis of the enolization of acetone by acids involves, first, oxonium ion
formation and, second, removal of an a proton with water or other proton
acceptors.
sec 12.1 halogenation of aldehydes and ketones 305
O ®OH
II _ fast II
CH 3 — C— CH 3 + H ffi ; CH 3 — C— CH 3
®OH OH
B f "^ slow I $
CH 3 -C-CH/+ H 2 > CHj-C-CHj +H 3
This differs from base-catalyzed enolization in that the enol is formed
directly and not subsequently to the formation of the enolate anion. Also,
proton addition to the carbonyl oxygen greatly facilitates proton removal
from the a carbon by the electron-attracting power of the positively charged
oxygen. Nevertheless, the rate of enolization (or halogenation) is determined
by this last step.
The characteristics of acid- and base-catalyzed enolization, as revealed
by the halogenation of acetone, are displayed in a wide variety of other,
usually more complicated, reactions. For this reason the halogenation reaction
has been considered in rather more detail than is consistent with its intrinsic
importance as a synthetic reaction.
C. HALOFORM REACTION
The preceding discussion on the halogenation of ketones is incomplete in
one important respect concerning base-induced halogenation. That is, once
an a-halo ketone is formed, the other hydrogens on the same carbon are
rendered more acidic by the electron-attracting effect of the halogen and are
replaced much more rapidly than the first hydrogen.
OOO
II slow H fast II
CH3-C-CH3 ' CH 3 -C-CH 2 Br > CH 3 -C-CHBr 2
fast
O
II
CH 3 -C-CBr 3
The result is that if the monobromo ketone is desired, the reaction is best
carried out with an acidic catalyst rather than a basic catalyst. A further
complication in the base-catalyzed halogenation of a methyl ketone' is that the
trihalo ketone formed is readily attacked by base with cleavage of a carbon-
carbon bond.
o o e o
11 * j^ ... in^ s .ow^ CHj _ c // +
OH OH
:CBr 3 e . CH 3 COf + HCBr 3
bromoform
This sequence is often called the haloform reaction because it results in the
production of chloroform, bromoform, or iodoform, depending on the
chap 12 aldehydes and ketones II 306
halogen used. The haloform reaction is a useful method for detecting methyl
ketones, particularly when iodine is used because iodoform is a highly
insoluble, bright yellow solid. The reaction is also useful for the synthesis of
carboxylic acids when the methyl ketone is more available than the corres-
ponding acid. Because halogens readily oxidize alcohols to carbonyl com-
o
i^ II l.Br 2 ,OH e , H 2 r-.
P-C-CH 3 rS5 ► [>-C0 2 H + CHBr 3
85%
pounds it follows that a positive haloform test will also be given by alcohols
containing the — CHOHCH 3 group.
12-2 reactions of end ate anions
A. THE ALDOL ADDITION
Many of the most important synthetic reactions of carbonyl compounds
involve enolate anions, either as addends to suitably activated double bonds
or as participants in nucleophilic substitutions. When the addition is to a
carbonyl double bond, it is often called an aldol addition. S N reactions of
enolate anions are considered in Chapter 13 with regard to synthetic applica-
tions.
The course of the aldol addition is typified by the reaction of acetaldehyde
with base, and, if carried out under reasonably mild conditions, gives
/?-hydroxybutyraldehyde (acetaldol). If the mixture is heated, the product is
dehydrated to crotonaldehyde (2-butenal).
OH
2 CH3CHO
dilute NaOH
>
1
CH 3 CHCH 2 CHO
OH
CH3-CH-
-CH,-CHO
► CH 3 CH=
Formation of the enolate anion by removal of an a hydrogen by base is the
first step in the aldol addition.
o
e^ II
HO +CH,-C-H
O o°
e II I
:CH,— C — H « ► CH 2 =C— H
The anion then adds to the carbonyl bond in a manner analogous to the
addition of cyanide ion in cyanohydrin formation (Section 1 1 ■ 4A). You would
expect from consideration of the two resonance forms of the enolate anion
that addition might take place in either of two ways: The anion may attack
sec 12.2 reactions of enolate anions 307
to form either a carbon-carbon or a carbon-oxygen bond, leading to the
aldol [2] or to a-hydroxyethyl vinyl ether [3]. Although the formation of [3] is
O a O
I II
CH 3 -C-CH 2 -CH
I
H
H®
OH
i CH,— C— CH,CHO
I
H
[2]
CH,
O
II
-C— H +
CH,
O e
I
=C-H <-
O
e II
-> :CH 2 — C-
O fc
CH, — C— O— CH=CH, 5P
I
H
OH
I
=t CH,— C— O— CH=CH,
I
H
[3]
mechanistically reasonable, it is much less so on thermodynamic grounds.
Indeed, AH for the formation of [3] from acetaldehyde (calculated from
vapor-state bond energies) is +20 kcal.
The equilibrium constant is favorable for the aldol addition of acetaldehyde,
as in fact it is for most aldehydes. For ketones, however, the reaction is much
less favorable. With acetone, only a few percent of the addition product
" diacetone alcohol " [4] is present at equilibrium.
o
II
2CH,CCH,
OH
OH O
I II
CH3 C~~ CH2 C CH 3
I
CH,
[4]
This is understandable on the basis of steric hindrance and the fact that the
ketone-carbonyl bond is about 3 kcal stronger than the aldehyde-carbonyl
bond. Despite the unfavorable equilibrium constant, it is possible to prepare
diacetone alcohol in good yield with the aid of an apparatus such as shown in
Figure 12-1.
The acetone is boiled and the hot condensate from the reflux condenser
flows back through the porous thimble over the solid barium hydroxide
contained therein and comes to equilibrium with diacetone alcohol. The
barium hydroxide is retained by the porous thimble and the liquid phase is
returned to the boiler where the acetone (boiling 110° below diacetone alcohol)
is selectively vaporized and returned to the reaction zone to furnish more
diacetone alcohol.
The fundamental ingredients in the key step in aldol addition are an elec-
tron-pair donor and an electron-pair acceptor. In the formation of acetaldol
chap 12 aldehydes and ketones II 308
porous thimble
containing
Ba(OH) 2
Figure 12-1 Apparatus for preparation of diacetone alcohol.
and diacetone alcohol, both roles are played by one kind of molecule, but
there is no reason why this should be a necessary condition for reaction.
Many kinds of mixed additions are possible. Consider the combination of
formaldehyde and acetone: Formaldehyde cannot form an enolate anion
because it has no a hydrogens, but it should be a particularly good electron-
pair acceptor because of freedom from steric hindrance and the fact that it has
an unusually weak carbonyl bond (166 kcal vs. 179 kcal for acetone). Acetone
forms an enolate anion easily but is relatively poor as an acceptor. Conse-
quently, the addition of acetone to formaldehyde should and does occur
readily.
o
CH,-C-CH,
OH
o
II
+ CH 3 — C-CH 2 CH 2 OH
The problem is not to get addition, but rather to keep it from going too far.
Indeed, all six a hydrogens can be easily replaced by — CH 2 OH groups.
o
II
CH,-C-CH, +
6
OH
(HOH 2 C) 3 C-
O
II
-c-
C(CH 2 OH) 3
To obtain high yields of the monohydroxymethylene derivative, it is usually
necessary to use an apparatus such as shown in Figure 12-2. The scheme here
is to have the addition take place in the presence of a large excess of acetone
to assure favorable formation of the monoadduct. The reaction is then
sec 12.2 reactions of enolate anions 309
quenched and the acetone separated and used again. This is achieved by
boiling rapidly a solution of acetone containing an excess of a nonvolatile
weak organic acid, such as succinic acid (CH 2 )2(C0 2 H) 2 . The vapor is
condensed and then mixed with a very slow trickle of an alkaline formalde-
hyde solution. The addition then occurs while the mixture flows down over a
column of glass beads, and gives the monoadduct because the acetone is
present in great excess. The reaction stops and reversal is prevented when the
alkali is neutralized by the acid in the boiler. The excess acetone is revaporized
and sent up to react with more formaldehyde.
Aldol addition products can be converted to a variety of substances by
reactions that have been discussed previously. Of particular importance is the
dehydration of aldols to a,/?-unsaturated carbonyl compounds, which occurs
spontaneously in the presence of acid. The formation of crotonaldehyde by
dehydration of acetaldol has already been mentioned in this section. Another
example is the dehydration of diacetone alcohol to mesityl oxide.
CH 3 O
I II
CH 3 -C-CH 2 -C-CH 3
I
OH
H e
( - H 2 0)
CH 3
\
C=CH-
CH,
O
II
-c-
CH,
4-methyl-3-penten-2-one
(mesityl oxide)
Figure 12-2 Apparatus for preparation of monohydroxymethylene aldol-
addition products from formaldehyde and carbonyl compounds with more
than one a hydrogen.
cold formaldehyde
solution containing
dilute sodium
hydroxide
volatile carbonyl
compound containing
a weak nonvolatile
organic acid
chap 12 aldehydes and ketones II 310
B. NUCLEOPHILIC SUBSTITUTION INVOLVING ENOLATE ANIONS
An enolate anion can be formed in good yield from a ketone and a power-
fully basic reagent, such as sodium or potassium amide, provided that the
ketone has an a hydrogen. The enolate anion so formed can theoretically
undergo S N reactions with an alkyl halide in two different ways. Thus, for
f-butyl methyl ketone and methyl iodide, we could have the reactions shown
in Scheme I, which differ only in the position of attack at the enolate anion.
H 3 C O
CH ,_c-C-CH, KNH >
( - NH 3 )
H,C
H 3 C O
I II e
CH 3 — C— C — CH 2 :
-+ CH,— C— C=CH 2
H,C
CH 3 -C-C-CH
C-alkylation
O-alkylation
CH,
CH,
SCHEME I
The possibility of the enolate anion's acting as though its charge were
effectively concentrated on carbon or on oxygen was discussed in the pre-
vious section in connection with aldol addition (Section 12-2A). However, the
situation there is actually quite different from the one here, because the
reaction on oxygen was indicated to be thermodynamically unfavorable over-
all (AH = + 20 kcal). However, O- and C-alkylation of the anion are both
thermodynamically favorable. Furthermore, alkylation, unlike the aldol
addition, is not reversible under ordinary conditions, and therefore the
O-alkylation product is not expected to go over to the C-alkylation product,
even though the latter is considerably more stable.
Whether C- or O-alkylation occurs often depends on the reactivity of the
halide; the lower the S N 2 reactivity of the halide, the more C-alkylation is
favored.
Useful alkylation procedures for the preparation of a-substituted ketones
will be discussed below and in Chapter 13.
unsaturated carbonyl compounds
The combination of a carbonyl function and a double bond in the same
molecule leads to exceptional properties only when the groups are close to one
another. The cumulated and conjugated arrangements are of particular
interest. We shall consider first the conjugated or a,/?-unsaturated carbonyl
sec 12.3 a,(3-unsaturated aldehydes and ketones 311
compounds, because their chemistry is closely related to that of the substances
already discussed in this chapter and in Chapter 11.
12-3 a, ^-unsaturated aldehydes and ketones
The most generally useful preparation of a,/?-unsaturated carbonyl com-
pounds is by dehydration of aldol addition products, as described in the
previous section. Conjugation of the carbonyl group and double bond has a
marked influence on spectroscopic properties, particularly on ultraviolet
spectra, as the result of stabilization of the excited electronic states which, for
n-*n* transitions, can be described in terms of important contributions by
\e I I e
polar-resonance structures such as C — C = C — O (see also Sections 7-5 and
11-2B). /
The effect of conjugation is also reflected in nmr spectra. The protons on
the P carbon of a,/?-unsaturated carbonyl compounds usually come at 0.7 to
1 .7 ppm lower than ordinary olefmic protons. The effect is smaller for the a.
proton.
cc,/5-Unsaturated carbonyl compounds may undergo the usual addition and
condensation reactions at the carbonyl group, such as cyanohydrin and
hydrazone formation and addition of organometallic compounds. These
reactions, however, may be complicated, if not overshadowed, by " 1,4 addi-
tion " (conjugate addition, Section 6-2) which gives as the overall result addi-
tion to the carbon-carbon double bond. The balance between the two modes
of reaction is so delicate that relatively small changes in steric hindrance are
sufficient to cause one or the other process to predominate.
With hydrogen cyanide, cyanohydrin formation is usually more rapid than
1,4 addition, and if the equilibrium is favorable, as with most aldehydes, only
1,2 addition is observed.
OH
e |
CH 3 -CH=CH-CHO + HCN OH > CH 3 — CH=CH-C-H
I
With ketones, cyanohydrin formation is less favorable, and 1,4 addition
results to give an enol intermediate which is unstable with respect to the
jS-cyano ketone.
O
II
CH,= CH-C-CH, + HCN
OH O
I k II
CH 2 =CH-C-CH 3 ;= ' N=C-CH 2 -CH 2 -C-CH 3
C=N
Addition of hydrogen halides to a,/?-unsaturated aldehydes, ketones, and
acids occurs 1,4 and places the halogen on the /? carbon atom. The mechanism
of this reaction is illustrated for the reaction of hydrogen chloride with pro-
chap 12 aldehydes and ketones II 312
penal (acrolein). 1,2 Addition to the carbonyl group would lead to an unstable
o
II
CH,= CH-C-H + H s
ffi OH
II
CH, = CH-C-H <-
OH
B CH, — CH = C — H
CI°
OH
C1CH, - CH=C - H -^r-
O
II
-C-H
a-halo alcohol (Section 1 1 -4E).
0,y-Unsaturated aldehydes and ketones are usually relatively difficult to
synthesize and are found to rearrange readily to the a, jS-un saturated isomers,
particularly in the presence of basic reagents. (See Exercise 12-14.)
CH,=CH-CH,-CHO
base
+ CH,-CH=CH-CHO
12-4 ketenes
Substances with cumulated carbonyl and carbon-carbon double bonds,
C = C = 0, are called ketenes and, as might be expected, have interesting
and unusual properties.
There are few general preparations for ketenes although several special
methods are available for ketene itself. The most convenient laboratory prep-
aration is to pass acetone vapor over a coil of resistance wire heated electri-
cally to a dull red heat. Air is excluded to avoid simple combustion.
750°
+ CH,=C=0 + CH.
O
II
CH 3 -C— CH 3
ketene
bp-56°
Ketene is a very useful acetylating agent for ROH and RNH 2 compounds.
It reacts rapidly, and since the reactions involve additions, there are no by-
products to be separated.
p
CH,= C=0
H 2
CH 3 C0 2 H
CH 3 CH 2 OH
+ CH,
\
OH
O O
II II
-C-O-C-CHj
o
* CH 3 — C-0-CH 2 CH 3
O H
CH 3 NH 2 II I
— ^-> CH,-C-N-CH,
sec 12.5 1,2-dicarbonyl compounds 313
The considerable convenience of ketene as an acetylating agent would
make it an excellent candidate for commercial sale in cylinders except for the
fact that the substance is unstable with respect to formation of a dimer known
as diketene. The dimer is itself a highly reactive substance with such unusual
characteristics that its structure was not firmly established until the early
1950's, some 40 years after it was first prepared.
CH 2 =C=0 C-O
i i ► I I
H 2 C=C=0 H 2 C— C
O
diketene
(vinylaceto-£-lactone)
polycarbonyl compounds
12-5 1 ,2-dicarbonyl compounds
The structures of some typical and important members of this class are shown.
00 9 9 9 9
n II ii II II II
H-C-C-H CH3-C-C-CH3 C 6 H 5 -C-C-C 6 H 5
glyoxal biacetyl benzil
(ethanedial) (2, 3-butanedione) (diphenylethanedione)
Most of the 1,2-dicarbonyl compounds are yellow in color. Glyoxal is
unusual in being yellow in the liquid state, but green in the vapor state. It has
very reactive aldehyde groups.
Glyoxal undergoes an internal Cannizzaro reaction (Section 11-4H) with
alkali to give glycolic acid.
OO OH OH o
II II e I h® I //
H-C-C-H + OH » H-C-COf ► H-C-C
I I \
H H OH
An analogous reaction occurs with benzil, except that the migrating group
is phenyl rather than hydrogen and this results in a rearrangement of the
carbon skeleton. This is one of a very few carbon-skeleton rearrangements
brought about by basic reagents, and is known as the benzilic acid rearrange-
ment.
OO OH OH
II II e I H ® I //
C 6 H 5 -C-C-C 6 H 5 + OH ► C 6 H 5 -C-CO? ► C 6 H 5 -C-C x
benzil C 6 H 5 C 6 H 5 OH
benzilic acid
chap 12 aldehydes and ketones II 314
12-6 1 ,3-dicarhonjl compounds
Most of the important properties of 1,3-dialdehydes, aldehyde ketones, and
diketones that are characteristic of the 1 ,3 relationship are well illustrated by
2,4-pentanedione (acetylacetone). This substance is unusual in existing to the
extent of 85 % as the enol form.
o o
II i II
CH-C-s-CH 2 -C-CH 3
2, 4-pentanedione
O O OH O
II 1 I II
,c „c.
~CH- - C H 3
15% 85%
The nmr spectrum of 2,4-pentanedione (Figure 12-3) is very informative
about the species present in the pure liquid. Resonance lines for both the keto
and enol forms can be readily distinguished. The keto form has its CH 2 reson-
ance at 218 Hz and its CH 3 resonances at 120 Hz, whereas the enol form
shows its CH 3 and vinyl-CH resonances at 110 Hz and 334 Hz, respectively.
The enol-OH proton comes at the very low field value of 910 Hz with respect
to tetramethylsilane. That each form may be observed separately indicates
that the lifetime of each form is longer than 0.1 sec at room temperature (see
Section 7-6D). However, when a basic catalyst is added, the lines broaden
Figure 12-3 Nuclear magnetic resonance spectrum of 2,4-pentanedione,
CH 3 COCH 2 COCH 3 , at 60 MHz. Calibrations are relative to tetramethylsilane.
800
600
400
200
ii/.
enol
MC.H ,-....
kc-ni
IliBiifliii'iilSi
(ch»-), j;
=c—
iiiiilpliill
enol
-CH-
-OH
i
' :
i
.. i
1 J
_ ._ _
16.0 12.0 8.0 4.0 Oppm
sec 12.6 1,3-dicarbonyl compounds 315
considerably; when the mixture is heated, the lines coalesce to an average
spectrum as expected for rapid equilibration.
The very large chemical shift of the enol-OH proton is the consequence of
internal hydrogen bonding involving the carbonyl group. This type of hydro-
gen bonding is also important in stabilizing the enol form, as evidenced by an
increase in the percentage of enol in those solvents, such as hexane, that can-
not effectively solvate the ketone groups of the keto form.
-hydrogen bond
o
1 II
H 3 C^ C CH 3
I
H
The enol form is also considerably stabilized by resonance which, in turn,
increases the strength of the hydrogen bond. Such stabilization is, of course,
not possible for the keto form.
o /H "o t „ »o^ H "-o e
I II II I
h 3 c" C \h C ^ch 3 h 3 c /C ^c^ v ch 3
The term conformer is often used to designate one of two or more stereo-
chemical arrangements that are interconverted by rotation about single bonds.
This is usually so rapid that it prevents the isolation of discrete conformers,
except at very low temperatures (see Section 3-4B). The term tautomer is
employed in exactly the same sense for structural isomers in rapid equilibrium,
such as the keto and enol forms of 2,4-pentanedione. When tautomerization
involves only the shift of a proton, as in the acetaldehyde-vinyl alcohol
equilibrium (Section 10-8), it is sometimes called a prototropic change. While
in principle the only difference between the rapid interconversion of 2,4-
pentanedione on the one hand and the slow isomerization of 1,4-pentadiene
on the other is a matter of relative reaction rate, rightly or wrongly, the term
tautomeric change is usually applied only to the more rapid process.
2,4-Pentanedione is moderately acidic with K HA ~ 1CT 9 compared with
K HA of 10~ 5 for acetic acid and 10~ 16 for ethanol, the charge derealization
in the anion being responsible.
o o o e o o o e
II II « > I II « — ► II I
H 3 C^ ^CH^ V CH 3 H 3 C^ V CH^ ^CH 3 H 3 C^ ^CH^ ^CH 3
Alkali metal salts of the compound can be alkylated with alkyl halides of
good S N 2 reactivity and generally give C-alkylation. A number of syntheti-
cally important alkylations of other 1,3-dicarbonyl compounds are discussed
in Chapter 13.
Polyvalent metal cations often form very stable and slightly polar enolate
salts with acetylacetone, better known as metal chelates. Cupric ion is a parti-
chap 12 aldehydes and ketones II 316
cularly good chelating agent. The corresponding beryllium compound is a
H
I
I:
O.
':cu;
o-' -o
il
il
o
,c*.
-A
I
H
cupric acetylacetonate (dark blue)
(Cu" salt of 2, 4-pentanedione)
CH,
further example of a metal chelate; it melts at 108°, boils at 270°, and is
soluble in many organic solvents.
summary
Aldehydes and ketones [5] undergo a number of reactions at the a position
involving either the enolate anion [6] or the enol [7]; [6] results only from the
action of a base, while [7] can be generated by the action of either an acid or a
base. The rates of interconversion of [7] and [5], not their equilibrium con-
centrations, are affected by acid or base.
(-H®K,
O
II
R-CH 2 — C-Z
[5]
O
e II
R— CH— C— Z
I
-» R— CH=C— Z
[6]
(+H«)
R-CH,
ffi OH
-C-Z
( - H®)_
\(+ H»)
OH
I
R-CH=C-Z
[7]
a-Halogenation can proceed via [6] or [7] with both aldehydes and ketones.
Methyl ketones in basic solution undergo trisubstitution and this is followed
by chain cleavage (the haloform reaction).
o
II
RCJHL C CH3
o
II
-► RCH 2 — C — CX 3
-► RCH,-CO,H + CHX,
Aldehydes with a hydrogens undergo aldol addition in base to give products
which often eliminate water to give qc,/?-unsaturated aldehydes. Although the
equilibrium is normally unfavorable for the corresponding condensation of
two molecules of a ketone, the reaction can nonetheless often be made to
occur (Figure 12-1).
summary 317
e I
RCH— CHO ► RCH,CH — CH— CHO
I
R
OH
RCH 2 CH-CH-CHO ► RCH 2 CH=C-CHO
I I
R R
Ketones are alkylated (predominantly at carbon) through reaction of the
enolate anions with alkyl halides.
o o
e II II
R— CH— C— R ► R— CH— C— R
I
R'
a,/MJnsaturated aldehydes and ketones absorb strongly in the ultraviolet
and the protons on their /J-carbon atoms appear at lower field in the nmr than
other alkenic protons : They are usually subject to 1,4-addition reactions of the
type RCH=CHCHO + HZ -> RCHZCH 2 CHO.
Ketenes contain cumulated double bonds and react rapidly with hydroxylic
(and amino) compounds.
O / o
II II
R 2 C = C = + ZOH ► R 2 CHCOZ \Z=H — , RC— , R-
Ketene itself, which is prepared in the laboratory by the pyrolysis of ace-
tone, readily dimerizes to give diketene, a /^-lactone.
1,2-Dicarbonyl compounds include glyoxal (OHCCHO), biacetyl
o o o o
II II II II
(CH3C-CCH3), and benzil (C 6 H 5 C-CC 6 H 5 ). In basic solution, glyoxal
undergoes an internal Cannizzaro reaction and benzil undergoes a carbon-
skeleton rearrangement to give benzilic acid, (C 6 H 5 ) 2 COHC0 2 H.
Two important characteristics of 1,3-dicarbonyl compounds are their
acidity and their tendency to enolize. Stabilization of the anion and enol can
be ascribed to resonance stabilization and hydrogen bonding, respectively.
OO O^O
li e i| I ||
R— Ci- .-C— R R— C*. ^C— R
CH^ V CH
The keto-enol forms are called tautomers (structural isomers in rapid
equilibrium). Enols form complex salts called chelates with many metal
cations.
chap 12 aldehydes and ketones II 318
exercises
12-1 At what point would the system shown in Figure 12-1 cease to produce more
diacetone alcohol? What would happen if some barium hydroxide were to
get through a hole in the thimble and pass into the boiler? Why is barium
hydroxide more suitable for the preparation than sodium hydroxide?
12-2 What would be the products expected from aldol additions involving pro-
panal, 2,2-dimethylpropanal, and a mixture of the two aldehydes?
12-3 Predict the principal products to be expected in each of the following reac-
tions; give your reasoning:
a. CH 3 CHO + (CH 3 ) 2 CO NaOH >
b. (CH 3 ) 2 C(OH)CH 2 COCH 3 ^^U
c. CH 2 + (CH 3 ) 3 CCHO NaOH >
12-4 Show how the following compounds can be synthesized from the indicated
starting materials by way of aldol-addition products :
a. CH 3 -CH-CH 2 -CH 2 from acetaldehyde
I I
OH OH
b. CH 3 CH=CH-CH 2 OH from acetaldehyde
c. (CH 3 ) 2 CHCH 2 CH 2 CH 3 from acetone
O
II
d. CH 3 CH— C— CH 2 CH 3 from propionaldehyde
I
CH 3
12-5 Although trivial names for organic compounds are slowly passing out of
common use a few such names remain; for example, diacetone alcohol
(Section 12-2A), benzilic acid (Section 12-5), and benzoin (Section 24-6 and
Exercise 12-27). Provide the IUPAC names for these three compounds and
suggest a reason for the reluctance of chemists to abandon the trivial names
completely.
12-6 Aldol additions also occur in the presence of acidic catalysts. For example,
acetone with dry hydrogen chloride slowly yields (CH 3 ) 2 C=CHCOCH 3
(mesityl oxide) and (CH 3 )2C=CHCOCH=C(CH 3 ) 2 (phorone). Write
mechanisms for the formation of these products giving particular attention to
the way in which the new carbon-carbon bonds are formed. Review Sections
4-4H and 11-4B.
12-7 The following reactions represent "possible" synthetic reactions. Consider
each carefully and decide whether or not the reaction will proceed as written.
Show your reasoning. If you think side reactions would be important, write
equations for each.
exercises 319
a. CH3COCH3 + 6 Br 2 + 8 NaOH ► 2 CHBr 3 +Na 2 C0 3 + 6 NaBr+ 6 H 2
b. CH3CHO + NaNH 2 + (CH 3 ) 3 CC1 ► (CH 3 ) 3 CCH 2 CHO + NH 3 + NaCl
c. (CH 3 ) 2 CHCOCH 3 + CH 2 = Ca(OH>2 . (CH 3 ) 2 C(CH 2 OH)COCH 3
OH e
d. CH3CHO + CH 3 C0 2 C 2 H s CH 3 CHCH 2 C0 2 C 2 H 5
OH
12-8 Write equations for a practical laboratory synthesis of each of the following
substances, based on the indicated starting materials (several steps may be
required). Give reagents and conditions.
O O
P^CirO-CH 2 ^ from [>-C-CH 3
a
1
b. CH 2 =CHCOCH 3 from CH 3 COCH 3
c. (CH 3 ) 3 CC0 2 H from (CH 3 ) 2 C(OH)C(CH 3 ) 2 OH
d. (CH 3 ) 3 CCOC(CH 3 ) 3 from CH 3 CH 2 COCH 2 CH 3
e. (CH 3 ) 2 CHCH 2 CH(CH 3 ) 2 from CH 3 COCH 3
/. (CH 3 ) 3 CCH 2 CH 2 CH 3 from (CH 3 ) 3 CCOCH 3
12-9 Give for each of the following pairs of compounds a chemical test, preferably
a test tube reaction, that will distinguish between the two compounds. (You
may wish to review Section 1 1 -41 in connection with some of these.)
a. CH 3 COCH 2 CH 2 COCH 3 and CH 3 COCH 2 COCH 3
b. (CH 3 CH 2 CH 2 CH 2 ) 2 CO and [(CH 3 ) 3 C] 2 CO
c. (C 6 H 5 ) 2 CHCH 2 CHO and (C 6 H 5 CH 2 ) 2 C=0
d. C 6 H 5 COCOC 6 H 5 and C 6 H 5 COCH 2 COC 6 H 5
e. CH 3 CH=C=0 and CH 2 =CH-CH=0
12-10 How might spectroscopic methods be used to distinguish between the two
isomeric compounds in the following pairs :
a. CH 3 CH=CHCOCH 3 and CH 2 =CHCH 2 COCH 3
b. C 6 H 5 COCH 2 COC 6 H 5 and /,-CH 3 C 6 H 4 COCOC 6 H 5
c. CH 3 CH=C=0 and CH 2 =CH-CHO
0>
and CH 3 COCH 2 CH 3
12-11 Sketch out an energy profile with the various transition states for the reaction
CH3COCH3 + OH e + Br 2 -> CH 3 COCH 2 Br + H 2 + Br e described in
Section 12-1A, using the general procedure of Section 8-9. Note that in this
case the enol form, unlike the carbonium ion in Figure 8-2, is a rather stable
intermediate.
12-12 Interpret the proton nmr spectra given in Figure 12-4 in terms of structures
of compounds with the molecular formulas C 6 H 10 O and C 9 H s O. The latter
substance has a phenyl (C 6 H 5 ) group.
chap 12 aldehydes and ketones II 320
ppm
1
3f,0
i
500
450
i l
4uo ;i r )0 ii/.
—r-
C.,H,0
-'\
7
/
I
r ^j~ j ~~^~
fllil
t^^^^/t:
...J
*J
rV fWl
V» Iflk
y " * -" -fj—r~r
i i i i
9.0
8.0
7.0
6.0 ppm
Figure 12-4 Proton nmr spectra at 60 MHz with TMS as standard. See Exer-
cise 12-12.
12-13 Calculate AH for vapor-phase 1,2 and 1,4 additions of hydrogen cyanide to
methyl vinyl ketone. Write a mechanism for 1,4 addition that is consistent
with catalysis by bases and the fact that hydrogen cyanide does not add to
an isolated carbon-carbon double bond.
12-14 Write a reasonable mechanism for the base-induced rearrangement of
3-butenal to 2-butenal. Why is 2-butenal the more stable isomer?
12-15 Write reasonable mechanisms for the reaction of ketene with alcohols and
amines. Would you expect these reactions to be facilitated by acids or bases
or both?
exercises 321
12-16 The following structures have been proposed or could be proposed for
diketene. Show how infrared, ultraviolet, and nmr spectroscopy might be
used to distinguish between the possibilities. (If necessary, review Chapter 7.)
CH 2
V
1
-0
1
H 2 C-
1
- c % (
[i]
I
CH 2
V
1
-o
1
1
O-
1
-s
M
o
o
CH,
\
C-CH 2
I I
H,C-C.
\
[i>]
O
H 2 C-C
H 2 C— C,
[vi]
//
P
V
HO
\
C=CH
H,C— C
V
[iii]
//
H 2 C-C
I I
HC=C
OH
[vii]
CH 3 — C— CH=C=0 (the favored structure for many years)
[ix]
HO
C=CH
I I
HC=C
OH
[iv]
OH
HC=C
I I
HC = C
\
OH
[viii]
12-17 2,6-Bicyclo[2.2.2]octanedione exhibits no enolic properties. Explain.
O^ y^ JO
12-18 What experiments might be done to prove or disprove the following mecha-
nism for rearrangement of glyoxal to glycolic acid ?
HC — CH
O
II e
H— C— C=0
I
H-C=C=0
OH
1
c=c=
=o
OH i
-^°. H-C-C 7 '
H
X OH
12-19 Write a mechanism analogous to that for the Cannizzaro reaction for the
benzil-benzilic acid transformation. Would you expect the same type of
reaction to occur with biacetyl ? Why or why not ?
12-20 Account for the considerable K H a of the enol of acetylacetone with respect
to ethyi alcohol. Arguing from the proportions of each at equilibrium,
which is the stronger acid, the keto or the enol form of acetylacetone?
Explain.
chap 12 aldehydes and ketones II 322
400
300
200
t
US. 1 ppni
100
11/
C,„H,,.0,
I
8.0
6.0
4.0
2.0
ppm
*K
(:i00
! I :
400
(i:hi:h=C-0)
ion
1
AVW*«»V^WN«Mty^*wrtjM>*»v<»fSU»v^^
Hz
Owiv
10.0
8.0
4.0
ppm
Figure 12-5 Proton nmr spectra at 60 MHz with TMS as standard. See Exer-
cise 12-21.
12-21 Interpret the proton nmr spectra shown in Figure 12-5 in terms of structures
of the compounds with molecular formulas C10H10O2 and (CH 3 CH =
C=0) 2 . See also Exercise 12-16.
12-22 Write a reasonable mechanism, supported by analogy, for the acid-catalyzed
dehydration of 2,4-pentanedione to 2,5-dimethylfuran.
H,C^O CH,
\J
2, 5-dimethylfuran
exercises 323
300 :
200
— j —
Mil'!
Hz
Wr-
h
O.H-OCl
:H
ppm
_! —
200 :
n
n 11/
5.0
J J
rr'r '
:(' H-()Ht:
I
4.0
r
3.0
2.0
1.0
t
ppm
Figure 12-6 Proton nmr spectra at 60 MHz with TMS as standard. See Exer-
cise 12-23.
12-23 The nmr spectra of two compounds of formulas C 4 H 7 OCl and CUH 7 OBr
are shown in Figure 12-6. Assign to each compound a structure that is con-
sistent with its spectrum. Show your reasoning. Give a concise description of
the chemical properties to be expected for each compound.
12-24 When the formation of /3-hydroxybutyraldehyde is carried on in DjO con-
taining OD e , using moderate concentrations of undeuteriated acetaldehyde,
the product formed in the early stages of the reaction contains no deuterium
chap 12 aldehydes and ketones II 324
bound to carbon. Assuming the mechanism shown in Section 12-2A to be
correct, what can you conclude as to which step in the reaction is the slow
step? What would then be the kinetic equation for the reaction? What
would you expect to happen to the kinetics and the nature of the product
formed in D 2 at very low concentrations of acetaldehyde ?
12-25 1,2-Cyclopentanedione exists substantially as the monoenol, whereas
biacetyl exists as the keto form. Suggest explanations for this behavior that
take into account possible conformational differences between the two sub-
stances. How easily would you expect dione [8] to enolize? Why?
O
o
[8]
12-26 A detailed study of the rate of bromination of acetone in water, using acetic
acid-acetate buffers, has shown that
v={6x 10" 9 + 5.6x 10- 4 [H 3 O®]+1.3x 10- 6 [CH 3 CO 2 H] + 7[OH e ]
+ 3.3 x 10- 6 [CH 3 CO 2 e ]+ 3.5 x 10- 6 [CH 3 CO 2 H][CH 3 CO 2 e ]}
[CH 3 COCH 3 ]
in which the rate is expressed in moles per liter per second when the con-
centrations are in moles per liter.
a. Calculate the rate of the reaction for 1 M acetone in water at pH 7 in
the absence of acetic acid or acetate ion.
b. Calculate the rate of the reaction for 1 M acetone in a solution made
by neutralizing 1 M acetic acid with sufficient sodium hydroxide to
give pH 5.0 (X HA of acetic acid = 1.75 x 10 - 5 ).
12-27 The carbon skeletons of diphenylethanedione (benzil) and benzoin are
identical, as are the skeletons of benzilate ion and diphenylhydroxyethanal.
Yet, diphenylethanedione rearranges under the influence of base to give
benzilate ion and the aldehyde rearranges under the influence of acid to
give benzoin. Explain why these two reactions proceed in the directions that
they do and provide reasonable mechanisms for both processes.
O O
C 6 H 5 -C-C-C 6 H 5 -531» (C 6 H 5 ) 2 COHC0 2 e
(diphenylethanedione) (benzilate ion)
O
II H®
C 6 H 5 -C-CHOHC 6 H 5 *- 2 — (C 6 H 5 ) 2 COHCHO
(benzoin) (diphenylhydroxyethanal)
12-28 Describe the course of the following reaction:
O O O
2 (C 6 H 5 ) 3 CCCH 3 < c ' H '>» ceNa ' t (C 6 H 5 ) 3 CCCH 2 CCH 3 + (C 6 H 5 ) 3 CH
What would be a suitable solvent in which to conduct this reaction ?
exercises 325
12-29 The commercially important tetrahydroxy alcohol C(CH 2 OH) 4 known as
pentaerythritol is prepared by alkaline addition of formaldehyde and acet-
aldehyde according to the following equation:
CH3CHO + 4CH 2 -^ L -» C(CH 2 OH) 4 + HC0 2 H
Work out a sequence of steps which reasonably accounts for the course of the
reaction.
js. iX-v&i'A vi-i*i«^
chapter 13
carboxylic acids and
: ,,, i derivatives
chap 13 carboxylic acids and derivatives 329
We shall be concerned in this chapter with the chemistry of the carboxylic
acids, RC0 2 H, and some of their functional derivatives of the type RCOX.
P
Although the carboxyl function — C is a combination of a hydroxyl
O — H
and a carbonyl group, the combination is such a close one that neither group
behaves independently of the other. However, we shall be able to make a
number of helpful comparisons of the behavior of the hydroxyl groups of
alcohols and acids, and of the carbonyl groups of aldehydes, ketones, and
acids.
The carboxyl group is acidic because of its ability to donate a proton to a
suitable base. In water most carboxylic acids are only slightly dissociated
(K HA ~ 10" 5 , degree of ionization of a 1 M solution ~0.3%).
RCO,H + H,0
RCO, e + H,O a
Aqueous solutions of the corresponding carboxylate salts are basic because of
the reaction of the carboxylate anion with water (hydrolysis).
CH 3 C0 2 e Na® + H 2
sodium acetate
CH 3 C0 2 H + Na® OH e
acetic acid
The nomenclature of carboxylic acids, which was discussed previously
(Section 8-4), is illustrated with some representative compounds in Figure 13-1.
Figure 13-1 Representative carboxylic acids. The IUPAC names are given
first and some common names in parentheses.
CH 3 CH 2 C0 2 H
propanoic acid
(propionic acid)
CH 3 CH 2 CH 2 CH 2 CH 2 C0 2 H
hexanoic acid
(caproic acid)
BrCH 2 C0 2 H
bromoethanoic acid
(bromoacetic acid)
propenoic acid
(acrylic acid)
I CHC0 2 H
cyclopropane-
carboxylic acid
(same)
CH 3 CHC0 2 H
I
OH
CHsCC0 2 H
propynoic acid
(propiolic acid)
CO,H
benzoic acid
(same)
NCCH 2 C0 2 H
2-hydroxypropanoic acid cyanoethanoic acid
(lactic or a-hydroxypropionic acid ) (cyanoacetic acid)
CH 3 CHC0 2 H
NH 2
2-aminopropanoic acid
(alanine or a-aminopropionic acid)
O
II
butan-3-on-l-oic acid
(acetoacetic acid)
CH 2 C0 2 H
CH 2 C0 2 H
butanedioic acid
(succinic acid)
chap 13 carboxylic acids and derivatives 330
Some common names are given in parentheses. The IUPAC names will be
used wherever practicable in this chapter although the common names for the
C x and C 2 compounds, formic acid and acetic acid, will be retained.
Carboxylic acids with R as an alkyl or alkenyl group are also called fatty
acids, but this term is more correct applied to the naturally occurring continuous
chain, saturated and unsaturated aliphatic acids which, in the form of esters,
are constituents of the fats, waxes, and oils of plants and animals. The most
abundant of the fatty acids are palmitic, stearic, oleic, and linoleic acids ; they
occur as glycerides, which are esters of the trihydroxy alcohol glycerol.
CH 3 (CH 2 ) 14 C0 2 H palmitic acid
CH 3 (CH 2 ) 16 C0 2 H stearic acid
CH 3 (CH 2 ) 7 CH=CH(CH 2 ) 7 CO 2 H oleic acid (cis)
CH 3 (CH 2 ) 4 CH=CHCH 2 CH=CH(CH 2 ) 7 C0 2 H linoleic acid
Alkaline hydrolysis of fats affords salts of the fatty acids, those of the alkali
metals being useful as soaps. The cleansing mechanism of soaps is described
in the next section.
o
II
CH 2 OCR
I O CH 2 OH
II NaOH i . ~ ffl H® ,„„„,.
CHOCR > CHOH + 3RC0 2 a Na tt
I
O CH 2 OH
II
CH 2 OCR
fat
(a glyceride) glycerol soap fatty acid
13-1 physical properties of carboxylic acids
The physical properties of carboxylic acids reflect a considerable degree of
association through hydrogen bonding. We have encountered such bonding
previously in the case of alcohols (Section 10-1); however, acids form stronger
hydrogen bonds than alcohols because their O— H bonds are more strongly
8e Se
polarized as — O — H. In addition, carboxylic acids have the possibility of
forming hydrogen bonds to the rather negative oxygen of the carbonyl dipole
rather than just to the oxygen of another hydroxyl group. Indeed, carboxylic
acids in the solid and liquid states exist mostly as cyclic dimers. These dimeric
Se
O-
■H — O
i®//
\«
-c
c
\
//
o-
-H-0
se
structures persist in solution in hydrocarbon solvents and to some extent even
in the vapor state.
The physical properties of some representative carboxylic acids are listed in
sec 13.1 physical properties of carboxylic acids 331
Table 134 Physical properties of representative carboxylic acids
solubility,
mp,
bp,
JSTha(H 2 0)
acid
structure
g/100gH 2 O
°C
°C
at 25°
formic
HC0 2 H
00
8.4
100.7
1.77 x 10" 4
acetic
CH 3 C0 2 H
00
16.6
118.1
1.75 x 10- 5
propanoic
CH 3 CH 2 C0 2 H
CO
-22
141.1
1.3 x 10~ 5
butanoic
CH 3 CH 2 CH 2 C0 2 H
GO
-8
163.5
1.5 x 10- 5
2-methylpropanoic
(CH 3 ) 2 CHC0 2 H
20
-47
154.5
1.4 x 10- 5
pentanoic
CH 3 (CH 2 ) 3 C0 2 H
3.3
-34.5
187
1.6 x 10- 5
palmitic
CH 3 (CH 2 ) 14 C0 2 H
64
390
stearic
CH 3 (CH 2 ) 16 C0 2 H
69.4
360 d
chloroacetic
C1CH 2 C0 2 H
63
189
1.4 x 10- 3
dichloroacetic
2 CHC0 2 H
8.63
5
194
5 x 10- 2
trichloroacetic
C1 3 CC0 2 H
120
58
195.5
3 x 10- 1
trifluoroacetic
F 3 CC0 2 H
00
-15
72.4
strong"
2-chlorobutanoic
CH 3 CH 2 CHC1C0 2 H
1 Ai 1 5mm
1.4 x 10~ 3
3-chlorobutanoic
CH 3 CHC1CH 2 C0 2 H
44
1 1/j22ram
8.9 x 10- 5
4-chlorobutanoic
C1CH 2 CH 2 CH 2 C0 2 H
16
1Qg22mm
3.0 x 10- 5
5-chloropentanoic
C1CH 2 (CH 2 ) 3 C0 2 H
18
130 llmm
2 x 10" 5
methoxyacetic
CH 3 OCH 2 C0 2 H
203
3.3 x 10- 4
cyanoacetic
N=CCH 2 C0 2 H
66
l 08 15mm
4 x 10~ 3
vinylacetic
CH 2 =CHCH 2 C0 2 H
-39
163
3.8 xlO- 5
benzoic
C 6 H 5 C0 2 H
0.27
122
249
6.5 X 10" 5
phenylacetic
C 6 H 5 CH 2 C0 2 H
1.66
76.7
265
5.6 x 10" 5
" The term "strong" acid means essentially complete dissociation in dilute aqueous solution;
that is, the concentration of the neutral molecule is too low to be measured by any analytical
technique now available.
Table 13-1. The notably high melting and boiling points of acids relative to
alcohols and chlorides can be attributed to the strength and degree of hydro-
gen bonding. The differences in volatility are shown more strikingly by Figure
13-2, which is a plot of boiling point versus n for the homologous series
Figure 13-2 Boiling points of acids, CH 3 (CH 2 )„_ 2 C0 2 H, alcohols,
CH 3 (CH 2 )„_ 2 CH 2 OH, and chlorides, CH 3 (CH 2 )„_ 2 CH 2 C1.
200
^^ ''.'''
^^ ^ ,'
160
^^ alcohols^ - s
jS^ s' *'
^y^ ** ''
j^ ^ ,*
C 120
^ ^ y
^
^^^^^^^^^^^^^^^^^^^f^^m
80
^'chloric! os
:##itsfflst«^
40
Wlmtm^^S^^X9^^^^^^^,
1 1 . . 1 1 1 1
chap 13 carboxylic acids and derivatives 332
CH 3 (CH 2 )„_ 2 X, in which X is -C0 2 H, -CH 2 OH, and -CH 2 C1.
Hydrogen bonding is also responsible for the high water solubility of the
simple aliphatic acids — formic, acetic, propanoic, and butanoic — which are
completely miscible with water in all proportions. As the alkyl chain increases
in length (and in degree of branching) the solubility decreases markedly. On
the other hand, the salts of carboxylic acids retain their moderately high solu-
bilities in water even when the alkyl group becomes large. This enables car-
boxylic acids to be extracted from solutions in benzene and other low-
polarity solvents by aqueous base. Sodium bicarbonate is sufficiently basic
to convert any carboxylic acid to the anion, RC0 2 H + HCOf -> RCOf
+ H 2 + C0 2 , and is usually used for this purpose. Separation of the liquid
layers, followed by acidification of the aqueous layer, then precipitates the free
carboxylic acid. The separation of a mixture of a water-insoluble alcohol and
water-insoluble carboxylic acid is illustrated in Scheme I.
2 H
1 . dissolve mixture in benzene
2 OH
2. extract benzene solution in
separatory funnel with aqueous
NaHCOj solution
benzene layer
aqueot
is layer
e Na 9 )
(RCO,
distill off
benzene
H (b
RCH
2 OH
RC(
) 2 H
SCHEME I. Thesef
aration
af a mix
ure of
a carboxylic acid.
Though the salts of long-chain carboxylic acids are moderately soluble in
water, the resulting solutions are usually opalescent as a result of the grouping
together of molecules to form colloidal particles. These are called micelles, and
their formation reflects the antipathy of the long hydrocarbon chains for the
aqueous environment into which they have been drawn by the attraction of
the water for the anionic group at the carboxylate end of the molecule. The
alkyl groups cluster together in the micelle with the charged groups on the
outside in position to be solvated by water in the usual way (Figure 13-3).
Ordinary soaps are sodium or potassium salts of C 16 and C 18 acids, such as
palmitic and stearic acids (Table 1 3-1), and their cleansing action results from
the abilities of their micelles to dissolve grease and other nonpolar substances
that are insoluble in water alone.
In minute concentrations, salts such as sodium stearate, C 17 H 35 COf Na®
(sodium octadecanoate), do not form micelles in water but, instead, concen-
trate at the surface of the liquid with the charged ends of the salt molecules
immersed in the water and the hydrocarbon parts forming a surface layer.
This results in a sharp drop in surface tension of water by even minute con-
sec. 13.1 physical properties of carboxylic acids 333
Figure 13-3 A micelle, in which long-chain carboxylate salt molecules group
together in aqueous solution. The interior of the micelle is a region of very
low polarity. The total negative charge on the micelle is balanced by the
positive charge of sodium ions in the solution.
centrations of soap. As the concentration of long-chain carboxylate salt is
increased and after the surface has become saturated, the system can either
form micelles or attempt to increase its surface. Agitation will allow the latter
to occur (frothing) but otherwise, at a certain concentration, micelles will
begin to form. This point is called the critical micelle concentration.
Micelles have some interesting catalytic properties. Not only do they pro-
vide a nonpolar environment in an aqueous system, but they have a large
charge concentrated at their surface. Each of these characteristics can be
important in accelerating the rates of certain reactions, and the catalytic
behavior of micelles is being actively investigated.
The lower-molecular-weight aliphatic acids have quite characteristic
odors. Although formic, acetic, and propanoic acids have sharp odors, those
of the C 4 to C 8 acids (butanoic to octanoic) are disagreeable and can be
detected in minute amounts, especially by dogs. 1 It has been shown that a dog's
tracking ability stems from its recognition of the particular blend of com-
pounds, mostly aliphatic acids, released by the sweat glands in the feet of the
person being followed. Each person's metabolism produces a characteristic
X A dog can detect butanoic acid at a concentration of 10~ 17 mole per liter of air, about a
million times less than the concentration required by man (R. H. Wright, The Science of
Smell, George Allen and Unwin, London, 1964).
chap 13 carboxylic acids and derivatives 334
spectrum of compounds although those from identical twins differ little from
each other. The higher-molecular-weight carboxylic acids have low volatilities
and hence are essentially odorless.
13-2 spectra of carboxylic acids
The infrared spectra of carboxylic acids provide clear evidence of hydrogen
bonding. This is illustrated in Figure 13-4, which shows the spectrum of
acetic acid in carbon tetrachloride solution, together with those of ethanol and
acetaldehyde for comparison. The spectrum of ethanol has two absorption
bands, characteristic of the OH bond; one is a sharp band at 3640 cm" 1 ,
corresponding to free or unassociated hydroxyl groups, and the other is a
broad band centered on 3350 cm -1 due to hydrogen-bonded groups. The
spectrum of acetic acid shows no absorption due to free hydroxyl groups but,
like that of ethanol, has a broad intense absorption ascribed to associated OH
groups. However, the frequency of absorption, 3000 cm -1 , is shifted appre-
ciably from that of ethanol and reflects a stronger type of hydrogen bonding
than in ethanol. The absorption due to the carbonyl group of acetic acid
(1740 cm -1 ) is broad but not shifted significantly from the carbonyl absorp-
tion in acetaldehyde.
The carboxyl function does absorb ultraviolet radiation, but the wavelengths
at which this occurs are appreciably shorter than for carbonyl compounds
such as aldehydes and ketones, and, in fact, are barely in the range of most
commercial ultraviolet spectrometers. Some idea of how the hydroxyl sub-
stituent modifies the absorption properties of the carbonyl group in carboxylic
acids can be seen from Table 13-2, in which are listed the wavelengths of
maximum light absorption (l max ) and the extinction coefficients at maximum
absorption (e max ) of several carboxylic acids, aldehydes, and ketones.
In the nmr spectra of carboxylic acids, the carboxyl proton is found to
absorb at unusually low magnetic fields. The chemical shift of carboxylic acid
protons comes about 5.5 ppm toward lower magnetic fields than that of the
hydroxyl proton of alcohols. This behavior parallels that of the enol hydro-
gens of 1,3-dicarbonyl compounds (Section 12-6) and is probably similarly
related to hydrogen-bond formation.
Table 13'2 Ultraviolet absorption properties
of carboxylic acids, aldehydes, and ketones
compound
^-max
solvent
acetic acid
204
40
water
acetic acid
197
60
hexane
acetaldehyde
293
12
hexane
acetone
270
16
ethanol
butanoic acid
207
74
water
butyraldehyde
290
18
hexane
sec 13.2 spectra of carboxylic acids 335
Figure 13-4 Infrared spectra of ethanol (a), acetic acid (b), and acetaldehyde
(c); 10% in carbon tetrachloride.
chap 13 carboxylic acids and derivatives 336
13-3 preparation of carboxylic acids
The first three methods listed below have already been met in earlier
chapters.
1. Oxidation of a primary alcohol or aldehyde (Sections 10-6 and 11-4G);
RCH,OH ► RCHO ► RCO,H
2. Cleavageof alkenes or 1,2-glycols (Sections 4-4Gand 10-7). Any powerful
RCH=CHR
RCHOHCHOHR ► 2RC0 2 H
oxidant may be used ; carboxylic acids are produced only if the carbons being
cleaved possess hydrogen atoms — otherwise, ketones result. Cleavage of
aryl side chains can also be brought about by drastic oxidation, ArCH 2 R -»
ArC0 2 H (Section 24-1).
3. Carbonation of Grignard reagents (Section 9-9C). This is a useful method
O
t H 2
RMgX + C0 2 > R-C H e > RC0 2 H
OMgX
of extending a chain by one carbon atom.
4. Hydrolysis of nitriles (to be described in Section 16-2B):
RC=N W^ RCO > H
5. Malonic ester synthesis (to be described in Section 13-9C): This is a
RX + e CH(C0 2 Et) 2 ► RCH(C0 2 Et) 2 ► RCH(C0 2 H) 2
RCH 2 C0 2 H
useful method of extending a chain by two carbon atoms.
O
II
Hydrolysis of esters (RC0 2 R), amides (RC— NH 2 ), and acid chlorides
O
II
(RC— CI) also gives carboxylic acids, but these compounds are usually pre-
pared from carboxylic acids in the first place.
13-4 dissociation of carboxylic acids
A. THE RESONANCE EFFECT
Compared with mineral acids such as hydrochloric, perchloric, nitric, and
sulfuric acids, the fatty acids, CH 3 (CH 2 )„_ 2 C0 2 H, are weak. The extent of
sec 13.4 dissociation of carboxylic acids 337
dissociation in aqueous solution is relatively small, the acidity constants,
K HA , being approximately 10~ 5 (see Table 13-1).
RC0 2 H + H 2 ■ ' RC0 2 e + H 3 O e
[RC0 2 e ][H 3 O e ]
[RC0 2 H]
10" 5 for R = CH 3 (CH 2 )„
Even though they are weak, the fatty acids are many orders of magnitude
stronger than the corresponding alcohols, CH 3 (CH 2 )„_ 2 CH 2 OH. Thus,
the K HA of acetic acid, CH 3 C0 2 H, is 10 10 times larger than that of ethanol,
CH 3 CH 2 OH.
The acidity of the carboxyl group can be accounted for by resonance stabili-
zation of the carboxylate anion, RCOf , which has the unit of negative charge
distributed to both oxygen atoms (Section 6-4).
R-C
[la]
The neutral carboxylic acid is expected to possess some stabilization asso-
ciated with the ionic resonance structure [2b], but this is a minor contributor
to the hybrid compared to [2a]. For the carboxylate anion, on the other hand,
the two contributing forms [la] and [lb] are equivalent:
O o e
// /
-C < > R-C
\ \m
OH OH
[2a] [2b]
P
-C
\
OH
Alcohols are much weaker acids than are carboxylic acids because the
charge in the alkoxide ion is localized on a single oxygen atom.
B. THE INDUCTIVE EFFECT
Although unsubstituted alkanoic acids with two carbons or more vary
little in acid strength, substitution in the alkyl group can cause large acid-
strengthening effects to appear (Table 13T). Formic acid and almost all the
a-substituted acetic acids of Table 13-1 are stronger than acetic acid; trifluoro-
acetic acid is in fact comparable in strength to hydrochloric acid. The nature of
the groups which are close neighbors of the carboxyl carbon obviously has a
profound effect on the acid strength, a phenomenon which is commonly
called the inductive effect (symbolized as +/). The inductive effect is dis-
tinguished from resonance effects of the type discussed earlier by being
associated with substitution on the saturated carbon atoms of the fatty acid
chain. It is taken as negative ( — /) if the substituent is acid enhancing, and
positive ( + /) if the substituent is acid weakening.
o
arrows show
//
c
movement of average
position of electrons
0<~H
toward chlorine
(-/effect)
chap 13 carboxylic acids and derivatives 338
The high acid strength of a-halogen-substituted acids (e.g., chloroacetic),
compared with acetic acid, results from the electron-attracting power (elec-
tronegativity) of the substituent halogen relative to the carbon to which it is
attached. The electron-attracting power of three such halogen atoms is of
course expected to be greater than that of one halogen; hence trichloroacetic
acid (K HA , 3.0 x 1CT 1 ) is a markedly stronger acid than chloroacetic acid
(^ HA ,1.4xlO- 3 ). ,
C1<-CH,
As would be expected the inductive effect falls off rapidly with increasing
distance of the substituent from the carboxyl group. This is readily seen by the
significant difference between the K HA values of the 2-, 3-, and 4-chlorobuta-
noic acids (see Table 13T).
Many other groups besides halogen exhibit an acid-enhancing, electron-
withdrawing (-/) effect. Among these are nitro (— N0 2 ); methoxyl
(CH 3 0— ); carbonyl ( C = 0, as in aldehydes, ketones, acids, esters, and
amides); cyano (—C=N); and trialkylammonio (R 3 N— ). Alkyl groups —
methyl, ethyl, isopropyl, etc. — are the only substituents listed in Table 13T
that are acid weakening relative to hydrogen (as can be seen by comparing
their ^ HA 's with those of formic and acetic acids). This means that alkyl
groups release electrons to the carboxyl group and thus exhibit a + / effect.
The magnitude of the electrical effects of alkyl groups does not appear to
change greatly in going from methyl to ethyl to propyl, and so on (compare
the K HA values of acetic, propanoic, butanoic, and pentanoic acids).
CH,-»C
the arrows represent shifts
/ in the average positions of the
bonding electrons from the
0->H methyl group toward the car-
boxyl group ( + / effect)
In addition to their acidic properties, carboxylic acids also can act as
weak bases, the carbonyl oxygen accepting a proton from a strong acid such
as H 2 S0 4 or HC10 4 (Equation 13T). Such protonation is an important step
in acid-catalyzed esterification, as discussed in Section 10-4C.
RCQ 2 H + H 2 S0 4 , RC0 2 H 2 ' e + HS0 4 e (13-1)
It requires a 12.8 AT solution of sulfuric acid (74 % H 2 S0 4 , 26 % H 2 0) to
" half-protonate " acetic acid. This means that if a small amount of acetic
acid is dissolved in 12.8 M sulfuric acid, half of the acetic acid molecules at
any instant would be in the cationic form, RC0 2 Hf , whereas in 1 M sulfuric
acid, only about one in a million would be. (The acidity of solutions of strong
acids rises very sharply as the medium becomes less aqueous.)
The cation formed by protonation of acetic acid (" acetic acidium ion "
sec 13.5 reactions at the carbonyl carbon of carboxy lie acids 339
or "conjugate acid of acetic acid") has its positive charge distributed to both
oxygen atoms and, to a much lesser extent, to carbon.
CH 3 -C
f H
\
OH
OH
OH
OH
CH,-C«
OH
OH
= ch,— c;<
= CH,C0 2 H?
OH
Although oxygen is more electronegative than carbon, the resonance forms
with oxygen bearing the positive charge are expected to be more important
than the one with carbon bearing the positive charge because the former have
one more covalent bond than the latter.
Another cation can be reasonably formed by protonation of acetic acid,
CH, — C
O
//
OH,
This ion is in rapid equilibrium with the isomer that has a proton on each
oxygen, but is present in smaller amount. Note that these isomeric ions are
tautomers (Section 12-6) and not resonance forms, because they are inter-
converted only by changing the atomic positions.
13-5 reactions at the carbonyl carbon
of carboxy lie acids
Many important reactions of carboxylic acids involve attack on carbon of
the carbonyl group by nucleophilic species. These reactions are frequently
catalyzed by acids, since addition of a proton or formation of a hydrogen
bond to the carbonyl oxygen makes the carbonyl carbon more strongly
electropositive and hence more vulnerable to nucleophilic attack. The follow-
ing equations illustrate an acid-catalyzed reaction involving a negatively
charged nucleophile (:Nu e ):
R-C
/°
-OH
+ H*
OH
R— C>
:Nu e
OH
OH
R— C— OH
Nu
Subsequent cleavage of a C— O bond and loss of a proton yields a displace-
ment product :
OH
R-C-OH
Nu
-OH e
R-C
\
r
,0
R-C
Nu
Nu
An important example of this type of reaction is the formation of esters as dis-
cussed in Section 10-4C. Similar addition-elimination mechanisms occur in
chap 13 carboxylic acids and derivatives 340
many reactions at the carbonyl groups of acid derivatives. A less obvious
example of addition to carboxyl groups involves hydride ion (H : e ) and takes
place in lithium aluminum hydride reduction of carboxylic acids (Section
13-5B).
A. ACID-CHLORIDE FORMATION
Carboxylic acids react with phosphorus trichloride, phosphorus pentachlo-
ride, or thionyl chloride with replacement of OH by CI to form acid (acyl)
chlorides, RCOC1.
O O
// sort v
(CH 3 ),CHCH 2 C — ^^ (CH 3 ) 2 CHCH 2 C + S0 2 + HC1
OH CI
3-methylbutanoic acid 3-methylbutanoyl chloride
(isovaleric acid) (isovaleryl chloride)
Formyl chloride, HCOC1, is unstable and decomposes rapidly to carbon
monoxide and hydrogen chloride at ordinary temperatures.
B. REDUCTION OF CARBOXYLIC ACIDS
In general, carboxylic acids are difficult to reduce either by catalytic hydro-
genation or by sodium and alcohol. Reduction to primary alcohols proceeds
smoothly, however, with lithium aluminum hydride, Li A1H 4 .
RC q 2 h y™± ^^°* RCH 2 OH
I i A 1 H H ® H O
CH 2 =CHCH 2 C0 2 H *-> L - ± -* CH 2 =CHCH 2 CH 2 OH
3-butenoic acid 3-buten-l-ol
(vinylacetic acid) (allylcarbinol)
The first step in lithium aluminum hydride reduction of carboxylic acids is
formation of a complex aluminum salt of the acid and liberation of 1 mole of
hydrogen :
O O
/ t
R— C + LiAlH 4 ► R-C + H 2
\ \ e ffi
OH OAlHj Li
Reduction then proceeds by successive transfers of hydride ion, H: e , from
aluminum to carbon. Two such transfers are required to reduce the acid salt to
the oxidation level of the alcohol :
RC0 2 s + 2 H e > RCH 2 O e + 2e
The anions shown as products in this equation are actually in the form of
complex aluminum salts from which the product is freed in a final hydrolysis
operation. The overall reaction can be shown as follows :
4RC0 2 H + 3LiAlH 4
sec 13.6 decarboxylation of carboxylic acids 341
[(RCH 2 0) 4 Al]Li + 4H 2 + 2LiA10 2
H 2 0, HC1
4RCH,0H + A1C1, + LiCl
13-6 decarboxylation of carboxylic acids
The ease of loss of carbon dioxide from the carboxyl group varies greatly
with the nature of the acid. Some acids require to be heated as their sodium
salts in the presence of soda lime (in general, however, this is not a good
preparative procedure).
CH,
Na a
NaOH, CaO
-> CH 4
CO,
sodium acetate
Other acids lose carbon dioxide simply by being heated at moderate tempera-
tures.
/ 140M60
CH 2 ► CH 3 C0 2 H + C0 2
C0 2 H
malonic acid acetic acid
Thermal decarboxylation occurs most readily when the a carbon carries a
strongly electron-attracting group (i.e., — / substituent), as in the following
examples :
NC-CH 2 -COOH
CH 3 CO-CH 2 -COOH
CCI,CO,H
nitroacetic acid
malonic acid
cyanoacetic acid
acetoacetic acid
trichloracetic acid
decarboxylation occurs
readily at 100°-150°
The mechanisms of thermal decarboxylation are probably not the same in
all cases, but decarboxylation of acids having a /?-carbonyl group is prob-
ably a cyclic process of elimination in which hydrogen bonding plays an
important role :
'i) tf
CH 2
malonic acid
OH
/
HO-C
\
CH 2
enol form of
acetic acid
O
II
c
II
O
CHjCOOH + C0 2
acetic acid
chap 13 carboxylic acids and derivatives 342
Stepwise decarboxylation also occurs, particularly in reactions in which the
carboxylate radical (RC0 2 • ) is formed. This radical can decompose further to
a hydrocarbon radical R- and C0 2 . The overall decarboxylation product is
determined by what R- reacts with: If a good hydrogen atom donor is
present, RH is formed; if a halogen donor such as Br 2 is present, RBr is
formed.
RC0 2 - ► R-+C0 2
R- + RH > RH + R'.
R- + Br 2 > RBr + Br-
Carboxylate radicals can be generated several ways. One is the thermal
decomposition of diacyl peroxides, which are compounds with a rather weak
O— O bond:
O O O
II i II II
R— C— O+O-C- R > 2R— C— O
Another method involves electrolysis of sodium or potassium carboxylate
solutions, known as Kolbe electrolysis, in which carboxylate radicals are
formed by transfer of an electron from the carboxylate ion to the anode.
Decarboxylation may occur simultaneously with, or subsequent to, the forma-
tion of carboxylate radicals, leading to hydrocarbon radicals, which sub-
sequently dimerize.
RC0 2 e ► RC0 2 -+e anode reaction
K.® + e + H 2 > KOH + i H 2 cathode reaction
RC0 2 - > R-+C0 2
R-+R- > RR
In the Hunsdiecker reaction, an alkyl bromide is formed when a silver salt
of a carboxylic acid is treated with bromine in the absence of water. Carboxyl-
ate radicals are probably involved. This reaction provides a means for remov-
ing a carbon from the end of a chain with retention of a functional group in
the product.
-AgBr
RBr + CO,
13-7 reactions at the 2 position of carboxylic acids
HALOGENATION
Bromine reacts smoothly with carboxylic acids in the presence of small
quantities of phosphorus to form 2-bromo acids. The reaction is slow in the
RCH,C0 2 H + Br 2 — ^— > RCHBrC0 2 H + HBr
sec 13.7 reactions at the 2 position of carboxylic acids 343
absence of phosphorus, whose function appears to be to form phosphorus
O
//
tribromide which reacts, with the acid to give the acid bromide, — C a
Br
compound known to be substituted readily by bromine. Substitution occurs
exclusively at the 2 position (a position) and is therefore limited to carboxylic
acids with a hydrogens. Chlorine with a trace of phosphorus reacts similarly
but with less overall specificity. Concurrent radical chlorination can
occur at all positions along the chain (as in hydrocarbon halogenation; see
Section 3-3B).
CH 3 CH 2 C0 2 H ,
ci 2 , p
> CH 3 CHC0 2 H
CI
CI 2 , ku
■> CH 3 CHC0 2 H + CICH 2 CH 2 C0 2 H
CI
2-chIoropropanoic 3-chloropropanoic
acid acid
B. SUBSTITUTION REACTIONS OF 2-HALO ACIDS
The halogen of a 2-halo acid is activated by the adjacent electron-withdraw-
ing carboxyl group and is readily replaced by nucleophilic reagents such as
CN e , OH e , I e , and NH 3 . Thus, a variety of 2-substituted carboxylic acids
may be prepared by reactions that are analogous to S N 2 substitutions of
alkyl halides (Scheme II).
CH 3 CHC0 2 H
I
I
2-iodopropanoic
acid
CH 3 CHC0 2 e
I
OH
-> CH 3 CHC0 2 H
OH
OH
lactic acid
CH 3 CHCO,H eXCeSS > CH,CHC0,NH 4 HS > CH 3 CHC0 2 H
I
Br
2-bromopropanoic acid
CN e
CH 3 CHC0 2 H
I
CN
2-cyanopropanoic acid
H 2
NH,
* CH 3 CHCO ? H
C0 2 H
methylmalonic acid
NH 2
alanine
SCHEME II
chap 13 carboxylic acids and derivatives 344
functional derivatives of carboxylic acids
A functional derivative of a carboxylic acid is a substance formed by
replacement of the hydroxyl group of the acid by some other group, X, that
can be hydrolyzed back to the parent acid according toEquation 13-2. By this
definition, an amide, RCONH 2 , but not a ketone, RCOCH 3 , is a functional
o o
R— C + H 2 ► R-C + HX (13-2)
X OH
derivative of a carboxylic acid. A number of types of acid derivatives are given
in Table 13-3.
The common structural feature of the compounds listed in Table 13-3 is the
P
acyl group R— C . Nitriles, RC=N, however, are often considered to be
acid derivatives, even though the acyl group is not present as such, because
hydrolysis of nitriles leads to carboxylic acids. The chemistry of nitriles is dis-
cussed in Chapter 16.
CH 3 C=N " ' H2 °> CH3COOH
acetonitrile acetic acid
The carbonyl group plays a dominant role in the reactions of acid deriva-
tives, just as it does for the parent acids. The two main types of reactions of
acid derivatives with which we shall be concerned are the replacement of X by
attack of a nucleophile : Nu e at the carbonyl carbon with subsequent cleavage
of the C— X bond (Equation 13-3), and substitution at the 2-carbon facilita-
ted by the carbonyl group (Equation 13-4).
O 9 o
R _ c > + :N e > R _^/x ► R-C + :X e (13-3)
\ I \
X Nu Nu
O O
RCH 2 -C + YZ ► RCH-C + HZ (13-4)
\ I \
X Y *
13- 8 displacement reactions of acid derivatives
The following are the more important displacement reactions :
1 . Acid derivatives are hydrolyzed to the parent acids. These reactions are
commonly acid and base catalyzed, but acid chlorides usually hydrolyze
rapidly without the agency of an acid or base catalyst :
sec 13.8 displacement reactions of acid derivatives 345
O P
// H e or OH e "
R-C + H 2 ° » R-C^ + HX
\ OH
X = -OR (ester), halogen (acid halide), -NH 2 (amide), and -0 2 CR (acid anhydride)
2. Acid or base catalysts are usually required for ester interchange.
o p
/ H® or 9 OR /
CH 3 -C + CH 3 CH;,OH .... CH 3 -C + CH3OH
OCH 3 OCH 2 CH 3
methyl acetate ' ethanol ethyl acetate methanol
3. Esters are formed from acid chlorides and anhydrides.
O
//
o
R-C + R'OH — > R-C + HC1
CI OR'
O
R-C
\
O
o
R-C.
O + R'OH
-► R-C + R-C
W OH
O
4. Amides are formed from esters, acid chlorides, and anhydrides.
R-C
?
OR'
//
R— C
\
CI
o
R-C
R-C
O
NH 3
R-C
+ R'OH
NH 2
R-C
R-C
\
NH,
P
NH,
e
NH, ffi Cl
RCO, s NHi
All of these reactions are rather closely related, and we shall illustrate the
principles involved mostly by the reactions of esters, since these have been
particularly well studied. Acid-catalyzed hydrolysis of esters is the reverse of
acid-catalyzed esterification discussed previously (Section 10-4C). In contrast,
base-induced hydrolysis (saponification) is, in effect, an irreversible reaction.
The initial step is the attack of hydroxide ion at the electron-deficient carbonyl
carbon; the intermediate anion [3] so formed then has the choice of losing
OH e and reverting to the original ester, or of losing CH 3 O e to form the
chap 13 carboxylic acids and derivatives 346
Table 13*3 Functional derivatives of carboxylic acids
derivative
structure
exa
mple
structure
name
esters
' P
R-C
OR
P
CH 3 -C x
OC 2 H 5
ethyl
acetate
acid halides
P
R-C x
of
benzoyl
(acyl halides)
X
X = F, CI, Br, I
^- / Br
bromide
P
R-C
P
CH 3 -C
anhydrides
\
O
CH 3 -<
O
acetic
anhydride
amides
(primary)
P
R-C x
NH 2
NH 2
benzamide
amides
O
II
O
//
N-methyl-
(secondary)
RCNHR'
CH 3 -C x
NHCH 3
O
acetamide
amides
O
II
//
H — C
N,N-dimethyl-
(tertiary)
RCNR'R'
N(CH 3 ) 2
formamide
sec 13.8 displacement reactions of acid derivatives 347
Table 13-3 Functional derivatives of carboxylic acids (continued)
derivative
structure
example
structure
itnides
acyl azides
hydrazides
hydroxamic
acids
O
R-C
NH
R-C.
II
H 2 C-- C /
NH
succinimide
O
P
R— C
P
N,
acetyl
azide
P
R— C
\
C,H,— C
NHNH,
O
propanoyl
\ hydrazide
NHNH,
P
p
R-C.
\
NHPH
C1CH,C
\
NHOH
chloroacetyl-
hydroxamic
acid
lactones
(cyclic esters)
O
II
(CH 2 )„|
most stable
with n — 3, 4
O
II
H 2 C^ C \
1 o
H * C ^CH 2
y-butyrolactone
lactams
(cyclic amides)
P
II
^"l
(CH 2 )„ 1
V_NH
most stable
O
II
H 2/ C-C x
HaC^ NH
H 2 C — CH
1
S-caprolactam
with n — 3, 4
CH 3
chap 13 carboxylic acids and derivatives 348
acid. The overall reaction is irreversible since, once the acid is formed, it is
immediately converted to the carboxylate anion, which is not further attacked
o
f OCH 3
o e
I
CH 3 -C-OCH ;
OH
[3]
by base. As a result, the reaction goes to completion in the direction of
hydrolysis.
CH 3 — C— OCHj
OH
[3]
CH 3 -C + CH 3 O e
\
OH
-» CHjCOf + HOCH3
Base-catalyzed ester interchange is analogous to the saponification reaction,
except that an alkoxide base is used in catalytic amounts in place of hydroxide.
The equilibrium constant is much nearer to unity, however, than for saponi-
fication, because the salt of the acid is not formed.
o
,0
CH 3 -C
\
OCH,
RO e II
+ CH 3 CH 2 OH , CH 3 C
+ CH3OH
OCH,CH 3
The mechanism is as shown in Equation 13-5. Either methoxide or ethoxide
O
II
CH 3 -C
\)CH 3
methyl acetate
O a
I
CH 3 -C-OCH 2 CH 3
OCHj
O
II
CH 3 -C
3 \
+ CH,O e
OCH 2 CH 3
ethyl acetate
(13-5)
ion can be used as the catalyst since the equilibrium of Equation 13-6 is
rapidly established.
CH 3 O e + CH 3 CH 2 OH
CH 3 CH 2 O e + CH3OH
(13-6)
Acid-catalyzed ester interchange is entirely analogous to acid-catalyzed
esterification and hydrolysis and requires no further discussion.
sec 13.8 displacement reactions of acid derivatives 349
The reactions of a number of carboxylic-acid derivatives with organo-
magnesium and organolithium compounds were described in Chapter 9
(Section 9-9C).
Esters, acid chlorides, and anhydrides are reduced by lithium aluminum
hydride in the same general way as described for the parent acids (Section
13-5B), the difference being that no hydrogen is evolved. The products are
primary alcohols.
o
R-C
1. LiAIH„
\ 2. H®, H 2
z
* RCH 2 OH Z = CI, OR, RC0 2
Nitriles can be reduced to amines by lithium aluminum hydride. An imine
salt is an intermediate product; if the reaction is carried out under the proper
conditions, this salt is the major product and provides an aldehyde on
hydrolysis.
R _ C = N M^Ei, R-CH=N e Li ffi
(imine salt)
H 2
LiAlH* H®, H 2
RC
Amides can be reduced to primary amines, and N-substituted amides to
secondary and tertiary amines.
o
II
RC— NH 2
O
RC— NHR'
O
II
RC— NR,'
LiAIH 4 |
H®, H 2
RCH 2 NH 2
RCH 2 NHR
RCH 2 NR 2 '
Although lithium aluminum hydride is a very useful reagent, it is sometimes
too expensive to be used on a large scale. Other methods of reduction may then
be necessary. Of these, the most important are reduction of esters with sodium
and ethanol (acids do not reduce readily) and high-pressure hydrogenation
over a copper chromite catalyst.
C 2 H 5 OH
RCO,R' + 4Na + 4C 2 H 5 OH
-> RCH 2 OH + R'OH + 4C 2 H 5 O e Na s
RC0 2 R' + 2H 2
200°
Cu(Cr)
♦ RCH,OH + R'OH
chap 13 carboxylic acids and derivatives 350
13-9 reactions at the 2 position (a position)
of carboxylic acid derivatives
A. THE ACIDIC PROPERTIES OF ESTERS WITH a HYDROGENS
Many important synthetic reactions in which C— C bonds are formed
involve esters and are brought about by basic reagents. This is possible because
the a hydrogens of an ester such as RCH 2 C0 2 C 2 H 5 are weakly acidic, and a
strong base, such as sodium ethoxide, can produce a significant concentration
of the ester anion at equilibrium.
i 2 <~w 2 >~2ii5 -r L 2 n s i
RCHCO,C 2 H, + C 2 H s OH
The acidity of a hydrogens is attributed partly to the — / inductive effects of
the ester oxygens, and partly to resonance stabilization of the resulting anion.
O
e //
RCH-C
\
OC,H 5
/
-♦ RCH=C
\
When the 2 position of the ester carries a second strongly electron-attracting
Figure 13*5 Nuclear magnetic resonance spectrum of ethyl acetoacetate at
60 MHz; calibrations are relative to tetramethylsilane at 0.00 ppm. Peaks
marked a, b, and c, are assigned respectively to the protons of the enol form,
whereas peaks d and e are assigned to the a-CH 2 and methyl protons, respec-
tively, of the keto form. The quartet of lines at 4.2 ppm and the triplet at 1.3
ppm result from the ethyl groups of both keto and enol forms.
600
400
200
11/
12.0
10.0
8.0
6.0
III
4.0
2~0
\ f
piliiiiiliigiiil)
ppm
sec 13.9 reactions at the 2 position of carboxylic acid derivatives 351
group, the acidity of an a hydrogen is greatly enhanced. Examples of such
compounds follow:
C 2 H 5 2 CCH 2 C0 2 C 2 H 5
NCCH 2 C0 2 C 2 H 5
CH 3 COCH 2 C0 2 C 2 H s
ethyl nitroacetate
diethyl malonate
ethyl cyanoacetate
ethyl acetoacetate
The stabilization of the anions of these specially activated esters is greater
than for simple esters because the negative charge can be distributed over
more than two centers. Thus, for the anion of ethyl acetoacetate, we can
regard all three of the resonance structures [4a] through [4c] as important con-
O o
ii r
CH 3 -C-CH 2 -C
\
OC,H,
-H®
o
II e //
CHj-C-CH-C
[4a]
P
O e o
I /
CH 3 -C=CH-C
\
OC 2 H 5
[4b]
or
O
O
CH 3 -C=-CH--C
[4]
O
/
<— ► CH,-C— CH=C
OC,H,
[4c]
tributors to the hybrid [4]. Since the anion [4] is relatively stable, the K nh of
ethyl acetoacetate is about 10 _u in water solution. Although this compound
is about 10 5 times as strong an acid as ethanol it is much more sluggish in its
reaction with bases. Removal of a proton from carbon is a process with a
finite energy of activation and only a small fraction of the collisions of such a
molecule with hydroxide ion result in proton transfer. On the other hand,
acids that have their ionizable protons attached to oxygen (even feeble acids
such as ethanol) transfer their protons to strong bases on almost every colli-
sion.
Ethyl acetoacetate, like 2,4-pentanedione (Section 12-6), ordinarily exists
at room temperature as an equilibrium mixture of keto and enol tautomers in
the ratio of 92.5 to 7.5. This can be shown by rapid titration with bromine but
is more clearly evident from the nmr spectrum (Figure 13-5), which shows
chap 13 carboxylic acids and derivatives 352
absorptions of the hydroxyl, vinyl, and methyl protons of the enol form, in
addition to the absorptions expected for the keto form.
o o o o
II II I II
CH 3 -C. .C-OC 2 H 5 ' -^ CH 3 -C^ ,C-OC 2 H 5
CH 2 CH
keto form, 92.5 % enol form, 7.5 %
Interconversion of the enol and keto forms of ethyl acetoacetate is power-
fully catalyzed by bases through the anion [4] and less so by acids through the
conjugate acid of the keto form with a proton adding to the ketone oxygen.
If contact with acidic and basic substances is rigidly excluded (to the extent
of using quartz equipment in place of glass, which normally has a slightly
alkaline surface), then interconversion is slow enough to enable separating
the lower-boiling enol from the keto form by fractional distillation under
reduced pressure. The separated tautomers are indefinitely stable when stored
at —80° in quartz vessels.
B. THE CLAISEN CONDENSATION
One of the most useful of the base-induced reactions of esters is illustrated
by the self-condensation of ethyl acetate under the influence of sodium ethox-
ide to give ethyl acetoacetate.
o
CH 3 cioC 2 H 5 + H-fCH 2 C0 2 C 2 H 5 Na ° C2H5 » CH 3 COCH 2 C0 2 C 2 H 5 + C 2 H 5 OH
This reaction is called the Claisen condensation and its mechanism has some
of the flavor of both the aldol addition (Section 12-2A) and the nucleophilic
reactions of acid derivatives discussed earlier (Section 13-5). The first step,
as shown in Equation 13-7, is the formation of the anion of ethyl acetate,
which, being a powerful nucleophile, attacks the carbonyl carbon of a second
ester molecule (Equation 13-8). Elimination of ethoxide ion then leads to the
/?-keto ester, ethyl acetoacetate (Equation 13-9).
sec 13.9 reactions at the 2 position of carboxylic acid derivatives 353
C 2 H 5 O e + CH 3 C0 2 C 2 H 5 . e CH 2 C0 2 C 2 H 5 + C 2 H 5 OH (137)
I
- CH 3 -C-CH 2 C0 2 C 2 H 5
OC,H,
(13-8)
o
II
CH 3 -C— CH 2 C0 2 C 2 H 5 + C 2 H 5 O e
(13-9)
The sum of these steps represents an unfavorable equilibrium, and satisfactory
yields of the /?-keto ester are obtained only if the equilibrium can be shifted by
removal of one of the products. One simple way of doing this is to remove the
ethyl alcohol by distillation as it is formed; this may be difficult, however, to
carry to completion and, in any case, is self-defeating if the starting ester is
low boiling. Alternatively, one can use a large excess of sodium ethoxide.
This is helpful because ethanol is a weaker acid than the /?-keto ester, and
excess ethoxide shifts the equilibrium to the right through conversion of the
ester to the enolate salt.
O O
II II e
CH 3 -C-CH 2 O0 2 C 2 H 5 + C 2 H 5 O e , ' CH 3 -C-CHC0 2 C 2 H 5 + C 2 H 5 OH
Obviously the condensation product must be recovered from the enol salt
and isolated under conditions that avoid reversion to starting materials. The
best procedure is to quench the reaction mixture by pouring it into an excess
of cold, dilute acid.
Claisen condensations can be carried out between two different esters but,
since there are four possible products, serious mixtures often result. This
objection is obviated if one of the esters has no a hydrogen and reacts readily
with a carbanion according to Equations 13-8 and 13-9. The reaction then has
considerable resemblance to the mixed aldol additions, discussed in Section
12-2A. Among the useful esters without a hydrogens and with the requisite
electrophilic reactivity are those of benzoic, formic, oxalic, and carbonic
acids. Two practical examples of mixed Claisen condensations are shown.
C 6 H 5 C0 2 C 2 H 5 + CH 3 C0 2 C 2 H 5 '' ^ > C 6 H 5 COCH 2 C0 2 C 2 H 5 + C 2 H 5 OH
ethyl benzoate ethyl benzoylacetate
55%
HC0 2 C 2 H 5 + C 6 H 5 CH 2 C0 2 C 2 H 5
ethyl ethyl
formate phenylacetate
1. C 2 H 5 O e
2. H®
CHO
ethyl formylphenylacetate
90%
II
CHOH
chap 13 carboxylic acids and derivatives 354
An important variation on the Claisen condensation is to use a ketone as
the anionic reagent. This often works well because ketones are usually more
acidic than simple esters and the base-induced self-condensation of ketones
(aldol addition) is thermodynamically unfavorable (Section 12-2A). A typical
example is the condensation of cylclohexanone with ethyl oxalate.
o o
6JI COC0 2 C 2 H 5
ethyl oxalate cyclohexanone 2-(ethyl oxalyl)-
cyclohexanone
C. ALKYLATION OF ACETOACETIC AND MALONIC ESTERS
Alkylation of the anions of esters such as ethyl acetoacetate and diethyl
malonate is a useful way of synthesizing carboxylic acids and ketones. The
ester is converted by a strong base to the enolate anion (Equation 13-10),
and this is then alkylated by an S N 2 attack on the alkyl halide (Equation
13-11). Usually, C-alkylation predominates.
o o
II II e (13-10)
t 2 C0 2 C 2 H 5 + C 2 H 5 O e , CH 3 C-CHC0 2 C 2 H 5 + C 2 H 5 OH v '
O O
CH 3 I + CH 3 C-CHC0 2 C 2 H 5 ► CH 3 C-CHC0 2 C 2 H 5 + l e (13-11)
CH 3
Esters of malonic acid can be alkylated similarly.
C0 2 C 2 H 5 C0 2 C 2 H 5
/ NaOQH^ CH3CH.Br, CH /
2 \ \
C0 2 C 2 H 5 C0 2 C 2 H 5
Alkylacetoacetic and alkylmalonic esters can be hydrolyzed under acidic
conditions to the corresponding acids and, when these are heated, they
readily decarboxylate (see Section 13-6). Alkylacetoacetic esters thus yield
methyl alkyl ketones, while alkylmalonic esters produce carboxylic acids.
O CH 3 O CH 3 O
B I H®. HjO II I heat «
CH 3 C-CHC0 2 C 2 H 5 ILiUZU CH 3 C-CHC0 2 H J^ > CH 3 C-CH 2 CH 3
methyl ethyl ketone
C0 2 C 2 H 5 ^ C0 2 H
CH 3 CH 2 CH H<B ' H2 °» CH 3 CH 2 CH ^^ CH 3 CH 2 CH 2 C0 2 H
C0 2 C 2 H 5 C0 2 H
butanoic acid
sec 13.10 reactions of unsaturated carboxylic acids 355
13-10 reactions of unsaturated carboxylic acids
and their derivatives
Unsaturated carboxylic acids of the type RCH=CH(CH 2 )„COOH usually
exhibit the properties characteristic of isolated double bonds and isolated
carboxyl groups when n is large and the functional groups are far apart. As
expected, exceptional behavior is most commonly found when the groups are
sufficiently close together to interact strongly, as in 2-alkenoic acids. These
compounds are invariably called a,/?-unsaturated acids, RCH=CHC0 2 H,
and we shall use this term herein.
A. HYDRATION AND HYDROGEN BROMIDE ADDITION
Like alkenes, the double bonds of a,/?-unsaturated acids can be brominated,
hydroxylated, hydrated, and hydrobrominated, although the reactions are
often relatively slow. With unsymmetrical addends, the direction of addition
is opposite to that observed for alkenes (anti-Markownikoff). Thus pro-
penoic acid (acrylic acid) adds hydrogen bromide and water so that 3-bromo-
and 3-hydroxypropanoic acids are formed. These additions are closely anal-
ogous to the addition of halogen acids to propenal (Section 12-3).
HBr
CH 2 =CHCOOH
propenoic acid n. jj 2 q
BrCH 2 CH 2 COOH
3-broraopropanoic acid
(acrylic acid) h®
OH
3-hydroxypropanoic acid
B. LACTONE FORMATION
When the double bond of an unsaturated acid lies farther down the carbon
chain than between the a and /? positions, conjugate addition is not possible.
Nonetheless, the double bond and carboxyl group frequently interact in the
presence of acid catalysts because the carbonium ion that results from addition
of a proton to the double bond has a built-in nucleophile (the carboxyl group),
which may attack the cationic center to form a cyclic ester (i.e., a lactone).
Lactone formation usually occurs readily by this mechanism only when a
five- or six-membered ring can be formed.
CH 3
O ,o \
// h® ® t -H® HC-CH 2
CH 2 =CHCH 2 CH 2 C — S — ► CH 3 -CHCH 2 CH 2 C — ^ / \
X OH OH \/ C " 2
II
O
4-pentenoic acid (y-valerolactone)
(allylacetic acid)
chap 13 carboxylic acids and derivatives 356
Five- and six-membered lactones are also formed by internal esterification
when either 4- or 5-hydroxy acids are heated. Under similar conditions,
3-hydroxy acids are dehydrated to a,/?-unsaturated acids, while 2-hydroxy
acids undergo bimolecular esterification to substances with six-membered
dilactone rings called lactides.
H0CH 2 CH 2 CH 2 C0 2 H > O CH 2 + H 2
C
II
o
4-hydroxybutanoic acid y-butyrolactone
(y-hydroxybutyric acid)
CH 3 CHCH 2 C0 2 H heat > CH 3 CH=CHC0 2 H + H 2
OH
3-hydroxybutanoic acid 2-butenoic acid
A J°
heat CH 3 HC C
2CH 3 CHC0 2 H ► I I + 2H 2
I ,^-L ^CHCH 3
oh or o^
2-hydroxypropanoic acid lactide
(lactic acid)
13-11 dicarb oxyli c aci ds
Acids in which there are two carboxyl groups separated by a chain of more
than five carbon atoms (n > 5) have, for the most part, unexceptional proper-
ties, the carboxyl groups behaving more or less independently of one another.
C0 2 H
(CH 2 ),
C0 2 H
When the carboxyl groups are closer together, however, the possibilities for
interaction increase; we shall be primarily concerned with such acids. A
number of important dicarboxylic acids are listed in Table 13-4.
A. ACIDIC PROPERTIES OF DICARBOXYLIC ACIDS
The inductive effect of one carboxyl group is expected to enhance the acidity
of the other and, from Table 13-4, we see that the acid strength of the dicar-
boxylic acids, as measured by the first acid-dissociation constant, K u is
higher than that of acetic acid (K HA =1.8 x 10~ 5 ) and falls off with increasing
distance between the two carboxyl groups. Two other factors operate to
raise K x in comparison to the K HA of acetic acid. First, the statistical factor:
sec 13.11 dicarboxylic acids 357
Table 13*4 Dicarboxylic acids
acid
formula
mp,
°C
K ± x 10 5
at 25°
K 2 x 10 5
at 25°
oxalic
C0 2 H
189
3500
5.3
(ethanedioic)
C0 2 H
malonic
p0 2 H
136
171
0.22
(propanedioic)
CH 2
C0 2 H
C0 2 H
dec.
succinic
(C X H 2 ) 2
CO,H
185
6.6
0.25
(butanedioic)
glutaric
(pentanedioic)
C0 2 H
/
(C^ 2 ) 3
CO,H
7 C0 2 H
(CH 2 ) 4
C0 2 H
98
4.7
0.29
adipic
(hexanedioic)
152
3.7
0.24
7 C0 2 H
(CH 2 ) 5
pimelic
105
3.4
0.26
(heptanedioic)
C0 2 H
maleic (cis-
HCC0 2 H
II
130
1170
0.026
butenedioic)
HCC0 2 H
fumaric (trans-
HCC0 2 H
II
sub.
93
2.9
butenedioic)
H0 2 CCH
200
phthalic (benzene-
|f^C0 2 H
231
130
0.39 18
1 ,2-dicarboxylic)
l^C0 2 H
there are two carboxyl groups per molecule instead of one. Second, there can
be stabilization of the monoanion by internal hydrogen bonding, when the
geometry of the molecule allows it.
chap 13 carboxylic acids and derivatives 358
The second acid-dissociation constant, K 2 , is smaller than K HA for acetic
acid in most cases, and this must also be largely due to the hydrogen-bonding
effect. Comparison of K 1 and K 2 for maleic and fumaric acids is especially
instructive. Only the cis monoanion can be stabilized by internal hydrogen
bonding and we find K± to be larger and K 2 smaller for the cis acid.
B. THERMAL BEHAVIOR OF DICARBOXYLIC ACIDS
The reactions that occur when diacids are heated depend critically upon the
chain length separating the carboxyl groups. Cyclization is usually favored if a
strainless five- or six-membered ring can be formed. Thus adipic and pimelic
acids cyclize and decarboxylate to give cyclopentanone and cyclohexanone,
respectively.
COOH
(CH 2 ) 4 -
COOH
adipic acid
300°
H,C
XH 2
\ _
~CH,
O + CO,
cyclopentanone
COOH
(CH 2 ) 5
COOH
pimelic acid
300°
H,C— CH,
/ \
H 2 C C=0 + C0 2 + H 2
H 2 C— CH 2
cyclohexanone
Succinic and glutaric acids take a different course. Rather than form the
strained cyclic ketones — cyclopropanone and cyclobutanone — both acids
form cyclic anhydrides — succinic and glutaric anhydrides — having five- and
six-membered rings, respectively. Pbthalic and maleic acids behave similarly
giving five-membered cyclic anhydrides.
COOH
(CH 2 ) 2
\
COOH
acid
COOH
(CH 2 ) 3
COOH
;lutanc
acid
300°
-H,0
300°
-H,0
P
\
H 2 C
H 2 C^ C /
O
o
anhydride
O
H 2 C O
\ _/
O
glutaric
anhydride
CO,H
CO,H
230°
-H 2
phthalic
acid
^^co
phthalic
anhydride
P
O
HCC0 2 H 200 Q ) HC'
HCC0 2 H - H ^ 0> HC-./"
O
maleic
acid
maleic
anhydride
summary 359
Malonic and oxalic acids behave still differently, each undergoing decar-
boxylation when heated (Section 13-6).
COOH
/ 140°-160°
CH 2 ► CH3COOH + C0 2
COOH
malonic acid
COOH
COOH
oxalic acid
160M80 °. CO, + HCOOH
summary
Carboxylic acids, such as (CH 3 ) 2 CHC0 2 H (2-methylpropanoic acid or
isobutyric acid), have higher melting and boiling points than alcohols of the
same molecular weight. They ionize weakly in aqueous solution (K HX ~ 10" 5 )
but associate as dimers in hydrocarbon solvents.
Carboxylate salts (RCOf Na®) are quite soluble in water and this fact
permits carboxylic acids to be separated from other organic compounds by
extraction with appropriately basic solutions. Acids with long alkyl or alkenyl
groups are called fatty acids. Their salts form colloidal particles in water
called micelles in which the charged carboxyl end groups point outward and
the hydrocarbon chains point inward. The mechanism of soap action is
related to the ability of micelles to dissolve nonpolar substances ; the tendency
of salts of fatty acids to concentrate at interfaces is also a factor.
The C 4 to C 8 carboxylic acids have strong unpleasant odors. The infrared
spectra of carboxylic acids shows broad absorption near 3000 cm" 1 (hydrogen-
bonded O— H) and near 1750 cm" 1 (C=0 stretch). The carboxyl proton in
the nmr absorbs at very low field (> 10 ppm from TMS).
Some methods of preparing carboxylic acids are illustrated here.
RMgX
-► RCHO ► RC0 2 H < RCOZ Z = CI, OR, NH 2
RCH=CHR RC^N RCHOHCHOHR
In addition to these methods RX can be converted to RCH 2 C0 2 H by the
malonic ester synthesis (see below).
The acidity of the carboxyl group can be attributed to the inductive effects
chap 13 carboxylic acids and derivatives 360
of the carbonyl group and resonance stabilization of the ion RCOf. Electron-
withdrawing substituents such as CI in R increase the acid strength by induc-
tive withdrawal of charge from the carboxyl group (-/effect).
Carboxyl groups can be protonated by strongly acidic systems to give
OH
cations of formula
reaction.
R-C
\
These are intermediates in the esteriflcation
ie
OH
In summary, the reactions of the carboxyl group are :
RCO,H
O
«
RC
\
CI
RCH 2 OH
RH + C0 2
R— R
R— Br
(with PC1 3 , PC1 5 , or SOCl 2 )
(with LiAlH 4 )
(occurs readily only if C-2
carries a. —I substituent)
(Kolbe electrolysis)
(Hunsdiecker reaction)
The 2 position of carboxylic acids can be halogenated via the acid halide
(RCH 2 C0 2 H -*RCH 2 COX -» RCHXCOX -» RCHXC0 2 H). A halogen at
the 2 position suffers ready displacement by nucleophiles.
Derivatives of carboxylic acids include esters (RC0 2 R), acid halides
(RCOX), anhydrides ((RCO) 2 0), and amides (RCONH 2 ). They can all be
hydrolyzed to carboxylic acids and the first three also react with alcohols or
amines to give esters and amides.
II
RC0 2 H
R-C-X
O
O
II
II
RC-OR"
R-C- OR
O
(RCO) 2
RC-NH
*(est
er interchang
e in
case of
O
O
RC-OR - RC-OR)
Lithium aluminum hydride reduction of carboxylic acid derivatives gives
primary alcohols or amines.
O
II
RC— NH 2 ^
RCH,OH
RCH,NH,
RC=N
exercises 361
Esters with anion-stabilizing substituents are moderately acidic and some
of these, especially the /?-keto esters, undergo a number of useful reactions.
They can be prepared by the Claisen condensation between two molecules of
ester.
O
II
2RCH 2 C0 2 C 2 H 5 ► RCH 2 CCHC0 2 C 2 H 5
R
Acetoacetic and malonic esters may be alkylated via their anions; acid
hydrolysis then gives ketones and acids, respectively (acetoacetic and malonic
ester syntheses).
o o o
II II II
CH 3 CCH 2 C0 2 C 2 H 5 ► CH 3 CCHC0 2 C 2 H 5 ► CH 3 CCH 2 R
R
CH 2 (C0 2 C 2 H 5 ) 2 ► RCH(C0 2 C 2 H 5 ) 2 > RCH 2 CO a H
a,/?-Unsaturated acids (double-bond between C-2 and C-3) undergo typical
alkene-addition reactions except that unsymmetrical addends add in the anti-
Markownikoff manner. y,5- or <5,e-Unsaturated acids (4- or 5-alkenoic acids)
form lactones readily.
Dicarboxylic acids have exalted values of K 1 and depressed values of K 2
relative to monocarboxylic acids and this is mainly due to internal hydrogen
bonding in the monoanion.
Heating of dicarboxylic acids gives five- or six-membered rings if this is
possible (either ketones by decarboxylation and dehydration or anhydrides by
dehydration). The C 2 and C 3 dicarboxylic acids tend to undergo simple
decarboxylation.
o
II II /^\ ^c^
HO— C C— OH ► C=0 or ^O or RC0 2 H
o
exercises
13-1 Explain why the chemical shift of the acidic proton of a carboxylic acid, dis-
solved in a nonpolar solvent like carbon tetrachloride, varies less with con-
centration than that of the OH proton of an alcohol under the same condi-
tions (see Section 13-1).
13-2 A white solid contains ammonium octanoate mixed with naphthalene
(CioHs) and sodium sulfate. Describe the exact procedure you would follow
to obtain pure octanoic acid from this mixture.
s>
13-3 Would you expect the compound Ci 5 H3iN(CH 3 )3Cl e to form micelles in
water ?
chap 13 carboxylic acids and derivatives 362
13-4 Write equations for a practical laboratory synthesis of each of the following
substances from the indicated starting materials (several steps may be
required). Give reagents and conditions.
a. butanoic acid (w-butyric acid) from 1-propanol
b. trimethylacetic acid from f-butyl chloride
c. 2-methylpropanoic acid (isobutyric acid) from 2-methylpropene
d. 2-bromo-3,3-dimethylbutanoic acid from r-butyl chloride
e. /3-chloroethyl bromoacetate from ethanol and (or) acetic acid
/. 2-methoxypentanoic acid from pentanoic acid
g. 3,5,5-trimethyl-3-hexanol from 2,4,4-trimethyl-l-pentene (commer-
cially available)
h. 3,3-dimethylbutanal from 3,3-dimethylbutanoic acid
i. 2,3,3-trimethyl-2-butanol from 2,3-dimethyl-2-butene
j. cyclopentane from hexanedioic acid (adipic acid)
k. cyclopropyl bromide from cyclopropanecarboxylic acid
13.5 Give for each of the following pairs of compounds a chemical test, preferably
a test tube reaction with a visible result, that will distinguish between the two
substances. Write an equation for each reaction.
a. HC0 2 H and CH 3 C0 2 H
b. CH 3 C0 2 C 2 H 5 and CH 3 OCH 2 C0 2 H
c. CH 2 =CHC0 2 HandCH 3 CH 2 C0 2 H
d. CH 3 COBr and BrCH 2 C0 2 H
H 2 C-CH 2
I \
e. (CH 3 CH 2 CO) 2 and 0=C C=0
O
CO,H C0 2 H C0 2 H H
\ / _, \ /
/. C=C and C=C
/ \ / \
H H H C0 2 H
g. HC^CC0 2 CH 3 andCH 2 =CHC0 2 CH 3
h. CH 3 C0 2 NH 4 and CH 3 CONH 2
i. (CH 3 CO) 2 and CH 3 C0 2 CH 2 CH 3
13-6 Explain how you could distinguish between the pairs of compounds listed in
Exercise 13-5 by spectroscopic means.
13-7 Write structural formulas for all 13 carboxylic acids and esters of formula
CsHi O 2 . Provide the IUPAC name and, if possible, one other suitable name
for each compound.
13-8 Only two different products are obtained when the following four compounds
are reduced with an excess of lithium aluminum hydride; what are they?
(CH 3 ) 2 CHC0 2 H (CH 3 ) 2 CHC0 2 CH 3 (CH 3 ) 2 CHCONH 2 (CH 3 ) 2 CHC=N
13-9 At high current densities, electrolysis of salts of carboxylic acids in hydroxylic
solvents produce (at the anode) alcohols and esters of the type ROH and
RC0 2 R. Explain.
exercises 363
13-10 Name each of the following substances by an accepted system:
H 2/ C-CH 2 C0 2 C 2 H 3
[ 2 C c
H 2 C-CH 2 N C0 2 C 2 H 3
b. CH 3 COCH[CH(CH 3 ) 2 ]C0 2 C 2 H 5
c. C 6 H 5 CH 2 CH 2 COCl
d. HOCH=CHC0 2 C 2 H 5
e. C 2 H 5 OCOCOCH 2 C0 2 C 2 H 5
/. HC0 2 C 2 F 5
H,r c " 2
g. | C=0
n ^"-C-C0 2 CH 3
I
CH,
CH 2 =CH— CH 2
h. Yhco 2 h
i. CH 3 CH 2 COCHCH 3
I
CH 2 CH 2 CH(CH 3 ) 2
/. CH 3 CH 2 CH(CH=CH 2 )C0 2 H
k. CH 3 COCH(C0 2 C 2 H 5 ) 2
13-11 Write equations for the effect of heat on the 2, 3, 4, and 5 isomers of hydroxy-
pentanoic acid.
13-12 Predict the relative volatility of acetic acid, acetyl fluoride, and methyl
acetate. Give your reasoning.
13-13 By analogy with ester hydrolysis, propose a mechanism for each of the
following reactions :
a. C 6 H 5 C0 2 CH 3 + C 2 H 5 OH > C 6 H 5 C0 2 C 2 H 5 + CH 3 OH
b. CH3COCI + CH 3 CH 2 OH * CH 3 C0 2 CH 2 CH 3 + HC1
c. (CH 3 CO) 2 + CH 3 OH > CH 3 C0 2 CH 3 + CH 3 C0 2 H
d. CH 3 CONH 2 + H 3 O ffi * CH 3 C0 2 H + NH 4 ®
e. CH 3 CONH 2 + e OH * CH 3 C0 2 e + NH 3
/. CH 3 COCl + 2NH 3 > CH 3 CONH 2 + NH4CI
13-14 Why is a carboxylate anion more resistant to attack by nucleophilic agents,
such as CH 3 O e , than the corresponding ester?
chap 13 carboxylic acids and derivatives 364
13-15 What can you conclude about the mechanism of acid-catalyzed hydrolysis
of /3-butyrolactone from the following equation :
18 OH
H 2 C— C=0 h 2 18 Q, H® H 2C — Q
H 2 C-0 H 2 COH °
O
II
13-16 Amides of the type R— C— NH 2 are much weaker bases (and stronger
acids) than amines. Why?
13-17 Write a plausible mechanism for the following reaction:
P
CH 3 C
OC(CH 3 ) 3 + CH 3 OH — =_> CH 3 C0 2 H + CH 3 OC(CH 3 ) 3
13-18 Other conceivable products of the Claisen condensation of ethyl acetate are
O
O O OCCH,
II II / 3
CH 3 CCHCOC 2 H 5 and CH 2 =C
I \
CH 3 C=0 OC 2 H 5
Explain how these products might be formed and why they are not formed
in significant amounts.
13-19 Suggest a reason why 2,4-pentanedione (acetylacetone) contains much more
enol at equilibrium than ethyl acetoacetate. How much enol would you
expect to find in diethyl malonate? In butan-3-on-l-al (acetylacetaldehyde) ?
Explain.
13-20 Write structures for all of the Claisen condensation products that may
reasonably be expected to be formed from the following mixtures of sub-
stances and sodium ethoxide :
a. ethyl acetate and ethyl propanoate
b. ethyl carbonate and acetone
c. ethyl oxalate and ethyl trimethylacetate
13-21 Show how the substances below may be synthesized by Claisen-type con-
densations based on the indicated starting materials. Specify the reagents
and reaction conditions as closely as possible.
a. ethyl 2-propanoylpropanoate from ethyl propanoate
b. CH 3 COCH 2 COC0 2 C 2 H 5 from acetone
c. diethyl phenylmalonate from ethyl phenylacetate
d. 2,4-pentanedione from acetone
e. 2,2,6,6-tetramethyl-3,5-heptanedione from pinacolone Obutyl methyl
ketone).
exercises 365
13-22 Why does the following reaction fail to give ethyl propanoate?
CH 3 C0 2 C 2 H 5 + CH 3 I a °/ 2 5 > CH 3 CH 2 C0 2 C 2 H 5
13-23 Show how one could prepare cyclobutanecarboxylic acid starting from
diethyl malonate and a suitable dihalide.
13-24 Would you expect vinylacetic acid to form a lactone when heated with a
catalytic amount of sulfuric acid ?
13-25 Fumaric and maleic acids give the same anhydride on heating, but fumaric
acid must be heated to much higher temperatures than maleic acid to effect
the same change. Explain. Write reasonable mechanisms for both reactions.
13-26 7-Butyl acetate is converted to methyl acetate by sodium methoxide in
methanol about one-tenth as fast as ethyl acetate is converted to methyl
acetate under the same conditions. With dilute hydrogen chloride in metha-
nol, ?-butyl acetate is rapidly converted to f-butyl methyl ether and acetic
acid, whereas ethyl acetate goes more slowly to ethanol and methyl acetate.
a. Write reasonable mechanisms for each of the reactions and show how
the relative-rate data agree with your mechanisms.
b. How could one use ls O as a tracer to substantiate your mechanistic
picture?
chapter 14
i Optical isomerism^ enantiomers
and diastereomers
chap 14 optical isomerism, enantiomers and diastereomers 369
Isomers are compounds that have the same molecular formula (e.g.,
C 4 H 1Q 0) but differ in the way in which the constituent atoms are joined
together. The simplest form of isomerism is structural isomerism, in which the
bonding sequence differs. Two of the structural isomers of C 4 H 10 O are
1-butanol, CH 3 CH 2 CH 2 CH 2 OH, and 2-butanol, CH 3 CH 2 CHOHCH 3 .
Stereoisomerism is the isomerism of compounds having the same structural
formula but different arrangements of groups in space. We have already met
one of the two forms of stereoisomerism, called geometrical (cis-trans) iso-
merism, and we will now encounter the other, optical isomerism. We shall
see that 2-butanol, but not 1-butanol, exhibits this rather subtle form of
isomerism.
Isomers, whether structural, geometrical, or optical are generally long-lived
and isolable because isomerization usually requires that bonds be broken. In
this way they differ from conformers, the many different spatial arrangements
that result from rotations about single bonds (Section 2-2). It should be under-
stood that isomers and conformers are not mutually exclusive. Thus while 2-
butanol will be seen to have two stable optical isomers, each of these optical
isomers exists as a dynamic mixture of conformations. We shall return to
this point frequently in subsequent discussions.
What are optical isomers? They are stereoisomers, some or all of which
have the ability to rotate the plane of polarized light, that is, exhibit optical
activity. What quality do optically active molecules possess that causes them
to affect polarized light this way ? We shall see that it is actually a property they
lack that is responsible for their optical activity and that this property is
symmetry. Before going further, however, we shall examine the phenomenon
of the polarization of light.
14-1 plane-polarized light and the
origin of optical rotation
Electromagnetic radiation, as the name implies, involves the propagation
of both electric and magnetic forces. At each point in a light beam, there is a
component electric field and a component magnetic field which are perpendi-
cular to each other and which oscillate in all directions perpendicular to the
direction in which the beam is propagated. In plane-polarized light, the
oscillation of the electric field is restricted to a single plane, the plane of
polarization, while the magnetic field of necessity oscillates at right angles to
that plane. Passing ordinary light through a split prism of calcite (a form of
CaC0 3 ) known as a Nicol prism resolves the light into two beams, each of
which is polarized and has half of the intensity of the original beam. (A sheet
of Polaroid can also be used.) Light polarized by passage through one
Nicol prism will not pass through a second Nicol prism set at right angles to
the first one. Now if a transparent sample (usually a solution) of an optically
active substance is placed between the two prisms, any change in the angle
chap 14 optical isomerism, enantiomers and diastereomers 370
of the plane of polarization in the solution can be detected (Figure 14-1),
because the second prism will have to be rotated a certain number of degrees
to be at right angles to the new plane of polarization and stop the light from
coming through. An instrument that measures optical rotation this way is
called a polarimeter (Figure 14-2).
A clockwise rotation of the prism to produce extinction, as the observer
looks toward the beam, defines the substance as dextrorotatory (rotates to the
right), and we say that it has a positive ( + ) rotation. If the rotation is counter-
clockwise, the substance is Ievorotatory (rotates to the left) and the compound
has a negative ( — ) rotation. The angle of rotation is designated a.
The question naturally arises as to why compounds whose molecules lack
symmetry interact with polarized light in this manner. We shall oversimplify
the explanation since the subject is best treated rigorously with rather complex
mathematics. However, it is not difficult to understand that the electric forces
in a light beam impinging on a molecule will interact to some extent with the
electrons within the molecule. Although radiant energy may not actually be
absorbed by the molecule to promote it to higher excited electronic-energy
states (see Chapter 7), a perturbation of the electronic configuration of the
molecule can occur. One can visualize this process as a polarization of the
electrons brought about by the oscillating electric field associated with the
radiation. This kind of interaction is important to us here because it causes
the electric field of the radiation to change its direction of oscillation. The
effect produced by any one molecule is extremely small, but in the aggregate
may be measurable as a net rotation of the plane-polarized light. Molecules
such as methane, ethane, and acetone, which have enough symmetry so that
each is identical with its reflection, do not give a net rotation of plane-
polarized light. This is because the symmetry of each is such that every optical
rotation in one direction is canceled by an equal rotation in the opposite
direction. However, a molecule with its atoms so disposed in space that it is
Figure 14-1 Schematic representation of the vibrations of (a) ordinary
light, and (b) plane-polarized light that is being rotated by interaction with
an optically active substance.
(b)
sec 14.2 specific rotation 371
ordinary
light Y"
polarized light
(with new angle
of polarization)
V
A-
V
adjustable
Nicol prism
■ tube containing solution of
optically active substance
Figure 14-2 Schematic diagram of a polarimeter. The plane of polarization has
been rotated by passage through the solution of the optically active substance,
and extinction of the beam of polarized light can only be restored by rotating
the adjustable Nicol prism.
not symmetrical to the degree of being superimposable on its mirror image will
have a net effect on the incident polarized light. The electromagnetic inter-
actions do not average to zero and such substances we characterize as being
optically active. The structural characteristics of optically active molecules
will be discussed beginning in Section 14-3.
14-2 specific rotation
The angle of rotation of the plane of polarized light a depends on the
number and kind of molecules the light encounters — it is found that a varies
with the concentration of a solution (or the density of a pure liquid) and on
the distance through which the light travels in the sample. A third important
variable is the wavelength of the incident light, which must always be specified
even though the sodium D line (5893 A) is commonly used. (See also Section
14-10.) To a lesser extent, a varies with the temperature and with the solvent
(if used), which also should be specified. Thus, the specific rotation, [a], of a
substance is generally expressed by the following formulas :
for solutions,
MS =
100 a
T~c~
for neat liquids,
™-— t
where a is measured degree of rotation; f is temperature; X is wavelength of
chap 14 optical isomerism, enantiomers and diastereomers 372
light; / is length in decimeters of light path through the solution; c is con-
centration in grams of sample per 100 ml of solution; and d is density of
liquid in grams per milliliter.
For example, when a compound is reported as having [a]o 5 ° = — 100
(c = 2.5, chloroform), this means that it has a specific levorotation of 100
degrees at a concentration of 2.5 g per 100 ml of chloroform solution at 25°C
when contained in a tube 1 decimeter long, the rotation being measured with
sodium D light, which has a wavelength of 5893 A.
Frequently, molecular rotation [M] is used in preference to specific rotation.
It is related to specific rotation by the following equation :
r^f Kft ' M
M = Hiob-
where M is the molecular weight of the optically active compound. Expressed
in this form, optical rotations of different compounds can be compared
directly because differences in rotation arising from differences in molecular
weight are taken into account.
14-3 optically active compounds with
asymmetric carbon atoms
A. ONE ASYMMETRIC CARBON
Having discussed how optical activity is measured experimentally, we shall
now consider the conditions of asymmetry (lack of symmetry) which are
necessary for a compound to be optically active. The inflexible condition for
optical activity is : the geometric structure of a molecule must be such that it is
nonsuperimposable on its mirror image. Unless this condition holds, the mole-
cule cannot exist in optically active forms. Asymmetry is, of course, a property
of many objects you see around you. Each of your hands is asymmetric, that
is, your right hand cannot occupy the same space that its mirror image (your
left hand) fits into, as can be seen by trying to put your right hand into a glove
that fits your left hand. The term chirality 1 is often applied to asymmetric
objects (or molecules); it refers to their "handedness." At the molecular
level, there are a number of types of structural elements that can make a
molecule asymmetric and nonidentical with its mirror image. The most common
and important of these is the asymmetrically substituted carbon atom, which
is a carbon atom bonded to four different atoms or groups. If a molecule has
such an asymmetrically substituted atom, the molecule will be nonidentical
with its mirror image and will therefore be optically active. A simple example
is 2-butanol [1 ], the C-2 of which is said to be asymmetric since it carries four
different groups, hydrogen, hydroxyl, methyl, and ethyl.
1 Pronounced ki'ralsd-e.
sec 14.3 optically active compounds with asymmetric carbon atoms 373
CH 3 H
\V
C
/ \
CH 3 CH 2 OH
[1]
However, 2-butanol, as prepared from optically inactive materials (e.g., by
the reduction of 2-butanone with lithium aluminum hydride), is optically
inactive :
CH 3 COCH 2 CH 3 — > CH 3 CH(OH)CH 2 CH 3
It is a mixture of two isomeric forms, [2] and [3], which are mirror images of
one another.
The chemical and physical properties of the two forms are identical,
except that they rotate the plane of plane-polarized light equally but in oppo-
site directions. Mirror image forms of the same compound, such as [2] and
[3], are called enantiomers. The 2-butanol, as prepared by the reduction of
inactive 2-butanone, is optically inactive because it is a mixture of equal
numbers of molecules of each enantiomer; the net optical rotation is there-
fore zero. Such a mixture is described as racemic and is often designated by the
symbol (+).
Separation of the enantiomers in a racemic mixture is known as resolution,
and conversion of the molecules of one enantiomer into a racemic mixture of
both is called racemization.
chap 14 optical isomerism, enantiomers and diastereomers 374
Table 14-1 Physical properties of tartaric acids
specific specific solubility
rotation, [a]^ melting gravity in H 2 0,
tartaric acid in H 2 point, °C of solid g/100gat25°
meso
(-)
( + )
(±)
-11.98°
+ 11.98°
140
170
170
205
1.666
1.760
1.760
1.687
]20 (i5->
147
147
25
" meso-Tartaric acid is discussed in Section 14-3C.
Although all the physical properties of pure enantiomers (apart from their
optical properties) are identical, their melting points, solubilities, and any
other properties involving the solid state are usually different from those of
the racemic mixture. This is because a mixture of enantiomers packs differently
in a crystal lattice (often more efficiently) than either enantiomer in the pure
form. Tartaric acid is one such compound, and the physical properties of its
various forms are given in Table 14T.
B. PROJECTION FORMULAS
We have distinguished the two enantiomers of 2-butanol, [2] and [3], with
a picture of a three-dimensional model to show the tetrahedral arrangement of
the groups about the asymmetric carbon atom. Clearly it will be inconvenient
to do this in every case, particularly for more complex examples. It is necessary
therefore to have a simpler convention for distinguishing between optical
isomers. The so-called Fischer projection formulas are widely used for this
purpose and, by their use, the enantiomers of 2-butanol are represented by
[4] and [5].
CH 3
H— C-OH
I
CH 2 CH 3
[4]
CH 3
I
HO— C— H
I
CH 2 CH 3
[5]
North
The convention of the Fischer projections is such that the east and west bonds
of the asymmetric carbon are considered to extend in front of the plane of
the paper and the north and south bonds extend behind the, plane of the paper.
This is shown more explicitly in structures [6] and [7]. Structures [2], [4],
and [6] all correspond to one enantiomer while [3], [5], and [7] correspond to
the other.
CH 3
H— C— OH
CH 2 CH 3
[6]
CH 3
HO— C— H
CH 2 CH 3
[7]
sec 14.3 optically active compounds with asymmetric carbon atoms 37S
With projection formulas, configuration is inverted (i.e., one enantiomer is
changed into the other) each time two atoms or groups about the asymmetric
atom (or asymmetric center, as it is often called) are interchanged. Clearly, if
we interchange hydrogen for hydroxyl in [4], we have the enantiomer [5]. Less
obvious is the interchange of methyl and hydrogen in [4] to give [8], which by
our convention is equivalent to [5]. (Inspection of models may be helpful if
the results of these operations are not clear.)
H
I
CH 3 -C— OH
CH 2 CH 3
[8]
It should be noted that [8] is not strictly a Fischer projection formula
because, by the Fischer convention, the carbon chain is always written verti-
cally. Note also that rotation of a Fischer projection formula 1 80° (but not
90° or 270°) in the plane of the paper leaves the configuration unchanged.
CH 3 CH 2
I I
-C— OH = HO— C —
I I
CH2CH3 CH 3
For sake of uniformity, we normally show the carbon chain vertically with
C-l at the top.
C. COMPOUNDS WITH TWO ASYMMETRIC CARBON ATOMS.
DIASTEREOMERS
We have considered how a compound with one asymmetric carbon atom
can exist in two optically active forms. However, it would be incorrect to
infer from this that asymmetric carbon is a necessary condition for optical
activity, because many compounds are known that have no asymmetric atoms
but still exhibit optical isomerism (Section 14-4). It would be no more correct
to infer that, because a molecule has two or more asymmetric carbons, it will
necessarily be optically active.
For example, consider a molecule with structure, configuration, and con-
formation as in [9] with two asymmetric atoms, 1 and 2, the groups attached
to atom 1 being the same as for atom 2, and the structure being so oriented
that atom 1 is toward the front and atom 2 toward the rear. It can be seen
that [9] is identical with its mirror image [10] by simply turning [9] end for
end to give [11], which, when rotated 180° about the 1,2 bond axis as shown
by the arrow, superimposes on [10]. A molecule with this configuration will
be optically inactive, despite the presence of two asymmetric carbons, because
it is superimposable on its mirror image.
chap 14 optical isomerism, enantiomers and diastereomers 376
mirror plane
One could argue, however, that this condition does not hold for all con-
formations of [9]. Certainly, the conformation [12] is not superimposable on
its mirror image [13].
mirror plane
Nevertheless, the molecule represented by [12] will not be optically active,
because the asymmetric conformation [12] is rapidly converted into its
enantiomer [13] by rotation about the bond joining the two asymmetric
centers. Optical activity would be possible only if it were possible to " freeze "
the molecule in one of the asymmetric conformations.
It will be seen that the eclipsed conformation [14] of the same system has a
plane of symmetry that bisects the molecule into two halves, each half being
the mirror image of the other. Molecules that possess this sort of symmetry
are frequently said to be internally compensated, since the optical rotations
contributed by each asymmetric half are equal in degree but opposite in sign;
the net rotation is therefore zero.
sec 14.3 optically active compounds with asymmetric carbon atoms 377
[14]
This is perhaps more easily visualized from the Fischer projection formula
of the conformations [9] through [14].
(+)
— >
zero net rotation
(-)
"W
To generalize, if a substance has a plane of symmetry in at least one con-
formation, it will not be resolvable into optically active forms.
Among the many examples of compounds that have two asymmetric carbon
atoms but are optically inactive because their molecules are free to pass
through a conformation with a plane of symmetry are meso-taitatic acid [15];
m&yo-2,3-dibromobutane [16]; and cw-cyclohexane-l,2-dicarboxylic acid
[17]. The asterisks in the formulas denote the asymmetric carbons.
C0 2 H
1*
c-
-OH
I*
c-
1
-OH
1
cc
2 H
[15]
CH 3
I.
H-C-Br
I*
H-C-Br
I
CH 3
[16]
CH 2 — CH.H
CH H C*
N CH 2 — C* C0 2 H
C0 2 H
[17]
The prefix meso denotes an optically inactive optical isomer of a compound
that can exist in other optically active modifications. The meso form is con-
sidered to be an optical isomer because it is a stereoisomer of the optically
active forms and its lack of optical activity does not of itself change the type
of isomerism involved. This will be clearer when we discuss erythro and threo
forms later in this section.
Tartaric acid and 2,3-dibromobutane each have a total of three optical
chap 14 optical isomerism, enantiomers and diastereomers 378
isomers, two optically active enantiomers, and one optically inactive meso
form. These are shown in structures [18a], [18b], and [1 5] for tartaric acid,
and [19a], [19b], and [16] for 2,3-dibromobutane.
C0 2 H C0 2 H CH 3 CH 3
I I I I
H— C— OH HO— C-H H— C— Br Br— C-H
I I I I
HO— C-H H— C-OH Br-C-H H— C-Br
I I I I
C0 2 H CO z H CH 3 CH 3
[18a] [18b] [19a] [19b]
Stereoisomeric structures that are not enantiomers and thus not mirror
images are called diastereomers. meso-Tartaric acid [15] and either one of the
optically active tartaric acids [18a or 18b] are therefore diastereomers. Only
[18a] and [18b] are enantiomers. Diastereomers usually have substantially
different physical properties, whereas enantiomers have identical properties
apart from the direction in which they rotate the plane of polarized light. This
is illustrated in Table 14-1 for the tartaric acids.
The reason for the difference in physical properties between diastereomers
can be seen very simply for a substance with two asymmetric centers by
noting that a right shoe on a right foot can be a mirror image and non-
identical with a left shoe on a left foot, but is not expected to be a mirror
image or have the same physical properties as a left shoe on a right foot or a
right shoe on a left foot. In chemical terms, a pair of diastereomers have
different internal distances in their molecules. If the groups about the central
bonds in [15] and [18a] are rotated so that, for example, the two hydrogen
atoms are at their closest, then the two hydroxy! groups will be separated by
different distances in the two isomers. Although free rotation can take place
about any of the single bonds in [15] and [18a], there are no conformations
for which all the internal distances correspond. Enantiomers such as [18a] and
[18b], on the other hand, can be arranged so that all the internal distances in
one are identical with those in the other.
Many compounds have two asymmetric carbons but cannot exist in an
internally compensated meso form. This situation occurs when the two
asymmetric carbons are differently substituted so that there is no conforma-
tion in which any of the isomers has a plane of symmetry. As an example,
consider the possible diastereomers of 2,3,4-trihydroxybutanal, [20] and [21],
which are commonly known as erythrose and threose, respectively. They are
represented below by the projection formulas [20a] and [21a], as well as by
the conformational, or so-called "sawhorse," structures, [20b] and [21b]:
CHO H CHO OH
H-C-OH OHC^OH HO-C-H OHCf^H
| or / | or /
H-C-OH H^OH H-C-OH H^-OH
CH 2 OH CH 2 OH CH 2 OH CH 2 OH
erythrose threose
[20a] [20b] [21a] [21b]
Neither diastereomer has a plane of symmetry in any conformation, and
sec 14.4 optically active compounds having no asymmetric carbon atoms 379
consequently there are two pairs of enantiomers, or a total of four optical
isomers. In general, a compound with n asymmetric carbons will have 2"
possible optical isomers, provided there are no isomers with a plane of sym-
metry arising from similarly substituted asymmetric carbons as in meso forms.
The structures assigned to erythrose and threose have been established
beyond question by the finding that ( — )-erythrose, which is a naturally
occurring sugar, on oxidation with nitric acid gives wejo-tartaric acid,
whereas ( + )-threose, which does not occur naturally, gives (-l-)-tartaric acid.
CHO
I
H-C-OH
I
H-C-OH
I
CH 2 OH
( — )-erythrose
hno 3
C0 2 H
-C— OH
I
H-
H-C-OH
I
CO,H
oieso-tartaric acid
CHO
I
H— C— OH
I
HO— C— H
I
CH 2 OH
( + )-threose
HNOj
C0 2 H
H— C— OH
I
HO— C— H
I
( + )-tartaric acid
The terms erythro and threo are often used to designate pairs of diastereo-
mers related to threose and erythrose. The erythro isomers, like ( + ) or ( — )
erythrose, are the ones which give a meso compound when the end groups are
made identical while the ( + ) or ( — ) threo isomers are converted to optically
active forms by the same transformation.
14-4 optically active compounds having no
asymmetric carbon atoms
A. ALLENES AND SPIRANES
Many compounds have no asymmetric carbon atoms, yet exhibit optical
isomerism. This condition sometimes exists when there is a possibility for
restricted rotation. For instance, in a molecule of allene, the two planes that
contain the terminal methylene (CH 2 ) groups are mutually perpendicular
because of the rigidity and directional character of the two cumulated double
bonds.
Consequently, an allene of the type XYC=C=CXY, in which X and Y are
different, is asymmetric and can exist in two, nonsuperimposable, optically
active forms.
C = C=C
-X
-Y
J^C-C-
mirror plane
chap 14 optical isomerism, enantiomers and diastereomers 380
The optical isomerism of allenes was predicted by van't Hoff some 60 years
before experiment proved him to be correct. The delay was mainly caused by
practical difficulties in resolving asymmetric allenes. The first successful resolu-
tions were achieved with the allenes [22] and [23].
^
c = c=cQ ! *^, c=c=c:
"CO,CH,COiH
[22J [231
Other structures that can have the same type of asymmetry are the spiranes,
which are bicyclic compounds with one atom (and only one) common to both
rings. The simplest example is spiro[2.2]pentane [24].
CH 2 .CH 2
CH 2 CH 2
[24]
The two rings of [24], or any spirane, cannot lie in a common plane; hence,
provided that each ring is substituted so that it has no plane of symmetry, the
substance can exist as one or the other of a pair of optically active enantio-
mers. An example of a spirane that has been resolved is [25].
H.. / H \ ..CH 2v /" H 2 R / H \ ,.CH 2v /"
H * N W CH ' X NH 2 H \h 2 / CH ' X NH 2
[25]
B. OPTICALLY ACTIVE BIPHENYLS
In contrast to the asymmetric allenes, optical activity in the biphenyl series
was discovered before it could be explained adequately. In fact, when the
first biphenyl derivative was resolved (1922), there was considerable confusion
as to the correct structure of biphenyl compounds, and the source of asym-
metry was not known. It was subsequently established by dipole-moment and
X-ray diffraction data that the benzene rings in biphenyls are coaxial.
-?*5>-.- common axis
With this information, the existence of stable optical isomers of o,o'-
dinitrodiphenic acid [26] can be explained only if rotation about the central
bond does not occur and, in addition, the two rings lie in different planes. A
molecule of [26], which fulfills these requirements, is not superimposable on
its mirror image, and will therefore be optically active.
sec 14.5 absolute and relative configuration 381
C ° 2H N0 2
The lack of rotation about the pivot bond is caused by steric hindrance
between the bulky ortho substituents. Evidence for this stems from the failure
to resolve any biphenyl derivatives that are not substituted in ortho positions.
Also, resolution of ortAo-substituted derivatives can be achieved only if the
ortho substituents are sufficiently large. Thus, o,o'-difluorodiphenic acid [27],
like the corresponding dinitro derivative [26], is resolvable but is more easily
racemized than [26]. This is due to the smaller size of the fluorine atom relative
to the nitro group, and with less interference from the ortho substituents the
rings can more easily pivot about the central bond. Once they reach the
planar conformation [27b] the asymmetry is lost and racemization results.
HO,C F
[27a] planar
[27b]
Racemization of hindered biphenyls does not involve bond breaking and
hence these compounds are exceptions to the statement made earlier (Section
2-6B) about the clear distinction between stereoisomers and conformers.
14-5 absolute and relative configuration
The sign of rotation of plane-polarized light by an enantiomer is not easily
related to either its absolute or relative configuration. This is true even for
substances with very similar structures, and we find that an optically active
acid derivative having the same sign of rotation as the parent acid need not
have the same configuration. Thus, given lactic acid (2-hydroxypropanoic
acid), CH 3 CHOHC0 2 H, with a specific rotation + 3.82°, and methyl lactate,
CH 3 CHOHC0 2 CH 3 , with a specific rotation — 8.25°, we cannot tell from the
rotations alone whether the acid and ester have the same or a different arrange-
ment of groups about the asymmetric center. The relative configurations have
to be obtained by other means.
If we convert ( + )-lactic acid into its methyl ester, we can be reasonably
certain that the ester will be related in configuration to the acid, because
esterification should not affect the configuration about the asymmetric
carbon atom. It happens that the methyl ester so obtained is levorotatory so
we know that (+)-lactic acid and (— )-methyl lactate have the same relative
configuration at the asymmetric carbon, even if they possess opposite signs
of optical rotation. However, we still do not know the absolute configuration;
that is, we are unable to tell which of the two possible configurations of
chap 14 optical isomerism, enantiomers and diastereomers 382
lactic acid, [28a] or [28b], corresponds to the dextro or ( + ) acid and which
to the levo or ( — ) acid. The term chirality, whose meaning was given as
" handedness " in Section 14-3A, is often used for what we are calling absolute
configuration. Chirality is the more general term — molecules and environ-
ments can both possess chirality.
C0 2 H
C0 2 H
— C-OH
HO— C — H
CH 3
CH 3
[28a]
[28b]
Until recently, the absolute configuration of no optically active compound
was known with certainty. Instead, configurations were assigned relative to a
standard, glyceraldehyde, which was originally chosen for the purpose of
correlating the configurations of carbohydrates but has also been related to
many other classes of compounds, including a-amino acids, terpenes, and
steroids, and other biochemically important substances. Dextrorotatory
glyceraldehyde was arbitrarily assigned the configuration [29a] and is known
as d-( + )-glyceraldehyde. The levorotatory enantiomer [29b] is designated as
L-( — )-glyceraldehyde. In these names, the sign in parentheses refers only to
the direction of rotation, while the small capital letter d or L denotes the
absolute configuration. The sign of rotation is sometimes written as dior ( + )
and / for ( — ), or dl for (±).
CHO CHO
H— C— OH
HO— C— H
CH 2 OH
CH 2 OH
[29a]
[29b]
D-( + )-glyceraldehyde
l-( — )-gylceraldehyde
At the time the choice of absolute configuration for glyceraldehyde was
made, there was no way of knowing whether the configuration of ( + )-
glyceraldehyde was in reality [29a] or [29b]. However, the choice had a 50%
chance of being correct and we now know that [29a], the d configuration, is in
fact the correct configuration of (+)-glyceraldehyde. This was established
through use of a special X-ray crystallographic technique, which permitted
determination of the absolute disposition of the atoms in space of sodium
rubidium ( + )-tartrate. The configuration of ( + )-tartaric acid [18a] had been
previously shown chemically to be the same as that of ( + )-glyceraldehyde.
Consequently, the absolute configuration of any compound is now known
once it has been correlated directly or indirectly with glyceraldehyde. 2
2 Relating a compound's configuration to that of glyceraldehyde works well when the
compound shares two or three of the same groups with the standard (H, OH, CHO, and
CH 2 OH), but is rather arbitrary otherwise. For this reason a new procedure has been
introduced, the Cahn-Ingold-Prelog system, in which a series of sequence rules determines
configuration. The symbols R and s are used to designate configurations by this system
instead of d and l. In the case of glyceraldehyde and closely related compounds d corres-
ponds to r, and l corresponds to s. The r and s system has been extended to chiral mole-
cules in general and it is possible, for example , to designate the optical isomers of [27]
specifically as r and s.
sec 14.5 absolute and relative configuration 383
C T° 2H OHe T^ 2 " mo 9°> H C0 2 H
CH 3 CH 3 in, ^
CH 3
L-( + )-lactic ( + )-2-bromo- / ,\ i ■
acid propanoic acid ( + )-alanme
Figure 14-3 Chemical tranformations showing how the configuration of
natural (+)-alanine has been related to L-(+)-lactic acid and hence to
L-(— )-glyceraldehyde. The transformations shown involve two S N 2 reactions
which are stereospecific and invert configuration (Section 14-9). Reduction of
the azide group leaves the configuration unchanged.
In general, the absolute configuration of a substituent at an asymmetric center
is specified by writing a projection formula with the carbon chain vertical
and the lowest numbered carbon at the top. The D configuration is then the
one that has a specified substituent on the bond extending to the right of the
asymmetric carbon, while the l configuration has the substituent on the left.
R, R,
R 2 — C— X X— C-R 2
I I
R 3 R 3
D configuration L configuration
Compounds whose configurations are related to D-( + )-glyceraldehyde
belong to the d series, and those related to l-( — )-glyceraldehyde belong to
the l series.
Many of the naturally occurring a-amino acids have been correlated with
glyceraldehyde by the type of transformations shown in Figure 14-3. Here,
natural alanine (2-aminopropanoic acid) is related to L-( + )-lactic acid and
hence to L-( — )-glyceraldehyde. Alanine therefore belongs to the L series, and
by similar correlations it has been shown that all of the a-amino acids which
are constituents of proteins are L-amino acids. Many D-amino acids are com-
ponents of other biologically important substances.
When there are several asymmetric carbon atoms in a molecule, the configu-
ration at one center is usually related directly or indirectly to glyceraldehyde,
and the configurations at the other centers are determined relative to the
first. Thus in the aldehyde form of the important sugar, ( + )-glucose, there
are four different asymmetric centers, and so there are 2 4 = 16 possible
stereoisomers. The projection formula of the isomer which corresponds to
natural glucose is [30]. By convention for sugars, the configuration of the
highest numbered asymmetric carbon is referred to glyceraldehyde to deter-
mine the overall configuration of the molecule. For glucose, this atom is C-5,
next to the CH 2 OH group, and has the hydroxyl on the right. Therefore,
naturally occurring glucose belongs to the d series and is properly called
D-glucose (see also Section 15-2).
chap 14 optical isomerism, enantiomers and diastereomers 384
'CHO
2 I *
H-C-OH
si.
HO— C— H
H
-C*-OH
51*
H— C— OH
-~vr
CH 2 OH
[30]
On the other hand, the configurations of a-amino acids possessing more
than one asymmetric center are determined by the lowest numbered asym-
metric carbon, which is the carbon alpha to the carboxyl group. Thus, even
though the natural a-amino acid threonine has exactly the same kind of
arrangement of substituents as the natural sugar threose, threonine by the
amino acid convention belongs to the l series, while threose by the sugar con-
vention belongs to the d series.
C0 2 H
~~-t-~~~
H 2 N— C — H l
------I-
H— C— OH
I
CH 3
L-threonine
CHO
HO-C-H
r -» -
: H— C— OH d
L 1--
CH 2 OH
d-( — )-threose
14-6 separation or resolution of enantiomers
Since the physical properties of enantiomers are identical, they cannot
usually be separated by physical methods such as fractional crystallization or
distillation. It is only in the presence of another optically active substance that
the enantiomers behave differently, and almost all methods of resolution (and
asymmetric synthesis) are based on this fact.
Perhaps the most general resolution procedure is to convert enantiomers to
diastereomers, whose physical properties are not identical. For instance, if a
racemic or d,l mixture of an acid is converted to a salt with an optically
active base of the d configuration, the salt will be a mixture of two diastereo-
mers, (d acid + d base) and (l acid + d base). These diastereomeric salts are
not identical and not mirror images and will therefore differ in their physical
properties. Hence, separation by physical means, such as crystallization, is in
principle possible. Once separated, the acid regenerated from each salt will be
either the pure d or l enantiomer :
d,l acid
d base
(d acid + d base)
-> (l acid + d base)
d acid
l acid
sec 14.6 separation or resolution of enantiomers 38S
Resolution of optically active acids through formation of diastereomeric
salts requires adequate supplies of suitable optically active bases. Brucine
[31a], strychnine [31b], and quinine [32] are most frequently used because
they are readily available, naturally occurring, optically active bases.
brucine, R=OCH 3 [31a]
strychnine, R=H [31b]
quinine
[32]
CH=CH 2
For the resolution of a racemic base, optically active acids are used, such as
( + )-tartaric acid, ( — )-malic acid, ( — )-mandelic acid, and ( + )-camphor-10-
sulfonic acid.
CH,CO,H
I
CHOH
I
C0 2 H
malic acid
C 6 H 5
CHOH
I
C0 2 H
mandelic acid
H 3 C CH 3
A,CH 2 S0 3 H
AT
camphor- 10-sulfonic acid
To resolve an alcohol, an optically active acid may be used to convert the
alcohol to a mixture of diastereomeric esters. High-molecular-weight acids
(~400) are advantageous since they are likely to give crystalline esters, and
these may usually be separated by fractional crystallization.
Other, more specialized methods of resolution are also available. One
procedure, which is excellent when applicable, takes advantage of differences
in reaction rates of enantiomers with optically active substances. One enan-
tiomer may react more rapidly, leaving an excess of the other enantiomer
behind. As one example, racemic tartaric acid can be resolved with the aid of
certain penicillin molds that consume the dextrorotatory enantiomer faster
than the levorotatory enantiomer; as a result, almost pure ( — )-tartaric acid
can be recovered from the mixture.
(±)-tartaric acid + mold
( — )-tartaric acid + more mold
A crystallization procedure was employed by Louis Pasteur for his classical
resolution of D,L-tartaric acid, but this technique is limited to very few cases.
It depends upon the formation of individual crystals of each enantiomer.
Thus, if the crystallization of sodium ammonium tartrate is carried out below
27°, the usual racemate salt does not form; a mixture of crystals of the D and
L salts forms instead. The two different kinds of crystals, which are mirror
chap 14 optical isomerism, enantiomers and diastereomers 386
images of one another, can be separated manually with the aid of a micro-
scope and may be subsequently converted to the tartaric acid enantiomers by
strong acid.
Optical activity had been observed in quartz crystals and in solutions of
various natural substances such as sugars well before Pasteur effected the
first resolution in 1848. The explanation of optical activity on a molecular
basis had to await the development of structural organic chemistry in the
years following 1860 (Chapter 1). In 1874, Le Bel and van't Hoff showed that
all known examples of optically active organic compounds possess asym-
metrically substituted carbon atoms and, if the valences of carbon are
tetrahedral, then each of the known optically active compounds would
have to be able to exist in two mirror-image forms. This not only explained
the existence of optically active organic compounds, it strengthened belief in
the tetrahedral character of carbon and nurtured the growth of structural
organic chemistry.
14-7 asymmetric synthesis and asymmetric induction
If you could prepare 2-hydroxypropanonitrile from acetaldehyde and
hydrogen cyanide in the absence of any optically active substance and
produce an excess of one enantiomer over the other, this would constitute an
absolute asymmetric synthesis — that is, creation of an optically active com-
pound in a symmetrical environment from symmetrical reagents.
CN / f— ; 7 CN
H~C^OH < HS / h" / -■■"-■* HO~C-H
CH, I i / CH
D-2-hydroxypropanonitrile L-2-hydroxypropanonitrile
(product of attack (product of attack
of CN e from above) of CN e from below)
This is obviously unlikely for the given example because there is no reason
for cyanide ion to have anything other than an exactly equal chance of attack-
ing above or below the plane of the acetaldehyde molecule, thus producing
equal numbers of molecules of each enantiomer.
However, when an asymmetric center is already present and a second
center is created, an exactly 1 :1 mixture of the two possible isomers (which are
now diastereomers) is not expected because the transition states are diastereo-
meric also and the reaction rates will differ. The optically active aldehyde [33]
and methylmagnesium iodide react, for example, to give the two diastereo-
meric alcohols [34a] and [34b] in a 2 : 1 ratio.
sec 14.7 asymmetric synthesis and asymmetric induction 387
O
II
C-H
H 3 C ^ /h
[33]
1. CH 3 MgI
.2. H®
OH
CH
[34a]
The formation of unequal amounts of diastereomers when a second
asymmetric center is created in the presence of a first is called asymmetric
induction. The degree of stereochemical control displayed by the first asym-
metric center usually depends on how close it is to the second. The more
widely separated they are, the less steric control there is. Another factor is the
degree of asymmetry at the first asymmetric center. If all the groups there are
very nearly the same electrically and sterically, not much stereochemical
control is to be expected.
Even when the asymmetric centers are close neighbors, asymmetric induc-
tion is seldom 100% efficient in simple molecules. In biochemical systems,
however, asymmetric synthesis is highly efficient. The photosynthesis of
glucose [30] by plants from carbon dioxide and water gives the d enantiomer
only, which means a completely specific synthesis at each of four asymmetric
carbons. The l enantiomer is "unnatural" and, furthermore, is not even
metabolized by animals. Similarly, all of the cc-amino acids which can be
asymmetric and are constituents of proteins have the l configuration.
CO a H
NH,— C— H
I
R
L-ct-amino acid
The stereospecificity of biochemical reactions is a consequence of their
being catalyzed in every case by enzymes, which are large protein molecules
that possess many asymmetric centers and hence are themselves highly
asymmetric. The stereospecificity of living organisms is related to their
efficient operation since no organism could deal with all of the possible
isomers of molecules with many asymmetric centers. Thus, if a protein mole-
cule has 100 different asymmetric centers (a not uncommon or, in fact, large
number), it will have 2 100 or 10 30 possible optical isomers. A vessel with a
capacity of about 10 7 liters would be required to hold all of the possible
stereoisomeric molecules of this structure if no two were identical. An organism
so constituted as to be able to deal specifically with each one of these isomers
would be very large indeed.
chap 14 optical isomerism, enantiomers and diastereomers 388
14-8 racemization
Racemization, which is loss of optical activity, occurs with optically active
biphenyls (Section 14-4B) if the two aromatic rings at any time pass through a
coplanar configuration by rotation about the central bond. This can be brought
about by heat, unless the ortho substituents are very large.
The way in which other compounds — for example, those with asymmetric
carbon atoms — are racemized is more complicated. Optically active carbonyl
I I
compounds of the type — CH— C=0, in which the a carbon (C-2) is asym-
metric, are racemized by both acids and bases. From the discussion in Section
12-1 on halogenation of carbonyl compounds, this is surely related to enoliza-
tion. Formation of either the enol or the enolate anion will destroy the asym-
metry at the a carbon so that, even if only trace amounts of enol are present
at any given time, eventually all of the compound will be racemized.
Base-catalyzed enolization :
HO R 2 so HO
\ / (-H®), \ ./ (+H®) \ //
D ..c-c . c=-c , D --c-c
R, R R, R R 2 R
\
//
.<:-
-c
i/
\
R 2
R
Acid-catalyzed enolization:
H O R 2 OH
\ // \ /
_...c-c ^ ' c=c
R 2 / \ / \
R, R R, R
The racemization of an optically active secondary halide (e.g., 2-chloro-
butane) may occur in solution. Usually, the more polar and better ionizing
the solvent is, the more readily the substance is racemized. Ionization of the
halide by an S N 1 process is probably responsible, and this would certainly
be promoted by polar solvents (see Section 8-1 ID). All indications are that
an alkyl carbonium ion once dissociated from its accompanying anion is
planar; and, when such an ion recombines with the anion, it has equal prob-
ability of forming the D and L enantiomers.
I -a 9
H-C-Cl ;=
I
A
H X CH,CH,
CH 3
Cl e
Cl-C-H
I
CH 2 CH 3
D L
Asymmetric alcohols are often racemized by strong acids. Undoubtedly,
ionization takes place, and recombination of the carbonium ion with water
leads to either enantiomer.
sec 14.10 optical rotatory dispersion 389
CH 3
I
H— C-OH
I
CH 2 CH 3
D
CH 3
I
HO-C-H
I
CH 2 CH 3
L
CH 3
H ffl I e
=± H-C-OH 2 , u _
CH 2 CH 3 ^^
CH 3 H^
(_H®) e I ^y^
. H 2 0-C-H '
I
CH 3
H CH 2 CH 3
14-9 inversion of configuration
In discussing the mechanism of S N 2 displacements we pointed out that
backside attack would reduce electrostatic repulsions in the transition state
to a minimum. Such a mechanism would cause inversion of configuration at
HO e + /C-Cl
[8e I Sel
HO-C-Cl]
-»" HO-C^ + Cl e
the central carbon atom. When an optically active compound such as d-(+)-
2-chlorobutane is converted to 2-butanol by aqueous base the product is,
indeed, found to have an inverted configuration :
CH 3
H— C^Cl
CH 2 CH 3
d isomer
HO e
CH 3
HO— C— H
CH 2 CH 3
The rotation of L-2-butanol is negative and that of D-2-chlorobutane is
positive, but these relative rotations do not themselves prove that inversion
occurs. The relative configurations of reactant and product must be deter-
mined according to the principles discussed earlier in Section 14-5. Because
secondary alkyl halides can also react, though slowly, by an S N 1 mechanism
(Section 8-11 A) a certain amount of racemization usually accompanies this
reaction.
14-10 optical rotatory dispersion
The sodium D line (5893 A) is used as the light source in most polarimeters.
If we use light of a different wavelength can we expect a, the measured rota-
tion, to change? Yes, and in many cases drastic changes occur even to the
extent of a change in sign of rotation. The variation of optical activity with
wavelength is known as optical rotatory dispersion (ORD).
chap 14 optical isomerism, enantiomers and diastereomers 390
Figure 14-4 Rotatory dispersion curves for ft-ans-lO-methyl-2-decalone [35]
and cw-10-methyl-2-decalone [36]. (By permission from C. Djerassi, Optical
Rotatory Dispersion, McGraw-Hill, New York, 1960.)
Figure 14-4 shows a as a function of wavelength for the two ketones [35]
and [36], the trans and cis isomers of 10-methyl-2-decalone, which have quite
different stable conformations.
O
CH,
CH,
O
[35]
O
[36]
CH,
CH,
It can be seen that the effect of [35] on the polarization angle of the light
increases as the wavelength of the light decreases, reaching a maximum just
above 3000 A. A drastic drop then occurs followed by a change in sign. This
type of behavior is called a positive Cotton effect. With some compounds, for
example [36], a decrease in wavelength causes a change of sign to occur before
the maximum is reached; this is the negative Cotton effect.
The change in sign of the optical rotation can be linked to the presence of
summary 391
the carbonyl chromophore in [35] and [36] since the « ->• tt* absorption
maximum of nonconjugated ketones occurs near 3000 A (Section 1 1 -2B).
Light absorption and rotatory dispersion are hence associated phenomena.
We can expect that any molecular property that is highly dependent on
structure and configuration will find analytical application and ORD is no
exception. The quite different ORD curves that are often obtained for various
members of a set of diastereomers can be highly useful in assigning config-
urations.
summary
Optical activity, the ability to rotate plane-polarized light, is exhibited by
compounds lacking molecular symmetry and is detected and measured by an
instrument called a polarimeter. The angle of rotation of a liquid or solute is
expressed either in terms of a, the measured degree of rotation; [a], the specific
rotation (adjusted for concentration and tube length); or molecular rotation
[M] (adjusted for molecular weight).
At the molecular level, the structural feature most commonly associated
with optical activity is the asymmetrically substituted carbon atom, a carbon
x
I
atom with four different groups attached, w— C— y. A molecule with a single
z
such structural unit is not superimposable on its mirror image and there are
two possible configurations, called enantiomers.
Optical isomers, like geometrical isomers, have the same bond structures
and differ only in the spatial arrangements of the atoms and hence are stereo-
isomers. Unlike cis-trans pairs, enantiomers have identical internal distances
and hence identical melting points, solubilities, and so on. A 50 : 50 mixture
of enantiomers, which is called a racemic mixture and does not rotate the
plane of polarized light, may have different melting or solubility characteristics
than either of its components because of crystal-packing effects. Resolution
is the process of separation of a racemic mixture into its components and
racemization is the reverse process.
Fischer projection formulas are used to represent in two dimensions the
three-dimensional configurations of enantiomers, such as 2-butanol.
CH 3 CH 3
H-C-OH = H— C-OH
I !
CH 2 CH 3 CH 2 CH 3
Compounds with two identical asymmetric carbon atoms exist in three
forms, two optically active enantiomers and an optically inactive meso form,
which possesses a plane of symmetry. In addition, the two enantiomers in
equal amount form a racemic mixture. If a compound possesses two non-
identical asymmetric carbon atoms, four optical isomers are possible — two
chap 14 optical isomerism, enantiomers and diastereomers 392
pairs of enantiomers. Molecules of different enantiomeric pairs are called
diastereomers of one another and have different physical properties. (Dia-
stereomers are stereoisomers that are not mirror images and hence a meso
compound and one of the enantiomers of the same structure are also dia-
stereomers.) Thus, 2,3-butanediol [1] exists in two enantiomeric forms and one
meso form whereas 2,3-pentanediol [2] exists in four optically active forms
which constitute two pairs of enantiomers.
CH3CHOHCHOHCH3 CH 3 CHOHCHOHCH 2 CH 3
[1] [2]
Optical activity results from molecular asymmetry and certain allenes,
spiranes, and hindered biphenyls that do not possess asymmetric carbon
atoms can exist in optically active forms.
The sign of rotation of an enantiomer, ( + ) or d, ( — ) or /, reveals neither the
molecule's absolute configuration nor its configuration relative to some other
compound. Chemical means, however, can be used to determine the latter
and this knowledge, combined with X-ray diffraction studies, has enabled
many absolute configurations to be determined. The symbols D and l are
used to designate absolute configuration and configurations are assigned
relative to glyceraldehyde. ( + )-Glyceraldehyde is known to be the D isomer.
CHO
H-C-OH
CH 2 OH
d-( + )-glyceraldehy de
The number of optical isomers possible for a compound with n different
asymmetric carbon atoms is 2", which corresponds to 2"/2 pairs of enantio-
mers. Enantiomers A D and A h can be separated by appropriate combination
of the racemic mixture with a second optically active compound, B D , which
thus produces a pair of diastereomers, A D B D and A L B D . Because the members
of the pair of diastereomers possess different physical properties, they can be
separated and converted to the separate optical isomers.
. B D A D B D ► A D
A D A L mixture ►
A L B D ► A L
Occasionally a racemic mixture will crystallize to give a mixture of d crystals
and L crystals, which can be separated mechanically (method of Pasteur).
A chemical reaction that creates an asymmetric center in a molecule will
produce equal amounts of the two enantiomers unless asymmetry is already
present in the molecule, in which case unequal amounts of two diastereoiso-
mers are expected by asymmetric induction.
Racemization occurs when a symmetrical substance is produced at any
stage in a reaction undergone by an optically active compound. Inversion of
configuration normally occurs during S N 2 reactions as a result of backside
attack by the nucleophile.
exercises 393
When the wavelength of polarized light is varied the amount of rotation
caused by an optically active substance changes (optical rotatory dispersion),
and may even undergo a change in sign. The sign change is normally associated
with the absorption of visible or ultraviolet light by a chromophore in the
molecule.
exercises
14-1 Many familiar objects, such as gloves, and screws, are nonidentical with their
mirror images. Is it reasonable to expect such objects to be optically active
provided they are transparent to light, or are further conditions necessary?
14-2 Which of the following compounds exist in optically active forms? Identify
those that have a meso form.
a. 3-heptanol g. bis(4-chlorophenyl)carbinol
b. 4-heptanol h. 1,1-dimethylcyclobutane
c. 3,4-dibromohexane i. 1,2-dimethylcyclobutane
d. 1,6-dimethoxy-l-hexene j. 1,3-dimethylcyclobutane
e. diphenylcarbinol k. 2,3-dimethylbutanoic acid
/. 4-chlorodiphenylcarbinol (Section 20-1A)
14-3 Identify the compounds listed in Exercise 14-2 that exhibit geometrical
isomerism.
14-4 Citric acid (2-hydroxy-l,2,3-propanetricarboxylic acid) is the principal acid in
citrus fruits. Can citric acid or any of its methyl esters exhibit optical activity ?
14-5 The compound l,l,l-trifluoro-2-bromo-2-chloroethane is the well-known
anesthetic halothane. Can it exist in stable optically active forms? Make
sawhorse drawings of the different optically active conformations of this
substance.
14-6 Draw the chair form of cw-cyclohexane-l,2-dicarboxylic acid. Is it identical
with its mirror image? Why is the compound not resolvable? How many
stereoisomers are possible for cyclohexane-l,3-dicarboxylic acid and, of these,
which are optical isomers and which are geometric isomers ?
14-7 Draw structures similar to [9] through [13] for all the possible different
staggered conformations of (+)-tartaric acid [18]. Are any of these identical
with their mirror images ? How many optically active forms of tartaric acid
could there be altogether if rotation were not possible about the 2,3 bond
and only the staggered conformations were allowed ?
14-8 Write projection formulas for (+)-erythrose and (— )-threose. Which tartaric
acids will they give on oxidation?
14'9 Draw projection formulas for all of the possible optical isomers of 2,3,4-
trihydroxypentanoic acid.
chap 14 optical isomerism, enantiomers and diastereomers 394
14-10 Camphor has two asymmetric carbons, but only two optical isomers are
known. Explain. (Models may be helpful.)
CH,
CH,
O
camphor
14-11 Would the following structures be resolvable into optically active isomers?
Show the structures of the possible isomers.
w c H,C-CH 2 H
3 ^\ 7 \ /
a. ,C C=C
f/ \ / \
H
H,C— CH,
CO,H
H,C H 2, c_ CH 2
X c=c=c c,
H H 2 C-CH 2 H 2 C-CH 2
14-12 Which of the following biphenyl derivatives would you expect might give
stable enantiomers ? Show your reasoning.
b.
d.
C0 2 H
14-13 Which of the following projection formulas represent the same optical
isomers ? Write each in its proper form as a Fischer projection formula of
3-amino-2-butanol.
H
CH 3
I
H— C— OH
I
H-C— NH 2
I
CH 3
H
I
CH 3 -C-NH 2
I
H— C— OH
I
CH 3
CH 3 — C— OH
I
CH 3 -C-NH 2
I
H
CH 3
I
HO— C— H
I
H— C— NH 2
I
CH 3
OH
I
CH 3 -C-H
I
C
I
CH 3
H
I
CH 3 -C— OH
I
H 2 N-C-CH 3
I
H
exercises 395
14-14 Draw Fischer projection formulas for all the possible different optical
isomers of the following substances :
a. 1,2,3,4-tetrachlorobutane
b. methylethylpropylboron
c. 2,3-dibromopropanoic acid
d. triisopropylmethane
e. 3-bromo-2,5-hexanediol
/ C0 2 CH 3
CHO
CH 2
/
CHO
C0 2 CH 3
g. methyl hydrogen tartrate
h, s-butyl lactate
1445 Predict the stereochemical configuration of the products from each of the
following reactions. Write projection formulas for the starting materials and
products.
a. D-2-butanol with acetic anhydride
b. D-methylethylisobutylcarbinol with hydrochloric acid
c. D-glycerol monoacetate with aqueous sodium hydroxide
d. D-s-butyl ?-butyl ketone with bromine and dilute base
14-16 Explain how one could determine experimentally whether hydrogen peroxide
in formic acid adds cis or trans to cyclopentene, assuming the possible
addition products to be unknown.
14-17 Devise a reaction scheme for relating configuration of (+)-2-butanol to
glyceraldehyde. Think carefully about the reaction mechanisms involved in
devising your scheme.
14-18 Discuss possible procedures for resolution of ethyl D,L-lactate (ethyl
2-hydroxypropanoate, bp 155°) into ethyl D-lactate and ethyl L-lactate.
14-19 How could you tell whether a chloroform solution of an optically active
compound showing a rotation of —100° was actually levorotatpry by —100°
or dextrorotatory by +260°?
14-20 Solutions of optically active 2,2'-diiodobiphenyl-5,5'-dicarboxylic acid race-
mize at a measurable rate on heating. Racemization of active 2,3,2'3'-
tetraiodobiphenyl-5,5'-dicarboxylic acid goes many thousand times more
slowly. (For nomenclature see Section 20-1 A.) Make a scale drawing of the
transition state (planar) for racemization; deduce from it the reason for
the very slow racemization of the tetraiodo diacid. Use the following bond
distances (note that the benzene ring is a regular hexagon) :
chap 14 optical isomerism, enantiomers and diastereomers 396
C—C (benzene ring) =1.40 A
C— C (between rings) = 1.47 A
C-H =1.07 A
C-I = 1.63 A
The interference radii of iodine and hydrogen are 2.15 and 1.20 A, respec-
tively.
14-21 Compounds of the type shown below have been found to be resolvable into
two optically active forms. Explain.
-C0 2 H
H 3 C CH 3
14-22 Can the structures CH 2 =C=CBr 2 and BrHC=C=C=CHBr be optically
active ? Explain.
14-23 Write Fischer projection formulas for each of the following substances,
remembering, where necessary, that t> and l isomers of substances with
more than one asymmetric carbon are always enantiomers, not diastereo-
mers.
a. L-alanine (L-2-aminopropa- e. D-?Areo-2,3-dihydroxybutanoic
noic acid) acid
b. D-2,3-butanediol / L-ery?/i/"0-2,3-butanediol mono-
c. D-threonine methyl ether
d. L-glucose
chap IS carbohydrates 399
Carbohydrates are a major class of naturally occurring organic compounds
which came by their name because they usually have the general formula
C x (H 2 0) y . Among the more well-known carbohydrates are the various
sugars, the starches, and cellulose, all of which are important for the
maintenance of life in both plants and animals.
Carbohydrates are formed in green plants as the result of photosynthesis,
which is the chemical combination or " fixation " of carbon dioxide and water
by utilization of energy gained through absorption of visible light :
xC0 2 +xH 2 — > (CH 2 0), + x0 2
green plants
carbohydrate
Although many aspects of photosynthesis are not yet well understood, the
primary process is clearly the excitation of the green plant pigment chloro-
phyll-a (Figure 15-1) by absorption of light; the energy of the resulting
activated chlorophyll-a molecules is used to oxidize water to oxygen and to
reduce carbon dioxide. One of the first-formed products in the fixation of
carbon dioxide is believed to be D-glyceric acid.
C0 2 H
I
H-C-OH
CH 2 OH
D-glyceric acid
From this compound, the plant carries out a series of enzyme-catalyzed
reactions which result in the synthesis of simple sugars, such as glucose
(C 6 H 12 6 ), and polymeric substances, such as the starches and cellulose
(C 6 H 10 O 5 )„, with«> 1000.
Figure 15-1 The structure of chlorophyll-a. The coordination of the un-
shared electron pairs on two of the nitrogens to the magnesium is indicated
by dashed lines. Other resonance structures can also be written leading to the
conclusion that all four bonds to magnesium are equivalent.
H .-■
CH 2 C0 2 CH£>
I
CO 2 C 20 H39
chap 15 carbohydrates 400
Table 15*1 Some classes and examples of naturally occurring carbohydrates
MONOSACCHARIDES
Pentoses (CsHjoOs)
Hexoses (C 6 H 12 6 )
L-arabinose
D-glucose
D-ribose
D-fructose
D-xylose
D-galactose
D-mannose
OLIGOSACCHARIDES
Disaccharides (C12H22OU)
Trisaccharides (C 18 H 3 20 16 )
sucrose (D-glucose + D-fructose)
raffinose (D-glucose + D-fructose
maltose (D-glucose + D-glucose)
+ D-galactose)
lactose (D-galactose + D-glucose)
POLYSACCHARIDES
(C6H 10 O 5 )„
Plants
Animals
starch
glycogen
cellulose
15-1 classification of carbohydrates
The simplest sugars, called monosaccharides, are polyhydroxy aldehydes
or ketones, usually containing five or six carbon atoms. If several of these are
joined together by acetal-type linkages the molecule is called an oligosac-
charide. If 10 or more are joined this way the resulting polymer is called a
polysaccharide. The names of all individual monosaccharides and oligosac-
charides (sugars) end in -ose. Table 15T shows some of the important natur-
ally occurring carbohydrates.
The aldopentoses are five-carbon sugars containing an aldehyde function.
The most abundant of these are L-arabinose, D-ribose, D-xylose, and 2-deoxy-
D-ribose. (Deoxy means without oxygen; thus, 2-deoxy-D-ribose is D-ribose
in which the 2-hydroxyl group is replaced with hydrogen.) Their structures
and configurations are given in Table 15-2. We shall see later that they exist
predominantly in a cyclic form involving combination of the carbonyl group
and a hydroxyl group further down the chain. D-Ribose is a component of
ribonucleic acid (RNA) and vitamin B 12 and some coenzymes. 2-Deoxy-D-
ribose is part of the deoxyribonucleic acid(DNA) chain. Both RNAandDNA
will be met again later in the book.
There are three important aldohexoses: D-glucose, D-mannose, and
D-galactose. Of these D-glucose is by far the most abundant in nature and we
shall examine its chemistry in detail in the next section.
There is one other important monosaccharide, D-fructose. This is a keto-
hexose which is found in fruit juices and in honey. Linked to glucose it forms
the disaccharide sucrose, which is common table sugar. The structures and
sec IS. 1 classification of carbohydrates 401
Table IS -2 Typical pentoses and hexoses
pentoses
hexoses
CHO
1
CHO
|
H-C-OH
j
H— C— OH
I
HO-C-H
I
HO— C— H
|
HO— C— H
|
H— C— OH
1
CH 2 OH
H— C— OH
j
CH 2 OH
L-arabinose
D-glucose
CHO
1
CH 2 OH
t
H— C— OH
|
c=o
j
H— C— OH
1
HO— C— H
j
H— C— OH
I
H— C— OH
1
CH 2 OH
H— C— OH
J
D-ribose
CH 2 OH
D-fructose
CHO
1
CHO
1
CH 2
|
HO— C— H
1
H— C— OH
1
HO— C— H
1
H— C— OH
|
H— C— OH
1
CH 2 OH
H— C— OH
|
2-deoxy-D-ribose
CH 2 OH
D-mannose
CHO
1
CHO
1
H— C— OH
1
H— C— OH
1
HO— C— H
|
HO— C— H
1
H— C— OH
i
HO— C— H
1
CH 2 OH
H— C—OH
J
D-xylose
CH 2 OH
D-galactose
configurations of fructose and the three important aldohexoses are given in
Table 15-2. As with the aldopentoses, these molecules exist largely in the
cyclic form.
Some carbohydrates found in nature contain an amino group in place of
chap 1 S carbohydrates 402
an hydroxyl group. The antibiotic streptomycin, for example, contains an
amino derivative of glucose, as do other compounds of structural and immu-
nological importance (Sections 15-8 and 15-9).
IS- 2 glucose
D-Glucose, the most abundant monosaccharide, occurs free in fruits, plants,
and honey, and in the blood and urine of animals, and combined in many
oligosaccharides and polysaccharides. It is one of the optical isomers of the
aldohexoses, all of which have structure [1].
CHO
*CHOH
*CHOH
*CHOH
*CHOH
I
CH 2 OH
[1]
The carbons labeled with an asterisk in [1] are asymmetric, and there are
therefore 2 4 , or 16, possible optically active forms. All are known — some
occur naturally and others have been synthesized. The problem of identifying
glucose as a particular one of the 16 possibilities was solved by Emil Fischer
during the latter part of the nineteenth century. The configurations he deduced
for each of the asymmetric carbons (C-2 to C-5) are shown in the projection
formula [2]. (Remember that the horizontal bonds in Fischer projection
formulas such as [2] are understood to extend forward out of the plane of the
paper and the vertical bonds extend back behind the paper.)
'CHO
HO— 3 C— H
J
H-C-OH
'?
°CH 2 OH
[2]
Fischer was well aware that natural glucose could be the enantiomer of
[2]. His original guess proved to be correct, because the configuration at C-5
is that of the simplest "sugar," D-(+)-glyceraldehyde. This was arbitrarily
assigned as [3] and later shown to be correct (Section 14-5). Therefore,
natural glucose is specifically D-glucose.
sec IS. 2 glucose 403
CHO
H— C— OH
CH 2 OH
[3]
The relationship between naturally occurring glucose, mannose, and
fructose was uncovered by Fischer with the help of the phenylhydrazine reac-
tion. Phenylhydrazine is one of the reagents used to characterize aldehydes
and ketones (Table 11-4), and even though only a small fraction of the sugar
molecules are in the noncyclic carbonyl form, hydrazone formation occurs and
eventually all the sugar is converted to a phenylhydrazone. With 2-hydroxyal-
dehydes or ketones the reaction does not stop at this stage, and the adjacent
alcohol group is oxidized by a second molecule of phenylhydrazine; the
resulting carbonyl group then reacts with a third molecule of reagent. The
reaction stops at this stage giving a crystalline derivative called an osazone.
With glucose, the product would be named glucose phenylosazone. Although
CHO C 6 H 3 NHNH 2 CH=NNHC 6 H 5 CH=NNHC 6 H 5
| ► | ► |
CHOH CHOH C=0
I I I
glucose
glucose
phenylhydrazone
CH=NNHC 6 H 5
I
C=NNHC 6 H 5
I
glucose
phenylosazone
glucose, mannose, and fructose all give different phenylhydrazones, they give
the same phenylosazone.
CHO
(CHOH), C * HsNHNH -
I * excess
CH,OH
CH=NNHC 6 H 5
C=NNHC 6 H 5
(CHOH),
I
CH 2 OH
C<,H 5 NHNH 2
glucose and phenylosazone from glucose,
mannose mannose, and fructose
CH 2 OH
I
c=o
I
(CHOH) 3
CH 2 OH
fructose
This shows that the configuration at C-3, C-4, and C-5 must be the same for
all three sugars. Further, glucose and mannose differ only in configuration at
C-2 ; they are said to be epimers. Fischer used many pieces of evidence such as
this to deduce the configuration of each asymmetric carbon atom in each of
the 16 optical isomers of the aldohexoses (an amazing accomplishment in the
days when instrumental analysis, other than polarimetry, was unknown).
Glucose and related sugars have the properties expected of compounds con-
taining several alcoholic hydroxyl groups. They tend to have high water
solubilities, their hydroxyl groups can be oxidized to give aldehydes and
ketones, and they form esters ; being glycols they are cleaved by periodic acid,
and so on.
Glucose is also an aldehyde and although it has many of the reactions of
aldehydes it lacks others. For example, it forms certain carbonyl derivatives
chap 15 carbohydrates 404
(e.g., oxime, phenylhydrazone, and cyanohydrin) ; it can be reduced to the
hexahydric alcohol sorbitol, and oxidized with bromine to gluconic acid (a
monocarboxylic acid). With nitric acid, oxidation proceeds further to give the
dicarboxylic acid, D-glucaric acid.
CH 2 OH
H— C-OH
I
HO-C-H
H-C-OH
I
H-C-OH
I
CH 2 OH
sorbitol
CHO
I
H-C-OH
Na-Hg HO-C-H
H-C-OH
I
H-C-OH
I
CH 2 OH
D-glucose
Br 2
I
H-C-OH
I
HO-C-H
I
H-C-OH
I
H-C— OH
I
D-gluconic acid
HN0 3
C0 2 H
-C
I
HO-C-H
H-
OH
H-C— OH
H-C-OH
C0 2 H
D-glucaric acid
Glucose will also reduce Fehling's solution (Cu'^Cu 1 ) and Tollen's
reagent (Ag'-^Ag ). However, it fails to give a bisulfite addition com-
pound and it forms two different monomethyl derivatives (called methyl
a-D-glucoside and methyl /?-D-glucoside) under conditions which normally
convert an aldehyde to a dimethyl acetal.
H
/
R-C + 2CH 3 OH
O
C 6 H 12 6 + CH 3 OH
H
H a>
-► R-C-OCH3 + H,0
I
OCH3
(C 6 H u 5 )OCH 3 + H 2
methyl a- and /?-D-glucoside
The above behavior suggests that the carbonyl group is not free in glucose
but is tied up in combination with one of the hydroxyl groups, which turns
out to be the one at C-5, to form a cyclic hemiacetal represented by [4].
,1
CHOH
2 I
H— C— OH
,1
HO— C— H
H-C-OH
,1
H-C-O—
[4]
A new asymmetric center is created at C-l by hemiacetal formation, and
there are therefore two stereoisomeric forms of D-glucose, a-D-glucose and
/?-D-glucose.
H-C— OH
a-D-glucose
,1
HO— C — H
I
/?-D-glucose
sec 15.3 cyclic structures 405
A specific term is used to describe carbohydrate stereoisomers differing only
in configuration at the hemiacetal carbon; they are called anomers. Although
Fischer projection formulas are useful for indicating configuration in open-
chain molecules they are less suitable for cyclic structures such as [4] because
they do not clearly show the spatial relationships of the molecules.
15-3 cyclic structures
Because glucose and most other sugars exist predominantly (>99%) in the
cyclic hemiacetal structure we will want to draw the structures and configura-
tions as clearly as possible. The Haworth projection formulas [5] and [7] were
adopted before chemists became aware of the conformational mobility of six-
membered rings. They are still used extensively but are rather less informative
than conformational formulas such as [6] and [8].
H CH,OH
HO
OH HO
H OH
[5]
Haworth projection
formula
H" OH
[6]
conformational
formula
a-D-glucose
X-Ray diffraction studies have shown that crystalline a-D-glucose has the
chair conformation [6]. The Haworth and conformational formulas can be
related to the chainlike Fischer projection formulas in the following way.
A group that extends to the right in a Fischer projection formula extends
downward in a Haworth projection or conformational formula. Furthermore,
for D sugars the OH at C-l will be down in the a form and up in the fi form.
/9-D-Glucose differs from a-D-glucose only in the configuration at C-l and
its Haworth and conformational formulas are shown in [7] and [8]. Note that
all the OH and CH 2 OH groups in this molecule occupy equatorial positions.
This suggests that the /? anomer should be of slightly lower energy because the
hydroxyl at C-l in the a anomer will suffer 1,3 interactions with the hydrogens
at C-3 and C-5.
CH 2 OH
HON^H
H OH
[7]
Haworth projection
formula
HCH,OH
HO
[81
conformational
formula
/?-D-glucose
chap IS carbohydrates 406
Since the oxide ring is six membered in some sugars and five membered in
others, it is helpful to use names that indicate the ring size. The five- and
six-membered oxide rings bear a formal relationship to the cyclic ethers,
furan and pyran. Hence, the terms furanose and pyranose have been coined
II II HC* CH
pyran furan
to denote five- and six-membered rings, respectively, in cyclic sugars. The
two forms of glucose are appropriately identified by the names a-D-gluco-
pyranose and /?-D-glucopyranose. Likewise, L-arabinose, D-xylose, D-galactose,
and D-mannose occur naturally as pyranoses — but D-ribose and D-fructose
usually occur as furanoses.
IS- 4 mutarotation
Although the crystalline forms of a- and /?-D-glucose are quite stable, in
solution each form slowly changes into an equilibrium mixture of both. The
process can be readily observed as a decrease in specific optical rotation
from that of the a anomer (+ 1 12°) or an increase from that of the fi anomer
(+18.7°) to the equilibrium value of +52.5°. The phenomenon is known as
mutarotation (Figure 15-2) and is commonly observed for reducing sugars
(i.e., sugars with their carbonyl function in the form of a hemiacetal). Mutaro-
tation is catalyzed by both acids and bases and by molecules that can change
from one tautomeric form to another (Section 18-1E).
At equilibrium, there is present some 64 % of the ji anomer and 36 % of
the a anomer. The amount of the free aldehyde form present at equilibrium
is very small (0.024%). Preponderance of the fi anomer is to be expected
because the hydroxyl substituent at C-l is equatorial in the fS anomer [8] and
Figure 15-2 Mutarotation of D-glucose in solution via the open-chain
aldehyde form.
°- H
OH
\c?> -=- -^y «
H
[6] [7] [8]
a-D-glucose open-chain form /!-D-glucose
(chair conformation) (one of many conformations) (chair conformation)
sec 15.5 glycosides 407
axial in the a anomer [6]. Oddly enough, compounds such as those described
in the next section having a methoxy group at C-l tend to have the methoxy
group axial (anomeric effect).
15-5 glycosides
Although abundant quantities of glucose and fructose occur in the free state
in nature, they and the less common sugars are also found combined with
various hydroxy compounds. The generic name for these combinations is
glycoside, or, more specifically, O-glycoside, to denote that the linkage to the
hydroxy compound is through oxygen. The simplest glycosides are those
formed by the acid-catalyzed reaction of methanol with a molecule such as
jS-D-glucose ; this reaction is shown in Equation 15-1. (Since the a and P forms
of glucose are in equilibrium the a-glucoside will also be formed.) The cyclic
sugar is a hemiacetal and the glycoside is an acetal. The additional group in
the glycoside (methyl in Equation 15-1) is called the aglycone group. This
H CH 2 OH ^ H CH2 0H
H® ^
OH + CH 3 OH ► HO hoXJ-^-V OCH3 + H2 °
methyl ^-D-glucoside
(plus a anomer) (15T)
group is another sugar in many compounds found in nature, in which case the
molecule is a disaccharide. Polysaccharides are formed by the union of many
sugars by such linkages.
Of particular importance biologically are the N-glycosides, in which the
sugar residue is D-ribose and the aglycone is attached to the sugar by a C-N
bond to a nitrogen base, usually a pyrimidine or purine derivative. These
glycosides are better known as ribonucleosides and deoxyribonucleosides.
N
J
N
purine
Furanose rings are usually shown by a Haworth projection formula because
there is less need to indicate conformational mobility than with the six-
membered pyranose rings. The latter are much like cyclohexane except that
the ring is not puckered to quite the same extent. The furanose rings are much
like cyclopentane, one of the atoms being slightly out of the plane of the
other four.
Adenosine is one example of a purine ribonucleoside, and when esterified
HOH 2 C/°^N^
HOH 2 C/°\Xj^
rT^N
,N.
ANMJ/
IfajA
V
<
i r
T—T
N
N'
OH OH
OH H
H
ribonucleoside
deoxyribonucleoside
pyrimidine
P
(partial structure)
(partial structure)
chap IS carbohydrates 408
at the 5' position with the triphosphoryl group (a phosphoric acid anhydride)
OH OH OH
I I I
— P— O— P— O— P— OH
II II II
o o o
it is known as adenosine triphosphate (ATP), a so-called "energy-rich"
compound present in muscle tissue.
5'-v
adenosine adenosine triphosphate (ATP)
15-6 disaccharides
The simplest and most important oligosaccharides are the disaccharides.
These, on acid or enzymic hydrolysis, give the component monosaccharides,
which are frequently hexoses. The bond between the hexoses is an O-glycoside
linkage, but only one hemiacetal hydroxyl need be involved. In fact, most
disaccharides have reducing properties indicating that one of the sugar
residues has the easily opened hemiacetal function. However, when both
hexoses are joined through their anomeric carbons, as in sucrose, the sugar
is an acetal (like a methyl glycoside) and has no reducing properties, and
forms no phenylosazone or other carbonyl derivative (provided that the
experimental conditions do not effect hydrolysis of the acetal function).
Among the more important disaccharides are sucrose, maltose, cellobiose,
and lactose (Figure 15-3). Sucrose and lactose occur widely as the free sugars,
lactose in the milk of mammals and sucrose in plants, fruit, and honey
(principally in sugar cane and sugar beet). Maltose is the product of enzymic
hydrolysis of starch, and cellobiose is a product of hydrolysis of cellulose.
To fully establish the structure of a disaccharide we must know (1) the
identity of the component monosaccharides ; (2) the ring size (furanose or
pyranose) in each monosaccharide, as it exists in the disaccharide: (3) the
positions which link one monosaccharide with the other; and (4) the anomeric
configuration (a or j6) of this linkage.
The hydrolysis products of these four disaccharides are shown here.
sec 15.6 disaccharides 409
CH,OH
HO HO
H CH,OH
H OH
maltose
[9]
CH,OH
HO HO
'OH cellobiose
[10]
HO CH 2 OH x HO
rO OHO/ '
CH
I
OH
O
OH lactose
[11]
CH,OH
HO'ho
O v
HO
CH,OH
O
■0>
HO
CH,OH
sucrose
[12]
HO
Figure 15-3 Conformational formulas for maltose [9], cellobiose [10], lactose
[11], and sucrose [12]. For maltose, cellobiose, and lactose only one of the
anomeric forms of the right-hand ring is shown. In the case of cellobiose and
lactose the right-hand rings have been turned upside down to permit reason-
able bond angles to be shown at the oxygens between the rings.
C 12 H 22 11 + H 2
H«
- C 6 H 12 6 + C 6 H 12 6
(or enzymes)
maltose ► D-( + )-glucose + D-( + )-glucose
cellobiose ► D-( + )-glucose + D-( + )-glucose
lactose ► D-( + )-glucose + D-( + )-galactose
sucrose ► D-( + )-glucose + d-( — )-fructose
The hydrolysis products of maltose and cellobiose are identical — two mole-
cules of glucose — because these two disaccharides differ only in the configura-
tion at the anomeric linkage (see Figure 15-3). Although both disaccharides
can be hydrolyzed with acid, they are much more discriminating in their
chap IS carbohydrates 410
behavior toward enzymes. Hydrolysis of maltose [9] and many other a-linked
oligosaccharides is catalyzed by the action of an enzyme called maltase
whereas hydrolysis of cellobiose [10] and other /Winked compounds is cata-
lyzed by the enzyme emulsin.
Sucrose [12] is a nonreducing nonmutarotating sugar because its compon-
ent hexose units are joined at their anomeric carbons. Sucrose has a positive
sign of rotation ([a] = +66.5°) as does D-glucose ([a] = +52°). D-Fructose,
on the other hand, has a large negative rotation, [a] = — 92°. The complete
hydrolysis of sucrose to glucose and fructose thus causes an inversion of the
sign of rotation and the product is known as invert sugar. Honey is chiefly
invert sugar because bees contain the enzyme invertase which catalyzes the
hydrolysis. Sucrose has an extraordinarily high solubility in water — 1.5 g of
sucrose will dissolve in 1 g of water at room temperature.
The sign of rotation of naturally occurring glucose is revealed by one of the
common names for this sugar : dextrose.
15-7 polysaccharides
The fibrous tissue in the cell walls of plants and trees contains the poly-
saccharide cellulose, which consists of long chains of glucose units, each of
which is combined by a jS-glucoside link to the C-4 hydroxyl of another
glucose unit, as in the disaccharide cellobiose.
Indeed, enzymic hydrolysis of cellulose leads to cellobiose. The molecular
weight of cellulose varies with the source but is usually high; cotton cellulose,
for example, consists of some 3000 glucose units per molecule.
Cellulose is the natural fiber obtained from cotton, wood, flax, hemp, and
jute and is used in the manufacture of textiles and paper. In addition to its
use as a natural fiber, cellulose is used to make cellulose acetate (for making
rayon acetate yarn, photographic film, and cellulose acetate plastics), cellulose
nitrate (gun cotton and celluloid), and cellulose xanthate (for making viscose
rayon fibers). The process by which viscose rayon is manufactured involves
converting wood pulp or cotton linters into cellulose xanthate by treatment
first with sodium hydroxide and then with carbon disulfide.
-C-OH
NaOH
CS 2
-C-0-C-S e N
I
cellulose xanthate
The degree of polymerization of the original cellulose generally falls to
around 300 monomer units in this process. At this degree of polymerization
sec IS. 7 polysaccharides 411
the cellulose is regenerated in the form of fine filaments by forcing the
xanthate solution through a spinneret into an acid bath.
S
I II H ® I
-C-O-C-S 6 H > -C-OH + CS 2
Wood owes its strength to the presence of lignin, a highly cross-linked
polymeric substance that binds the cellulose fibers together in a rigid mass.
Cellulose is obtained from wood by pulping it with various chemicals that will
dissolve the lignin and leave the cellulose fibers behind. Most woods are about
50% cellulose and about 30% lignin, the remainder being other carbohy-
drates, fats, and terpenoid resins (Section 29-3).
Unlike cellulose there is no general agreement about the exact structure of
lignin, possibly because it seems to lack the structural regularity of cellulose.
There is no doubt, however, that a dioxyphenylpropyl moiety is an important
part of the polymer.
\
o
-o^y-c-c-c
a segment of lignin
Lignin can be dissolved from wood in a number of ways but the method
that least damages the cellulose fiber and can be applied to most varieties of
wood involves digesting the wood with a solution of sodium hydroxide and
sodium sulfide. This is called the kraft process because of the strength of the
cellulose fibers that remain. (Kraft means strength in Swedish and in German.)
The length of the cellulose fiber varies greatly from one wood to another and
this is important in determining the strength of paper produced from it.
Douglas fir has the longest fiber of the common woods — about 4 mm.
The chemistry of lignin degradation that occurs during kraft pulping is not
completely understood. A black liquor containing a wide variety of organo-
sulfur compounds, some of them volatile and evil smelling, is formed. This
liquor is burned to provide power and to enable the inorganic pulping chemi-
cals to be recovered. In most other pulping methods, the waste liquor cannot
be recycled.
The principal alternative to kraft pulping involves dissolving the lignin
through the action of sulfite in acid solution. The waste sulfite liquor that
remains after the cellulose has been removed contains pulping chemicals,
degraded lignin, and other substances. These were formerly discharged directly
into rivers or inlets with drastic ecological effects. Largely as a result of anti-
pollution legislation but partly to obtain useful organic products the waste
sulfite liquors are now generally treated before being discharged.
The per capita consumption of paper each year in North America is more
than a quarter of a ton. The reader may wish to ponder the benefits and the
drawbacks of this enormous rate of consumption.
A few creatures (e.g., ruminants and termites) are able to metabolize
cellulose with the aid of appropriate microorganisms in their intestinal tracts;
chap IS carbohydrates 412
but man cannot utilize cellulose as food because he lacks the necessary
hydrolytic enzymes. However, such enzymes are widely distributed in nature
and cause cellulosic materials, either textiles, paper, or wood, to deteriorate
slowly.
The second very widely distributed polysaccharide is starch, which is stored
in the seeds, roots, and fibers of plants as a food reserve — a potential source
of glucose. The number of glucose units in starch varies with the source, but
in any one starch there "are two structurally different polysaccharides. Both
consist entirely of glucose units, but one is a linear structure (amylose) and the
other is a branched structure (amylopectin).
The amylose form of starch consists of repeating 1,4-glucopyranose links
as in cellulose, but unlike cellulose the linkage is a rather than /?. Hydrolysis
by the enzyme diastase leads to maltose.
O
maltose unit
o s
o
o'
In amylopectin, amylose-like chains are apparently branched by 1,6
linkages.
O'
O
O
O
/
CH
O*
O'
Animals also store glucose in the form of starchlike substances called
glycogens. These resemble amylopectin more than amylose in that they are
branched chains of glucose units with 3,4- and 1,6-glucoside links.
A polysaccharide which resembles cellulose in structure and stability is
chitin, which forms the hard shells of crustaceans and insects. Chitin is a
polymer of N-acetyl-D-glucosamine; that is, the —OH groups at C-2 of the
O
II
glucose units of cellulose are replaced by — NHCCH 3 groups. Crab shells
boiled with hydrochloric acid produce D-glucosamine (2-amino-2-deoxy-D-
glucose) [13].
sec 1S.9 immunologically important carbohydrates 413
[13]
D-glucosamine (/? anomer)
15-8 vitamin C
The " antiscorbutic " factor of fresh fruits which prevents the development
of the typical symptoms of scurvy in man is a carbohydrate derivative known
as vitamin C or ascorbic acid. This substance is not a carboxylic acid but a
lactone and owes its acidic properties (and ease of oxidation) to the presence
of an enediol grouping conjugate to a carbonyl group. It belongs to the l
HO /° H
I ,c=o
H-CV
HO— C— H
I
CH 2 OH
L-ascorbic acid
series by the glyceraldehyde convention. L-Ascorbic acid is formed from
D-glucose in certain plants and in the liver of most animals (see Exercise
15-10).
15-9 immunologically important carbohydrates
One of the most active areas of carbohydrate chemistry at the present is the
study of the polysaccharides present in microorganisms and their influence
on immunological specificity. The production of antibodies in the bloodstream
when foreign bacteria are introduced is a well-known phenomenon, and the
extraordinarily high degree of specificity of these antibodies can be traced to
the chemical composition of that part of the cell wall of bacteria called the
antigen. The antigen is a complex combination of polysaccharides, lipids
(esters of fatty acids), and proteins. The antigen can be separated into these
three fractions and the carbohydrate fraction degraded.
The Salmonella bacteria, for example, have been intensively studied, and
it has been shown that all of the 100 or more different cell- wall antigens that
have been characterized contain five sugars: D-glucose; D-galactose; D-glucos-
amine [13]; a C 7 sugar (a heptose); and a C 8 sugar (an octose). A polysac-
charide of these five sugars makes the basal chain to which are attached side
chap IS carbohydrates 414
chains containing a number of other pentoses and hexoses. The way in which
these sugar units are arranged is evidently the source of the specificity of the
antigen-antibody interaction.
summary
Carbohydrates are polyhydroxyaldehydes and polyhydroxyketones —
monosaccharides — or substances that yield these on hydrolysis — oligosac-
charides (two to nine components) or polysaccharides (10 or more com-
ponents). The monosaccharides are further classified according to the number
of carbon atoms in the chain and to whether they are aldehydes or ketones ;
that is, aldopentoses, ketohexoses, and so on. Most carbohydrates exist pre-
dominantly in cyclic hemiacetal or hemiketal forms.
There are four nonidentical asymmetric centers in the open-chain form of
an aldohexose which means that there are 2 4 or 16 possible optical isomers
(eight pairs of enantiomers), all of which are known. The most important of
these is D-(+)-glucose (also called dextrose), whose Fischer projection for-
mula is shown.
CHO
H-C-OH
I
HO-C— H
I
H-C-OH
I
H-C-OH
I
CH 2 OH
D-( + )-glucose
The relation of D-glucose to another of the aldohexoses (D-mannose) and
one of the eight ketohexoses (D-fructose) was revealed by the fact that all three
gave the same phenylosazone on treatment with phenylhydrazine. The con-
figurations at C-3, C-4, and C-5 must be identical in all three compounds.
The two aldohexoses are called epimers of one another since they differ only
in configuration at C-2.
CH=NNHC 6 H 5
I
C = NNHC 6 H 5
I
HO— C— H
H— C— OH
I
H-C— OH
phenylosazone from D-glucose,
D-mannose, and D-fructose
D-Glucose can be reduced to a hexahydric alcohol (sorbitol) or oxidized to
a monocarboxylic acid (D-gluconic acid) or a dicarboxylic acid (D-glucaric
summary 415
acid). It reacts with methanol and acid to form a pair of acetal-like substances
called methyl glucosides (general term — glycoside) whose structures are
analogous to the two cyclic forms of D-glucose itself. The latter, designated
a and /?, are anomers — they differ in configuration only at C-l. Two ways of
representing the cyclic structure' of one of these anomers (a-D-glucose) and
its methyl glucoside are shown here.
CH 2 OH
H CH 2 OH
"Jr°^
HO \tT\ h
Ho\° H I jj/0H
H OH (CH3)
Ho\i---V--V
Th oh 1
° H (CH 3 )
Haworth projection formula
conformational formula
The equilibrium between the open-chain form and the two cyclic anomers
of D-glucose strongly favors the cyclic forms. The latter, being diastereomers
of one another, can be separated by crystallization. When dissolved in
water, each anomer reverts at a measurable rate to the equilibrium mixture.
This interconversion process is known as mutarotation.
The additional group in a glycoside (methyl in the formulas above) is called
the aglycone group. Two of the important kinds of aglycones are nitrogen
bases and other monosaccharides. The former leads to compounds such as
the ribonucleosides — adenosine, for example — and the latter to di- and poly-
saccharides.
Four important disaccharides are sucrose (D-glucose and D-fructose joined
at C-l and C-2, respectively), maltose and cellobiose (two D-glucose units
joined at C-4 and C-l, respectively), and lactose. The two components of
sucrose are bound together through their anomeric carbons and hence this
sugar does not undergo mutarotation and is not oxidized by reagents such as
Fehling's solution unless the disaccharide linkage is first hydrolyzed. The other
three disaccharides have one free anomeric carbon and they can undergo
mutarotation and reduce Fehling's solution. Maltose and cellobiose differ only
in the configuration at the glycosidic link between the glucose units. Hydroly-
sis of maltose and some other a-linked compounds is catalyzed by maltase,
and hydrolysis of cellobiose and some other /Minked compounds is catalyzed
by emulsin.
Polysaccharides include cellulose and starch. Cellulose is a polymer of
D-glucose with all the glycosidic links (S and is the fibrous material in cotton,
wood, flax, and so on. It can be converted to various esters, some of which are
useful in their own right (cellulose acetate) and from some of which a shorter-
chain cellulose can be regenerated (viscose rayon). Starch is a mixture of
polymers of D-glucose with all the glycosidic links a, one a linear polymer
(amylose) and the other a branched-chain polymer (amylopectin).
Vitamin C (ascorbic acid) is a carbohydrate derivative. Other important
biological substances include the antigens, parts of which are polysaccharide
in nature. Immunological response is related to the arrangement of monosac-
charides in the polymer chain.
chap IS carbohydrates 416
exercises
15-1 A naturally occurring optically active pentose (C 5 H 10 Os) reduces Tollen's
reagent and forms a tetraacetate with acetic anhydride. It gives an optically
inactive phenylosazone. Write all the possible structures for this pentose
which are in accord with all the experimental facts.
15-2 A hexose, C 6 H 12 6 , which we shall call X-ose, on reduction with sodium
amalgam gives pure D-sorbitol, and, upon treatment with phenylhydrazine
gives an osazone different from that of D-glucose. Write a projection formula
for X-ose and equations for its reactions.
15-3 D-Arabinose and D-ribose give the same phenylosazone. D-Ribose is reduced
to the optically inactive pentahydric alcohol ribitol. D-Arabinose can be
degraded by the Ruff method, which involves the following reactions :
iCHO
I
2 CHOH
Br 2 , H 2 Q ,
iC0 2 H
I
,CHOH
Ca 2 ®.
iCOf
2 CHOH
Ca
M ^TTT* aCHO + C0 2 3 e
rt2U2 I
The tetrose, D-erythrose, so obtained can be oxidized with nitric acid to meso-
tartaric acid. What are the configurations of D-arabinose, D-ribose, ribitol,
and D-erythrose ?
15-4 The logic necessary to solve this problem is essentially that used by Fischer in
his classic work which established the configurations of glucose, arabinose,
and mannose.
a. Write projection formulas for all the theoretically possible D-aldopen-
toses, HOH 2 C(CHOH) 3 CHO.
b. One of the D-aldopentoses is the naturally occurring D-arabinose,
enantiomeric with the more abundant L-arabinose. Oxidation of
D-arabinose with nitric acid gives an optically active five-carbon
trihydroxydicarboxylic acid. Which of the D-aldopentoses could be
D-arabinose ?
c. D-Arabinose is converted by the following transformations into D-glu-
CHO
I
(CHOH) 3
CH 2 OH
D-arabinose
NaCN
pH9
CN
I
CHOH
I
(CHOH) 3
CH 2 OH
o=c
I
CHOH
I
CHOH
I
CH
O
CHOH
I
CH 2 OH
y-lactone
H 2 Q, H®,
Na-Hg
pH3
C0 2 H
I
CHOH
(CHOH) 3
CH 2 OH
CHO
I
(CHOH) 4
CH 2 OH
D-glucose
+
D-mannose
-H,0.
exercises 417
cose and D-mannose. (This is the classic Kiliani-Fischer cyanohydrin
synthesis of sugars). What do these transformations tell about the
relationship between the configurations of mannose and glucose?
d. Oxidation of D-glucose and D-mannose gives the six-carbon, tetrahy-
droxydicarboxylic acids, glucaric and mannaric acids, respectively.
Both are optically active. What then are the configurations of the d-
/ and L-arabinoses ?
e. D-Glucaric acid can form two different y-monolactones, whereas
D-mannaric acid can form only one monolactone. What then are the
configurations of D-glucose and D-mannose ?
15-5 Deduce possible configurations of natural galactose from the following:
a. The Wohl degradation is a means of reducing the chain length of a
sugar by one carbon through the following reaction sequence:
CHO CH=NOH CN
I NH 2 OH I (CHjCO) 2 I (-HCN)
CHOH * CHOH — ( _h 2 o) ' CHOH > CHO
D-Galactose gives a pentose by one Wohl degradation. This pentose
on nitric acid oxidation gives an optically active, five-carbon, trihy-
droxydicarboxylic acid.
b. The pentose by a second Wohl degradation followed by nitric acid
oxidation gives D-tartaric acid.
c. Write reasonable mechanisms for the reactions involved in the Wohl
degradation.
15-6 Draw Haworth- and conformation- type formulas for each of the following:
a. methyl 2,3,4,6-O-tetramethyl-a-D-glucopyranoside
b. a-L-arabinofuranose
c. L-sucrose
15-7 Sugars condense with anhydrous acetone in the presence of an acid catalyst
to form isopropylidene derivatives.
CH,
I
-C-OH / 3 HS -C-O /CH 3
I + o=c — jf^ V
"f-° H X CH 3 2 -A-C^CH,
cis
Predict the products of reaction of oc-D-galactopyranose, a-D-glucopyranose,
and a-D-glucofuranose with acetone and an acid catalyst.
15-8 How can the /3-D-glucoside units of cellulose produce a polymer with a
stronger, more compact physical structure than the a-D-glucose units of
starch ? Models will be helpful.
15-9 Complete the following sequence of reactions, writing structures for all the
products, A-I:
acetone
a. a-D-glucofuranose — ^j" > A (see Exercise 15-7)
chap IS carbohydrates 418
b.
A
c.
B
d.
C+ D
e.
E+F
/•
G + H
NalO*
»
Na 1A CN
1. H 2 Q,0H 9
2. H 9 , H 2 '
A
"VH 2 0) '
NaBH 4
H 2
B
C+D
E + F + acetone
G + H
I + D-glucose-6- 14 C
15-10 The following sequence of steps has been worked out for the conversion of
D-glucose to L-ascorbic acid in nature.
H CH,OH
HO
OH
H CO,H
^ HO
O
H H
[14]
HO
HC v
OH
.OH
~H
115]
HO-
O
II
OH
c
HO 1
/\ HH
\ _J-L_ ^OH -
1 c-
=o
'V^r^H
H-CV
H H
HO— C— H
[16]
1
CH,OH
Formulas [14], [15], and [16] are drawn to show stereochemical interrela-
tionships and not stable conformations.
a. Identify the type of chemical reaction (reduction, lactone formation,
etc.) that occurs in each of the steps.
b. Account for the change from the d series to the l series that accom-
panies the reaction.
15-11 Ascorbic acid (see Exercise 15-10) has a p^Tha of 4.2, making it stronger than
acetic acid, pK a x = 4.7. Identify the ionizable proton in ascorbic acid and
account for the compound's acidity.
15-12 A compound called inositol that is widely distributed in nature bears some
resemblance to simple sugars. Its formula is 1,2,3,4,5,6-hexahydroxycy-
clohexane and it can exist in nine possible stereoisomeric forms, two of
which are optically active and seven of which are not. Draw the chair forms
of the all-m and all-trans isomers of inositol. Which of these isomers will be
the more stable? Will either of these isomers rotate the plane of polarized
light?
_ chapter 16
organic nitrogen compounds
chap 16 organic nitrogen compounds 421
Nitrogen is an element with many oxidation levels, ranging from the most
reduced state, NH 3 or NH 4 ®, to the most oxidized state, HN0 3 or N 2 5 .
With a compound at an intermediate oxidation level, particularly one with
nitrogen-nitrogen bonds, such as HN 3 , it is often not helpful to assign
numerical oxidation states to the atoms. (The same situation occurs with
compounds of carbon.) The important inorganic states of nitrogen are listed
in Table 16T together with their organic analogs. The groupings there are
made on the basis of bonding arrangements at the nitrogen atoms rather than
on formal oxidation state.
16-1
amines
A. TYPES AND NOMENCLATURE
The nomenclature of alkyl-substituted ammonias, or amines, was considered
briefly in Chapter 8. We shall give a short review here to help focus attention
on the types of substitution which are commonly encountered. Classification
is made according to the number of alkyl or aryl groups attached to nitrogen,
since this number is important in determining the chemical reactions that are
possible at the nitrogen atom.
RNH 2
R 2 NH
R 3 N
R 4 NX
primary
secondary
tertiary
quaternary
amine
amine
amine
ammonium salt
Amino compounds can be named either as derivatives of ammonia or as
amino-substituted compounds. Thus, HOCH 2 CH 2 NH 2 can be named almost
equally well as 2-hydroxyethylamine or as 2-aminoethanol, although by con-
vention 2-aminoethanol is favored, since hydroxyl normally takes precedence
over amino. With halogens the situation is reversed, and 2-chloroethylamine
is favored over 2-aminoethyl chloride. Some typical amines with the names
which they have in common use are listed in Table 16-2 together with their
physical properties.
Salts of amines with inorganic or organic acids are usually best named as
substituted ammonium salts. Often, however, the name of the corresponding
CH3NH3 CI CH 2 =CH-CH 2 — N-CH 3 S 2 CCH 3
CH 3
methylammonium chloride allyldimethylammonium
acetate
amine is used in conjunction with the name of the acid, for instance, methyl-
amine hydrochloride for methylammonium chloride. With quaternary salts
chap 16 organic nitrogen compounds 422
Table 16-1 Inorganic compounds of nitrogen and their organic analogs"
inorganic compound
methyl derivative
acetyl derivative
NH 3
CH 3 NH 2
CH 3 -C
NH 2
ammonia
methylamine
NH 4 ® Cl e
CHN 3 H 3 S C1 9
acetamide
ammonium chloride
methylammonium chloride
NH 2 NH 2
CH 3 NHNHCH 3
hydrazine
1 ,2-dimethylhydrazine
HN=NH
CH 3 N=NCH 3
diimine
azome thane
(unstable)
e e
^°
H-N=N=N
CH 3 N 3
CH 3 -C
hydrazoic acid
methyl azide
N N 3
acetyl azide
HC=N
CH 3 C=N
CH 3 -C
hydrogen cyanide
acetonitrile
acetyl cyanide
N=COH ±> HN=C=0
CH 3 N=C=0
cyanic isocyanic
methyl isocyanate
acid acid
NH 2 OH
(CH 3 ) 2 NOH
CH 3 — C
hydroxylamine
N,N-dimethylhydroxylamine
NHOH
N-acetylhydroxylamine
a e
© e
0=N=N
CH 2 =N=N
nitrous oxide
dizaomethane
■N=0
nitric oxide
HON=0
CH 3 -N=0
nitrous acid
nitrosomethane
CH 3 0— N=0
methyl nitrite
■NO 2 ±5:N0 2 -NO 2
nitrogen dinitrogen
dioxide tetroxide
HO-N0 2
CH 3 -N0 2
nitric acid
nitrome thane
P
CH 3 0-N0 2
CH 3 -C
methyl nitrate
ON0 2
acetyl nitrate
" Arranged according to the type of bonding at the nitrogen atoms ; the alkyl or acyl group
replaces a hydrogen atom in the inorganic compound in some cases and a hydroxyl group or an
oxygen atom in others.
sec 16.1 amines 423
Table 16-2 Typical amines and their properties
amine
name
bp,
°C
mp,
°C
water solubility,
g/100 ml, 25°
in water"
NH 3
ammonia
-33
-77.7
90
1.8 x 10- 5
CH 3 NH 2
methylamine
-6.5
-92.5
1156
4.4 x 10" 4
CH 3 CH 2 NH 2
ethylamine
16.6
-80.6
00
5.6 x 10~ 4
(CH 3 ) 3 CNH 2
r-butylamine 6
46
-67.5
CO
2.8 x 10~ 4
(CH 3 CH 2 ) 2 NH
diethylamine
55.5
-50
very soluble
9.6 xlO- 4
(CH 3 CH 2 ) 3 N
triethylamine
89.5
-115
1.5
4.4 x 10" 4
(CH 3 CH 2 CH 2 CH 2 ) 3 N
tri-«-butylamine
214
slightly soluble
O h
piperidine
106
-9
00
1.6 x 10- 3
o
pyridine
115
-42
CO
1.7 x 10~ 9
O nh2
cyclohexylamine
134
slightly soluble
4.4 x 10" 4
/ Vnh 2
aniline
184.4
-6.2
3.4
3.8 x 10- 10
H 2 NCH 2 CH 2 NH 2
ethylenediamine
116
8.5
soluble
8.5 x 10" 5
' Usually at 20°-25°.
' Note that f-butylamine is a primary amine.
an extension of the same system leads to trimethylamine methiodide for
tetramethylammonium iodide. Whenever possible, however, the substituted
ammonium ion name should be used because a name such as trimethylamine
methiodide conceals the fact that the bonds to the four methyl groups are
identical.
B. PHYSICAL AND SPECTROSCOPIC PROPERTIES OF AMINES
The properties of amines depend in an important way on the degree of substi-
tution at nitrogen. For example, tertiary amines have no N— H bonds and
are thus unable to form hydrogen bonds of the type N— H---N. In general,
N— H— N bonds are somewhat weaker than those of corresponding types,
O— H— O and F— H---F, because the electronegativity of nitrogen is less than
that of oxygen or fluorine. Even so, association of the molecules of primary
and secondary amines (but not tertiary amines) through hydrogen bonding
is significant and decreases their volatility relative to hydrocarbons of similar
size, weight, and shape, as the accompanying examples show.
chap 16 organic nitrogen compounds 424
SS
nr 1
m
wavelength, jJL
j T
-i 1 rr
ch.nh :
. \ II stretch
(.'. N siix'tcli
3600 3200 2800 2400 2000 2000
Jtfclll-L
frequency, cm
Figure 16-1 Infrared spectra of cyclohexylamine and N-methylaniline.
CH 3 CH 2 CH 2 CH 2 CH 2 NH 2
rt-pentylamine
mol. wt. 87; bp 130°
CH 3 CH 2 NHCH 2 CH 3
diethylamine
mol. wt. 73; bp 55.5°
CH 2 CH 3
I
CH 3 CH 2 -N— CH 2 CH 3
triethylamine
mol. wt. 101 ; bp 89.5°
CH 3 CH 2 CH 2 CH 2 CH 2 CH
hexane
mol
wt. 86; bp 69°
CH 3 CH 2 CH 2 CH 2 CH 3
pentane
mol.
wt. 72; bp 36°
CH 2 CH 3
CH 3 CH 2 CHCH 2 CH 3
3-ethylpentane
mol. wt. 100; bp 93.3°
sec 16.1 amines 425
I
300
200
100
Hz
OH -N
V
V
CH-C
■I V N ~"
_jy i- pj J iv A ty
i
5.0
: L
_Lj
4.0
3.0
2.0
1.0
ppm
Figure 16-2 Nuclear magnetic resonance spectrum of diethylamine at 60
MHz relative to tetramethylsilane, 0.00 ppm.
The water solubilities of the lower-molecular-weight amines are generally
greater than those of alcohols of comparable molecular weights. This is the
result of hydrogen bonding between the amine and water, which leads to
I
hydrogen bonds (of considerable strength) of the type — N:— H— O— H.
I
A characteristic feature of the infrared spectra of primary and secondary
amines is the moderately weak absorption at 3500 to 3300 cm -1 , correspond-
ing to N— H stretching vibrations. Primary amines have two such bands in
this region, whereas secondary amines generally show only one band. Absorp-
tion is shifted to lower frequencies on hydrogen bonding of the amine, but
because NH---N hydrogen bonding is weaker than OH— O hydrogen bonding,
the shift is not as great and the bands are not as intense as are the absorption
bands of hydrogen-bonded O— H groups (see Table 7-1). Absorptions corre-
sponding to'G—N vibrations are less easily identifiable, except in the case of
aromatic amines, which absorb fairly strongly near 1300 cm -1 . Spectra that
illustrate these effects are shown in Figure 16-1.
I
The nmr spectra of amines show characteristic absorptions for H— C— N
I
protons around 2.7 ppm. The resonances of N— H protons are not so easily
identifiable; considerable variability arises from differences in degree of hydro-
gen bonding and matters are further complicated when, as with diethylamine
(Figure 16-2), the N— H resonance has nearly the same chemical shift as the
resonances of C— CH 3 protons.
C. STEREOCHEMISTRY OF AMINES
The bond angles of nitrogen in amines and ammonia are less than tetrahedral
as a consequence of electrostatic repulsion between the bonding electrons and
chap 16 organic nitrogen compounds 426
the unshared electron pair (Section 1-2). The configuration at nitrogen is
pyramidal and, if three different groups are attached, optically active forms
are, in principle, possible because there is no plane or center of symmetry in
the molecules.
V
~Ri
Ri
,1SL
-R2
The resolution of such a mixture of forms has not as yet been achieved
because they are rapidly interconverted by an inversion process involving a
planar transition state.
\
— R,
,-R,
R2 N-
Ri
planar transition
state
With ammonia, inversion of this type occurs at about 4 x 10 10 times per
second at room temperature; with aliphatic tertiary amines, the rate is of the
order of 10 3 to 10 5 times per second. Such inversion rates are much too great
to permit separation of amines into stable optical isomers at room tempera-
ture. There are a few specially substituted amines such as [1] which invert at
nitrogen sufficiently slowly at room temperature to permit isolation of the
separate diastereomers [la] and [lb].
CI /
CH,
\
N H
[la]
CH,
CH 2 — C
N H
/
CI
[lb]
D. AMINES AS ACIDS AND BASES
Although perhaps the most characteristic chemical property of amines is their
ability to act as bases by accepting protons from a variety of acids, it should
not be forgotten that primary and secondary amines are also able to act as
acids, albeit very weak acids. The lithium salts of such amines are readily
preparable in ether solution by treatment of the amine with phenyllithium :
ether e ®
> (C 2 H 5 ) 2 N Li + C 6 H 6
lithium diethylamide
sec 16.1 amines 427
The anions from aliphatic amines, being conjugate bases of very weak acids
(K HA ~ 10" 33 ), are powerfully basic reagents and will remove protons even
from many notably weak carbon acids.
The base strengths of saturated aliphatic amines, as given by K B , are
usually about 1CT 4 in water solution.
K B © e
RNH 2 + H 2 , RNHj + OH
Ammonia and primary, secondary, and tertiary amines have the same base
strengths within perhaps a factor of 50, as can be seen from the data in
Table 16-2. There is no evidence for formation of undissociated amine hy-
droxides such as R3NHOH, any more than there is for NH 4 OH.
Unsaturated amines are often very weak bases. An example with C— N
unsaturation is pyridine, C 5 H 5 N, which is a nitrogen analog of benzene, often
called a heterocycle because not all of the atoms in the ring are of the same
element. Pyridine, K B = 1.7 x 10" 9 , is less basic by a factor of about 10 5 than
aliphatic amines.
pyridine
Vinylamines or enamines, RCH=CH— NH 2 , are not usually stable and
rearrange to imines, RCH 2 CH=NH. An exception of a particular sort is
aniline (phenylamine, C 6 H 5 NH 2 ), which has an amino group attached to a
benzene ring. Here, the imine structure is less favorable because of the con-
siderable stabilization energy of the aromatic ring:
H
Q-NH 2 ^_ Q=NH
The K B of aniline is 10" 10 , which is less by a factor of 10 6 than that of
cyclohexylamine (and is even less than that of pyridine). The decrease in
stabilization associated with forming a bond to the unshared electron pair
of nitrogen accounts for the difference ; it prevents the electron pair from being
delocalized over the benzene ring as represented by the following structures :
<^S-NH 2 < > ^\=NH 2 < ► ?/ V=NH 2 < ► / \=NH 2
Some or all of the low basicity of aniline may also be accounted for by the
electron-attracting power of unsaturated carbons relative to saturated car-
bons (see Section 5-5).
chap 16 organic nitrogen compounds 428
E. THE PREPARATION OF AMINES
1 . Alkylation. We discussed the reactions of ammonia and amines with
alkyl halides in Chapter 8. Such processes would be expected to provide
straightforward syntheses of amines, at least with those halides which under-
go S N 2 but not E2 reactions readily. For example,
CH3I + NH3 ► CH3NH3I
The methylamine can be recovered by treating the salt with a strong base,
such as sodium hydroxide.
e e e e
CH 3 NH 3 I+NaOH
In practice, such reactions lead to mixtures of products because of equilibria
of the following kind and subsequent reactions to give more than mono-
alkylation.
CH3NH3I + NH3 ; ' CH 3 NH 2 + NH 4 I
CH 3 NH 2 + CH 3 I ► (CH 3 ) 2 NH 2 I
The reaction continues and ultimately gives some tetramethylammonium
iodide.
(CH 3 ) 3 N + CH 3 I ► (CH 3 ) 4 NI
The latter product, of course, is not readily converted to an amine by treat-
ment with base.
Nevertheless, the alkylation reaction is by no means hopeless as a practical
method for the preparation of amines because usually the starting materials
are readily available and the boiling-point differences between mono-, di-, and
trialkylamines are sufficiently large to make for easy separations by fractional
distillation. Separations may also be achieved by chemical means.
The tetraalkylammonium halide salts formed by exhaustive alkylation of
amines resemble alkali salts and, with moist silver oxide, can be converted to
tetraalkylammonium hydroxides. These compounds are strong bases and are
true ammonium hydroxides.
(CH 3 ) 4 N e I e Ag2 ° ,H2 °. (CH 3 ) 4 N ffi OH e + Agl(s)
Tetramethylammonium hydroxide, when heated, decomposes slowly accord-
ing to the following equation :
(CH 3 ) 4 N OH > CH3OH + (CH 3 ) 3 N
With a higher alkylammonium hydroxide, thermal decomposition leads to the
formation of an alkene. The reaction is a standard method for the prepara-
tion of alkenes.
CH 2 N(CH 3 ) 3 OH ( Hz0) > < >=CH 2 + N(CH 3 ) 3
sec 16.1 amines 429
Many of the- drugs that have been used in cancer therapy are chloroalkyl-
amines whose effectiveness appears to be associated with their alkylating
ability. The so-called nitrogen mustards [2], containing two chloroethyl
groups, react by a sequence of displacement steps. The chlorine is displaced
CH 2 CH 2 C1 CH 2 — CH 2 CH 2 CH 2 Z
/ \ffi/ ZH /
R— N ► N — > R— N
K \ (~Cl e ) / \ (-H®) K \
CH 2 CH 2 C1 R CH 2 CH 2 C1 CH 2 CH 2 C1
[2]
by the neighboring amino group and the resulting ion rapidly alkylates an
amino or hydroxy lie compound (ZH). Alkylating agents react with many
cellular constituents but there is evidence to suggest that reaction with
deoxyribonucleic acid (DNA; Section 17-6) is the biologically important
process.
The name nitrogen mustards arises from the structural resemblance of
these compounds to the toxic agent mustard gas S(CH 2 CH 2 C1) 2 , and some of
them share its vesicant (blistering) action on the skin. The nitrogen mustards
contain two chloroethyl groups and both can undergo displacement, each
reaction being aided by the neighboring amino group. It is significant that
almost all the alkylating agents that exhibit tumor-inhibiting properties con-
tain two or more alkyl groups, suggesting that some form of cross-linking
process takes place within the cell.
Some of the more successful chemotherapeutic agents are chlorambucil [3],
used extensively in treating chronic lymphocytic leukemia, and merophan [4].
CH,CH 2 C1
I
N— CH 2 CH 2 C1
C,CH 2 CH 2 ^ = ^ /=(
N-^ J>-CH 2 CH 2 CH 2 C0 2 H <( ^-CH 2 CHC0 2 H
C1CH 2 CH 2 NH 2
[3] [4]
Merophan has been used successfully in the treatment of Burkitt's lymphoma,
a disease which mainly affects children in parts of Africa and which is often
curable by chemotherapy alone.
2. The Beckmann and Related Rearrangements. Rearrangement of oximes of
ketones (Table 1 1 -4) by the action of concentrated sulfuric acid often pro-
vides a useful synthesis of amines through formation of intermediates with
positive nitrogen called nitrenium ions. 1 This reaction is called the Beckmann
rearrangement. The nitrenium ion has only a fleeting existence at best and,
indeed, may not be a true intermediate at all. The departure of the water
molecule from the protonated oxime is probably accompanied by the 1 ,2-shift
1 A more appropriate name for such an ion might be nitronium ion, analogous to car-
bonium ion, but this term is already in use for the species N0 2 ®.
chap 16 organic nitrogen compounds 430
of the R group from the carbon to nitrogen. The amide is not usually hy dro-
ll OH R OH 2
\ / H,S0 4 \ /
C=N > C=N
/ /
R R
-H 2
R— CO,H + RNH,
H 2 Q
© e
H(OH)
o
II
R— C-NH— R *
H 2
R
R
\ e
C=N:
a nitrenium
ion
R-C=N-R
lyzed under the conditions of the reaction. If the amine is desired, a separate
hydrolysis step has to be carried out. The Beckmann rearrangement is often
conducted using phosphorus pentachloride instead of sulfuric acid.
Three other reactions that proceed by way of neutral intermediates possess-
ing electron-deficient nitrogen and also give amines are the Schmidt, Curtius,
and Hofmann reactions, shown in that order (the influence of late nineteenth
century German chemists is seen in the number of reactions that bear their
names).
R-C
O
OH
O
R— C
\
HN 3
H 2 SO*
NHNH 2
O
R— C + Br 2 + NaOH
HNO
\
NH,
♦ N 2 +
O
R-C
N:
-♦ R— N=C=0
H 2
RNH 2 + C0 2
3. Formation of Amines by Reduction. Excellent procedures are available
for preparation of primary, secondary, and tertiary amines by the reduction
of a variety of types of nitrogen compounds. Primary amines can be obtained
by hydrogenation or lithium aluminum hydride reduction of nitro compounds,
azides, oximes, nitriles, and unsubstituted amides.
RCH=NOH
RC=N
O
//
RC
\
NH,
LiAlH*
(or cat. H 2 )
* RCH,NH 2
sec 16.1 amines 431
Some care has to be exercised in the reduction of nitro compounds since
reduction is highly exothermic. For example, the reaction of 1 mole (61 g)
of nitromethane with hydrogen to give methylamine liberates sufficient heat
to raise the temperature of a 25-lb iron bomb by 100°.
► CH 3 NH, +2H,0 Aff=-85kcal
Secondary and tertiary amines, particularly those with different R groups,
are advantageously prepared by lithium aluminum hydride reduction of
substituted amides (Section 13-8).
F. REACTIONS OF AMINES
1. With Acids. The formation of salts from amines and acids is the most
characteristic reaction of amines, and, since amines are usually soluble in
organic solvents, amines are often very useful when a mild base is required for
a base-catalyzed reaction or when it is desirable to tie up an acidic reaction
product. Pyridine has excellent properties in this regard, being a tertiary amine
with a K B of about 10~ 9 , reasonably volatile (bp 115°), and soluble in both
water and hydrocarbons. When a stronger base is required, triethylamine is
commonly used. The strengths of various amines as bases were considered in
Section 16- ID.
2. Acylation of Amines. The unshared electrons on nitrogen play a key role
in many other reactions of amines besides salt formation. In fact, almost all
reactions of amines at the nitrogen atom have, as a first step, the formation of
a bond involving the unshared electron pair on nitrogen. A typical example is
acylation, wherein an amide is formed by the reaction of an acid chloride, an
anhydride, or an ester with an amine (Section 13-8). The initial step in these
reactions is as follows, using benzoyl derivatives and methylamine as illus-
trative reactants.
e
=± C 6 H 5 -C-X
H,N-CH
O
II
X = halogen, -0-C-C 6 H 5 or -OR
The reaction is completed by loss of a proton and elimination of X e .
r o e o
1 -H® H P --X e II
: 6 H 5 -C-X ^ C 6 H 5 -C-X ^ - C 6 H 5 -C-NHCH 3
H 2 N— CH 3 HN— CH,
A serious disadvantage to the preparation of amides through the reaction
chap 16 organic nitrogen compounds 432
of an amine with an acid chloride (or anhydride) is the formation of 1 mole of
amine salt for each mole of amide. This is especially serious if the amine is the
O O
II II H e e
CH 3 -C— CI + 2 RNH 2 ► CH 3 — C— N— R + RNH 3 CI
expensive ingredient in the reaction. In such circumstances, the reaction is
usually carried on in a two-phase system with the acid chloride and amine in
the nonaqueous phase and sodium hydroxide in the aqueous phase. As the
amine salt is formed and dissolves in the water, it is converted to amine by the
sodium hydroxide and extracted back into the nonaqueous phase. This
© e © e ® e
RNH 3 Cl + NaOH ► RNH 2 + Na CI + H 2
procedure requires an excess of acid chloride, since some of it is wasted by
hydrolysis.
3. Amines with Nitrous Acid. Nitrous acid reacts with all amines, but the
nature of the products depends very much on whether the amine is primary,
secondary, or tertiary. Indeed, aqueous nitrous acid is a useful reagent to
distinguish these compounds. Thus, with primary amines, nitrous acid
evolves nitrogen gas; with secondary amines, an insoluble yellow liquid or
solid N-nitroso compound (R 2 N— N=0) separates; tertiary amines dis-
solve in and react with aqueous nitrous acid without evolution of nitrogen,
usually to give complex products. These reactions are of little preparative
value with many aliphatic amines because mixtures of products result. With
aromatic amines such as aniline, however, the reaction with nitrous acid is
extremely useful (Section 22-6).
4. Halogenation. Primary amines in the presence of base react with hypo-
chlorous acid [or f-butyl hypochlorite, (CH 3 ) 3 C— OC1] to produce both
mono- and disubstitution products :
H CI
DXIU C ' 2 ' R-N-Cl —^ R-N-Cl
2 OH e OH 6
Secondary amines give mono-N-haloamines. These substances are rather
weak bases, K B ~ 10" 13 ; they are not very stable and are oxidizing agents.
They hydrolyze in water, particularly in acid solution, to regenerate the
halogen.
R 2 NC1 + HC1 ► R 2 NH + C1 2
5. Oxidation of Amines. Oxidation with permanganate. Potassium per-
manganate and most other strong oxidants oxidize amines in much the same
way that they oxidize alcohols, giving aldehydes, ketones, or carboxylic
acids. It should be remembered that the terms primary, secondary, and
tertiary mean different things when applied to alcohols and amines. A
sec 16.1 amines 433
secondary alcohol, for example, is an alcohol with one hydrogen atom on the
alcoholic carbon atom (R 2 CHOH); a secondary amine is an amine with one
hydrogen on the nitrogen atom, R 2 NH. We should focus our attention on the
alkyl groups in the two cases; a primary alkyl group, whether attached to
—OH, — NH 2 , — NHR, or — NR 2 , will give an aldehyde or carboxylic acid
on oxidation:
[O]
-► R-C
primary alcohol RCH 2 OH
primary amine RCH 2 NH 2
secondary amine RCH 2 NHCH 3
tertiary amine RCH 2 N(CH 3 ) 2
A secondary alkyl group will give a ketone :
secondary alcohol R 2 CHOH
primary amine R 2 CHNH 2
secondary amine R2CHNHCH3
tertiary amine R 2 CHN(CH 3 )
[O]
■* R-C
O
OH
[O]
+ R 2 C=0
The amino nitrogen in the above reactions is converted largely to ammonia.
A tertiary alcohol is not oxidized unless the conditions are drastic enough
to cleave a carbon-carbon bond; a tertiary alkyl group in an amine is likewise
stable. In this case, however, the amino group succumbs slowly and it is often
possible to obtain high yields of the nitro compound :
(CH 3 ) 3 C-NH 2
r-butylamine
KMnd
(CH 3 ) 3 C-N0 2
2-nitro-2-methylpropane
83%
A compound such as (CH 3 ) 3 C— N(CH 3 ) 2 will be demethylated by per-
manganate by rapid oxidation of the two methyl groups, producing even-
tually two moles of C0 2 .
Acid helps protect amines from oxidation by tying up the pair of electrons
on nitrogen and this is a matter of some importance because many common
oxidizing agents, such as Cr VI , are vigorous oxidants only in acid solution.
Permanganate oxidations, however, do not require acid catalysis and amines
are readily oxidized by this reagent in basic solution.
Oxidation with peracids. Oxidation of tertiary amines by peracids gives
amine oxides. Thus, triethylamine can be oxidized with peracetic acid to
triethylamine oxide:
CH,CH 2
\
— f
/
O
\
CH 3 CH 2 o
\e e /
-» CH 3 CH 2 -N-0 + CH 3 C
/ \
CHXH, OH
CH 3 CH 2 O-OH
Peracids are excellent donors of oxygen atoms to amines (and alsotoalkenes;
chap 16 organic nitrogen compounds 434
see Section 4-4G) because bond breaking in the transition state is accompanied
by bond formation, and high-energy intermediates are thus avoided:
Ah /
-c' | + :N-
A-H
(hydrogen bonded) , transition state
OH
/ B /
R-C + e O-N-
xX o
With secondary amines, peracids give hydroxylamines, presumably as the
result of rearrangement of the N-oxide :
r 2 NH > R 2 NH-0 ► R 2 NOH
Primary amines react similarly, but with an excess of peracid they go all
the way to the nitro compound, though the yields are only moderate.
Unlike amines, amine oxides would not be expected to undergo inversion
at the nitrogen atom, and the oxides from amines with three different R
groups should be resolvable into optically active forms. This has been realized
for several amine oxides, including the one from methylethylallylamine.
Amine oxides are one of the few types of organic nitrogen compounds that
do not have analogs in known inorganic nitrogen compounds. The inorganic
e e
model would be H 3 N— O, a surely unstable tautomer of hydroxy lamine,
H 2 NOH.
16-2 amides
An understanding of the chemistry of simple amides is particularly important
because peptides and proteins, substances that are fundamental to all life
as we know it, are polyamides.
o o
// //
-c -c
\ \
NH 2 NR 2
simple amide N,N-disubstituted amide
An important characteristic of the amide group is its planarity — the carbon,
oxygen, nitrogen, and the first atoms of the R groups of an N,N-disubstituted
amide all lie in the same plane. This planarity can be regarded as reflecting the
importance of the following type of resonance in the amide group :
sec 16.2 amides 435
o o e
/ /
R-C „ < ► R-C
\ ,R \©/R
N N
II
R R
Coplanarity is required if the dipolar structure is to be significant. The
stabilization energy of acetamide is 1 1 kcal/mole, a value typical of most
amides.
A. PHYSICAL AND SPECTRAL CHARACTERISTICS OF AMIDES
The amides have rather high melting and boiling points as a result of extensive
intermolecular hydrogen bonding. Formamide is the only simple amide that
is liquid at room temperature. Acetamide (mp 82°, bp 222°) has melting and
boiling points far above the values for acetic acid (mp 17° and bp 118°), which
has almost the same molecular weight. Disubstituted amides such as N,N-
dimethylacetamide have lower boiling and melting points because of the
absence of hydrogen bonding.
O o O
J // //
H-C CH 3 -C CHj-C
NH 2 NH 2 N(CH 3 ) 2
formamide acetamide N,N-dimethylacetamide
(methanamide) (ethanamide) (N,N-dimethylethanamide)
mp 2° mp 82° mp -20°
bp 193° bp222° bp 165"
Considerable information is available on the infrared spectra of amides. By
way of example, the spectra of three typical amides with different degrees of
substitution on nitrogen are shown in Figure 16-3.
As we might expect, a strong carbonyl absorption is evident in the spectra
of all amides, although the frequency of absorption varies slightly with the
structure of the amide. Thus, unsubstituted amides generally absorb near
1690 cm" 1 , whereas mono-N-substituted and di-N-substituted amides
absorb at slightly lower frequencies. The N— H stretching frequencies of
amides are close to those of amines and show shifts of 100 to 200 cm -1 to
lower frequencies as the result of hydrogen bonding. Unsubstituted amides
have two N — H bands of medium intensity near 3500 and 3400 cm" 1 ,
whereas monosubstituted amides, to a first approximation, have only one
N— H band near 3440 cm -1 .
The nmr resonance of the N — H protons of amides are usually somewhat
different from any we have discussed so far. Customarily, these will appear as
a quite broad ragged singlet absorption which may turn to a broad triplet at
high temperatures. A typical example is shown by propanamide (Figure
16-4). The reason for this is associated with the special nuclear properties of
14 N, the abundant isotope of nitrogen. When the 14 N is replaced by 15 N, the
chap 16 organic nitrogen compounds 436
-~\
* (II CH 4 C— NH 2
wavelength, jX
6 7
Y|[^ h\clnii;i-n-
T Ixmcl.il N— H
1 1 i i i ,l ;
3600 3200 2800 1400 2000 2000
1800 1600
frequency, cm
_1 i lJ
1400 1200 1000 800
wavelength, /X
3 4 5
5 6 7
8
p-
(Y
1 1
9
~ I —
v
10 12 14
1 1 1
1 I
1 1 1
~Vvv
If
H!/ '
iji/
a
o
S
=
a i
I r °
J ' CH.,C— N
/■v. H
/ ^ I..TC
■hi
*=/ Ml
yen- bonded
A
II A
. ■ !
/ li i '
1 UK
1 II I
HI
1 '
I
free N-H
nmMmHH
=() slM-tdi — n ! Ij
1 'I
1 ij
I
i i i i i
1 , - , L .J/ f -^ B j
1
(
3600 3200 2800 2400 2000
2000 1800 1600 , 1400
frequency, cm
1200
1 000 800
wavelength, jU
3
4 5
5 6 7.
8 9
10
12 14
w
' 1
1 1
1 j
1 1
gMMMfef
lllllllilip
1 1 1
~**~\1 " — V
V / 1 M
\ A
i ,i
if- 1
y^~
lliiliiilllllll
i
1
1 11
ii-
O GH, A :'
II / hi
CH. . • 1
Mi
if* 1 ' i
II i
11 jl
f
1
1
1
. "■ \ L
a
(. <) stretch '*— ***!"| ] .■;■• . 1
. 1
1 1 1
•
W * f .' U t - 4 •' t • (
t ,
^i L ' « -
3600 3200 2800
2400 2000
2000 1800 1600 _, 1400
frequency, cm
1200
1000
800
sec 16.2 amides 437
<- Figure 16-3 Infrared spectra of propanamide, acetanilide, and N,N-
dimethylformamide in chloroform solution. Note the appearance of both free
NH bands (sharp, 3300-3S00 cm" 1 ) and hydrogen-bonded N-H bands
(broad, 3100-3300 cm -1 ) for unsubstituted and monosubstituted amides.
lines become completely sharp. A more detailed explanation of this behavior
is beyond the scope of this book.
The ultraviolet spectra of amides generally resemble those of carboxylic
acids.
In general, the amide group is reasonably polar and the lower-molecular-
weight amides are reasonably high melting and water soluble as compared to
esters, amines, alcohols, and the like. N,N-Dimethylformamide and N-
methylpyrrolidone have excellent solvent properties for both polar and non-
polar substances.
O / CH 3
H-C— N(CH 3 )
3'2
a
N, N-dimethylformamide N-methylpyrrolidone
(N-methyl-y-butyrolactam)
Amides with N— H bonds are weakly acidic, the usual K HA being about
10
-16
CH 3 -C
\
NH,
P
NH NHJ
Amides, then, are far more acidic than ammonia with K HA ~ 10 33 , and
this reflects a very substantial degree of stabilization of the amide anion.
Figure 16-4 Nuclear magnetic resonance spectrum of propanamide, CH 3 CH 2 -
CONH 2 , in chloroform solution (solvent not shown) at 60 MHz relative to
TMS at 0.00 ppm.
ppm
chap 16 organic nitrogen compounds 438
However, amides are still very weak acids and, for practical purposes, are to
be regarded as essentially nonacidic in aqueous solutions.
The degree of basicity of amides is very much less than that of aliphatic
amines. For acetamide, K B is about 10~ 15 (the K BHS of the conjugate acid is
~10) and acetamide is " half-protonated " in 1 M sulfuric acid.
NH,
H,0
o
//
CH 3 — C
\e
NH 3
e
+ OH
OH
/
CH,— C
e
+ OH
NH 2
The proton can become attached either to nitrogen or to oxygen. Nitrogen
is, of course, intrinsically more basic than oxygen, but formation of the
N-conjugate acid would cause loss of all the resonance stabilization energy of
the amide. Infrared and nmr studies of amide cations reveal that the O-
protonated form predominates; the equilibrium between the two is established
so rapidly, however, that the JV-protonated form appears to serve as an inter-
mediate in some reactions.
B. PREPARATION OF AMIDES
Two of the three reactions given below have been discussed in some detail
earlier. The third, hydrolysis of nitriles, has been met previously only as a
means of preparing carboxylic acids.
1. Reaction of esters, acyl chlorides, or anhydrides with ammonia or
amines (Section 13-8).
p o
R-C^ + NH 3 > R-C + EtOH
OEt NH 2
P °
R-C + 2NH 3 > R-C + NH?Cl e '
CI NH 2
P
P
O + 2NH 3 ► R-C
/ \
R ~ C XX NH 2
O
If primary or secondary amines are used in place of ammonia, N-substituted
amides result.
p o
CH 3 -C + 2CH 3 NH 2 CH 3 -C + CH 3 NHf CI e
CI NHCH 3
N-methylacetamide
sec 16.2 amides 439
2. Beckmann rearrangement of oximes (Section 16TE2).
R2 C=NOH ^^ RC^R -^ R-/
\
NHR
N-Substituted amides are formed ; hydrolysis beyond the amide stage gives an
amine and a carboxylic acid.
3. Hydrolysis of nitriles.
O
dhs //
R-C=N + H 2 2 > R-C + J0 2
NH 2
Nitriles can be hydrolyzed to amides in strongly acidic or basic solution but a
better method is to use hydrogen peroxide in mildly basic solution, thus
avoiding further hydrolysis of the amide to the carboxylic acid. The effective-
ness of hydrogen peroxide can in part be traced to the very high nucleophilicity
of the hydroperoxide anion H0 2 e , compared to the hydroxide ion itself
(see Exercise 16-24).
C. REACTIONS OF AMIDES
In general, amides can be hydrolyzed in either acid or base solutions although
the reactions are usually slow. The mechanisms are much like that of ester
hydrolysis (Section 13-8).
Amides can be converted to amines by reduction (Sections 13-8 and 16TE3),
or by the Hofmann hypobromite reaction (Section 16TE2). In the latter case
the amine that is formed has one less carbon atom than the amide :
O UAIH4 .» RCH,NH,
R-C
\
NH > nSh* RNHa
NaOH
D. IMIDES
Imides are N-acyl amides. Unlike amides they are considerably ionized in
aqueous solution (p^ H A ~ 9) as a result of effective charge dispersal in the
anion.
00 OO
11 II k ffl I: • il
R-C^ /C-R « H ffi + R-C- e .X-R
N ^N
I
H
an imide
Examples of cyclic imides are succinimide [5] (succinic acid is 1,4-butanedioic
chap 16 organic nitrogen compounds 440
acid) and the compound [6]. The common name of [6] is thalidomide, the
drug which attained notoriety when its unforeseen teratogenic (fetus-deform-
ing) properties were discovered.
o
o
9 H
//
ll
ll /
H,C-C
sO*^
c
C— N
1 \
r
if x
/ \
NH
N-
-HC C=0
1 /
^w
^/
V /
H 2 C-C
^^
C
H 2 C— CH 2
\
II
O
o
[5] [6]
16-3 nitriles
The carbon-nitrogen triple bond differs considerably from the carbon-carbon
triple bond by being stronger (213 kcal vs. 200 kcal) and much more polar.
Liquid nitriles have rather high dielectric constants compared to most organic
liquids and are reasonably soluble in water.
Nitriles absorb in the infrared in the region 2000 to 2300 cm -1 , owing to
stretching vibrations of the carbon-nitrogen triple bond.
The preparation of nitriles by S N 2 reactions of alkyl or allyl halides with
cyanide ion has been mentioned before (Section 8-7), and this is the method
of choice where the halide is available and reacts satisfactorily. Other useful
syntheses involve cyanohydrin formation (Section 11-4A) or dehydration of
the corresponding amide.
The reduction of nitriles to amines and the hydrolysis of nitriles to amides
have been discussed earlier (see Sections 16-1E3, 13-8, and 16-2B).
Hydrogens on the a carbons (C-2) of nitriles are about as acidic as the
hydrogens a to carbonyl groups; accordingly, esters of cyanoacetic acid
undergo many reactions similar to those of the esters of malonic and aceto-
acetic acids (Section 13-9C). The a positions of nitriles can be alkylated with
alkyl halides by processes like the following:
CH 3 CH 3
H CH 3
66%
16'4 nitroso compounds
Although C-nitroso compounds, R— N=0, have no special synthetic
importance at present, they do possess some interesting properties. Primary
sec 16.5 nitro compounds 441
and secondary nitroso compounds are unstable and rearrange to oximes.
H C H CH 3 OH
C — C = N
H 3 C / N N=0 CH 3
2-nitrosopropane
Tertiary and aromatic nitroso compounds are reasonably stable substances,
which, although usually blue or green in the gas phase or in dilute solution,
are isolated as colorless or yellow solids or liquids. The color changes are
due to dimerization.
e O O
I II
2R— N=0 . R— N— N— R
©
(green or blue) (yellow or orange)
16-5 nitro compounds
Nitro compounds make up a very important class of nitrogen derivatives.
The nitro group (— N0 2 ), like the carboxylate anion, is well formulated as a
hybrid of two equivalent resonance structures.
O O e O ie
<$>// <&/ mv
R _ N < > R _ N or R _ N
The hybrid structure is seen to have a full positive charge on nitrogen and a
half-negative charge on each oxygen. The polar character of the nitro group
results in lower volatility of nitro compounds than ketones of about the
same molecular weight; thus the boiling point of nitromethane (mol. wt. 61)
is 101°, whereas acetone (mol. wt. 58) has a boiling point of 56°. Surprisingly,
the water solubility is low; a saturated solution of nitromethane in water is
less than 10% by weight, whereas acetone is infinitely miscible with water.
Nitro groups of nitroalkanes can be identified by strong infrared bands at
about 1580 and 1375 cm -1 , whereas the corresponding bands in the spectra
of aromatic nitro compounds occur at slightly lower frequencies. A weak
transition occurs in the electronic spectra of nitroalkanes at around 2700 A;
aromatic nitro compounds, such as nitrobenzene, have extended conjuga-
tion and absorb at longer wavelengths (~3300 A).
Nitro compounds are quite unstable in the thermodynamic sense and the
heat of decomposition of nitromethane, according to the following stoichio-
metry, is 67.4 kcal/mole :
CH 3 N0 2 ► |N 2 + C0 2 +fH 2 AH= -67.4 kcal
The rate of decomposition under ordinary conditions is immeasurably slow,
however, and pure nitromethane is a stable, easily handled, compound. On
chap 16 organic nitrogen compounds 442
the other hand, some polynitro compounds, such as tetranitromethane,
explode on shock and require very careful handling.
2,4,6-Trinitrotoluene (TNT) is not set off easily by simple impact and is
used in high-explosive shells. However, once set off, TNT explodes violently.
0,N
N0 2
2,4,6-trinitrotoluene
The characteristics of reasonable handling stability and high thermodyna-
mic potential make the chemistry of nitro compounds particularly interesting
and useful.
Nitro compounds can be prepared in a number of ways, including the direct
substitution of hydrocarbons with nitric acid. This reaction was discussed
RH + HON0 2 ► RN0 2 + H 2
earlier (Section 3-3B) in connection with the nitration of alkanes, and it was
there noted that reaction is successful only when conducted at high tempera-
tures in the vapor phase. Mixtures of products are invariably obtained. Direct
nitration of aromatic compounds such as benzene, in contrast, takes place
readily in the liquid phase. The characteristics of aromatic nitration are
discussed in Chapter 22.
Other routes to aliphatic nitro compounds include the reaction of an
alkyl halide (of good S N 2 reactivity) with sodium nitrite. Suitable solvents are
dimethyl sulfoxide and dimethylformamide. As can be seen below, formation
of the nitrite ester by O- instead of N-alkylation is a competing reaction.
CH 3 (CH 2 ) 6 Br + NaN0 2 ► CH 3 (CH 2 ) 6 N0 2 + CH 3 (CH 2 ) 6 ONO
60% 30%
Tertiary nitro compounds may be prepared by the oxidation of the corre-
sponding amine with aqueous potassium permanganate solution (Section
16-1F5).
Nitro compounds are readily reduced to amines (Section 16TE3) and this
offers a particularly useful synthesis of aromatic amines, as will be discussed
in Chapter 22. Most aliphatic amines are more easily prepared other ways.
16-6 some compounds with nitrogen-nitrogen bonds
There are a number of important compounds containing nitrogen-nitrogen
bonds. Among these are hydrazines, azo and diazo compounds, and azides.
A. HYDRAZINES
Organic hydrazines are substitution products of NH 2 — NH 2 and have many
properties similar to those of amines in forming salts and acyl derivatives as
sec 16.6 some compounds with nitrogen-nitrogen bonds 443
well as undergoing alkylation and condensations with carbonyl compounds
(Table 11-4). Unsymmetrical hydrazines can be prepared by careful reduction
of N-nitrosoamines.
CH 3 CH 3 CH 3
\ \ 2 H 2 \
NH+HONO > N — NO ► N-NH,
/ / /
CH 3 CH 3 CH 3
Aromatic hydrazines are best prepared by reduction of aromatic diazonium
salts (Chapter 22). H H
I I
Hydrazines of the type R— N— N— R are usually easily oxidized to the
corresponding azo compounds, R— N=N— R.
B. AZO COMPOUNDS
Azo compounds possess the — N=N— grouping. Aliphatic azo compounds
of the type R— N=N— H are highly unstable and decompose to R — H and
nitrogen. Derivatives of the type R— N=N— R are much more stable and
can be prepared as mentioned above by oxidation of the corresponding hydra-
zines. Aromatic azo compounds are available in profusion from diazonium
coupling reactions (Chapter 22) and are of commercial importance as dyes
and coloring materials.
A prime characteristic of azo compounds is their tendency to decompose
into organic radicals and liberate nitrogen:
R-N=N-R ► 2R-+N 2
The ease of these reactions is usually a fairly reasonable guide to the stabil-
ities of the radicals that result. For instance, it is found that azomethane
(CH 3 N=NCH 3 ) is stable to about 400°, and azobenzene (C 6 H 5 N=NC 6 H 5 )
is also resistant to thermal decomposition; but, when the azo compound
decomposes to radicals that are stabilized by resonance, the decomposi-
tion temperature is greatly reduced. Thus 2,2'-azobis(2-methylpropano-
nitrile) decomposes to radicals at moderate temperatures (60° to 100°), and
for this reason is a very useful agent for the initiation of polymerization of
vinyl compounds.
CN CN CN
CH 3 — C — N=N— C— CH 3 6Q °~" )0 °> 2CH 3 — C-+N,
I I I
CH 3 CH 3 CH 3
2,2-azobis(2-methylpropanonitrile)
C. DIAZO COMPOUNDS
e e
The parent of the diazo compounds, diazomethane CH 2 =N=N, has been
mentioned before in connection with formation of carbenes (Section 9-7).
It is one of the most versatile and useful reagents in organic chemistry, despite
the fact that it is highly toxic, dangerously explosive, and cannot be stored
without decomposition.
chap 16 organic nitrogen compounds 444
Diazomethane is an intensely yellow gas, bp —23°, which is customarily
prepared and used in diethyl ether or methylene chloride solution. It can be
synthesized a number of ways, such as by the action of base on an N-nitroso-
N-methylamide.
o
R-C + NaOH ether > R-C0 2 Na + CH 2 N 2 + H 2
N— CH 3
I
NO
As a methylating agent for moderately acidic substances, diazomethane
has nearly ideal properties. It can be used in organic solvents ; it reacts very
rapidly without need for a catalyst; the coproduct is nitrogen, which offers
no separation problem; it gives essentially quantitative yields; and, because
of its color and the appearance of bubbles of nitrogen, it acts as its own indi-
cator to show when reaction is complete. With acids it gives esters and with
enols it gives O-alkylation.
\S~<\ +CH 2 N 2 ► \/~ C \ +N 2
X==/ OH X=/ OCH 3
O O OCH 3 O
I II I II
CH,-C ,C-CH, + CH 2 N 2 ► CH 3 — C C— CH 3 + N 2
CH CH
Diazomethane was originally believed to possess the three-membered,
diazirine ring structure, but this was disproved by electron-diffraction studies,
which show the linear structure to be correct.
H 2 C II
N
CH 2 =N=N
diazirine
diazomethane
Recently, a variety of authentic " cyclodiazomethanes " or, more properly,
diazirines have been prepared, and these have been found to have very
different properties from the diazoalkanes. The simple diazirines are colorless
and do not react with dilute acids, bases, or even bromine. The syntheses of
these substances are relatively simple. The route shown is one of the several
possible ones.
R R NH R N
\ \ /\ Cl-Oj \ /ll
C=0 + NH 3 + NH 2 C1 ► C > C
/ 32 / \l / \ll
R 7 R NH R N
an " isohydrazone "
summary
Organic nitrogen compounds include amines (RNH 2 ), amine salts
(RNH 3 ®X e ), amides (RCONH 2 ), nitriles (RC=N), isocyanates (RNCO),
summary 445
hydrazines (RNHNHR), azo compounds (RN=NR), diazo compounds
(RCHN 2 ), azides (RN 3 ), nitroso compounds (RNO), and nitro compounds
(RN0 2 ).
Amines are associated by hydrogen bonding to a moderate extent and as a
result they are more volatile than hydrocarbons but less volatile than alco-
hols of the same molecular weight. However, amines are more soluble in
water than alcohols because they form strong hydrogen bonds with the
protons of hydroxylic compounds. Amines, like ammonia, undergo rapid
inversion at nitrogen. Aliphatic amines are weak bases (K n ~ 10~ 4 ) and are
very' feeble acids (K HA ~ 10" 33 ).
Amines can be prepared as illustrated.
RNO,
-» RNH 2
O
II
RCNH,
RCH,NH,
RX R 2 C=NOH RC^N
*Hofmann reaction (see also Schmidt and Curtius reactions)
RCH=NOH
Some of the reactions of amines are
RCH 2 NH 2
RCH 2 NH 3 ®
O
(with acids)
> RCH 2 NHCCH 3 (with acetyl halides)
► N 2 + complex products (with nitrous acid)
> RCHO ► RC0 2 H (with oxidants like Mn™; f-alkyl
amines give nitro compounds)
► RCH 2 N0 2 (with peracids; secondary amines give
oximes, tertiary amines give amine oxides)
Amides have high melting and boiling points as a result of strong hydrogen
bonding. They absorb in the infrared near 3400 cm -1 (N— H stretch) and
near 1690 cm -1 (C=0 stretch). They are weak acids (K HA ~ 10~ 16 ) and
weak bases (K B ~ 10~ 15 ). Their preparations and reactions are summarized
here.
II
RCOCH3
II
N.
O
II
RCNH 2
^ RC^N
.
(RCO) 2
^
^ R 2 C=NOH
w
ICNH 2
RC0 2 H
y
RNH 2
»
RCH 2 NH 2
chap 16 organic nitrogen compounds 446
Nitriles are rather polar compounds with moderate water solubility. The
cyano group activates an adjacent methylene like a carbonyl group. Nitriles
absorb in the infrared near 2200 cm -1 (C=N stretch). Some methods of
preparation and reactions of nitriles are summarized.
O
II
RX > RC^N < RCNH 2 RCHO ► RCHOHC=N
O
II
RC=N ► RCNH 2 ► RCO z H
^"~-* RCH 2 NH 2
Nitro compounds absorb strongly in the infrared near 1580 cm -1 and
1375 cm -1 . Polynitro compounds are often explosive. Nitro compounds can
be prepared by nitration of hydrocarbons (works best with arenes) or by the
route RX + N0 2 e -» RN0 2 + X e .
Azo compounds can be prepared by oxidation of their dihydro derivatives
(hydrazines). They are used as sources of radicals (RN==NR -+N 2 +2R-).
Diazo compounds also tend to lose N 2 and the simplest of them, CH 2 N 2
(diazomethane), is an excellent methylating agent for carboxylic acids and
enols.
exercises
16-1 Provide a suitable name for each of the following compounds :
a. H 2 N(CH 2 ) 7 NH 2 g. H 2 NCH 2 C0 2 H
b. (CH 3 ) 2 CHC N h. H 2 NCH 2 CH 2 NH 3 Cl e
NHCH
c. C 6 H 5 CHC1CHC1CN /, /"A-j/
d. (CH 3 ) 3 CCH 2 N0 2 ~ CH 2 CH 3
e. CH 2 =CHN(CH 3 ) 3 Br e J- I /^~ CH 3 l °
\
f. (HOCH 2 CH 2 ) 3 N
16-2 How could you show with certainty that the peak at 47 Hz with reference to
tetramethylsilane in the nmr spectrum of diethylamine (Figure 6-2) is
actually due to the N— H resonance?
16-3 Show how structures can be deduced for the substances (a) and (b) of
molecular formulas C 8 HnN, whose nmr and infrared spectra are shown in
Figure 16-5.
... —
■_
o
- o
04 •
tipliiillpii
1 J
^^^^^B
6
S
Q
" 2
l
V
u
o
"3
S
/^
"8
C
a
3
Q-
E
o
y
chap 16 organic nitrogen compounds 448
16-4 Guanidine (K B ~ 1) is a very strong base and an exception to the generaliza-
tion that unsaturated amines are weaker bases than saturated amines.
Consider various ways of adding a proton to guanidine and the kind of
changes in stabilization energies which would be expected for each.
/
HN=C . guanidine
NH 2
16-5 Write equations for the reaction that occurs when each of the following
compounds is refluxed with an excess of aqueous sodium hydroxide.
a. heptanamide
b. N-chlorocyclohexylamine
c. allyl 2,3-dimethylbutanoate
d. heptanonitrile
16-6 Write equations for the reaction that occurs when each of the following
compounds is treated with an excess of lithium aluminum hydride and the
resulting mixture decomposed with water and acid.
a. diphenylacetonitrile
b. 1,2-dinitrocyclopentane
c. diphenylacetic acid
d. 4-nitrohexanal
16-7 Write structures and provide names for the simplest amine and the simplest
nitrile that can be separated into stable optical isomers at room temperature.
16-8 Write equations for a practical laboratory synthesis of each of the following
compounds based on the indicated starting materials. Give reagents and
conditions.
a. dimethyl-?-pentylamine from 2-chloro-2-methylbutane
b. (CH 3 ) 3 CCH 2 NH 2 from (CH 3 ) 3 CC0 2 H
c. 1,6-diaminohexane from 1,3-butadiene
d. butanonitrile from 1-butanol .
e. (CH 3 C0 2 CH 2 ) 3 C-N0 2 from nitromethane
/. N-;-butylacetamide from f-butyl alcohol
g. methylethyl-M-butylamine oxide from «-butylamine
16-9 a. Make a chart of the mp, bp, and solubilities in water, ether, dilute
acid, and dilute base of each of the following compounds:
«-octylamine N,N-dimethylacetamide
di-«-butylamine 1-nitrobutane
tri-«-propylamine 2-nitro-2-methylbutane
b. Outline a practical procedure for separation of an equimolal mixture
of each of the above compounds into the pure components. Note that
selective reactions are not suitable unless the reaction product can be
reconverted to the starting material. Fractional distillation will not
be accepted here as a practical means of separation of compounds
boiling less than 25° apart.
exercises 449
16-10 Give for each of the following pairs of compounds a chemical test, preferably
a test tube reaction, which will distinguish between the two compounds.
a. (CH 3 ) 3 CNH 2 and (CH 3 ) 2 NC 2 H 5
b. CH 3 CH 2 N0 2 and CH 3 CONH 2
c. CH 3 CH 2 C=N and CHs=C-CH 2 NH 2
d. CH 3 CH 2 NHC1 and CH 3 CH 2 NH 3 C1
e. CH 3 OCH 2 CH 2 NH 2 and CH 3 NHCH 2 CH 2 OH
/. CH 3 CH 2 c' and CH 3 OCH 2 CH 2 NH 2
NH 2
16-11 Arrange the following pairs of substances in order of expected base strengths.
Show your reasoning.
a. (CH 3 ) 3 N and (CF 3 ) 3 N
b. V \-CH 2 NH 2 and CH 3 -f V" NH '
c. CH 3 C=N: and 4 N:
NH O
// //
H— C and H— C (review Exercise 16-4)
NH, NH 2
(review Section 6-7)
16-12 Using spectroscopic methods, how could you distinguish one isomer from
the other in the following pairs ?
CH 3
a. / V-NH 2 and / V-NHCH 3
O O
II II
b. CH 3 CH 2 -C-NH 2 and H~C-N(CH 3 ) 2
c. CH 3 CH 2 -N0 2 and CH 3 CH 2 -ONO
16-13 It is usually possible to obtain two different stable oximes from an unsym-
metrical ketone. These so-called syn and anti isomers are related to cis-trans
isomers of alkenes.
R OH R
\ / \
C=N C=N
/ / \
R' R' OH
(syn to R, anti to R') (syn to R', anti to R)
chap 16 organic nitrogen compounds 450
An important characteristic of these isomers is that they give different
products in the Beckmann rearrangement. In each case, the group anti to the
OH group migrates to nitrogen. Decide whether or not the mechanism
given in Section 16-1E2 for the Beckmann rearrangement can account for
this fact and, if not, how it might be modified to do so. What products
might be expected from the syn and anti forms of benzaldehyde oxime ?
16-14 Show how one could synthesize and resolve methylethylallylamine oxide
from allylamine with the knowledge that amine oxides are somewhat basic
substances having K B values of about 10"".
16-15 The proton nmr spectrum of N,N-dimethylformamide shows a single proton
resonance at 8.06 ppm and two separate three-proton resonance at 2.78 and
2.95 ppm at room temperature. At 150°, the two three-proton lines are
found to have coalesced to a single six-proton line, while the single-proton
line is unchanged. Explain the nmr spectrum of this compound and its
behavior with temperature. What would you predict the energy barrier
would be for the process by which the lines are caused to coalesce at elevat-
ed temperatures ?
16-16 Amides with structures like the following are difficult to prepare and are
relatively unstable. Explain.
16-17 Benzamidine [7] has a p^ B of 2.4, making it about 10 14 times as strong a
base as benzamide [8].
NH O
t t
C 6 H 5 -C^ C 6 H 5 -C^
NH 2 NH 2
[7] [8]
How do you account for this large difference in view of the fact that pro-
tonation produces a resonance-stabilized cation in both cases ?
16-18 Show how structures can be deduced for the two substances with the mo-
lecular formula C5H9NO3 and Ci H ]3 NO from their infrared and nmr
spectra, as given in Figure 16-6.
16-19 Nitriles of the type RCH 2 CN undergo an addition reaction analogous to
the aldol addition in the presence of strong bases such as lithium amide.
Hydrolysis of the initial reaction product with dilute acid yields a cyano-
O CN
II I
ketone, RCH 2 — C— CH— R. Show the steps that are involved in the
mechanism of the overall reaction and outline a scheme for its use to synthe-
size large-ring ketones of the type (CH 2 )„C=0 from dinitriles of the type
NC(CH 2 )„CN.
wavelength, jJL
8 9 10 12 14
~i 1 i ^t r
n \ !
M
*J'
i i i _j j _l_j
<- U — ^
J . 1 1 ,J L_
3600 3200 2800 2400 200O 2000 1800 1600 ,1400 1200 1000 800
frequency, cm
i
400
1
i
oil/
IIIIIIJ
'
i /--
c:..H,
NO
III|iIlI|illlll|i|iSlliillllli
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1 1
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1
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wavele
ngth, [X
6
7
8
9
10
12
14
i
1
1
1
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1
1
( : 1 1 \( )
_L_- J I i.
3600 3200 2800 2400 2000 2000
1800 1600 ,1400 1200
frequency, cm
1 000 800
'" 1
400
1
200
i
:, 11/
>
C H.No
; —
,
/~
■
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II:
1
1
— w
i
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■
»-
6.0 4.0 2.0 ppm 8.0 6.0 4.0 2.0
Figure 16-6 Infrared and nmr spectra of a substance C 10 H 13 NO and a substance C 5 H 9 N0 3 . See Exercise 1648.
o ppm
chap 16 organic nitrogen compounds 452
16-20 Show how the following substances may be synthesized from the indicated
starting materials.
a. (CH 3 ) 3 CCN from (CH 3 ) 3 CC1
b. CH 3 CH=CHCN from CH 2 =CHCH 2 Br
c. CH 2 =CHC0 2 HfromCH 3 CHO
16-21 Consider possible ways of formulating the electronic structures of nitroso
dimers with the knowledge that X-ray diffraction studies indicate the presence
of nitrogen-nitrogen bonds.
16-22 Show from the electronic structure of nitrite ion how it could react with an
alkyl halide in the S N 2 manner to give either a nitrite ester or a nitro com-
pound. What kind of properties would you expect for a nitrite ester and
how could they be removed from the reaction products ?
16-23 Arrange the following azo substances in order of their expected rates of
thermal decomposition to produce nitrogen. Give your reasoning.
a. I V-CH 2 -N=N-CH 2 ^ \ d. CH 3 -N=N-CH 3
b. (CH 3 ) 3 C-N=N-C(CH3)3 e - ILJJI
c. /\\-n=n
16-24 Nitriles are converted readily to amides with hydrogen peroxide in dilute
sodium hydroxide solution. The reaction is
P
RC=N + 2H 2 2 ° H > RC + 2 + H 2
NH 2
The rate equation is
e
v = /t[H 2 2 ][OH][RC=N]
When hydrogen peroxide labeled with ls O (H 2 ,8 2 ) is used in ordinary
water (H 2 1<s O), the resulting amide is labeled with ls O (RC I8 ONH 2 ).
Write a mechanism for this reaction which is consistent with all the
experimental facts. Note that hydrogen peroxide is a weak acid (K A ~ 10~ 12 )
and, in the absence of hydrogen peroxide, dilute sodium hydroxide attacks
nitriles only very slowly.
16-25 An amine, A, forms a precipitate with chloroplatinic acid of formula
(AH®) 2 PtCl 6 2e . A sample of 0.1834 g of this salt is found to contain 0.0644 g
of platinum. On treatment with nitrous acid the amine, A, gives an alcohol
which gives a positive iodoform test. What is the structure of A ?
16-26 The oxidation of an aldehyde to an acid and a secondary alkyl amine to a
ketone can be carried out as shown in the following equations, which ap-
exercises 453
pear to involve merely addition or removal of water. How do the oxidations
arise?
RCHO + H 2 NOH -^ RCH=NOH — ^+ RC=N -^^* RCONH,
+ H 2
RC0 2 H
HO
- R 2 C=N^}
o o
R 2 CHNH 2 + 0=/ \ ^ H2 °> R.CHNH^ J>
H 2
HO
16-27 Use bond energies (Table 2-1) to evaluate qualitatively the position of the
following equilibrium.
CH,=CH-NH 2 < ' CH,-CH=NH
1
V:VS 3
and "nucleic acids
chap 17 amino acids, proteins, and nucleic acids 457
The chemistry of life is largely the chemistry of polyfunctional organic com-
pounds. The functional groups are usually of types which interact rather
strongly and are often so located with respect to one another that both
intra- and intermolecular interactions can be important. Carbohydrates offer
one example, and we have seen how the alcohol and carbonyl functions
interact in these substances, leading both to the cyclization of the simple
sugars and to the formation of bonds between sugar molecules to give poly-
saccharides. This chapter is devoted to the chemistry of amino acids, pro-
teins, and nucleic acids.
Apart from water, protein is the principal component of muscle and many
other kinds of tissue. Nucleic acids, the substances which control heredity, are
just as widely distributed in living organisms although they are present in
smaller amounts. We shall see that both proteins and nucleic acids are poly-
meric materials built up with polyfunctional compounds as units. In proteins,
these units are amino acids and we shall begin with a discussion of their
chemistry.
17-1 amino acids
All the natural amino acids which occur as constituents of proteins are
carboxylic acids with an amino group at the a position (C-2), RCHNH 2 C0 2 H.
All, with the exception of the simplest one (glycine, R = H), have a center of
asymmetry at the a position and belong to the l series, corresponding to the
projection formula shown (see also Section 14-3B).
C0 2 H
I
H 2 N— C-H
I
R
L-amino acid
In the case of two amino acids, proline and hydroxyproline, the amino
group is secondary by virtue of being part of a ring. The structures and names
of these and other important a-amino acids are shown in Table 17-1. You
can see that the names in common use for amino acids are not very descriptive
of their structural formulas ; but they do have the advantage of being shorter
than the systematic names. As you will see later, the abbreviations Gly, Glu,
and so on listed in Table 17-1 are particularly useful in designating the se-
quences of amino acids in proteins and peptides. Amino acids that have an
excess of amine over acid groups are called basic amino acids (e.g., lysine and
arginine) ; those with an excess of acid groups are called acidic amino acids
(e.g., aspartic and glutamic acids). The additional amino or carboxyl groups
that these four amino acids possess and the functional groups that amino
acids such as serine possess are important in providing points of attachment
for other groups to the protein chain. These may be covalent, ionic, or
hydrogen-bond links.
Three of the amino acids listed in Table 17-1, cysteine, cystine, and methio-
nine, contain sulfur, and the making and breaking of S— S linkages in the
chap 17 amino acids, proteins, and nucleic acids 458
interconversion of cysteine and cystine are important processes in the bio-
chemistry of sulfur-containing peptides and proteins. Further characteristics
of the general reaction
[O]
2RSH . R-S-S-R
2[H]
are considered in Chapter 19.
Organisms differ considerably in their ability to synthesize amino acids.
The eight acids that are indispensable for human beings, yet which the body
cannot synthesize, are often called " essential " amino acids and are so marked
in Table 17T. Of the 24 amino acids listed in the table only 20 are fundamental
building blocks. The presence in proteins of the remaining four (see Table
17T) results from in vivo conversions of other amino acids after the protein
has been synthesized. Protein synthesis, both in vitro and in vivo, is considered
in more detail later in the chapter.
A. SYNTHESIS OF a-AMINO ACIDS
Many of the types of reactions useful in preparing amino acids in the labora-
tory have been discussed earlier in connection with separate syntheses of
carboxylic acids (Chapter 13) and amino compounds (Chapter 16). Two
examples are included here.
1 . Amination of chloroacetic acid to yield glycine, which works best with
a large excess of ammonia.
50° e ffl ® e
3 NH 3 + C1CH 2 C0 2 H ► NH 2 CH 2 C0 2 NH 4 + NH 4 C1
H©
NH 2 CH 2 C0 2 H
glycine
2. Strecker synthesis; in its first step, it bears a close relationship to cyano-
hydrin formation.
f VCHO + NH 3 + HCN ► / VCH-C = N H* B ,H 2 > / Y-CH— C0 2 H
NH 2 NH 2
Many amino acids are very soluble in water and it may be necessary to
isolate the product either by evaporation of an aqueous solution or by precip-
itation induced by addition of an organic solvent such as alcohol. Difficul-
ties are often encountered in obtaining a pure product if inorganic salts are
coproducts of the synthesis.
B. THE ACID-BASE PROPERTIES OF AMINO ACIDS
The behavior of glycine is typical of that of the simple amino acids. Since
glycine is neither a strong acid nor a strong base, we shall expect a solution of
sec 17.1 amino acids 4S9
Table 17-1 Amino acids important as constituents of proteins
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arginine
aspartic acid
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glutamic acid
glutamine
cysteine
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Asp
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NH 2
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I
NH 2
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I
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[H]
[O]
c= 1-2 g
HCl solut
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cystine" 1
CyS
CyS
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I 1
1 NH 2
S-CH 2 CHC0 2 H
per 100
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14-3A).
methionine'
Met
1
NH 2
CH 3 S(CH 2 ) 2 CHC0 2 H
3
NH 2
+21.8°
-6.7°
-7.4°
+ 17.7°
+ 9.2°
-20.0°
^509°
(1 iVHCl)
-14.9°
isoelectric
point,
pH units
water solubility at
isoelectric point,*
g/100 g, 20°
11.2
2.8
5.4
3.2
5.7
5.1
5.0
5.7
very sol.
0.4
2.4
0.7
3.6 1
very sol.
0.009
3.0
sec 17.1 amino acids 461
Table 17-1 (continued)
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1 Formed by conversion of the other amino acids after the protein has been synthesized.
' In ethanolic sodium hydroxide solution.
chap 1 7 amino acids, proteins, and nucleic acids 462
glycine in water to contain four species in rapid equilibrium.
NH 2 CH 2 CO,H
-H©
t-H©
NH 3 CH 2 C0 2
dipolar ion
(zwitterion)
-H©
+H©
NH 2 CH 2 C0 2
conjugate base
of glycine
NH 3 CH 2 C0 2 H
conjugate acid
of glycine
The proportions of these species are expected to change with pH, the con-
jugate acid being the predominant form at low pH values and the conjugate
base being favored at high pH values. Since the establishment of equilibrium
between the uncharged molecule and the dipolar ion (often called a " zwit-
terion") involves no net change in hydrogen or hydroxide ion concentrations,
the ratio of these two substances is independent of pH. The position of equi-
librium, however, strongly favors the zwitterion.
NH,CH 2 CO,H
NH,CH 2 C0 2
A titration curve starting with glycine hydrochloride is shown in Figure
17T. Two equivalents of base are required to convert ffi NH 3 CH 2 C0 2 H to
NH 2 CH 2 C0 2 e . The pH of half-neutralization during addition of the first
equivalent of base corresponds to proton loss from the carboxyl group of the
conjugate acid of glycine, K BK ® = 5 x 10~ 3 , whereas the pH of half-neutral-
ization during the addition of the second equivalent of base corresponds to
proton loss from the ammonium group of the zwitterion, K HA = 2 x 10~ 10 .
There will be a pH on the titration curve where the concentration of zwit-
terion is at a maximum and where the concentration of NH 3 CH 2 C0 2 H will
be just equal to the concentration of NH 2 CH 2 C0 2 e . If these two ions con-
duct electric current equally well, then, in an electrolytic experiment, there
Figure 17-1 Titration curve of the conjugate acid of glycine, NH 3 CH 2 C0 2 H,
with base.
PH
moles of OH
sec 17.1 amino acids 463
will be no net migration of the ions at this particular pH, which is called the
isoelectric point. Generally, the isoelectric point corresponds also to the pH
at which the amino acid's water solubility is least. Isoelectric points are
listed for most of the amino acids shown in Table 17-1.
Because the basic dissociation constant, K B , of most aliphatic amines and
the acid dissociation constant, K UA , of most aliphatic acids are comparable, we
expect the isoelectric point for simple amino acids like glycine to be not far
from neutrality. The value of 6.0 shown in Table 17-1 indicates that the car-
boxyl group in glycine is actually very slightly stronger than the amino group.
A basic amino acid such as lysine exists as a neutral molecule (actually an
equilibrium mixture containing one of the zwitterions as the principal
component) at a somewhat higher pH. The isoelectric point of this compound
is 9.7.
NH 2 CH 2 CH 2 CH 2 CH 2 CHC0 2 e ^zzr^ NH 3 CH 2 CH 2 CH 2 CH 2 CHC0 2
I I
NH 3 NH,
An acidic amino acid such as glutamic acid, by contrast, is only electrically
neutral in the presence of enough excess acid to prevent the second carboxyl
group from ionizing. Its isoelectric point is 3.2, which means that the electri-
cally neutral forms shown here are at their highest concentrations at this pH.
(The free amino or carboxyl groups in protein chains provide acidic or basic
centers in these molecules in addition to serving as points of attachment for
other groups.)
H0 2 CCH 2 CH 2 CHC0 2 e -^=-* ®0 2 CCH 2 CH 2 CHC0 2 H
I I
NH, NH,
C. ANALYSIS OF AMINO ACIDS
Nitrous Acid Reactions. The action of nitrous acid on amino acids pro-
ceeds in a manner similar to that discussed earlier for ordinary amines (Sec-
tion 16-1F3). Primary amino groups are lost as nitrogen; secondary amino
groups are nitrosated, whereas tertiary amino functions react to give complex
products without evolution of nitrogen. Measurement of the nitrogen evolved
on treatment of amino acids or their derivatives with nitrous acid provides a
useful analysis for free — NH 2 groups in such materials (Van Slyke amino-
nitrogen determination). With amino acids, as with amines, the nitrous acid
reaction is not to be regarded as a generally satisfactory preparative method
for conversion of RNH 2 to ROH.
The Ninhydrin Test. In many kinds of research it is important to have
simple means of detecting compounds in minute amounts. Detection of
a-amino acids is readily achieved by the " ninhydrin color test." An alcoholic
chap 17 amino acids, proteins, and nucleic acids 464
solution of the triketone hydrate called " ninhydrin," heated with a solution
containing an amino acid, produces a blue-violet color. The sensitivity and
reliability of this test is such that 0.01 micromole of amino acid gives a
colored solution whose absorbance is reproducible to a few percent, provided
that oxidation of the colored ion by dissolved oxygen is prevented by the
addition of a reducing agent such as stannous chloride.
o o
II II
c=o ;=± \ T C
II II
o o
indane-l,2,3-trione "ninhydrin"
The color-forming reaction is interesting because all amino acids except
Figure 17-2 The color-forming reaction of ninhydrin (in the trione form)
with an amino acid.
O
O
■H 2
^V C \ i
C=0 + RCH-C0 2 H ^^ C=N-CH-CO,H
9 NH ^^C 7
II NH 2 ||
o o
o o
blue-violet (/l max 5700 A)
sec 17.1 amino acids 465
Figure 17-3 Diagram of apparatus used to develop a paper chromatogram.
Paper is suspended from its top edge within an airtight container (here a
glass box closed with a glass plate) having an atmosphere saturated with sol-
vent vapor; the lower edge of paper dips into a trough containing the liquid
solvent.
proline and hydroxyproline give the same color (x max = 5700 A). The sequence
of steps that leads to the color is shown in Figure 17-2. The secondary amino
acids proline and hydroxyproline give a yellow color (A max = 4400 A) with
ninhydrin.
Chromatography. The analysis of mixtures of amino acids (or other
compounds) can be conveniently carried out by any of three chromatographic
techniques — paper chromatography, column chromatography, or thin-layer
chromatography (tic). In Chapter 7 we described the principles of chroma-
tography on which each of these methods is based.
In paper chromatography, amino acids are separated as the consequence of
differences in their partition coefficients between water and an organic solvent.
The aqueous phase is held stationary in the microporous structure of the
paper. The differences in partition coefficients show up as differences in rates
of migration on the surface of moist (but not wet) filter paper over which is
passed a slow flow of water-saturated organic solvent.
We shall discuss one of several useful modes of operation. In this, a drop of
the solution to be analyzed is placed on the corner of a sheet of moist filter
paper, which is then placed in an apparatus such as shown in Figure 17-3,
arranged so that the organic solvent can migrate upward by capillarity across
the paper, carrying the amino acids with it along one edge. The acids that have
the greatest solubility in the organic solvent move most rapidly and, before
the fastest moving acid reaches the top of the paper, the paper is removed,
dried, then turned sideways and a different solvent allowed to diffuse across
the width. This double migration process gives a better separation of the
amino acids than a single migration and results in concentration of the
different amino acids in rather well-defined zones or spots. These spots can
methionine
®
tryptophan .
«k alanine
® ®
arginine
® , ■
lysine
®
glycine
' ®
aspartic acid
®
1 1
1
1
chap 17 amino acids, proteins, and nucleic acids 466
0.4 s
0.6 0.4
phenol-water, 5 : 1
0.2
0.2
- start
Figure 17-4 Idealized two-dimensional paper chromatogram of a mixture
of amino acids. The horizontal and vertical scales represent the distance of
travel of a component of the mixture in a given solvent in a given time relative
to that of the solvent itself. This is known as the Rf value and is fairly constant
for a particular compound in a given solvent. A rough identification of the
amino acids present in the mixture may therefore be made on the basis of
their Rf values
solvent
front
amino
acid
$ Rf=-
be made visible by first drying and then spraying the paper with ninhydrin
solution. The final result is as shown in Figure 17-4 and is usually quite
reproducible under a given set of conditions. The identities of the amino acids
that produce the various spots are established by comparison with the beha-
vior of known mixtures.
Paper chromatography has proved very useful in following the mechanisms
of biological processes using radioactive tracers. For example, in the study of
the fixation of carbon dioxide in photosynthesis, it was found possible to
determine the rate of incorporation of radioactive carbon from carbon dioxide
into various sugars, amino acids, and the like, by separating the products of
photosynthesis at a succession of time intervals on paper chromatograms,
then analyzing their radioactivities by scanning the paper with a Geiger
counter or by simply measuring the degree of fogging of an X-ray film laid
over the chromatograms.
A quantitative method of analysis of amino acids can be achieved using
column chromatography (Section 7-1). The solution to be analyzed is passed
through columns packed with an ion-exchange resin and this separates the
amino acids according to their ability to be complexed with the highly polar
sites of the resin. The effluent from the column is mixed with ninhydrin solu-
tion and the intensity of the blue color developed is measured with a photo-
electric colorimeter and plotted as a function of time at constant flow rates. A
typical analysis of a mixture of amino acids by a machine constructed to carry
out the procedure automatically is shown in Figure 17-5.
sec 17.2 lactams 467
Thin-layer chromatography (tic) is similar to paper chromatography
except that the adsorbent (usually silica gel) is applied in a thin layer to a
glass plate. Silica gel is mixed with plaster of Paris (CaS0 4 ) and a small
amount of water and the resulting slurry is coated on a plate which may be as
small as a microscope slide or as large as a medium-sized window pane. The
samples are then spotted on the adsorbent as in paper chromatography and
the Rf values determined the same way.
Thin-layer chromatography is now very widely used because it combines
the best features of paper and column chromatography — that is, the ease of
locating compounds by spraying with various reagents as in paper chroma-
tography and the wide range of adsorbents available in column chromato-
graphy. It is rapid, and more drastic reagents can be used for locating spots
than is possible with paper chromatographs.
17-2 lactams
The cyclization of hydroxy acids through lactone formation has been dis-
cussed in Chapter 13. The corresponding cyclization of amino acids leads to
lactams.
O
//
H,C-C
2 I \
H 2 C V O
CH 2
O
//
H 2 C-C
I \
H 2 C N ^NH
CH 2
y-butyrolactone
(lactone of 4-hydroxybutanoic acid)
y-butyrolactam
(lactam of 4-aminobutanoic acid)
Figure 17-5 Section of amino acid chromatogram obtained by the method of
automatic amino acid analysis from a hydrolyzed sample of the enzyme
ribonuclease. The amino acids are identified by their position of elution and
are quantified by integration of the area under the curve.
i
i
f Thr S
llllliSttilllliSlil
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Ala
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260
chap 17 amino acids, proteins, and nucleic acids 468
Formation of a- and /^-lactams is expected to generate considerable ring
strain, and other more favorable reactions usually intervene. Thus, while
y-butyrolactam can be prepared by heating ethyl 4-aminobutanoate, the
corresponding a-lactam is not formed from ethyl 2-aminobutanoate but,
instead, the dimeric diethyldiketopiperazine [1] with a six-membered ring
results.
- CH2 "'° „c /°
HP or h - c * OH H 2 C I
H2C -NH° C2H5 hV NH
CH
2 I -2 C 2 H 5 OH
NH,
CH n
O" CH
I
diethyldiketopiperazine
[1]
^-Lactams have been rather intensively investigated following the discovery
that the important antibiotic penicillin G [2], produced by fermentation with
Penicillium notatum, possesses a /Mactam ring.
O H
/~\ 'I Us ch
\=/ I I A
^ C - N -CH X CH 3
COjH
penicillin G (benzylpenicillin)
[2]
The problem of determining the correct structure of penicillin was an
extraordinarily difficult one because the molecule is very labile and undergoes
extensive rearrangements to biologically inactive products even under very
mild conditions. The /Wactam structure was finally established by X-ray
diffraction analysis. Penicillin G and many closely related compounds with
different groups in place of the benzyl group have been synthesized.
17 '3 peptides
We saw earlier that the reaction of a carboxyl function with an amine pro-
duces an amide.
o o
R-C + NH 2 R' ► R-C + HZ
Z NHR'
sec 17.3 peptides 469
If both the reactants are bifunctional, each containing an a-amino group
and a carboxyl function, the reaction can proceed further to form a poly-
amide.
o o o
II II II
R-C-NH-CH-C-NH-CH-C-NH-CH
I I I
R R R
Such molecules are called peptides (or polypeptides) and, of course, may be
so constituted that all of the R groups are not the same. They are classified
according to the number of amino acid groups in the chain and are named as
derivatives of the amino acid with the free carboxyl group, the amide group
being called the peptide linkage.
SH
I
O CH 3 O CH 2 O CH 2 OH
e II I e II I II I
H 3 N-CH 2 -C-NH-CH-C0 2 e H 3 N-CH-C-NH-CH-C-NH-CH-C0 2 e
CH 3
glycy lalanine (H • Gly • Ala • OH) alanylcysteinylserine (H • Ala • CySH • Ser • OH)
a dipeptide a tripeptide
Peptides, being polyamides, can be hydrolyzed under the influence of acids
or bases (or enzymes) to give their constituent amino acids.
The distinction between a protein and a peptide is not completely clear.
One arbitrary choice is to call proteins only those substances with molecular
weights greater than 10,000. The distinction might also be made in terms of
differences in physical properties, particularly hydration and conformation.
The naturally occurring peptides have relatively short flexible chains and are
hydrated reversibly in aqueous solution ; proteins, by contrast, have very long
chains which appear to be coiled and folded in rather particular ways, with
water molecules helping to fill the interstices. Under the influence of heat,
organic solvents, salts, and so on, protein molecules undergo more or less
irreversible changes, called denaturation, in which both the conformations of
the chains and the degree of hydration are altered. The result is usually a
decrease in solubility and loss of ability to crystallize. Proteins thus have a
very high degree of conformational specificity. Recent success in synthesizing
polypeptides with enzymic activity (Section 17-3C) suggests that the folding
of the peptide chain to give the conformationally correct enzyme is a conse-
quence of the way the amino acids are arranged in sequence.
Proteins, particularly those with hormonal or enzymic functions, often
have other groups attached to the polypeptide chain. These groups are called
prosthetic groups.
A. PEPTIDE ANALYSIS
A wide variety of peptides occur naturally. However, of those whose struc-
tures have been determined, a considerable proportion contain one or more
amino acids which are not found as constituents of proteins. Indeed, many
chap 17 amino acids, proteins, and nucleic acids 470
peptides are cyclic, and in some even D-amino acids occur. Most of the well-
characterized peptides contain 3 to 10 amino acid units.
The properties of peptides and of proteins are a critical function of not only
the number and kind of their constituent amino acids but also the sequence in
which the amino acids are linked together. Analyses for amino acid content
can be made by complete hydrolysis and ion exchange separations, as des-
cribed in Section 17-1C. Establishment of the sequence of amino acids is
much more difficult but has been carried through to completion on peptide
chains having more than 100 amino acid units.
The general procedure for determining amino acid sequences is to estab-
lish the nature of the end groups and then, by a variety of hydrolytic or
oxidative methods, break up the chain into peptides having two to five
amino acid units. The idea in using a variety of ways of cutting the chains is
to obtain fragments with common units which can be matched up to one
another to obtain the overall sequence.
Determination of the amino acid that supplies the terminal amino group in
a peptide chain (the N-terminal acid) is best made by treatment of the peptide
with 2,4-dinitrofluorobenzene, a substance which is very reactive in nucleo-
philic displacements with amines but not with amides. The product is a
N-2,4-dinitrophenyl derivative of the peptide which, after hydrolysis of the
amide linkages, yields a N-2,4-dinitrophenylamino acid. See Figure 17-6.
This substance can be separated from the ordinary amino acids resulting
from hydrolysis of the peptide, owing to the low basicity of the 2,4-dinitro-
phenyl-substituted nitrogen, which greatly reduces the solubility of the com-
pound in acid solution and alters its chromatographic behavior.
B. PEPTIDE SYNTHESIS
The problem of synthesizing peptides is of great importance and has received
considerable attention. The major difficulty in putting together a chain of, say
Figure 17-6 Determination of the terminal amino acid possessing the free
amino group in a peptide chain.
N0 2 NO,
O / 2 o
2 N^ V-F + NH 2 CH,C-Z ^* 2 N-f VnH-CH,C-
\=s peptide
2,4-dinitrofluorobenzene ^/H 2
Z
N0 2
2 N-f V-N~CH 2 -C0 2 H + amino acids
N-(2,4-dinitrophenyl) glycine
(low solubility)
sec 17.3 peptides 471
100, amino acids in a particular order is one of overall yield. At least 100
separate synthetic steps would be required and, if the yields in each step are all
equal to n x 100%, the overall yield is (« 100 x 100%). Thus, if each yield is
90%, the overall yield is only 0.003%. Obviously, a laboratory synthesis of a
peptide chain comparable in size to those which occur in proteins must be a
highly efficient process. The extraordinary ability of living cells to achieve
syntheses of this nature, not of just one but of a wide variety of such substances,
is truly impressive.
Several methods for the formation of amide bonds have been discussed
in Chapters 13 and 16. The most generally useful reactions are of the type
where X is halogen, alkoxyl, or acyloxy, corresponding to acyl halides,
esters, or acid anhydrides.
o o
/ /
R-C + NH 2 -R' ► R-C + HX
\ \
X NHR'
When these are applied to join up two different amino acids, difficulty is to be
expected, because the same reactions can link together two amino acids of the
same kind.
o o
II PCb II
NH 2 CH 2 C-OH ► NH 2 CH 2 C-C1
O O O
II -HCl II II
2NH 2 CH 2 C-C1 ► NH 2 CH 2 CNHCH 2 C-C1, etc.
To avoid such reactions, a " protecting group " is substituted on the amino
function of the acid that is to act as the acylating agent. A good protecting
group must be easily attached to the amino group without causing racemiza-
tion of an optically active acid. Moreover, it must be easily removed without
affecting the peptide linkages or sensitive functional groups on the amino
acid side chains, such as the sulfur-containing groups of cysteine, cystine, and
methionine. O
II
The benzyloxycarbonyl group, C 6 H 5 CH 2 OC— , is a useful protecting
group that can be removed at the appropriate time by catalytic hydro-
genolysis.
o o
II II
C 6 H 5 CH 2 OC-NHCHC-NHCHC0 2 H
R R
H 2
o
© II
C 6 H 5 CH 3 + C0 2 + NH 3 CHC-NHCHC0 2 e
R R
Another protecting group that has been found to be particularly useful in
solid-phase peptide synthesis, described in the next section, is the ?-butoxy-
chap 17 amino acids, proteins, and nucleic acids 472
o
ii
carbonyl group, (CH 3 ) 3 COC— . Treatment of an amino acid such as glycine
with ?-butoxycarbonyl azide [3] in basic solution produces the protected
amino acid [4] after acidification.
O O
II l.base II
(CH 3 ) 3 COCN 3 +NH 2 CH 2 C0 2 e >• (CH 3 ) 3 COC-NHCH 2 C0 2 H
2, H©
[3] [4]
The product dissolved in methylene chloride can then be coupled with a
second amino acid, such as alanine, by treatment with dicyclohexylcarbodi-
imide, C 6 H 11 N=C=NC 6 H U , an efficient, nonacidic dehydrating agent. 1
o
II e
(CH 3 ) 3 COC-NHCH 2 C0 2 H + NH 3 CHC0 2 e + C 6 H ll N=C=NC 6 H 1 i
I
CH 3
O O O
>■ (CH 3 ) 3 COC-NHCH 2 C-NHCHC0 2 H + C 6 H! jNH-C-NHCeHj t
CH 3
The chain can then be extended by treating this dipeptide with a third amino
acid, and so on. Cleavage of the protecting group, which occurs readily on
treatment with hydrochloric acid dissolved in acetic acid, gives the polypep-
tide.
O o w
(CH 3 ) 3 COC-NHCH,C — (CH 3 ) 2 C = CH 2 + C0 2 + NH 3 CH 2 C-
C. SOLID-PHASE PEPTIDE SYNTHESIS
The difficulty with the method of peptide synthesis described in the previous
section is the number of steps involved in order to make a peptide of even
modest size. We have shown earlier how poor the overall yield in a multi-
stage process can be if each stage is not highly efficient.
In recent years, R. B. Merrifield has developed an approach to peptide
synthesis which permits preparation of peptides of some size (and even
enzymically active substances) in acceptable yields. The advantage of the
method is that it avoids the intermediate isolation steps which characterize
the usual multistage synthesis. At the start, the amino acid that will ulti-
mately be at the free-carboxyl end of the peptide is bonded to active groups
on a solid polymer through its carboxyl group. The polymer is usually an
insoluble polystyrene resin containing chloromethyl groups and is pre-
pared as small spherical beads. The binding reaction is brought about by
nucleophilic displacement between the chloride and the salt of the amino
acid to give an ester.
1 Great care should be exercised when working with this compound — it is a potent
contact allergen.
sec 17.3 peptides 473
NH 2 CHC0 2 e +C1CH 2 - [POLYMER]
I
Rx
O
II
► NH 2 CHC-0-CH 2 -[POLYMER]+Cl e
Ri
The resulting solid, insoluble, amino acid-polymer complex is quite
porous and, when treated with a methylene chloride solution of a second
amino acid (suitably protected at the amino group by a ?-butoxycarbonyl
group) and dicyclohexylcarbodiimide, yields a dipeptide, attached at one end
to the solid resin.
o o
II II
(CH 3 ) 3 COC-NHCHC0 2 H + NH 2 CHC-0-CH 2 - [POLYMER]
R 2 Ri
C 6 HiiN=C=NC 6 Hi
CH2CI2
OOO
II II II
(CH 3 ) 3 COC-NHCHC-NHCHC-0-CH 2 -[POLYMER]
Ra Ri
The protecting group can be removed, as described in the previous section,
and the process continued. The advantage of the procedure is that the prod-
ucts at each stage need not be isolated and purified as would normally be
required for reactions in solution. Instead, the solid resin with its attached
peptide chain can be washed free of impurities and excess reagents at each
stage with virtually no loss of peptide. The method lends itself beautifully to
automatic control, and machines suitably programmed to add reagents and
wash the product at appropriate times have been developed. At present, the
chain can be extended by six or so amino acid units per day.
When the synthesis of the peptide chain has been completed, it is removed
from the resin surface with hydrogen bromide in anhydrous trifluoroacetic
acid. This treatment removes the final N-protecting group at the same time.
00 o
II II II
(CH 3 ) 3 COC-NHCHC NHCHC-0-CH 2 -[POLYMER]
R* Ri
HBr
O
CF 3 C0 2 H
NH 3 CHC NHCHCO, + (CH 3 ) 2 C=CH 2 + C0 2 + BrCH 2 -[POLYMER]
K R,
chap 17 amino acids, proteins, and nucleic acids 474
•
h:
•
,N«
• C
r\ ,
• //
H C.
H P ,V
A; J~\
."
ii cr
•
9 7 1
H
: :c
: *<5
' V
: h /\
: >?^/
h *<£ : w
V W H
•
C • ^
ii '
e
9 •
\ N
: H » r—
\\:
o *.
^NH---0 hydrogen
bonds
Figure 17-7 Peptide chain of a protein coiled to form an a helix. Configura-
tion of the helix is maintained by hydrogen bonds, shown as vertical dotted
(or solid) lines. The helix on the left shows the detailed atom structure of the
peptide chain (the side chain groups are not shown). The helix on the right
is a schematic representation without structural detail.
The Merrifield method has been used to synthesize a polypeptide with 124
amino acids arranged in the sequence present in the enzyme ribonuclease.
After removal of the peptide from the resin, it was purified and then exposed
to air to oxidize the SH bonds in eight cysteine units to form the four S— S
bonds that are largely responsible for stabilizing the folded pattern of the
peptide chains in the enzymically active state (see the next section). The prod-
uct showed enzymic activity although it was less efficient than the natural
enzyme, probably because minute amounts of impurities were introduced
during the individual reactions. The synthesis involved 369 reactions and
almost 12,000 individual operations of the automated peptide-syn thesis
machine without isolation of any intermediates.
17-4 protein structures
Considerable attention has been given to the possible ways in which peptide
chains can be arranged to give stable conformations. An especially favorable
arrangement that is found to occur in many peptides and proteins is the
sec 17.4 protein structures 475
a helix. The principal feature of the a helix is the coiling of peptide chains in
such a way as to form hydrogen bonds between the amide hydrogens and
carbonyl groups that are four peptide bonds apart. The hydrogen bonds are
nearly parallel to the long axis of the coil and the spacing between the turns is
about 5.4 A (see Figure 17-7). The amino acid side chains lie outside the coil
of the a helix. However, proteins are not perfect a helices, because steric
hindrance between certain of the amino acid side chains or the lack of hydro-
gen bonding is sometimes sufficient to reduce the stability of the normal
a helix and allow the chain to fold.
Various levels of complexity therefore exist in any one protein structure.
The primary structure is the specific sequence of amino acids in the polypep-
tide chain; the Secondary structure is the way the chain is coiled, often to
form an a helix; and the tertiary structure is the way in which the coiled
chain(s) is folded and hydrated in the natural state. Some proteins, in fact,
have a quaternary structure as a result of the grouping together of two or
more of these folded units. Hemoglobin, for example, is a tetramer and
insulin a hexamer. Ionic forces, van der Waals forces, and hydrogen bonds
(but not covalent bonds) are responsible for quaternary structure.
The primary structure of the antidiabetic hormone insulin was elucidated
in 1950 by Sanger, work for which he received the Nobel Prize. The sequence
of the 51 amino acids in the peptide chain of beef insulin is shown in Figure
17-8. Sheep, horse, and hog insulin all have a slightly different arrangement
Figure 17-8 Amino acid sequence in beef insulin. In agreement with con-
vention the amino acids on the left-hand side of the chain have free amino
groups and the other two terminal amino acids have free carboxyl groups.
chap 17 amino acids, proteins, and nucleic acids 476
of amino acid residues at one location in the molecule, but this does not affect
the hormone's physiological function, probably because substitution at this
location does not greatly affect the higher structures of the protein. Insulin
from man is identical with pig insulin except that threonine replaces alanine
at the very end of one of the chains.
The solution to the problem of the quaternary structure of crystalline insu-
lin has only recently been, announced, almost 50 years after Banting and Best
first isolated insulin and 20 years after Sanger established its primary structure.
The English chemist Dorothy Crowfoot Hodgkin (already a Nobel Prize
winner for earlier work) has shown by X-ray diffraction studies of crystalline
insulin that the hormone is a roughly triangular ring made up of six polypep-
tide chains (such as that shown in Figure 17-8), two to each side of the triangle.
Two zinc atoms are complexed to the inner side of the ring.
The bewildering and almost random-appearing sequences of amino acids in
the peptide chains of proteins such as insulin probably have more than one
role in influencing the higher structures of proteins and hence their properties.
In the first place, the electrical behavior of proteins and their isoelectric points
are determined by the number and location of acidic and basic amino acids.
Second, the steric effects of substituent groups determine the stabilities and
positions of folds in the peptide helices. The nature of the amino acid se-
quences may also influence the degree of intermolecular interactions and pro-
tein solubilities. Peptides of only one kind of amino acid are often highly
insoluble, partly because of strong intermolecular forces. If the regularity of
the chain is broken by having different amino acids in it, the intermolecular
forces should diminish.
Proteins are found to occur in a very wide variety of sizes and shapes.
Determination of the molecular weights and dimensions of proteins has been
made with the aid of an impressive array of physical techniques. Molecular
weights can be obtained by analysis for- particular constituents (see Exercise
17T3), determination of diffusion rates, sedimentation velocities in the ultra-
centrifuge, light scattering, and even measurements of the sizes of individual,
very large protein molecules by electron microscopy. The shapes are deduced
from measurements of rates of molecular relaxation after electric polarization,
changes in optical properties (double refraction) resulting from streaming in
liquid flow, directly by electron microscopy, and perhaps most importantly
by the intensities of light or X-ray scattering as a function of scattering angle.
The application of all these methods is often rendered difficult by the high
degree of hydration of proteins and by the fact that many proteins undergo
reversible association reactions to give dimers, trimers, and so on. The mole-
cular weights, molecular dimensions, and isoelectric points of a few important
proteins are compared in Table 17-2.
It is found that many proteins contain metals such as iron, zinc, and copper,
and these metal atoms turn out to be intimately involved in the biological
functions of the molecules to which they are bound. The well-known oxygen-
carrying property of hemoglobin and the hemocyanins is a case in point.
These molecules have metal-containing heme rings as the prosthetic groups
attached to the polypeptide chain. The cytochrome enzymes that are in-
sec 17.6 the structure of DNA 477
volved in biological oxidation (Chapter 18) are constructed similarly. Like
many other substances we call proteins they are more than simple polymers
of amino acids.
The biological functions of proteins are extremely diverse. Some act as
hormones regulating various metabolic processes (e.g., insulin is responsible
for the control of blood sugar levels); some act as catalysts for biological
reactions (enzymes), and others as biological structural materials (e.g., col-
lagen in connective tissue and keratin in hair). The oxygen-carrying properties
of hemoglobin in mammals (and the copper-containing proteins called hemo-
cyanins, which function similarly for shellfish) have been mentioned already.
Some blood proteins function to form antibodies, which provide resistance
to disease, while the so-called nucleoproteins are important constituents of
the genes that supply and transmit genetic information in cell division. The
viruses, such as tobacco mosaic virus, are made up of nucleoproteins, nucleic
acids encased in a protein "coat." The structures of many viruses are so
regular that they can be obtained in nicely crystalline form. Viruses function
by invading the cells of the host and by supplying a genetic pattern that de-
stroys the normal functions of the cells and sets the cellular enzymes to work
synthesizing more virus particles.
11 -S biosynthesis of proteins
One of the most interesting and basic problems connected with the synthesis
of proteins in living cells is how the component amino acids are induced to
link together in the sequences which are specific for each type of protein.
There is also the related problem of how the information as to the amino acid
sequences is perpetuated in each new generation of cells. We now know that
the substances responsible for genetic control in plants and animals are pres-
ent in and originate from the chromosomes of cell nuclei. Chemical analysis
of the chromosomes has revealed them to be composed of giant molecules of
deoxyribonucleoproteins, which are deoxyribonucleic acids (DNA) bonded
to proteins. Since it is known that DNA rather than the protein component
of a nucleoprotein contains the genetic information for the biosynthesis of
enzymes and other proteins, we shall be interested mainly in DNA and will
first discuss its structure. Note that part or perhaps all of a particular DNA
is the chemical equivalent of the Mendelian gene — the unit of inheritance.
17-6 the structure of DNA
The role of DNA in living cells is analogous to that of a punched tape used for
controlling the operation of an automatic turret lathe. DNA supplies the in-
formation for the development of the cells, including synthesis of the necessary
enzymes and such replicas of itself as are required for reproduction by cell
division. Despite the enormous differences in gross structure of the many
name
mol. wt.
shape
isoelectric
point
occurrence
function
insulin"' 6
5800 c
5.4
pancreas
regulation of blood
sugar levels
ribonuclease"' 6
13,000
7.8
pancreas
hydrolysis of ribonucleic
acids
myoglobin (horse)"' 6
17,500
platelets
horse heart
respiratory protein
lysozyme 0,6
14,600
prolate
ellipsoid
10.7
egg white
breaks down the cell
walls of bacteria
by hydrolysis of
/3(1 -» 4) glucose
linkages
a-chymotrypsin"' 6
25,000
8.4
pancreas
hydrolysis of ester
and peptide linkages
papain"
21,000
8.8
latex of papaya
melons
hydrolysis of peptide
linkages
hemoglobin 0,6
64,450
nearly
spherical
6.7
red-blood
corpuscles
respiratory protein
catalase
250,000
blocks"
liver and kidney
destroys H 2 2
fibrogenin
330,000
elongated
6.8
blood plasma
blood clotting
tobacco mosaic virus
(protein part)"
41,000,000
hexagonal
prisms or
rods' 1
4.1
infected tobacco
or tomato plants
plant virus
H
wa
O
3
a
rt-
n*
~a
n
O
2
5'
" Complete sequence of amino acids has been established.
6 Structure investigated by X-ray diffraction methods.
c Molecular weight of monomeric insulin ; crystalline insulin consists of six such units complexed with two zinc atoms.
d From electron-microscope photographs.
sec 17.6 the structure of DNA 479
varieties of plants and animals the basic structural features of DNA from all
sources are surprisingly similar. We shall be mainly concerned with these
basic features in the following discussion.
In the first place, DNA molecules are quite large — sufficiently so that they
can be seen individually in photographs taken with electron microscopes. The
molecular weights vary considerably, but values of 1,000,000 to 4,000,000,000
are typical. X-ray diffraction indicates that DNA is made up of two long-
chain molecules twisted around each other to form a double-stranded helix
about 20 A in diameter.
.M
w
„bS#
-20A
#*^
As we shall see, the components of the chains are such that the strands can
be held together efficiently by hydrogen bonds. In agreement with the pro-
posed structure, it has been found that, when DNA is heated to about 80°
under proper conditions, the strands of the helix untwist and dissociate to two
randomly coiled fragments. Furthermore, when the dissociated material is
allowed to cool slowly (again, under proper conditions), the fragments recom-
bine and regenerate the helical structure.
Chemical studies show that the strands of DNA have the structure of a
long-chain polymer made of alternating phosphate and nitrogen base-sub-
stituted sugar residues [5]. The sugar is D-2-deoxyribofuranose [6], and each
— phosphate
sugar
phosphate — | sugar — ] phosphate | — sugar
base
base
[5]
sugar residue is bonded to two phosphate groups by ester links involving
the 3- and 5-hydroxyl groups.
-Ox
HOHX
OH
HO
2-deoxyribofuranose
[6]
chap 17 amino acids, proteins, and nucleic acids 480
The backbone of DNA is thus a polyphosphate ester of a 1,3-glycol.
OH OH OH
I III I III I III
-O-P-O-C-C-C-O-P-O-C-C-C— O-P— o-c— c-c-o—
II III II III II III
O o o
With the details of the sugar residue included, the structure of DNA be-
comes as shown in Figure 17-9.
Each of the sugar residues of DNA is bonded at the 1 position to one of
four bases, adenine [7], guanine [8], cytosine [9], and thymine [10], through
an N-glycosidic linkage. The four bases are derivatives of either 2-hydroxy-
pyrimidine or purine, both of which are heterocyclic nitrogen bases.
/N
OCX
H
purine
N
2-hydroxypyrimidine
adenine
[V]
NH
cytosine
[9]
guanine
OH
H 3C-^W N
^N^OH
thymine
[10]
For the sake of simplicity in illustrating N-glycoside formation in DNA, we
shall show the type of bonding involved for the sugar and base components
only (i.e., the nucleoside structure). Attachment of 2-deoxyribose to the
purines, adenine and guanine, is easily envisioned as involving the NH group
of the five-membered ring and the C-l of the deoxyribofuranose ring, the
union always being /?.
OH
2-deoxyribofuranose
NH,
-H 2
HOH,C
NH 2
N
J
HO
adenine deoxyriboside
(a nucleoside)
03)
However, an analogous process with the pyrimidines, cytosine and thymine,
has to involve tautomerization of the base to an amide-type structure.
sec 17.6 the structure of DNA 481
O
I
HO-P-0-CH 2/ .0^ R
O
O
I
HO — P-O— CH 2 (X r
O
R = nitrogen base ;
adenine, guanine,
cytosine, or thymine
O
HO-P-0-CH 2 /0^ R
O
O
Figure 17-9 Structure of the strands of deoxyribonucleic acid (DNA).
NH 2
Cx
N^^OH
cytosine
NH 2
N 2-deoxyribose
H
NH 2
-H 2
HO-H,C
i
HO
cytosine deoxyriboside
(a nucleoside)
00
Esterification of the 5-hydroxyl group of deoxyribose nucleosides, such as
cytosine deoxyriboside, with phosphoric acid gives the corresponding
nucleotides.
O
II
HO — P-O— H,C
OH
.O-
NH 2
-4 N
Ni O
OH
cytosine deoxyribonucleotide
(a nucleotide)
Thus DNA may be considered to be built up from nucleotide monomers
by esterification of the 3-hydroxyl group of one nucleotide with the phosphate
chap 17 amino acids, proteins, and nucleic acids 482
H
CH 3
,HN^^
„ /°v\
o vl T 1
HNH 1 1
11 »N N^
1 V HN N
.N^v^wu' II deoxyribose
\ 1 1 ..-°
F^Ti^N 1 '' If deoxyribose
\ J. J °
deoxyribose
deoxyribose
guanine-cytosine
adenine-thymine
Figure 17-10 Hydrogen bonding in the base pairs guanine-cytosine and
adenine-thymine, which leads to the two strands of DNA being linked. In
each case the distance between C-l of the two deoxyribose units is 11 A and
the favored geometry has the rings coplanar.
group of another. Enzymes are available which hydrolyze DNA to cleave the
linkage at C-3 and give the 5-phosphorylated nucleotides. There are other
enzymes which cleave DNA at C-5 to give the 3-phosphorylated nucleotides.
The number of nucleotide units in a DNA chain varies from a few thousand
Figure 17-11 Schematic representation of configuration of DNA, showing
the relation between the axes of hydrogen-bonded purine and pyrimidine
bases and the deoxyribose-phosphate strands. There are 10 pairs of bases per
complete 360° twist of the chain. The spacing between the strands is such that
there is a wide and a narrow helical " groove " which goes around the mole-
cule. Apparently in the combination of DNA with protein, the protein is
wound around the helix filling one or the other of the grooves.
-hydrogen
bond
axis of adenine-thymine
or guanine-cytosine pair
- deoxyribose-phosphate
chain
sec 17.7 genetic control and the replication of DNA 483
to well over a million. A single DNA molecule can be isolated from the
bacterium Escherichia coli which has a molecular weight of 2 x 10 9 and whose
extended length is almost a millimeter.
Although the sequences of the purine and pyrimidine bases in the chains
are not known, there is a striking equivalence between certain of the bases
regardless of the origin of DNA. Thus the number of adenine groups equals
the number of thymine groups, and the number of guanine groups equals the
number of cytosine groups (i.e., A = T and G = C). Also, the overall percent-
age composition of the bases is constant in a given species but varies widely
from one species to another.
The equivalence between the purine and pyrimidine bases in DNA was
accounted for by Watson and Crick (1953). They were the first to realize that
if two strands are twisted together to form a double helix, hydrogen bonds
can form between adenine in one chain and thymine in the other or cytosine
in one chain and guanine in the other. Thus, each adenine occurs paired with
a thymine and each cytosine with a guanine and the strands are said to have
complementary structures. The hydrogen bonds that form the base pairs are
shown in Figure 17-10, and the relation of the bases to the strands in Figure
17-11.
17 -7 genetic control and the replication of DNA
It is now clear that DNA provides the genetic recipe that permits cell division
to produce identical cells. In reproducing itself, it perpetuates the information
necessary to regulate the synthesis of specific enzymes and other proteins of
the cell structure. The genetic information inherent in DNA depends on the
arrangement of the bases (symbolized as A, T, G, and C) along the phosphate-
carbohydrate backbone — that is, on the arrangement of the four nucleotides
specific to DNA.
There are 20 amino acids that become joined together to form proteins but
only four nucleotide bases. A single base, therefore, cannot correspond to a
single amino acid and even a pair of adjacent bases gives only 4 2 or 16 com-
binations. A triplet of bases, however, provides 4 3 or 64 combinations, more
than enough to store the information required for the sequential addition of
20 different amino acids to form a protein of specific structure. Each of the
64 three-letter code words, called codons (for example, AGC, adenine-guan-
ine-cytosine), corresponds to an amino acid and it is apparent that an indi-
vidual amino acid may have several codons that direct its addition to the
growing polypeptide chain.
The base sequence in DNA can be modified chemically by treatment of
DNA in vitro (outside the cell) or in vivo (inside the cell) with nitrous acid,
which can convert the primary amino groups of adenine, cytosine, and
guanine to OH groups. This clearly changes the genetic message, since DNA
modified this way leads to mutations in the organisms from which it was
originally obtained. A drastic change may occur when the DNA of a bac-
teriophage (which is no more than a bundle of DNA enclosed in a protein
chap 17 amino acids, proteins, and nucleic acids 484-
coat) is introduced into a bacterium. The bacteriophage DNA acts as a primer
for the synthesis of DNA and proteins of its own kind, finally causing dis-
solution of the host cell and liberation of new bacteriophage particles.
Other important experiments which indicate that a given organism manu-
factures DNA of its own kind are based on the synthesis of DNA in vitro.
A mixture of the four DNA nucleotides, A, G, C, and T, with triphosphate
groups in the 5 position, can be polymerized to DNA in the presence of the
enzyme DNA-polymerase, magnesium ions, and a DNA primer. The last can
come from a variety of sources, but the synthetic DNA has the composition
of the primer DNA, even if the relative amounts of the nucleotides that are
supplied are varied. The role of magnesium is not clear, but it behaves as a
type of inorganic coenzyme, since the enzyme apparently does not function
in its absence. The triphosphate grouping on the nucleotides is necessary as
a source of energy to drive the reaction forward; some 7 kcal/mole is
liberated in the cleavage of the triphosphoryl group to pyrophosphate (see
Section 15-5).
OH OH
1 1
OH
n-HO— P— O — P— O— P-O— H 2 C
ii ii ii k
O O O '
> R
T
OH
DNA-
Mg 2 ®,
poly-
"DNA
merase
primer"
~ H ^ ^
O
II
-P— O-
1
O
\_yOH
+ n-HO-
II
-P-OH
OH
O P
II
O
n
OH
The mechanism of replication of DNA that takes place when the cell divides
probably involves the unwinding of the DNA double helix into two comple-
mentary chains. During the unwinding process, each chain serves as a template
on which is built the complement of itself.
The genetic information of cells is stored in DNA but protein synthesis
takes place on small subcellular particles called ribosomes. How does the in-
formation stored in DNA become translated into a protein molecule in the
ribosome ? This is accomplished through the intermediacy of ribonucleic acid
(RNA), a substance similar in structure to DNA 2 but containing ribose in-
2 Although DNA was first located in cell nuclei of plants and animals (hence the name
nucleic acid), it is now known to be present outside the nucleus, as well, that is, in the
cytoplasm. Indeed, bacterial cells, which contain no nuclei, use the same system of infor-
mation transfer (DNA->RNA-> protein) as do nucleated cells.
sec 17.7 genetic control and the replication of DNA 48S
stead of deoxyribose (see Section 15-5). RNA contains the base sequence
transcribed from DNA, but with the base uracil [11] replacing thymine [10].
In contrast to DNA most RNA molecules are single stranded.
H,C.
OH
I
OH
i
I k
V N-^OH
ll N
^•N^OH
thymine
uracil
[10]
[11]
There is a striking variation in size of RNA molecules and this seems to
depend on the particular role they play. One class of RNA molecules is called
transfer RNA (tRNA). The various molecules contain 75 or so nucleotide
units and have molecular weights of about 25,000. Specific tRNA molecules
are esterified enzymically with the corresponding amino acid and the amino
acids then are transferred to the growing protein chain on the ribosome in a
complex series of enzyme-catalyzed reactions. Because tRNA is the smallest
and most soluble form of RNA, it is sometimes called soluble RNA (sRNA).
Another kind of RNA with a somewhat bigger molecular weight is called
messenger RNA (mRNA). It carries the message from the DNA in the nucleus
to the tRNA at the ribosome. Its base sequence is complementary to a portion
of one strand of DNA and consequently it contains the sequence of codons
defining the sequence of amino acids in the protein.
The codon(s) for a particular amino acid can be determined by experiment.
For example, a synthetic RNA containing only one type of base, uracil, acts
as the mRNA for a cell-free preparation of the protein-synthesizing system of
the bacterium E. coli. The product is a polypeptide containing only phenylala-
nine. This suggests that the codon for phenylalanine is UUU. The messages
delivered by all 64 codons are now known, at least for E. coli, and it is
probable that the code is universal.
In some cases, the codon was determined by synthesis of the simple tri-
nucleotide molecule made up of the appropriate triplet. This is often sufficient
to cause amino acyl-tRNA to be bound to the ribosome. For example, the
trinucleotide UUU causes only phenylalanyl tRNA, and the trinucleotide
UCU only seryl tRNA, to be bound. Other trinucleotides are much less
efficient in promoting binding, however, making it difficult to determine the
amino acid to which they correspond. In these cases, the complex polynucleo-
tide having the correct base sequence had to be synthesized and its effect on
amino acid incorporation in polypeptides observed.
It turns out that only 61 of the 64 codons correspond to amino acids. The
other three, UAA, UAG, and UGA, are so-called "nonsense" codons.
Despite this name their message is clear — they stop the growth of the poly-
peptide chain.
A third class of RNA is called ribosomal RNA (rRNA). These molecules
are components of ribosomes but their roles are not as well understood as
those of tRNA and mRNA.
chap 17 amino acids, proteins, and nucleic acids 486
Phenomenal progress has been made in the past 20 years in understanding
the chemical basis of heredity and we can expect in the future to learn that
manipulation of human genetic material can be done on a clinical basis. It
remains to be seen whether or not we possess the wisdom to use such knowl-
edge in a wholly beneficial way.
17-8 chemical evolution
The term " chemical evolution " is used to refer to those events occurring on
the primitive Earth that led to the appearance of the first living cell. There is
general agreement that the Earth was formed about A\ billion years ago by
condensation from a dust cloud. Fossil evidence shows that unicellular orga-
nisms (protozoa) existed on Earth at least 3 billion years ago, which leaves
possibly a billion years for chemical evolution to produce the complex organic
molecules that are the components of a living cell.
There is good reason to believe that the atmosphere of the prebiotic Earth
was hydrogen dominated, rather than oxygen dominated as at present, and
the principal atmospheric constituents were probably methane, ammonia, and
water vapor. The change from a reducing to an oxidizing atmosphere may
have been caused by radiolysis of water vapor by ultraviolet radiation fol-
lowed by escape of hydrogen from the planet's atmosphere. This allowed the
ozone shield to develop in the upper atmosphere — the protection required by
cells from the lethal effects of high-energy ultraviolet light.
Experiments have been conducted in the laboratory which simulate
"natural" but prebiotic organic syntheses. Application of ultraviolet radia-
tion and electric discharges (the analogs of unshielded sunlight and lightning
storms, respectively) to mixtures of CH 4 , NH 3 , H 2 0, N 2 , and H 2 produces
both amino acids and nucleic acid bases. Other kinds of compounds, too, are
formed but it is interesting that the naturally occurring amino acid 2-amino-
propanoic acid (alanine) is always formed in larger amounts than its isomer
3-aminopropanoic acid.
Adenine, one of the nucleic acid bases, has the formula C 5 H 5 N 5 , or
(HCN) 5 , and it has been shown that adenine is one of the compounds formed
when aqueous solutions of ammonia and hydrogen cyanide (products of
CH 4 -N 2 irradiation) are heated at 90° for several days. One of several
possible routes for this reaction begins with the stepwise trimerization of
hydrogen cyanide to give aminomalononitrile:
HCN
2 HCN >• [HN=CHCN] > H 2 NCH(CN) 2
dimer aminomalononitrile
This compound, which has been detected in the reaction mixture, is known to
be able to condense with one mole of formamidine (formed by addition of
ammonia to hydrogen cyanide) to give the imidazole [12]. The imidazole [12]
summary 487
NH
//
HCN + NH, ► H— C
\
NH,
formamidine
NQ ^NH,
rH HN NC XT
1 + C-H > II > + NH 3
H,N
N
>-. T^ V^ II I
Jl H 2 N H 2 N X N'
[12]
can react with a second mole of formamidine to give adenine. All of the
NH 2
NH 2 NC V- N \ N^V N
J N > — L,l
W % NH H 2 N^N N ^
[12] adenine
NH 3
above compounds except the HCN dimer have been identified in the aqueous
solution. There is little doubt that many of the units of biopolymers were
present under prebiotic conditions and it is not difficult to visualize the for-
mation of proteins and nucleic acids taking place also. There is still, of course,
an enormous gap in our understanding of how these substances became
organized into the first living cell able to replicate itself.
summary
Of the 24 a-amino acids that are important constituents of proteins, all except
glycine, NH 2 CH 2 C0 2 H, are optically active. Eight of them are essential to
human nutrition in the sense that the body cannot synthesize them. Four of
the remainder are formed by conversion of other amino acids only after the
protein has been synthesized.
Amino acids can be prepared from a-halo acids or by the Strecker synthesis
(RCHO -► RCHNH 2 CN -+ RCHNH 2 C0 2 H).
Amino acids with one carboxyl and one amino group (neutral amino acids)
exist in the dipolar (zwitterionic) form, RCHC0 2 e , which is converted by
NH 3 ®
acids to a cation RCHCO,H, and by bases to an anion RCHCO, 6 .
I I
NHj® NH 2
The isoelectric point is the pH at which the concentration of the zwitterion
is at a maximum and is near pH 6 for many simple amino acids. Basic amino
acids such as lysine (NH 2 CH 2 CH 2 CH 2 CH 2 CHNH 2 C0 2 H), which have an
excess of amino over carboxyl groups, have isoelectric points near pH 9,
chap 17 amino acids, proteins, and nucleic acids 488
while acidic amino acids such as glutamic acid (HOjCCHjCHjCHNHjCOjH)
with an excess of carboxyl over amino groups have isoelectric points near
pH3.
Analysis and detection of amino acids can be carried out with nitrous acid
(Van Slyke method), by the ninhydrin color test, or by chromatography.
Paper chromatography involves the partitioning of compounds caused by
differences in their rates of migration on the surface of moist filter paper.
These are expressed as Rf values, the distances that compounds migrate rela-
tive to that of the solvent front. Thin-layer chromatography (tic) is similar
except that the filter paper is replaced by a thin layer of absorbent, such as
silica gel, on glass plates.
Cyclization of esters of y- and (5-amino acids (amino at C-4 or C-5) produces
lactams (cyclic amides) whereas a-amino esters form six-membered rings by
dimeric cyclization.
Peptides (polypeptides) are poly amides formed by the condensation of
a-amino acids. Synthesis of peptides in the laboratory normally requires the
O
II
use of a protective group, such as ROC — , on the amino group of the amino
acid that is being linked to the chain to prevent it from reacting with its own
carboxyl function.
o o o o o
II II II II II
ROC-NHCHC0 2 H + NH 2 CHCNH~~~ > ROC-NHCHC-NHCHC-NH-
II II
Rj R-2 Ri R^
Formation of the peptide linkage can be brought about by mild dehydrating
agents, such as RN=C=NR, or via the acid chloride. The protective group
can be removed and the process continued. Solid-phase peptide synthesis can
be achieved by attaching the first amino acid in the chain to a polystyrene
resin and then using this granular material in all subsequent chemical and
washing operations. In the final step, the peptide is liberated from the resin
by a suitable reaction.
Proteins are peptides with special structural features beyond the primary
structure, which refers to the sequence of amino acids in the chain. Proteins
have a secondary structure, which refers to the way the chain is coiled; a
tertiary structure, which refers to the manner of folding of the coiled chain;
and a quaternary structure, which refers to the association of the folded units
by noncovalent links.
Many proteins, such as hemoglobin, contain non-amino acid functions
called prosthetic groups. Viruses consist of protein-nucleic acid combinations.
Deoxyribonucleic acid (DNA) is a polymer of 2-deoxyribose and phos-
phoric acid, with nitrogen bases (adenine, guanine, cytosine, and thymine)
attached to the sugar units. The combination of an individual sugar and a
base is called a nucleoside; the combination of a sugar, a base, and phosphoric
acid is a nucleotide. Coded genetic information is contained in the sequence
of bases along the polymer chains, which are coiled around one another in
the form of a double-stranded helix.
exercises 489
Ribonucleic acid (RNA) differs from DNA in the following respects: it
contains ribose rather than deoxyribose; it contains uracil rather than thy-
mine ; and it has a much greater variation in molecular weight (corresponding
to the three different functional types, tRNA, mRNA, and rRNA). The
genetic information coded in the base triplets of DNA becomes manifest in
protein synthesis through the action of RNA.
The appearance of life on Earth was presumably preceded by the synthesis
of rather complex organic molecules. The effects of radiation on the highly
reduced atmosphere believed to exist in prebiotic times can be duplicated in
the laboratory and shown to give rise to compounds such as amino acids and
nucleic acid bases.
exercises
17-1 Pick out the amino acids in Table 17-1 which have more than one asymmetric
center and draw projection formulas for all the possible stereoisomers of
each which possess the l configuration for the a carbon.
17-2 Which of the amino acids in Table 17-1 are "acidic" amino acids and which
"basic" amino acids? Which of the structures shown would have the most
basic nitrogen? The least basic amino nitrogen? The most acidic and least
acidic carboxyl group ? Give the reasons for your choices.
17-3 Show the sequence of steps involved in the Strecker synthesis of a-amino
acids.
17-4 Show how the following amino acids can be prepared from the indicated
starting materials by the methods described above or earlier.
a. leucine from 2-methyl-l-propanol
b. lysine from 1 ,4-dibromobutane
c. proline from hexanedioic acid (adipic acid)
d. glutamic acid from a-ketoglutaric acid
17-5 Devise physical or chemical ways to determine directly or calculate the
equilibrium constant between neutral glycine and its dipolar ion. Arguing
from substituent effects on the ionization of carboxylic acids and amines,
would you expect the equilibrium constant to be closer to 0.1, 1.0, or 10?
Explain.
17-6 Suppose one were to titrate an equimolal mixture of ammonium chloride
and acetic acid with two equivalents of sodium hydroxide. How would the
titration curve be expected to differ from that of glycine hydrochloride
shown in Figure 17-1? Take K HA for acetic acid equal to 2x 10"" 5 and
Kbu® for ammonium ion to be 5 x 10~ 10 .
17-7 Write mechanisms based insofar as possible on analogy for each of the steps
involved in the ninhydrin test using glycine as an example. Would you
expect ammonia or methylamine to give the blue color ?
chap 17 amino acids, proteins, and nucleic acids 490
17-8 Arrange the following amino acids in the order in which you would expect
each to move in a paper chromatogram with the weak organic base 2,4,6-col-
lidine as the organic phase: glycine, phenylalanine, arginine, and glutamic
acid. Show your reasoning.
CH,
2,4,6-collidine
17-9 Draw out the complete structure (using projection formulas) of the impor-
tant hormonal peptide oxytocin.
H • CyS • Tyr • He- Gin • Asn • CyS • Pro • Leu • Gly • NH 2
17-10 On what theoretical grounds can we expect the C— O bonds of benzyloxy
groups to undergo hydrogenolysis more readily than ethoxy groups ?
17-11 Show how each of the following substances can by synthesized starting with
the individual amino acids.
a. glycylalanylcysteine
b. H0 2 C(CH 2 ) 2 CH(NH 2 )CONHCH 2 C0 2 H
c. glutamine from glutamic acid
17-12 Most nonfatty tissue is about 80% water and 15% protein by weight with
the remainder being made up of carbohydrates, lipids, nucleic acids,
inorganic salts, and so on. Assuming an. average molecular weight of protein
of 10 5 calculate the molar ratio of water to protein in such tissue.
17-13 Hemoglobin, the protein responsible for carrying oxygen from the lungs
to the body tissues, contains 0.355% of iron. Hydrolysis of 100 g of hemo-
globin gives 1.48 g of tryptophan; calculate the minimum molecular weight
of hemoglobin which is consistent with these results.
17-14 Write equations for the steps involved in hydrolysis of adenine deoxyri-
bonucleoside to deoxyribose and adenine. Would you expect the reaction
to occur more readily in acidic or basic solution ?
17-15 Escherichia coli bacteria grown in a medium containing 15 N-labeled ammo-
nium chloride produce 15 N-containing DNA. This can be distinguished
from ordinary 14 N-DNA by ultracentrifugation in concentrated cesium
chloride solution — at equilibrium 14 N-DNA and 15 N-DNA form separate
bands of differing density. When the bacteria grown in an 15 N medium
are transferred to a 14 N medium, DNA replication continues but, after
one generation, all the DNA present appears to be of one kind, containing
equal amounts of 15 N and 14 N; after two generations, the DNA is now of
two kinds present in equal amounts — all 14 N-DNA and 14 N, 15 N-DNA.
What do these results tell about the replication of DNA and its stability in
the cell?
exercises 491
17-16 Draw structures for the tautomeric forms of uracil (formula [11], Section
17-7) and show how a nucleotide of uracil can form hydrogen bonds with
adenine.
17-17 Propynonitrile (cyanoacetylene), which is a product of CH 4 -N 2 irradiation,
has been suggested as a precursor for the amino acid aspartic acid (2-
aminobutanedioic acid) under "primitive Earth" conditions. Write a
reaction path for this conversion making use only of NH 3 , HCN, and H 2
as reactants.
17-18 Write reasonable mechanisms for the cyclization steps shown in Section
17-8 for the conversion of HCN to its pentamer, adenine. (Two of the
reactions involved bear resemblance to reactions met earlier, the conden-
sation of aldehydes with amines, Section 11-4D, and the addition of nucleo-
philes to nitriles. Section 16-2B.)
i chapter 18
and net*
chap 18 enzymic processes and metabolism 495
The time scale of man's awareness ranges from about 10 10 seconds to
possibly 10" 2 second. The former is a lifetime; the latter is the relaxation
period of the eye. A person's reaction time — the time between observation
and action — is measured in tenths of a second and we might well wonder
how the complex physiological processes that result in a particular response —
the batter's swing, the fencer's parry — can possibly occur in such brief periods
of time. How fast can chemical reactions occur? Is a few tenths of a second
long enough for nerve impulses to be translated into muscle action, a process
essentially chemical in nature?
The fastest chemical reactions that can occur in solution are those that are
diffusion controlled. This means that, if the rate of the reaction of A and B
depends only on their encounter rate, then every encounter produces product.
For solvents of normal viscosity at room temperature, the rate of diffusion,
expressed as a bimolecular rate constant, is 10 10 liters mole -1 sec -1 . This
means that if the reactants A and B are each 1 M, the initial rate of
production of product will be 10 10 moles liter" 1 sec -1 , a staggeringly high
rate. Put another way, the reaction between A and B would be 99 % complete
in 1CT 8 second.
A number of diffusion-controlled reactions are known; one simple example
is H® + OH e -> H 2 0. Such reactions require no activation of the reactants
for the reaction to occur. At the other extreme are countless reactions with
heats of activation greater than 50 kcal, which means that their half-lives (the
time for half of the reactants to be consumed) at room temperature would be
measured in thousands or millions of years.
If the fastest known chemical reactions can be substantially complete in
10~ 8 second or so at room temperature, a 10" 2 -second period does not appear
to be quite so short, even though the chemistry of physiological processes is
clearly much more complicated than the H® + OH® reaction.
The study of enzymes and the way in which they accelerate and control
biological processes is a fascinating area of study that combines the disciplines
of organic chemistry, physical chemistry, biochemistry, and physiology.
Because enzymes are essentially catalysts which operate by lowering the
activation energy of what are ordinarily slow processes, we shall begin with
a discussion of catalysis in simple organic systems.
18-1 catalysis in organic systems
A catalyst is a substance that will increase the rate of a reaction without itself
being consumed. We saw in Chapter 8 that the rate of a reaction is governed
by the energy difference between reactants and transition state, the latter
being the highest point on the lowest energy path from reactants to products.
Catalysis simply provides another path from reactants to products with a
lower-energy transition state. A simple example should suffice to illustrate
the point.
The reaction between chloromethane and hydroxide ion to give methanol
chap 18 enzymic processes and metabolism 496
and chloride ion is accelerated by the addition of small amounts of iodide ion.
ie
CH 3 C1 + OH e ► CH3OH + Cl e
The uncatalyzed reaction is a one-step S N 2 displacement and its rate is
determined by the free-energy difference between the reactants and the tran-
sition state having a configuration roughly like the following :
H
HO— C — CI
(The free energy of activation, AG*, is made up of the heat of activation, AH*,
and the entropy of activation, AS 1 *, Section 8-9.)
The addition of iodide ion to the system provides another pathway — a two-
stage route — to products. Iodide ion is a large polarizable ion and is both a
good nucleophile and a good leaving group in displacement reactions. Ac-
cordingly, it reacts rapidly with chloromethane to give iodomethane but this,
in turn, suffers rapid displacement by hydroxide ion. The iodide ion is thus
regenerated and is a true catalyst.
CH3CI + I e
CH 3 I + OH e
CH3I + Cl e
CH30H + I s
The energetics of this process are shown in Figure 18-1. (The analysis of
the activation process in terms of AH X and AS 1 * need not concern us at this
point.)
Figure 18-1 Energy profiles for the reaction of chloromethane with hy-
droxide ion in the presence (solid line) and absence (dashed line) of iodide
H n
ge | ge
^ —
HO— C— CI
-- "C
A
'' X
H H
/ \
H
- ge | ge
I— C— CI
A
H H
>>
f*
H
<0
ge | ge
HO — C— I
A
H H
CH 3 C1 + OH e
c
H3OH + CI e
reaction coordinate
sec 18.1 catalysis in organic systems 497
The two-step reaction has two transition states that correspond to energy
maxima, but only the higher of the two determines the rate of the overall
reaction. If the second transition state is the higher one, the overall rate of the
reaction will be proportional to the concentrations of the catalyst (iodide ion)
and hydroxide ion. If the first transition state is the higher one, the rate will
be proportional to the concentration of iodide ion and not the concentration
of hydroxide. Thus, in either case, iodide ion is a catalyst for the overall re-
action. Catalysts have no influence on the position of equilibrium of a system 1
and it follows that iodide ion must catalyze the reverse reaction also. The rate
of interconversion of chloromethane and methanol will be increased by the
presence of iodide even though their equilibrium concentrations are unchanged.
There are two main categories of catalysis : homogeneous catalysis, in which
all the components are in a single phase as in the above example, and hetero-
geneous catalysis, in which interactions occur at a solid surface. The hydro-
genation of alkenes catalyzed by finely divided metal surfaces (Section 2-6A)
is an example of heterogeneous catalysis. Most enzymic processes can be con-
sidered to be homogeneous although the way in which some high-molecular-
weight enzymes orient small reactant molecules on their surfaces bears a
strong resemblance to the action of heterogeneous catalysts.
The iodide ion in the example above is a nucleophilic catalyst and we shall
see that some enzymes also operate this way. Many other organic processes
are catalyzed by acids and bases. Since all bases are also nucleophiles it is
sometimes difficult to tell if catalytic action is due to a molecule or ion acting
as a base (removing a proton) or as a nucleophile (supplying the electrons to
form a bond to carbon). Furthermore, acid catalysis and nucleophilic catalysis
often go together, as we shall see in the following sections.
A. ACID CATALYSIS
A number of acid-promoted reactions have been met previously, such as the
hydration of alkenes and dehydration of alcohols (Sections 4-4 and 10-5B),
the formation and hydrolysis of hemiacetals (Section 11-4B), the formation
and hydrolysis of esters (Section 10-4C), and the acid hydrolysis of amides.
The course of these reactions is shown in Equations 18-1 to 18-4.
ffi OH 2
RCH=CH 2 + H® < ' RCH-CH 3 , + 2 -^ RCH-CH, 5=
-H 2 3
(18-1)
O OH OH OH
/ ~ „ // +EtOH I ffi I
-C + H e < R-C , R-C-OEt « R-C-OEt + H®
\ \ -EtOH I I I
H H H H H (18-2)
1 The only exception would be where the catalyst forms a complex with one or more of
the reactants or products and is present in such high concentration as to change appreciably
the concentrations from the values they would otherwise have. An effect of this kind will
change the position of equilibrium but not the equilibrium constant.
chap 18 enzymic processes and metabolism 498
OH
R — C-OEt
EtOH | |
OH H
OH OH O
■ I -HjO /; //
R- C-OEt ^ R-C© j ► R-C + H®
I +H2O % \
®OH 2 OEt OEt
(18-3)
,0
OH
+ H 2 0.
OH OH
1 1 e
\
NH 2
NH 2
'-H 2
s>OH 2 y> OH
OH
R— C® + NH 3 ,_ " RC0 2 H + NH 4
OH (18-4)
The dual role of the proton in each of the four reactions should be clear.
At one stage, a carbon atom is activated toward an attacking nucleophile by
protonation of the adjacent atom; at another stage, protonation increases the
leaving ability of a substituent group. Proton transfers between oxygen atoms
have low activation energies, and most of the protolytic equilibria shown in
Equations 18-1 to 18-4 are fast. Despite the mechanistic similarity between
these four processes, only the first three are examples of simple catalysis. In
the fourth, the acid-promoted hydrolysis of amides, acid is consumed instead
of regenerated as the reaction proceeds. Thus, although a catalytic quantity
of acid would initiate the hydrolysis of an amide, it would not be sufficient to
carry the reaction to completion.
If we examine the esterification reaction as a function of the concentration
of reactants we find that the reaction has the following kinetic form (rate =
A;[RC0 2 H][EtOH[[H ffi ]. The rate is proportional to the first power of the
concentration of each of the two reactants and the catalyst. If the concentra-
tion of catalyst is doubled the rate doubles. Can the rate be indefinitely in-
creased by addition of more and more catalyst ? Only up to a point. When
most of the carboxylic acid that is present in the system is already in the pro-
tonated form, further increases in acidity can have only a marginal effect on
the concentration of protonated acid. Furthermore, protonation of the alcohol
gives a non-nucleophilic species and therefore decreases the alcohol concentra-
tion. Carboxylic acids and alcohols are rather weak bases and it requires a
considerable amount of acid to reach this point. Amides, however, are less
weakly basic, and the rate of acid-induced hydrolysis of amides reaches a
plateau much earlier as the acid concentration is increased than for esterifi-
cation.
sec 18.1 catalysis in organic systems 499
B. BASE CATALYSIS
Base-promoted reactions already met include the aldol addition (Section
12-2A), hemiacetal (but not acetal) formation and hydrolysis (Section 1 1-4B),
and alkylation of ketones (Section 12-2B). The course of these reactions is
shown in Equations 18-5 to 18-7.
HO fc
p
CH,
-+ H,0 +°CH 2 -C,
CH 3 CHO
I
CH 3 -CH-CH 2 -C
\
H 2
OH
I
CH,— CH-CH,
P
H
OH e
(18-5)
RO e + CH,CH,OH 5=
ROH + CH,CH,O a
RCH0
O u
I
R— CH— OCH 2 CH 3
/ROH
o
e II
NH, + R-C-CH3
OH
R-CH-OCH 2 CH 3 + RO to
O
-» NH,
R-C-CH
(18-6)
(18-7)
For these reactions, the added base (hydroxide ion, alkoxide ion, and
amide ion) generates an organic anion which undergoes further reaction to
give the product. In the last reaction (18-7), however, the base is consumed as
the reaction proceeds, so this reaction does not qualify as an example of
base catalysis. In the other two reactions, base is regenerated in the final steps,
so only catalytic amounts of base are required.
C. NUCLEOPHILIC CATALYSIS
The chloromethane-hydroxide ion reaction catalyzed by iodide ion (Section
18T) is an example of nucleophilic catalysis.
chap 18 enzymic processes and metabolism 500
ie
CH 3 Cl + OH e ► CH 3 OH + Cl e
The catalyst forms a covalent bond to the substrate during the course of
the reaction (CH 3 I is a discrete intermediate). This type of reaction, particu-
larly when it involves an enzyme, is sometimes called " covalent catalysis."
Bases are also nucleophiles and it is reasonable to ask how we distinguish
base catalysis from nucleophilic catalysis. A reagent is a base when it re-
moves a proton, and a nucleophile when it bonds to any atom other than H.
We pointed out earlier that nucleophilicity does not always parallel basicity.
A number of polarizable ions such as I e , N 3 e , HS e , and HOO e have much
greater nucleophilicities than their basicities would indicate.
The molecules of the heterocyclic compound imidazole (Section 25-3) are
neutral and possess high nucleophilicity.
HN N
imidazole
Although the basicity of imidazole is low (pK B = 7), it is effective in cata-
lyzing the hydrolysis of certain esters in neutral solution. These reactions
follow the course shown in Equation 18-8.
— /--"^x ° — ° e — °
HN N: + CH 3 — C ►HNoN-C— OR ► N N-C— CH 3 + ROH
\^ \ ^s i •%/ ...
OR CH 3 [']
.0
*3 — *"
H2 ° CH 3 -C + N NH
\ ^V
R= -C„H t NO,-p OH
The intermediate N-acetylimidazole [1] can be isolated and there is no
doubt that the imidazole is acting here as a nucleophile rather than as a base.
The imidazole ring is present in the amino acid histidine, which is a key
constituent of enzymes catalyzing hydrolytic reactions. This, of course, has
led to speculation that the enzyme operates in the same general manner as
shown in Equation 18-8. It is doubtful, however, that the catalysis is this
simple. Thus, in enzyme-catalyzed hydrolyses of acid derivatives, the acyl
group often becomes attached to the alcohol hydroxyl group of the amino
acid serine in the enzyme. Nonetheless, the imidazole ring in the enzyme plays
an important role in the hydrolysis and we shall examine this reaction further
in Section 18-3.
D. GENERAL ACID AND BASE CATALYSIS
It might be expected that the rate of an acid-catalyzed reaction in buffered
aqueous solution would depend only on the pH of the solution and that the
concentration of buffer would be unimportant, except possibly for a small
salt effect. Some reactions are indeed like this. For example, the rate of the
(18-8)
sec 18.1 catalysis in organic systems SOI
acid-catalyzed hydrolysis of acetals (or its reverse) depends only on the pH
of the solution. This is called specific-acid catalysis.
OH
CH 3 CH(OEt) 2 +H 2 « " CH 3 CHOEt + EtO pH dependent
(specific acid catalysis)
Other acid-catalyzed reactions depend on the nature and the concentration
of the buffer solution as well as on the pH. For example, the rate of the acid-
catalyzed bromination of ketones, which takes place through the enol form,
varies with the identity and concentration of the buffers used to control the pH.
O OH
II H e I
R-C-CH 3 » R-C=CH 2
O
Br? , p _r_rH Rr , H Rr P H and buffer de P endent
R C CH 2 Br + HBr ( genera l acid catalysis)
It is difficult to see the cause of the difference without a complete kinetic
analysis of the mechanisms in the two cases. Suffice it to say here that specific-
acid catalysed reactions are those in which the substrate reacts in an equilib-
rium step with a proton and then suffers a rate-controlling unimolecular
decomposition.
Z + H® < > ZH®
slow
ZH® » products
In the case of acid-catalyzed acetal hydrolysis, the protonated acetal de-
®,OEt
composes slowly to the cation R — C , which then undergoes a rapid
H
reaction with water to give the hemiacetal. The rate now depends simply and
directly on the pH because the concentration of ZH® depends on the pH.
General acid catalysis results when the intermediate ion, ZH®, can only
decompose with the help of a base or a nucleophile.
Z +H® , ZH®
slow
ZH® + :B ► products
®OH
II
For acid-catalyzed enolization, the protonated ketone, R— C— CH 3 ,
requires a base to remove a proton from the methyl group. The base might be
a water molecule or a hydroxide ion (if present in significant concentrations),
or it might be the anion A® of the acid used as buffer. The intervention of the
base A® alters the kinetic form of the equation from one containing [H ffi ] to
one containing [H ffi ][A®]. Because [H®][A®] is kinetically equivalent to
[HA], 1 we will have contributions to the rate which appear to depend on all
iH®irA®i
1 K «* = J A1 : therefore [H®][A®] = K HA [HA] and [H®][AS] oc [HA].
[HA]
chap 18 enzymfc processes and metabolism 502
of the undissociated acids (HA, HA', etc.) which are present, provided
that A e , A' e , and so on are effective bases in removing a proton from the
carbon of the protonated ketone.
A number of enzymic processes are known to be subject to general acid
catalysis, but it is not always easy to distinguish between the action of a base
and a nucleophile in the second step. In an enzyme, the proton source is often
a protonated free amino group in the protein chain. The base or nucleophile
is often an imidazole ring on a histidine unit, also in the protein chain.
The situation with respect to base catalysis is similar and examples of both
specific and general base catalysis are known.
E. INTRAMOLECULAR CATALYSIS
One of the great advantages that enzymes have in accelerating reactions is
that their precisely coiled and folded protein chains place two or more groups
in a position where they can simultaneously interact with the substrate(s). In
some simple molecules, a neighboring group to the reaction site can behave
similarly and cause rate enhancements.
The conversion of 2-bromopropanoic acid to lactic acid can be accomp-
lished in strong base in the normal way, with the product having the inverted
configuration expected for an S N 2 reaction.
CH 3 CHBrC0 2 e + OH e > CH 3 CHOHC0 2 e + Br e
2-bromopropanoate ion lactate ion
d series l series
However, if the concentration of hydroxide ion is lowered by the use of
appropriate buffers, this reaction becomes slower and is eventually superseded
by a process that has a moderate rate, independent of pH. The resulting pro-
duct is lactate ion as before, but it now has the same configuration as the start-
ing material.
The explanation is that the bromide is displaced by the neighboring car-
boxylate group in an internal nucleophilic substitution reaction (called S N i).
The intermediate then suffers a second displacement by a water molecule,
which restores the original configuration.
H 2
Br ) OH
CH 3 -CH-C=0 v.w 3 -
D series L series D series
The intervention of a neighboring group this way is called anchimeric
assistance. Because the reaction illustrated here is accelerated by the neigh-
boring carboxylate group, and because this group emerges from the reaction
intact, it is, in effect, an intramolecular catalyst.
Many other examples of intramolecular catalysis are known. The two phos-
phonate esters [2] and [3] differ enormously in their hydrolysis rates. The
difference is clearly due to intramolecular catalysis by the neighboring car-
boxyl group in [2].
sec 18.2 enzymes and coenzymes 503
° 9
n ii
P(OEt) 2 ^\.P(OEt) 2
half-time for hydrolysis in 22
30% aq. dimethyl sulfoxide 15 minutes > 10 years
at 36° [2] [3]
In nonhydroxylic solvents, molecules that can change from one tautomeric
form to another by donating a proton at one site and accepting a proton at
another are effective catalysts for enolization and other processes. a-Pyridone
[4] is such a molecule because it exists in equilibrium with its tautomer [5].
"N-^o ^isr X)H
H
W [5]
The mutarotation of tetramethylglucose in chloroform solution and a
number of other reactions in which hydrogen shifts are important are
catalyzed by this reagent (Equation 18-9).
in^o
tr T>H
H A ► « (18-9)
A carboxylic acid can also act as a catalyst of this type; it exists in two
tautomeric forms that are exactly equivalent, R — C and R — C
X OH N
Even though Equation 18-9 shows proton shifts, these are concerted so as
not to give free ions at any stage of the reaction. Tautomeric catalysis of the
type shown above appears to be important only in nonhydroxylic media. In
hydroxylic solvents, it is likely that separate protonation and deprotonation
steps occur.
18-2 enzymes and coenzymes
Enzymes are invariably proteins. Some enzymes consist only of peptide chains
and others require the presence of non-amino acid groups or molecules as
well. If these other groups are attached directly to the peptide chain they are
often called prosthetic groups (Section 17-3). If they are complexed to the
enzyme in a looser fashion, they are called coenzymes. In some ways the co-
enzyme resembles a reagent which undergoes a chemical change under the
chap 18 enzymic processes and metabolism 504
influence of the enzyme, just as does the substrate. The difference is that a
coenzyme is restored to its original condition in a subsequent step. Although
all biological oxidation systems make use of coenzymes, many hydrolytic
systems do not.
The most remarkable characteristics of enzymes are their catalytic effective-
ness and their specificity. A striking example of their effectiveness is provided
by the way in which the enzyme urease catalyzes the hydrolysis of urea, a
product of protein metabolism. The nonenzymic reaction under neutral con-
o
II urease
NH 2 -C-NH 2 + H 2 > 2NH 3 +C0 2
ditions in water is so slow that the reaction is virtually undetectable at room
temperature. The rate can be measured at high temperatures, however, and
extrapolated to room temperature. This reveals that at low concentrations of
urea the enzymic hydrolysis is about 10 1A times faster than the uncatalyzed
reaction.
There is an important limitation on the catalytic effectiveness of enzymes ;
it is commonly observed that as the concentration of substrate is increased
the rate of reaction tends to level off. The explanation for this is that the sub-
strate and enzyme form a complex which then decomposes to products. De-
spite the large sizes of enzyme molecules, there are usually only a few sites
(often only one) at which reaction occurs ; these are called the active sites. The
function of the rest of the molecule is normally to bring substrate(s) and active
site together. With a large excess of substrate, the active sites are continually
being filled and the rate or decomposition to products and their removal
from the active sites is the rate-limiting factor. Increasing the number of sub-
strate molecules awaiting reaction increases the rate of product formation only
up to the point where the enzyme becomes saturated with substrate. This
phenomenon is called the Michaelis-Menten effect.
The reasons for the high specificity of enzymes have been the subjects of
lively debate. According to one view — the " induced-fit " theory — the catalytic
groups at the active site in an enzyme only take up positions in which they can
interact with a substrate as a result of a conformational change that forces
the enzyme into a slightly less energetically favorable, but catalytically active,
spatial arrangement. This theory accounts for the observation that certain
compounds, even though they may bind to the active site of an enzyme, do
not undergo further reaction. They do not have the necessary structural
features to induce the critical conformation at the active site.
18 -3 hydrolytic enzymes
A large number of hydrolytic enzymes that catalyze esters and amide hydrol-
ysis are known. Undoubtedly the most intensively studied of these is chymo-
trypsin, an enzyme of the digestive tract. It is a protein molecule with a
molecular weight of 24,500, consisting of three peptide chains. There are
two amino acid units in the enzyme that are known to be intimately involved
sec 18.3 hydrolytic enzymes SOS
in the bond-breaking steps of ester hydrolysis. These are histidine [6] and
serine [7].
CH 2 CHC0 2 H HOCH,CHC0 2 H
HN N NH 2 NH 2
histidine serine
[6] [7]
When an ester such as phenyl acetate, CH 3 — C , is hydrolyzed
OC 6 H 5
by the action of chymotrypsin, the acetyl group, CH 3 — C , is actually
transferred to the enzyme. In a subsequent step the acetylated enzyme is
hydrolyzed to acetic acid and the enzyme is regenerated. The hydroxyl group
O °
/ II
E — H + CH 3 — C ► E— C — CH 3 + C 6 H 5 OH
OC 6 H 5
acetylated
enzyme enzyme
O O
II /
E — C— CH 3 + H 2 ► EH + CH 3 C
OH
in the serine unit in the chain has been identified as the group that becomes
acetylated. The imidazole ring of the histidine unit is known to aid this trans-
fer, possibly by acting as a base. In the mechanism shown in Figure 18-2, the
Figure 18-2 Possible mechanism for the chymotrypsin-catalyzed hydrolysis
of phenyl acetate; E = enzyme.
* \ ri )T
HN \^ N! ^ H ~°~" ' C-CH 3 -HN. ? ,HN O-C-CH,
C 6 H s O oc H
[8]
O
HN \J* 6— C + C 6 H s OH
X CH 3
[9]
H,0
+ CH 3 C0 2 H
NH. N OH
chap 18 enzymic processes and metabolism 506
imidazole accepts a proton from the serine hydroxyl as the latter attacks the
carbonyl carbon of the ester.
The ester must be held in position at the active site of the enzyme by com-
plex formation. This presumably involves hydrogen bonds to the carbonyl
oxygen atom, thus avoiding a full negative charge being generated at this
site in the intermediate [8]. The cleavage of the phenoxy group in [8] and the
deacylation of [9] that restores the enzyme to its original state also seem to be
assisted by the imidazole ring, acting as a base in each case. There are, in
fact, two histidine units in the peptide chain of chymotrypsin, and it is possible
that both are involved in one or more of these steps.
Another important hydrolytic enzyme is acetylcholinesterase. Nerve cells
contain the molecule acetylcholine [10] in a bound state. Stimulation of the
cell releases acetylcholine, which stimulates the neighboring cell to release
acetylcholine and this, in turn, its neighbor, thus transmitting the nerve im-
pulse. Deactivation of the stimulant must be done very quickly once the im-
pulse is transmitted. Deactivation is achieved by the enzyme acetylcholines-
terase, which catalyzes the hydrolysis.
o
II ffi acetylcholinesterase ? T ,^r, s
CH 3 -C-OCH 2 CH 2 N(CH 3 ) 3 + H 2 ► CH 3 C0 2 H + HOCH 2 CH 2 N(CH 3 ) 3
acetylcholine choline
[10]
A nerve poison such as diisopropyl ftuorophosphate, [(CH 3 ) 2 CHO] 2 POF,
forms a stable ester with the serine hydroxyl at the active site in the enzyme,
thus preventing the deactivation step from occurring.
18-4 oxidative enzymes
The groups ordinarily present in a peptide chain do not undergo facile oxi-
dation or reduction and, as a consequence, the enzymes involved in biological
oxidation and reduction processes utilize a coenzyme which serves as the
actual oxidant or reductant. One of the most important coenzymes in this
regard is the molecule nicotinamide-adenine dinucleotide (Figure 18-3), ab-
breviated NAD®. [This substance is often called " diphosphopyridine nucleo-
tide" (DPN®). The name used here is that approved by the International
Union of Biochemistry.] The structure of this molecule is not unlike that of
adenosine triphosphate (ATP) met earlier (Section 15-5). It contains the
adenosine ring (upper right in Figure 18-3) attached to a ribose molecule
which in turn has a phosphate link. In NAD®, this is diphosphate, not tri-
phosphate, and is further linked through another ribose ring to a nicotinamide
unit (upper left in the formula). The pyridinium ring in the latter unit is the
active oxidant. Since the molecule contains two nitrogen bases, two sugar
units, and two phosphates it is a dinucleotide.
Ethanol is oxidized in the liver by NAD® under the influence of the enzyme
alcohol : NAD oxidoreductase. (This enzyme is often called alcohol dehydro-
genase, but such a name implies that the enzyme acts in one direction only.
Like all catalysts, enzymes increase the rates of both forward and reverse
sec 18.4 oxidative enzymes 507
H,N'
Xa — kc
L/OHHON
CH,— O-
o e
I
-p— o—
II
o o
NH 2
P-0-H 2 ^0^\ N J^ N J
HO OH
Figure 18-3 The coenzyme nicotinamide-adenine dinucleotide (NAD®).
Although it is anionic at neutral pH, because of the ionization of the diphos-
phate linkage, the reactive part of the coenzyme bears a positive charge,
hence the abbreviation NAD®.
reactions). In the oxidation of ethanol to acetaldehyde a hydride ion is trans-
ferred from C-l to the pyridinium ring in the coenzyme at the same time as
a proton is lost by the hydroxyl group.
CH 3 CH 2 OH +
H,N
CH,-C + H e
HH
1SK
There is extensive evidence in support of this mechanism which will not
be covered here. Instead we will consider three important general questions.
First, what is the function of the remainder of the coenzyme molecule?
Second, what is the function of the enzyme itself? And third, how is the re-
duced form of the coenzyme (abbreviated NADH) oxidized back to NAD®
so that it can be used again ?
The coenzyme contains a number of hydrogen-bonding groups that must
function to bind the coenzyme to the enzyme in such a way that the pyri-
dinium ring is in a favorable position to react. For its part, the enzyme func-
tions to complex both the coenzyme and the substrate. But it must also be
involved in removing the hydroxyl hydrogen as a proton because otherwise
the energetically unfavorable species CH 3 CHOH® (protonated acetaldehyde)
would be formed.
Either a carboxylate ion or an amino group in the coiled protein chain of
the enzyme might be hydrogen bonded to the hydroxyl group of the alcohol
and be able to accept the proton completely at the critical stage of C— H bond
rupture. We saw in the previous chapter that a number of amino acids contain
such additional groups. Because amino groups are extensively protonated at
physiological pH, we show a carboxylate ion as the proton acceptor in Figure
18-4, which shows a plausible, but rather simplified, view of the enzyme-
catalyzed oxidation of ethanol by NAD®.
The NADH that is formed is reoxidized by another enzyme-coenzyme
system. The ultimate oxidizing agent for most physiological oxidations is, of
course, molecular oxygen, but its reaction with NADH is extremely slow.
chap 18 enzymic processes and metabolism 508
transition state
Figure 18-4 Possible mechanism for the NAD© oxidation of ethanol under
the influence of the enzyme alcohol: NAD oxidoreductase; E= enzyme.
A whole battery of enzymes is required to catalyze the overall reaction :
CH 3 CH 2 OH + 3 2
-* 2C0 2 + 3H 2
We have seen that NAD®, a hydride acceptor, reacts directly with ethanol.
The enzyme that reacts with oxygen must have rather different characteristics
because oxygen is a substance which invariably reacts by one-electron steps.
(Transfer of hydride ion, H e , amounts to a two-electron or two-equivalent
group oxidation-reduction step. Transfer of H® is neither oxidation nor re-
duction, transfer of H- is a one-electron step, and transfer of H : e is a two-
electron step.)
The enzyme systems that react directly with oxygen in these reactions are
called cytochromes. They contain an iron atom complexed in a cyclic system
that resembles that in hemoglobin (Section 25-4). Whereas the ferrous ion in
hemoglobin complexes with oxygen, the ferrous ion in the cytochromes is
oxidized to the ferric state, each iron atom undergoing a one-electron change.
4 Fejl, + 2 + 4 H s
-» 4Fe m ,+2H 2
Between Fe'" t and NADH come a number of other enzyme systems, one
of which must be capable of reacting both with a one-equivalent couple such
as Fe n -Fe m and with a two-equivalent couple such as NAD®-NADH. The
enzyme systems that play this role are known as flavins.
Batteries of enzymes able to bring about the overall oxidation of ethanol
sec 18. S the energetics of metabolic processes 509
to acetaldehyde (and similar processes) are located in the mitochondria. These
are subcellular, oblong bodies found in the oxygen-consuming cells of plants
and animals. They are reponsible for oxidizing carbohydrates and fats to
carbon dioxide and water and supplying the energy for processes such as
muscle action, nerve impulses, and chemical synthesis. The sequence of re-
actions is often called the electron-transport chain, although this name ob-
scures the fact that most of the reactions, including the oxidation steps, are
not, in fact, simple electron transfer processes.
18-5 the energetics of metabolic processes
The mitochondrial enzymes not only speed up the rate of the overall reaction
of oxygen with say, glucose, by an enormous factor (probably in excess of
10 20 ), but they also control the energy release so that it can be used for a
multitude of purposes and not simply appear as heat. This is done by har-
nessing the many oxidation steps to the synthesis of adenosine triphosphate
(ATP) from adenosine diphosphate (ADP) and inorganic phosphate (Equa-
tion 18T0). Hydrolysis of ATP releases this energy in such a way that the
system can utilize it as work. Neither the mechanisms of the coupling of the
oxidation steps to ATP synthesis (oxidative phosphorylation) nor the coupling
of the hydrolysis step to production of work are very well understood at
present.
e
^-I'-
ll
o
I
O-P — OH,C
II
o
NH 2
+ HP0 4 + H £
OH OH
ADP
H,0
(18-10)
AG = +7 kcal (at pH 7.0, 25°)
ATP and ADP are shown in Equation 18T0 in the ionic forms which
predominate at pH 7.
The complete oxidation of one mole of glucose releases 673 kcal of heat
and the standard free energy change for the reaction is almost the same. It is
chap 18 enzymic processes and metabolism 510
Table 18*1 Heats of combustion of various substances
compound
state
formula
Ml,
kcal
per mole
per gram
ethane
g
CH3CH3
370
12.3
octane
1
■ CH 3 (CH 2 ) 6 CH 3
1303
11.4
cetane
s
CH 3 (CH 2 ) 14 CH 3
2560
11.3
ethanol
1
C2H5OH
328
7.1
glyceryl tri-
stearate
(a typical fat)
s
CH 2 2 CCi7H 35
1
CHO2CC17H35
1
CH 2 2 CCnH 35
8290
9.3
glucose
s
CeHi 2 6
673
3.7
starch
s
(CeHioOs)*
x-678
4.2
glycine
protein
s
s
NH 2 CH 2 C0 2 H
O
11
(-NHCHC-),
1
R
235
159"
3.1
2.1"
<4"
" To give carbon dioxide, liquid water, and nitrogen. (Some of these values differ from those
given in Chapter 2, where all the products were assumed to be gases.)
* To give carbon dioxide, liquid water, and urea.
clear that such a process, even if it could occur rapidly in a cell, has to be
partitioned into small packets of energy for ATP synthesis (AG = +7 kcal)
to be accomplished.
C 6 H 12 6 +6 2
-*• 6 C0 2 + 6 H 2
AG = -686 kcal
A#= -673 kcal
Oxidation (in effect combustion) of fats, carbohydrates, and proteins pro-
vides the energy for metabolic processes of animals. A comparison of the
heats of combustion of these classes of compounds reveals that fats release
far more heat on a weight basis than do either carbohydrates or proteins.
Table 18T gives the heats of combustion of compounds of each type and in-
cludes for comparison those of some other fuels. The combustion energy
clearly decreases as the degree of oxidation of the compound increases. Thus,
hydrocarbons (AH ~ —11 kcal g _1 ) release the most energy, followed by
fats (A//~ —9.3 kcal g _1 ) which contain long hydrocarbon-like chains.
Carbohydrates (AH ~ —4.0 kcal g _1 ) are already in a partly oxidized state
and so their available combustion energy is less. (This is reflected in the smaller
amounts of oxygen they consume during combustion.)
Why are proteins (AH 4 kcal g _1 or less), which contain less oxygen
than carbohydrates, not better sources of energy? To a great extent because
summary 5 1 1
they do not undergo complete combustion. In man and other terrestrial verte-
brates most of the nitrogen in proteins is converted to urea and excreted as
such or as its hydrolysis product, ammonia. This is rather wasteful energetic-
ally because the combustion of urea with formation of nitrogen would release
an additional 2.5 kcal g -1 .
O
NH 2 -C-NH 2 + | 2 ► C0 2 +N 2 +2H 2 AH= -152 kcal
ur ea (2.5 kcal g" 1 )
However, having urea as the end product of protein metabolism provides
those organisms that are unable to fix N 2 with a source of nitrogen for
chemical synthesis.
The fixation of N 2 by certain bacteria is a biological reduction reaction of
great interest. Very few nonbiochemical systems are known which will react
with N 2 at room temperature and atmospheric pressure. Lithium metal com-
bines slowly with nitrogen to form lithium nitride Li 3 N. Another is the
titanium(II) compound titanocene, whose simplest formula is (C 5 H 5 ) 2 Ti, sug-
gesting that it might be a sandwich compound like ferrocene (C 5 H 5 ) 2 Fe
(Section 9-9F). Titanocene appears to be a dimer, however, and its true struc-
ture has yet to be established. It reacts with nitrogen at room temperature to
give a compound (C 5 H 5 ) 2 TiN 2 (again apparently dimeric) which can be
reduced to ammonia.
summary
The fastest chemical reactions are those which occur at each encounter be-
tween reactants. The controlling factors for such reactions are the rates of
diffusion of the reactant molecules ; in solution at room temperature, these have
rate constants of about 10 10 liters mole -1 sec -1 . The rates of other chemical
reactions depend on the energy differences between reactants and transition
states (the activation energy). A catalyst speeds up a reaction by providing an
alternate path from reactants to products via a lower-energy transition state.
Heterogeneous catalysts operate by providing a favorable surface for the re-
action to occur on, while homogeneous catalysts form reactive combinations
in solution which subsequently give the reaction products and regenerate the
catalyst.
Many acid-catalyzed reactions of carbonyl compounds take place by way
of this general path:
O e OH OH OH
# +H ®. / HY I ®
R-C . > R-C > R-C-YH
z z
chap 18 enzymic processes and metabolism 512
The rate of such a reaction is proportional to [RCOZ] [HY][H e ], provided
the concentration of acid catalyst is not so great as to substantially proto-
nate the carbonyl compound.
Many base-catalyzed reactions of carbonyl compounds occur by this
general path:
ZH + RO e
=t Z + ROH
R-C
O e OH
R _C-Y -5£»* R-C-Y + RO e
I I
z z
Closely related to base catalysis is nucleophilic catalysis, in which the
catalyst forms a bond to the substrate rather than removing a proton from it.
Imidazole is particularly effective in this regard.
General acid catalysis occurs when the reaction rate depends on the con-
centration of all the acids present in the system, not simply on the hydrogen
ion concentration. Most reactions of this type involve attack of a base on a
protonated intermediate. The combined effect of the proton H e and the base
A e appears in the kinetic expression as the function [HA].
Some reactions are subject to neighboring group (anchimeric) assistance.
If the neighboring group is regenerated in a subsequent step, this can be
thought of as intramolecular catalysis.
■col
-X s
o
O
Y s
-co?
Tautomeric catalysts are those which can donate and accept protons si-
multaneously, such as a-pyridone, which is especially effective for catalysis
of mutarotation of sugars.
Enzymes are highly efficient biological catalysts. They are protein molecules
that sometimes have smaller units such as coenzymes associated with them.
The active site is the place in the protein chain where the substrate becomes
bound and where reaction actually occurs.
A hydrolytic enzyme such as chymotrypsin does not require a coenzyme.
Instead, histidine and serine units in the protein chain appear to function
together to effect the hydrolytic cleavage of esters and amides. Histidine con-
tains an imidazole ring which probably acts as a base in removing a proton
from the serine hydroxyl group at the same time that the oxygen of the latter
bonds to the carbonyl carbon of the ester. The acylated serine that is thus
formed is subsequently cleaved to give the free acid.
HN N
exercises SI 3
Oxidative enzymes and coenzymes include nicotinamide-adenine dinucleo-
tide, NAD®; the flavins; and the cytochromes. NAD® is a coenzyme that
behaves as a two-equivalent oxidant by removing hydride ion from com-
pounds such as ethanol. The pyridinium ring is thereby reduced and the com-
pound NADH is formed. The function of the enzyme is to orient the co-
enzyme and substrate in such a way as to facilitate the reaction.
o o
II II H H
N-"
N'
R R
In those parts of living cells called mitochondria, the biological oxidation
chain includes NAD® at one end (oxidants for various covalent organic
compounds) and the cytochromes at the other (systems that are oxidized by
molecular oxygen). These disparate kinds of redox systems are linked by a
number of other enzyme-coenzyme systems.
Much of the energy released by virtue of combustion of organic compounds
in living cells is stored by synthesis of adenosine triphosphate (ATP) from the
diphosphate (ADP) and inorganic phosphate, and subsequently used to drive
a multitude of physiological processes.
Hydrocarbons, fats, carbohydrates, and proteins release on combustion
about 1 1 , 9, 4, and less than 4 kcal per gram, respectively. This order reflects
to a great extent the state of oxidation of the compounds themselves.
exercises
18-1 Will the rate of a diffusion-controlled reaction be affected by a change in
temperature of the system ?
18-2 The reaction of 1-chlorobutane with sodium hydroxide to give w-butyl
alcohol is catalyzed by sodium iodide. Work out the stereochemistry to be
expected for both the catalyzed and the uncatalyzed reactions if right-handed
1 -chlorobutane- 1 -D
H
I
(CH 3 CH 2 CH 2 — C— CI) were used as the starting material. Show your
I
D
reasoning.
18-3 Is the hydrolysis of amides brought about by hydroxide ion an example of a
base-catalyzed reaction ?
18-4 Why do the laws of conservation of energy require that a catalyst increase
both the forward and reverse rates of a chemical reaction ? Is there a viola-
tion of this principle in the system used for the preparation of diacetone
alcohol? (See Figure 12-1.)
chap 18 enzymic processes and metabolism 514
18-5 Draw resonance structures for the cation and for the anion of imidazole
(formed by protonation and deprotonation, respectively).
18-6 What might one conclude about the active site of a-chymotrypsin from the
fact that negatively charged inhibitors are less effective in reducing catalytic
activity than neutral molecules of the same type of structure ?
18-7 Is important conjugation possible between the amide group and the ring
nitrogen in the dihydropyridine ring of NADH? (See Figure 18-4).
1 8-8 Which of the following reagents are likely to be one-equivalent oxidants and
which two-equivalent oxidants ?
O
Co'", TV", Pd", (CH 3 ) 3 C®, ©OC1, Fe(CN),
36
CH 3 °
18-9 Assuming the carboxylate group shown in Figure 18-4 belongs to a non-
terminal amino acid in the enzyme, which amino acids could fill this role ?
18-10 Arrange the following compounds in the order of their expected heats of
combustion (on a per gram basis): 1,4-butanediol, 1,3-butadiene, 1,2-
butadiene, 2-methylpropanoic acid.
18-11 Let us assume that memory depends on proteins with particular amino acid
sequences being deposited in the brain. Calculate the approximate number
of amino acid molecules that would be deposited per second if one gram
(0.04 ounce) of protein is added to the brain in this way in one year. In your
opinion is this number sufficiently high that the source of memory could be
explained on this basis ?
<m- $?& m.
mmmMm%MMfM : m
1 &*gjf?ii^ !
phosphorus, silicon,
' and boron
tegn !
Hi:
^11
^
■'SV
IHIjBi
.;■;*{■■;'
£.5
,--> \
', * 'i'--
af S iSJ
L "'.-. v "'.'-'- '^' -V='i
chap 19 organic compounds of sulfur, phosphorus, silicon, and boron 517
The four elements we shall consider in this chapter occupy positions in the
periodic table that are adjacent to carbon, nitrogen, and oxygen, the three
elements whose compounds have been our chief concern up to this point.
Figure 19-1 shows the locations of these seven elements and the number of
valence-shell electrons that each possesses.
A similarity is to be expected between the bonding pattern exhibited by a
second-row element and by the element immediately above it, because both
possess the same number of valence electrons. However, a second-row element
has an additional degree of freedom since it is not necessarily restricted to a
maximum of eight electrons in its bonding shell. The compounds SF 6 and
PF 5 are both stable gaseous compounds, and it is clear that sulfur and
phosphorus in these molecules have a share in 12 and 10 bonding electrons,
respectively. The electron configurations of atomic oxygen and sulfur are
shown in Figure 19-2. It appears that sulfur must make use of its 3d orbitals in
forming SF 6 , as does phosphorus in forming PF 5 . Although silicon can
also use its d orbitals in bonding (SiF 6 2e is known), it generally tends to be
tetracovalent like carbon. Boron is different from any of the elements we have
been discussing and we shall consider its pattern of bonding in Section 19-5.
19-1 d orbitals and chemical bonds
The maximum number of s electrons is two, of p electrons six, and of d
electrons 10 in any atomic shell. Although s orbitals are spherical and p
orbitals dumbbell shaped, it was shown in Chapter 1 that the shape of the
bonding orbitals in a molecule may bear little resemblance to these atomic
precursors. Thus, CH 4 has a tetrahedral configuration for its bonds because
this is the arrangement in which repulsion between the bonding electrons is at
a minimum.
The three p orbitals on an isolated atom run along the three geometric
axes, x, y, and z, and are all clearly equivalent. The four bonding orbitals in a
molecule such as CH 4 are tetrahedrally arranged and, again, all four are
clearly equivalent. When we come to the five d orbitals that assume impor-
tance in the bonding of second-row elements, we encounter a new situation.
If five bonds around a central atom are separated to the maximum extent they
cannot be equivalent. This may not seem obvious at first glance. One might
Figure 19*1 The first two rows of the periodic table showing the relative
positions of boron, silicon, phosphorus, and sulfur with respect to carbon,
nitrogen, and oxygen, and the numbers of valence electrons of each.
Li
Be
•B
•C-
:N-
:6:
F
Ne
Na
Mg
Al
•Si-
:P-
:S:
CI
Ar
chap 19 organic compounds of sulfur, phosphorus, silicon, and boron S18
SB
1-
c
o
.5
oxygen
3 d o o o o o
3PO O O
3s O
sulfur
ooooo
© © © M
©
2p © © ©
2s ©
@ © ©
©
Is ©
@ K
Figure 19-2 Electronic configurations of oxygen and sulfur.
expect that five lines can be drawn radiating from a central point so that all
are equivalent, just as four lines can.
Solid geometry shows us that this is not so. There are only five regular
polyhedra, the tetrahedron (four sides, four apexes), the cube (six sides,
eight apexes), the octahedron (eight sides, -six apexes), the dodecahedron
(12 sides, 20 apexes), and the eicosahedron (20 sides, 12 apexes). This means
that only those three-dimensional spatial arrangements with four, six, eight,
12, and 20 apexes have their apexes in identical and equivalent positions.
Since the five atomic d orbitals are, in fact, exactly equivalent in energy, what
shapes do they assume? If they are all completely filled or half-filled, the
resulting electron cloud is spherically symmetrical. But this does not help to
provide us with a picture of the five component orbitals. A mathematical
solution to the electronic wave equation, however, provides the shapes of the
five d orbitals as shown in Figure 19-3. Despite the different appearance of the
d z 2 orbital, it is equivalent in energy to the other four rosette-shaped d orbitals.
O
Should we assume that the bonds in molecules such as SF fi or HO— S-
II
O
OH
point in directions corresponding to the directions of maximum extent of the
d orbitals? The same problem arises here as in inferring the tetrahedral ar-
rangement of bonds in methane from the shapes of s or p orbitals. The maxi-
mum number of electrons that are found in the valence shell of sulfur is 12
and, if the bonds are all equivalent (as they are in SF 6 ), then the six pairs of
electrons will on the average be located at the corners of a regular octahedron.
sec 19.1 d orbitals and chemical bonds 519
The six bonds are sometimes designated d 2 sp 3 hybrids, or octahedral
bonds, just as the four single bonds to carbon are designated sp 3 or tetra-
hedral bonds.
Double bonds to tetravalent or hexavalent sulfur, as in (CH 3 ) 2 S=0 or
O
II
CH,— S— CH, , differ from double bonds to carbon in that the n bonds are
II
O
formed not by p orbitals on sulfur but by something close to d orbitals.
Divalent sulfur compounds, on the other hand, such as thioketones, R 2 C=S,
are formed by interaction of p orbitals on both carbon and sulfur, Such com-
pounds are relatively uncommon and often are unstable with respect to
polymerization, which can be ascribed to low effectiveness of 71-type interac-
action involving 3p orbitals. In this connection we may note that S 2 , unlike
2 , is highly unstable and that elemental sulfur is most stable in the cyclic S g
form. The reluctance of sulfur to form double bonds to carbon is also exhib-
ited by phosphorus and silicon, and no stable compounds are known with
C=Si or C=P bonds.
Dimethyl sulfoxide, (CH 3 ) 2 S=0, has an unshared pair of electrons on
sulfur and, unlike acetone, (CH 3 ) 2 C=0, is nonplanar.
Figure 19-3 The five atomic d orbitals; all are equivalent in energy.
A,2__ v 2
ld 2 2
chap 19 organic compounds of sulfur, phosphorus, silicon, and boron 520
/h 3 c^ „
/ x
/ H 3 C
V
o
\ \® e ||
Some persons prefer to write S=0 bonds as S— O and — S— bonds as
e / / II
I °
— S— , thus preserving an octet arrangement about sulfur. The difference in
e
electronegativity between oxygen and sulfur suggests that such structures
should make important contributions to the resonance hybrid. Nonetheless,
we shall use the double-bonded formulas in this book because they emphasize
the d-orbital participation in the bonding. It is important to recognize that
drawing S— O does not imply any necessary correspondence to carbon-
oxygen or carbon-nitrogen double bonds.
19-2 types and nomenclature of organic
compounds of sulfur
A number of typical sulfur compounds with their common and IUPAC
names are listed in Table 19-1. It can be seen that the divalent sulfur deriva-
tives are structurally analogous to oxygen compounds of types discussed in
earlier chapters. These sulfur derivatives are often named by using the prefix
thio in conjunction with the name of the corresponding oxygen analog. The
prefix thia is occasionally used when sulfur replaces carbon in an organic
compound.
CH 3 CH 2 SH
ethanethiol
CH 3 -C x
S-H
dithioaeetic acid
(ethanethionthioic acid)
Q-SH
thiophenol
C„H,
-CH,
I "
-CH,
thiacyclobutane
(trimethylene sulfide)
(thietane)
C„H
C„H<
6"5 "j* V '6' J 5
C 6 H 5
1 ,2,4,6-tetraphenylthiabenzene
1 Terms such as organosulfur, organophosphorus, and so on actually refer to those com-
pounds containing the bonds C— S, C— P, and so on. Just as sodium acetate is not regarded
as an organometallic compound, so dimethyl sulfate, (CH 3 0) 2 S0 2 , is not regarded as an
organosulfur compound; the links between carbon and the other element are through
oxygen in both cases.
sec 19.2 types and nomenclature of organic compounds of sulfur 521
Table 19-1 Typical organic compounds of sulfur
compound
oxygen analog
common name
IUPAC name
CH 3 SH
ROH
methyl mercaptan
methanethiol
C2H5SC2H5
ROR
diethyl sulfide
diethyl thioether
ethylthioethane
C 6 HsSSC6H 5
R-O
-0-R
diphenyl disulfide
phenyldithio-
benzene
© e
(CH 3 ) 3 S Br
R3O
e
X
trimethylsulfonium
bromide
(C 6 H 5 )2C=S
R 2 C=
O
thiobenzophenone
N0 2
2N -^-s-
-CI ROCi
2,4-dinitrobenzene-
sulfenyl chloride
2,4-dinitrobenzene-
sulfenyl chloride
O
II
C2H5-S-OH
ethanesulfinic acid
ethanesulfinic acid
O
II
CH 3 -S— OH
II
O
methanesulfonic
acid
methanesulfonic ■
acid
O
II
CH 3 -S— CI
II
O
methanesulfonyl
chloride
methanesulfonyl
chloride
O
II
CH3 S — C2H5
II
CeHs S CeH 5
11
ethyl methyl
sulfoxide
methylsulfinyl-
ethane
diphenyl sulfone
phenylsulfonyl-
benzene
11
CH3O-S— 0CH3
11
dimethyl sulfate
dimethyl sulfate
A. THIOLS
The thiols (or mercaptans) are derivatives of hydrogen sulfide in the same way
that alcohols are derivatives of water. The volatile thiols, both aliphatic and
aromatic, are like hydrogen sulfide in possessing characteristically disagree-
able odors.
chap 19 organic compounds of sulfur, phosphorus, silicon, and boron 522
A variety of thiols occurs along with other sulfur compounds to the extent
of several percent in crude petroleum. Besides having objectionable odors,
these substances cause difficulties in petroleum refining, particularly by
poisoning metal catalysts. The odors from pulp mills arise from volatile
sulfur compounds formed during the digestion operation (Section 15-7).
Thiols also have animal and vegetable origins; notably, butanethiol is a
component of skunk secretion; propanethiol is evolved from freshly chopped
onions, and, as we have seen in Chapters 17 and 18, the thiol groups of
cysteine are important to the chemistry of proteins and enzymes.
In many respects, the chemistry of thiols is like that of alcohols. Thus
thiols can be readily prepared by the reaction of sodium hydrosulfide (NaSH)
with those alkyl halides, sulfates, or sulfonates which undergo S N 2 displace-
ments. This synthesis parallels the preparation of alcohols from similar
substances and hydroxide ion (Chapter 8).
C 2 H 5 Br + SH e ► C 2 H 5 SH + Br e
Since thiols are acids with strength comparable to hydrogen sulfide
C^ha — 6 x 10~ 8 ), some thioethers may be produced by the following
sequence of reactions, unless the sodium hydrosulfide is used in large
excess :
C 2 H 5 SH + SH e . C 2 H 5 S e +H 2 S
C 2 H 5 S e + C 2 H 5 Br ► (C 2 H 5 ) 2 S + Br e
Thiols can also be prepared by the reaction of Grignard reagents with sulfur
(Section 9-9C).
Br MgBr SMgBr SH
Mg f) S f] H ffi ,H 2
ether
cyclohexyl cyclohexane-
bromide thiol
Thiols do not form as strong hydrogen bonds as do alcohols, and conse-
quently the low-molecular-weight thiols have lower boiling points than
alcohols; thus ethanethiol boils at 35° compared to 78.5° for ethanol. The
difference in boiling points diminishes with increasing chain length.
The lack of extensive hydrogen bonding is also evident from the infrared
spectra of thiols, wherein a weak band characteristic of S— H linkages
appears in the region 2600 to 2550 cm -1 . In contrast to the O— H absorption
of alcohols, the frequency of this band does not shift significantly with
concentration, physical state (gas, solid, or liquid), or the nature of the solvent.
It is perhaps surprising, in view of the smaller electronegativity of sulfur
than oxygen, that thiols are considerably stronger acids than the correspond-
ing alcohols. Thus K UA of ethanethiol is about 10" u , compared to 10~ 17 for
ethanol. However, this behavior is not unusual, in that H 2 is a weaker acid
than H 2 S, HF is weaker than HC1, and NH 3 is a weaker acid than PH 3 .
Thiols form insoluble salts with heavy metals, particularly mercury. This
behavior is the origin of the common name (now out of favor), for thiols,
mercaptan. As mentioned above, alkali metal salts of thiols react readily in
sec 19.2 types and nomenclature of organic compounds of sulfur 523
S N 2-type displacements to yield thioethers, and this provides a general
method of synthesis of these substances. The pronounced nucleophilicity of
sulfur combined with its relatively low basicity makes for rapid reaction with
little competition from elimination, except for those compounds where
S N 2-type displacements are quite unfavorable and E2-type elimination is
favorable.
Thiols react with carboxylic acids and acid chlorides to yield thioesters and
with aldehydes and ketones to yield dithioacetals and dithioketals, respec-
tively.
o o
II II
CH,CH,SH + CH,-C-C1
ethyl thioacetate
O H 3 C S— CH 2
« HO \ / \
HSCH 2 CH 2 CH 2 SH + CH3-C-CH3 — ^-* C CH 2
1 ,3-propanedithiol H 3 C S— CH
acetone trimethylene
dithioketal
An important difference between thiols and alcohols is their behavior
toward oxidizing agents. In general, oxidation of alcohols occurs with increase
of the oxidation level of carbon rather than that of oxygen ; carbonyl groups,
not peroxides, are formed. It takes a powerful oxidizing agent (e.g., Co 111 ) to
achieve one-electron oxidation of oxygen by removing a hydrogen atom from
the hydroxyl group of an alcohol.
R— O— H + -X ► RO • + HX (a generally unfavorable reaction)
In addition, the hydroxyl oxygen of an alcohol does not accept an oxygen
atom from reagents like hydrogen peroxide, although these same reagents
readily donate an oxygen atom to nitrogen of amines to form amine oxides
(see Section 16-1F5). Why does the oxidation of thiols take a different course?
:0: 9
ROH + H 2 2 / > R:5:H ► R-O-O-H
RN(CH 3 ) 2 + H 2 2 ► RN(CH 3 ) 2 + H 2
First, because the strength of S— H bonds (83 kcal) is considerably less than
that of O— H bonds (111 kcal); there is therefore good reason to expect that
reaction mechanisms that are unfavorable with alcohols might well occur
with sulfur. Thus we find that oxidation of thiols with a variety of mild
oxidizing agents, such as atmospheric oxygen, halogens, sulfuric acid, and so
on, produces disulfides, probably by way of thiyl radicals. The coupling of
the amino acid cysteine to give cystine is an important example of this
reaction (Section 17-1).
R-S-H + [O] »■ R-S- + H [O]
2RS- * RS-SR
disulfide
chap 19 organic compounds of sulfur, phosphorus, silicon, and boron 524
The second reason for the difference between alcohol and thiol oxidations
is that compounds in which sulfur is in a higher oxidation state are frequently
stable. Thus, vigorous oxidation of thiols with nitric acid, permanganate, or
hydrogen peroxide gives sulfonic acids, possibly by way of the disulfides, or
else through intermediate formation of the sulfenic and sulfinic acids, which
are themselves too readily oxidized to be isolated under these conditions.
R — S— S— R
disulfide
O
II
-♦ R-S — S-R -
O
thiosulfonate ester
O O
II II
->• R— S — S— R
o o
disulfone
R — SH
sulfonic acid
R-S-OH
sulfenic acid
O
II
R— S — OH
sulfinic acid
B. ALKYL SULFIDES
Organic sulfides or thioethers, R— S— R', are readily obtained by displace-
ment reactions between alkyl compounds and salts of thiols (Section 19-2A).
HOCH 2 CH 2 SH + (CH 3 ) 2 S0 4
ethan-l-ol-2-thiol
aq. 25% NaOH
1
60°-70°
HOCH 2 CH 2 SCH 3
2-(methylthio)ethanol
Sulfides undergo two important reactions involving the electron pairs on
sulfur. They are rather easily oxidized to sulfoxides and sulfones (see next
section), and they act as nucleophilic agents toward substances that undergo
nucleophilic displacement readily to give sulfonium salts. The formation of
sulfonium salts from alkyl halides is reversible, and heating of the salt
CH 3
:sfTcH 3
/
CH 3
n
CH 3
\ e
®S-CH 3 I
/
CH 3
trimethylsulfonium iodide
causes dissociation into its components. Sulfonium salts are analogous in
structure and properties to quaternary ammonium salts ; sulfonium hydrox-
ides, R 3 S e OH e , like quaternary ammonium hydroxides, R 4 N e 0H e
(Section 16-IE1), are strong bases.
A noteworthy feature of sulfonium ions is that, when substituted with three
different groups, they can usually be separated into optical enantiomers. Thus
the reaction of methyl ethyl sulfide with bromoacetic acid gives a sulfonium
ion that is separable into dextro- and levorotatory forms by crystalliza-
tion as the salt of an optically active amine. The asymmetry of these ions
sec 19.2 types and nomenclature of organic compounds of sulfur S25
stems from the nonplanar configuration of the bonds formed by sulfonium
's'f .s®
H 3 C V"CH 2 CH 3 CH 3 CH 2 y CH 3
CH 2 C0 2 H H0 2 CH 2 C
enantiomers of methylethyl(carboxymethyl)— sulfonium ion
sulfur. The optically active forms of unsymmetrically substituted sulfonium
ions are quite stable — surprisingly so, in view of the very low configurational
stability of analogously constituted amines. Apparently, nonplanar com-
pounds of the type R 3 Y:, where Y is an element in the second row of the
periodic table, undergo inversion much less readily than similar compounds
for which Y is a first-row element. Thus phosphorus compounds resemble
sulfur compounds in this respect, and several asymmetric phosphines
(R 1 R 2 R 3 P:) have been successfully resolved into enantiomeric forms.
C. SULFOXIDES AND SULFONES
Oxidation of sulfides, preferably with hydrogen peroxide in acetic acid, yields
sulfoxides and sulfones. The degree of oxidation is determined by the ratio of
the reagents, and either the sulfoxide or the sulfone can be obtained in good
yield.
O NH 2
30% H 2 2 , 1.5 moles „„ | „„„.!,
NH 2
CI
methionine
CH 3 C0 2 H
30% H Z Q 2 , 3.2 moles
CH 3 CQ 2 H
-+. CH,S-CH 2 CH 2 CHC0 2 H
methionine sulfoxide
O NH 2
II I 2
- CH 3 S-CH 2 CH 2 CHC0 2 H
II 2 2 2
O
methionine sulfone
Dimethyl sulfoxide (DMSO) is a particularly useful substance in the
laboratory, both as a solvent and as a reagent. It is a polar substance with a
o
II
CH 3 -S-CH 3
dimethyl sulfoxide
mp 18°, bp 189°
fairly high dielectric constant (s = 48) and hence it dissolves polar and ionic
substances quite well. It lacks hydrogen-bonding protons, however, and the
activity of anions, particularly those whose charge is not dispersed, is high in
DMSO solution. We have seen how this property greatly enhances S N 2
reactivity (Section 8-1 ID). It is also responsible for the powerfully basic
character of solutions of hydroxide or alkoxide ions in DMSO. Judging by
chap 19 organic compounds of sulfur, phosphorus, silicon, and boron 526
their ability to remove protons from feeble acids such as aromatic amines
(Table 22-1, footnote) and hydrocarbons these solutions are about 10 14 times
more basic than the corresponding aqueous solutions. DMSO itself is very
weakly acidic (pK HA = 33). Its anion, CH 3 SOCHf , called the dimsyl ion, has
found wide use as a powerful base in elimination and other reactions.
One of DMSO's most unusual solvent properties is its extraordinary ability
to penetrate through cell membranes. When this property was discovered
it was thought that DMSO might provide a vehicle for introducing medicinals
directly into cells through the skin. However, large doses of DMSO have
been found to cause retinal damage and this plan has been discarded.
DMSO can also function as a mild but effective oxidant for alcohols.
Treatment of an alcohol with DMSO and dicyclohexylcarbodiimide (a mild
nonacidic dehydrating agent) produces high yields of aldehydes or ketones.
o
II
RCH 2 OH + CH 3 SCH 3 + C 6 H! iN=C=NC 6 H! i
O
II
* RCHO + CH3SCH3 + C 6 H! iNHCNHC 6 H! t
This reaction is particularly useful if the alcohol is sensitive to acid rearrange-
ment (Section 10-5B) or if, as in the case of the secondary hydroxyl groups in
many carbohydrates, the alcohol resists oxidation by conventional means.
D. SULFENIC, SULFINIC, AND SULFONIC ACIDS
The sulfenic acids, RSOH, are unstable with respect to self-oxidation and
reduction and generally cannot be isolated. However, certain derivatives of
sulfenic acids are relatively stable, notably the acid halides RSC1.
Sulfinic acids, RS0 2 H, are more stable than sulfenic acids but are none-
theless easily oxidized to sulfonic acids, RS0 3 H. They are moderately strong
acids with K HA values comparable to the first ionization of sulfurous acid
(K HA ~10- 2 ).
Many sulfonic acids, RS0 3 H, have considerable commercial importance as
detergents in the form of their sodium salts, RS0 3 Na. Many commercial
detergents are sodium alkylarylsulfonates of types which are readily syn-
thesized from petroleum by reactions discussed in the next chapter.
C9.! S H I9 . 3 ,-f VsOjNa
The resistance of highly branched alkyl chains of arylalkylsulfonates to
biochemical degradation and the water pollution that results led to their
elimination as detergents for domestic purposes. Sodium arylalkylsulfonates
with nonbranched side chains or sodium alkylsulfonates derived from long-
chain alcohols are more easily degraded by bacteria. The principal advantage
that sodium sulfonates have as detergents over the sodium salts of fatty acids
(Section 13T) used in ordinary soaps is that the corresponding calcium and
magnesium salts are much more soluble, and hence the sulfonates do not pro-
duce scum (bathtub ring) when used in hard water.
sec 19.2 types and nomenclature of organic compounds of sulfur 527
Sulfonic acid groups are often introduced into organic molecules to increase
water solubility. This is particularly important in the dye industry, where it is
desired to solubilize colored organic molecules for use in aqueous dye baths
(see Section 28-7A).
Aliphatic sulfonic acids can be prepared by the oxidation of thiols (Sec-
tion 19-2A).
CH 3 CH 3
I CH3CO2H I
CiCH 2 CH 2 C-SH + 3 H 2 2 > C1CH 2 CH 2 C-S0 3 H + 3 H 2
I I
CH 3 CH3
4-chloro-2-methyI- 4-chloro-2-methyI-
2-butanethiol butane-2-sulfonic acid
92%
a-Hydroxysulfonate salts result from the addition of sodium bisulfite to
aldehydes (Section 11-41). The free sulfonic acid RCHOHS0 3 H is unstable
since addition of acid to the salt drives the reaction back to aldehyde by
converting HS0 3 e to S0 2 .
p OH
R— C + NaHS0 3 y > R-CH-SOf Na®
H
Arylsulfonic acids are almost always prepared by sulfonation of the cor-
responding hydrocarbon (see next chapter). They are strong acids, comparable
in strength to sulfuric acid. Furthermore, the sulfonate group is an excellent
leaving group from carbon in nucleophilic displacement reactions and, in
consequence, conversion of an alcohol to a sulfonate ester is a means of
activating alcohols for replacement of the hydroxyl group by a variety of
nucleophilic reagents. A sulfonate ester is best prepared from a sulfonyl
chloride and an alcohol, and many sulfonyl chlorides that can be used for
this purpose are available commercially. The use of ^-toluenesulfonyl chloride
(often called tosyl chloride) is illustrated in Equation 19-1.
CH 3 -<f \-S0 2 Ci -
(CH 3 CH 2 ) 2 CHOH *=* > (CH 3 CH 2 ) 2 CHO-S-/ V
O
C 2 H 5 S e
jr~\ (i9-i)
(CH 3 CH 2 ) 2 CH-S-C 2 H 5 + CH 3 -f V-SOf
A number of important antibiotic drugs, the so-called sulfa drugs, are
sulfonamide derivatives.
NH
//
H 2 N-^f Vs0 2 NH-f \ H 2 N-f \-S0 2 NH-c'
sulfadiazine sulfaguanidine
chap 19 organic compounds of sulfur, phosphorus, silicon, and boron 528
E. SULFATE ESTERS
Sulfate esters such as dimethyl sulfate lack a sulfur-carbon bond and as
mentioned earlier are not classified as organosulfur compounds. Dimethyl
o
II
CH3-0-S-0-CH3
II
o
dimethyl sulfate, bp 188°
sulfate is a good methylating agent; the methyl carbon easily undergoes
attack by the substance being methylated because the group being displaced is
a good leaving group. The leaving group in this reaction is the anion of a
strong acid CH 3 — O— S0 3 H, methylsulfuric acid or methyl hydrogen sul-
fate. (It should not be confused with the compound methanesulfonic acid,
CH 3 — SO3H, also a strong acid.)
O
Nu + CH3-O-S-O-CH3 ► Nu— CH 3 + CHj-O-SOf
O
Dimethyl sulfate on hydrolysis produces sulfuric acid.
(CH 3 0) 2 S0 2 + 2 H 2 >■ H 2 S0 4 + 2CH 3 OH
Like most volatile esters of inorganic acids, dimethyl sulfate is toxic and
should be handled with care. Contact of the vapors with the eye can cause
permanent corneal damage.
19-3 phosphorus compounds
The two important groups of organic compounds of phosphorus are the
phosphate esters, which contain oxygen-phosphorus bonds, and the organo-
phosphorus compounds, which contain carbon-phosphorus bonds.
A. PHOSPHATE ESTERS
Phosphoric acid, H 3 P0 4 , has a tendency (absent in nitric acid) to exist in
polymeric forms, such as diphosphoric acid, H 4 P 2 7 , and triphosphoric
acid, H 5 P 3 O 10 .
OO OOO
II II II II II II
HO-P-OH HO-P-O-P-OH HO-P-O-P-O-P-OH
1 II III
OH OH OH OH OH OH
phosphoric acid diphosphoric acid triphosphoric acid
(mono)
Polyphosphate salts such as the sodium salts of triphosphoric acid are
used in large amounts (up to 40 %) in detergents to bring clay and similar
particles into suspension. Because of their high phosphorus content, deter-
gents are believed to be a major contributor to eutrophication of lakes —
sec 19.3 phosphorus compounds 529
overfertilization caused by nutrient abundance. Runoff from fertilized
agricultural land is also an important factor. Phosphorus being a nutrient
for plant life stimulates the growth of algae to such an extent that other forms
of marine life may be extinguished. Unlike nitrogen, which also contributes
to eutrophication, phosphorus does not enter into biochemical reactions that
allow it to escape from water as a gas.
We have already met extremely important derivatives of each of the three
acids, monophosphoric acid, diphosphoric acid, and triphosphoric acid.
Nucleic acids are derivatives of monophosphoric acid (Figure 17-9) while
adenosine diphosphate, ADP, and adenosine triphosphate, ATP (Section
15-5), are derivatives of diphosphoric acid and triphosphoric acid, respec-
tively.
NH,
-»© r>e
H 2 C /°\\-S^
o° cr o"
I I I
R— O— P— O— P— O— P— OH
II II II
o o o
OH OH
adenosine triphosphate (ATP) adenosine group
At pH 7, only one of the four phosphate hydroxyl groups in ATP remains
un-ionized in the cell. The resulting triple negative charge on the triphosphate
group is considerably reduced, however, by complex formation with mag-
nesium ions.
The energies of the ADP-ATP system have been extensively studied be-
cause it is the link between high-energy phosphate donors, formed during
the oxidation of foods (Section 18-5), and low-energy phosphate acceptors.
The latter are activated by phosphorylation and can then perform cellular
work: muscle contraction, biological transport, biosynthesis, and so on.
The hydrolysis of ATP has a negative free energy ; that is, hydrolysis is
favored at equilibrium. The free energy is more negative still in living cells,
because of magnesium complexing in the cell.
ATP + H 2 > ADP + HP0 4 2e AG standard = -7 kcal
AGcellular ~ — 12 kcal
Thus ATP is a high-energy phosphate compound. The frequently used phrase
"high-energy bond" in connection with the ATP-phosphate link is a mis-
nomer. We saw in Chapter 2 that the higher the energy of a bond, the more
stable it is. The sense of this is opposite to the hydrolysis of ATP, which is
energetically favorable.
Phosphorous acid, H 3 P0 3 , has the structure [1], not [2], although organic
OH
II I
H-P-OH :P-OH
1 I
OH OH
[1] [2]
chap 19 organic compounds of sulfur, phosphorus, silicon, and boron 530
derivatives of both of these structures are known. Ironically, it is the esters of
[2] rather than the esters of [1] that are known as phosphites. The latter are
called phosphonates.
O OC 2 H 5
II I
C 6 H 5 -P-OC 2 H s :P-OC 2 H 5
0-C 2 H 5 OC 2 H 5
diethyl phenylphosphonate triethyl phosphite
B. ORGANOPHOSPHORUS COMPOUNDS
These compounds contain carbon-phosphorus bonds and resemble to some
extent their nitrogen analogs. Thus trimethylphosphine is a weak base that
can form phosphonium compounds analogous to ammonium compounds.
(CH 3 ) 3 P:+HC1 >■ (CH 3 ) 3 PHC1
trimethylphosphonium chloride
(CH 3 ) 3 P: +CH 3 C1 ► (CH 3 ) 4 P ffi Cl e
tetramethylphosphonium chloride
Despite being weaker bases than the corresponding amines the phosphines
are actually more nucleophilic, probably because phosphorus is a larger, more
electropositive atom than nitrogen, and its outer-shell electrons are conse-
quently less firmly held and more polarizable.
C. REACTIONS OF QUATERNARY PHOSPHONIUM COMPOUNDS
There are interesting differences in behavior of quaternary ammonium and
quaternary phosphonium salts toward basic reagents. Whereas tetraalkyl-
ammonium salts with hydroxide or alkoxide ions generally form alkenes and
trialkylamines by E2-type elimination (Section 8-12), corresponding reactions
of tetraalkyl- or arylphosphonium salts lead to phosphine oxides and hydro-
carbons.
(CH 3 ) 3 NCH 2 CH 3 + e OH >■ (CH 3 ) 3 N + CH 2 =CH 2 +H 2
O
© II
(C 6 H 5 ) 3 PCH 2 CH 3 + e OH > (C 6 H 5 ) 2 PCH 2 CH 3 + C 6 H 6
There is an alternative course of reaction of quaternary phosphonium salts
with basic reagents. It involves attack of a base, usually phenyllithium, at a
hydrogen a to phosphorus. The product [3] is called an alkylidenephos-
phorane.
a e e
R 3 P-CH 2 R' + C 6 H 5 Li ► R 3 P=CHR' + C 6 H 6 + Li X
X e [3]
Compounds of this type are frequently written as dipolar structures such as
sec 19.4 organosilicon compounds 531
[4a]. However, they are better considered as hybrids of the contributing struc-
tures [4a] and [4b], the latter involving p n -d K bonding.
© e
R 3 P-CHR < — > R 3 P=CHR
[4a] [4b]
Compounds in which two adjacent atoms bear opposite formal charges 2
are called ylids (pronounced " illids. "). Although [4a] is only a contributor
to the hybrid, alkylidenephosphoranes are often regarded as ylids.
Alkylidenephosphoranes are reactive, often highly colored substances,
that rapidly react with oxygen, water, acids, alcohols, and carbonyl com-
pounds — in fact, with most oxygen-containing compounds. Two of these
reactions are illustrated here for methylenetriphenylphosphorane and again
the driving force is formation of a phosphorus-oxygen bond at the expense of
a phosphorus-carbon bond.
(C 6 H 5 ) 3 PCH 3 Bre -%Mi>. (C 6 H 5 ) 3 P=CH 2
methyltriphenylphosphonium
bromide
methylenetriphenyl-
phosphorane
(C 6 H 5 ) 3 P=CH 2 + H 2
♦ (C 6 H 5 ) 2 P=0 + C 6 H 6
I
CH 3
methyldiphenylphosphine
oxide
(C 6 H 5 ) 3 P=CH 2 + (~/=0
(C 6 H 5 ) 3 P=0 + <^)=CH 2
triphenylphosphine methylene-
oxide cyclohexane
The preparation of alkenes from the reactions of alkylidenetriphenylphos-
phoranes with aldehydes and ketones is known as the Wittig reaction. The
example given here probably proceeds by way of the following intermediate.
19-4 organosilicon compounds
Silicon, like carbon, normally has a valence of four and forms reasonably
stable bonds to other silicon atoms, carbon, hydrogen, oxygen, and nitrogen.
Compounds of some of these types are listed in Table 19-2, together with the
2 Betaine is a term given to compounds in which two nonadjacent atoms bear opposite
charges. An amino acid zwitterion (Section 17-1B) is an example of a betaine.
chap 19 organic compounds of sulfur, phosphorus, silicon, and boron S32
Table 19-2 Principal types of silicon compounds and their carbon analogs
silicon compound
carbon compoun
d
silanes and organosilanes
alkanes
H 3 Si-SiH 3
disilane
CH 3 -CH 3
ethane
CH 3 -SiH 3
methylsilane
CH 3 -CH 3
ethane
(CH 3 ) 4 Si
tetramethylsilane
(CH 3 )*C
neopentane
organosilyl halides (halosilanes)
alkyl halides (haloalkanes)
(CH 3 ) 3 SiCl
trimethylsilyl chloride (CH 3 ) 3 CC1
r-butyl chloride
H 2 SiCl 2
dichlorosilane
CH 2 C1 2
dichloromethane
silanols
alcohols
H 3 SiOH
silanol
H 3 COH
methanol (carbinol)
(CH 3 ) 3 SiOH
trimethylsilanol
(CH 3 ) 3 COH
trimethylcarbinol (t-
butyl alcohol)
(CH 3 ) 2 Si(OH) 2
dimethylsilanediol
(CH 3 ) 2 C(OH) 2
acetone hydrate
(unstable)
CH 3 Si(OH) 3
methylsilanetriol
CH 3 C(OH) 3
orthoacetic acid
(unstable)
siloxanes and alkoxysilanes
ethers
(CH 3 ) 3 SiOSi(CH 3 ) 3
hexamethyldisiloxane (CH 3 ) 3 COC(CH 3 ) 3
di-r-butyl ether
(CH 3 ) 3 SiOCH 3
trimethylmethoxy-
silane
(CH 3 ) 3 COCH 3
methyl Nbutyl ether
(CH 3 ) 2 Si(OCH 3 ) 2
dimethyldimethoxy-
silane
(CH 3 ) 2 C(OCH 3 ) 2
acetone dimethyl ketal
CH 3 Si(OCH 3 ) 2
methyltrimethoxy-
silane
CH 3 C(OCH 3 ) 3
methyl orthoacetate
corresponding carbon compounds. Some idea of the strength of bonds to
silicon relative to analogous bonds to carbon may be obtained from the
average bond energies shown in Table 19-3. Significantly, the Si — Si bond is
weaker than the C— C bond by some 30 kcal/mole, whereas the Si— O bond
Table 19-3 Average bond energies
bond
bond energy,
kcal/mole
bond
bond energy,
kcal/mole
Si— Si
53
C— C
83
Si— C
76
C— Si
76
Si— H
76
C— H
99
Si— O
108
C— O
86
sec 19.4 organosilicon compounds 533
is stronger than the C— O bond by some 22 kcal/mole. These bond energies
account for several differences in the chemistry of the two elements. Thus,
while carbon forms a great many compounds having linear and branched
chains of C— C bonds, silicon is less versatile; the silanes of formula Si„H 2 „ +2
analogous to the alkanes of formula C„H 2n + 2 are relatively unstable and
react avidly with oxygen. On the other hand, the silicone polymers have
chains of Si — O— Si bonds and have a high thermal stability as corresponds to
the considerable strength of the Si— O bond.
No compounds containing silicon double bonds of the type
\ / \ / \ \
Si = Si , Si = C , Si=0, or Si=N—
/ \ / \ / /
have been prepared to date. Thus, there are no organosilicon compounds that
are structurally analogous to alkenes, alkynes, arenes, aldehydes, ketones,
carboxylic acids, esters, or imines. One clear illustration is the formation of
silanediols of the type R 2 Si(OH) 2 . The silanediols do not lose water to form
"silicones" of structure R 2 Si=0 in the way the alkanediols, R 2 C(OH) 2 ,
which are normally unstable, lose water to form the corresponding ketones,
R 2 C=0. Loss of water from silanediols results in formation of Si— O— Si
bonds, and this is the basic reaction by which silicon polymers are formed.
R R R
I -H 2 I I
2 HO-Si-OH * HO-Si-O-Si-OH
I I I
R R R
In its inability to form the p n -p % type of double bond, silicon resembles
other second-row elements of the periodic table, such as sulfur and phos-
phorus.
A. BONDING INVOLVING d ORBITALS IN ORGANOSILICON
COMPOUNDS
Silicon is normally tetracovalent in organosilicon compounds and, by analogy
with carbon, we may reasonably suppose the bonds involved to be of the sp 3
type and the substituent groups to be tetrahedrally disposed in space. Evi-
dence that this is so comes from the successful resolution of several silicon
compounds having a center of asymmetry at the silicon atom; for example,
both enantiomers of l-naphthylphenylmethylsilane [5] have been isolated.
[5]
M D =+32°
X-Ray and electron-diffraction studies of silicon tetraiodide, silicon tetra-
chloride, and tetramethylsilane also indicate tetrahedral structures. Sub-
chap 19 organic compounds of sulfur, phosphorus, silicon, and boron 534
stances with hexacovalent silicon such as hexafluosilicate ion, SiF 6 2e , are
known, however, and this shows that silicon can expand its valence shell to
accommodate 10 electrons by utilizing the 3d orbitals. The silicon 3d orbitals
\
may also be involved in the bonds of compounds of the type —Si — X, Where
X is an atom or group having electrons in a p orbital so situated as to be able
to overlap with an empty. 3d orbital of silicon. The result would be a Si— X
bond with partial double-bond character of the d„-p n type, in which the
silicon has an expanded valence shell. The bonding can be symbolized by
these resonance structures (examples of X include oxygen, nitrogen, and the
halogens, as well as unsaturated groups such as the vinyl and phenyl groups) :
\ •• \ e B
-Si— X < ► — Si=X
/ /
B. PREPARATION AND PROPERTIES OF ORGANOSIL1CON
COMPOUNDS
Organosilicon compounds are prepared from elementary silicon or the silicon
halides. A particularly valuable synthesis of organochlorosilanes involves
heating an alkyl chloride or even an aryl chloride with elementary silicon in
the presence of a copper catalyst. A mixture of products usually results;
nonetheless, the reaction is employed commercially for the synthesis of
organochlorosilanes, particularly the methylchlorosilanes.
CH 3 C1 + Si C " ( ^ %) -^ SiCl 4 + CH 3 SiHCl 2 + CH 3 SiCl 3 + (CH 3 ) 2 SiCl 2
9% 12% 37% 42%
/ V C1 + Sl samu ( Vsicu + (f Vl-s lC ,
The physical properties of some organosilanes may be seen from Table
19-4 to be roughly similar to those of the analogously constituted carbon
compounds.
C. SILANOLS, SILOXANES, AND POLYSILOXANES
The silanols are generally prepared by hydrolysis of silyl halides and some-
times by hydrolysis of hydrides and alkoxides.
R 3 SiCl + H 2 ► R 3 SiOH + HCl
R 2 SiCl 2 + 2H 2 >• R 2 Si(OH) 2 + 2 HC1
e
OH
R 3 SiH + H a O > R 3 SiOH + H 2
The reaction conditions have to be controlled to avoid condensation of the
sec 19.4 organosilicon compounds 535
Table 19-4 Physical properties of some representative silicon compounds
and their carbon analogs
silicon
bp,
mp,
carbon
bp,
mp,
compound
°C
°C
compound
°C
°C
SiH 4 °
-112
-156.8
CH 4
-162
-183
SiH 3 SiH 3 "
-14.5
-133
CH 3 CH 3
-88.6
-172
CH 3 SiH 3
-57.5
-156.8
CH 3 CH 3
-88.6
-172
(CH 3 ) 4 Si
27
(CH 3 ) 4 C
9.5
-20
(CH 3 ) 3 SiC 6 H 5
172
(CH 3 ) 3 CC 6 H 5
169
-58
(C 6 H 5 ) 4 Si
430
237
(C 6 H 5 ) 4 C
431
285
SiCl 4
57.6
-70
CC1 4
76.8
-22.8
SiHCl 3
33
-134
CHC1 3
61
-63.5
SiH 2 Cl 2
8.3
-122
CH 2 C1 2
40
-96.7
CH 3 SiCl 3
65.7
CH 3 CC1 3
74
C 6 H 5 SiCl 3
201
C 6 H 5 CC1 3
214
-5
(CH 3 ) 3 SiOH
98.6
(CH 3 ) 3 COH
82.8
25.5
(CH 3 ) 2 Si(OH) 2
100
' Spontaneously flammable in air.
silanols to siloxanes, especially when working with silanediols. This may
necessitate working in neutral solution at high dilution.
R 2 Si(OH) 2 + R 2 Si(OH) 2
-H 2
R R
I I
HO— Si-O— Si-OH
R
R
The silanols are less volatile than the halides and siloxanes because of
intermolecular association through hydrogen bonding, and the diols,
R 2 Si(OH) 2 , are more soluble in water than the silanols, R 3 SiOH. Compared
to alcohols, silanols are more acidic and form stronger hydrogen bonds. This
can be ascribed to d n -p n bonding of the Si— O bond.
e ©
R 3 Si=0-
■H
R 3 Si-0-H «-
In the presence of either acids or bases, most silanols are unstable and
condense to form siloxanes. The ease with which these reactions occur
compared to corresponding reactions of alcohols is likely to be associated
with the ease of formation of pentacoordinate silicon intermediates.
Nu + X— Si-
Nu \le
Si-
z» Nu — Si- + X"
Acid-catalyzed condensation:
R 3 SiOH + H® .. R 3 SiOH 2
R 3 SiO + R 3 Si — OH 2
H
R 3 SiOSiR 3 + H 3
chap 19 organic compounds of sulfur, phosphorus, silicon, and boron 536
Base-catalyzed condensation:
R 3 SiOH + OH , R 3 SiO + H 2
e e
R 3 SiO + R 3 Si-OH ► R 3 SiOSiR 3 + OH
The same type of condensation reaction, when carried out with the silane-
diols, leads to linear chains and cyclic structures with Si— O and Si— C bonds
which are called polysiloxanes.
(CH 3 ) 2
/ si \
H® nr ©OH ^ ^
(CH 3 ) 2 Si(OH) 2 " ° r > I I
(CH 3 ) 2 Si^ /Si(CH 3 ) 2
+ HO
The higher-molecular-weight products are the "silicone polymers."
The linear silicone polymers are liquids of varying viscosity depending on
the chain length. They remain fluid to low temperatures and are very stable
thermally, which makes them useful as hydraulic fluids and lubricants.
Cross-linking results in hard and sometimes brittle resins, depending upon
the ratio of methyl groups to silicon atoms in the polymer.
19-5 organoboron compounds
Boron has three valence shell electrons available for bonding and it utilizes
these to form trigonal (sp 2 ) bonds in compounds of the type BX 3 . Typical
examples are boron trifluoride, BF 3 ; trimethylborane, B(CH 3 ) 3 ; and boric
acid, B(OH) 3 . In such compounds the boron normally has only six electrons
in three of the four available bonding orbitals and therefore is said to be
"electron deficient." There is a considerable tendency for boron to acquire an
additional electron pair to fill the fourth orbital and so attain an octet of
electrons. The boron halides and the organoboranes (BR 3 ) are Lewis acids
and may accept an electron pair from a base to form tetracovalent boron com-
pounds in which the boron atom has a share of eight electrons.
b1 CH3 3b.
|Vi20° + :NH 3 ► H 3 C<4"'CH 3
CH 3 109° CH 3
trimethylborane ammonia trimethylborane
(planar) (tetrahedral)
A change in configuration at boron occurs in these reactions because
sec 19.S organoboron compounds 537
tetracovalent boron is tetrahedral (sp 3 hybrid orbitals), whereas tricovalent
boron is trigonal and planar (sp 2 ).
A particularly interesting class of compounds is the borazines. These
compounds are six-membered heterocycles with alternating boron and nitro-
gen atoms. They are formally analogous to benzene in that there are six
electrons — one pair at each nitrogen — which could be delocalized over six
orbitals, one from each boron and nitrogen in the ring.
H H e H e
HN: :NH HI^T NH HN ^NH
I
HB. ..^,BH HB^ .BH HB. ^BH
H H 95 H e
[6a] [6b] [6c]
The similarity between benzene and borazine is obvious from the Kekule
structures [6b] and [6c]. The degree to which these structures can be regarded
as contributing to the actual structure of the borazine molecule, however, has
been a topic of controversy. The borazine molecule has a planar ring with
120° bond angles and six equivalent B — N bonds of length 1.44 A, which is
shorter than the expected value of 1 .54 A for a B— N single bond and longer
than the calculated value of 1.36 A for a B=N double bond.
A. MULTICENTER BONDING AND BORON HYDRIDES
The simple hydride of boron, BH 3 , is not stable, and the simplest known
hydride is diborane, B 2 H 6 . Higher hydrides exist, the best known of which are
tetraborane, B 4 Hi ; pentaborane, B 5 H 9 ; dihydropentaborane, B 5 H U ;
hexaborane, B 6 H 10 ; and decaborane, B 10 H 14 . These compounds are especial-
ly interesting with regard to their structures and bonding. They are referred to
as "electron deficient" because there are insufficient electrons with which to
form all normal electron-pair bonds. This will become clear from the following
description of the structure of diborane.
The configuration and molecular dimensions of diborane resemble ethene
in that the central B— B bond and four of the B— H bonds form a planar
framework. However, the remaining two hydrogens are centered above and
below this framework and form bridges across the B— B bond, as shown in
Figure 19-4. The presence of two kinds of hydrogens in diborane is also con-
sistent with its infrared and nmr spectra.
If we try to write a conventional electron-pair structure for diborane, we
see at once that there are not enough valence electron pairs for six normal
B— H bonds and one B— B bond. Seven normal covalent bonds require 14
bonding electrons, but diborane has only 12 bonding electrons. The way the
atoms of diborane are held together would therefore appear to be different
from any we have thus far encountered, except perhaps in some carbonium
ions (Section 4-4B). Nonetheless, it is possible to describe the bonds in
diborane in terms of electron pairs if we adopt the concept of having three
(or more) atomic centers bonded by an electron pair in contrast to the usual
chap 19 organic compounds of sulfur, phosphorus, silicon, and boron 538
1.33 k/ \
121. 5°?^
rflft ' ' "" A 4
'^ HS ^ v y , ioo J
ljT^^jjIlfci
Figure 19-4 Configuration of diborane.
bonding of two atomic centers by an electron pair. We can formulate diborane
as having two three-center bonds, each involving an electron pair, the two
boron atoms, and a bridge hydrogen.
The three-center bonds can be represented in different ways — one possible
way being with dotted lines, as in [7].
U X V H
[7]
The structures of many of the higher boron hydrides, such as B 4 H 10 , B 5 H 9 ,
B 5 H n , B 6 H 10 , and B 10 H 14 , have been determined by electron and(or)
X-ray diffraction. These substances resemble diborane in having an overall
deficiency of electrons for the total number of bonds formed unless some are
formulated as multicenter bonds.
The structure of pentaborane is shown in Figure 19-5. This molecule has 24
Figure 19-5 Structure of pentaborane.
H
B v
i ! \ s
-H
.*-!/ \ 1 \
H'' // \ / \
\ // \ / -H
\ i' \ i , -
n -B'
\T
sec 19.5 organoboron compounds 539
valence electrons; of these, 10 can be regarded as utilized in forming five
two-center B— H bonds (solid lines), and eight in forming four three-center
BHB bonds (dashed lines). The remaining six electrons can be taken to con-
tribute to multicenter binding of the boron framework (dashed lines).
A number of alkylated diboranes are known, and their structures are similar
to diborane.
H 3 C x ,h., CH 3
H 3 C / ~'H''' X CH 3
.ym-tetramethyldiborane
However, when a boron atom carries three alkyl groups, three-center
bonding does not occur, and the compound is most stable in the monomeric
form. Apparently, alkyl groups are unable to form very strong three-center
bonds with boron.
B. NOMENCLATURE OF ORGANOBORON COMPOUNDS
The literature on organoboron compounds is inconsistent as to nomenclature,
and many compounds are called by two or more names. For example, the
simple substance of formula B(CH 3 ) 3 is called variously trimethylborane,
trimethylborine, or trimethylboron. Insofar as possible, we will name organo-
boron compounds as derivatives of borane, BH 3 . Thus, substitution of all the
B — H hydrogens by methyl groups gives B(CH 3 ) 3 , trimethylborane. Several
more examples follow:
B(C 6 H 5 ) 3
B 2 H 6
C6H5BG2
triphenylborane
diborane
phenyldichloroborane
(CH 3 ) 2 BCi
© e
(CH 3 ) 3 N-BH 3
(CH 3 ) 2 N-BH 2
dimethylchloroborane
trimethylamine borane
dimethylaminoborane
C. HYDROBORATION
Trialkylboranes can be prepared by addition of boron hydrides to multiple
bonds. In general, these reactions of boron hydrides conform to a pattern of
e e
cleavage of B— H bonds in the direction B: H, with boron acting as an electro-
phile.
\0\ / \ f> I I
C = C + B — H _ - - —C — C —
/ \ / II
Addition of a B— H linkage across the double bond of an alkene is known
as hydroboration and has been discussed earlier (Section 4-4F). Cleavage of
the B— C bond with a carboxylic acid gives an alkane, with alkaline hydrogen
peroxide, an alcohol. (Note that the alcohol that is formed is the anti-
Markownikoff product.)
chap 19 organic compounds of sulfur, phosphorus, silicon, and boron 540
CH 3 CH=CH 2 + BH 3 ► CH 3 CH 2 CH 2 BH 2 CH3CH=CH * . (CH 3 CH 2 CH 2 ) 2 BH
(CH 3 CH 2 CH 2 ) 3 B
RCO^H^/ H0 e\H 2 2
CH 3 CH 2 CH 3 CH 3 CH 2 CH 2 OH
summary
Sulfur, phosphorus, and silicon, being second-row elements in the periodic
table, have low-lying d orbitals available and are not restricted to an octet of
bonding electrons as are the elements in the first row. Sulfur can have as many
as 12 bonding electrons (six covalent bonds), and phosphorus 10 bonding
electrons (five covalent bonds). Silicon is usually tetravalent although even
here there is often some d orbital participation in bond formation. Boron is
unique in having only three electrons in its valence shell. Neutral boron can
form either three covalent bonds and be electron deficient or four covalent
bonds and be anionic, as in BH 4 e . Many compounds are known with three-
center bonds between two boron atoms and a hydrogen atom.
Sulfur in its divalent state is analogous to oxygen. Thiols, also called
mercaptans (RSH), correspond to alcohols (ROH); sulfides, also called
thioethers (RSR), correspond to ethers (ROR); and disulfides (RSSR) cor-
respond to peroxides (ROOR). There are no oxygen analogs for the sulfur
compounds with four and six bonds, the most important of which are sul-
o o o
II II II
foxides, R— S— R, sulfones, R— S— R, and sulfonic acids, R— S— OH.
O O
Thiols are more acidic than alcohols and also more nucleophilic. Oxida-
tion of thiols produces disulfides.
RSH [ ° ] > RS-SR (disulfide)
Alkylation of thiols, RSH, gives sulfides, RSR, which can be converted to
sulfonium salts, R 3 S®X e . If the R groups are all different the salts can be
resolved into optical enantiomers.
Oxidation of sulfides gives sulfoxides and sulfones.
O
jj
^. R-S-R (sulfoxide)
R-S-R
O
^» R— S— R (sulfone)
1!
o
Dimethyl sulfoxide (DMSO) is an example of a polar aprotic solvent. It
summary 541
enhances the reactivity of small anions and is often used as a solvent for S N 2
reactions. It is also an excellent mild oxidant for alcohols.
There are three kinds of organosulfur acids: sulfenic acids (RSOH),
sulfinic acids (RS0 2 H), and sulfonic acids (RS0 3 H). The last are strong
acids, and are the most important of the series. They will be met again in the
next chapter.
O
II
Sulfate esters, RO— S— OR, lack a carbon-sulfur bond and hence are not
II
O
classed as organosulfur compounds. They are useful alkylating agents.
Organic compounds of phosphorus include phosphate esters, R— O—
PO(OH) 2 , phosphonic acids, R— PO(OH) 2 , and organophosphines, R 3 P.
Phosphate esters may exist as polyphosphates, an important example of
which is adenosine triphosphate, ATP.
Phosphines can form phosphonium-salts, R 4 P®X e , analogous to ammo-
nium salts. When treated with phenyllithium, a methylphosphonium ion loses
a proton to give a methylenephosphorane.
© -H®
R 3 P— CH 3 ► R 3 P=CH 2 (methylenephosphorane)
These compounds can convert ketones to ethene derivatives as a result of
the exchange of a carbonyl and a methylene group (the Wittig reaction).
R 3 P=CH 2 + R' 2 C=0 > R' 2 C=CH 2 + R 3 P=0
Silicon, like carbon, has four valence electrons but, unlike carbon, it forms
only single bonds. Compounds containing only silicon and hydrogen (silane
SiH 4 , disilane Si 2 H 6 , etc.) ignite spontaneously in air. Alkylsilanes, such as
R 4 Si, are more stable. Silanediols, R 2 Si(OH) 2 , can be prepared whereas their
carbon analogs can not. They are made from alkyl chlorides via the chloro-
silanes.
RCl + Si — ^—> R 2 SiCl 2 (+ other chlorosilanes)
H 2
► R 2 Si(OH) 2
Silanediols tend to polymerize to form siloxanes, compounds of extremely
high thermal stability.
R R R
I I I
R 2 Si(OH) 2 ► -O-Si-O-Si-O— Si— O-
I I I
R R R
Boron possesses only three valence electrons and as a result its tricovalent
compounds, such as BF 3 and B(CH 3 ) 3 , are electron deficient and highly
reactive as electron-pair acceptors — that is, Lewis acids. When an electron
pair is accepted an octet arrangement is achieved, for example, BF 4 e . In the
chap 19 organic compounds of sulfur, phosphorus, silicon, and boron 542
borazines n bonding tends to complete the octet of boron.
H H
I | < > e l He (borazine)
,B. .. .B. / B: =%x^/ B \
H H
Diborane and higher boranes are constructed with three-center bonds, each
consisting of an electron pair, two boron atoms, and a hydrogen bridge.
Hydroboration is the addition of boron hydrides, particularly BH 3 , to
multiple bonds. Treatment of an alkene with diborane results in the addition
of BH 3 to the double bond. The reaction continues and finally gives a tri-
alkylborane. These compounds can then be converted to alkanes or alcohols.
rco^h^, RCH 2 CH 3
RCH=CH 2 — 1 -^ (RCH 2 CH 2 ) 3 B
H 2 2 , OH e
exercises
19-1 Write structural formulas for the following substances:
a. di-s-butyl thioketone e. tris-(methylsulfonyl)-methane
b. ethyl sulfide /. trimethylene disulfide
c. methyl thioacetate g. 5-thia-l,3-cyclopentadiene
d. /3,/3'-dichloroethyl sulfide (thiophene)
(mustard gas)
19-2 Formulate each of the following substances in terms of electronic structure,
types of bonds (i.e., a and n) and probable molecular geometry (i.e., linear,
angular, planar, pyramidal, etc.) with rough estimates of bond angles.
/. S 6 (six-membered ring)
g. CS 2
h. SOCl 2
/. S s (eight-membered ring)
19-3 Thiols are unlike alcohols in that they do not react readily with hydrogen
bromide to yield bromides. Explain how a difference in behavior in this
respect might be expected.
19-4 Write mechanisms for the conversion of a thiol to a disulfide by oxidation
with air or iodine which are in accord with the observation that the reaction
with either oxidizing agent is accelerated by alkali.
19-5 Dimethyl sulfide reacts with bromine in the absence of water to produce a
a.
H 2 S
b.
so 2
c.
SF 4
d.
H 2 S0 4
e.
Na 2 SO :
exercises 543
crystalline addition compound which reacts with water to produce dimethyl
sulfoxide. What is the likely structure of the addition compound and the
mechanism of its formation and reaction with water ?
19-6 How many and what kinds of stereoisomers would you expect for each of the
following compounds?
a. methylethyl-s-butylsulfonium bromide
b. [CH3(C 2 H 5 )SCH 2 CH 2 S(CH3)C 2 H 5 ] 2 ® 2Br e
H 2 C— CH 2
© / \ ® -
c. CH 3 S SCH 3 2Br e
3 \ / 3
H 2 C-CH 2
19-7 Unsymmetrically substituted sulfoxides, but not the corresponding sulfones,
exhibit optical isomerism. Write structures for the stereoisomers you
would expect for
a. methyl ethyl sulfoxide
b. the disulfoxide of 1,3-dithiacyclohexane
19-8 Write equations for a practical synthesis of each of the following substances
based on the specified starting materials. Give reagents and approximate
reaction conditions.
O
II
a. CH 3 -C-S-CH 2 CH 2 CH 3 from «-propyl alcohol
b. optically active methylethyl-«-butylsulfonium bromide from «-butyl
alcohol
c. neopentanethiol from neopentyl chloride
19-9 Suppose it were desired to study the addition of bromine to an alkene double
bond in water in the absence of organic solvents. A possible substrate for
this purpose would be CH 2 =CHCH 2 CH 2 CH 2 CH 2 -X, where -X is a
solubilizing group. What would be the merits of having —X = — S0 3 e Na®
over X= -OH, -NH 2 , -C0 2 e Na®, -N(CH 3 )3Br e ?
19-10 Give for each of the following pairs of compounds a chemical test, prefer-
ably a test tube reaction, which would serve to distinguish one from the
other.
a. CH 3 CH 2 SH and CH 3 SCH 3
b. CH 3 S(0)OCH 3 and CH 3 CH 2 S0 3 H
c. CH 3 S(0)OCH 3 and CH 3 S(0) 2 CH 3
d. CH 3 SCH 2 CH 2 OH and CH 3 OCH 2 CH 2 SH
19-11 Name the following compounds:
a. CH 3 PHCH 2 CH 3
b. CH 3 P(C 5 H 5 ) 2
II
O
chap 19 organic compounds of sulfur, phosphorus, silicon, and boron 544
c. P(OC 2 H 5 ) 3
d. 0=P(OC 2 H 5 ) 3
e. / Vp(CH 3 ) 3 B°r
<2
/• (CH 3 ) 3 P
19-12 Write structures for the following compounds :
a. methyl diphosphate c. diisopropyl methylphosphonate
b. tricyclohexyl phosphate d. tetraphenylphosphonium iodide
19-13 Using the Wittig reaction (Section 19-3C) in one of the steps, show how you
could convert 1,1-dicyclopropylpropene to 1,1-dicyclopropylethene.
19-14 Name the following compounds according to the nomenclature used in
Table 19-2.
a. (C 6 H 5 ) 4 Si c. (C 6 H 5 ) 2 Si(OH) 2
b. (C 2 H 5 ) 2 SiBr 2 d. (CH 3 ) 3 SiOSiH 3
19-15 Write resonance structures for trimethylsilanol and vinylsilane involving
silicon d orbitals, that is, with five bonds to silicon.
19-16 Explain why trisilylamine, (SiH 3 ) 3 N, is a weaker base than trimethylamine
and why trimethylsilanol, (CH 3 ) 3 SiOH, is a stronger acid than ?-butyl
alcohol.
19-17 With reference to the discussion of reactivity of silicon compounds in Sec-
tion 19-4C, explain how it is possible for the following reaction to occur
e
readily by the rate law, v = fc[R 3 SiCl][OH].
o + *
-Si
CI OH
Refer also to Exercise 8-15.
19-18 Which compound in each of the following pairs would you expect to be
more stable? Give your reasons.
a. B,B,B-trimethylborazine or N,N,N-trimethylborazine
b. borazine or B,B,B-trichloroborazine
c. B-methoxyborazine or B-(trifluoromethyl)-borazine
d. ammonia complex of (CH 3 ) 2 B— N(CH 3 ) 2 or the ammonia complex of
(CH 3 ) 2 B-P(CH 3 ) 2
exercises 545
19-19 Write names for the following compounds:
a. CH 2 =CH-CH 2 -B(CH 3 ) 2
b. (C 2 H 5 ) 2 BHBH 3
Oe e
^-BH 3
d. (CH 3 ) 2 N-B(CH 3 ) 2
CI
I
/ B \
e. HN NH
I I
.B- ^B.
H
C 6 H 5
^ B \
f. o o
I I
/B. .B.
QH^ ^O^ ^C 6 H 5
19-20 Write structures for the following:
a. di-«-butyl-(p-dimethylaminopheny])-borane
b. di-p-tolylchloroborane
c. dichloromethoxyborane
d. tri-(dimethylphosphino)-borane
19-21 Would you expect boron-phosphorus analogs of borazines to have aromatic
character ?
19-22 Which would you expect to form a more stable addition compound with
ammonia, trivinylborane or triethylborane ? What all-carbon system has an
electronic structure analogous to dimethylvinylborane ?
mx- «"•*'«£>■: &-i
L^^&Si-
arenes. electr#pjulic aromatic
chap 20 arenes. electrophilic aromatic substitution 549
Benzene, C 6 H 6 , and the other aromatic hydrocarbons usually have such
strikingly different properties from typical open-chain conjugated polyenes,
such as 1,3,5-hexatriene, that it is convenient to consider them as a separate
class of compounds called arenes. In this chapter we shall outline their salient
features, and in subsequent chapters we shall discuss the chemistry of their
halogen, oxygen, and nitrogen derivatives.
Some of the important properties of benzene were discussed in Chapter 6
in connection with the resonance method. Most noteworthy is the fact that
benzene has a planar hexagonal structure in which all six carbon-carbon
bonds are of equal length (1.397 A), and each carbon is bonded to one hydro-
gen. If each carbon is considered to form sp 2 -<7 bonds to its hydrogen and
neighboring carbons, there remain six electrons, one for each carbon atom,
which are termed % electrons. These electrons are not to be taken as localized
in pairs between alternate carbon nuclei to form three conventional con-
jugated bonds. Rather, they should be regarded as delocalized symmetrically
through the p z orbitals of all six carbons (Section 6-1). The bonds between the
carbons are therefore neither single nor double bonds. In fact, they are
intermediate between single and double bonds in length.
However, there is more to the bonding than just the simple average of
C— C single and double bonds, because benzene C— C bonds are substan-
tially stronger than the average of the strengths of single and double bonds.
This is reflected in the heat of combustion of benzene, which is substantially
less than expected on the basis of bond energies ; the extra stability of benzene
by virtue of its stronger bonds is what we have called its stabilization energy.
A large part of this stabilization energy can be ascribed to derealization or
resonance energy of the six carbon -n, electrons.
The choice of a suitable and convenient graphical formula to represent the
structure of benzene presents a problem, since the best way to indicate de-
localized bonding electrons is by dotted lines, which are quite time consuming
to draw. Dotted-line structural formulas are preferred when it is necessary to
show the fine details of an aromatic structure — as when the degree of bonding
is not equal between different pairs of carbons, in phenanthrene, for example.
Shorthand notations are usually desirable, however, and we shall most often
use the conventional hexagon with alternating single and double bonds (i.e.,
Kekule cyclohexatriene) despite the fact that benzene does not possess
ordinary double bonds. Another and widely used notation for benzene is a
hexagon with an inscribed circle to represent a closed shell of n electrons.
However, as we have mentioned before (Section 6-1), this is fine for benzene
but can be misleading for polynuclear hydrocarbons (Section 20- IB).
20-1 nomenclature of arenes
A. BENZENE DERIVATIVES
A variety of substituted benzenes are known with one or more of the hydrogen
atoms of the ring replaced with other atoms or groups. In almost all of these
chap 20 arenes. electrophilic aromatic substitution 550
compounds, the special stability associated with the benzene nucleus is
retained. A few examples of " benzenoid " hydrocarbons follow, and it will be
noticed that the hydrocarbon substituents include alkyl, alkenyl, alkynyl, and
aryl groups.
CH
CH,
CHXH,
CH,
CH=CH,
toluene ethylbenzene cumene styrene
(methylbenzene) (isopropylbenzene) (vinylbenzene)
C = CH
5 6 6' 5'
phenylacetylene biphenyl
(ethynylbenzene) (phenylbenzene)
r\ rH fi
CH
diphenylmethane
The naming of these hydrocarbons is fairly straightforward. Each is named
as an alkyl, alkenyl, or arylbenzene, unless for some reason the compound has
a trivial name. The hydrocarbon group (C 6 H 5 — ) from benzene itself is called
a phenyl group and is sometimes abbreviated as the symbol cf> or as Ph.
Aryl groups in general are often abbreviated as Ar. Other groups that have
trivial names include
CYcH.
benzyl
,- ^„ o-
benzal benzo
x ' • \=/ I \=J
benzhydryl
When there are two or more substituents on a benzene ring, position isom-
erism arises. Thus, there are three possible isomeric disubstituted benzene
derivatives according to whether the substituents have the 1,2, 1,3, or 1,4
relationship. The isomers are commonly designated as ortho, meta, and para
(or o, m, and/?) for the 1,2, 1,3, and 1,4 isomers, respectively. The actual sym-
metry of the benzene ring is such that only one 1,2-disubstitution product is
found despite the fact that two would be predicted if benzene had the 1,3,5-
cyclohexatriene structure.
x (X-CX
not
CH,
CH,
ortho-xylene tneta-xylene para-xylene
(1 ,2-dimethylbenzene) ( 1 ,3-dimethy lbenzene) ( 1 ,4-dimethylbenzene)
sec 20.1 nomenclature of arenes SSI
CH 3
CH 3
■.-***•
o-bromotoluene
B. POLYNUCLEAR AROMATIC HYDROCARBONS
A wide range of polycyclic aromatic compounds are known that have benzene
rings with common ortho positions. The parent compounds of this type are
usually called polynuclear aromatic hydrocarbons. Three important examples
are naphthalene, anthracene, and phenanthrene. In anthracene, the rings are
connected linearly, while in phenanthrene they are connected angularly.
naphthalene
5 10 *
anthracene
&5 43
phenanthrene
There are two possible monosubstitution products for naphthalene, three
for anthracene, and five for phenanthrene. The accepted numbering system
for these hydrocarbons is as shown in the formulas; however, the 1 and 2
positions of the naphthalene ring are frequently designated as a and /?. Some
illustrative substitution products are shown.
CH,
CH,
1 -methylnaphthalene 2-methylnaphthalene
(a-methylnaphthalene) (/?-methylnaphthalene)
1 -methylanthracene
Substances that can be regarded as partial or complete reduction products
of aromatic compounds are often named as hydro derivatives of the parent
system — the completely reduced derivatives being known as perhydro com-
pounds.
9,10-dihydro-
1,2,3,4-tetrahydro-
decahydro-
perhydro-
anthracene
naphthalene
naphthalene
phenanthrene
(tetralin)
(decalin)
The names that have been given to the more elaborate types of polynuclear
aromatic hydrocarbons are for the most part distressingly uninformative in
relation to their structures. (A thorough summary of names and numbering
chap 20 arenes. electrophilic aromatic substitution S52
systems has been published by A. M. Patterson, L. T. Capell, and D. F.
Walker, " Ring Index," 2d Ed., American Chemical Society, 1960.) Two such
compounds are shown here, with their systematic names given in parentheses.
naphthacene
(benz[b]anthracene)
pyrene
(benz[d,e,f]phenanthrene)
These are named as derivatives of simpler polynuclear hydrocarbons such as
naphthalene or phenanthrene, to which are fused additional rings. An extra,
ring, which adds only four carbons at the most, is designated by the prefix
benzo 1 (or benz if followed by a vowel), and its positions of attachment either
by numbers or, as shown, by letters. (The sides of the parent compound are
lettered in sequence beginning with the 1 ,2 side, which is a.)
One can insert a Kekule structure in any of the rings in the above com-
pounds and be reasonably confident that alternating double and single bonds
can be placed in the remaining rings. This is not true for the compound
phenalenyl, a rather reactive hydrocarbon of formula C 13 H 9 (Figure 20-1).
Note that the Kekule formula [1] reveals that one of the carbon atoms in the
molecule has only three bonds to it whereas formula [2] does not. There
are 10 contributing resonance structures for this molecule, each containing a
three-bonded carbon atom having one unpaired electron. The molecule is
thus a radical. The various Kekule structures of other polynuclear hydro-
carbons are discussed in Section 20-6.
1 Confusion between the two meanings of benzo (see Section 20-1 A) seldom arises since
I
it is usually clear from the context whether it refers to a C 6 H 5 C— group or a fused ring.
Figure 2(M Two ways [1] and [2] of representing phenalenyl, C 13 H 9 . The
skeleton showing only the location of the carbon and hydrogen atoms is also
given.
H
1
C^
C
^ C \ c / C \ c/ H
C
!
H
- Cv C^H
H
sec 20.2 physical properties of arenes 553
Many polynuclear hydrocarbons, like many aromatic amines (Section
22-9B), are carcinogens.
20-2 physical properties of arenes
The pleasant odors of the derivatives of many arenes are the reason they are
often called aromatic hydrocarbons. The arenes themselves, however, are
generally quite toxic and inhalation of their vapors should be avoided. The
volatile arenes are highly flammable and burn with a luminous, sooty flame,
in contrast to alkanes and alkenes, which burn with a bluish flame leaving
little carbon residue.
A list of common arenes and their physical properties is given in Table 20- 1 .
They are less dense than water and are highly insoluble. Boiling points are
found to increase fairly regularly with molecular weight, but there is little
correlation between melting point and molecular weight. The melting point is
highly dependent on the symmetry of the compound; benzene thus melts
100° higher than toluene, and the more symmetrical p- xylene has a higher
melting point than either the o~ or the w-isomer.
Table 20-1 Physical properties of arenes
compound
mp,
°C
bp,
°C
density,
dl°
benzene
5.5
80
0.8790
toluene
-95
111
0.866
ethylbenzene
-94
136
0.8669
rc-propylbenzene
-99
159
0.8617
isopropylbenzene
-96
152
0.8620
(cumene)
/-butylbenzene
-58
168
0.8658
o-xylene
-25
144
0.8968
m-xylene
-47
139
0.8811
p-xylene
13
138
0.8541
mesitylene
-50
165
0.8634
(1 ,3,5-trimethylbenzene)
durene
80
191
(1,2,4,5-tetramethylbenzene)
naphthalene
80
218
anthracene
216
340
phenanthrene
101
340
chap 20 arenes. electrophilic aromatic substitution 554
20-3 spectroscopic properties of arenes
A. INFRARED SPECTRA
The presence of a phenyl group in a compound can be ascertained with a
fair degree of certainty from its infrared spectrum. Furthermore, the number
and positions of substituent groups on the ring can also be determined from
the spectrum. For example, in Figure 20-2, we see the individual infrared
spectra of four compounds: toluene and o-, m-, and /^-xylene. That each
spectrum is of a benzene derivative is apparent from certain common features,
notably the two bands near 1600 cm -1 and 1500 cm - - 1 which, although of
variable intensity, have been correlated with the stretching vibrations of the
carbon-carbon bonds of the aromatic ring. In some compounds, there is an
additional band around 1580 cm -1 . The sharp bands near 3030 cm -1 are
characteristic of aromatic C— H bonds. Other bands in the spectra, especially
those between 1650 and 2000 cm -1 , between 1225 and 950 cm -1 , and below
900 cm -1 , have been correlated with the number and positions of ring sub-
stituents. Although we shall not document all these various bands in detail,
each of the spectra in Figure 20-2 is marked to show some of the types of
correlations that have been made.
B. ELECTRONIC ABSORPTION SPECTRA
Compared to straight-chain conjugated polyenes, aromatic compounds have
relatively complex absorption spectra with several bands in the ultraviolet
region. Benzene and the alkylbenzenes possess two bands in which we shall be
primarily interested, one lying near 2000 A and the other near 2600 A.
The 2000 A band is of fairly high intensity and corresponds to excitation of
a % electron of the conjugated system to a %* orbital (i.e., a n ~* n* transition).
The excited state has significant contributions from dipolar structures such as
[3]. This is analogous to the absorption bands of conjugated dienes (Section
[3]
7-5) except that the wavelength of absorption of benzene is shorter. In fact,
benzene and the alkylbenzenes absorb just beyond the range of most com-
mercial quartz spectrometers. However, this band (which we say is due to the
benzene chromophore) is intensified and shifted to longer wavelengths when
the conjugated system is extended by replacement of the ring hydrogens by
unsaturated groups (e.g., -HC=CH 2 , -C^CH, -HC=0, and -C=N;
see Table 20-2). The absorbing chromophore now embraces the electrons of
the unsaturated substituent as well as those of the ring. In the specific case
sec 20.3 spectroscopic properties of arenes SSS
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chap 20 arenes. electrophilic aromatic substitution 556
Table 20-2 Effect of conjugation on the ultraviolet spectrum of the benzene chromophore
o
benzene
/ \-CH=CH 2
styrene
/ V-CH— O
benzaldehyde
biphenyl
stilbene
A m „,A 1980
£ ma , 8000
2440
12,000
2440
15,000
2500
18,000
2950
27,000
Table 20-3 Effect of substituents on the ultraviolet spectrum of the benzene
chromophore
benzene phenol
phenoxide ion iodobenzene aniline
1980
8000
2100
6200
2350
9400
2260
13,000
2300
8600
of styrene, the excited state is a hybrid structure, composite of [4a] and [4b]
and other related dipolar structures.
C
etc.
[4b]
Similar effects are observed for benzene derivatives in which the substituent
has unshared electron pairs in conjugation with the benzene ring (e.g.,
— NH2 > — OH, —CI:). An unshared electron pair is to some extent delocal-
ized to become a part of the aromatic 7i-electron system in both the ground
and excited states, but more importantly in the excited state. This may be illus-
trated for aniline by the following structures, which can be regarded as con-
tributing to the hybrid structure of aniline. (The data of Table 20-3 show
the effect on the benzene chromophore of this type of substituent.)
NH,
®NH,
As already mentioned, the benzene chromophore gives rise to a second
band at longer wavelengths, as shown in Figure 20-3. This band, which is of
low intensity, is found to be a composite of several equally spaced (1000
sec 20.3 spectroscopic properties of arenes 557
Table 20-4 The effect of substituents on absorption corresponding
to the benzenoid band
o
benzene
o- o
CH=CH 2
toluene
styrene
O^ 1
iodobenzene
Q-NH 2
aniline
''max » A
' v max
c-max
2550
230
2610
300
2820
450
2560
800
2800
1430
Table 20- S Benzenoid band of linear polycyclic aromatics
benzene naphthalene anthracene
naphthacene
A m „,A 2550
3140
316
3800
7900
4800
11,000
5800
12,600
cm" 1 ) narrow peaks. It is remarkably characteristic of aromatic hydro-
carbons, for no analogous band is found in the spectra of conjugated polyenes.
For this reason, it is often called the benzenoid band. The position and intensity
of this band, like the one at shorter wavelengths, are affected by the nature of
the ring substituents, particularly by those which extend the conjugated
system, as may be seen from the data in Table 20-4 and Table 20-5.
Figure 20-3 Ultraviolet absorption spectrum of benzene (in cyclohexane)
showing the "benzenoid" band.
2300
2400 2500 2600
wavelength, A *-
chap 20 arenes. electrophilic aromatic substitution 558
C. NUCLEAR MAGNETIC RESONANCE SPECTRA
The chemical shifts of aromatic protons (6.5 to 8.0 ppm) are characteristi-
cally toward lower magnetic fields than those of protons attached to ordinary
double bonds (4.6 to 6.9 ppm). The difference is usually about 2 ppm and
has special interest because we have already formulated the hydrogens in both
types of systems as being bonded to carbon through sp 2 -<7 bonds.
In general, the spin-spin' splittings observed for phenyl derivatives are
extremely complex. An example is given by nitrobenzene (Figure 20-4), which
has different chemical shifts for its ortho, meta, and para hydrogens and six
different spin-spin interaction constants: / 23 , J 24 , J 2 s, J26' ^34 > ^35 ( tne
subscripts correspond to position numbers of the protons).
Such a spectrum is much too complex to be analyzed by any very simple
procedure. Nonetheless, as will be seen from Exercise 20-7, nuclear magnetic
resonance can be useful in assigning structures to aromatic derivatives,
particularly in conjunction with integrated line intensities and approximate
values of the coupling constants between the ring hydrogens, as shown here.
Figure 20-4 Nuclear magnetic resonance spectrum of nitrobenzene at 60
MHz with reference to tetramethylsilane at 0.00 ppm.
_ p— . . p . , .
500 450 400 Hz
ill
/! '1* It -
'i'i iii.
in n ]
>
8.0 7.0 ppm
sec 20.4 reactions of aromatic hydrocarbons 559
20-4 reactions of aromatic hydrocarbons
A. ELECTROPHILIC AROMATIC SUBSTITUTION
In this section we shall be mainly interested in the reactions of arenes that
involve attack on the aromatic ring. We shall not at this point elaborate on
the reactions of substituent groups around the ring, although, as we shall see
later, these and reactions at the ring are not always independent.
The principal types of reactions involving aromatic rings are substitution,
addition, and oxidation. Of these, the most common are electrophilic
substitution reactions. A summary of the more important substitution reac-
tions of benzene is given in Figure 20-5 and includes halogenation, nitration,
sulfonation, alkylation, and acylation.
There are certain similarities between the aromatic substitution reactions
listed in Figure 20-5 and electrophilic addition reactions of alkenes (Section
4-4). Indeed, many of the reagents that commonly add to the double bonds of
alkenes also substitute an aromatic nucleus (e.g., Cl 2 , Br 2 , H 2 S0 4 , HOC1,
HOBr). Furthermore, both types of reaction are polar, stepwise processes
involving electrophilic reagents. The key step for either is considered to be the
attack of an electrophile at carbon to form a cationic intermediate. We may
represent this step by the following general equations in which the attacking
reagent is represented either as a formal cation, X®, or as a neutral but
a® se
polarized X— Y molecule.
Electrophilic aromatic substitution (first step) :
5e Se
(or X - Y)
Electrophilic addition to alkenes (first step) :
Se Se e
H 2 C=CH 2 + X® (or X - Y) ► H 2 C-CH 2 X
The intermediate depicted for aromatic substitution no longer has an
aromatic structure; rather, it is an unstable cation with four n electrons
delocalized over five carbon nuclei, the sixth carbon being a saturated carbon
forming sp 3 -hybrid bonds. It may be formulated in terms of the following
contributing structures, which are assumed here to contribute essentially
equally. (Note that the partial charges are at three positions, the two ortho
XH XH XH XH X^ H
« >
positions and the para position.)
Loss of a proton from this intermediate to Y e results in regeneration of an
aromatic ring, which is now a substitution product of benzene.
chap 20 arenes. electrophilic aromatic substitution 560
Figure 20-5 Typical benzene substitution reactions.
HN0 3 , H 2 SO»
Qhno 2
nitration
nitrobenzene
Br 2 , FeBr 3
/ Y-Br + HBr
bromination
bromobenzene
CI 2 , FeCl 3
/ V-Cl + HC1
chlorination
chlorobenzene
' 1 1
HOC1, H®, Ag®
/ '
O-c,
chlorobenzene
chlorination
cone. H2SO4
/ VS0 3 H + H 2
sulfonation
., \ \
benzenesulfonic acid
\ CH 3 CH 2 C1 .
/^-CH 2 CH 3
alkylation
AICI3
ethylbenzene
\ CH 3 CH=CH 2
H 3 P0 4
f>CH /H '
isopropylbenzene
(cumene)
alkylation
\ O
\ "
O
\ CH 3 CC1
(yi- CH ,
acylation
AICI3
methyl phenyl ketone
(acetophenone)
\ D 2 SQ 4
<y°
deuteration
monodeuteriobenzene
sec 20.4 reactions of aromatic hydrocarbons 561
Electrophilic aromatic substitution (second step) :
X H ?
The gain in stabilization attendant on regeneration of the aromatic ring is
sufficiently advantageous that this, rather than combination of the cation
with Y e , is the actual course of reaction. Here is the difference between aro-
matic substitution and alkene addition. With alkenes, there is usually no
substantial resonance energy to be gained by loss of a proton from the inter-
mediate, which tends instead to react by combination with a nucleophilic
reagent.
Electrophilic addition to alkenes (second step) :
CH 2 -CH 2 X + Y e > YCH 2 -CH 2 X
B. NATURE OF THE SUBSTITUTING AGENT
It is important to realize that in aromatic substitution the electrophilic sub-
Se Se
stituting agent, X® or X— Y, is not necessarily the reagent that is initially
added to the reaction mixture. For example, nitration in mixtures of nitric
and sulfuric acids is not usually brought about by attack of the nitric acid
molecule on the aromatic compound, but by attack of a more electrophilic
species, the nitronium ion, N0 2 ®. There is good evidence to show that this ion
is formed from nitric acid and sulfuric acid according to the following equa-
tion:
HN0 3 +2H 2 S0 4 „ N0 2 ® + H 3 O a + 2 HS0 4 e
The nitronium ion so formed then attacks the aromatic ring to give an
aromatic nitro compound.
NO,
-H®
NOf
nitrobenzene
In general, the function of a catalyst (which is so often necessary to promote
aromatic substitution) is to generate an electrophilic substituting agent from
the given reagents.
C. NITRATION
We have already mentioned that the nitronium ion, N0 2 ffi , is the active
nitrating agent in nitric acid-sulfuric acid mixtures. The nitration of toluene
is a fairly typical example of a nitration that proceeds well using nitric acid
in a 1 : 2 mixture with sulfuric acid. The nitration product is a mixture of o-,
m-, and ^-nitrotoluenes.
chap 20 arenes. electrophilic aromatic substitution 562
CH 3 CH 3 CH 3 CH 3
HN0 3 , H 2 S0 4
62% 5%
The presence of any appreciable concentration of water in the reaction
mixture is deleterious since water tends to reverse the reaction by which
nitronium ion is formed.
HNO3 + H 2 S0 4 . N0 2 ® + HS0 4 e + H 2
It follows that the potency of the mixed acids can be increased by using
fuming nitric and fuming sulfuric acids, which have almost negligible water
contents. With such mixtures, nitration of relatively unreactive compounds
can be achieved. For example,/?-nitrotoluene is far less reactive than toluene but
when heated with an excess of nitric acid in fuming sulfuric acid (H 2 S0 4 +
S0 3 ), it can be converted successively to 2,4-dinitrotoluene and to 2,4,6-
trinitrotoluene (TNT).
CH 3 CH 3 CH 3
-NOi 0,N JL NO,
HNO 3> 50° fi T HNO 3 ,120°
so 3 ,h 2 so 4 K^y so 3 ,h 2 so4 \^
I
N0 2 NO a
^-nitrotoluene 2,4-dinitrotoluene 2,4,6-trinitrotoluene
There are several interesting features about the nitration reactions thus far
discussed. In the first place, the conditions required for nitration of j?-nitro-
toluene would, in contrast, rapidly oxidize an alkene by cleavage of the double
bond.
/ CP V
HNO, CH 2 "C0 2 H
" I
CH 2 C0 2 H
CH 2
adipic acid
We may also note that the nitration of toluene does not lead to equal
amounts of the three possible mononitro toluenes. The methyl substituent
apparently orients the entering substituent preferentially to the ortho and para
positions. This aspect of aromatic substitution will be discussed later in the
chapter in conjunction with the effect of substituents on the reactivity of
aromatic compounds.
D. HALOGENATION
The mechanism of halogenation is complicated by the fact that molecular
halogens, Cl 2 , Br 2 , and I 2 , form complexes with aromatic hydrocarbons.
sec 20.4 reactions of aromatic hydrocarbons 563
Although complex formation assists substitution by bringing the reactants
in close proximity, it does not always follow that a substitution reaction will
occur. A catalyst is usually necessary. The catalysts most frequently used are
metal halides that can act as Lewis acids (FeBr 3 , A1C1 3 , and ZnCl 2 ). Their
catalytic activity may be attributed to their ability to polarize the halogen-
halogen bond:
S® Se
Br-Br-FeBr 3
The positive end of the halogen dipole attacks the aromatic compound
while the negative end is complexed with the catalyst. We may then represent
the reaction sequence as in Figure 20-6, with the slow step being formation of
a a bond between Br® and a carbon of the aromatic ring.
The order of reactivity of the halogens is F 2 > Cl 2 > Br 2 > I 2 • Fluorine is
too reactive to be of practical use for the preparation of aromatic fluorine
compounds and indirect methods are necessary (see Chapter 21). Iodine is
usually unreactive and, in fact, its reaction with some arenes is energetically
unfavorable. Use of iodine monochloride instead of iodine usually improves
both the rate and the equilibrium condition to the point where good yields of
iodination products are obtained: C 6 H 6 + IC1 ->■ C 6 H 5 I + HCL Alterna-
tively, molecular iodine can be converted to a more active species (perhaps
I®) with an oxidizing agent such as nitric acid. With combinations of this
kind, good yields of iodination products are obtained.
I
o-iodotoluene />-iodotoluene
Figure 20-6 A mechanism for the bromination of benzene in the presence of
ferric bromide catalyst.
So
Br Br-FeBr,
I , i
Br dffi Br
/ Y-Br + FeBr, + HBr
chap 20 arenes. electrophilic aromatic substitution 564
E. ALKYLATION
An important method of synthesizing alkylbenzenes utilizes an alkyl halide
as the alkylating agent together with a metal halide catalyst, usually aluminum
chloride.
CH,CH,
+ CH,CH,Br
benzene ethyl bromide
(large excess)
AICI3
80°
ethylbenzene
83%
HBr
The class of reaction is familiarly known as Friedel-Crafts alkylation. The
metal-halide catalyst functions much as it does in halogenation reactions;
that is, it provides a source (real or potential) of a positive substituting agent,
which in this case is a carbonium ion.
CH,
CH,
\
CH— CI + A1C1,
/ -
CH,
CH 3
■^i \e> e
+ CH— C1-A1C1,
/ 3
CH 3
CH — CI— A1C1,
/ 3
CH
+ A1C1 3 +
HC1
cumene
(isopropylbenzene)
Alkylation is not restricted to alkyl halides ; any combination of reagents
giving carbonium ions will serve. Frequently used combinations are alcohols
and alkenes in the presence of acidic catalysts, such as H 3 P0 4 , H 2 S0 4 , HF,
BF 3 , or HF - BF 3 . Ethylbenzene is made commercially from benzene and
ethene using phosphoric acid as the catalyst. Cumene is made similarly from
benzene and propene.
CH 2 =CH 2
h 3 po 4
^C H 3 CH=CH 2
H3P04
CH
CH,
sec 20.4 reactions of aromatic hydrocarbons 565
Under these conditions, the carbonium ion, which is the active substituting
agent, is generated by protonation of the alkene.
CH 2 =CH 2 +H® . CH 3 CH 2 ®
CH 3 CH=CH 2 +H® . CH3CHCH3
It is not possible to make K-propylbenzene satisfactorily by direct alkylation
of benzene because the rc-propyl cation rearranges to the isopropyl cation as
quickly as it is formed. Thus, cumene is the product of the reaction of benzene
with either «-propyl chloride or isopropyl chloride.
+ or > 1 + HC1
%^ (CH 3 ),CHC1
A serious drawback to Friedel-Crafts alkylation is the tendency for poly-
substitution to occur. This is because the alkyl group enhances further substi-
tution (Section 20-5). The use of a large excess of arene is helpful in favoring
monosubstitution.
F. ACYLATION
Acylation and alkylation of arenes are closely related. Friedel-Crafts acylation
introduces an acyl group, RCO— , into an aromatic ring, and the product is an
aryl ketone. Acylating reagents commonly used are acid halides, RCOC1,
or anhydrides, (RCO) 2 0. The catalyst is usually aluminum chloride, and its
function is to generate the active substituting agent, which potentially is an
acyl cation.
CH3COCI + AICI3 , CH 3 CO®-CI-AICl 3
H COCH3
+ CH3CO— CI-AICI3 ► I ® j] + A1CU
COCH3
+ HC1 + AICI3
methyl phenyl ketone
(acetophenone)
Acylation differs from alkylation in that the reaction is usually carried out
in a solvent, commonly carbon disulfide or nitrobenzene. Furthermore, acyla-
chap 20 arenes. electrophilic aromatic substitution 566
tion requires more catalyst than alkylation because much of the catalyst is
effectively removed by complex formation with the product ketone.
C 6 H 5
C 6 H 5 COCH 3 + AICI3 ■ C=0-A1C1 3
CH 3
1 : 1 complex
When an acylating reagent such as carboxylic anhydride is used, still more
catalyst is required because some is consumed in converting the acyl com-
pound to the acyl cation.
(RCO) 2 + 2 A1CU > RCO A1CU + RC0 2 A1C1 2
Unlike alkylation, acylation is easily controlled to give monosubstitution
because, once an acyl group is attached to a benzene ring, it is not possible to
introduce a second acyl group into the same ring. For this reason, arenes are
sometimes best prepared by acylation, followed by reduction of the carbonyl
group with amalgamated zinc and hydrochloric acid (Section 11-4F). For
example, rc-propylbenzene is best prepared by this two-step route since, as we
have noted, the direct alkylation of benzene with H-propyl chloride will give
considerable amounts of cumene and poly substitution products.
+ CH 3 CH,COCl
COCH 2 CH 3 CH 2 CH 2 CH 3
AICI3 (i^l Zn(Hg), HC1
nitrobenzene
propanoyl chloride /z-propylbenzene
G. SULFONATION
Substitution of the sulfonic acid (— S0 3 H) group for a hydrogen of an aro-
matic hydrocarbon is usually carried out by heating the hydrocarbon with a
slight excess of concentrated or fuming sulfuric acid.
SO,H
H 2 S0 4 , S0 3
30°-50°
+ H 2
benzenesulfonic acid
H 2 S0 4
.no°-i20°
+ H 2
p-toluenesulfonic acid
The actual sulfonating agent is normally the S0 3 molecule, which, although
it is a neutral reagent, has a powerfully electrophilic sulfur atom.
sec 20.5 effect of substituents on reactivity and orientation 567
O
II
/A
o o
o
c©
o' V
+ so,
Q e
o x o
o
J.
°o o
S0 3 H
H. DEUTERATION
It is possible to replace the ring hydrogens of many aromatic compounds by
exchange with deuteriosulfuric acid. The mechanism is analogous to other
electrophilic substitutions.
H + D,SO,
=o +
HDS0 4
Perdeuteriobenzene can be made from benzene in good yield if a suf-
ficiently large excess of deuteriosulfuric acid is used. Sulfonation, which might
appear to be a competing reaction, requires considerably more vigorous
conditions.
20-5 effect of substituents on reactivity and
orientation in electrophilic aromatic
substitution
In planning syntheses based on substitution reactions of mono- or polysubsti-
tuted benzenes, you must be able to predict in advance which of the available
positions of the ring are most likely to be substituted. This is now possible
with a rather high degree of certainty, thanks to the work of many chemists
over the last 100 years. Few, if any, other problems in organic chemistry have
received so much attention, and there is now accumulated enough data on the
orienting and reactivity effects of ring substituents in electrophilic substitution
to permit the formulation of some valuable generalizations.
Basically, three problems are involved in the substitution reactions of
aromatic compounds : (a) proof of the structures of the possible isomers,
o, m, and p, that are formed ; (b) the percentage of each isomer formed, if the
product is a mixture ; and (c) the reactivity of the compound being substituted
relative to some standard substance, usually benzene.
Originally, the identity of each isomer formed was established by Korner's
absolute method, which involves determining how many isomers each will give
on further substitution, this number being diagnostic of the particular isomer
(see Exercise 20-1). In practice, Korner's method is often very tedious and
lengthy, and it is now primarily of historical interest except in its application
to substitution reactions of unusual types of aromatic systems. For benzenoid
chap 20 arenes. electrophilic aromatic substitution 568
compounds, structures can usually be established with the aid of correlations
between spectroscopic properties and positions of substitution, as we have
indicated earlier in this chapter. Also, it is often possible to convert the
isomers to compounds of known structure by reactions that do not lead to
rearrangement. For example, trifluoromethylbenzene on nitration gives only
one product, which has been shown to be the meta-nitro derivative by con-
version to the known m-nitrobenzoic acid.
hno 3
CO,H
H 2 S0 4
NO,
NO,
A. THE PATTERN OF ORIENTATION IN AROMATIC SUBSTITUTION
The reaction most studied in connection with the orientation problem is ni-
tration, but the principles established also apply for the most part to the
related reactions of halogenation, sulfonation, alkylation, and acylation. Some
illustrative data for the nitration of a number of monosubstituted benzene
derivatives are given in Table 20-6. The orientation data are here expressed as
the percentage of ortho, meta, and para isomers formed, and the rate data are
Table 20-6 Orientation and rate data for nitration of some monosubstituted
benzene derivatives
R
rV
R
1 NO
u
R
■•6
+ 1
V N0 2
R
>
N0 2
ortho
meta
para
substituent, R
orientation
relative
reactivity
partial rate factors
%o
%m
%P
/.
fn.
fp
-CH 3
56.5
3.5
40
24
42
2.5
58
-C(CH 3 ) 3
12.0
8.5
79.5
15.7
5.5
4.0
75
-CH 2 C1
32.0
15.5
52.5
0.302
0.29
0.14
0.951
—CI
29.6
0.9
68.9
0.033
0.029
0.0009
0.137
-Br
36.5
1.2
62.4
0.030
0.033
0.0011
0.112
-NO,
6.4
93.2
0.3
~10" 7
1.8 x 10 " 6
2.8 x 10
" 5 2xl0" 7
-C0 2 C 2 H 5
28.3
68.4
3.3
0.0003
2.5 X 10~ 4
6x 10"
" 4 5xl0" 5
-CF 3
100
low
-N(CH 3 ) 3
89
11
low
sec 20.5 effect of substituents on reactivity and orientation 569
overall rates relative to benzene. Rates are also expressed as partial rate
factors, symbolized asf ,f m , and/ p , which are, respectively, the rate of sub-
stitution at one of the ortho, meta, and para positions relative to one of the
six equivalent positions in benzene. Consideration of the partial rate factors
is particularly useful, since it lets you tell at a glance if, for example, a
substituent gives ortho, para substitution with activation (f ,f p > 1), but meta
substitution with deactivation (f m < 1).
Inspection of the data in Table 20-6 shows that each substituent falls into
one of three categories :
1. Those substituents [e.g., CH 3 and — C(CH 3 ) 3 ] which activate all the ring
positions relative to benzene (/> 1), but are more activating for the ortho
and para positions than for the meta position. These substituents lead to pre-
dominance of the ortho and para isomers. As a class, they give ortho, para
orientation with activation. Other examples, in addition to those included in
Table 20-6, are -OH, -OCH 3 , -NR 2 , and -NHCOCH 3 .
2. Those substituents (e.g., CI, Br, and CH 2 C1) which deactivate all of the
ring positions (/< 1) but deactivate the ortho and para positions less than
the meta position so that formation of the ortho and para isomers is favored.
These substituents are classified as giving ortho, para orientation with
deactivation. e
3. Those substituents [e.g., -N0 2 , -C0 2 C 2 H 5 , -N(CH 3 ) 3 , and — CF 3 ]
that deactivate all the ring positions (/< 1) but deactivate the ortho and para
positions more than the meta position. Hence, mostly the meta isomer is
formed. These substituents give meta orientation with deactivation.
There is no known example of a substituent that activates the ring and, at
the same time, directs an electrophilic reagent preferentially to the meta
position.
A more comprehensive list of substituents which fall into one of the three
main categories is given in Table 20-7. It may be convenient to refer to this
table when in doubt as to the orientation characteristics of particular substi-
tuents. An explanation of these substituent effects follows, which should make
clear the criteria whereby predictions of the behavior of other substituents
can be made with considerable confidence. First, however, we must examine
more closely the energetics of electrophilic substitution.
The distribution of products in most aromatic electrophilic substitutions of
benzene derivatives is determined not by the relative stabilities of the products
but by the rates at which they are formed. Thus nitration of chlorobenzene
gives mostly o- and ^-nitrochlorobenzene, whereas chlorination of nitro-
benzene produces mostly the meta isomer. This means that benzene can be
converted to one or the other set of products depending on the sequence of
the nitration and chlorination reactions (Figure 20-7). Furthermore, there is
virtually no isomerization of the products.
To rationalize the orientation effects of ring substituents, then, we should
compare the transition states leading to the various products. The rate-con-
trolling step in electrophilic aromatic substitution is normally the first step —
the attack of the electrophile at the activated position — not the second step
in which a proton is lost from the intermediate ion. The energy profile for the
attack of an electrophile Z® on benzene is shown in Figure 20-8.
chap 20 arenes. electrophilic aromatic substitution 570
Table 20-7 Orientation and reactivity effects of ring
substituents
o,p orientation
o,p orientation
m orientation
■with activation
with deactivation
with deactivation
-OH
— CH 2 C1
-N0 2
_ e
— F
-NH 3
-OR
-CI
e
-NR 3
-OC 6 H 5
-Br
©
-PR3
-NH 2
—I
©
-SR 2
-NR 2
— CH=CHN0 2
-IC 6 H 5
-NHCOCH3
-CF 3
-alkyl(e.g.,CH 3 )
-CCU
-aryl (e.g., C 6 H 5 )
-SO3H
-S0 2 R
-C0 2 H
-C0 2 R
-CONH 2
-CHO
-COR
-C=N
The transition states are closer in energy to the intermediate ion than they
they are to either the products or the reactants. It is convenient to take the
intermediate as equivalent to the transition states in the discussion that
follows.
B. ELECTRICAL EFFECTS
An important effect of substituent groups on aromatic substitution is the in-
ductive effect which we have encountered previously in connection with the
ionization of carboxylic acids (Section 13-4B). An electron-attracting group
( — /effect) will exert an electrostatic effect such as to destabilize a positively
charged intermediate, while an electron-donating group ( + /effect) will have the
e
opposite effect. We shall illustrate this simple principle, using the (CH 3 ) 3 N—
group as an example. This group is strongly electron-attracting. If we write
the hybrid structure of the substitution intermediate with the group X repre-
senting some electrophilic substituting agent, we see at once that the charge
e
produced in the ring is unfavorable when the (CH 3 ) 3 N— substituent is
sec 20.5 effect of substituents on reactivity and orientation 571
/
CI,
\hno 3
/FeCl 3 \H 2 S0 4
CI NO,
HN0 3 , \
H 2 S0 4 FeCl 3 \ci 2
CI CI
NO,
CI
NO,
ortho
meta
Figure 20-7 The sequence of chlorination and nitration reactions required
to give the three isomers of nitrochlorobenzene.
Figure 20-8 Energetics of the reaction of an electrophile Z® with benzene
showing the formation of the intermediate, C 6 H 6 Z ffi , and its decomposition to
products. The transition state which determines the rate of the overall re-
action is that of the first step.
chap 20 arenes. electrophilic aromatic substitution 572
present, particularly for substitution at the ortho and para positions where
adjacent atoms would carry like charges. Thus, although all three intermediates
should then be less stable than the corresponding intermediate for benzene,
the ortho and para intermediates should be less favorable than the one for
meta substitution. This should lead to meta orientation with deactivation, as
indeed is observed. (We show the charge distribution in the intermediate ions
in these examples.)
N(CH 3 ) 3
' H
N(CH 3 ) 3
N(CH 3 ) 3
w X H' "X
ortho substitution meta substitution para substitution
Other substituents that are strongly electron attracting and that also orient
e
meta with deactivation include — N0 2 , — CF 3 , — P(CH 3 ) 3 , — S0 3 H,
-C0 2 H, -C0 2 CH 3 , — CONH 2 , — CHO, -COC 6 H 5 , and — C=N.
The activating and ortho, /?ara-orienting influence of alkyl substituents can
also be rationalized on the basis of inductive effects. Thus, the substitution
intermediates for ortho, para, and meta substitution of toluene are stabilized
by the capacity of a methyl group to release electrons ( + / effect) and partially
compensate for the positive charge.
CH,
H X
ortho substitution meta substitution para substitution
Furthermore, the stabilization is most effective in ortho and para substitu-
tion where part of the positive charge is adjacent to the methyl substituent.
(For other examples of stabilization of positive carbon by alkyl groups see
Section 4-4C). The result is ortho,para orientation with activation.
In addition to the inductive effects of substituents, conjugation effects may
be a factor in orientation and are frequently decisive. This is especially true of
substituents that carry one or more pairs of unshared electron pairs on the
atom immediately attached to the ring (e.g., — OH, ~0: e , — OCH 3 ,
— NH 2 , — NHCOCH 3 , —CIO- An electron pair so situated helps to stabilize
the positive charge of the substitution intermediate, as the extra resonance
forms [5] and [6] will indicate for ortho and para substitution of anisole
(methyl phenyl ether).
ortho substitution
sec 20. S effect of substituents on reactivity and orientation 573
OCH 3 ®OCH 3
para substitution
H X
[6]
In meta substitution, however, the charge is not similarly stabilized as no
resonance structures analogous to [5] or [6] can be written. Accordingly, the
favored orientation is ortho,para, but whether substitution proceeds with
activation or deactivation depends on the magnitude of the inductive effect
of the substituent. For example, halogen substituents are strongly electro-
negative and deactivate the ring at all positions ; yet they strongly orient ortho
mdpara through conjugation of the unshared electron pairs. Apparently the
inductive effect is strong enough to reduce the overall reactivity, but not
powerful enough to determine the orientation. Thus for para substitution of
chlorobenzene the intermediate stage is formed less readily than in the
substitution of benzene itself.
®C1
(unfavorable, because positive
carbon is next to chlorine)
Other groups such as — NH 2 , — NHCOCH 3 , and — OCH 3 are electron
attracting but much less so than the halogens, and the inductive effect is
completely overshadowed by the conjugation effect. Therefore, substitution
proceeds with ortho,para orientation and activation. The most activating
common substituent is — 0' e , which combines a large electron-donating in-
ductive effect with a conjugation effect.
C. ORIENTATION IN DISUBSTITUTED BENZENES
The orientation and reactivity effects of substituents discussed for the substi-
tution of monosubstituted benzenes also hold for disubstituted benzenes ex-
cept that the directing influence now comes from two groups. Qualitatively,
the effects of the two substituents are additive. We would therefore expect
/7-nitrotoluene to be less reactive than toluene because of the deactivating
effect of a nitro group. Also, the most likely position of substitution should be,
and is, ortho to the methyl group and meta to the nitro group.
N0 2 e
_____
NO,
NO,
chap 20 arenes. electrophilic aromatic substitution 574
When the two substituents have opposed orientation effects, it is not always
easy to predict what products will be obtained. For example, 2-methoxy-
acetanilide has two powerful ortho, para-directing substituents, — OCH 3 and
— NHCOCH3 . Nitration of this compound gives mainly the 4-nitro derivative,
which indicates that the — NHCOCH 3 exerts a stronger influence than OCH 3 .
NHCOCH3 NHCOCH3
i. ,OCH 3 /L XDCHj
u
-H®
20-6 substitution reactions of polynuclear
aromatic hydrocarbons
Although naphthalene, phenanthrene, and anthracene resemble benzene in
many respects, they are more reactive than benzene in both substitution and
addition reactions. This is expected theoretically because quantum mechanical
calculations show that the loss in stabilization energy for the first step in
electrophilic substitution or addition decreases progressively from benzene to
anthracene; therefore the reactivity in substitution and addition reactions
should increase from benzene to anthracene.
In considering the properties of the polynuclear hydrocarbons relative to
benzene, it is important to recognize that the carbon-carbon bonds in poly-
nuclear hydrocarbons are not all alike nor do they correspond exactly to
benzene bonds. This we may predict from the hybrid structures of these
molecules, derived by considering all of the electron-pairing schemes having
normal bonds, there being three such structures for naphthalene, four for
anthracene, and five for phenanthrene. See Figure 20-9. If we assume that
each structure contributes equally to its resonance hybrid, then, in the case of
naphthalene, the 1,2 and 2,3 bonds have § and -J double-bond character, re-
spectively. Accordingly, the 1,2 bond should be shorter than the 2,3 bond,
and this has been verified by X-ray diffraction studies of crystalline naphtha-
lene.
bond lengths of naphthalene, A units
Similarly, the 1,2 bond of anthracene should have f double-bond character
and should be shorter than the 2,3 bond, which has only \ double-bond
character. The 1,2 bond is indeed shorter than the 2,3 bond.
bond lengths of anthracene, A units
sec 20.6 substitution reactions of polynuclear aromatic hydrocarbons 575
Naphthalene
Anthracene
Phenanthrene
Figure 20-9 Resonance structures for naphthalene, anthracene, and phenanthrene.
The trend toward greater inequality of the carbon-carbon bonds in poly-
nuclear hydrocarbons is very pronounced in phenanthrene. Here, the 9,10
bond is predicted to have f double-bond character, and experiment verifies
that this bond does resemble an alkene double bond, as we shall see in sub-
sequent discussions.
A. NAPHTHALENE
In connection with orientation in the substitution of naphthalene, the picture
is often complex, although the 1 position is the more reactive (Figure 20-10).
Sometimes, relatively small changes in the reagents and conditions change
the pattern of orientation. One example is sulfonation, a reversible reaction
leading to 1-naphthalenesulfonic acid at 120° but to the 2 isomer on pro-
longed reaction or at temperatures above 160°C. Another example is supplied
by Friedel-Crafts acylation: the major product in carbon disulfide is the
1 isomer, while in nitrobenzene it is the 2 isomer.
chap 20 arenes. electrophilic aromatic substitution - 576
HN0 3 H 2 S0 4
1-nitronaphthalene
Br
Br 2
50% CH 3 C0 2 H,H 2
1-bromonaphthalene 2-bromonaphthalene
99% !•/
COCH,
CH3COCI-AICI3
CS 2 , -15°
CH3COCI
C 6 H 5 NQ 2 , AICI3
25°
COCH3
1 -aeetonaphthalene 2-acetonaphthalene
7 5% 25%
COCH,
Figure 20-10 Electrophilic substitution pattern of naphthalene.
Normally, substitution of naphthalene occurs more readily at the 1 position
than at the 2 position. This may be accounted for on the basis that the most
favorable resonance structures for either the 1- or the 2-substituted inter-
mediate are those which have one ring fully aromatic. We see then that 1
substitution is favored over 2 substitution since the positive charge in the
1 intermediate can be distributed over two positions, leaving one aromatic
ring unchanged; but this is not possible for the 2 intermediate without
affecting the benzenoid structure of both rings.
/ substitution:
H X
rL .X
2 substitution:
e H
sec 20.6 substitution reactions of polynuclear aromatic hydrocarbons 577
B. PHENANTHRENE AND ANTHRACENE
The substitution patterns of the higher hydrocarbons are more complex than
for naphthalene. For example, phenanthrene can be nitrated and sulfo-
nated, but the products are mixtures of 1-, 2-, 3-, 4-, and 9-substituted
phenanthrenes.
sulfonation
nitration
(percentages are yields of sulfonic (figures at the 9, 1, 2, 3, and 4
acids with H 2 S0 4 at 60°. At 120°, positions are partial rate
mostly the 2- and 3-sulfonic acids factors)
are obtained)
The 9,10 bond in phenanthrene is quite reactive; in fact, almost as much so
as an alkene double bond. Addition therefore occurs readily, giving both
9,10 addition and 9-substitution products (Scheme I).
Br 2
phenanthrene
SCHEME I
Anthracene is even more reactive than phenanthrene and has a great tendency
to add various reagents to the 9,10 positions. The addition products
of nitration and halogenation readily give the 9-substitution products on
warming.
Br
Br 2
-HBr
chap 20 arenes. electrophilic aromatic substitution 578
20-7 nonbenzenoid conjugated cyclic compounds
A. AZULENE
There are a number of compounds that possess some measure of aromatic
character typical of benzene, but that do not possess a benzenoid ring.
Appropriately, they are classified as nonbenzenoid aromatic compounds. One
example of interest is azulene, and, like benzene, it tends to react by substitu-
tion, not addition. It is isomeric with naphthalene and has a five- and a seven-
membered ring fused through adjacent carbons. As the name implies, it is
azulene
deep blue in color. It is less stable than naphthalene and isomerizes quanti-
tatively on heating above 350° in the absence of air.
>350°
Azulene can be represented as a hybrid of neutral and ionic structures.
e
The polarization shown above puts weight on those ionic structures having
six electrons in both the five- and seven-membered rings (see Section 6-7).
B. CYCLOOCTATETRAENE
Of equal interest to azulene is cyclooctatetraene, which is a bright yellow,
nonbenzenoid, nonaromatic compound with alternating single and double
bonds. If the carbons of cyclooctatetraene were to occupy the corners of a
regular planar octagon, the C— C— C bond angles would have to be 135°.
Cyclooctatetraene does not conform to the Hiickel 4n + 2 rule (Section 6-7)
and it is not surprising that the resonance energy gained in the planar struc-
ture is not sufficient to overcome the unfavorable angle strain. Cycloocta-
tetraene, instead, exists in a "tub" structure with alternating single and
double bonds.
tub
♦ summary 579
There is, however, nmr evidence that indicates that the tub form is in quite
rapid equilibrium with a very small amount of the planar form at room tem-
perature. Probably there is not much more than a 10-kcal energy difference
between the two forms.
summary
The rules of nomenclature for arenes (aromatic hydrocarbons) are similar to
those for aliphatic systems except that pairs of substituents at different ring
positions may be designated ortho, meta, and para. A number of important
arenes are C 6 H 6 (benzene), C 6 H 5 CH 3 (toluene), C 6 H 5 CH(CH 3 ) 2 (cumene),
and C 6 H 5 CH=CH 2 (styrene). A number of important aryl or aralkyl groups
/ 1
are C 6 H 5 - (phenyl), C 6 H 5 CH 2 - (benzyl), C 6 H 5 CH (benzal), C 6 H 5 C—
\ I
(benzo), and (C 6 H 5 ) 2 CH— (benzhydryl).
Polynuclear aromatic hydrocarbons have aromatic rings fused together so
that the rings have one or more sides in common. Important examples of these
are naphthalene, anthracene, and phenanthrene. Fusing an additional ring
to an arene normally adds C 4 H 2 to the molecular formula; the extra ring is
designated benzo or benz.
naphthalene (C 10 H 8 ) anthracene (G 14 H 10 ) phenanthrene (C 14 H 10 )
Aromatic rings have characteristic absorption bands in the infrared (near
1500, 1600, and just above 3000 cm" 1 ), in the ultraviolet (near 2000 A but
shifting to higher wavelengths with conjugation), and in nmr spectra (6.5 to
8.0 ppm for aromatic protons).
Electrophilic substitution serves to introduce the following groups into an
O
II
aromatic ring: — N0 2 , -CI (or Br or I), -S0 3 H, -R (alkyl), R-C—
(acyl), and — D. The actual electrophilic reagents in these cases are electron-
deficient cations (except for S0 3 ). Substituents already present in the ring
determine the position taken by the incoming group. Some important sub-
stituents that direct the incoming electrophile to the ortho and para positions
are — R (alkyl), —OR, — NH 2 , and X (halogen). Those that direct toward
O
© II
the meta position include — N0 2 , — NH 3 , — C— , and — C=N.
The orienting effect of a substituent Y on an electrophile Z ffi is determined
by how Y affects the dispersal of the positive charge in the transition state,
a reasonable model for which is the intermediate ion [1] (shown for the case
chap 20 arenes. electrophilic aromatic substitution 5S0
of para substitution).
fast „
> H e +
All of the common ortho,para-directing substituents, with the exception of
halogen, activate the ring toward substitution and all the meta-directing sub-
stituents deactivate the ring; nitro to such an extent that the Friedel-Crafts
reaction cannot be applied to nitrobenzene.
Naphthalene is normally substituted at the 1 position (a) but sulfonation
at high temperatures and Friedel-Crafts acylation in nitrobenzene give sub-
stitution at the 2 position (/?). Phenanthrene gives mixtures of substitution
products but anthracene tends to react by addition at the 9,10 positions.
Other cyclic hydrocarbons that have been considered are phenalenyl [2], a
resonance-stabilized radical; azulene [3], which has aromatic character; and
cyclooctatetraene [4], which does not. There are a number of other resonance
structures for [2] and [3].
[2] [3] [4]
exercises
20-1 How many isomeric products could each of the xylenes give on introduction
of a third substituent? Name each isomer using chlorine as the third sub-
stituent.
20-2 Name each of the following compounds by an accepted system:
a. (C 6 H 5 ) 2 CHC1
b. C 6 H 5 CHC1 2
c. C 6 H 5 CC1 3
CH,
d.
exercises 581
20-3 How many possible disubstitution (X,X and X,Y) products are there for
naphthalene, phenanthrene, anthracene, and biphenyl? Name each of the
possible dimethyl derivatives.
20-4 A number of polynuclear hydrocarbons are shown below with their con-
jugated rings shown as hexagons with inscribed circles.
d.
/•
20-5
(i) Determine which of these compounds are radicals by drawing Kekule
structures, (ii) Three of the structures above represent compounds whose
structures have been given earlier in the chapter in a somewhat different
form. Identify them.
Identify the two compounds with molecular formula C 7 H 7 C1 from their
infrared spectra in Figure 20-11.
20-6 Predict the effect on the ultraviolet spectrum of a solution of aniline in water
when hydrochloric acid is added. Explain why a solution of sodium phen-
oxide absorbs at longer wavelengths than a solution of phenol (see Table
20-3).
20 "7 Establish the structures of the following benzene derivatives on the basis of
their empirical formulas andnmr spectra as shown in Figure 20-12. Remem-
ber that equivalent protons do not normally split each other's resonances
(Section 7-6B).
a.
b.
CsHto
C 8 H 7 OCl
c. C 9 H 10 2
d. C9H12
20-8 Calculate from appropriate bond and stabilization energies the heats of
reaction of chlorine with benzene to give (a) chlorobenzene and (b) 5,6-
dich!oro-l,3-cyclohexadiene. Your answer should indicate that substitution
is energetically more favorable than addition.
chap 20 arenes. electrophilic aromatic substitution S82
^V
4 5
i r
~\ -r
rAT-f^
wavelength, jU
9 10 12 14
t — i i — ~r
\H" f \^ /Anf\ ni
T\
mm
CH-Cl
ai:
i i i i i _j i i_
3600 3200 2800 2400 2000 2000 1800
1 600 _. 1 400
frequency, cm
i I I Jt
w
w
I
J I [_
I 1_
1 000 800
~v
4 5
m
r' v *A/~~ — :
iC,H,Cl
wavelength, jjl
i i i ' i i ■ i . w' .
3600 3200 2800 2400 2000 2000 1800 1600
frequency, cm
1000 800"
Figure 20-11 Infrared spectra of two isomeric compounds of formula C 7 H 7 C1
(see Exercise 20- 5).
20-9 On what basis (other than the thermodynamic one suggested in Exercise
20-8) could we decide whether or not the following addition-elimination
mechanism for bromination of benzene actually takes place ?
+ Br 2
Br
kJr Br
H
Br
+ HBr
g
o
g
o
u
s-
D
X
u
E
o
s
H
u
c
o
£
3°
N
Ice
K
1
s
o
v*
-H
J
(S
C/l
sg
4)
i u.
' o.
-H
rs
iO
>
u
o
-o
u
a
D
N
S
<U
!<_)
J3
! O
1°
a,
o
to
o
S
c
s
o
u
ft.
. Ju:
___;
o
CO
3
chap 20 arenes. electrophilic aromatic substitution 584
20-10 Explain with the aid of an energy diagram for aromatic nitration how one
can account for the fact that hexadeuteriobenzene undergoes nitration with
nitric acid at the same rate as ordinary benzene.
20-1 1 From the fact that nitrations in concentrated nitric acid are strongly retarded
by added nitrate ions and strongly accelerated by small amounts of sulfuric
acid, deduce the nature of the actual nitrating agent.
20-12 Account for the fact that fairly reactive arenes (e.g., benzene, toluene, and
ethylbenzene) are nitrated with excess nitric acid in nitromethane solution at
a rate that is independent of the concentration of the arene (i.e., zeroth
order). Does this mean that nitration of an equimolal mixture of benzene
and toluene would necessarily give an equimolal mixture of nitrobenzene
and nitrotoluenes ? Why or why not ?
20-13 Write a mechanism for the alkylation of benzene with isopropyl alcohol
catalyzed by boron trifluoride.
20-14 Suggest possible routes for the synthesis of the following compounds:
a - (~y-CU 2 -(~\ c. CH,-/ \-CH 2 CH 3
o o
11 f~~\ II
b. CH 3 --C-f VC-CH 3
20-15 Calculate the partial rate factors for each different position in the mono-
nitration of biphenyl, given that the overall reaction rate relative to benzene
is 40, and the products are 68% o-, 1% m-, and 31% /j-nitrobiphenyl.
(Remember, there are two benzene rings in biphenyl.)
20-16 Explain why the — CF 3 , — N0 2 , and — CHO groups should be meta
orienting with deactivation.
20-17 Explain why the nitration and halogenation of biphenyl goes with activation
at the ortho and para positions but with deactivation at the meta position.
Suggest a reason why biphenyl is more reactive than 2,2'-dimethylbiphenyl
in nitration.
20-18 Explain why the bromination of aniline gives 2,4,6-tribromoaniline, whereas
the nitration of aniline with mixed acids gives /n-nitroaniline.
20-19 Predict the favored positions of substitution in the nitration of the following
compounds:
rv<
-CH 2 N(CH 3 ) 3
CI
Br
/ %
CH
Br
exercises S8S
F
/
/■
6
-OCH 3
8
'111
fl
ff-
5
4
Br (consider the character of
. / the various resonance
( V
Br
structures for substitution
\ / in the 1- and 2- positions)
20-20 Predict the orientation in the following reactions:
a. 1-methylnaphthalene + Br 2
b. 2-methylnaphthalene + HNO3
c. 2-naphthoic acid + HNO3
20-21 How would you go about proving that the acylation of naphthalene in the
2 position in nitrobenzene solution is not the result of thermodynamic
control?
20-22 Show how you can predict qualitatively the character of the 1,2 bond in
acenaphthylene.
20-23 Write structural formulas for all of the possible isomers of C 8 Hi containing
one benzene ring. Show how many different mononitration products each
could give if no carbon skeleton rearrangements occur but nitration is con-
sidered possible either in the ring or side chain. Name all of the mononi-
tration products by an accepted system.
20-24 Write structural formulas (more than one might be possible) for aromatic
substances that fit the following descriptions :
a. CsHio, which can give only one theoretically possible ring nitration
product
b. C 6 H 3 Br 3 , which can give three theoretically possible nitration prod-
ucts
c. C 6 H 3 Br 2 Cl, which can give two theoretically possible nitration prod-
ucts
d. C s Hs(N0 2 )2 , which can give only two theoretically possible different
ring monobromo substitution products
20-25 1 ,3-Cyclohexadiene cannot be isolated from reduction of benzene by hydro-
gen over nickel. The isolable reduction product is always cyclohexane.
chap 20 arenes. electrophilic aromatic substitution 586
Explain why the hydrogenation of benzene is difficult to stop at the
1,3-cyclohexadiene stage, even though 1,3-butadiene is relatively easy
to reduce to butenes.
How could an apparatus for determining heats of hydrogenation be
used to obtain an accurate AH value for the reaction?
+ H,
Calculate a AH of combustion for benzene as 1,3,5-cyclohexatriene
(no resonance) from bond energies and compare it with a calculated
value for heat of combustion of benzene obtained from the experi-
mental AH, +5.9 kcal, for the hydrogenation in (b).
20-26 Predict the most favorable position for mononitration for each of the follow-
ing substances. Indicate whether the rate is greater or less than for the nitra-
tion of benzene. Give your reasoning in each case.
a. fiuorobenzene
b. trifiuoromethylbenzene
c. acetophenone
d. nitrosobenzene
e. benzyldimethylamine oxide
/. diphenylmethane
g. p-methoxybromobenzene
h.
J-
k.
diphenyl sulfone
/?-?-butyltoluene
(C 6 H 5 ) 2 IN0 3
m-diphenylbenzene
(m-terphenyl)
4-acetylaminobiphenyl
20-27 Predict which of the following compounds have some aromatic character.
Give your reasons.
Q OH
© Bre
tropylium bromide
aceplieadylene
n> : i '*?•■•;;•*,{*•!
IK
mmmm&mmmm
chap 21 aryl halogen compounds, nucleophilic aromatic substitution S89
The chemical behavior of aromatic halogen compounds depends largely on
whether the halogen is attached to carbon of the aromatic ring, as in bromo-
benzene, C 6 H 5 Br, or to carbon of an alkyl substituent, as in benzyl bromide,
C 6 H 5 CH 2 Br. Compounds of the former type are referred to as aryl halides,
and those of the latter as arylalkyl halides.
Aryl halides are expected to resemble vinyl halides to some extent since
both have their halogen atoms attached to unsaturated carbon.
bromobenzene vinyl bromide
(phenyl bromide) (bromoethene)
Consequently, it is no surprise to find that most aryl halides are usually
much less reactive than alkyl or allyl halides toward nucleophilic reagents in
either S N 1 or S N 2 reactions. Whereas ethyl bromide reacts easily with sodium
methoxide in methanol to form methyl ethyl ether, vinyl bromide and bromo-
benzene completely fail to undergo nucleophilic displacement under similar
conditions. Also, neither bromobenzene nor vinyl bromide reacts appreciably
with boiling alcoholic silver nitrate solution even after many hours.
In contrast to phenyl halides, benzyl halides are quite reactive. In fact, they
are analogous in reactivity to allyl halides (Section 9-6).
CH,=CH-CH,-Br
benzyl bromide allyl bromide
Benzyl halides are readily attacked by nucleophilic reagents in both S N 1
and S N 2 displacement reactions. The ability to undergo S N 1 reactions is
clearly related to the stability of the benzyl cation, the positive charge of
which is expected, on the basis of the resonance structures [la] through [Id],
to be extensively delocalized.
[la] [lb] [lc] [Id]
■*
When the halogen substituent is located two or more carbons from the aro-
matic rings — as in 2-phenylethyl bromide, C 6 H 5 CH 2 CH 2 Br — the pronounced
activating effect evident in benzyl halides disappears, and the reactivity of the
halide is essentially that of a primary alkyl halide (e.g., CH 3 CH 2 CH 2 Br).
Since, in general, the chemistry of arylalkyl halides is related more closely to
that of aliphatic derivatives than to aryl halides, we shall defer further dis-
cussion of arylalkyl halides to Chapter 24, which is concerned with the
chemistry of aromatic side-chain derivatives.
chap 21 aryl halogen compounds, nucleophilic aromatic substitution 590
Table 21-1 Physical properties of aryl halides
name
bp,
°C
mp,
°C
rf 20/4
<'
fluorobenzene
85
-42
1.024
1.4646 22 - 8
chlorobenzene
132
-45
1.1066
1.5248
bromobenzene
155
-31
1.4991 15 ' 15
1.5598
iodobenzene
189
-31
1.832
1.6214 185
o-chiorotoluene
159
-34
1.0817
1.5238
m-chlorotoluene
162
-48
1.0732
1.5214 19
p-chlorotoluene
162
8
1.0697
1.5199 19
1 -chloronaphthalene
263
1.1938
1.6332 20
2-chloronaphthalene
265
55
21 -1 physical properties of aryl halogen compounds
There is nothing unexpected about most of the physical properties of aryl
halides. They are slightly polar substances and accordingly have boiling
points approximating those of hydrocarbons of the same molecular weights ;
their solubility in water is very low, whereas their solubility in nonpolar
organic solvents is high. In general, they are colorless, oily, highly refractive
liquids with characteristic aromatic odors and with densities greater than that
of water. A representative list of halides and their physical properties is given
in Table 21-1.
With respect to the infrared spectra of aryl halides, correlations between
structure and absorption bands of aromatic carbon-halogen bonds have not
proved to be useful.
21-2 preparation of aryl halides
Many of the methods that are commonly used for the preparation of alkyl
halides simply do not work when applied to the preparation of aryl halides.
Thus, it is not possible to convert phenol to chlorobenzene by reagents such as
HC1— ZnCl 2 , SOCl 2 , and PC1 3 which convert ethanol to chloroethane. In
fact, there is no very practical route at all for conversion of phenol to chloro-
benzene. In this situation, it is not surprising that some of the methods by
which aryl halides are prepared are not often applicable to the preparation of
alkyl halides. One of these methods is direct halogenation of benzene or its
derivatives with chlorine or bromine in the presence of a metal halide catalyst,
as discussed in Section 20-4C.
Br
FeCl 3
■ci,
sec 21.2 preparation of aryl halides 591
Direct halogenation of monosubstituted benzene derivatives often gives a
mixture of products, which may or may not contain practical amounts of the
desired isomer. A more useful method of introducing a halogen substituent
into a particular position of an aromatic ring involves the reaction of an
aromatic primary amine with nitrous acid under conditions that lead to the
formation of an aryldiazonium salt. Decomposition of the diazonium salt
to an aryl chloride or bromide is effected by warming a solution of the
diazonium salt with cuprous chloride or bromide in an excess of the corre-
sponding halogen acid. The method is known as the Sandmeyer reaction.
CH
CH,
NH,
o-toluidine
o-methylbenzenediazonium
chloride
(not isolated)
CH
(CuCl)
HC1, 60°
o-chlorotoluene
74-79°/
For the formation of aryl iodides from diazonium salts, the cuprous cata-
lyst is not necessary since iodide ion is sufficient to cause decomposition of the
diazonium salt. Both cuprous ion and iodide ion appear to be involved in
an oxidation-reduction process at the diazo group that promotes the de-
composition.
NH 2
1 -phenanthrylamine
1. NaNQ 2 , H 2 SQ 4 , H 2 Q ;
2. KI-H 2 *
1 -iodophenanthrene
53%
Aryl fluorides may also be prepared from diazonium salts if the procedure
is slightly modified. The amine is diazotized in the usual way; then fiuoboric
acid or a fluoborate salt is added, which usually causes precipitation of a
sparingly soluble diazonium fluoborate. The salt is collected and thoroughly
dried, then carefully heated to the decomposition point, the products being
an aryl fluoride, nitrogen, and boron trifluoride.
© e
C 6 H 5 N 2 BF 4
heat
-> C 6 H 5 F + N 2 +BF 3
The reaction is known as the Schiemann reaction. An example (which gives a
rather better than usual yield) follows :
NH,
1. NaNQ 2 ,H 2 SQ 4
2. HBF 4
4-bromo-l-
naphthylamine
4-bromonaphthalene
-1-diazonium fluoborate
l-fluoro-4-
bromonaphthalene
97%
chap 21 aryl halogen compounds, nucleophilic aromatic substitution 592
2. (CuCl)
Figure 21-1 Preparation of m-dichlorobenzene from benzene. The nitration
reaction gives very largely meta substitution (see Table 20-6) and the m-dinitro
product is easily purified by crystallization.
The arylamines necessary for the preparation of aryl halides by the Sand-
meyer and Schiemann reactions are usually prepared by reduction of the cor-
responding nitro compounds (see Chapter 22), which in turn are usually ob-
tained by direct nitration of an aromatic compound. For example, although
ra-dichlorobenzene cannot be prepared conveniently by direct chlorination
of benzene, it can be made by dinitration of benzene followed by reduction
and the Sandmeyer reaction (Figure 21-1). In connection with this synthesis,
it should be noted that tetrazotization (double diazotization) of 1,2- and 1,4-
diaminobenzene derivatives is not as easy to achieve as with the 1,3 compound,
because the 1,2- and 1,4-diaminobenzenes are very easily oxidized.
21 -3 reactions of aryl halides
A. ORGANOMETALLIC COMPOUNDS FROM ARYL HALIDES
Grignard reagents can be prepared with fair ease from aryl bromides or
iodides and magnesium metal.
ether
C 6 H 5 Br + Mg ► C 6 H 5 MgBr
phenylmagnesium bromide
Chlorobenzene and other aryl chlorides are usually unreactive unless added
to the magnesium admixed with a more reactive halide. 1,2-Dibromoethane
is particularly useful as the second halide because it is converted to ethene,
which does not then contaminate the products, and it continually produces a
fresh magnesium surface, which is sufficiently active to be able to react with
the aryl chloride.
The reactions of arylmagnesium halides are analogous to those of alkyl-
magnesium halides (see Chapter 9) and require little further comment.
Aryllithiums can usually be prepared by direct reaction of lithium metal
with chloro or bromo compounds.
sec 21.3 reactions of aryl halides S93
ether
C 6 H 5 C1 + 2 Li ► C 6 H 5 Li + LiCl
phenyllithium
As with the Grignard reagents, aryllithiums react as you might expect by
analogy with alkyllithiums.
B. NUCLEOPHILIC DISPLACEMENT REACTIONS OF ACTIVATED
ARYL HALIDES
While the simple aryl halides are inert to the usual nucleophilic reagents, con-
siderable activation is produced by strongly electron-attracting substituents,
provided these are located in either the ortho or para positions, or both. As
one example, the displacement of chloride ion from l-chloro-2,4-dinitroben-
zene by dimethylamine occurs measurably fast in ethanol solution at room
temperature. Under the same conditions, chlorobenzene completely fails to
react ; thus, the activating influence of the two nitro groups easily amounts
to a factor of at least 10 8 .
H 3 C CH 3
\ / 3
e NH Cl e •
N °2 J^ N0 2
+ (CH 3 ) 2 NH C2 " 5 5 o° H >
N0 2
A related reaction is that of 2,4-dinitrofluorobenzene with peptides and
proteins, which is used for analysis of the N-terminal amino acids in polypep-
tide chains. (See Section 17-3A.)
In general, the reactions of activated aryl halides bear a close resemblance
to S N 2 displacement reactions of aliphatic halides. The same nucleophilic re-
agents are effective (e.g., CH 3 O e , HO e , and RNH 2 ); the reactions are second
order overall — first order in halide and first order in nucleophile. For a given
halide, the more nucleophilic the attacking reagent, the faster is the reaction.
There must be more than a subtle difference in mechanism, however, since an
aryl halide is unable to pass through the same type of transition state as an
alkyl halide in S N 2 displacements.
A generally accepted mechanism of nucleophilic aromatic substitution vis-
ualizes the reaction as proceeding in two steps closely analogous to those
postulated for electrophilic substitution (Chapter 20). The first step involves
attack of the nucleophile Y : e at the carbon bearing the halogen substituent
to form an intermediate anion [2]. The aromatic system is of course* destroyed
on forming the anion, and the hybridization of carbon at the reaction site
changes from sp 2 to sp 3 .
X
I
In the second step, loss of an anion, X° or Y e , regenerates an aromatic
chap 21 aryl halogen compounds, nucleophilic aromatic substitution 594
system, and, if X e is lost, the reaction is one of overall nucleophilic displace-
ment of X for Y.
In the case of a neutral nucleophilic reagent, Y or HY, the reaction se-
quence would be the same except for the necessary adjustments in charge of
the intermediate.
Formation of [2] is highly unfavorable for the simple phenyl halides, even
with the most powerful nucleophilic reagents. It should be clear how electron-
attracting groups, — N0 2 , —NO, — C=N, — N 2 ®, and so on, can facilitate
nucleophilic substitution by this mechanism through stabilization of the
intermediate. The effect of such substituents can be illustrated in the case of
/?-bromonitrobenzene and its reaction with methoxide ion. The structure of
the reaction intermediate can be described in terms of the resonance structures
[3a] through [3d]. Of these [3d] is especially important because the negative
charge can be located on oxygen, an electronegative atom.
Br ,OCH 3
Br ,OCH 3
V
kJ
N ffi
[3a]
[3b]
Br OCH3
Br OCH
-
N e
V
[3c] [3d]
The reason that substituents in the meta positions have much less effect on
the reactivity of an aryl halide is the substituent's inability to contribute di-
rectly to the derealization of the negative charge in the ring ; no structures
can be written analogous to [3d].
CHXt Br CH 3 C) Br CH,0 Br
e
e
e ^ s
N ^-^ N^ ^^^N
II II e II
o o o
C. ELIMINATION-ADDITION MECHANISM OF NUCLEOPHILIC
AROMATIC SUBSTITUTION
The reactivity of aryl halides such as the halobenzenes and halotoluenes is
exceedingly low toward nucleophilic reagents that normally effect smooth
sec 21.3 reactions of aryl halides 595
displacements with alkyl halides and activated aryl halides. Substitutions,
however, do occur under sufficiently forcing conditions involving either high
temperatures or very strong bases. For example, the reaction of chlorobenzene
with sodium hydroxide solution at temperatures around 340° is an important
commercial process for the production of phenol.
OH
aq. NaOH ./^
3W * I + NaCl
Also, aryl chlorides, bromides, and iodides can be converted to arylamines
by amide ions, which are very strong bases. In fact, the reaction of potassium
amide with bromobenzene is extremely rapid, even at temperatures as low as
— 33°, with liquid ammonia as solvent.
NH 2
© e nh, fi^l e e
+ KNH, "o ' + K Br
Displacement reactions of this type, however, differ from the previously
discussed displacements of activated aryl halides in that rearrangement often
occurs. That is to say, the entering group does not always take up the same
position on the ring as that vacated by the halogen substituent. For example,
the hydrolysis of /?-chlorotoluene at 340° gives an equimolar mixture of m-
and p-cresols.
CH, CH,
aq. NaOH
340° *
Even more striking is the exclusive formation of m-aminoanisole in the
amination of o-chloroanisole.
OCH, OCH
© 6
NaNH 2 , NH 3
NH,
Mechanisms of this type have been widely studied, and much evidence has
accumulated in support of a stepwise process, which proceeds first by base-
catalyzed elimination of hydrogen halide (HX) from the aryl halide. This
first reaction resembles the E2 elimination reactions of alkyl halides discussed
earlier (Section 8-12) except that the abstraction of the proton appears to
precede loss of the bromide ion. The reaction is illustrated below for the
amination of bromobenzene.
chap 21 aryl halogen compounds, nucleophilic aromatic substitution 596
6
e
+ :NH,
H^y
NH 3
-33°
+■ NH, + Br fc
benzyne
[4]
The product of the elimination reaction is a highly reactive intermediate [4]
called benzyne, or dehydrobenzene. Its formula is C 6 H 4 and it differs from
benzene in having an extra bond between two ortho carbons. Benzyne reacts
rapidly with any available nucleophile, in this example the solvent ammonia,
to give an addition product.
<r\
| + :
:NH,
NH,
NH,
[4]
aniline
The occurrence of rearrangements in these reactions follows from the possi-
bility of the nucleophile's attacking the intermediate at one or the other of the
carbons of the extra bond. With benzyne itself, the symmetry of the molecule
is such that no rearrangement would be detected. However, this symmetry is
destroyed if one of the ring carbons is labeled with 14 C isotope, so that two
isotopically different products can be formed. Studies of the amination of halo-
benzenes labeled with 14 C at the 1 position have demonstrated that essentially
equal amounts of 1- and 2- 14 C-labeled anilines are produced, as predicted
by the elimination-addition mechanism.
KNH 2
NH,.-33°
NH 3
NH,
NH,
X = CI, Br, I
* = 14 C
50°
50°
21-4 organochlorine pesticides
The general term pesticide includes insecticides, herbicides, and fungicides. A
number of the most important pesticides are chlorinated aromatic hydro-
carbons or their derivatives (Figure 21-2). Prodigious quantities have been
used throughout the world in the past 25 years with, as we now know, tragic
consequences.
Chlorinated hydrocarbons such as DDT have low water solubility but high
solubility in nonpolar media such as fatty tissue. Their slow rate of decompo-
sition causes them to accumulate in nature, and predatory birds and animals
are particularly vulnerable. The food chain running from plankton to small
fish to bigger fish to predatory birds results in a magnification of the residue
concentration at each stage. As a result the world's population of falcons,
hawks, and eagles has dropped drastically in the past decade. A remarkable
sec 21.4 organochlorine pesticides 597
CI
\
h
CH -CC1,
OH
yx
CI
Cl
l,l,l-trichloro-2,2-
bis(p-chlorophenyl)ethane (DDT)
an insecticide
pentachlorophenol (PCP)
a fungicide
Cl
)=\
CI-/ \-O-CH 2 C0 2 H
Cl-/ V-0-CH 2 C0 2 H
\
CI
\
Cl
2,4-dichlorophenoxyacetic acid
a herbicide
2,4,5-trichlorophenoxyacetic acid
a herbicide
Figure 21-2 Some organochlorine pesticides. The abbreviation DDT arises
from the semisystematic name rfichlorodiphenyl/richloroethane. Bis, tris, and
tetrakis are used in place of di, tri, and tetra for substituents whose names contain
two parts; thus, the compound ^-CH 3 C 6 H 4 CH 2 C 6 H4.CH 3 -p can be named
either di-p-tolylmethane or bis (p-methylphenyl)methane.
effect of high pesticide residues in these birds is extreme fragility of the shells
of their eggs. Experiments have shown that DDE [5], the principal decom-
position product of DDT, causes this effect when present in very small amount.
It is believed to inhibit the action of the enzyme carbonic anhydrase which
controls the supply of calcium available for shell formation.
V
4
C=CC1,
-(
i
)
/
Cl
,1,1 -dichloro-2,2-bis(/>-chloropheny l)ethene
[5]
It has been estimated that there are now a billion pounds of DDE spread
throughout the world ecosystem and traces of it have been found in animals
everywhere, including the Arctic and Antarctic. Even though the use of DDT
chap 21 aryl halogen compounds, nucleophilic aromatic substitution 598
has now been severely curtailed by legislation it will take many years for the
level of DDE to decrease to tolerable levels. Man, like predatory birds, is at
the top of a food chain and human beings now carry in their fatty tissue 10
to 20 ppm of chlorinated hydrocarbon insecticides and their conversion
products. The effect on human health is still not known with certainty.
The herbicides 2,4-D [6] and 2,4,5-T[7] have come under fire recently because
their indiscriminate use as defoliants threatens the ecology of large areas.
Furthermore, 2,4,5-T is suspected of being a teratogen (a fetus-deforming
agent). Mice given 2,4,5-T in the early stages of pregnancy have a high inci-
dence of fetal mortality and there is a high incidence of abnormalities in the
survivors. There is some indication that 2,3,7,8-tetrachlorodibenzodioxin [8],
sometimes present as an impurity in commercial samples of 2,4,5-T, may
actually be the teratogenic agent.
OCH 2 C0 2 H
OCH 2 C0 2 H
^Y cl
rV
c 'rYYY'
Y
cr
V
ci-^^o-^^ci
Cl
Cl
2,3,7,8-tetrachlorodibenzodioxin
[6]
[7]
[8]
summary
Aryl halides such as bromobenzene, C 6 H 5 Br, are unreactive to most nucleo-
philes unless activating groups are present in the ring. Benzyl halides such as
C 6 H 5 CH 2 Br, on the other hand, react readily by nucleophilic displacement.
Aryl halides can be prepared from benzene by direct halogenation or from
aniline by the Sandmeyer reaction.
Grignard reagents can be prepared from aryl halides and their reactions
are analogous to those of alkylmagnesium compounds.
A halogen which is ortho or para to one or more nitro groups is activated
toward nucleophilic substitution.
exercises 599
+ N§ ► |ej > IB + X"
1^ I
N0 2 N0 2
Those aryl halides that lack activating groups may suffer displacement of
halogen under forcing conditions via an elimination-addition reaction.
NH 2 e NH 3
C 6 H 5 Br -* C 6 H 4 Br e — — — » C 6 H 4 ► C 6 H 5 NH 2
( — H©) ( — Bra)
The amino group does not necessarily occupy the position vacated by the
bromine atom since the intermediate, benzyne (C 6 H 4 ), is symmetrical and
ammonia can add to it in either direction.
Many chlorinated aromatic hydrocarbons or their derivatives are widely
used as pesticides.
exercises
21-1 Suggest a feasible synthesis of each of the following compounds based on
benzene as the starting material :
Br
a. F-C N )-NH 2 c. (' ^>-Br
N0 2
CH 3
f\a d. cnA-f\i
b. I-f VC1 d. CH 3 -C-<' y-Br
CH 3 ^ p
21-2 Suggest a method for preparing the following compounds from the indicated
starting materials and any other necessary reagents:
a. j p-ClC 6 H4C(CH 3 ) 2 OH from benzene
b. 1 -naphthoic acid from naphthalene
c. H0 2 C— ^ rf— D from toluene
21-3 Why is the following mechanism of S N 2 substitution of an alkyl halide un-
likely for aryl halides?
e \ !e I 8e / n
X:+ ,.C— Y , X-C— Y . X— C. + e Y :
7 / \ V
transition state
chap 21 aryl halogen compounds, nucleophilic aromatic substitution 600
214 a. Write resonance structures analogous to structures [3a] through [3d] to
show the activating effect of — C=N, — S0 2 R, and — CF 3 groups in
nucleophilic substitution of the corresponding ^-substituted chloro-
benzenes.
b. How would you expect the introduction of methyl groups ortho to the
activating group to affect the reactivity of p-bromonitrobenzene and
^-bromocyanobenzene toward ethoxide ion ?
21-5 Would you expect p-bromonitrobenzene or (p-bromophenyl)-trimethyl-
ammonium chloride to be more reactive in bimolecular replacement of
bromine by ethoxide ion ? Why ?
21-6 Would you expect p-chloroanisole to be more or less reactive than chloro-
benzene toward methoxide ion? Explain.
21-7 Devise a synthesis of each of the following compounds from the indicated
starting materials :
a> //—O — C 2 H 5 fromp-nitrochlorobenzene
CC1 3
\
b, [I from toluene
c. 2 N— / \-N > from benzene
NO,
21-8 In the hydrolysis of chlorobenzene-l- 14 C with 4 M aqueous sodium hydrox-
ide at 340°, the products are 58% phenol-l- 14 C and 42% phenol-2- 14 C.
• Calculate the percentage of reaction proceeding (a) by an elimination-
addition mechanism, and (b) by direct nucleophilic displacement. (You may
disregard the effect of isotopic substitution on the reaction rates.) Would
you expect the amount of direct displacement to increase or decrease if the
reaction were carried out (a) at 240°, and (b) in aqueous sodium acetate in
place of aqueous sodium hydroxide ? Give the reasons on which you base
your answers.
21 -9 Explain the following observations :
a, 2,6-Dimethylchlorobenzene does not react with potassium amide in
liquid ammonia.
b. Fluorobenzene, labeled with deuterium in the 2 and 6 positions, under-
goes rapid exchange of deuterium for hydrogen in the presence of
potassium amide in liquid ammonia, but does not form aniline.
exercises 601
21-10 Predict the principal product of the following reaction:
^CH,CH 2 NHCH, 2 moles
C 6 H 5 Li, ether
21-11 Give for each of the following pairs of compounds a chemical test, preferably
a test tube reaction, that will distinguish between the two compounds. Write
a structural formula for each compound and equations for the reactions
involved.
a. chlorobenzene and benzyl chloride
b. /7-nitrochlorobenzene and m-nitrochlorobenzene
c. /?-chloroacetophenone and a-chloroacetophenone
d. p-ethylbenzenesulfonyl chloride and ethyl ^-chlorobenzenesulfonate
e. p-bromoaniline hydrochloride and p-chloroaniline hydrobromide
21-12 Show by means of equations how each of the following substances might be
synthesized starting from the indicated materials. Specify reagents and
approximate reaction conditions. Several steps may be required.
a. 1,3,5-tribromobenzene from benzene
b. p-fluorobenzoic acid from toluene
c. m-bromoaniline from benzene
d. i?-nitrobenzoic acid from toluene
e. m-dibromobenzene from benzene
/. m-nitroacetophenone from benzene
g. 2,4,6-trinitrobenzoic acid from toluene
h. benzyl m-nitrobenzoate from toluene
21-13 Write a structural formula for a compound that fits the following descrip-
tion:
a. an aromatic halogen compound that reacts with sodium iodide in
acetone but not with aqueous silver nitrate solution
b. an aryl bromide that cannot undergo substitution by the elimination-
addition (benzyne) mechanism
c. the least reactive of the monobromomononitronaphthalenes toward
ethoxide ion in ethanol
21-14 Explain why the substitution reactions of a-halonaphthalenes in Equations
21-1 through 21-3 show no significant variation in the percentage of a- and
/S-naphthyl derivatives produced either with the nature of the halogen
substituent or with the nucleophilic reagent.
N(C 2
Li N(C;H 5 ) 2)
ether
N(C 2 H 5 ) 2
(21-1)
38'
62°/
chap 21 aryl halogen compounds, nucleophilic aromatic substitution 602
(21-2)
(21-3)
33%
67'
21-15 The conversion of DDT to DDE (Section 21-4) is catalyzed by the enzyme
DDT dehydrochlorinase, which, as you might expect, is a protein. What
groups normally present as substituents on protein chains (Table 17-1) might
aid the simultaneous removal of a proton and a chloride ion?
■'•.ft*. ST. *!•>;
'Wfi%^0%?iM CS^^
&*££* ' "Jt ■■
i-'JsfiS
is*5i
btf-i.'*^JJ5? ,:
chap 22 aryl nitrogen compounds 605
Many of the properties of aryl halides, such as their lack of reactivity in
nucleophilic substitution reactions, are closely related to the properties of
vinyl halides. Attempts to make similar comparisons between vinyl oxygen
and nitrogen compounds and the related aryl oxygen and nitrogen compounds
are often thwarted by the unavailability of suitable vinyl analogs. Thus,
while vinyl ethers are easily accessible, most vinyl alcohols and primary or
secondary amines are unstable with respect to their tautomers with C=0
and C=N bonds. (The enol forms of 1,3-dicarbonyl compounds are notable
exceptions; see Sections 12-6 and 16TD.)
\ /
N-H H N
\ / I II
C=C ► — C — C— Atf=-16kcal
/ \ I
O-H H O
\ / I II
C = C ► — C — C— A/f=-18kcal
/ \ I
That the same situation does not hold for most aromatic amino and hy-
droxy compounds is a consequence of the stability of the benzene ring. This
stability would be almost completely lost by tautomerization. For aniline, the
stabilization energy based on its heat of combustion is 41 kcal/mole, and we
can expect a stabilization energy (S.E.) of about 5 kcal/mole for its tautomer,
2,4-cyclohexadienimine. Thus the AH of tautomerization is unfavorable by
(41 - 16 - 5) = 20 kcal/mole.
Alcaic.) = 20 kcal
S.E. = 41 kcal S.E. ~ 5 kcal
Phenol is similarly more stable than the corresponding ketone by about 17
kcal/mole.
OH
Alcaic.) = 17 kcal
S.E. = 40 kcal S.E. ~ 5 kcal
Since aromatic amino and hydroxy compounds have special stabilization,
their behavior is not expected to parallel in all respects that of the less stable
vinylamines and vinyl alcohols. Nonetheless, similar reactions are often
encountered. Both enols and phenols are acidic; they react readily with halo-
gens, and their anions undergo either C or O alkylation with organic halides.
The qualitative differences observed in these reactions will be considered in
more detail later in this chapter (see also Chapter 23) ; but, as already indicated,
such differences can usually be accounted for in terms of the stabilization of
the aromatic ring.
chap 22 aryl nitrogen compounds 606
aromatic nitro compounds
22-1 synthesis of nitro compounds
The most generally useful way to introduce a nitro group into an aromatic
nucleus is by direct nitration, as previously discussed (Section 20-4B). This
method is obviously unsatisfactory when the orientation determined by sub-
stituent groups does not lead to the desired isomer. Thus, /j-dinitrobenzene
and p-nitrobenzoic acid cannot be prepared by direct nitration, since nitra-
tions of nitrobenzene and benzoic acid give practically exclusively m-dini-
trobenzene and m-nitrobenzoic acid, respectively. To prepare the para
isomers, less direct routes are necessary. The usual stratagem is to use benzene
derivatives with substituent groups that produce the desired orientation on
nitration and then to make the necessary modifications in these groups to
produce the final product. Thus, /7-dinitrobenzene can be prepared from aniline
by nitration of acetanilide (acetylaminobenzene), followed by hydrolysis to
p-nitroaniline and replacement of amino by nitro through the action of nitrite
ion, in the presence of cuprous salts, on the corresponding diazonium salt
(see Section 22-8). Alternatively, the amino group of /?-nitroaniline can be
oxidized to a nitro group by trifluoroperacetic acid. In this synthesis, acetani-
lide is nitrated in preference to aniline itself, since not only is aniline easily
oxidized by nitric acid, but the reaction leads to extensive meta substitution
by nitration involving the anilinium ion. Another route to /7-nitroaniline is to
nitrate chlorobenzene and subsequently replace the chlorine with ammonia.
See Figure 22 T for representation of these reactions.
The nitrations mentioned give mixtures of ortho and para isomers, but
these are usually easy to separate by distillation or crystallization. The same
approach can be used to synthesize /?-nitrobenzoic acid. The methyl group of
toluene directs nitration preferentially to the para position, and subsequent
oxidation with chromic acid yields /?-nitrobenzoic acid.
CO,H
HN0 3 f \ Na 2 Cr 2 Q,
H 2 SO* '
In some cases, it may be necessary to have an activating group to facilitate
substitution, which would otherwise be very difficult. The preparation of
1,3,5-trinitrobenzene provides a good example — direct substitution of m-
dinitrobenzene requires long heating with nitric acid in fuming sulfuric acid.
However, toluene is more readily converted to the trinitro derivative and this
substance, on oxidation (Section 24-1) and decarboxylation (Section 13-6),
yields 1,3,5-trinitrobenzene.
sec 22.1 synthesis of nitro compounds 607
CH,
HN0 3
>
H 2 SO*
0,N
CH,
"^^ N ° 2 Na 2 Cr 2 7
CO a H
0,N^ ^L NO,
H 2 SO»
NO,
heat ,
N0 2
65°/
<-co 2
v
NO,
NO,
Acylamino groups are also useful activating groups and have the advantage
that the amino groups obtained after hydrolysis of the acyl function can be
Figure 22-1 Schemes for the preparation ofp-dinitrobenzene from aniline or
chlorobenzene.
NH 2 NHCOCH, NHCOCH,
(CH 3 CO) 2 ff ^ HNO3
CH 3 C0 2 Na Ks?
H 2 S0 4> 0°
aniline
acetanilide
N0 2
p-nitroacetanilide
NaOH, H 2
100°
NO
e e
N 2 BF 4
NH,
NaN0 2 , Cu ffi
NO
/>-dinitrobenzene
CI
HNO3
CI
NO,
chlorobenzene p-nitrochlorobenzene
chap 22 aryl nitrogen compounds 608
NH
/j-toluidine aceto-/)-toluidide
c=o
CH,
NaOH
Figure 22-2 Preparation of m-nitrotoluene starting with p-aminotoluene
(p-toluidine).
removed from an aromatic ring by reduction of the corresponding diazonium
salt with hypophosphorous acid, preferably in the presence of copper ions. An
example is the preparation of m-nitrotoluene from/?-aminotoluene (j?-toluidine)
via 4-acetylaminotoluene (aceto-/?-toluidide) as shown in Figure 22-2.
The acetylamino derivatives of the amines are usually used in the nitration
step in preference to the amines themselves because, as mentioned in connec-
tion with the formation of />-nitroaniline, they are less susceptible to oxidation
by nitric acid and give the desired orientation.
The physical properties and spectra of aliphatic and aromatic nitro com-
pounds were touched on briefly (Section 16-5). Nitrobenzene itself is a pale-
yellow liquid (bp 210°), which should be handled with care because like many
nitro compounds it is toxic when inhaled or when absorbed through the skin.
A nitro group usually has a rather strong influence on the properties and
reactions of other substituents on an aromatic ring, particularly when it is
in an ortho or para position. A strong activating influence in displacement
reactions of aromatic halogens was discussed in the preceding chapter
(Section 21-3B). We shall see later how nitro groups make aromatic amines
weaker bases and phenols stronger acids.
22-2 reduction of aromatic nitro compounds
The most important synthetic reactions of nitro groups involve reduction,
particularly to the amine level. In fact, aromatic amines are normally pre-
sec 22.2 reduction of aromatic nitro compounds 609
pared by nitration followed by reduction. They may also be prepared by
halogenation followed by amination. But since amination of halides requires
the use of either amide salts or ammonia and high temperatures, which often
lead to rearrangements (Section 21 -3C), the nitration-reduction sequence is
usually preferred. Direct amination of aromatic compounds is not generally
feasible.
A. REDUCTION OF NITRO COMPOUNDS TO AMINES
The reduction of nitrobenzene to aniline requires six equivalents of reducing
agent and appears to proceed through the following principal stages :
^ N0 ^0" N= ° "^ (^N-OH
nitrobenzene nitrosobenzene N-phenylhydroxylamine
2[H]/
^-H 2
NH 2
aniline
Despite the complexity of the reaction, reduction of aromatic nitro com-
pounds to amines occurs smoothly in acid solution with a variety of reducing
agents of which tin metal and hydrochloric acid or stannous chloride are
often favored on a laboratory scale. Hydrogenation is also useful but is
strongly exothermic and must be carried out with care.
NO,
1. Sn.HCl
50°-100°
' 2. NaOH
Ni,25°
30atm
Ammonium (or sodium) sulfide has the interesting property of reducing
one nitro group in a dinitro compound much faster than the other. It is
not always easy to predict which of two nitro groups will be reduced more
readily.
In contrast to the reduction of 2,4-dinitroaniline, reduction of 2,4-dinitro-
toluene leads to preferential reduction of the 4-nitro group.
chap 22 aryl nitrogen compounds 610
CH 3 CH 3
N 2 NH 3 ,H 2 S
NO, NH 2
B. REDUCTION OF NITRO COMPOUNDS IN NEUTRAL AND
ALKALINE SOLUTION
In neutral or alkaline solution, the reducing power of some of the usual
reducing agents toward nitrobenzene is less than in acid solution. A typical
reagent is zinc, which gives aniline in the presence of excess acid, but pro-
duces N-phenylhydroxylamine when buffered with ammonium chloride.
" \-NO, + 3 Zn + 6 HC1 Hz ° > ( VNH, + 3 ZnCl, + 2 H,0
// ^ H 2 / \
? N >— N0 2 + 2Zn + 4NH 4 C1 ► <f VNHOH + 2 Zn(NH 3 ) 2 Cl 2 + H 2
Nitrosobenzene is too easily reduced to be prepared by direct reduction of
nitrobenzene and is usually made by oxidation of N-phenylhydroxylamine
with chromic acid.
// \ H K 2 Cr 2 0, // \
f Vn-oh ► ( Vn=o
H 2 SO 4 ,0° \ /
Nitrosobenzene exists as a colorless dimer in the crystalline state. When the
solid is melted or dissolved in organic solvents, the dimer undergoes rever-
sible dissociation to the green monomer (see Section 16-4).
Reduction of nitrobenzene with methanol in the presence of sodium hydrox-
ide produces azoxybenzene. The methanol is oxidized to formaldehyde.
// ^> NaOH // ^ I f/ \
2f VNO, + 3 CH,OH ► V VN=N-f x > + 3 CH 2 + 3 H 2
\ / 2 ' \ / © \— — /
azoxybenzene
The reason that azoxybenzene is produced instead of aniline is partly
because methanol in alkali is a less powerful reducing agent than tin and
hydrochloric acid. Also, in the presence of alkali, the intermediate reduction
products can condense with one another; thus azoxybenzene probably arises
in the reduction by a base-induced reaction of nitrosobenzene with N-phenyl-
sec 22.3 polynitro compounds 61 1
hydroxylamine. In fact, azoxybenzene can be prepared separately from these
same reagents. This condensation reaction does not occur readily in acid
OH
f \_n=0 + H— N-f \
NaOH
O w
* f \-N=N-/ \ + H 2
solution; furthermore, azoxybenzene is reduced to aniline by tin and hydro-
chloric acid.
Reduction of nitrobenzene in the presence of alkali with stronger reducing
agents than methanol produces azobenzene and hydrazobenzene. Both of
these compounds are reduction products of azoxybenzene and can be formed
from azoxybenzene as well as from nitrobenzene by the same reducing re-
agents (Scheme I).
CH 3 OH, NaOH
O 6
azoxybenzene
SnCl 2
SnCl z
NaOH
NaOH
C 6 H 5 -N=N-C 6 H 5 Zn
azobenzene
Zn
NaOH
NaOH
Zn, NaOH
Sn
HC1
- C.H.-NH,
FT T-f
* C 6 H 5 -N-N-C 6 H 5
hydrazobenzene
SCHEME I
When hydrazobenzene is allowed to stand in strong acid solution, it
undergoes an extraordinary rearrangement to form the technically important
dye intermediate, benzidine (4,4'-diaminobiphenyl).
<Q-£-£^3 -£- h 2 n^WVnh 2
hydrazobenzene
benzidine
22-3 polynitro compounds
A number of aromatic polynitro compounds have important uses as high
explosives (Section 16-5). Of these 2,4,6-trinitrotoluene (TNT), 2,4,6-trinitro-
phenol (picric acid), and N,2,4,6-tetranitro-N-methylaniline (tetryl) are
particularly important. 1,3,5-Trinitrobenzene has excellent properties as an
explosive but is difficult to prepare by direct nitration of benzene (Section
22-1).
chap 22 aryl nitrogen compounds 612
NO,
NO, NO,
2,4,6-trinitrotoluene 2,4,6-trinitrophenol N,2,4,6-tetranitro-
(TNT) (picric acid) N-methylaniline
(tetryl)
The trinitro derivatives of 3-/-butyltoluene and l,3-dimethyl-5-f-butyl-
benzene possess musklike odors and have been used as ingredients of cheap
perfumes and soaps.
2 N
C(CH 3 ) 3 (CH 3 ) 3 C
NO,
^*
1 -raethyl-3-/-butyI- 1 ,3-dimethyl-5-f-butyl-
2,4,6-trinitrobenzene 2,4,6-trinitrobenzene
22-4 charge-transfer and tc complexes
An important characteristic of polynitro compounds is their ability to form
more or less stable complexes with aromatic hydrocarbons, especially those
that are substituted with alkyl groups or are otherwise expected to have elec-
tron-donating properties. The behavior is very commonly observed with
picric acid, and the complexes therefrom are often nicely crystalline solids,
which are useful for the separation, purification, and identification of aro-
matic hydrocarbons. These substances are often called "hydrocarbon pic-
rates" but the name is misleading since they are not ordinary salts; further-
more, similar complexes are formed between aromatic hydrocarbons and
trinitrobenzene, which shows that the strongly electron-attracting nitro
groups rather than the acidic hydroxyl group are essential to complex for-
mation. The binding in these complexes results from attractive forces between
electron-rich and electron-poor substances. The designation charge-transfer
complex originates from a resonance description in which the structure of the
complex receives contributions from resonance forms involving transfer of an
electron from the donor (electron-rich) molecule to the acceptor (electron-
poor) molecule. However, the name n complex is also used because usually at
least one component of the complex has a 7i-eIectron system. Charge-
transfer complexes between polynitro compounds and aromatic hydro-
carbons appear to have sandwich-type structures with the aromatic rings in
parallel planes, although not necessarily coaxial. (See Figure 22-3.)
Charge-transfer complexes are almost always more highly colored than
sec 22.4 charge-transfer and tt complexes 613
their individual components. A spectacular example is shown by benzene and
tetracyanoethene, each of which separately is colorless, but which give a
bright-orange complex when mixed. A shift toward longer wavelengths of
absorption is to be expected for charge-transfer complexes relative to their
components because of the enhanced possibility for resonance stabilization
of the excited state involving both components. (See Sections 7-5 and 26-2.)
With good electron donors such as carbanions, nitrobenzene itself will
undergo charge transfer by adding an electron (Equation 22-1). The resulting
radical anion [1] has both the negative charge and the spin of the odd electron
distributed over the nitro group and the phenyl ring.
R:+C 6 H 5 N0 2 < > R-+C 6 H 5 N0 2 -
[1]
A few of the many contributing structures for [1] are shown below.
(22-1)
etc.
Many autoxidation reactions occur under basic conditions and are cata-
lyzed by nitroarenes. The base generates a carbanion which is converted to a
radical as in Equation 22T and this combines with molecular oxygen to form
a peroxyradical, ROO-. The next step produces the hydroperoxide and re-
generates more radical. Thus production of one radical can account for the
consumption of many molecules of substrate. The initiation and propagation
steps of this, a typical chain reaction, are shown below.
RH + OH e < > R e +H 2
R e +C 6 H 5 N0 2 < > R-+C 6 H 5 N0 2 '
R- +0 2
R—0-0- +RH
R-O-O-
> ROOH + R-
initiation
propagation
Figure 22-3 Formulation of charge-transfer complex between 1,3,5-trinitro-
benzene (acceptor) and l,3>5-trimethylbenzene (donor).
2 N
CH
CH 3
5 n electrons
chap 22 aryl nitrogen compounds 614
aromatic amines
22- 5 general properties
Aniline, C 6 H 5 MH 2 , is a rather musty smelling liquid which is only slightly
soluble in water. It solidifies at —6°, boils at 184°, and is colorless when pure.
Like most aromatic amines, however, it tends to discolor on standing because
Table 22-1 Physical properties of some representative aromatic amines
name
formula
basicity,"
*B
H 2 0, 25°C
ultraviolet absor
3tion
Amax
£
Amax
e
aniline
CerisNIr^
4.6 x 10 - 10
2300
8600
2800
1430
N-methylaniline
C 6 H 5 NHCH 3
2.5 x 10 - 106
2450
11,600
2950
1800
N, N-dimethylaniline
C 6 H 5 N(CH 3 )
.
2.42 x 10 ~ 106
2510
14,000
2980
1900
p-toluidine
2 N
-NH 2
1.48 x 10 '"
2320
8900
2860
1600
m-nitroaniline
h\
4.0 x 10- 13
2800
4800
3580
1450
V> NH2
p-nitroaniline
°>"-{~}
-NH 2
1.1 x lO" 12
3810
13,500
/j-phenylenediamine
H 2 NhQ
-NH 2
3210
1550
benzidine c
H 2 N-^-
\J~
-NH 2 1.4X10- 12
2840
24,500
diphenylamine
(C 6 H 5 ) 2 NH
~10~ 14
2850
20,600
triphenylamine
(C 6 H 5 ) 3 N
NH,
1
d
2950
23,000
1-naphthylamine
^^\^
9.9 x lO" 11
3200
5000
2-naphthylamine c
ca
NH 2
2.0 x 10 " 10
3400
2000
Often given as K Ba ®, the dissociation constant of the conjugate acid, ArNH 3 ® + H 2 O^ArNH 2 + H 3 O ffl ;
K B = W-^/Kbh® and ftuS) for aniline is 2.2 x 10~ 5 . The K H a values for aromatic amines, corresponding to the
reaction ArNH 2 + H 2 O^ArNH e + H 3 O s , are low, but measurable, e.g., K HA for aniline is 10 -27 .
6 At 18°C.
c Hazardous substances; see Section 22-9B.
d Not measurably basic in water solution.
sec 22.5 general properties 615
of air oxidation. Table 22-1 gives the basicities and the ultraviolet spectral
properties of aniline and many of its derivatives.
The chemical properties of the aromatic amines are in many ways similar to
those of aliphatic amines. Alkylation and acylation, for example, occur in the
normal manner (Sections 16-1E1 and 16-1F2). We have noted before (Section
16- ID) that aniline is a weaker base than cyclohexylamine by a factor of 10 6 .
The stabilization which can be ascribed to derealization of the unshared
electron pair over the aromatic ring is lost in the cation because the electron
pair must be localized when the nitrogen-proton bond is formed. The changes
that occur in terms of the principal electron-pairing schemes for the aniline
and anilinium ion are shown in Figure 22-4.
A hybrid structure [4] for aniline, deduced from the structures [2a]
through [2e], has some degree of double-bond character between the nitrogen
and the ring, and some degree of negative charge at the ortho and para
positions.
Accordingly, the ability of the amine nitrogen to add a proton should be
particularly sensitive to the electrical effects of substituent groups on the
aromatic ring, when such are present. Many substituents such as nitro, cyano,
and carbethoxy have the ability to stabilize an electron pair on an adjacent
Figure 22-4 Electron-pairing schemes for aniline and anilinium ion.
[2a] [2b] [2c] [2d] [2e]
3 kcal extra stabilization attributed
to derealization of unshared electron pair
chap 22 aryl ntirogen compounds 616
carbon (see Section 21 -3B). Such groups, located in the ortho or para posi-
tion, should reduce substantially the base strength of the amine nitrogen. The
reason is that the substituted aniline, but not the anilinium ion, is stabilized by
contributions of electron-pairing schemes such as [5].
To gain some idea of the magnitude of this effect, we first note that aniline
as a base is 90 times stronger than m-nitroaniline and 4000 times stronger than
/>-nitroaniline. In contrast the acid-strengthening effect of a nitro group on
benzoic acid is only 5.1 times for meta nitro and 6.0 fox para nitro. Clearly,
the nitro groups in the nitroanilines exert a more powerful electrical effect
than in the nitrobenzoic acids. This is reasonable because the site at which
ionization occurs is closer to the benzene ring in the anilines than in the
acids. Even when this factor is taken into account, however, /?-nitroaniline is
much weaker than expected, unless forms such as [5] are important.
The contribution made by the polar form [5] becomes even more important
on excitation of p-nitroaniline by ultraviolet radiation (see Section 7-5). The
necessary excitation energies are therefore lower than for aniline, with the
result that the absorption bands in the electronic spectrum of ^-nitroaniline
are shifted to much longer wavelengths and are of higher intensity than are
those of aniline (cf. Table 22T). Since no counterpart to [5] can be written for
m-nitroaniline, the absorption bands of w-nitroaniline are not as intense and
occur at shorter wavelengths than those of />-nitroaniline.
The — NH 2 group of aniline leads to very easy substitution by electrophilic
agents (Section 20-5A) and high reactivity toward oxidizing agents. Bromine
reacts rapidly with aniline in water solution to give 2,4,6-tribromoaniline in
good yield. Introduction of the second and third bromines is so fast that it is
difficult to obtain the monosubstitution products in aqueous solution.
Br
Br 2 ,H 2 / = \
Br
f V >„, Br 2 , n 2 u / \
Other facets of the substitution of aromatic amines were discussed in con-
nection with the orientation effects of substituents (see Section 20-5).
22-6 aromatic amines with nitrous acid
Primary aromatic amines react with nitrous acid at 0° in a way different from
aliphatic amines in that the intermediate diazonium salts are much more
stable and can, in most cases, be isolated as nicely crystalline fluoborate salts
sec 22.7 preparation and general properties 617
(Section 21-2). Other salts can often be isolated, but some of these, such as
benzenediazonium chloride, are not very stable and may decompose with
considerable violence.
NH,
NaN0 2 , HC1
1
0°
s^n a ^^
N=N BR
benzenediazonium
chloride
(water soluble)
benzenediazonium
fluoborate
(water insoluble)
The reason for the greater stability of aryldiazonium salts compared with
alkyldiazonium salts seems to be related to the difficulty of achieving S N 1
reactions with aryl compounds (Section 21 -3C). Even the gain in energy,
associated with formation of nitrogen by decomposition of a diazonium ion,
is not sufficient to make production of aryl cations occur readily at less than
100°.
N = N
H 2 0, 100°
H 2
OH
This reaction has considerable general utility for replacement of aromatic
amino groups by hydroxyl groups. In contrast to the behavior of aliphatic
amines, no rearrangements occur.
Secondary aromatic amines react with nitrous acid to form N-nitroso
compounds in the same way as do aliphatic amines (Section 16-1F3).
Tertiary aromatic amines normally behave differently from aliphatic tertiary
amines with nitrous acid in that they undergo C-nitrosation, preferably in the
para position. It is possible that an N-nitroso compound is formed first, which
subsequently isomerizes to the ^-nitroso derivative.
CH,
w r\
CH,
HONO
CH
CH 3
I
N— N=0
0=N
CH 3
/
\
CH,
CH 3
CH 3
^-nitroso-N, N-dimethylaniline
diazonium salts
22-7 preparation and general properties
The formation of diazonium salts from amines and nitrous acid has been
described in the previous section. Most aromatic amines react readily, unless
strong electron-withdrawing groups are present.
chap 22 aryl nitrogen compounds 618
Tetrazotization of aromatic diamines is usually straightforward if the
amino groups are located on different rings, as with benzidine, or are meta to
each other on the same ring. Tetrazotization of amino groups para to one
another, or diazotization of /?-aminophenols, has to be conducted carefully to
avoid oxidation to quinones (Section 23-3).
Diazonium salts are normally stable only if the anion is one derived from a
reasonably strong acid. Diazonium salts of weak acids usually convert to
covalent forms from which the salts can usually be regenerated by strong acid.
Benzenediazonium cyanide provides a good example in being unstable and
forming two isomeric covalent benzenediazocyanides, one with the N=N
bond trans and the other with the N=N bond cis. Of these, the trans isomer
is the more stable.
C 6 H 5 _ _
\ / \
© jt~- e \ /
C 6 H 5 N==N: CN . N=N
raj-benzenediazocyanide /ra/w-benzenediazocyanide
N=N
- X CN
In strong acid, the covalent diazocyanides are unstable with respect to
benzenediazonium ion and hydrogen cyanide.
The covalent forms are sometimes significant in the reactions of diazonium
salts, since they offer a convenient path for the formation of free radicals (see
Section 16-6B).
o
C 6 H 5 N=N + 2 CCH 3 , C 6 H 5 N=N-0-C-CH 3
O
slow II
► C 6 H 5 -+N 2 +-0-C-CH 3
22-8 replacement reactions of diazonium salts
The utility of diazonium salts in synthesis is largely due to the fact that they
provide the only readily accessible substances that undergo nucleophilic
substitution reactions on the aromatic ring under mild conditions without the
necessity of having activating groups, such as nitro or cyano, in the ortho or
para position.
A. THE SANDMEYER REACTION
The replacement of diazonium groups by halogen is the most important
reaction of this type and some of its uses for the synthesis of aryl halides were
discussed previously (Section 21-2). Two helpful variations on the Sandmeyer
reaction employ sodium nitrite with cuprous ion as catalyst for the synthesis
of nitro compounds (Section 22-1), and cuprous cyanide for the synthesis of
cyano compounds.
sec 22.9 reactions of diazonium compounds 619
Cu 2 (CN) 2
50°
CH,
B. THE SCHIEMANN REACTION
The replacement of diazonium groups by fluorine was also covered earlier
(Section 21-2). This reaction, like the replacement of the diazonium group by
hydroxyl (Section 22-6), may well involve aromatic cations as intermediates.
One strong piece of evidence for this is the fact that benzenediazonium
fluoborate yields 3-nitrobiphenyl along with fluorobenzene when heated in
nitrobenzene. Formation of 3-nitrobiphenyl is indicative of an electrophilic
attack on nitrobenzene.
bf 4 s r^
F + BF,
© e -N 2
N 2 BF 4
22-9 reactions of diazonium compounds that occur
without loss of nitrogen
A. REDUCTION TO HYDRAZINES
Reduction of diazonium salts to arylhydrazines can be carried out smoothly
with sodium sulfite or stannous chloride, or by electrolysis.
® e 1. Na 2 S0 3 ,H 2 / \
N=N CI - ► { />-NH-NH 2
2. H^H.O, 100° ^ // 2
3. NaOH
B. DIAZO COUPLING
A very important group of reactions of diazonium ions involves aromatic
substitution by the diazonium salt acting as an electrophilic agent to yield azo
compounds.
chap 22 aryl nitrogen compounds 620
This reaction is highly sensitive to the nature of the substituent (X), and
coupling to benzene derivatives normally occurs only when X is a strongly
activating group such as — O e , — N(CH 3 ) 2 , and — OH; however, coupling
with X = OCH 3 may take place with particularly active diazonium com-
pounds. Diazo coupling has considerable technical value, because the azo
compounds that are produced are colored and often useful as dyes and color-
ing matters. A typical example of diazo coupling is afforded by formation of
/7-dimethylaminoazo benzene from benzenediazonium chloride and N,N-
dimethylaniline.
© e
N 2 C1
Q- n x
CH,
-HC1
CH,
*\ /
N=N
CH,
N
CH,
/>-dimethylaminoazobenzene
(yellow)
The product was once used to color edible fats and was therefore known as
"Butter Yellow" but its use in foods and cosmetics has been banned by
many countries because of its ability to cause cancer in rats. There are indi-
cations, but no firm evidence, that it causes cancer in humans.
Certain other nitrogen-containing compounds, particularly aromatic
amines, have been definitely shown to be carcinogenic for man. One of the
most dangerous of these is 2-aminonaphthalene, formerly used as an anti-
oxidant to protect the insulation on electric cables. In Britain a study showed
that men continually exposed to this amine during its manufacture had a
bladder cancer incidence of 50 % at 30 years from first exposure. One parti-
cularly unfortunate group of 15 men involved in its distillation showed a
100% incidence. Other dangerous amines are 4-aminobiphenyl and benzidine.
NH,
2-aminonaphthalene
(2-naphthylamine)
-NH,
-NH,
4-aminobiphenyl
benzidine
(4,4'-diaminobiphenyl)
summary
Aryl nitrogen compounds include amines, such as aniline, C 6 H 5 NH 2 ; nitro
compounds, such as nitrobenzene, C 6 H 5 N0 2 ; and a number of substances
exercises 621
with nitrogen-nitrogen bonds, benzenediazonium salts, C 6 H 5 NfX e ;
G e
I
azoxybenzene, C 6 H 5 N=NC 6 H 5 ; azobenzene, C 6 H 5 N=NC 6 H 5 ; and
hydrazobenzene, C 6 H 5 NHNHC 6 H 5 .
Aromatic nitro compounds are prepared by direct nitration using
HN0 3 -H 2 S0 4 mixtures. Polynitration is difficult because of the deactivating
effect of the nitro group, and use is often made of acylamino or alkyl sub-
stituents to counteract this effect. The groups are removed at a later stage.
Reduction of aromatic nitro compounds in acid solution (route A) gives
amines directly, but in neutral or basic solution (route B), a number of com-
pounds with nitrogen-nitrogen bonds can be isolated as intermediates.
C 6 H 5 N0 2 ^ ► QH.NH,
I
(B)
QH 5 NHNHC 6 H 5
Nitroarenes abstract electrons from certain electron donors. Some good
donors such as carbanions convert the nitrobenzene to a radical anion and
this reaction can be important in initiating radical processes.
R e +C 6 H 5 N0 2 < > R-+C 6 H 5 N0 2 -
Poly nitroarenes form complexes with many neutral donors such as
alkylbenzenes or polynuclear hydrocarbons by charge transfer. Such com-
plexes are usually highly colored and can be described as two radical ions held
together by electrostatic attraction
Aromatic amines resemble aliphatic amines in most of their reactions but
are considerably weaker bases because of resonance interaction between the
amino group and the ring. Aromatic amines also differ in that they give fairly
stable diazonium ions on treatment with nitrous acid ; these undergo a number
of useful synthetic reactions.
ArX
ArCN
ArNH 2 ► ArNj"
ArN = NAr
Certain aromatic amines, such as 2-aminonaphthalene, are carcinogenic.
exercises
22-1 Show how the following compounds could be synthesized from the indicated
starting materials. (It may be necessary to review parts of Chapters 20 and
21 to work this exercise.)
chap 22 aryl nitrogen compounds 622
from toluene
NO
b. 2 N\/^ ;; ^-N02 from /7-toluenesulfonic acid
/V NH2
N0 2
0,N^^1
2 N,.^L^N0 2
from chlorobenzene
from chlorobenzene
from p-chlorobenzenesulfonic acid
22-2 Tetracyanoethene in benzene forms an orange solution, but when this solu-
tion is mixed with a solution of anthracene in benzene, a brilliant blue-green
color is produced, which fades rapidly; colorless crystals of a compound of
composition Ci 4 Hio - C 2 (CN)4 are then deposited. Explain the color changes
that occur and write a structure for the crystalline product.
22-3 Anthracene (mp 217°) forms a red crystalline complex (mp 164°) with
1,3,5-trinitrobenzene (mp 121°). If you were to purify anthracene as this
complex, how could you regenerate the anthracene free of trinitrobenzene ?
22-4 N,N,4-Trimethylaniline has Z B = 3xlO- 9 ; quinuclidine, K B =4x\Q-*;
and benzoquinuclidine, Z B =6xlO~ 7 . What conclusions may be drawn
from these results as to the cause(s) of the reduced base strength of aromatic
amines relative to saturated aliphatic or alicyclic amines? Explain.
benzoquinuclidine
Would you expect a nitro group meta or para to the nitrogen in benzo-
quinuclidine to have as large an effect on the base strength of benzoquinu-
clidine as the corresponding substitution in aniline ?
22-5 Pure secondary aliphatic amines can often be prepared free of primary and
tertiary amines by cleavage of a p-mtroso-N.N-dialkylaniline with strong
alkali to p-nitrosophenol and the dialkylamine. Why does this cleavage occur
readily? Show how the synthesis might be used for preparation of di-w-
butylamine starting with aniline and «-butyl bromide.
exercises 623
22-6 N,N-Dimethylaniline, but not N,N,2,6-tetramethylaniline, couples readily
with diazonium salts in neutral solution. Explain the low reactivity of
N,N,2,6-tetramethylaniline by consideration of the geometry of the transi-
tion state for the reaction.
22-7 Some very reactive unsaturated hydrocarbons, such as azulene(Section20-7A),
couple with diazonium salts. At which position would you expect azulene
to couple most readily? Explain.
22-8 1-Naphthol couples with benzenediazonium chloride in the 2 position;
2-methyl-l-naphthol, in the 4 position; and 2-naphthol, in the 1 position.
However, l-methyl-2-naphthol does not couple at all under the same condi-
tions. Why?
22-9 Give for each of the following pairs of compounds a chemical test, preferably
a test tube reaction, that will distinguish the two compounds. Write a struc-
tural formula for each compound and equations for the reactions involved :
a. p-nitrotoluene and benzamide
b. aniline and cyclohexylamine
c. N-methylaniline and p-toluidine
d. N-nitroso-N-methylaniline and />-nitroso-N-methylaniline
22-10 Show by equations how each of the following substances might be synthesized
starting from the indicated materials. Specify reagents and approximate
reaction conditions.
a. o-dinitrobenzene from benzene
b. 2,6-dinitrophenol from benzene
c. 2-amino-4-chlorotoluene from toluene
d. ji-cyanonitrobenzene from benzene
e. 2-amino-4-nitrophenol from phenol
/. m-cyanotoluene from toluene
22-11 Write structural formulas for substances (one for each part) that fit the
following descriptions :
a. an aromatic amine that is a stronger base than aniline
b. a substituted phenol that would not be expected to couple with ben-
zenediazonium chloride in acidic, alkaline, or neutral solution
c. a substituted benzenediazonium chloride that would be a more active
coupling agent than benzenediazonium chloride itself
22-12 Explain why triphenylamine is a much weaker base than aniline and why its
absorption spectrum is shifted to longer wavelengths compared with the
spectrum of aniline (see Table 22-1). Would you expect N-phenylcarbazole
to be a stronger or weaker base than triphenylamine? Explain.
N-phenylcarbazole
aryl oxygeii compounds
chap 23 aryl oxygen compounds 627
In the previous chapter, we indicated that, although there are considerable
structural similarities between vinyl alcohols (enols) and phenols, and
between vinylamines (enamines) and aromatic amines, the enols and enamines
are generally unstable with respect to their keto and imine tautomeric forms,
whereas the reverse is true of phenols and aromatic amines because of the
stability associated with the aromatic ring.
OH *jl O
c=c — ^^ -c-c
/ \ I \
H j_|
O" 0H ~ Qr°
In this chapter, after considering some of the more general procedures for
the preparation of phenols, we shall take up the effect of the aromatic ring
on the reactivity and reactions of the hydroxyl group of phenols and the effect
of the hydroxyl group on the properties of the aromatic ring. The chapter
concludes with discussions of the chemistry of quinones and of some non-
benzenoid seven-membered ring substances with aromatic properties.
23-1 synthesis and physical properties of phenols
Considerable amounts of phenol and cresols (o-, m-, and ^-methylphenols)
can be isolated from coal tar, which is formed in the destructive distillation of
coal. Phenol itself is used commercially in such large quantities that alternate
methods of synthesis are necessary. Direct oxidation of benzene is unsatis-
factory because phenol is much more readily oxidized than is benzene. The
more usual procedures are to sulfonate or chlorinate benzene and then intro-
duce the hydroxyl group by nucleophilic substitution using strong alkali.
/^/S0 3 H
HiSOt (T ^f 1. NaOH fusion
CI 2
CI
FeCI 3 IL ^fi 250°
These reactions are general for introduction of hydroxyl substituents on
aromatic rings; however, in some cases, they proceed by way of benzyne
intermediates (Section 21 -3C) and may lead to rearrangement.
A more recent commercial synthesis of phenol involves oxidation of iso-
propylbenzene (cumene). This is made more commercially attractive by
virtue of acetone being formed at the same time. The sequence of reactions
starting with benzene and propene is shown in Figure 23-1. Some interesting
chemistry is involved in this process. The first step, conversion of benzene
to cumene, is a Friedel-Crafts alkylation (Section 20-4D). The second step,
chap 23 aryl oxygen compounds 628
f j + CH 3 CH=CH,
H 3 C
HaPO. (j^V ^CH 3
u
isopropylbenzene
(cumene)
o 2
II + (CH 3 ) 2 C=0 <
H s
CH 3
l/OOH
fV^CH,
U
cumene hydroperoxide
Figure 23-1 Commercial preparation of phenol and acetone starting with
benzene and propene.
conversion of cumene to the hydroperoxide, is a radical chain reaction
(Section 2-5B). The third step is an acid-catalyzed rearrangement that resem-
bles the Beckmann rearrangement (Section 16-1E2). (For more on the mecha-
nism, see Exercises 23-13 and 23-14.)
Phenol is a colorless crystalline solid when pure, but samples of it are often
pink or brown because, like aniline, it is subject to air oxidation. Phenols are
more polar and are able to form stronger hydrogen bonds than the corre-
sponding saturated alcohols. A comparison of the physical properties of phe-
nol and cyclohexanol shown in Table 23-1 shows that phenol has the higher
melting point, higher boiling point, and higher water solubility, and is the
more acidic.
The acid dissociation constants and the ultraviolet spectral properties of
phenols are shown in Table 23-2. There is a considerable effect of substituents
on the wavelength and intensity of the absorption maxima.
Table 23-1 Comparative physical properties
of phenol and cyclohexanol
phenol
cyclohexanol
mp
43°
26°
bp
181°
161°
water solubility,
9.3
3.6
g/100g,20°
Kha.
1.0 x 10~ 10
~10~ 18
sec 23.1 synthesis and physical properties of phenols 629
Table 23*2 Physical properties of some representative phenols
formula
H 2 0, 25°C X„
phenol
ji-cresol
salicylaldehyde
CfiHsOJK
/>-nitrophenol
o 2 nh! f~ OH
N0 2
/
picric acid
2 N-{ VoH
\
N0 2
OH
/
catechol
{_y° H
HO
\
resorcinol
vJ^ OH
1.3xlO~ 10 2105 6200 2700 1450
H,C-<1 j>~OH 1.5xl0~ 10 2250 7400 2800 1995
6.5xl0" 8 3175 10,000
6 x 10 - 1 3800 13,450
3.3xlO- 10 " 2140 6300 2755 2300
3.6xl0~ 10 " 2160 6800 2735 1900
hydroquinone HO— 4^ />— OH
p-aminophenol H 2 N— ^ h— OH
\ /
OH
CHO
p-hydroxybenzal-
dehyde HO
1-naphthol
OH
2-naphthol
OH
1 x 10 - 10
2900 2800
6.6X10- 9 " 2330 8000 2800 3200
3.0xl0~ 9 2560 12,600 3240 3400
CHO 2.2xl0~ 8 2835 16,000
4.9X10- 10 2325 33,000 2950 5000
2.8X10" 10 2260 76,000 2735 4500
« it 18°
At 18°C.
chap 23 aryl oxygen compounds 630
23-2 some chemical properties of phenols
A. REACTIONS INVOLVING O-H BONDS
The acidity of phenols compared to alcohols can be accounted for by an
argument similar to that used to explain the acidity of carboxylic acids
(Section 13-4). There is a small amount of resonance stabilization in phenol
that is due to derealization of one of the unshared electron pairs on oxygen
over the aromatic ring, as can be described in terms of the resonance struc-
tures [la] through [lc].
■ e „ n — *
[la] [lb] [lc]
Conversion of phenol by loss of the hydroxyl proton to phenoxide anion
leads to much greater derealization of the unshared pair because, as can be
seen from the resonance structures [2a] through [2c], no charge separation is
involved of the type apparent in [la] through [lc].
[2a] [2b] [2c]
The greater stabilization energy of the anion makes the ionization process
energetically more favorable than for a saturated alcohol such as cyclohexa-
nol.
The reactions of the hydroxyl groups of phenols that involve breaking
the O— H bonds and formation of new bonds from oxygen to carbon are
generally similar to those of alcohols. It is possible to prepare esters with
carboxylic acid anhydrides and to prepare ethers by reaction of phenoxide
anions with halides, sulfate esters, sulfonates, and so on, which react well by
S N 2 mechanisms.
o
OH JCH^i^ ^O-C-CH,
\ ff acid or base \ //
catalyst
phenyl acetate
/ \_ oh NaOH ) / \_0 N CH3l » /~~\— OCH
\ — / \ — V \ (CH 3 0) 2 S0 2 s* \ 'J
methoxybenzene
(anisole)
sec 23.2 some chemical properties of phenols 631
Phenols are sufficiently acidic to be converted to methoxy derivatives with
diazomethane (Section 16-6C) with no need for an acidic catalyst.
OH + CH,N,
ether
<Q-OCH 3
However, they are weaker than carboxylic acids (by a factor of 10 5 ) and
this is the basis for separating phenols and carboxylic acids by extraction with
aqueous bicarbonate solution. Carboxylic acids can be extracted from ether
or benzene solution by this reagent whereas phenols can not (Section 13-1).
Almost all phenols and enols (such as those of 1,3-diketones) give colors
with ferric chloride in dilute water or alcohol solutions. Phenol itself produces
a violet coloration with ferric chloride and the cresols give a blue color. The
products are apparently ferric phenoxide salts, which absorb visible light to
give an excited state having electrons delocalized over both the iron atom and
the unsaturated system.
B. C- vs. O-ALKYLATION OF PHENOLS
The same type of problem with respect to O- and C-alkylation is encountered
with phenoxide salts as with enolate anions (Section 12-2B). Normally, only
O-alkylation is observed. However, with allyl halides either reaction can be
made essentially the exclusive reaction by proper choice of solvent. With
sodium phenoxide, more polar solvents such as acetone tend to lead to
phenyl allyl ether while in nonpolar solvents, such as benzene, o-allylphenol is
the favored product.
I V()CH 2 CH=CH 2
phenyl allyl ether
polar
solvents
\ /
-O Na + CH, = CH-CH 2 Br
nonpolar
solvents
\
o
CH 2
I
CH=CH,
CH 2 CH=CH 2
o-allylphenol
Apparently, in nonpolar solvents, the lack of dissociation of the — ONa
part of the phenoxide salts tends to increase the steric hindrance at oxygen
and makes attack on the ring more favorable.
chap 23 aryl oxygen compounds 632
The C-allylation product is thermodynamically more stable than the O-
allylation product, as shown by the fact that phenyl allyl ether rearranges
to o-allylphenol above 200°. Such rearrangements are quite general and are
called Claisen rearrangements.
£H,CH=CH 2
CH 2 CH = CH,
It should be noted that C-allylation of sodium phenoxide as observed in
nonpolar solvents is not the result of O-allylation followed by rearrangement,
because the temperature of the allylation reaction is far too low to obtain the
observed yield of o-allylphenol by rearrangement.
C. REACTIONS INVOLVING THE C— O BONDS
It is very difficult to break the aromatic C— O bond in reactions involving
phenols or phenol derivatives. Thus, concentrated halogen acids do not
convert phenols to aryl halides, and cleavage of phenyl alkyl ethers with
hydrogen bromide or hydrogen iodide produces the phenol and an alkyl
halide, not an aryl halide and an alcohol. Diaryl ethers, such as diphenyl ether,
do not react with hydrogen iodide even at 200°.
f VoH + CH 3 Br
rv<>
CH 3 + HBr
^ / \-Br + CH3OH
Such behavior is very much in line with the difficulty of breaking aromatic
halogen bonds in nucleophilic reactions (Chapter 21). There is no very
suitable way for converting phenols to aryl halides, except when activation is
provided by ortho or para nitro groups. Thus, 2,4-dinitrophenol is smoothly
converted to 2,4-dinitrochlorobenzene with phosphorus pentachloride.
PCI5
NO,
D. REACTIONS OF THE AROMATIC RING
The —OH and — O e groups of phenol and phenoxide ion make for easy
electrophilic substitution. The situation here is very much like that in aniline
(see Section 22-5; see also Section 20-5A). Phenols react rapidly with bromine
sec 23.2 some chemical properties of phenols 633
in aqueous solution to substitute the positions ortho or para to the hydroxyl
group, phenol itself giving 2,4,6-tribromophenol in high yield.
Br
\ /
OH
Br 2
H 2
Br A f~ 0H
Br
A number of important reactions of phenols involve electrophilic aromatic
substitution of phenoxide ions. One example, which we have discussed in the
previous chapter, is the diazo coupling reaction (Section 22-9B). Another
example, which looks quite unrelated, is the Kolbe reaction (Figure 23-2) in
which carbon dioxide reacts with sodium phenoxide to give the sodium salt
of o-hydroxybenzoic acid (salicylic acid).
Sodium phenoxide absorbs carbon dioxide at room temperature to form
sodium phenyl carbonate and, when this is heated to 125° under a pressure of
several atmospheres of carbon dioxide, it rearranges to sodium salicylate.
However, there is no reason to expect that this reaction is anything other than
a dissociation-recombination process, in which the important step involves
electrophilic attack by carbon dioxide on the aromatic ring of phenoxide ion.
e e
CO,Na
HO
e e
CO,Na
With sodium phenoxide and temperatures of 125° to 150°, ortho substi-
tution occurs ; at higher temperatures (250° to 300°) and particularly with the
potassium salt, the para isomer is favored.
Figure 23-2 The reaction of sodium phenoxide with carbon dioxide (the
Kolbe reaction).
O e Na®
0H e e
itS
^L/ c °2 Na
K^ ™°
u
!■
sodium salicylate
co 2
O
II e ©
O-C — O Na
A,
sodium phenyl carbonate
chap 23 aryl oxygen compounds 634
Many substances such as salicylaldehyde, salicylic acid, and o-nitrophenol
that have hydroxyl groups ortho to some substituent to which they can
form hydrogen bonds have exceptional physical properties compared with the
meta or para isomers. This is because formation of intra- rather than inter-
molecular hydrogen bonds reduces intermolecular attraction, thus reducing
boiling points, increasing solubility in nonpolar solvents, and so on. Com-
pounds with intramolecular hydrogen bonds are often said to be chelated
(Gk. chele, claw) and the resulting ring is called a chelate ring.
OH
intramolecular only intermolecular
hydrogen bond hydrogen bonds
Table 23-3 Physical properties of some o, m, and p
disubstituted benzene derivatives
compound
bp,°C
mp,
°C
volatility with
steam
NO,
ortho
meta
para
ortho
meta
para
ortho
meta
para
ortho
meta
para
ortho
meta
para
191
203
202
196.5
240
244
230
248
211 2
216
j 9470mm
31
12
35
-7
108
117
38
2.5
158
201
215
45
97
114
+ +
+ +
+
+
+
+
+
+
sec 23.3 polyhydric phenols 635
The physical constants for the different isomers of some substances that can
and cannot form reasonably strong intramolecular hydrogen bonds are given
in Table 23-3. It will be seen that intramolecular hydrogen bonding between
suitable ortho groups has the effect of reducing both the melting and boiling
points. An important practical use of this is often made in isomer separations,
because many of the substances which can form intramolecular hydrogen
bonds turn out to be volatile with steam, whereas the corresponding meta and
para isomers are much less so.
Formation of intramolecular hydrogen bonds shows up clearly in nmr
spectra, as we have seen before in the case of the enol forms of 1,3-dicarbonyl
compounds (Section 12-6). Figure 23-3 shows that there is a difference of 2.3
ppm between the O— H resonance positions of o-nitrophenol and /7-nitro-
phenol. Intramolecular hydrogen-bond formation also influences the OH
stretching frequencies in the infrared.
Phenols generally can be successfully reduced with hydrogen over nickel
catalysts to the corresponding cyclohexanols. A variety of alkyl-substituted
cyclohexanols can be prepared in this way.
OH
H 2 (Ni)
H3C-C-CH3 H3C-C-CH3
CH 3 CH 3
23.3 polyhydric phenols
A number of important aromatic compounds have more than one phenolic
hydroxyl group. These are most often derivatives of the following dihydric
and trihydric phenols, all of which have commonly used but poorly descrip-
tive names.
H(X /^ /OH HO^ /-^ ^OH
OH OH
catechol resorcinol hydroquinone pyrogallol phloroglucinol
The polyhydric phenols with the hydroxyls in the ortho or para relationship
are normally easily oxidized to quinones — the chemistry of which substances
will be discussed shortly.
L JL m 8 so 4 L 1
^-^OH ether ^-^O
o-benzoquinone
chap 23 aryl oxygen compounds 636
600
...u
OH
500
400 117
1
ijfri
ft^Y-*"**
(b)
IK.)
**Jr***-***~**j~»*^ l jj-**» r H* t ^
W w
■» • l W»^v<> r « 1 ^A»
(C)
Mill
^■ ^ ^* ••+m*'*ir , +m*-*1*
10.0
7.0 ppm
Figure 23-3 Nmr spectra at 60 MHz of o-nitrophenol (a), m-nitrophenol (b),
and p-nitrophenol (c) in diethyl ether solution (the solvent bands are not
shown).
sec 23.4 quinones 637
OH
p-benzoquinone
The m-dihydroxybenzenes undergo oxidation but do not give m^quinones,
since these are substances for which no single unstrained planar structure can
be written. Oxidation of resorcinol gives complex products — probably by way
of attack at the 4 position, which is activated by being ortho to one hydroxyl
and para to the other. The use of hydroquinone and related substances as
reducing agents for silver bromide in photography will be discussed later.
Substitution of more than one hydroxyl group on an aromatic ring tends to
make the ring particularly susceptible to electrophilic substitution, especially
when the hydroxyls are meta to one another, in which circumstance their
activating influences reinforce one another. For this reason, resorcinol and
phloroglucinol are exceptionally reactive toward electrophilic reagents,
particularly in alkaline solution.
23-4 quinones
Strictly speaking, quinones are conjugated cyclic diketones rather than aro-
matic compounds ; hence a discussion of the properties of quinones is, to a
degree, out of place in a chapter covering aromatic oxygen compounds, even
though quinones have more stability than expected on the basis of bond
energies alone. Thus, /7-benzoquinone has a stabilization energy of 5 kcal,
which can be ascribed largely to resonance structures such as [3], there being a
total of four polar forms equivalent to [3]. The fact that quinones and poly-
hydric phenols are normally very readily interconvertible results in the
chemistry of either class of compound being difficult to disentangle from the
other; consequently, we shall discuss quinones at this point.
A variety of quinones have been prepared, the most common of which are
the 1,2- and 1,4-quinones as exemplified by o-benzoquinone and ^-benzo-
quinone. Usually the 1,2-quinones are more difficult to make and are more
reactive than the 1,4-quinones. A few 1,6- and 1,8-quinones are also known.
chap 23 aryl oxygen compounds 638
CI
,5-dichloro-2,6-naphthoquinone 3, 1 0-pyrenequinone
A. REDUCTION OF QUINONES
The most characteristic and important reaction of quinones is reduction to
the corresponding dihydroxyaromatic compounds.
2e
(23-1)
-2e
These reductions are sufficiently rapid and reversible to give easily repro-
ducible electrode potentials in an electrolytic cell. The position of the quinone-
hydroquinone equilibrium (Equation 23-1) is proportional to the square of the
hydrogen ion concentration. The electrode potential is therefore sensitive to
pH, a change of one unit of pH in water solution changing the potential by
0.059 volt. Before the invention of the glass electrode pH meter, the half-cell
potential developed by the quinone-hydroquinone equilibrium was widely
used to determine pH values of aqueous solutions. The method is not very
good above pH 9 or 10 because quinone reacts irreversibly with alkali.
Numerous studies have been made of half-cell potentials for the reduction
of quinones. As might be expected, the potentials are greatest when the
greatest gain in resonance stabilization is associated with formation of the
aromatic ring.
The hydroquinone-quinone oxidation-reduction system is actually some-
what more complicated than presented above. This is evident in one way
from the fact that mixing alcoholic solutions of hydroquinone and quinone
gives a brown-red solution, which then deposits a crystalline green-black 1 : 1
complex known as quinhydrone. This substance is apparently a charge-transfer
complex (of the type discussed in Section 22-4) with the hydroquinone acting
as the electron donor and the quinone as the electron acceptor. Quinhydrone
is not very soluble and dissociates considerably to its components in solution.
The reduction of quinone requires two electrons, and it is of course possible
that these electrons could be transferred either together or one at a time. The
product of a single electron transfer leads to what is appropriately called a
semiquinone [4] with both a negative charge and an odd electron. The forma-
sec 23.4 quinones 639
+ e
dimer
semiquinone
[4]
tion of relatively stable semiquinone radicals by electrolytic reduction of
quinones has been established by a variety of methods. Some semiquinone
radicals undergo reversible dimerization reactions to form peroxides.
B. PHOTOGRAPHIC DEVELOPERS
A particularly important practical use of the hydroquinone-quinone oxida-
tion-reduction system is in photography. Exposure of the minute grains of
silver bromide in a photographic emulsion to blue light (or any visible light
in the presence of suitable sensitizing dyes ; see Chapter 26) produces a stable
activated form of silver bromide, the activation probably involving generation
of some sort of crystal defect. Subsequently, when the emulsion is brought
into contact with a developer, which may be an alkaline aqueous solution of
hydroquinone and sodium sulfite, the particles of activated silver bromide are
reduced to silver metal much more rapidly than the ordinary silver bromide.
Removal of the unreduced silver bromide with sodium thiosulfate ("fixing")
leaves a suspension of finely divided silver in the emulsion in the form of the
familiar photographic negative.
OH
+ 2 AgBr + 2 OH
OH
+ 2 Ag +
e
2 Br
+ 2H 2
AgBr* = activated silver bromide
C. ADDITION REACTIONS OF QUINONES
Being oe,/?-unsaturated ketones, quinones are expected to have the possibility
of forming 1,4-addition products in the same way as their open-chain analogs
(Section 12-3). ^-Benzoquinone itself undergoes such additions rather readily.
Two examples are provided in Figure 23-4 by the addition of hydrogen
chloride and the acid-catalyzed addition of acetic anhydride. In the second
reaction, the hydroxyl groups of the hydroquinone are acetylated by the
acetic anhydride. Hydrolysis of the product affords hydroxyhydroquinone.
chap 23 aryl oxygen compounds 640
HC1
OH
H®
(CH 3 CO) 2
HO
OH
O-C-CHj
O— C — CH,
+ CH,CO,H
Figure 23-4 Some addition reactions ofp-benzoquinone.
D. NATURALLY OCCURRING QUINONES
Many naturally occurring substances have quinone-type structures, one of
the most important being the blood antihemorrhagic factor, vitamin K l5
which occurs in green plants and is a substituted 1,4-naphthoquinone. The
structure of vitamin K t has been established by degradation and by syn-
thesis. Surprisingly, the long alkyl side chain of vitamin K t is not necessary for
its action in aiding blood clotting because 2-methyl- 1,4-naphthoquinone is
almost equally active on a molar basis.
CH,
I
CH,
CH,CH=C-eCH 2 -CH 2 -CH 2 -CH^CH 3
vitamin K,
CH,
2-methyl- 1, 4-naphthoquinone
(menadione)
A molecule that is structurally similar to vitamin K L is coenzyme Q. There
are, in fact, several of these differing in the length of the side chain. Coenzyme
Q 10 is shown below, the subscript in the name revealing the number of repeat-
ing C 5 units in the side chain. The Q coenzymes are widely distributed in
nature and are particularly important constituents of mitochondria. They are
sec 23. S tropolones and related compounds 641
links in the so-called electron-transport chain (Section 184), appearing
between the flavins and the cytochromes, and seem to be able to function
both as one- and two-equivalent oxidants.
CH,0
CH 2 CH=C-fCH,-CH 2 -CH=C^- CH 3
coenzyme Q 10
The repeating C 5 moieties in the side chains of vitamin K x and coenzyme Q
are referred to as isoprenoid units. These will be met again in Chapter 29.
23-5 tropolones and related compounds
The tropolones make up a very interesting class of nonbenzenoid aromatic
compounds which were first encountered in several quite different kinds of
natural products. As one example of a naturally occurring tropolone, the
substance called /?-thujaplicin or hinokitiol has been isolated from the oil of
the western red cedar. The wood of these trees rots extremely slowly and this
characteristic has been traced to the presence of this compound, and its y
isomer, which are natural fungicides. The outer butt heartwood of older
cedars contains as much as 1 % thujaplicins whereas young trees lay down
very little of these materials. This accounts for the hollow center often seen
in very old cedars — the core, which has a low thujaplicin content, rots.
/Mhujaplicin
(4-isopropyltropolone)
Tropolone itself can be prepared in a number of ways, the most convenient
of which involves oxidation of 1,3,5-cycloheptatriene (" tropilidene ") with
alkaline potassium permanganate. The yield is low but the product is readily
isolated as the copper salt.
Cu 2S>
KMnO^ [/ ^ ^=± copper salt
H 2 S
tropilidene tropolone
Tropolone is an acid with an ionization constant of 10~ 7 , which is inter-
chap 23 aryl oxygen compounds 642
mediate between that of acetic acid and that of phenol. Like phenols, tropo-
lones form colored complexes with ferric chloride solution. Tropolone has
many properties which suggest that it has some aromatic character. Thus, it
resists hydrogenation, undergoes diazo coupling, and can be nitrated, sul-
fonated, and substituted with halogens. Its stability can be attributed to
resonance involving the two nonequivalent structures [5] and [6] and to the
several structures such as [7] and [8] which correspond to the stable tropylium
cation with six n electrons (Section 6-7). There is a strong intramolecular
hydrogen bond between the carbonyl oxygen and the hydroxylic proton
and this fact reflects the importance of structure [6].
&~Cf
[5]
[6]
OH
[7]
e O
®
[8]
etc.
The tropylium cation itself is easily prepared by transfer of hydride ion
from tropilidine to triphenylmethyl cation in sulfur dioxide solution.
(QH 5 ) 3 C®
so 2
I A + (C 6 H 5 ) 3 CH
tropylium cation
Seven equivalent resonance structures can be written for the cation so that
only one-seventh the positive charge is expected to be on each carbon. Since
the cation also has just six n electrons, it is anticipated to be unusually stable
for a carbonium ion.
hybrid structure for
tropylium ion
summary
Phenols, ArOH, although enols, are stable because of the stabilization energy
of the benzene ring. Phenol can be prepared from benzene via benzenesulfonic
acid or via halobenzenes.
Phenols resemble alcohols in forming esters and ethers but their considera-
summary 643
bly greater acidity (midway between alcohols and carboxylic acids) allows them
to form salts with sodium hydroxide, though not with sodium bicarbonate.
O
II
ArCOR
ArOH > ArOR
^ ArO e
Ether formation via phenoxide ion may be accompanied by C-alkylation.
Cleavage of an aryl alky] ether with hydrogen halide always gives alkyl halide
and a phenol.
The hydroxyl group in phenols activates the ring toward electrophilic
attack. Ionization of the hydroxyl causes further activation and enables feeble
electrophiles such as carbon dioxide to react (Kolbe reaction).
Intramolecular hydrogen bonding in or^o-substituted phenols is revealed
by downfield nmr spectral shifts and by higher vapor pressures in comparison
to analogous para compounds.
A number of polyhydric phenols are known; those with two hydroxyl
groups ortho or para to one another can usually be oxidized to quinones. A
quinone can undergo a number of addition reactions.
O e
OH
[O]
(semiquinone)
OH
Two important naturally occurring quinones are vitamin Kj and coenzyme
Q. Tropolones, including the natural product /Mhujaplicin, are seven-mem-
bered cyclic enols. A major factor in stabilizing the enol form is intramolecu-
lar hydrogen bonding. Resonance stabilization as in the tropylium ion may
also be important.
(tropolone) (tropylium ion)
chap 23 aryl oxygen compounds 644
exercises
23*1 Would you expect phenyl acetate to be hydrolyzed more readily or less
readily than cyclohexyl acetate in alkaline solution ? Use reasoning based on
the mechanism of ester hydrolysis (Section 13 '8).
23-2 Rearrangement of phenyl allyl-3- 14 C ether at 200° gives o-allyl-l- l4 C-
phenol. What does this tell you about the rearrangement mechanism? Can
it be a dissociation-recombination process ? What product(s) would you ex-
pect from a para Claisen rearrangement of 2,6-dimethylphenyl allyl-3- l4 C
ether? From 2,6-diallylphenyl allyl-3- 14 C ether?
23-3 Explain why phenol with bromine gives tribromophenol readily in water
solution and o- and ^-monobromophenols in nonpolar solvents. Note that
2,4,6-tribromophenol is at least a 300-fold stronger acid than phenol in
water solution.
23-4 The herbicide 2,4-D is 2,4-dichlorophenoxyacetic acid (Figure 21-2). Show
how this substance might be synthesized starting from phenol and acetic
acid.
23-5 How much difference in physical properties would you expect for o- and
p-cyanophenol isomers ? Explain.
23-6 Resorcinol (/n-dihydroxybenzene) can be converted to a carboxylic acid with
carbon dioxide and alkali. Would you expect resorcinol to react more or less
readily than phenol ? Why ? Which is the most likely point of monosubsti-
tution ? Explain.
23-7 Arrange the following quinones in order of increasing half-cell potential
expected for reduction: />-benzoquinone, 4,4'-diphenoquinone, cw-2,2'-di-
phenoquinone, 9,10-anthraquinone, and 1 ,4-naphthoquinone. Your reason-
ing should be based on difference in stabilization of the quinones and the
hydroquinones, including steric factors (if any).
23-8 Tropone (2,4,6-cycloheptatrienone) is an exceptionally strong base for a
ketone. Explain.
23-9 At which position would you expect tropolone to substitute most readily
with nitric acid ? Explain.
23-10 Give for each of the following pairs of compounds a chemical test, preferably
a test tube reaction, that will distinguish between the two compounds. Write
a structural formula for each compound and equations for the reactions
involved.
a. phenol and cyclohexanol
b. methyl p-hydroxybenzoate and i>-methoxybenzoic acid
c. hydroquinone and resorcinol
d. hydroquinone and tropolone
exercises 645
23-11 Show by means of equations how each of the following substances might
be synthesized, starting from the indicated materials. Specify reagents and
approximate reaction conditions.
a. methyl 2-methoxybenzoate from phenol
b. 2,6-dibromo-4-/-butylanisole from phenol
c. 2-hydroxy-5-nitrobenzoic acid from phenol
d. 4-cyanophenoxyacetic acid from phenol
e. cyanoquinone from hydroquinone
23-12 Write structural formulas for substances (one for each part) that fit the
following descriptions :
a. a phenol that would be a stronger acid than phenol itself
b. that isomer of dichlorophenol that is the strongest acid
c. the Claisen rearrangement product from a-methylallyl-2,6-dimethyl-
phenyl ether
d. the Claisen-type rearrangement product from allyl 2,6-dimethyl-4-
(j8-methylvinyl)-phenyl ether.
e. a quinone that would be a better charge-transfer agent than quinone
itself
/. the expected product from addition of hydrogen cyanide to mono-
cyan oquinone
g. a nonbenzenoid, quinone-like substance with its carbonyl groups in
a 1,3 relationship
23-13 The chain reaction involved in the conversion of isopropylbenzene (cumene)
to its hydroperoxide (Figure 23-1) can be written as follows, using a 7-butoxy
radical (formed by the decomposition of di-^-butyl peroxide) as the initiator.
C 6 H 5 CH(CH 3 ) 2 -M-BuO- ► A + /-BuOH initiation step
A + 2 > B
OOH
I
B + C 6 H 5 CH(CH 3 ) 2 ► A + C 6 H 5 C(CH 3 ) 2
propagation
steps
a. Deduce the structure of A and B and suggest a reason for A, rather
than one of its structural isomers, being formed in the initiation step.
b. Suggest a termination step (Section 2-5B) for the chain.
23-14 The acid-catalyzed rearrangement involved in the conversion of cumene
hydroperoxide to phenol and acetone (Figure 23-1) can be written as follows :
OOH OOH 2
I I -H 2 ©
C 6 H 5 C(CH 3 ) 2 +H ffl < > C 6 H 5 C(CH 3 ) 2 ► C 6 H s O=C(CH 3 ) 2
+ H 2 -H«>
► C ► D ► C 6 H 5 OH + (CH 3 ) 2 C=0
a. Write a structure for the transition state for the rearrangement that
occurs in the second step.
b. What are the structures of the cation C and the neutral molecule D
and to what class of compounds does D belong?
chap 23 aryl oxygen compounds 646
23-15 Reduction of 9,10-anthraquinone with tin and hydrochloric acid in acetic
acid produces a solid, light-yellow ketone, mp 156°, which has the formula
Ci<tH 10 O. This ketone is not soluble in cold alkali but does dissolve when
heated with alkali. Acidification of cooled alkaline solutions of the ketone
precipitates a brown-yellow isomer of the ketone of mp 120°, which gives
a color with ferric chloride, couples with diazonium salts, reacts with bro-
mine, and slowly is reconverted to the ketone.
What are the structures of the ketone and its isomer ? Write equations for
the reactions described.
23-16 Devise syntheses of each of the following photographic developing agents
based on benzene as the aromatic starting material. Give approximate
reaction conditions and reagents.
a. hydroquinone
b. /)-aminophenol
c. p-amino-N,N-diethylaniline
d. (p-hydroxyphenyl)-aminoacetic acid
e. 2,4-diaminophenol
23-17 Addition of hydrogen chloride to /?-benzoquinone yields some 2,3,5,6-tetra-
chloroquinone. Explain how the latter could be formed in the absence of
an external oxidizing agent.
23-18 Consider the possibility of benzilic acid-type rearrangements of 9, 1 0-phenan-
threnequinone and anthraquinone. Give your reasoning.
23-19 When quinone is treated with hydroxylamine and phenol is treated with
nitrous acid, the same compound of formula C 6 H 5 2 N is produced. What
is the likely structure of this compound and how would you establish its
correctness ?
23-20 How would you expect the properties of 3- and 4-hydroxy-2,4,6-cyclohepta-
trienone to compare with those of tropolone ? Explain.
23-21 Make an atomic orbital model of phenol, showing in detail the orbitals and
electrons at the oxygen atom (it may be desirable to review Chapters 6 and 20
in connection with this problem). From your model, would you expect either
or both pairs of unshared electrons on oxygen to be delocalized over the
ring ? What would be the most favorable orientation of the hydrogen of the
hydroxyl group for maximum derealization of an unshared electron pair ?
aromatic side~chai»
chap 24 aromatic side-chain derivatives 649
The pronounced modification in the reactivity of halogen, amino, and
hydroxyl substituents when linked to aromatic carbon rather than saturated
carbon was discussed in Chapters 21, 22, and 23. Other substituents, par-
ticularly those linked to an aromatic ring through a carbon-carbon bond, are
also influenced by the ring, although usually to a lesser degree. Examples
include -CH 2 OH, -CH 2 OCH 3 , -CH 2 C1, -CHO, -COCH 3 , -C0 2 H,
and — CN, and we shall refer to aromatic compounds containing substi-
tuents of this type as aromatic side-chain derivatives.
preparation of aromatic side-chain compounds
Since the utility of any method of synthesis is limited by the accessibility of the
starting materials, we may anticipate that the most practical methods for the
preparation of benzenoid side-chain compounds will start from benzene or an
alkylbenzene. These methods may be divided into two categories — those that
modify an existing side chain, and those by which a side chain is introduced
through substitution of the aromatic ring. We shall consider first the reactions
that modify a side chain and for which the obvious starting materials are the
alkylbenzenes, especially toluene and the xylenes.
24-1 aromatic carboxjlic acids
An alkylbenzene can be converted to benzoic acid by oxidation of the side
chain with reagents such as potassium permanganate, potassium dichromate,
or nitric acid.
C0 2 H
KMnO„,H 2 0, OH
(reflux)
benzoic acid
Under the conditions of oxidation, higher alkyl or alkenyl groups are
degraded and ring substituents, other than halogen and nitro groups, often
fail to survive.
In fact, the presence of a hydroxyl or amino substituent causes the whole
ring to be degraded long before the alkyl group undergoes appreciable
oxidation.
CH, CO,H
H,N ^ H,N
By contrast, prolonged oxidation of 5-nitro-2-indanone gives a good yield
of product with the substituent untouched and the ring intact.
dil. hno 3
, ^ ^ ^ 24hr, 25° , ^ ^ _
2 N ^-" 2 N ^^ "C0 2 H
5-nitro-2-indanone 4-nitrophthalic acid
chap 24 aromatic side-chain derivatives 650
To retain a side-chain substituent, selective methods of oxidation are
required. For example, /7-toluic acid may be prepared from p-tolyl methyl
ketone by the haloform reaction (Section 12-1C).
H 3 C-^y C OCH3 ^^ H,C^Q-CO a H
The Cannizzaro reaction (Section 11-4H) is sometimes useful for the prep-
aration of substituted benzoic acids and (or) benzyl alcohols, provided that
the starting aldehyde is available.
H 2 0, SQH
^OH "^ "OH ^ OH
2-iodo-3-hydroxy- 2-iodo-3-hydroxy- 2-iodo-3-hydroxy-
benzaldehyde benzoic acid benzyl alcohol
80% 80%
24-2 preparation of side-chain aromatic
halogen compounds
Although many side-chain halogen compounds can be synthesized by reac-
tions that are also applicable to alkyl halides, there are several other methods
especially useful for the preparation of arylmethyl halides. The most important
of these are the radical halogenation of alkylbenzenes and chloromethylation
of aromatic compounds (Section 24-4B).
The light-induced, radical chlorination or bromination of alkylbenzenes
with molecular chlorine or bromine gives substitution on the side chain rather
than on the ring. Thus, toluene reacts with chlorine to give successively benzyl
chloride, benzal chloride, and benzotrichloride.
C6H5CH3
Cl 2
C.6H5CH2CI
Ch
C6H5CHC12
ci 2
hv
hv
hv
' ^etis^^-h
toluene
benzyl
chloride
benzal
chloride
benzo-
trichloride
This reaction was met when the chlorination of methane was discussed in
Chapter 2. The major effect of the phenyl ring is to facilitate the reaction by
making the intermediate benzyl radicals more stable.
CH,- CH,
24-3 side-chain compounds derived from
arylmethyl halides
Arylmethyl halides, such as benzyl chloride (C 6 H 5 CH 2 C1), benzal chloride
(C 6 H 5 CHC1 2 ), and benzotrichloride are quite reactive compounds. They are
sec 24.4 preparation of aromatic side-chain compounds 6S1
CH,C1
benzyl chloride
/ VCHC1 2 + H 2
benzal chloride
f VCH 2 OH
benzyl alcohol
f VCH 2 CN
phenylacetonitrile
100°
CHO + 2 HC1
benzaldehyde
CC1 3
benzotrichloride
+ 2H 2 10 °° » <f V"C0 2 H + 3HC1
benzoic acid
Figure 24-1 Reactions of benzyl chloride, benzal chloride, and benzotri-
chloride.
readily available or easily prepared and are useful intermediates for the
synthesis of other side-chain derivatives. See Figure 24-1 for examples.
24-4 preparation of aromatic side-chain compounds
by ring substitution
A. FRIEDEL-CRAFTS REACTION
The Friedel-Crafts alkylation and acylation reactions have been discussed
(Sections 20-4D and 20-4E). For alkylation, catalytic amounts of A1C1 3 are
+ RCl
AICI,
+ HC1
usually sufficient and polysubstitution may be an important side reaction
because of the activating effect of the R group.
For acylation, large amounts of A1C1 3 are required and only monosubsti-
O
II
tution occurs because of the deactivating effect of the — C— R group.
o
II Aids
+ RC-Cl
O
II
CR
+ HC1
chap 24 aromatic side-chain derivatives 652
B. CHLOROMETHYLATION
The reaction of an aromatic compound with formaldehyde and hydrogen
chloride in the presence of zinc chloride as catalyst results in the substitution
of a chloromethyl group, — CH 2 C1, for a ring hydrogen.
QH 6 + CH 2 + HC1
ZnCh
-» C 6 H 5 CH 2 C1 + H 2
The mechanism of the chloromethylation reaction is related to that of
Friedel-Crafts alkylation and acylation and probably involves an incipient
chloromethyl cation, ®CH 2 C1.
O
OH
H— C + HC1 ;=
\
H
8e
HOZnCl 2
H CH,C1
+ HOZnCl,
Se
HOZnCl,
I ZnCI 2 :
H — C— CI ^- ' H — C— CI
CH,C1
+ ZnCl,
C. ALDEHYDES BY FORMYLATION
Substitution of the carboxaldehyde group (— CHO) into an aromatic ring is
known as formylation. This is accomplished by reaction of an aromatic
hydrocarbon with carbon monoxide in the presence of hydrogen chloride and
aluminum chloride. Cuprous chloride is also required for reactions proceeding
at atmospheric pressure but is not necessary for reactions at elevated pressures.
CH(CH 3 ) 2
+ CO
HCI, AICI3 (1 mole)
500 psi, 25°-30°
CH(CH 3 ) 2
CHO
p-isopropylbenzaldehyde
60%
CO
HCI, AICI3
Cu 2 CI 2 , 35°-40° ' \ /
-CHO
p-phenylbenzaldehyde
73%
Formylation of reactive aromatic compounds such as phenols, phenolic
ethers, and certain hydrocarbons can be brought about by the action of
hydrogen cyanide, hydrogen chloride, and a catalyst, usually zinc chloride or
aluminum chloride. A convenient alternative is to use zinc cyanide and
hydrogen chloride. The product is then hydrolyzed to an aldehyde.
sec 24.5 arylmethyl halides 653
CHO
OH
+ HCN + HC1
I. ZnCl 2 , ether.
2. H 2
OH
+ NHX1
2-naphthol
2-hy droxy- 1 -naphthaldehyde
properties of aromatic side-chain derivatives
24-5 arylmethyl halides. stable carbonium ions,
carbanions, and radicals
The arylmethyl halides of particular interest are those having both halogen
and aryl substituents bonded to the same saturated carbon. Typical examples
and their physical properties are listed in Table 24-1.
We noted in Chapter 21 that benzyl halides (C 6 H 5 CH 2 X) are comparable
in both S N 1 and S N 2 reactivity to allyl halides (CH 2 =CHCH 2 X) and, because
high reactivity in S N 1 reactions is associated primarily with exceptional car-
bonium ion stability, the reactivity of benzyl derivatives can be ascribed
mainly to resonance stabilization of the benzyl cation. Diphenylmethyl or
benzhydryl halides, (C 6 H 5 ) 2 CHX, are still more reactive than benzyl halides in
S N 1 reactions, and this is reasonable because the diphenylmethyl cation has
two phenyl groups over which the positive charge can be delocalized and is,
therefore, more stable relative to the starting halide than is the benzyl cation.
"^
CH
CH
etc.
diphenylmethyl cation
Table 24-1 Physical properties of* arylmethyl halides
bp,
mp,
d 20 '*,
compound
formula
°C
°C
g/ml
benzyl fluoride
CeHsCH^F
140
-35
1.0228 25 '*
benzyl chloride
CgHsCH^Cl
179
-43
1.1026 18 '*
benzyl bromide
CeH 5 CH^Br
198
-4.0
1.438"'°
benzyl iodide
C 6 H 5 CH 2 I
0310mm
24
1.733"'*
benzal chloride
C6H5CHCI2
207
-16
1.2557 1 *
benzotrichloride
C 6 H 5 CC1 3
214
-22
1.38
benzotrifluoride
C 6 H 5 CF 3
103
-29.1
1.1 886 20
benzhydryl chloride
(C 6 H 5 ) 2 CHC1
173 19mm
20.5
(diphenylmethyl chloride)
triphenylmethyl chloride
(C 6 H 5 ) 3 CC1
112.3
(trityl chloride)
chap 24 aromatic side-chain derivatives 654
Accordingly, we might expect triphenylmethyl or trityl halides, (C 6 H 5 ) 3 C
—X, to be more reactive yet. In fact, the C— X bonds of such compounds are
sufficiently labile that reversible ionization occurs in solvents that have reason-
ably high dielectric constants but do not react irreversibly with the carbonium
ion. An example of such a solvent is liquid sulfur dioxide, and the degrees of
ionization of a number of triarylmethyl halides in this solvent have been
determined by electrical-conductance measurements, although the equilibria
are complicated by ion-pair association.
so 2 , o°
(C 6 H 5 ) 3 C-C1 -r=- (C 6 H 5 ) 3 C®Cie ;=± (C 6 H S ) 3 C® + Cje
ion pair dissociated ions
Triarylmethyl cations are among the most stable carbonium ions known.
They are intensely colored and are readily formed when the corresponding
triarylcarbinol is dissolved in strong acids.
H2SO4 e (-H20)
(QH 5 ) 3 C-OH . (C 6 H 5 ) 3 C-OH 2 . (C 6 H 5 ) 3 C®
triphenylcarbinol triphenylmethyl cation
(colorless) (orange-yellow)
If electron-donating para substituents such as amino groups are placed in
each ring [1] the energy of the carbonium ion is lowered to such an extent that
it is stable in water at pH 7.
Q>-NH 2 C 6 H 4 ) 3 C®
[1]
In addition to forming stable cations, triarylmethyl compounds form stable
carbanions. Because of this, the corresponding hydrocarbons are relatively
acidic compared to simple alkanes. They react readily with strong bases such
as sodamide, and the resulting carbanions are usually intensely colored.
ether
(QH 5 ) 3 CH + Na e NH 2 e , (C 6 H 5 ) 3 C: e Na® +NH 3
triphenylmethane sodium triphenylmethide
(colorless) (blood red)
This carbanion can also be generated by the action of less basic reagents
such as sodium ethoxide, provided polar aprotic solvents such as dimethyl
sulfoxide or hexamethylphosphoramide are used (Sections 8-1 ID and 19-2C).
Just as the positive charge in triarylmethyl cations can be distributed over the
ortho and para positions of each ring, so can the negative charge in the tri-
phenylmethide ion.
Triarylmethyl compounds also form stable triarylmethyl radicals, and
indeed the first stable carbon radical to be reported was the triphenylmethyl
radical, (C 6 H 5 ) 3 0, prepared inadvertently by Gomberg in 1900. Gomberg's
objective was to prepare hexaphenylethane by a Wurtz coupling reaction of
triphenylmethyl chloride with metallic silver; but he found that no hydro-
carbon was formed unless air was carefully excluded from the system.
benzene
2 (C 6 H 5 ) 3 C-C1 + 2 Ag ► (C 6 H 5 ) 3 C-C(C 6 H 5 ) 3 + 2AgCl
hexaphenylethane (C 38 H 3 o)
sec 24.5 arylmethyl halides 655
In the presence of atmospheric oxygen, the product is triphenylmethyl
peroxide, (C 6 H 5 ) 3 COOC(C 6 H 5 ) 3 , rather than hexaphenylethane. In the
absence of oxygen a compound, C 38 H 30 , assumed to be hexaphenylethane,
was obtained and shown to dissociate slightly to triphenylmethyl radicals at
room temperature in inert solvents {K=2.2 x 10 ~ 4 at 24° in benzene).
However, equilibrium between this compound and triphenylmethyl radicals is
rapidly established so that oxygen readily converts the ethane into the rela-
tively stable triphenylmethyl peroxide.
benzene 24°
2(C 6 H 5 ) 3 C-
A = 2.2xlO- 4
triphenylmethyl radical
(C 6 H 5 ) 3 + 2 =i (C 6 H 5 ) 3 COO- (C<,H5)3C '» (C 6 H 5 ) 3 COOC(C 6 H 5 )3
triphenylmethyl
peroxide
While these reactions may now seem entirely reasonable, Gomberg's
suggestion that the triphenylmethyl radical could exist as a fairly stable
species was not well received at the time. Today, the stability of the radical has
been established beyond question by a variety of methods such as electron
paramagnetic resonance (epr) spectroscopy, which is discussed briefly at the
end of this chapter (Section 24-8). This stability can be attributed to stabili-
zation of the odd electron by the attached phenyl groups.
// \—C- < ► •< >=C < ► <f y— C < ► etc.
^5 ^b ^5
A curious sequel to Gomberg's work has occurred. The compound
C 38 H 30 that is in equilibrium with the radical was shown in 1968 to be not
hexaphenylethane [2] but its structural isomer [3] resulting from coupling of
two radicals through a para carbon in one of them. Presumably [3] is more
[2] [3]
stable than [2] because of lower steric strain. It is interesting that the difference
is sufficient to overcome the loss of the resonance energy of one benzene ring.
Some strain undoubtedly remains in [3] and is relieved by dissociation, al-
chap 24 aromatic side-chain derivatives 656
though the main driving force for this is the resonance stabilization of the
radical so formed.
The stability of a carbon radical, R 3 0, is reflected in the ease with which
the C— H bond of the corresponding hydrocarbon, R 3 CH, is broken homo-
lytically. A hydrogen atom bonded to a tertiary carbon is replaced in radical
chlorination faster than hydrogen at a secondary or primary position (see
Section 3-3B) showing that the order of stability of the resulting carbon
radicals is tertiary > secondary > primary. Hydrogen-abstraction reactions
by radicals other than chlorine atoms have been investigated to obtain some
measure of hydrocarbon reactivity and radical stability.
24-6 aromatic aldehydes
Most of the reactions of aromatic aldehydes involve nothing new or surpris-
ing in view of our earlier discussion on the reactions of aldehydes (Chapters 1 1
and 12). One reaction, which is rather different and is usually regarded as
being characteristic of aromatic aldehydes (although, in fact, it does occur
with other aldehydes having no a hydrogens), is known as the benzoin con-
densation. It is essentially a dimerization of two aldehyde molecules through
the catalytic action of sodium or potassium cyanide.
HO O
2 (' V-CHO ► (' ^)—C—C—(' V
K_7^ n,J C 2 H 5 OH,H 2 \ /| C \ /
N ' (reflux) N ' jlj x==/
benzoin
90%
The dimer so formed from benzaldehyde is an a-hydroxy ketone and is
called benzoin. Unsymmetrical or mixed benzoins may often be obtained in
good yield from two different aldehydes.
O OH
(reflux) jj
anisaldehyde benzaldehyde 4-methoxybenzoin
In naming an unsymmetrical benzoin, substituents in the ring attached to
the carbonyl group are numbered in the usual way while primes are used to
number substituents in the ring attached to the carbinol carbon.
Cl
3-nitro-4'-chlorobenzoin
The first step in the benzoin condensation involves conversion of the alde-
hyde to the cyanohydrin by attack of cyanide ion at the carbonyl group.
O
OH
c
>
II
1
-CH
>=
=/
NO,
sec 24.7 natural occurrence and uses of aromatic side-chain derivatives 657
The cyanohydrin [4] thus formed has a relatively acidic a hydrogen because
the resulting carbanion is stabilized by both a phenyl and a cyano group. At
the pH of a cyanide solution, a benzyl-type carbanion [5] is readily formed
and, in a subsequent slow step, attacks the carbonyl carbon of a second
aldehyde molecule. Loss of HCN from the addition product [6] leads to
benzoin.
O O e OH
C b H 5 C^ + CN e ^=± C 6 H 5 -C-H ^=± C 6 H 5 -C:e
H C=N C=N
[4] [5]
OH o HO O e
I \ II
+ C-C 6 H 5 ► C 6 H 5 -C-C-C 6 H 5
C=N H NC H
[6]
I
O OH
C 6 H 5 -C-C-C 6 H 5 -^» C 6 H 5 -C-CH-C 6 H 5
NC H benzoin
The unique catalytic effect of cyanide ion is due to its high nucleophilicity
which leads to the production of an adduct such as [4]; the electron-
withdrawing power of the cyano group that stabilizes ion [5] ; and the ease
with which the cyanide ion can be eliminated in the final step.
The benzoin condensation is a useful synthetic reaction when you want to
prepare a compound with the Ar-C-C-Ar skeleton. The carbonyl and hydroxyl
groups in benzoins are subject to the usual reactions of ketones and alcohols.
24-7 natural occurrence and uses of aromatic
side-chain derivatives
Derivatives of aromatic aldehydes occur naturally in the seeds of plants. For
example, amygdalin is a substance occurring in the seeds of the bitter almond;
it is a derivative of gentiobiose, which is a disaccharide made up of two glucose
units. One of the glucose units is bonded through the OH group of benzal-
dehyde cyanohydrin by a /?-glucoside linkage.
CHCN
amygdalin
chap 24 aromatic side-chain derivatives 658
The flavoring vanillin occurs naturally as glucovanillin (a glucoside) in the
vanilla bean, although it is also obtained commercially as a byproduct from
the treatment of lignin waste liquor (Section 15-7) and by oxidation of
eugenol, a constituent of several essential oils.
OCH,
= CH,
eugenol
OH
3 OH
OCH,
CH = CH— CH
isoeugenol
OH
OCH,
CHO
vanillin
H 2 0, H s
(-CH 3 C0 2 H)
OCH,
CH=CHCH,
CHO
Methyl salicylate, the major constituent of oil of wintergreen, occurs in
many plants, but it is also readily prepared synthetically by esterification of
salicylic acid, which in turn is made from phenol (see Section 23-2D).
C0 2 H
C0 2 CH 3
rV H
CH 3 OH,H 2 SO„. (| ^f
Kj
(-H 2 0)
\^
salicylic acid
methyl salicylate
(oil of wintergreen)
The acetyl derivative of salicylic acid is better known as aspirin and is
prepared from the acid with acetic anhydride using sulfuric acid as catalyst.
o
C0 2 H C0 2 H
/L X>H /L.OCCH3
f^f (CH,CO) 2 0, H 2 S0 4 (| ^T
acetylsalicylic acid
(aspirin)
The structures of several other side-chain compounds used as flavorings,
perfumes, or drugs are shown in Figure 24-2.
Numerals are used to indicate positions both on an alkane chain and in a
benzene ring and this can sometimes be awkward, as in the systematic name
for adrenaline shown in Figure 24-2. With a single substituent on a ring this
difficulty can be avoided by using the symbol 0, m, or p.
sec 24.8 electron paramagnetic resonance (epr) spectroscopy 659
CO,CH,
NH,
6
methyl 2-aminobenzoate
(methyl anthranilate)
grape flavoring
and perfume
CH 3
CH 2 -C-NH 2
I
H
l-phenyl-2-aminopropane
(benzedrine)
central nervous
system stimulant;
decongestant
CO,C 2 H 5
NH,
5-ethyl-5-phenylbarbituric acid
(phenobarbital)
sedative
CHO
ethyl 4-aminobenzoate
(benzocaine)
local anesthetic
OH
I
H-C-CH 2 NHCH 3
OH
OH
1 -(3,4-dihydroxyphenyl)-
2-methylaminoethanol
(adrenaline, epinephrine)
central nervous
system stimulant;
blood pressure
raising principle
of adrenal glands
NHCOCH,
4-ethoxyacetanilide
(phenacetin)
analgesic
CH,
3,4-methylenedioxybenzaldehyde
(piperonal)
perfume ingredient
OCH,
/?-(3,4,5-trimethyoxyphenyl)ethylamine
(mescaline)
a hallucinogen
Figure 24-2 Some aromatic side-chain compounds with physiological effects.
24- 8 electron paramagnetic resonance (epr)
spectroscopy
One of the most important methods of studying radicals that has yet been
developed is electron paramagnetic resonance (epr) or, as it is sometimes
chap 24 aromatic side-chain derivatives 660
called, electron-spin resonance (esr) spectroscopy. The principles of this
form of spectroscopy are in many respects similar to nmr spectroscopy, even
though the language used is often quite different. The important point is that
an unpaired electron, like a proton, has a spin and a magnetic moment such
that it has two possible orientations in a magnetic field corresponding to
magnetic quantum numbers +| and —\. The two orientations define two
energy states which differ in energy by about 1000 times the energy difference
between corresponding states for protons, and therefore the frequency of
absorption of electrons is about 1000 times that of protons at the same mag-
netic field. At magnetic fields of 3600 gauss, the absorption frequency of free
electrons is about 10,000 MHz, which falls in the microwave, rather than the
radiowave, region.
The basic apparatus for epr spectroscopy differs from that shown in Figure
7-11 for nmr spectroscopy by having the sample located in the resonant cavity
of a microwave generator. The spectrum produced by epr absorption of
unpaired electrons is similar to that shown in Figure 24-3a, except that epr
spectrometers are normally so arranged as to yield a plot of the first derivative
of the curve of absorption against magnetic field, rather than the absorption
curve itself, as shown in Figure 24-3b. This arrangement is used because it
gives a better signal-to-noise ratio than a simple plot of absorption against
magnetic field.
The sensitivity of epr spectroscopy for detection of radicals is high. Under
favorable conditions, a concentration of radicals as low as 10 ~ 12 M can be
readily detected. Identification of simple hydrocarbon free radicals is often
possible by analysis of the fine structure in their spectra. This fine structure
Figure 24-3 Plots of absorption (a) and derivative (b) epr curves.
sec 24.9 linear free-energy relations 661
arises from spin-spin splittings involving protons, which are reasonably close
to the centers over which the unpaired electron is distributed. The multiplicity
of hydrogens and their location in the ortho, meta, and para positions of the
triphenylmethyl radical produces an extremely complex epr spectrum with at
least 21 observable absorption lines. Other radicals may give simpler spectra.
Methyl radicals generated by X-ray bombardment of methyl iodide at
— 196° show four (n + 1) resonance lines, as expected, for interaction of the
electron with three (n) protons (see Section 7-6B).
One of the most exciting uses of epr is in the study of radical intermediates
in organic reactions. Thus, in the oxidation of hydroquinone in alkaline
solution by oxygen, the formation of the semiquinone radical (Section 23-4)
can be detected by epr. The identity of the intermediate is shown by the
fact that its electron spectrum is split into five equally spaced lines by the
four equivalent ring protons. The radical disappears by disproportionation
reactions and has a half-life of about 3 seconds.
Similar studies have shown that radicals are generated and decay in
oxidations brought about by enzymes. Radicals have been detected by
epr measurements in algae "fixing" carbon dioxide in photosynthesis. The
character of the radicals formed has been found to depend on the wavelength
of the light supplied for photosynthesis.
24-9 linear Jree-energy relations
Can we predict the effect a substituent on a benzene ring will have on the rate
or the position of equilibrium of a reaction taking place elsewhere in the
molecule ? Yes, to a very considerable degree, provided the substituent is in a
meta or para position and certain other information is available. Some idea
of the regularity of substituent effects can be seen in Figure 24-4, which shows
a plot of the logarithm of the equilibrium constants for the dissociation of
a series of benzoic acids against the logarithm of the rate constants for
the alkaline hydrolysis of the corresponding ethyl benzoates (Equations 24- 1
and 24-2).
/^\- C 2 H +=*=> /~\-cO? + H e (24-1)
z z
/~\-C0 2 Et + OH e — *— /"VcO? + EtOH (24-2)
A plot of log k against log Kis really a plot of free energies since log k cc A G %
and log K oc AG. Thus, we can say that the two reaction series (the meta and
para compounds, at least) obey a "linear free-energy relation."
Relations like this are not usually observed with o/t/zo-substituted com-
pounds (see Figure 24-4) or with aliphatic systems because of steric and other
chap 24 aromatic side-chain derivatives 662
60
o
-1.0
-
o/p-N0 2
'm-N0 2
-2.0
—
Jbm-CL
p-Vo/P- CX
o-N0 2 •
«o-F
mo-Cl
-3.0
h/
p-CH 3 o/ m " CH 3
-4.0
Xp-OCH 390 „ch 3
1
i
1.0 2.0
lOgl0 5 *HA
Figure 244 Plot of log k for the rates of alkaline hydrolysis of substituted
ethyl benzoates in 85% ethanol at 30° against log 10 5 K HA for the dissociation
of substituted benzoic acids in water at 25°.
Table 24-2 Substituent constants
substituent
0"
substituent
a
meta
para
meta
para
o e
-0.708
-1.00
SH
+0.25
+0.15
NH 2
-0.161
-0.660
CI
+0.373
+0.227
OH
+0.121
-0.37
C0 2 H
+0.355
+0.406
OCH 3
+0.115
-0.268
COCH3
+0.376
+0.502
CH 3
-0.069
-0.170
CF 3
+0.43
+0.54
(CH 3 ) 3 Si
-0.121
-0.072
N0 2
+0.710
+0.778
C 6 H 5
+0.06
-0.01
N(CH 3 ) 3
+0.88
+0.82
H
0.000
0.000
S(CH 3 ) 2
+ 1.00
+0.90
SCH 3
+0.15
0.00
N 2 ®
+ 1.76
+ 1.91
F
+0.337
+0.062
sec 24.9 linear free-energy relations 663
proximity effects. Meta- and para-substituted series can be related this way
because the substituents are far enough away from the reaction sites so that
steric and proximity effects are diminished and only the electrical effect of the
substituent is important. A p-nitro group is always electron withdrawing and
a p-amino group always electron donating and we can assign to these and
other substituents a value that represents their electron-donating or electron-
withdrawing ability relative to hydrogen taken as zero. These substituent
constants, symbol <x, are obtained from the ionization constants of substituted
benzoic acids. If a substituent increases the acidity of benzoic acid, a is
positive; if it decreases the acidity of benzoic acid, a is negative. The larger
the effect of the substituent on the benzoic acid ionization, the larger is the
absolute value of a. Table 24-2 lists the substituent constants for a number of
common groups.
To predict the effect of a substituent on a given rate or equilibrium con-
stant, a further factor must be considered — the sensitivity of the reaction site
to electrical effects of the substituents. The slope of the line in Figure 24-4 is
+ 2.2. The positive sign means that the reaction sites in both ester hydrolysis
and acid ionization have the same kind of response to substituent electrical
effects. Thus, p-mtxo speeds up the hydrolysis of the ester and also increases
the degree of dissociation of the acid. For the ester hydrolysis, the electron-
withdrawing group helps to make the carbonyl carbon more positive and
hence better able to attract hydroxide ion (Section 13-8); in ionization, it
helps to stabilize the anion by electron attraction. Since the slope is greater
than unity (2.2) the ester hydrolysis is more sensitive to the effects of substi-
tuents than is the acid dissociation.
The sensitivity of a reaction to substituents is given by the reaction constant,
symbol p, and is obtained by measuring the slope of the line when log k or
log K is plotted against log K HA for benzoic acids. If, as for the benzoic acid
dissociation, the reaction is facilitated by electron-withdrawing groups, p is
positive. If the reaction is more sensitive than the benzoic acid dissociation
(slope > 1), then p is greater than unity; if it is less sensitive, p is less than
unity. A reaction with the opposite electronic requirements has a negative p.
Values of p are obtained by plots such as that in Figure 24-4, and a number
of these reaction constants are listed in Table 24-3.
The combination of the two independent variables p and a defines the
effect of the meta or para substituent on the rate constant — that is, the dif-
ference between log k and log k , where k refers to the unsubstituted
compound.
log k = pa + log k
This equation (or its analog for equilibrium constants) is known as the
Hammett equation. It describes in a quantitative way the effect of substi-
tuents on reaction rates (or equilibrium constants) oimeta ox para substituted
aromatic compounds.
chap 24 aromatic side-chain derivatives 664
Table 24-3 Reaction constants
equilibria
ff\ H 2 Q // \
((, V-CO,H . </ >-co 2 e + H® 1.00
(, V-CH 2 C0 2 H . H2 ° ' /, \-CH 2 C0 2 e + H®
^— * 95% C 2 H 5 OH /— \
<£- VCHO + HCN ■ J/J)-CH(OH)CN
/~V nu -J^L r\
0.489
1.492
OH ^= 6 Vo e + H® 2.113-
25 ° R'
reaction rates
/7^S-C0 2 C 2 H 5 + OH e CzH ^° H - /TA-C0 2 e+ C 2 H 5 OH 2.431
/TS-CH^A + C 2 H 5 OH — ^- J^V? 1 *"^!^ + HC1 ~ 5 '° 90 *
R" X==/ a _ R _ OC 2 H 5 ~~
R £>- COCH > + ** "^r R Jc> COCH2Br + HBr
(7S + NO/ «»§>£ r ^-N0 2 + H*
" Nitro and similar groups have somewhat exalted orj>«™ values in reactions such as this in which
direct resonance interaction is possible between the anionic reaction site and the para position.
* Amino and similar groups have somewhat exalted opara values in reactions such as this in
which direct resonance interaction is possible between the cationic reaction site (in the transition
state in this case) and the para position.
summary 665
summary
Aromatic side chains are joined by carbon-carbon bonds to the aromatic
ring. Such compounds have reactions that are very like those of their aliphatic
analogs, but their methods of preparation are usually different. Vigorous
oxidation of any of these compounds (including those with longer side
chains) produces benzoic acid, [l]-[8] -> [9], although the presence of hydroxyl
or amino substituents on the ring causes the ring to be degraded.
O
II
ArCH 3 ArCH 2 X ArCHX 2 ArCX 3 ArCH 2 OH ArCHO ArCCH 3 ArC=N ArC0 2 H
[1] [2] [3] [4] [5] [6] [7] [8] [9]
X = halogen
Side-chain halogenation occurs readily, [1] -» [2] + [3] + [4], and the
resulting halo compounds can be readily hydrolyzed to [5], [6], and [9].
Friedel-Crafts methylation of arenes gives [1] (RX gives ArR) but poly-
O
II
substitution also occurs; Friedel-Crafts acylatioh by CH 3 CC1 gives [7]
O O
II II
(RCC1 gives ArCR) and only monosubstitution occurs. Introduction of the
formyl group, — CHO, is only successful with activated rings. Aromatic
O
II
aldehydes undergo the benzoin condensation to give benzoins, ArCHOHCAr.
Multiple substitution of aryl rings on one carbon atom allows carbonium
ions, carbanions, and radicals to be formed.
Ar 3 C e Z = OH, Y = H®
Ar 3 C-Z+Y ► Ar 3 C e Z = H, Y = NHf
Ar 3 C- Z = CI, Y = Ag
Steric and electronic effects are important in stabilizing these three enti-
ties. All absorb light in the visible region of the spectrum. Radicals, in addi-
tion, can be detected and identified by epr spectroscopy.
The reactions of meta- and /?ora-substituted aromatic systems obey linear
free-energy relationships, one of which is the Hammett equation, log k =
pa + log k . This expresses a rate constant for the reaction of a meta- or
/?«ra-substituted aryl compound in terms of k (the rate constant for the
rate of the unsubstituted compound), p (the reaction constant, which is
independent of the substituent), and a (the substituent constant, which is
independent of the reaction). A similar relationship holds for equilibrium
constants.
chap 24 aromatic side-chain derivatives 666
exercises
24-1 Suggest a practical synthesis of each of the following compounds from a
readily available aromatic hydrocarbon :
/^-\ /^ /^ .C0 2 H
a. H 2 N-f )-C0 2 H
b. H0 2 C-f VC0 2 H
CO,H
24-2 Write a mechanism for the formation of benzyl chloride by photochemical
chlorination of toluene with molecular chlorine. What other products would
you anticipate being formed? At what position would you expect ethyl-
benzene to substitute under similar conditions ?
24-3 Outline a suitable synthesis of each of the following compounds, starting
with benzene :
a. C 6 H 5 CH 2 COC 6 H 5
b. C 6 H 5 CH 2 CONHCH 2 CH 2 -4 />~ N0 2
c. ClHk J^-CHO
24-4 Suggest a reason why zinc chloride is used in preference to aluminum chloride
as a catalyst for chloromethylation reactions.
24-5 Give the principal product(s) of chloromethylation of the following
compounds :
a. 1-methylnaphthalene c. />-methoxybenzaldehyde
b. 1-nitronaphthalene d. anisole (using acetaldehyde in
place of formaldehyde)
24-6 Suggest a possible mechanism for formylation of arenes by carbon monoxide
(Section 24 -4C).
24-7 Formulate the steps that are probably involved in the formylation of a phenol
by the action of HCN, HC1, and ZnCl 2 .
24-8 How would you synthesize the following compounds from the indicated
starting materials ?
«■ h 3 c y^/
OH
CHO
from toluene
exercises
667
b. CH 3 CH 2
/~\
CH 2 OH from benzene
CI
c. CH 3 CH 2 0— i \-CHO from benzene
24-9 Write resonance structures for O-NHaCeH^C®. Would meta amino groups
be as effective in stabilizing the ion ?
24-10 a. Suggest why the extent of ionic dissociation of triarylmethyl chlorides
in liquid sulfur dioxide decreases for compounds [1], [2], and [3] in the
order [1] > [2] > [3]. Use of models may be helpful here.
(C 6 H 5 ) 3 C-C1
[1]
CI
I
C(C 6 H 5 ) 2
C1-C(C 6 H 5 ) 2
b. Which alcohol would you expect to give the more stable carbonium ion
in sulfuric acid, 9-fluorenol [4] or 2,3,6,7-dibenzotropyl alcohol [5]?
Explain.
OH
c. When triphenylcarbinol is dissolved in 100% sulfuric acid, it gives a
freezing-point depression that corresponds to formation of 4 moles of
particles per mole of carbinol. Explain.
24-11 . Write the important resonance structures for the triphenylmethide ion and
for the carbanion formed by proton loss from 4-cyanophenyldiphenyl-
methane.
24-12 Which of the following pairs of compounds would you expect to be the more
reactive under the specified conditions ? Give your reasons and write equa-
tions for the reactions involved.
a. p-N0 2 C 6 H 4 CH 2 Br orp-CH 3 OC6H 4 CH 2 Br on hydrolysis in aqueous
acetone
b. (C 6 H 5 ) 3 CH or C 6 H 5 CH 3 in the presence of phenyllithium
c. (C 6 H 5 ) 3 C-C(C 6 H 5 ) 3 or (C 6 H 5 )2CH-CH(C 6 H 5 ) 2 on heating
d. (C 6 H 5 ) 2 N-N(C6H 5 ) 2 or (C 6 H 5 ) 2 CH-CH(C 6 H 5 ) 2 on heating
chap 24 aromatic side-chain derivatives 668
Figure 24-5 Electron paramagnetic resonance spectrum of cycloheptatrienyl
radical produced by X-irradiation of 1,3,5-cycloheptatriene.
24-13 Draw structures and name all the possible benzoins that could be formed
from a mixture of (a) />-tolualdehyde and o-ethoxybenzaldehyde, and (b)
8-methyl-l-naphthaldehyde and anisaldehyde. An unsymmetrical benzoin
such as 4-methoxybenzoin is rather readily equilibrated with its isomer,
4'-methoxybenzoin, under the influence of bases. Explain.
24-14 The epr spectrum shown in Figure 24-5 is of a first-derivative curve of the
absorption of a radical produced by X-irradiation of 1,3,5-cycloheptatriene
present as an impurity in crystals of naphthalene. Make a sketch of this
spectrum as it would look as an absorption spectrum and show the structure
of the radical to which it corresponds. Show how at least one isomeric
structure for the radical can be eliminated by the observed character of the
spectrum.
24-15 The ionization constants of m- and p-cyanobenzoic acids at 20° are 2.51 x
10 ~ 4 and 2.82 x 10 ~ 4 , respectively. Benzoic acid has K HA of 6.76 X 10~ 5 at
20°. Calculate a meta and a para for the cyano substituent.
24-16 The effects produced by substituents are explained in terms of inductive,
conjugative (resonance), and steric influences. Show how it is possible,
within this framework, to account for the following facts :
a. The a constant of the methoxy group (— OCH 3 ) in the meta position
is positive and in the para position negative.
©
b. The — N(CH 3 ) 3 group has a larger positive a constant in the meta
position than in the para position, but the reverse is true for the — N 2 e
group.
chap 25 heterocyclic compounds 671
Heterocyclic organic compounds have cyclic structures in which one or more
of the ring atoms are elements other than carbon. In this chapter we shall
confine our attention to a discussion of the chemistry of heterocyclic nitro-
gen, oxygen, and sulfur compounds, and of these we shall be concerned
primarily with the aromatic heterocycles rather than their saturated analogs.
The chemistry of saturated heterocycles, such as ethylene oxide and the other
compounds shown in Figure 25-1, has been dealt with in earlier chapters. In
general, the properties of such substances can be correlated with those of their
open-chain analogs, provided appropriate account is taken of the strain and
conformational effects that are associated with ring compounds.
The importance of heterocyclic compounds is apparent from the wealth
and variety of such compounds that occur naturally or are prepared on a
commercial scale by the dye and drug industries. Many of these compounds
fulfill important physiological functions in plants and animals. We have
already encountered some of the important naturally occurring heterocycles
in earlier chapters. Thus, the carbohydrates may be classified as oxygen
heterocycles, whereas the nucleic acids and some amino acids, peptides, and
proteins possess nitrogen-containing ring systems.
We shall begin with a discussion of four important unsaturated hetero-
cyclic compounds: pyrrole, furan, thiophene, and pyridine (Figure 25-2;
their systematic names are shown in parentheses). The prefixes az-, ox-, and
thi- refer, respectively, to nitrogen, oxygen, and sulfur heterocycles. Suffixes
indicate the size of the ring, for example, -ole for five-membered unsaturated
rings, and -ine for six-membered unsaturated rings.
These four compounds are all liquid at room temperature; their boiling
points range from 32° for furan to 130° for pyrrole. The fairly high boiling
point of the latter is presumably the result of intermolecular hydrogen
bonding.
The conjugated bonding in pyridine bears an obvious resemblance to that
in benzene and it is no surprise to find that pyridine is an " aromatic" com-
pound; for instance, it reacts with electrophiles by substitution rather than by
addition. It is less obvious that pyrrole, furan, and thiophene should have
aromatic character and yet we shall see that these compounds, too, resemble
benzene in many ways.
Figure 25- 1 Some important saturated heterocycles.
/
/>
H 2 C-CH 2
V
Q
o
O h
ethylene
oxide
tetrahydrofuran
1,4-dioxane
lactones
lactams
chap 25 heterocyclic compounds 672
HC-CH g—z HC-CH
// w
HC .. CH
H O
H H
pyrrole furan
(azole) (oxole)
HC-CH r -» HC^ ^CH ^
HC^CH V HC^CH . N
thiophene pyridine
(thiole) (azine)
Figure 25-2 The structures of four important unsaturated heterocycles.
25' 1 aromatic character of pyrrole, Jur an, and
thiophene
The five-membered heterocyclic compounds, pyrrole, furan, and thiophene,
possess some degree of aromatic character because of the derealization of
four carbon % electrons and the two unshared electrons of the heteroatom.
This combination constitutes a sextet of delocalized electrons. We learned
earlier (Section 6-7) that cyclic systems with this electronic arrangement tend
to have special stabilization — for example, benzene, cyclopentadienide anion,
and cycloheptatrienyl (tropylium) cation.
The structure of each heterocycle can be described as a hybrid of several
electron-pairing schemes, as shown here for pyrrole. We shall have more to
say later about the degree of contribution of the dipolar resonance forms,
[lb] to [le].
H
[la]
H e
[lb]
[lc]
or
86,^^8 6
8e4 .^8e
N
j>8a>
H ffl
[Id]
H®
[le]
[1]
In terms of atomic orbitals, the structure of each of these heterocycles may
be regarded as a planar pentagonal framework of C— H, C— C, and C— Y a
bonds (Y being the heteroatom) made up of trigonally bonded (sp 2 ) atoms,
each with one p orbital perpendicular to the plane of the ring. The % system
formed by overlap of the p orbitals perpendicular to the plane contains four
sec 2S.2 chemical properties of pyrrole, furan, thiophene, and pyridine 673
C— C a boncH
,' > " ? ~^^ /
,,'''n -*^ >*"/ H^^-/'"' — H a bond-?
r f~-^ ^\- y L^-r^ /
,-*"* ~~^^^'- > <^/ ^ /
H-
-<T. /- ^0^»
/: .^i ; fe ,^V W'ff ^x
v'V- "_* \ V, ■■■■-■;
<. 1 ■•■ \ >-'•
N I \ -""
1 \ /
s ■■■■. \ /
1 V
\ -■:" -'■■' ; : x' V C— N a bond
m ••: ,y \_ ff bonding
#"
H
Figure 25-3 Atomic orbital description of pyrrole.
electrons from the carbons and two from the heteroatom. The overall
formulation is illustrated in Figure 25-3 for pyrrole.
The stabilization energies of pyrrole, furan, and thiophene obtained from
experimental and calculated heats of combustion are only about half of the
stabilization energy of benzene. However, the heterocycles differ from benzene
in that each has only one resonance structure with no formal bonds or charge
separation. Furthermore, on the basis of relative electronegativities of sulfur,
nitrogen, and oxygen, we may anticipate that the structures analogous to
[lb] to [le] should be important in the order thiophene > pyrrole > furan.
As a result, it is reasonable to expect furan to be the least aromatic of the
three heterocycles, and indeed it is.
25-2 chemical properties of pyrrole, furan, thiophene,
and pyridine
In discussing the reactivity of these heterocycles, we shall be interested pri-
marily in their degree of aromatic character, as typified by their ability to
exhibit electrophilic and nucleophilic substitution reactions rather than under-
go addition reactions. First, however, we shall consider their acidic and basic
properties.
A. ACIDIC AND BASIC PROPERTIES
Pyrrole, furan, thiophene, and pyridine are potential bases because each can
accept a proton at the heteroatom. Thiophene and furan, however, are too
weak to form salts with aqueous acid. Pyrrole and pyridine are somewhat
stronger bases, as might be expected from the lower electronegativity of
nitrogen. Pyrrole, however, polymerizes in acid solution (as does furan).
chap 25 heterocyclic compounds 674
Pyridine (K B = 1.1 x 1CT 9 ) is thus the only one of these heterocycles which
forms stable salts with aqueous acid.
HBr
^ H2 ° : "X o
H®Br e
pyridine pyridinium bromide
Turning to the acidic properties of these four compounds, a glance at their
structures tells us that pyrrole is the only one that is likely to be acidic because
it is the only one in which there is a hydrogen attached to the heteroatom.
Pyrrole is a rather weak acid (X HA = 10~ 15 ) and reacts completely only with
strong bases such as hydroxide ion or Grignard reagents.
0+H 2
pyrrylpotassium
+ ch *
MgBr
pyrrylmagnesium bromide
Although pyrrole is only weakly acidic it is a stronger acid than aliphatic
amines by a factor of about 10 18 (see Section 16-1D) and stronger than
aromatic amines by a factor of about 10 12 (see Table 22T, footnote). This
reflects the stability of the 7i-electron system of the resultant anion [2] relative
to that of pyrrole itself [1] where charge separation is associated with all but
one of the resonance structures.
o — o — o — O ,o — „
N N N N N
e
[2a] [2b] [2c] [2d] [2e]
The resonance structures [2a]-[2e] are useful for indicating charge dispersal
in the anion but do not reveal the special stabilization that is associated with
derealization of six n electrons.
B. ELECTROPHILIC SUBSTITUTION REACTIONS
Electrophilic substitution of pyrrole is rapid at the 2 position, although if this
site (and the 5 position) is blocked, the 3 position is attacked readily. As with
electrophilic substitution in benzene (Figure 20-8) a convenient model for the
transition state is the intermediate cation formed by addition of an electro-
phile X® to the pyrrole ring.
The stability that the heteroatom confers on the intermediate and, by
sec 25.2 chemical properties of pyrrole, furan, thiophene, and pyridine 675
analogy, on the transition state for substitution is illustrated in [3a]-[3c] for
the case of 2 substitution.
H
H X
[3a]
H X
[3b]
"H X
[3c]
The positive charge is located on nitrogen in [3c] and this is the most
important contributor to the resonance hybrid, even though nitrogen is more
electronegative than carbon. It is important to recognize the reason for this,
which is simply that there is more bonding in [3c] than in [3a] or [3b] — two n
bonds instead of one.
The analogous intermediates [4] or [5] that result from electrophilic attack
on benzene or pyridine do not have structures in which there are different
numbers of bonds.
+ z a
+ jy-
z x H
Z H
z x H
e ^S .
- A e -
~6
k)
u
«
[4a]
[4b]
[4c]
Z H
z x H
Z H
e fil ■
^Av
^0
u
u
[5a]
[5b]
[5c]
Although the nitrogen atoms in [3c] and [5c] are each cationic, that in [3c]
has an octet and that in [5c] only a sextet of electrons. Because nitrogen is more
electronegative than carbon, [5c] will make only a small contribution to the
resonance hybrid and, for this reason, electrophilic substitution in pyridine
occurs at the 3 position (although very slowly).
The principal electrophilic substitution reactions of pyrrole are summarized
in Figure 25-4 and a study of these reactions provides an opportunity to
review the reactions discussed earlier in our study of benzene. Note that
2 substitution predominates; nitration and sulfonation of pyrrole are pos-
sible, but only if strongly acidic conditions which would lead to polymerization
are avoided ; and pyrrole is sufficiently reactive for halogenation and Friedel-
Crafts acylation to proceed without a catalyst.
Furan resembles pyrrole in its behavior toward electrophilic reagents, and
its principal reactions of this type are summarized in Figure 25-5. Direct
chlorination and bromination of furan are hard to control and can lead to
violent reaction, possibly caused by the halogen acid that is formed.
Related reactions of thiophene are summarized in Figure 25-6. Because
thiophene is less subject to acid-induced polymerization than either pyrrole or
furan, it can be sulfonated or nitrated under strongly acidic conditions. In
fact, sulfonation and extraction are used as a means of freeing commercial
chap 25 heterocyclic compounds 676
CH 3 C0 2 N0 2
(CH 3 CO) 2 0, 5°
S0 3 , pyridine
90°
2 N-/ \-N 2 CI
1. HCN, HC1
2. H 2
(CH 3 CO) 2 Q
250°
Br 2 , C 2 H 5 OH
"N N0 2
^ SO3H
H
N N=NC 6 H 4 N0 2
^W CHO
H
X N C
H
O
Br Br
Br N Br
H
nitration
sulfonation
diazo coupling
formylation
Friedel-Crafts
acylation
bromination
Figure 25-4 Electrophilic substitution reactions of pyrrole.
Figure 25-5 Electrophilic substitution reactions of furan.
CH 3 C0 2 NO
3 «~u 2 r«_> 2
(CH 3 CO) 2 0, chilled
- n
-o
■NO,
so 3
o
N o^
pyridine
Cl-f VN 2 e Cl e
(1
N Q ,>~SO,H
nitration
sulfonation
-» // \ diazo coupling
< n X~-N = NC 6 H 4 C1
(CH 3 CO) 2
BF 3
1. HCN, HC1
2. H 2
V >~COCH 3
Friedel-Crafts
acylation
formylation
sec 25.2 chemical properties of pyrrole, furan, thiophene, and pyridine 677
H 2 SO»
^ s /~~S0 3 H
benzene Br '^ o/^Br
r\
sulfonation
nitration
bromination
iodination
Friedel-Crafts
CC 6 H 4 C0 2 H acylation
<. C A-CH,C1
chloromethylation
Figure 25-6 Electrophilic substitution reactions of thiophene.
Figure 25-7 Electrophilic substitution reactions of pyridine. In most of these
reactions the yields are low.
H 2 S0 4
Br 2
2O0°-3O0°
Br,
300°-500°
KN0 3 , H 2 S0 4
370°
NO,
H
S0 3 , H 2 S0 4 , HgS0 4
220°, 24 hr
SO,H
Br Br^^^Br
a + xj
(probably a
thermally
induced
"N^^Br Br" ^f>r"Br radical
substitution)
chap 25 heterocyclic compounds 678
benzene from thiophene, with which it is often contaminated. Thiophene is
sulfonated much more readily than benzene and the resulting product, being
acidic, can be extracted by aqueous base.
Electrophilic substitution of pyridine is hard to achieve, partly because of
deactivation of the ring by the heteroatom and partly because under acidic
conditions, as in sulfonation and nitration, the ring is further deactivated by
formation of the pyridinium ion. Three pertinent substitution reactions are
listed in Figure 25-7; their most striking feature is the vigorous conditions
necessary for successful reaction. Note that the Friedel-Crafts reaction does
not take place with pyridine.
C. NUCLEOPHILIC SUBSTITUTION REACTIONS
The most important substitution reactions of the pyridine ring are effected by
nucleophilic reagents. Thus, pyridine can be animated on heating with soda-
mide, hydroxylated with potassium hydroxide, and alkylated and arylated
with alkyl- and aryllithiums (Figure 25-8). Since related reactions with
benzene either do not occur or are relatively difficult, we can conclude that
the ring nitrogen in pyridine has a pronounced activating effect for nucleo-
philic attack at the ring analogous to the activation produced by the nitro
group in nitrobenzenes. The reason for this activation is that addition to the
Figure 25-8 Nucleophilic
substitution reactions of pyridine.
1. NaNHj, 100°
► + H 2 (Tschitchibabin reaction)
^N^-NH 2
2. H 2
/
2-aminopyridine
//
KOH
, n >f\
320° [O]
H
\\
C 6 H s Li
110°, toluene
2-pyridinol 2-pyridone
if] + LiH
k N^-c 6 H 5
2-phenylpyridine
v
«-C 4 H 9 Li
f] +LiH
^N^c 4 H 9
100°
2-butylpyridine
sec 25.3 polycyclic and polyhetero systems 679
2 or 4 but not the 3 position permits the charge to reside at least partially on
nitrogen rather than on carbon (see Equations 25-1 and 25-2).
:NH,
favorable
*N-
1ST
, unfavorable
H
NH,
H
H
N NH,
H
: N /-e
V N
H
NH,
H
NH,
(25-1)
"N
(25-2)
In the case of amination, the reaction is completed by loss of hydride ion and
subsequent formation of hydrogen (Equation 25-3).
e
(Th
' N NH,
+ :H
*N-
NH,
(25-3)
+ H,
^N
NH
H a>
N NH,
25-3 polycyclic and polyhetero systems
A number of heterocycles that have fused benzene rings attached are shown
in Figure 25-9. As might be expected, electrophilic substitution occurs in the
Figure 25-9 Some important polycyclic and polyhetero ring systems.
N'
H
indole
(benzopyrrole)
benzofuran
quinoline
%>^^N:
isoquinoline
imidazole
thiazole pyrimidine
H
purine
pteridine
chap 25 heterocyclic compounds 680
hetero ring in the case of indole and benzofuran but in the benzenoid ring
in the case of quinoline and isoquinoline.
There are several five- and six-membered heterocyclic ring systems con-
taining two or more heteroatoms within the ring that are particularly impor-
tant in that they occur in many natural products and in certain synthetic
drugs and synthetic dyes. The parent compounds of the most commonly
encountered ring systems are shown in Figure 25-9.
Each five- and six-membered ring compound has a delocalized sextet of n
electrons; the bicyclic compounds, purine and pteridine, resemble naph-
thalene in having 10 delocalized n electrons.
heterocyclic natural products
Some of the heterocyclic ring systems mentioned in this chapter are of special
interest and importance because certain of their derivatives are synthesized
naturally as part of the life cycles of plants and animals. The structures of
these naturally occurring compounds are often extremely complex and eluci-
dation of their structures has been and continues to be a major challenge to
organic chemists and biochemists alike. The approach to solving the struc-
ture of a complex natural product is discussed in some detail in Chapter 29 ;
at this point we shall briefly describe only a few natural products of known
structure which can be classified as heterocyclic compounds and which are of
some biological or physiological importance.
25-4 natural products related to pyrrole
An interesting compound having a fully conjugated cyclic structure of four
pyrrole rings linked together through their 2 and 5 positions by four methine
(=CH— ) bridges is known as porphyrin [6].
Although porphyrin itself does not exist in nature, the porphyrin or related
ring system is found in several very important natural products, notably
hemoglobin, chlorophyll, and vitamin B 12 .
Hemoglobin is present in the red corpuscles of blood and functions to carry
oxygen from the lungs to the body tissue ; it consists of a protein called globin
bound to an iron-containing prosthetic group called heme. Acid hydrolysis
of hemoglobin liberates the prosthetic group as a complex iron(III) salt called
sec 25.4 natural products related to pyrrole 681
hemin [7]. The structure of hemin was established by 1929 after years of work,
notably by W. Kiister, R. Willstatter, and H. Fischer. A complete synthesis of
hemin was achieved by Fischer in 1929, and his contributions were rewarded
with a Nobel Prize (1930). The structure of hemin [6] shows that the iron
(as Fe m ) is complexed to all four of the pyrrole nitrogens.
The poisonous action of carbon monoxide is due to its reaction with
hemoglobin to form carboxyhemoglobin. Carbon monoxide makes up about
4% of undiluted cigarette smoke and can produce up to 15% carboxyhemo-
globin in the blood.
CH=CH 2 CH 3
H,C— < 1 "I ^CH=CH,
CH,
CH 2
CH 2
CO,H
CH 2
CH 2
I
CO,H
Cl fe
hemin
[7]
Certain pigments in the bile of mammals, the so-called bile pigments, are
pyrrole derivatives. They contain four pyrrole rings linked in a chain through
a methine bridge between the 2 position of one ring and the 5 position of an-
other. As one might suspect, bile pigments are degradation products of he-
moglobin.
basic structure of a bile pigment
Chlorophyll was briefly mentioned in connection with photosynthesis, and
its structure is shown in Figure 15T. It is a porphyrin derivative in which the
four pyrrole nitrogens are complexed with magnesium (as Mg u ). The struc-
ture was established largely through the work of R. Willstatter, H. Fischer,
and J. B. Conant. A total synthesis was completed by R. B. Woodward and
co-workers in 1960.
The structure of vitamin B 12 [8], known also as the antipernicious anemia
factor and as cyanocobalamin, was finally established in 1955 as the result
of both X-ray diffraction and chemical studies. The vitamin has a reduced
porphyrin ring in which one methine bridge is absent and the nitrogen
heteroatoms are complexed with a cyanocobalt group. It also has a ribo-
furanoside ring and a benzimidazole ring. Intensive efforts have been under-
way for some time to achieve a synthesis of vitamin B 12 in the laboratory.
chap 25 heterocyclic compounds 682
o
II
H 2 NCCH 2
HjC'N
O
|| J
CH 2 CH 2 CONH 2
| CH 3
| I^^C cH 2 CONH 2
/ ^y\^\-- CH 2 CH,CONH 2
" CN > / "
^N | NJ
Co® \
^N ! N-A CH 3
HjNCchAJJ JL a
IN-CCH.CH^/T ^H 2 CH 2 CONH 2
1 ° / 3
CH 2
CHCH 3
o^ x o HO
• , "\^CH 3
H 2 C ^o^
OH
vitamin B 12
[8]
25- 5 natural products related to indole
The indole ring system is common to many naturally occurring compounds, for
example, the essential amino acid tryptophan which is a constituent of almost
all proteins.
CH 2 CHC0 2 H
I
\ N " 2
tryptophan
There are also many compounds related to indole that occur in plants. They
are part of a class of natural products known as alkaloids — the term being
used to designate nitrogen-containing compounds of vegetable origin com-
monly having heterocyclic ring systems and one or more basic nitrogen atoms.
Their physiological activity is often pronounced and their structures complex.
Alkaloids related to indole are called indole alkaloids, and some of these are
described here.
An indole derivative commonly known as serotonin, which is actually
5-hydroxytryptamine, is of interest because of its apparent connection with
mental processes. It occurs widely in plant and animal life, but its presence in
the brain and the schizophrenic state that ensues when its normal concen-
sec 25. S natural products related to indole 683
tration is disturbed indicates that it may have an important function in
establishing a stable pattern of mental activity.
HO
serotonin
The ergot alkaloids are produced by a fungus known as ergot, which
grows as a parasite on cereals, particularly rye. They are amides of the indole
derivative known as lysergic acid and their levorotatory forms are physiolog-
ically active in minute amounts. Ergot poisoning, or St. Anthony's fire, has
been known for centuries and still occurs occasionally. Several deaths follow-
ing fits of madness were reported in a village in France a few years ago and
were traced to bread baked with ergot-containing rye.
lysergic acid
The diethylamide of lysergic acid, while not itself a naturally occurring
compound, has achieved notoriety as a drug (LSD) that can produce a
temporary schizophrenic state, although permanent damage to the brain can
also result. Current theory suggests that the diethylamide of lysergic acid
upsets the balance of serotonin in the brain.
Another indole alkaloid called reserpine has important clinical use in the
treatment of high blood pressure (hypertension) and also as a tranquilizer for
the emotionally disturbed. The tranquilizing action is thought to be the
result of a reduction in the concentration of brain serotonin.
Two other alkaloids, strychnine and brucine, have been discussed (Section
14-6). The problem of elucidating their structures was solved only after more
than a century of research, the major contributions in recent years being made
by R. Robinson and R. B. Woodward.
chap 25 heterocyclic compounds 684
25-6 natural products related to pyridine,
quinoline, and isoquinoline
Among the natural products related to pyridine, we have already mentioned
the coenzyme nicotinamide-adenine dinucleotide (NAD®, Figure 18-3). Other
important pyridine derivatives include nicotine, nicotinic acid (niacin, anti-
pellagra factor), and pyridoxine (vitamin B 6 ). Coniine is a toxic alkaloid
which occurs in the shrub poison hemlock; it has a reduced pyridine (piperi-
dine) ring.
, — .
CH 2 OH
(l N
^*T CH 3
^yC0 2 H
ho^^ch 2 oh
H 3 C^N^
^N^CH 2 CH 2 CH 3
H 2 2 3
nicotine
(from tobacco)
nicotinic acid
(niacin)
pyridoxine
coniine
(poisonous component
of hemlock)
A group of related and rather poisonous compounds known as the tropane
alkaloids are derivatives of reduced pyrroles and reduced pyridines. Two of
the more important tropanes are atropine and cocaine.
CH,
II
CH,
N N CO z CH
atropine
(from Atropa belladonna plant,
" deadly nightshade "
( — )-cocaine
(from coca plant)
The cinchona alkaloids are quinoline derivatives which occur in cinchona
bark and have medicinal value as antimalarials. The most notable example is
quinine, the structure of which is shown in Section 14-6.
Many alkaloids have isoquinoline and reduced isoquinoline ring systems.
The opium alkaloids are prime examples, and include the compounds nar-
cotine, papaverine, morphine, codeine, and several others, all of which occur
in the seed of the opium poppy.
CH,0
JO-
H,C
O
N-CH,
CH
-O
I
OCH,
6; c=0
S^OCH 3
N-CH,
HO
OCH 3
papaverine
OCH,
narcotine
morphine, R = H
codeine, R = CH,
sec 25.7 natural products related to pyrimidine 68S
25-7 natural products related to pyrimidine
The pyrimidine ring system occurs in thymine, cytosine, and uracil, which are
component structures of the nucleic acids and certain coenzymes. A detailed
account of the structures of nucleic acids is given in Section 17-7. Thiamine
[9] is both a pyrimidine and a 1,3-thiazole derivative. The pyrophosphate of
thiamine is the coenzyme of carboxylase — the enzyme that decarboxylates
a-ketoacids ; thiamine is also known as vitamin B 1( and a deficiency of it in the
diet is responsible for the disease known as beri-beri.
NH 2 CH,
CH 3 -( VCH 2 -N
H
OH OH
thiamine, R = H | |
thiamine pyrophosphate, R = — P — O — P — OH
II II
O O
[9]
There are, in addition to the above-mentioned naturally occurring pyrim-
idine derivatives, many pyrimidines of synthetic origin which are widely
used as therapeutic drugs. Of these, we have already mentioned the sulfona-
mide drug, sulfadiazine (see Section 19-2D). Another large class of pyrimidine
medicinals is based on 2,4,6-trihydroxypyrimidine. Most of these substances
are 5-alkyl or aryl derivatives of 2,4,6-trihydroxypyrimidine — which is better
known as barbituric acid and can exist in several tautomeric forms.
OH
HN^H,
A N A 0H
i\ k HN^
**k N A 0H O^N"\>
(predominant
form)
barbituric acid
For simplicity we shall represent barbituric acid as the triketo tautomer. Two
of the more important barbituric acids are known as veronal (5,5-diethyl-
barbituric acid) and phenobarbital (5-ethyl-5-phenyl barbituric acid).
o
O
3 H
i r c2Hs
H
veronal
phenobarbital
chap 25 heterocyclic compounds 686
Barbituric acids are readily synthesized by the reaction of urea with substi-
tuted malonic esters.
O
R
II HNT XH
NH 2 -C-NH 2 + C 2 H 5 2 CCHC0 2 C 2 H 5 ► | | + 2C 2 H 5 OH
I X. X
r Q S ^ Nq
25-8 natural products related to purine and pteridine
Heterocyclic nitrogen bases (other than pyrimidines) present in nucleic acids
are the purine derivatives adenine and guanine (Section 17-6). Adenine is also
a component of the trinucleotide adenosine triphosphate (ATP), whose
structure is shown in Section 15-5. Nicotinamide-adenine dinucleotide
(NAD®, Figure 18-3) is also a derivative of adenine.
A number of alkaloids are purine derivatives. Examples include caffeine,
which occurs in the tea plant and coffee bean, and theobromine, which occurs
in the cocoa bean. The physiological stimulation derived from beverages such
as tea, coffee, and many soft drinks is due to the presence of caffeine.
O CH 3
I
CH 3
theobromine
25-9 natural products related to pjran
The six-membered oxygen heterocycles, a-pyran and y-pyran, do not have
aromatic structures and are rather unstable. Of more interest are the a- and
y-pyrones, which differ from the corresponding pyrans in having a carbonyl
group at the a- and y-ring positions, respectively.
a-pyran -y-pyran a-pyrone
The pyrones may be regarded as pseudoaromatic compounds — they are
expected to have considerable electron derealization through n overlap of
orbitals of the double bond, the ring oxygen, and the carbonyl group. Thus,
sec 25.9 natural products related to pyran 687
■y-pyrone should have at least some stabilization associated with contribu-
tions of the electron-pairing schemes [10a] to [10e].
[10e]
It is significant in this connection that y-pyrone behaves quite differently than
might be expected from consideration of structure [10a] alone. For example,
it does not readily undergo those additions characteristic of a,/?-unsaturated
ketones and does not form carbonyl derivatives.
The benzo derivatives of the pyrones are known as coumarin for benzo-a-
pyrone and chromone for benzo- y-pyrone.
o^o
coumarin
Coumarins occur in grasses, citrus peel, and the leaves of certain vegetables.
Coumarin itself occurs in clover and is used as a perfume; it can be prepared
by condensation of salicylaldehyde with acetic anhydride.
,T ^V CH,CO,Na r^>S^C^
I 1
CH 3 C0 2 Na (f Y C*
(CH 3 CO) 2 — > [ 1 ^
CHO ^^ CH
Chromones or benzo- y-pyrones are widely distributed in plant life, mostly
as pigments in plant leaves and flowers. Particularly widespread are the
flavones (2-phenylchromones), quercetin being the flavone most commonly
found.
HO
OH O
quercetin
The beautiful and varied colors of many flowers, fruits, and berries are due
to the pigments known as anthocyanins. Their structures are closely related
to the flavones, although they occur as glycosides, from which they are
obtained as salts on hydrolysis with hydrochloric acid. The salts are called
anthocyanidins. Two examples follow:
chap 25 heterocyclic compounds 688
OH
HO.
OH
e
CI
OH
pelargonidin chloride
CI
delphinidin chloride
(delphinium)
Glycoside formation is through the 3-hydroxy group of the anthocyanidin.
25-10 polyhetero natural products
Of the many important polyhetero natural products with two or more
different heteroatoms in one ring we have already mentioned penicillin
(Section 17-2) and thiamine (Section 25-7). Another interesting example is
luciferin, which is a benzothiazole derivative.
HO
N. N.
-"^
XJ
H
C0 2 H luciferin
Enzymic oxidation of luciferin is responsible for the characteristic lumi-
nescence of the firefly. The luminescence arises because the oxidation product
is formed in an excited state which liberates its excess energy as light rather
than as heat. The relation between ground states and excited states of mole-
cules will be pursued in the next chapter.
summary
In heterocyclic compounds at least one of the ring members is an atom other
than carbon. Some of the important unsaturated heterocyclic ring systems
containing nitrogen, oxygen, and sulfur are pyrrole [1], furan [2], thiophene
[3], and pyridine [4].
Q Q Q O
H
[1]
-o
[2]
S'
[3]
[4]
All have aromatic character, [4] because of its benzenoid bonding, and [1],
[2], and [3] because their heteroatoms have unshared pairs of electrons that
can interact with the n electrons in the ring, giving a stable aromatic sextet.
Strong acids cause polymerization of [1] and [2] and form salts with [4].
Strong bases form salts only with [1]. Electrophilic substitution occurs rapidly
with [1], [2], and [3] and substitution occurs preferentially at the 2 position.
exercises 689
The activation of the ring results because the unshared pair of electrons on the
heteroatom is able to stabilize the cationic intermediate [5].
o
[5]
All of the substitution reactions of activated benzene compounds, such as
aniline and phenol, also occur with pyrrole and furan. Thiophene is not quite
so reactive. Pyridine [4], on the other hand, is deactivated toward electro-
philic substitution because in the analogous intermediate [6] the electro-
negative nitrogen atom has a share in only six valence electrons.
z
[6]
Substitution under vigorous conditions occurs at the 3 position. Pyridine,
however, is subject to nucleophilic attack at the 2 position, and if hydride can
be removed, either directly or by oxidation, substitution is achieved.
z - H9 ,
N/ ^N^H ^N
e
Some important polycyclic and polyhetero compounds are indole, benzo-
furan, quinoline, isoquinoline, imidazole, thiazole, pyrimidine, purine, and
pteridine.
A number of important natural products contain heterocyclic rings. Hemo-
globin, bile pigments, chlorophyll, and vitamin B 12 all contain pyrrole rings.
Virtually all alkaloids contain heterocyclic rings. The indole ring is present
in serotonin, lysergic acid, and reserpine, all of which affect mental processes.
Pyridine, quinoline, and isoquinoline are present in the structures of the
tropane, cinchona, and opium alkaloids. The pyrimidine ring is present in
barbituric acid and its derivatives. The purine ring system (fused pyrimidine
and imidazole rings) occurs in nucleic acids and in caffeine.
The six-membered unsaturated oxygen heterocycles (pyrans) are not aro-
matic. Their keto derivatives (pyrones) are present in a number of natural
products, many of which are highly colored.
Compounds with two different heteroatoms in the same ring are also known
and include penicillin, thiamine, and luciferin.
exercises
25-1 Suggest a feasible synthesis of each of the following compounds from the
indicated starting material:
chap 25 heterocyclic compounds 690
a. II \ from thiophene
^ from thiophene
from benzothiophene
from furan
"CT "CH 2 CH 3
25-2 m-Dinitrobenzene in the presence of potassium hydroxide and oxygen yields
potassium dinitrophenoxide. Write a reasonable mechanism for this reaction
with emphasis on determining the most likely arrangement of groups in the
product.
25-3 Predict the product(s) of the following reactions:
0.
LI
MgBr
KOH CH 3 I
d.
quinoline -
knh 2
e.
isoquinoline
KNH2
>
254 Would you expect porphyrin to possess aromatic character and to what
degree would you expect the four N-Fe bonds to be equivalent ? Explain.
25-5 The dextrorotatory ergot alkaloids are amides of isofysergic acid. Hydrolysis
of these amides with aqueous alkali gives lysergic acid. What is the most
likely structure of isolysergic acid ? Why does rearrangement occur on basic
hydrolysis ?
25-6 Uric acid, a purine derivative found mainly in the excrement of snakes and
birds, has the molecular formula C5H4N4O3. On nitric acid oxidation it
breaks down to urea and a hydrated compound called alloxan of formula
C4.H 2 N204"H 2 0. Alloxan is readily obtained by oxidation of barbituric
acid. What is the probable structure of alloxan and uric acid? Why is
alloxan hydrated ?
exercises 691
25-7 2,6-Dimethyl-y-pyrone is converted by treatment with dimethyl sulfate and
then with perchloric acid to [C 8 Hi 1 2 ]®C104 e . Simple recrystallization of
this salt from ethanol converts it to [CgUnOz^ClO^. What are the
structures of these salts, and why does the reaction with ethanol occur so
readily ?
25-8 Show the probable mechanistic steps involved in the preparation of cou-
marin by the condensation of acetic anhydride with salicylaldehyde in the
presence of sodium acetate as catalyst (Section 25-9).
Si "IB
Btt| ;
8i§issiiii§ smS '-WW!
HHrhwR
f 11|SJ#gi§ «i^ till
ifl^ffe* ...»
^fill it i
'& ; -tB
i #*S^t tt!i# «SfSP pSm PiJbJ
I te^ft |p|i IPSNI Itipl |f%PI ■
MM #tfe*S«li
re 1$
Ml
.0f<mSSSP^
chap 26 photochemistry 695
Photochemistry deals with the chemical changes that are brought about by
the action of visible or ultraviolet light. In Chapter 7 we discussed organic
spectroscopy — how radiation from the various regions of the electromagnetic
spectrum interacts with organic molecules. In that chapter and in subsequent
references to light absorption we have dealt with it primarily as an analytical
tool. We turn now to the chemical changes that sometimes result from the
absorption of radiation. We shall see that the chemistry of electronically
excited states is often quite different from that of ground states and that we
can sometimes change the course of a reaction completely by activating the
reactants by light rather than by heat.
The regions of the electromagnetic spectum that we described in Chapter 7
and the changes they bring about in organic molecules are listed in Table
26-1.
Absorption of infrared or microwave radiation produces vibrationally or
rotationally excited molecules whose chemistry is almost unchanged. After all,
in any sample of compound at room temperature, there will be a distribution
of molecules among the various vibrational and rotational states. As the
temperature is increased, the higher states become more and more populated.
Although molecules do have more energy at higher temperatures and chemical
reactions do occur at faster rates, it should be clear that we will not expect to
encounter much new or unusual chemistry as a result of absorption of radia-
tion quanta of such low energy as to only duplicate the effects of increasing
temperature.
As we proceed to higher-energy radiation we reach the visible and then the
ultraviolet region of the spectrum. Here we find activation of a sort that can-
not be duplicated by heat. Absorption of the higher-energy light quanta
produces electronically excited states, and even the lowest of these are
normally so far above the electronic ground states in energy that they are
essentially completely unpopulated, even at temperatures of 100° or more.
Although the lifetimes of excited states are normally short they are often
quite long enough for important chemical reactions to ensue.
The energy of quanta of visible light — light of wavelength 7500 to 4000 A —
varies between 38 and 71 kcal/mole. These are energies of the same order of
magnitude as bond energies (Section 2-4 A). Although red light (A near 7500
A) is able to produce little in the way of chemical activation, the greater
Table 26-1 Effects of various kinds of radiation
type of radiation effect on absorbing molecule
incre
ene
asing
rgy
X-rays and y-rays
ultraviolet and
visible light
infrared radiation
microwaves and
radio waves
bond rupture, decomposition"
electronic excitation
vibrational excitation
rotational excitation
' The results of X-ray absorption, not X-ray diffraction.
chap 26 photochemistry 696
energy of blue light {k near 4000 A) is often able to induce chemical change.
Ultraviolet light is, of course, still more effective. As we pass to still higher
energy quanta, such as X rays, we find more and more molecular disintegra-
tion occurring as bonding electrons are not merely excited but are completely
removed from the influence of the molecule's nuclei. We shall, therefore,
concentrate on the effects of visible and ultraviolet light on organic mole-
cules in the remainder of the chapter. Before beginning our discussion of the
chemical reactions of excited states, however, we will review the principles of
spectroscopy since activation can only occur if the light is actually absorbed.
We will also examine more closely the ordinary fate of excited states ; that is,
when their deactivation does not produce chemical change.
26-1 light absorption, fluorescence, and
phosphorescence
When a quantum of visible or ultraviolet light is absorbed by a molecule, the
time required to produce the new electronic arrangement is extremely short
(~ 10~ 15 sec) and consequently the electronically excited state will be formed
with the atoms essentially in their original positions (Franck-Condon prin-
ciple). (The absorption of rf radiation in nmr spectroscopy is quite different.
The time required to absorb such low-energy quanta is actually much longer
than the vibrational times and is even longer than the reaction times of some
chemical processes — see Section 7-6D.)
What is the fate of the electronically excited molecule ? We have seen that
in the first instant it is produced, it is just like the ground-state molecule as far
as positions and kinetic energies of the atoms go, but has a very different
electronic configuration. What happens at this point depends on several
factors, some of which can be best illustrated by energy diagrams. We shall
talk in terms of diatomic molecules, but the argument is easily extended to
more complicated systems.
Consider the diagram of Figure 26-1, which shows schematic potential
energy curves for a molecule A — B in the ground state (A — B) and in an
excited electronic state (A— B*). Each curve represents the energy of the
molecule A— B as a function of the distance r between the two atoms. At
very large values of r there is no interaction ; at very small values of r there is
enormous repulsion and the energy of these configurations is very high; and
at intermediate values there are energy minima which correspond to bonding
between A and B. The vibrational levels of the bonds are represented by
horizontal lines in the figure.
The two curves in Figure 26-1 do not have identical shapes. The weaker
bonding in the excited state tends to make the average distance r e between
the nuclei at the bottom of the "potential well" greater in the excited state
than in the ground state.
The high-energy transition marked 1 in Figure 26-1 corresponds to ab-
sorption of energy by an A— B molecule existing in a relatively high vibra-
tional level. The energy change occurs with no change in r (Franck-Condon
principle), and the electronic energy of the A— B* molecule so produced is
sec 26.1 light absorption, fluorescence, and phosphorescence 697
•-A + B
Figure 26-1 Schematic potential energy diagram for ground and excited
electronic singlet states of a diatomic molecule, A — B and A — B*, respectively.
The horizontal lines represent vibrational energy levels. The wavy lines
represent the arrival or departure of light quanta.
seen to be above the level required for dissociation of A— B*. The vibration of
the excited molecule therefore has no restoring force and leads to dissociation
to A and B atoms. On the other hand, the somewhat lower-energy transition
marked 2 leads to an excited vibrational state of A— B* which is not expected
to dissociate but which can lose vibrational energy to the surroundings and
come down to a lower vibrational state. This is called " vibrational relaxation "
and usually requires about 10" 12 sec. The vibrationally "relaxed" excited
state can now undergo several processes. It can return to ground state with
emission of radiation (transition 3) ; this is known as fluorescence, the wave-
length of fluorescence being different from that of the original light absorbed.
Normally, fluorescence, if it occurs at all, occurs in 10~ 9 to 10~ 7 sec after
absorption of the original radiation. In many cases, the excited state can also
return to the ground state by nonradiative processes, the electronic excited
state being converted to a vibrationally excited ground state of the original
molecule which by vibrational relaxation proceeds to the ground state. This
means, in effect, that the excess energy is shuffled into vibrational modes and
thence by molecular collisions to the system as a whole. Sometimes, however,
decay to a triplet state occurs before either complete vibrational relaxation or
fluorescence takes place. Formation of a triplet state is of particular chemical
interest because triplet states, even though of high energy, are often relatively
long lived, up to a second or so, and can lead to important reaction products.
To understand these processes we must consider in more detail the nature of
singlet and triplet electronic states.
We have already noted that in the ground states of ordinary molecules all
the electrons are paired; we can also have excited states with all electrons
chap 26 photochemistry 698
paired. States with paired electrons are called singlet states. A schematic
representation of the ground state (S ) and lowest excited singlet (S t ) elec-
tronic configurations of a molecule with four electrons and two bonding and
two antibonding molecular orbitals is shown in Figure 26-2. The 7i-electron
system of butadiene (Section 6-7) provides a concrete example of this type of
system.
A triplet state has two unpaired electrons and is normally more stable than
the corresponding excited singlet state because, by Hund's rule, less inter-
electronic repulsion is expected with unpaired than paired electrons. An
example of the lowest energy triplet electronic configuration (7\) is shown in
Figure 26-2. The name "triplet" arises from the fact that two unpaired
electrons turn out to have three possible energy states in an applied magnetic
field. " Singlet" means that there is only one possible energy state in a mag-
netic field.
Conversion of the lowest singlet excited state to the lowest triplet state
(S l -> T t ) is energetically favorable but usually occurs rather slowly, in
accord with the so-called spectroscopic selection rules, which predict that
spontaneous changes of electronic configuration of this type should have
very low probabilities. Nonetheless, if the singlet state is sufficiently long
lived, the singlet-triplet change, Sj -* T 1 (often called intersystem crossing),
may occur for a very considerable proportion of the excited singlet molecules.
The triplet and singlet states are actually different chemical entities.
The triplet state, like the singlet state, can return to the ground state by a
nonradiative process or by a radiative transition (T l -> S ). Such radiative
transitions result in emission of light of considerably longer wavelength than
either that absorbed originally or that emitted by fluorescence. This type of
radiative transition is called phosphorescence. Because phosphorescence is a
process with a low probability, the 7\ state may persist from fractions of a
second to many seconds. For benzene at — 200°, absorption of light at 2540 A
leads to fluorescence centered on 2900 A and phosphorescence at 3400 A
with a half-life of 7 sec.
There are a number of possible fates for excited singlet or triplet molecules.
Figure 26-2 Schematic representation of the electronic configurations of
ground and lowest excited singlet and triplet states of a molecule with four
electrons and four molecular orbitals (i/j l , i/r 2 , <]i z , and i/r 4 ).
ground
lowest excited
lowest triplet
state (S )
singlet state (S l )
state (Ti)
^ O
o
antibonding
a
^3 O
©
/~\ orbitals
^ ©
{ij bonding
orbitals
*i ©
©
©
sec 26.2 light absorption and structure 699
A singlet state can lose some vibrational energy and radiate the remainder
(fluoresce) ; decay to a high vibrational state of the electronic ground state
and then undergo vibrational relaxation to dissipate its energy; undergo a
chemical reaction ; lose energy by vibrational relaxation and come down to a
lower singlet state (if there is one) ; or decay to a triplet state. A triplet state
can undergo similar changes except that intersystem crossing to an excited
singlet state is seldom possible because the latter is usually of higher energy.
We are chiefly concerned in this chapter with the chemical reactions of
excited states, but we must first examine more closely the relation between
molecular structure and the wavelength and intensity of absorption of ultra-
violet and visible light, because photochemical changes depend on the system
first being activated by the absorption of light quanta.
26-2 light absorption and structure
In Chapter 7 it was shown how the changes in wavelength of absorption of
conjugated systems could be accounted for in terms of differences in the
degree of resonance stabilization between ground and excited states. If the
conjugated system of multiple bonds is long enough the absorption occurs in
the visible part of the spectrum. Thus, 1 ,2-diphenylethene is colorless
(/l max 3190 A), whereas l,10-diphenyl-l,3,5,7,9-decapentaene is orange (A max
4240 A).
\ /- CH=CH A /
colorless
(A max 3190A)
I j>-CH=CH-CH=CH-CH=CH— CH=CH-CH=CH-^ J
orange
(A max 4240A)
In general, the more extended a planar system of conjugated bonds is, the
smaller is the energy difference between the ground and excited states. The
importance of having the bonds coplanar should be obvious from considera-
tion of preferred geometries of the resonance structures with formal bonds
and (or) charge separations. The contribution of such structures to stabiliza-
tion of the ground state increases with an increase in length of the con-
jugated system; but stabilization of the excited state increases even more
rapidly, so that the overall energy difference between ground and excited
states decreases and hence the wavelength required for excitation shifts to
longer wavelengths.
The effect of substituents on the colors associated with conjugated systems
is of particular interest in the study of dyes because, with the exception of
compounds such as /^-carotene, which is an orange-red conjugated polyene
occurring in a variety of plants and which is commonly used as a food color,
chap 26 photochemistry 700
most dyes have relatively short conjugated systems and would not be intensely
colored in the absence of substituent groups.
CH,
-carotene (all trans double bonds)
(A max 4500 A, £140,000)
A typical dyestuff is 2,4-dinitro-l-naphthol (Martius Yellow), a substance
that is used to dye wool and silk. (In addition to possessing color, dyes must be
able to interact with the fibers of these substances. The chemistry of dyestuffs
is considered in Chapter 28, which deals with polymers.)
OH
NO,
N0 2
Martius Yellow
Although naphthalene is a conjugated system it is colorless to the eye,
as is pure 1-naphthol. 2,4-Dinitronaphthalene is pale yellow, so the red-
orange color of crystalline Martius Yellow is clearly due to a special com-
bination of substituents with a conjugated system.
Substitution of a group on a conjugated system which is capable of either
donating or accepting electrons usually has the effect of extending the con-
jugation. This is particularly true if an electron-attracting group is connected
to one end of the system and an electron-donating group to the other. Thus,
withp-nitrophenolate ion, we can expect considerable stabilization because of
interaction between the strongly electron-donating — O e group and the
strongly electron-accepting — N0 2 group.
o
e
O
N-
■f>
r\ i
\
y) <
6/
\ /
/
o
O
e
The high degree of electron derealization which can be associated with this
system is clearly related to its absorption spectrum because, while p-nitxo-
phenolate ion in water gives a strongly yellow solution (2 max 4000 A, e 15,000),
/7-nitrophenol produces a less intensely colored greenish-yellow solution
(l max 3200 A, e 9000). The important structural difference here is that the
—OH group is not nearly so strong an electron-donating group as an — O e
group, and electron derealization is therefore likely to be less important.
O
N-
Oe
o
i~ll 1 .
e
O
\
vJri <
ed
OH
sec 26.2 light absorption and structure 701
There are several connections in which changes of color resulting from
interconversions of such substances as p-nitrophenol and the /?-nitropheno-
late ion are important, including the practical one of the colors of acid-base
indicators as a function of pH. However, before discussing some of these, it
will be well to make clear that, in visual comparisons of the colors of sub-
stances, it must be remembered that both wavelength and absorption coeffi-
cient are involved in judgments of color intensities. The change from />-nitro-
phenolate ion to j?-nitrophenol provides an excellent example of how both
wavelength and absorption coefficient are affected by a structural change. It is
possible for wavelength to shift without changing the degree of absorption
and vice versa, so in speaking of one substance as being more "highly
colored" than another we must be careful as to which features of the spectra
we are actually comparing.
Furthermore, a compound with an absorption maximum in the ultraviolet
may be colored if the absorption band extends into the visible (Figure 26-3). It
should be remembered that colored substances remove part of the white light
spectrum and the color that registers in the eye is complementary to that
which was absorbed. Thus compounds that absorb violet light (light of
wavelength near 4000 A) appear green-yellow and those that absorb red
light (light of wavelength near 7000 A) appear blue-green.
The problems of correlating wavelength and absorption coefficient with
structure can be approached in a number of ways. In an earlier discussion
(Section 7-5), the excited electronic states were considered to have hybrid
structures with important contributions from dipolar electron-pairing schemes.
Thus for the first excited singlet state of butadiene, we may write these contrib-
uting structures :
e e ® e
CH 2 -CH=CH-CH 2 < ► CH 2 -CH=CH— CH 2
[1] [2]
?. ©
< ► CH 2 =CH— CH — CH 2 < > etc.
[3]
Extension of this approach to benzene suggests the importance of reso-
nance structures such as [4], [5], and so on for the excited singlet state of
benzene.
// vo 4 * etc.
[4] [5]
It is not unreasonable to suppose that substitution of an electron-attracting
group at one end of such a system and an electron-donating group at the other
end should be particularly favorable for stabilizing the excited state relative
to the ground state wherein [4], [5], and so on are of negligible importance.
At the same time, we would not expect that two electron-attracting (or two
electron-donating) groups at opposite ends would be nearly as effective.
The problem of predicting the absorption intensities is a difficult and
complicated one. An important factor is the ease of displacement of charge
chap 26 photochemistry 702
visible -
3000
4000
5000
X, A
Figure 26-3 Absorption in the visible region by a substance that has A^
in the ultraviolet.
during the transition. On this account we expect substances such as j?-nitro-
phenolate ions, which have roughly equivalent electron-donating and electron-
attracting groups in each of their principal resonance structures, to absorb
particularly strongly.
e
° / \
O
electron
attracting
e
O
O
e
electron electron
donating donating
O
electron
attracting
Figure 26-4 Two of the many resonance structures of the dye Crystal Violet.
sec 26.3 photodissociation reactions 703
We expect this factor to be especially favorable where equivalent resonance
structures may be written. Many useful and intensely colored dyes have
resonance structures of this general sort. A typical example is Crystal Violet,
shown in Figure 26-4.
26-3 photodissociation reactions
We have already mentioned (Section 2-5B) that the chlorine molecule under-
goes dissociation with near-ultraviolet light to give chlorine atoms and thereby
initiates the radical chain chlorination of saturated hydrocarbons. Photo-
chemical chlorination is an example of a photochemical reaction which can
have a high quantum yield — that is, many molecules of chlorination product
can be generated per quantum of light absorbed. The quantum yield, <J>, of a
reaction is said to be unity when 1 mole of reactant ( s ) is converted to product(s)
per mole of photons absorbed. (This quantity of light is called one einstein.)
Acetone vapor undergoes a photodissociation reaction with 3130-A light
with <I> somewhat less than unity and is of interest in illustrating some of the
things which are taken into account in the study of photochemical processes.
Absorption of light by acetone results in the formation of an excited state
which has sufficient energy to undergo cleavage of a C— C bond (the weakest
bond in the molecule) and form a methyl radical and an acetyl radical.
o
ho
CH3-C-CH3
o
II
CH3-C-CH3
o
II
CH 3 -C- +CH3
At temperatures much above room temperature, the acetyl radical breaks
down to give another methyl radical and carbon monoxide.
o
II
CH3-O ► CH 3 -+C=0
If this reaction goes to completion, the principal reaction products are
ethane and carbon monoxide.
2 CH 3 - > CH3-CH3
If the acetyl radical does not decompose completely, then some biacetyl is
also formed. This reaction is quite important at room temperature or below.
O OO
II II II
2 CH3-O ► CH 3 -C-C-CH 3
biacetyl
Lesser amounts of methane, hydrogen, ketene (see Section 12-4), and so on
are also formed in the photochemical dissociation of acetone.
chap 26 photochemistry 704
A variety of dissociation-type photochemical reactions has been found to
take place with other carbonyl compounds. Two examples are
o o
II hv II
CH 3 — C— CH 2 CH 2 CH 3 ► CH 3 — C— CH 3 + CH,=CH,
vapor phase
O
II
CH 2 — CH 2
hv
CH, CH, r — ► + CO
2 2 vapor phase
\ /
CHi CHj
CH 2 — CH 2
26-4 photochemical reduction
One of the classic photochemical reductions of organic chemistry is the
formation of benzopinacol, as brought about by the action of light on a
solution of benzophenone in isopropyl alcohol. The yield is quantitative.
/=\ 1 /=\ .. f\.. „ _.M V... f •
2 4 /-C-\ / + H— C — OH > HO C C OH + C=0
CH 3 /=K )=\ CH 3
\J \J
The light functions to energize the benzophenone, and the activated ketone
removes a hydrogen from isopropyl alcohol.
o
CH 3 OH CH 3
H-j-OH ► {J^^^} + -{-° H
benzhydrol radical
[6]
Benzopinacol results from dimerization of benzhydrol radicals [6].
_ OH _
2
<( )>— C— L \ ► benzopinacol
The initial light absorption process involves excitation of one of the un-
shared electrons on the carbonyl oxygen atom (« -> 71*). However, the excited
singlet state undergoes facile intersystem crossing to give the longer-lived
triplet state (5 t -»■ 7^) and it is the latter that abstracts the hydrogen atom from
the alcohol.
Because the quantum yields of acetone and benzopinacol are both nearly
unity when the light intensity is not high, it is clear that two benzhydrol
radicals [6] must be formed for each molecule of benzophenone that becomes
sec 26.5 photochemical oxidation 705
activated. This is possible if the hydroxyisopropyl radicals formed by Equa-
tion 26- 1 react with benzophenone to give benzhydrol radicals.
CH 3 O CH 3 OH
i /=\ ii / = \ i r=\ i
C-OH + i^J-C-^J > C=0 + ^J-^^J (26-1)
CH 3 CH 3
This reaction is energetically favorable because of the greater possibility
for derealization of the odd electron in the benzhydrol radical than in the
hydroxyisopropyl radical.
Photochemical formation of benzopinacol can also be achieved from ben-
zophenone and benzhydrol.
O O
The mechanism is similar to that for isopropyl alcohol as the reducing agent
except that now two benzhydrol radicals are formed.
O
/ = \ I' / = \
OH . . OH
\ r?A / — > 2 V_y ? u
H
t
benzopinacol
The reduction is believed to involve the triplet state of benzophenone by
the following argument. Benzopinacol formation is reasonably efficient even
when the benzhydrol concentration is low; therefore, whatever excited state
of benzophenone accepts a hydrogen atom from benzhydrol, it must be a
fairly long-lived one. Because benzophenone in solution shows no visible
fluorescence, it must be converted to another state in something like 10~ 10
sec, but this is not long enough to seek out benzhydrol molecules in dilute
solution. The long-lived state is then most reasonably a triplet state.
26-5 photochemical oxidation
Molecular oxygen, 2 , is unusual in that its most stable electronic configura-
tion is that of a triplet, • O— O • , in which the spins of the odd electrons are the
same. The reactions of oxygen are in accord with this arrangement, for
example, rapid reaction with radicals (Sections 2-5B and 22-4) or paramag-
netic metal ions (Section 18-4). When oxygen is raised to its excited state by
absorption of energy we find a different set of reactions entirely. The first
excited state is a singlet and corresponds to the structure 0=0. Because
chap 26 photochemistry 706
oxygen does not absorb light in the accessible region of the visible or ultra-
violet spectrum we cannot easily obtain singlet oxygen by simply irradiating
oxygen. However, it is possible to obtain this chemical species if there is a
sensitizer present in the system. A sensitizer is a compound which can absorb
a light quantum and then transfer some of this energy to a second substance.
Benzophenone is particularly useful for this purpose. We saw in the previous
section how the excited singlet state of benzophenone changes to the excited
triplet which can then abstract a hydrogen atom from alcohols. The triplet
is also extremely efficient at transferring energy to oxygen. The sequence of
reactions is shown.
hv
(C 6 H 5 ) 2 C=0 > (C 6 H 5 ) 2 C=0* (singlet)
3665A
(C 6 H 5 ) 2 C=0* (singlet) ► (C 6 H 5 ) 2 C=0* (triplet)
(C 6 H 5 ) 2 C=0* (triplet) + 2 * (C 6 H 5 ) 2 C=0 + 0=0 (singlet)
The reactions of the excited state of oxygen, 0=0, are characteristic of a
molecule with paired electrons rather than of a diradical. It reacts with
alkenes in a concerted manner by attaching itself to one carbon atom of the
double bond while abstracting a hydrogen from the allylic position.
H 3 C CH 3 H 3 C^ ^CH 2
C C
II + 0=0 ► I
c c
HjC" ^CH 3 HjC^I^O-OH
33 3 CH 3
The concerted nature of the reaction is shown by the fact that the abstracted
hydrogen is always cis to the position of oxygen attack; see Exercise 26T0.
This suggests that the reaction proceeds through a cyclic transition state such
as the following :
. X
C' H
li i
Singlet oxygen reacts with conjugated dienes to form bicyclic compounds.
+ 0=0
^^
o
I
o
We shall encounter this type of cyclization reaction again in the next chapter
and we shall see that there is a distinct resemblance between the reactions of
0=0 and CH 2 =CH 2 .
Singlet oxygen can also be generated chemically by the oxidation of
hydrogen peroxide in alkaline solution with two-electron oxidizing agents
(Section 18-4) able to remove hydride ion from hydrogen peroxide. Hypo-
chlorite is useful for this purpose.
3 OCl ► 0=0 + HO e + Cl e
sec 26.7 photochemical cycloadditions 707
26-6 photochemical isomerization of cis- and trans-
unsaturated compounds
An important problem in many syntheses of unsaturated compounds is to
produce the desired isomer of a cis-trans pair. In many cases, it is necessary
to utilize an otherwise inefficient synthesis because it affords the desired
isomer, even though an efficient synthesis of the unwanted isomer or of an
isomer mixture may be available. An alternative way of attacking this prob-
lem is to use the most efficient synthesis and then to isomerize the undesired
isomer to the desired isomer. In many cases this can be done photochemically.
A typical example is given by cis- and ?ra«^-stilbene.
\=/ H H
trans cis
Here the trans form is easily available by a variety of reactions and is much
more stable than the cis isomer because it is less sterically hindered. However,
it is possible to produce a mixture containing mostly the cis isomer by
irradiating a solution of the trans isomer in the presence of a suitable photo-
sensitizer. This process in no way contravenes the laws of thermodynamics,
because the input of radiant energy permits the equilibrium point to be shifted
from what it would be normally.
Another example is provided by the equilibration of l-bromo-2-phenyl-l-
propene. The trans isomer is formed to the extent of 95 % in the dehydro-
halogenation of l,2-dibromo-2-phenylpropane.
W Br \_J H W Br
\ / NaOCH 3 \ / \ /
Br-C-C-H ^„ » C=C + C = C
/ \ HOCH 3 / \ / \
H 3 C H H 3 C Br H 3 C H
trans cis
95% 5%
Photoisomerization of the elimination product with 2-naphthyl methyl ketone
as sensitizer produces a mixture containing 85% of the cis isomer.
In the practical use of the sensitized photochemical equilibrium of cis and
trans isomers, it is normally necessary to carry out pilot experiments to
determine what sensitizers are useful and the equilibrium point which each
gives.
26-7 photochemical cycloadditions
In the next chapter cyclization reactions of various kinds will be discussed,
including those resulting from absorption of light. We shall only point out
chap 26 photochemistry 708
here how photochemistry has in recent years enabled some cyclic compounds
with unusual structures to be prepared.
R = 7-butyl [7] [8] [9]
Compounds [8] and [9] are moderately stable at room temperature
although they are clearly of higher energy than benzene derivatives. They will
be recognized as two of the structures that were suggested a century ago for
the structure of benzene by Dewar and Ladenburg (Chapter 6). The terms
Dewar benzene and Ladenburg benzene are often used for [8] and [9],
respectively; [9] is also called prismane, because of its resemblance to a
prism. Although the structure of Dewar benzene is often drawn as in [8]
it is preferable to show the molecule's partly folded geometry and the close-
ness of the bridgehead carbons, as in [10]. Thus [10] should not be regarded
as contributing to the resonance hybrid of benzene because the geometries of
[10] and benzene are very different.
H
H
[10]
summary
Absorption of visible or ultraviolet light by an organic molecule in a ground
singlet state, S , produces a short-lived electronically excited singlet state,
S (S t if the lowest singlet state), which may undergo a chemical reaction or
return to the ground state by one of the following means : it may fluoresce (lose
some energy by vibrational relaxation and then radiate the remainder) ; it may
undergo vibrational relaxation to a lower singlet state, if there is one, or all
the way to the ground state (5 ) ; or it may undergo intersystem crossing to
produce a longer-lived triplet state (5 1 -»7' 1 ) which may, in turn, either phos-
phoresce (lose energy by vibrational relaxation and then radiate the remain-
der), undergo a chemical reaction, or act as a photosensitizer by transferring
its energy to a second molecule.
exercises 709
Photoactivation requires that light be absorbed; photosensitizers (e.g.,
benzophenone) are useful for activating other compounds that do not absorb
light in an accessible part of the spectrum.
Conjugation stabilizes excited states more than ground states and conju-
gated compounds thus tend to absorb at the longer wavelengths.
Some of the reactions undergone by compounds that have been raised to
their excited electronic states (either by direct light absorption or by energy
transfer from a photosensitizer) include dissociation, oxidation or reduction,
trans-cis isomerization, and cycloaddition. Many of the sensitized reactions
involve the triplet state of aromatic ketones such as benzophenone.
HO OH
R 2 CHOH I I
Ar 2 C= 0*(triplet)
RCH=CHR((rans)
Ar 2 C-CAr 2 + R 2 C=0
-*■ singlet 0=0
■*- RCH=CHR(ra)
Singlet oxygen (0=0), which can also be generated chemically, undergoes
a number of reactions unknown to ground-state (triplet) oxygen, including
the following:
0=0-
«f I (cis mechanism)
' OOH
Derivatives of both Dewar benzene and Ladenburg benzene (prismane)
have been prepared by photochemical isomerization of derivatives of ordinary
benzene.
exercises
26-1 The fluorescence of many substances can be "quenched" (diminished or
even prevented) by a variety of means. Explain how concentration, tempera-
ture, viscosity, and presence of dissolved oxygen and impurities might affect
the degree of fluorescence observed for solutions of a fluorescent material.
Would you expect similar effects on phosphorescence ? Explain.
chap 26 photochemistry 710
26-2 Explain qualitatively how temperature could have an effect on the appear-
ance of the absorption spectrum of a system such as shown in Figure 26-1,
knowing that most molecules are usually in their lowest vibrational state
at room temperature.
26-3 Make diagrams of at least five different singlet states and three different
triplet states of the system shown in Figure 26-2.
26-4 What visible color would you expect the substance to have whose spectrum
is shown in Figure 26-3 ?
26-5 The 77 -> 77* absorption spectra of trans,trans-, trans,cis-, and cis,cis-l,4-
diphenylbutadiene show maxima and e values (in parentheses) at about
3300 A (5.5 X 10 4 ), 3100 A (3 x 10*), and 3000 A (3 x 10 4 ), respectively.
What is the difference in energy between the transitions of these isomers in
kilocalories per mole? Why should the trans,trans isomer have a different
A max than the other isomers? (It may be helpful to make scale drawings or
models.)
26-6 How would you expect the spectra of compounds [11] and [12] to compare
with each other and with the spectra of cis- and ?ra«^-l,2-diphenylethene
(stilbene) ? Explain.
26-7 Why must the resonance forms [1], [2], [3], etc., for butadiene correspond
to a singlet state ? Formulate the hybrid structure of a triplet state of buta-
diene in terms of appropriate contributing resonance structures.
26-8 a. p-Nitrodimethylaniline gives a yellow solution in water which fades
to colorless when made acidic. Explain.
b. p-Dimethylaminoazobenzene (Section 22-9B) is bright yellow in aqueous
solution (A max 4200A) but turns intense red (A max 5300 A) if dilute acid
is added. If the solution is then made very strongly acid, the red color
changes to a different yellow (A raax 4300 A) than the starting solution.
Show how one proton could be added to ^-dimethylaminoazobenzene
to cause the absorption to shift to longer wavelengths and how addition
of a second proton could shift the absorption back to shorter wavelengths.
26-9 The well-known indicator and laxative, phenolphthalein, undergoes the
following changes as a neutral solution is made successively more basic :
exercises
711
, H( v^
il f
>
.OH
HO -
i rV
V
\X
J
k.
KkJ
c
ii
- c
II
o
H( S^
e °r^
-U 1
><
=\
_ r\
, kl
>=o
d
— \J
n
U 1
"co 2 e
k>
v co 2 e
Some of these forms are colorless, some intensely colored. Which would you
expect to absorb at sufficiently long wavelengths to be visibly colored ? Give
your reasoning.
26-10 A steroid molecule, only part of whose structure is shown below, contained
one atom of deuterium in a position cis to the hydroxyl group. On irradiation
of a mixture of this compound, oxygen, and an aryl ketone sensitizer, one
of the following hydroperoxides was obtained in high yield and the other in
very small yield. Identify the major product. Give your reasoning.
HO'
o=0
£s
D
HO
0-OH
xrs
D
HO
O-OD
H
chap 27 cyclization reactions 715
Ring formation can take place if functional groups in the same molecule react
intramolecularly. Cyclic structures can also be formed by the addition re-
action of two unsaturated molecules with one another. In this chapter we
shall first examine intramolecular ring closure, especially as it involves car-
bonyl compounds, and then examine the addition reactions of alkenes and
polyenes that lead to cyclic structures. The first group of reactions enables us
to review some familiar chemistry; the second introduces new reactions and
new concepts and takes us deeper into molecular orbital theory than we have
hitherto gone. Those whose interests are less theoretical may not wish to
pursue this subject beyond Section 27 • 4.
27" I cyclization reactions of carhonyl compounds
Carboxylic acids react with alcohols and amines to form esters and amides.
RC0 2 H + HOR ► RC0 2 R + H 2
RC0 2 H + H 2 NR > RCONHR + H 2
Hydroxy acids and amino acids undergo the same reactions to give cyclic
structures (lactones and lactams, Sections 13-10B and 17-2), provided that
the functional groups are favorably situated with respect to one another.
O
o //
f H 2 C-C
HOCH 2 CH 2 CH 2 C ► / \ + H 2
OH
CH 2
y-butyrolactone
O
o //
// H 2 C-C
H 2 NCH 2 CH,CH,C * I \ + H,0
2 2 2 2 \ H,C ,NH
OH
CH,
y-butyrolactam
Indeed, these reactions occur much more readily than their intermolecular
counterparts; 7- and <5-hydroxyacids cyclize spontaneously to give lactones.
The same pattern applies to anhydride formation; heating acetic acid has
little effect but warming succinic acid or phthalic acid produces the an-
hydrides.
/°
-C H 2 C-C
OH A I \
<a \ /
H,C-C^ H 2 C-C
o
OH
V
o
chap 27 cyclization reactions 716
When more than three carbon atoms intervene between the carboxyl groups
of a dicarboxylic acid, pyrolysis of the acid (or its thorium salt) produces
ketones (Section 13 ■ 1 IB).
^C0 2 H ^^
(CH 2 )„ — ^-» (CH 2 ), C = + C0 2 + H 2
Vo 2 H ^-^ w>3
Spontaneous cyclization occurs with y- and cS-hydroxyaldehydes and
ketones to give hemiacetals (Section 1 1 ■ 4B).
OH
P '
/ H 2 C-C-H
HOCH 2 CH 2 CH 2 C ► I \
\ H 2 C O
H \H 2
The best known examples are provided by carbohydrates (Section 15-3).
The Claisen condensation of esters (Section 13-9B) has its intramolecular
counterpart in the Dieckmann reaction.
O O O O
// // NaOC 2 H 5 II II
CH 3 -C + CH 3 -C — — -—* CH 3 -C-CH 2 -C-OC 2 H 5 + C 2 H 5 OH
\ " \ C 2 H 5 OH J i 2 5 2 5
o
_ / o
h CH 2 C^ qc ^ ^ H 2/ C-^
I O ► H 2 C I + C 2 H 5 OH
S CH,-C 2 \
2 ^OC 2 H 5 C0 2 C 2 H 5
The course of this cyclization reaction is the same as that of the Claisen
reaction. Ethoxide ion abstracts a proton from one of the two activated
methylene groups in the diester to give an anion.
O o
II II
HC /CH 2 -C-OC 2 H 5
2| + C 2 H 5 O e
H 2 C. H,C^ e
^CH 2 -C-OC 2 H 5 2 ^CH-C-OC 2 H 5
II II
o o
The highly nucleophilic anion thus formed attacks a carbonyl group and,
particularly in dilute solution, this is likely to be the group in the same
molecule. Loss of ethoxide ion gives the product.
sec 27.1 cyclization reactions of carbonyl compounds 717
H 2 C
I
H,C.
O
II
,CH,— C-OC 2 H s
V CH— C— OC 2 H 5
II
o
- H 2 c(
C-OC 2 H 5
yi^CH CO2C2H5
H 2
H,C
H
.0
e
\ ^CHC0 2 C 2 H 5 + C 2 H 5
H 2
Another very useful ring closure reaction that bears a superficial resem-
blance to the above reaction is the acyloin condensation. The reactant is again
a dicarboxylic ester but the reagent is sodium dispersed in a hydrocarbon
solvent instead of sodium ethoxide dissolved in ethanol. This seemingly small
difference in the reagent changes the course of the reaction completely.
Sodium is unable to function as a base in a hydrocarbon solvent and instead
it reacts as a one-electron reducing reagent to produce a radical anion at each
carbonyl group. Ring closure followed by elimination of ethoxide ions and
further reduction produces the dianion [1] which on addition of water yields
the hydroxy ketone [2] (an acyloin).
CH
I
CH
I
CH 2 — C— OC 2 H 5
CH 2
-C — OC 2 H,
I
o 6
H 2 O fc
H 2 C /C ^ '
C-OC,H,
(-2 C 2 H 5 Oe)
H 2 C
I
H,C.
H, O e
2Na-
H 2
H 2 C^ ^<r
H,
H,C
-OH
1 2 , -\ / ^/^'\
H 2
OH
[1]
.O fc
^O fc
chap 27 cyclization reactions 718
This reaction, which works very well for large rings, has been used in an
ingenious synthesis of a catenane, a compound whose two rings are not joined
by bonds but are held together like links in a chain. A large-ring compound
[5] was prepared by the acyloin condensation followed by Clemmensen re-
duction (Section 1 1 ■ 4F) using deuterated reagents. This produced a large
carbocyclic ring containing some deuterium label. (Partial exchange of the
a hydrogens occurred and. produced a compound containing on the average
five deuterium atoms per molecule.)
DCl
Zn-Hg
The labeled compound was then dissolved in xylene, more [3] added, and
the acyloin condensation repeated. If the long chain of [3] happens to be
threaded through a molecule of [5] when ring closure occurs the catenane [6]
will be produced.
The product was purified by chromatography and after all traces of [5]
were removed, it was found that some deuterium label remained, suggesting
the presence of about 2% [6] mixed with [4]. Cleavage of the hydroxy ketone
ring by oxidation produced a dicarboxylic acid containing no deuterium and
the large-ring deuterium-containing hydrocarbon [5].
27-2 cjcloaddition reactions of carbon-carbon
multiple bonds
The tendency of an alkene such as ethene to undergo a cycloaddition reaction
with another unsaturated molecule depends on two important factors:
whether the other molecule contains isolated or conjugated double bonds,
and whether the system is activated by heat or by light. For example, most
alkenes show little tendency to dimerize to cyclobutanes thermally (A), but
the reaction can usually be brought about readily by the action of light (hv).
II + II -^ □
On the other hand, substituted alkenes usually react readily on being
warmed with conjugated dienes to give cyclohexenes. Light (hv) is not re-
quired for this reaction.
<r
sec 27.2 cycloaddition reactions of carbon-carbon multiple bonds 719
The reaction of a conjugated diene with an alkene is known as the Diels-
Alder reaction and is described in some detail in the next section.
A. D1ELS-ALDER REACTION
Although the Diels-Alder reaction can be conducted with ethene as the alkene
(often referred to as the dienophile), addition occurs much more readily if the
O
II
alkene contains electron-withdrawing groups such as — C— , — C=N, or
— N0 2 .
One of the reasons that the reaction has proved of value, especially in the
synthesis of natural products, is that it is highly stereospecific. First, and
most obvious, the diene reacts in the s-cis 1 conformation of its double bonds
because the double bond in the product (a six-membered ring) necessarily has
the cis configuration.
CH 2 h
I
CH,
^H
s-cis
conformation
CH 2 =CH 2
H
X
I II
2 ^(y ^H
H 2 C^ ^C^
H 2
stable cis
double bond
CH 2 H
I
H /C% CH 2
s-trans
conformation
CH 2 =CH 2
CH 2 H
V CH 2 /
c==c
/ ch\
H X CH 2
highly strained
trans double bond
Cyclic dienes with five- and six-membered rings usually react readily because
they are fixed in s-cis configurations.
C(CN) 2
+ II
C(CN) 2
25°
(CN) 2
(CN),
Second, the configurations of the diene and the dienophile are retained in
the adduct. This means that the reactants (or addends) come together to give
cis addition. Two illustrative examples follow which are drawn to emphasize
how cis addition occurs. In the first example, dimethyl maleate, which has cis
1 The designation s-cis means that the double bonds lie in a plane on the same side
(cis) of the single bond connnecting them. The opposite and usually somewhat more stable
conformation is called s-trans.
chap 27 cyclization reactions 720
ester (C0 2 CH 3 ) groups, adds to 1,3-butadiene to give a cw-substituted
cyclohexene.
ocH 3
.OCH,
V
(shows retention of
configuration in the
dienophile)
In the second example, cis addition of a dienophile to trans,trans-2,4-hexa.-
diene is seen to yield the product with the two methyl groups on the same side
of the cyclohexene ring.
CH,
H,C
CH,
(shows retention of
configuration of the
diene methyl sub-
stituents)
The Diels-Alder reaction is believed to occur by a one-step synchronous
process in which bonds form simultaneously between each end of the diene
and the dienophile.
The difference between thermal activation and photoactivation of dienes is
shown in Figure 27-1.
The thermal process is a Diels-Alder reaction between two molecules of
1,3-butadiene, one of which acts as the diene and the other as the dienophile.
The photochemical reaction is analogous to a reaction between two alkenes.
The absorption of a photon by 1,3-butadiene is expected to activate the
Figure 27-1 Dimerization of 1,3-butadiene by thermal activation and photo-
activation.
2CH,=CH-CH=CH,
1,4 addition
(trans) (cis)
n£>.
2 addition
sec 27.2 cycloaddition reactions of carbon-carbon multiple bonds 721
molecule, but it is less obvious why the excited state prefers to react by the
1,2-addition route rather than by the usual 1,4-path. There is no reason, how-
ever, to expect electronically excited states, particularly those with different
arrangements of electron spin, to undergo the same reactions as ground states.
A rationale for the different routes has been developed recently based on
orbital symmetry considerations and is discussed in Section 27 • 5.
B. CYCLIZATION REACTIONS OF ALKYNES
Alkynes can act as dienophiles in the Diels-Alder reaction to produce non-
conjugated cyclohexadienes.
Acetylene can be readily polymerized to cyclooctatetraene by the action of
nickel cyanide.
Ni(CN) 2
4HC = CH — ~^>
50°
80 90°
With this reaction, cyclooctatetraene could be manufactured easily on a
large scale; however, profitable commercial uses of the substance have yet
to be developed.
It is easy to become confused about the reactions of alkynes with transition-
metal ions. Acetylene, for example, is hydrated under the influence of Hg"
(Section 5-4); it forms salts with Ag 1 (Section 5-5); it is dimerized to vinyl-
acetylene by Cu 1 (Section 5-4); it is polymerized to cyclooctatetraene by Ni u
(above) ; and we shall see later in this chapter that it and other alkynes can be
oxidatively coupled by the action of Cu 11 .
C. 1,3-DIPOLAR ADDITIONS
Alkenes and some other compounds with multiple bonds undergo 1,3-cyclo-
addition with a variety of substances which can be formulated as 1,3-dipolar
© e
molecules of the type X — Y — Z.
C e e — C \
II + X-Y-Z ► I V
The 1,3-dipolar compounds seldom carry full formal charges on the terminal
atoms and, indeed, in the list of these reagents shown in Figure 27-2, the
1,3-dipolar form is not the one we would regard as the most important of the
forms contributing to the resonance hybrid. (Each of the 1,3-dipolar struc-
tures shown in Figure 27 • 2 has an atom with an incomplete octet whereas in
chap 27 cyclization reactions 722
a e
ozone ®0— 0— e < ► 0=0— O
® e a e e &
organic azides R-N~N=N < ► R— N=N=N < ► R— N-N=N
nitrile oxides R-C=N-0 < > R— C=N-0
diazoalkanes R 2 C— N=N < ► R 2 C=N=N
Figure 27-2 Some 1,3-dipolar reagents.
the 1,2-dipolar structures each atom has a rilled octet.) Nonetheless, alkenes
add 1,3 to these substances to give five-membered rings.
A simple example is the addition of phenyl azide to norbornene. Here the
azide is written to correspond to the resonance form that appropriately
accounts for the occurrence of the addition.
/C 6 H 5
•N
\
norbornene phenyl azide
In all of these reactions heterocyclic compounds are formed, although the
ozone adduct undergoes further reaction (Section 4-4G). The basis for the
names shown was given earlier (Chapter 25).
II + O -* I o a trioxole
' ^ O
R
^C \
II + N ► [ N a triazole
^ N
— c
1
-C-
1
\
o
R
I
1
— c-
1
— C-
1
N
R
I
C«
R
I
c \ -C'\\
II + N > | N an oxazole
R ^r< R I V R
|| + n ► I N a diazole
/C v e// -C^S
sec 27.3 fluxional systems 723
These reactions, which are believed to be one-step synchronous processes
like the Diels-Alder reaction, also take place with alkynes.
+ X-Y-Z ► [I Y
Z
27-3 fluxional systems
In earlier chapters we frequently encountered the phenomenon of tautom-
erism, the rapid equilibration of structural isomers.
O O O OH
2,4-pentanedione and || || || |
its enol form (Section CH 3 -C-CH 2 -C-CH 3 > CH 3 -C-CH=C-CH 3
12-6)
2-hydroxypyridine and
oc-pyridone (Section
18 -IE)
H
OH O
barbituric acid, keto -**\ ^\
and enol forms (Section ^ |] - > H ¥ |
25-7)
HO ^NT X)H Or ^N' X>
H
All of the above examples involve proton shifts but there is nothing in the
definition that restricts us to this kind of process. For example, a rapid
equilibrium exists at 100° between 1,3,5-cyclooctatriene and the bicyclic com-
pound shown here, which is also an example of tautomerism. (The term
"valence tautomerism" or "valence isomerism" is sometimes used to de-
scribe such equilibria and the reactions are sometimes called Cope rearrange-
ments.)
155
The nmr spectra of systems such as this clearly reveal the position of
equilibrium and even the rate at which the forward and reverse reactions
occur. (See Section 7-6D for a discussion of how nmr can be used to measure
the rates of conformational change.)
The situation with cyclooctatraene is similar. Although the eight-membered
ring is the major form in the equilibrium mixture some of its reactions are
those of the bicyclic tautomer.
chap 27 cyclization reactions 724
CU
\maleic anhydride
XI
-ci
Tautomerism, which involves the relocation of atoms, should not be con-
fused with resonance, which is formulated as a dispersal of electrons over
several nuclei and which can be represented by drawing two or more valence
structures in which the atomic locations are the same. Tautomers are thus
distinctly different chemical entities with different atomic locations. It is also
possible to have equilibria between molecules with the same formal struc-
ture — for example, the rapid shifting of a hydrogen atom between the two
oxygens of the carboxyl group in acetic acid or the slow equilibration of the
methylene groups in 1,5-hexadiene.
CH,
O*
OH
OH
J
\
O
50%
50%
50%
50%
This situation is very different from resonance because the atomic locations
are different, and it is not strictly tautomerism because the molecules are not
isomers. The term fluxional molecules has been coined to describe the partic-
ipants in such equilibria. In the absence of some sort of label it is not possible
to distinguish the two forms; nonetheless, a pathway between the fluxional
molecules must exist and this has become a matter of interest to many
chemists.
A facile pathway for the 1,5-hexadiene equilibration exists in which bond
rupture and bond formation occur at the same time and which has the cyclic
transition state shown.
■4?
transition state
A curious fluxional molecule, called barbaralane [7], is shown by its nmr
spectrum to exist in two equivalent forms that are in rapid equilibrium at
room temperature.
sec 27.4 annulenes 725
[7]
If the CH 2 group is replaced by a CH=CH group the number of fluxional
forms rises dramatically (see Exercise 27 • 4). The latter compound has been
given the name bullvalene. (The classical languages have heretofore provided
the basis for naming new compounds but this approach is now in some danger
of being replaced by whimsy.)
The ease with which the two forms of barbaralane interconvert reflects the
importance of synchronous bond breaking and bond making in lowering the
energy of a transition state. An important part of this is the fact that the re-
acting atoms are held in favorable positions by the ring structure.
The similarity between the equilibrium in 1,5-hexadiene and in barbaralane
can be seen if we draw the latter so that the hexadiene portion of the molecule
is clearly displayed.
27-4 annulenes
There has been considerable interest for many years in the synthesis of conju-
gated cyclic polyalkenes with a large enough number of carbons in the ring to
permit attainment of a strainless planar structure. Inspection of models shows
that a strainless structure can only be achieved with two or more of the double
bonds in trans configurations, and then only with a large enough ring that the
"inside" hydrogens do not interfere with one another.
In discussing compounds of this type, it will be convenient to use the name
[njannulene to designate the simple conjugated cyclic polyalkenes, with n re-
ferring to the number of carbons in the ring — benzene being [6]annulene. The
simplest conjugated cyclic polyolefin that could have a strainless planar ring
containing trans double bonds, except for interferences between the inside
hydrogens, is [10]annulene. Inside-hydrogen interferences are likely to be of
at least some importance in all annulenes up to [30]annulene.
chap 27 cyclization reactions 726
Several annulenes have been synthesized and found to be reasonably stable
— at least much more so than could possibly be expected for the corresponding
open-chain conjugated polyenes. An elegant synthesis of [18]annulene pro-
vides an excellent illustration of some of the more useful steps for preparation
of annulenes. The key reaction is oxidative coupling of alkynes by cupric
acetate in pyridine solution.
Cu"
2 RC=CH > RC=C— C=CR
C5H5N
This type of oxidative coupling with 1,5-hexadiyne gives a 6% yield of the
cyclic trimer [8], which rearranges in the presence of potassium ?-butoxide
to the brown, fully conjugated 1,2,7,8,13, 14-tridehydro[18]annulene [9].
3 HC=C-CH,-CH 2 -C=CH
C 5 H 5 N
[9] [18]annulene
Hydrogenation of [9] over a lead-poisoned palladium on calcium carbonate
catalyst (the Lindlar catalyst, of general utility for hydrogenation of alkynes
to alkenes) gives [18]annulene as a brown-red crystalline solid, reasonably
stable in the presence of oxygen and light.
27-5 orbital symmetry and cycloaddition
We pointed out earlier that an alkene cyclodimerization 2 usually requires
photoactivation whereas the Diels- Alder reaction between an alkene and a
conjugated diene occurs thermally. A rationale for this difference and for the
stereochemistry of a large number of cyclization and ring-opening reactions
has been developed recently by several theorists, including Longuet-Higgins,
Fukui, Woodward, and Hoffmann, using molecular orbital theory. In
Chapter 6 we described the four n molecular orbitals in 1,3-butadiene that
result from interaction of four p orbitals, one on each carbon atom. The
2 A few alkenes such as tetrafluoroethene, CF 2 = CF 2 , cyclodimerize thermally but these
reactions are known to go by a radical, not a concerted, pathway.
sec 27.5 orbital symmetry and cycloaddition 727
ff-bonded skeleton of the molecule is ignored in this treatment and only the
7i electrons are considered.
-c— c
The wave functions that describe the energies of an electron in each of the
four p orbitals of butadiene can be combined algebraically to give us an
approximation set of four molecular orbitals with different energies. (These
molecular orbitals are linear combinations of atomic orbitals and the pro-
cedure is thus known as the LCAO approach.) Two of these molecular orbitals
are bonding (energy lower than that of the isolated p orbitals) and two are
antibonding (energy higher than that of the isolated orbitals). In a crude
analogy the molecular energy levels can be compared with the energies of
the standing waves of a vibrating string. The energy of a standing wave with
a given amplitude increases with the number of nodes as shown on the left
side of Figure 27-3.
In a molecular orbital made up of a linear combination of p orbitals, the
coefficients of the p-orbital functions can have positive or negative values.
If the signs of the coefficients of two adjacent p orbitals overlapping in the %
manner are the same, then the positive parts of the atomic orbital lobes are
pointed in the same direction and we say that there is no node between the
atoms and that the molecular orbital is bonding. If the signs of the coefficients
for the two adjacent orbitals are different, the arrangement has a node and is
antibonding between these atoms. Figure 27 ■ 4 shows schematically the bond-
ing and antibonding arrangements for the two p-7t orbitals in ethene.
A schematic representation showing the nodes for the simple LCAO molec-
ular orbitals of butadiene is given on the right side of Figure 27-3. Here, the
relative sizes of the orbitals are drawn to reflect the values obtained by nu-
merical calculations. The first two molecular orbitals are bonding (zero and
one node) and the second two are antibonding (two and three nodes) (see
Section 6 ■ 7). In the ground state of butadiene, the first two orbitals are doubly
occupied whereas in the excited state an electron is raised from molecular
orbital ^ 2 t0 ^3 ( see Figure 26-3).
A rule for determining whether or not cycloadditions are allowed can be
stated as follows : The orbitals that overlap in the transition state between the
highest occupied level of one reactant and the lowest unoccupied level of the
other reactant must be of the same symmetry (sign). The % orbitals of ethene
and 1,3-butadiene are shown in Figure 27-5.
This rule predicts that concerted combination will not occur between two
molecules of ethene in their ground states because the lobes of the lowest
unoccupied level in one molecule and the highest occupied level in the other
do not have corresponding signs. However, if one of the ethene molecules is
raised to its first excited state by light absorption the situation is altered. The
lobes of the orbitals of the excited state and those of the lowest unoccupied
level of the second ethene molecule now correspond and combination can
occur (see Figure 27 -6).
chap 27 cyclization reactions 728
vibrating string
+ \/ ., \/
nodes"
"if ^4
"J fc
nodes
+'\ Is'-,
LCAO molecular orbitals
Figure 27-3 Nodes in a vibrating string in comparison with nodes in the
LCAO it molecular orbitals of butadiene.
Figure 27-4 Interaction of p orbitals in ethene.
fi
—
■■A*' : A
9:
"\ /"It
V w
■-■'■:
no
node,
bonding
.!?..
node, anti-bonding
sec 27.5 orbital symmetry and cycloaddition 729
"tfe
--i-V
;+;
::^v: :
,->.
-■'i
■\
••*;
; '--:
:>i.*
3S
,-;;
;+>;
antibonding
■;.-
Ys
-"'-■v'
'■■ + \.
C : +-v
: „^;
■■.'r-:
: '*: :
V
"J
v
ij^
f*i'
II
+
©
f
.';■:
:'':,
.:■"'-
bonding
•+A
; -'"-? :
^ r -'
#
#
>|
■':■;•■
<&:
a*s
:.'*!
=:■.-■■.:■"
■^y :
§§
n
~
CH 2 =
= CH 2
CH 2 =
=CH-
-CH
= CH 2
Figure 27-5 The molecular orbitals of ethene and 1,3-butadiene showing their
p-orbital precursors.
The Diels-Alder reaction is quite different. When both 1,3-butadiene and
ethene are in their ground states, the 1,4 lobes of the highest occupied level
of the diene match in sign those of the lowest unoccupied level of the alkene
and thermal reaction is allowed (see Figure 27-5). (This conclusion is also
reached if the lowest unoccupied level of the diene and highest occupied level
of the alkene are considered.) Photoexcitation of the reactants, however, de-
Figure 27-6 Orbital symmetries and cycloaddition pathways for ethene.
hv
highest occupied lowest unoccupied
thermal addition
mi
highest occupied lowest unoccupied
photochemical addition
chap 27 cyclization reactions 730
stroys this correspondence and 1,4-addition does not occur. Instead, 1,2
addition takes place.
2 ^^
^^
The 1,2 addition is allowed because the 1,2 lobes of the highest occupied
level in the excited state of the diene (the first antibonding level) match in
sign the lobes of the lowest unoccupied level of the alkene (the antibonding
level, also).
Many other cycloaddition reactions have been examined recently from the
point of view of orbital symmetry principles and these principles have been
found to predict not only the effect of thermal activation and photoactivation
but also the correct stereochemistry of the addition compounds. Furthermore,
many cyclization reactions, such as the Diels-AIder reaction, are reversible
and the same considerations are found to apply to the reverse reactions also.
summary
Intramolecular ring closure of bifunctional compounds occurs readily with
hydroxy or amino acids, with hydroxy aldehydes or ketones, with dicarboxylic
acids, and with diesters, provided the reacting groups are favorably situated
with respect to each other.
HO(CH 2 )„C0 2 H
H 2 N(CH 2 )„C0 2 H
HO(CH 2 )„CHO
H0 2 C(CH 2 )„C0 2 H
(CH,). C ~ H
c=o
summary 731
R0 2 C(CH 2 )„C0 2 R
2/.-1 ,
CHCO,R
(CH 2 )„ <y
V CHOH
Formation of five- and six-membered rings is favored, but in the case of
the conversion of diesters to hydroxy ketones (acyloin condensation) very
large rings can also be produced. This reaction has enabled a chain-link
compound called a catenane to be synthesized.
Alkenes dimerize to cyclobutanes under the influence of light, whereas the
reaction of an alkene and a conjugated diene to produce a cyclohexene (the
Diels-Alder reaction) occurs thermally.
The reaction has the following characteristics: electron-withdrawing sub-
stituents Z in the alkene (the dienophile) increase the reaction rate; the con-
figurations of the diene and dienophile are retained in the product showing
that cis addition occurs; and the reaction occurs via a one-step concerted
mechanism.
Photoactivation of a conjugated diene results in preferential formation of
a four-mernbered ring rather than the six-membered Diels-Alder product.
hv
□
2 i^^-
^-
Alkenes react with 1 ,3-dipolar compounds to form five-membered hetero-
cyclic rings.
\
+ Y
o /
The 1,3-dipolar compounds include ozone (0 3 ), organic azides (RN 3 ), nitrite
oxides (RCNO), and diazoalkanes (R 2 CN 2 ).
Fluxional molecules are those that have identical structures and configu-
rations but that can be distinguished either by means of isotopic labeling or
by the effect of their interconversion on their nmr spectrum. A number of
chap 27 cyclization reactions 732
these systems involve the rearrangement of 1,5-dienes via six-membered
cyclic transition states.
This type of reaction is greatly accelerated if the reacting atoms are held in
favorable positions by a network of bonds such as are present in barbaralane
[1] or bullvalene [2].
[1] PI
Oxidative coupling of alkynes, followed by base-catalyzed prototropic re-
arrangement and partial hydrogenation, gives large-ring conjugated poly-
alkenes called annulenes.
CH
n ■ III ► ► '
CH
Alkynes can act as dienophiles in the Diels-Alder reaction and acetylene,
itself, can be polymerized to give cyclooctatetraene.
Whether a cycloaddition will be subject to thermal activation or photo-
activation can be predicted using rules based on orbital symmetry arguments.
The 7i molecular orbitals of alkenes and alkadienes can be formulated as
combinations of p orbitals, the lobes of which have either a positive or nega-
tive sign. Reaction is allowed only between atoms whose lobes have the same
sign when the highest occupied level of one of the reactants and the lowest
unoccupied level of the other reactant are considered.
The allowed reactions are the following:
(1) Thermal alkene-alkadiene cyclization (Diels-Alder reaction).
highest occupied lowest unoccupied level
level of ethene of 1 ,3-butadiene
(or lowest unoccupied level of ethene +
highest occupied level of 1 ,3-butadiene)
(2) Alkene photodimerization.
■:+:i
highest occupied lowest unoccupied
level of the excited level of the ground
state of ethene state of ethene
Reactions that are not allowed include thermally activated concerted al-
kene cyclodimerization and the photoactivated Diels-Alder reaction. When
the latter reaction is attempted, cyclobutanes are formed.
exercises 733
exercises
27-1 What products would you expect from the Diels- Alder addition of tetra-
cyanoethene to cis,trans-2,4-hexa.diene and cw,cw-2,4-hexadiene? Explain.
27-2 Write structures for the products of the following reactions :
N
C 6 H sN V, 150° C 6 H 5 CHO
I C— C 6 H 5
"V
\ (C 2 H 5 ) 3 N CS 2
b. 2 C=N-NHC 6 H 5 _ Ha »
CI
X C=N-OH (C2Hs)3N C6HsCN -
/ -HC1
CI
27-3 The rate of the Diels-Alder addition between cyclooctatetraene and tetra-
cyanoethene is proportional to the tetracyanoethene concentration
[C 2 (CN) J at low concentrations of the addends but becomes independent
of [C 2 (CN) 4 ] at high concentrations. Write a mechanism which accounts for
this behavior.
27-4 The compound bullvalene, Ci H 10 , has the following structure:
a. Write several fluxional forms of this molecule (the total number is
greater than 10 6 ).
b. At 100° equilibration is rapid and at 0° it is slow. How many different
kinds of proton would you expect to be seen in a well-resolved nmr
spectrum at each of these temperatures ?
27-5 Work out a synthesis of [20]annulene from the coupling product of allyl-
magnesium bromide with l,4-dibromo-2-butene, which is reported to be
1,5,9-decatriene.
chapter 28 J
polymjers
chap 28 polymers 737
Polymers are substances made up of recurring structural units, each of which
can be regarded as derived from a specific compound called a monomer. The
number of monomeric units is usually large and variable, a given polymer
sample being characteristically a mixture of molecules with different molecular
weights. The range of molecular weights encountered may be either small or
very large.
The properties of a polymer, both physical and chemical, are in many ways
as sensitive to changes in the structure of the monomer as are the properties
of the monomer itself. This means that to a very considerable degree the
properties of a polymer can be tailored to particular practical applications.
We have already considered several methods of synthesis of monomers and
polymers and mechanisms of polymerization reactions in earlier chapters,
and much of the emphasis in this chapter will be on how the properties of
polymers can be related to their structures.
The thermal polymerization of cyclopentadiene by way of the Diels-Alder
reaction provides a simple concrete example of how a monomer and a polymer
are related.
tetramer polymer
The first step in this polymerization is formation of the dimer, which in-
volves cyclopentadiene' s acting as both diene and dienophile. This step occurs
readily on heating but slowly at room temperature. In subsequent steps, cyclo-
pentadiene adds to the relatively strained double bonds of the first-formed
polymer. These additions require higher temperatures (180° to 200°). If
cyclopentadiene is heated to 200° until substantially no further reaction oc-
curs, the product is a waxy solid having a degree of polymerization n ranging
from two to greater than six.
Polycyclopentadiene molecules have double bonds for end groups and a com-
plicated backbone of saturated fused rings. The polymerization is reversible,
and on strong heating the polymer reverts to cyclopentadiene.
28-1 types of polymers
Polymers can be classified several different ways : according to their structures,
the types of reactions by which they are prepared, their physical properties,
chap 28 polymers 738
polymer chains as
in elastomers and
thermoplastics
cross links
Figure 28-1 Schematic representation of a polymer with few cross links.
or their technological uses. However, these classifications are not all mutually
exclusive.
From the standpoint of general physical properties, we recognize three
types of solid polymers: elastomers (rubbers or rubberlike elastic substances),
thermoplastic polymers, and thermosetting polymers. These categories overlap
considerably but are nonetheless helpful in defining general areas of use and
types of structures. Elastomers (uncured) and thermoplastics typically have
long polymer chains with few, if any, chemical bonds acting as cross links
between the chains. This is shown schematically in Figure 28 ■ 1 .
Such polymers, when heated, normally become soft and more or less fluid
and can then be molded into useful shapes. The main difference between an
elastomer and a thermoplastic polymer is in the degree of attractive forces
between the polymer chains, as discussed in the next section. Thus, although
elastomers, which are not cross-linked, are normally thermoplastic, not all
thermoplastics are elastomers.
Cross links are extremely important in determining physical properties be-
cause they increase the molecular weight and limit the motion of the chains
with respect to one another. Only two cross links per polymer chain are re-
quired to connect together all the polymer molecules in a given sample to
produce one gigantic molecule. As a result, introduction of only a few cross
links acts to greatly reduce solubility and tends to produce a gel polymer,
which, although insoluble, will usually absorb (be swelled by) solvents in
which the uncross-linked polymer is soluble. The tendency to absorb solvents
decreases as the degree of cross linking is increased.
Thermosetting polymers are normally made from relatively low molecular
weight, usually semifluid substances which, when heated in a mold, become
highly cross linked, thereby forming hard, infusible, and insoluble products
having a three-dimensional space network of bonds interconnecting the
polymer chains (Figure 28-2).
Figure 28-2 Schematic representation of the conversion of an uncross-linked
polymer to a highly cross-linked polymer.
heat
uncross-linked polymer highly cross-linked polymer
(heavy lines represent cross links)
sec 28.2 forces between polymer chains 739
physical properties of polymers
28-2 Jorces between polymer chains
Polymers are produced on an industrial scale primarily, although not exclu-
sively, for use as structural materials. Their physical properties are particularly
important in determining their usefulness, be it as rubber tires, sidings for
buildings, or solid rocket fuels.
Polymers that are not highly cross-linked have properties that depend upon
the degree and kind of forces that act between the chains. By way of example,
consider a polymer such as Polythene (polyethene) which, in a normal commer-
cial sample, will be made up of molecules having 1000 to 2000 CH 2 groups
in continuous chains. Since the material is a mixture of different molecules,
it is not expected to crystallize in a conventional way. 1 Nonetheless, X-ray
diffraction shows polyethene to have very considerable crystalline character,
there being regions as large as several hundred angstrom units in length, which
have ordered, zigzag chains of CH 2 groups oriented with respect to one
another like the chains in crystalline low-molecular-weight hydrocarbons.
These crystalline regions are often called crystallites. Between the crystallites
of polyethene are amorphous, noncrystalline regions in which the polymer
chains are more randomly ordered with respect to one another (Figure 28 ■ 3).
These regions essentially constitute crystal defects.
The forces between the chains in the crystallites of polyethene are the so-
called van der Waals or dispersion forces, which are the same forces acting
between hydrocarbon molecules in the liquid and solid states and, to a lesser
extent, in the vapor state. These forces are relatively weak and arise through
synchronization of the motions of the electrons in the separate atoms as they
approach one another. The attractive force that results is rapidly overcome
by repulsive forces when the atoms get very close to one another.
In other kinds of polymers, much stronger intermolecular forces can be
produced by hydrogen bonding. This is especially important in the poly-
amides, such as the nylons, of which nylon (66) or polyhexamethyleneadip-
amide is most widely used.
O H O H
II I II I
-N-C-eCH 2 )rC-N-tCH 2 feN-C-eCH 2 )3-C-N-tCH 2 ^
H 9 H O
6 H 6 H
II I II I
-N-C-fCH^C-N-fCH^N-C-fCHAC-N-fCH^
H p H O
possible hydrogen-bonded structure for
crystallites of nylon (66), polyhexamethyleneadipamide
1 Quite good platelike crystals have been formed from dilute solutions of certain polymers
such as polyethene. In the crystals, the polymer chains seem to run back and forth in
folds between the large surfaces of the plates.
chap 28 polymers 740
The effect of temperature on the physical properties of polymers is very
important to their practical uses. At low temperatures, polymers become hard
and glasslike because the motion of the polymer chains in relation to each
other is slow. The approximate temperature below which glasslike behavior
is apparent is called the glass temperature and is symbolized by T g . When a
polymer containing crystallites is heated, the crystallites ultimately melt;
this temperature is usually called the melting temperature, symbolized as T m .
Usually, the molding temperature will be above T m and the mechanical strength
of the polymer will diminish rapidly as the temperature approaches T m .
Obviously, another temperature of great importance in the practical use of
polymers is the temperature near which thermal breakdown of the polymer
chains occurs. Decomposition temperatures will obviously be sensitive to im-
purities, such as oxygen, and will be influenced strongly by the presence of
inhibitors, antioxidants, and so on. Nonetheless, there will be a temperature
(usually rather high, 200° to 400°) at which uncatalyzed scission of the bonds
in a chain will take place at an appreciable rate, and, in general, you cannot
expect to prevent this type of reaction from causing degradation of the poly-
mer. Clearly, if this degradation temperature is comparable to T m , as it is for
polyacrylonitrile, difficulties are to be expected in simple thermal molding of
the plastic. This difficulty is overcome in making polyacrylonitrile (Orion)
fibers by dissolving the polymer in N,N-dimethylformamide and forcing the
solution through fine holes into a heated air space where the solvent evaporates.
Physical properties such as tensile strength, X-ray diffraction pattern, re-
sistance to plastic flow, softening point, and elasticity of most polymers can
be understood in a general way in terms of crystallites, amorphous regions,
the degree of flexibility of the chains, and the strength of the forces acting
between the chains (dispersion forces, hydrogen bonding, etc.). One way to
approach the problem is to make a rough classification of properties of solid
polymers according to the way the chains are disposed in relation to each
other.
1 . An amorphous polymer is one with no crystallites. If the forces between
the chains are weak and if the motions of the chains are not in some way
severely restricted, such a polymer would be expected to have low tensile
strength and be subject to plastic flow in which the chains slip by one another.
2. An unoriented crystalline polymer is one which is considerably crystal-
lized but has the crystallites essentially randomly oriented with respect to one
another as in Figure 28-3. Such polymers, when heated, often show rather
sharp T m points, which correspond to the melting of the crystallites. Above
T m , these polymers are amorphous and undergo plastic flow, which permits
them to be molded. Other things being the same, we expect T m to be higher
for the polymers with stiff chains (high barriers to internal rotation).
3. An oriented crystalline polymer is one in which the crystallites are ori-
ented with respect to one another, usually as the result of a cold-drawing
process. Consider a polymer such as nylon, which has strong intermolecular
forces and is in an unoriented state like the one represented by Figure 28-3.
If the material is subjected to strong stress, say along the horizontal axis, at
some temperature (most easily above T g ) where at least some plastic flow can
sec 28.2 forces between polymer chains 741
occur, elongation will take place and the crystallites will be drawn together
and oriented along the direction of the applied stress (Figure 28-4).
An oriented crystalline polymer usually has a much higher tensile strength
than the unoriented polymer. Cold drawing is an important step in the pro-
duction of synthetic fibers.
4. Elastomers are intermediate in character between amorphous and crys-
talline polymers. The key to elastic behavior is to have a polymer that has
either sufficiently weak forces between the chains or a sufficiently irregular
structure to be very largely amorphous. The tendency for the chains to orient
can often be considerably reduced by random introduction of methyl groups
which, by steric hindrance, inhibit ordering of the chains. An elastomer needs
to have some crystalline (or cross-linked) regions to prevent plastic flow and,
in addition, should have rather flexible chains (which means T g should be low).
The structure of a polymer of this kind is shown schematically in Figure 28 • 5.
The important difference between this elastomer and the crystalline polymer
of Figure 28 • 3 is the size of the amorphous regions. When tension is applied
and the material elongates, the chains in the amorphous regions straighten
Figure 28-3 Schematic diagram of crystallites (enclosed by dotted lines) in a
largely crystalline polymer.
chap 28 polymers 742
Figure 28-4 Schematic representation of an oriented crystalline polymer
produced by drawing in the horizontal direction. The crystalline regions are
enclosed with dotted lines.
out and become more nearly parallel. At the elastic limit, a semicrystalline
state is reached, which is different from the one produced by cold drawing a
crystalline polymer in that it is stable only while under tension. The forces be-
tween the chains are too weak in the absence of tension to maintain the crys-
talline state. Thus, when tension is released, contraction occurs and the
original, nearly amorphous, polymer is produced.
Probably the best known elastomer is natural rubber, which is a polymer
of 2-methyl-l,3-butadiene (isoprene) with virtually all the double bonds in
the cis configuration.
CH,
CH 2 =C-CH=CH 2
isoprene
natural rubber (c«-polyisoprene)
Figure 28'S Schematic representation of an elastomer in relaxed and stretched
configurations. The crystalline regions are enclosed by dotted lines.
stretch
relax
largely amorphous
polymer
largely crystalline
polymer
sec 28.3 correlation of polymer properties with structure 743
When pure isoprene is polymerized in the laboratory with the help of
radical initiators the product is hard and brittle, quite unlike natural rubber.
This material is similar to a naturally occurring substance known as gutta
percha that is used to make covers for golf balls. It owes its properties to
its trans arrangement of double bonds which allow the chains to lie alongside
one another in a semicrystalline array.
When the double bonds are cis, as in natural rubber, steric hindrance keeps
the chains from assuming a similar ordered structure and the bulk of the
material exists in an amorphous state with randomly oriented chains. When
the cis polymer is stretched, the chains are straightened and tend to become
oriented; but since this is an unfavorable state, the material snaps back to the
amorphous state when released. Although radical polymerization of isoprene
produces gutta percha, Ziegler polymerization (Section 28-5A) gives a cis
polymer that is identical with natural rubber. The correlation between poly-
mer structure and properties are examined further in the next section.
A good elastomer should not undergo plastic flow in either the stretched or
relaxed state, and when stretched should have a "memory" of its relaxed
state. These conditions are best achieved with natural rubber (cw-polyiso-
prene) by curing (vulcanizing) with sulfur. Natural rubber is tacky and under-
goes plastic flow rather readily, but when heated with 1 to 8 % by weight of
elemental sulfur in the presence of an accelerator, sulfur cross links are intro-
duced between the chains. These cross links reduce plastic flow and provide
a sort of reference framework for the stretched polymer to return to when it is
allowed to relax. Too much sulfur completely destroys the elastic properties
and gives hard rubber of the kind used in cases for storage batteries.
28-3 correlation of polymer properties
with structure
With the aid of the concepts developed in the previous section, it is possible
to correlate the properties of many of the technically important thermoplastic
and elastic polymers with their chemical structures. We can understand why
the simple linear polymers such as Polythene (polyethene), polyformaldehyde,
and Teflon (polytetrafluoroethene) are crystalline polymers with rather high
melting points. Polyvinyl chloride, polyvinyl fluoride, and polystyrene as
usually prepared are much less crystalline and have lower melting points;
with these polymers, the stereochemical configuration is very important in
chap 28 polymers 744
determining the physical properties. Polystyrene, made by radical polymeri-
zation in solution, is atactic. This means that, if we orient the carbons in the
polymer chain in the form of a regular zigzag, the phenyl groups will be ran-
domly distributed on one side or the other when we look along the chain, as
shown in Figure 28-6. Polymerization of styrene with Ziegler catalysts
(Sections 4-4H and 28 -5 A) produces isotactic polystyrene, which is different
from the atactic polymer in that all of the phenyl groups are located on one
side of the chain. The difference in properties between the atactic and isotactic
materials is considerable. The atactic polymer can be molded at much lower
temperatures and is much more soluble in most solvents than is the isotactic
product. There are many other possible types of stereoregular polymers, one
of which is called syndiotactic and has the side-chain groups oriented alter-
nately on one side and then the other, as shown in Figure 28 ■ 6.
Polypropene, made by polymerization of propene with Ziegler catalysts,
appears to be isotactic and highly crystalline with a melting point of 175°. It
can be drawn into fibers that resemble nylon fibers although, as might be
expected, they do not match the 270° melting point of nylon and are much
more difficult to dye.
Figure 28-6 Configurations of atactic, isotactic, and syndiotactic poly-
styrene. The conformations are drawn to show the stereochemical relations of
the substituent groups and are not meant to represent necessarily the stable
conformations of the polymer chains.
O^p?" 0^^ H h^=o
0-^i H C^a^ h 0^d^ H
Table 28-1 Representative synthetic thermoplastic and elastic polymers and their uses"
monomer(s)
formula
type of
polymerization
physical
type
°c
Tm,
°c
trade
names
uses
ethene
CH 2 =CH 2
radical
(high pressure)
semi-
crystalline
^0
110
Polythene
Alathon
film, containers,
piping, etc.
Ziegler
crystalline
-120
130
vinyl chloride
CH 2 =CHC1
radical
atactic,
semi-
crystalline
80
180
polyvinyl
chloride,
Geon
film, insulation,
piping, etc.
vinyl fluoride
CH 2 =CHF
radical
atactic,
semi-
crystalline
45
Tedlar
coatings 6
vinyl chloride
vinylidene chloride
CH 2 =CHC1
CH 2 =CC1 2
radical
crystalline
variable
Saran
tubing, fibers, film,
structural materials
chlorotrifluoroethene
CF 2 =CFC1
radical
atactic,
semi-
crystalline
<o
210
Kel-F
gaskets, insulation"
tetrafluoroethene
CF 2 =CF 2
radical
crystalline
<-100
330
Teflon
gaskets, valves, insu-
lation, filter felts,
coatings'"
propene
CH 2 =CHCH 3
Ziegler
isotactic,
crystalline
-20
175
fibers, molded
articles
hexafluoropropene
vinylidene fluoride
CF 2 =CFCF 3
CH 2 =CF 2
radical
amorphous
-23
Viton
rubber articles
Table 284 Representative synthetic thermoplastic and elastic polymers and their uses" {continued)
monomer(s)
formula
type of
polymerization
physical
type
°C
Tm,
°C
trade
names
uses
2-methylpropene
CH 2 =C(CH 3 ) 2
cationic
amorphous
-70
Vistanex,
Oppanol
pressure-sensitive
adhesives
2-methylpropene
CH 2 =C(CH 3 ) 2
cationic
amorphous
butyl
rubber
inner tubes
chloroprene
CH 2 =C(C1)CH=CH 2
radical
amorphous
-40
Neoprene
rubber articles 6
isoprene
CH 2 =C(CH 3 )CH=CH 2
Ziegler, Li
amorphous
(cw-1,4)
-70
28
natural
rubber,
Ameripol,
Coral
rubber
rubber articles,
styrene
CH 2 =CHC 6 H 5
radical
atactic,
semi-
crystalline
85
<200
Styron,
Lustron
molded articles,-
foam
styrene
C-H.2 ^^CriCetls
Ziegler
isotactic
100
230
vinyl acetate
CH 2 =CH0 2 CCH 3
radical
amorphous
40
polyvinyl
acetate
adhesives
vinyl alcohol
(CH 2 =CHOHK
hydrolysis of
polyvinyl
acetate
crystalline
dec.
polyvinyl
alcohol
water-soluble adhe-
sives, paper sizing
vinyl butyral
X C3H 7 '
polyvinyl alcohol
and butanal
amorphous
polyvinyl
butyral
safety-glass laminate
Table 28-1 (continued)
monomer(s)
formula
type of
polymerization
physical
type
°c
T m ,
°C
trade
names
uses
formaldehyde
CH 2 =0
anionic
crystalline
179
Delrin
molded articles
acrylonitrile
CH 2 =CHCN
radical
crystalline
100 9
>200
Orion
fiber
methyl methacrylate
CH 2 =C(CH 3 )C0 2 CH 3
radical
atactic,
amorphous
105
Lucite,
Plexiglas
coatings, molded
articles
anionic
isotactic,
crystalline
115
200
/=\
anionic
syndiotactic,
crystalline
45
160
ethylene glycol tereph-
thalate
H0 2 C^ ^>C0 2 C 2 H 4 OH
ester interchange
between dimethyl
terephthalate and
ethylene glycol
crystalline
56
260
Dacron,
Mylar,
Cronar,
Terylene
fiber, film
hexamethylenediamine
and hexanedioic acid
(adipic acid)
NH 2 (CH 2 ) 6 NH 2
H0 2 C(CH 2 ) 4 C0 2 H
anionic
condensation
crystalline
50
270
nylon,
Zytel
fibers, molded
articles
" Much useful information on these and related polymers is given by F. W. Billmeyer, Jr., A Textbook of Polymer Chemistry, Interscience, New York, 1957; J. K. Stille,
Introduction to Polymer Chemistry, Wiley, New York, 1962; F. Buecne, Physical Properties of Polymers, Interscience, New York, 1962; and W. R. Sorenson and T. W.
Campbell, Preparative Methods of Polymer Chemistry, Interscience, New York, 1961.
6 Exceptional outdoor durability.
c Used where chemical resistance is important.
d Excellent self-lubricating and electrical properties.
e Used particularly where ozone resistance is important.
f These monomers are not the starting materials used to make the polymers, which are actually synthesized from polyvinyl acetate.
9 T g is 60° when water is present.
•0
B
o
•0
a
chap 28 polymers 748
Although both linear polyethene and isotactic polypropene are crystalline
polymers, ethene-propene copolymers prepared with the aid of Ziegler cata-
lysts are excellent elastomers. Apparently, a more or less random introduction
of methyl groups along a polyethene chain reduces the crystallinity sufficiently
drastically to lead to a largely amorphous polymer.
Polyvinyl chloride, as usually prepared, is atactic and not very crystalline.
It is relatively brittle and glassy. The properties of polyvinyl chloride can be
improved by copolymerization, as with vinyl acetate, which produces a softer
polymer (Vinylite) with better molding properties. Polyvinyl chloride can
also be plasticized by blending it with substances of low volatility such as
tricresyl phosphate and di-«-butyl phthalate, which, when dissolved in the
polymer, tend to break down its glasslike structure. Plasticized polyvinyl
chloride is reasonably elastic and is widely used as electrical insulation, plastic
sheeting, and so on.
Table 28 • 1 contains information about a number of representative impor-
tant polymers and their uses.
preparation of synthetic polymers
A prevalent but erroneous notion has it that useful polymers, such as those
given in Table 28-1, can be, and are, made by slap-dash procedures applied
to impure starting materials. In actual fact the monomers used in most large-
scale polymerizations are among the purest known organic substances.
Furthermore, to obtain uniform, commercially useful products, extraordinary
care must be used in controlling the polymerization reactions. The reasons are
simple — namely, that formation of a high-molecular-weight polymer (high
polymer) requires a reaction that proceeds in very high yields, and purification
of the product by distillation, crystallization, and so on, is difficult, if not
impossible. Even a minute contribution of any side reaction that stops poly-
mer chains from growing will seriously affect the yield of high polymer.
In this section, we shall discuss some of the more useful procedures for the
preparation of high polymers, starting with examples involving condensation
reactions.
28-4 condensation polymers
There is a very wide variety of condensation reactions 2 that, in principle,
can be used to form high polymers. However, as explained above, high poly-
mers can only be obtained in high-yield reactions, and this limitation severely
restricts the number of condensation reactions having any practical import-
ance. A specific example of an impractical reaction is the formation of poly-
tetramethylene glycol by reaction of tetramethylene bromide with the sodium
salt of the glycol.
2 A condensation reaction is usually taken to mean one in which two molecules react to
split out water or some other simple molecule.
sec 28.4 condensation polymers 749
NaO-fCH^ONa + Br(CH 2 ) 4 Br
-fO-f CH^OJr + Na Br
It is unlikely that this reaction would give useful yields of any very high
polymer because E2 elimination, involving the dibromide, would give a
double bond end group and prevent the chain from growing.
A. POLYESTERS
A variety of polyester-condensation polymers are made commercially. Ester
interchange (Section 13-8) appears to be the most useful reaction for prepa-
ration of linear polymers (see Figure 28-7).
Figure 28-7 Reactions used to prepare the polymers Dacron and Lexan.
CH,0 2 C
a y-C0 2 CH 3 + HOCH 2 CH 2 OH
dimethyl terephthalate ethylene glycol
-200°
O
metal oxide catalyst
O-C-4 >-C-0-CH 2 -CH 2 + + CH 3 OH
polyethylene glycol terephthalate
(Dacron)
O
/=\ II
HO
CH,
CH 3
bisphenol A
OH + (C 6 H<0),CO
diphenyl
carbonate
300°
CH 3 O
°~\ //~°\ \ / °~ C+ " + CfiH5 ° H
CH 3
polybisphenol A carbonate
(Lexan)
chap 28 polymers 7S0
-0-CH 2 . CH 2 -
CrK
1
-o-
o
II II
■ C M C "°-
CH 2 . CH /CH 2 -
1
-0-
II II
-C C-
1
O
|
\J
o
1
O
^f C=0
r
^c=o
^x=o
L
\^C=0
1
1
CH
-O-CHr ^CH 2 -
-o-
-c c-o
II II
1
CH
CH2 CH2""
-0-
Q
-C c—
II II
o o
Figure 28-8 Glyptal resin.
Thermosetting space-network polymers are often prepared through the
reaction of polybasic acid anhydrides with polyhydric alcohols. A linear poly-
mer is obtained with a bifunctional anhydride and a bifunctional alcohol, but
if either reactant has three or more reactive sites, then formation of a three-
dimensional polymer is possible. For example, two moles of glycerol can
react with three moles of phthalic anhydride to give a highly cross-linked resin,
which is usually called a glyptal (Figure 28 • 8).
B. NYLONS
A variety of polyamides can be made by heating diamines with dicarboxylic
acids. The most generally useful of these is nylon (66), the designation (66)
arising from the fact that it is made from the six-carbon diamine hexamethyl-
enediamine, and the six-carbon dicarboxylic acid, hexanedioic acid (adipic
acid).
H0 2 C(CH 2 ) 4 C0 2 H + NH 2 (CH 2 ) 6 NH 2
280°
o o
II II H H
C(CH 2 ) 4 C-N-fCH 2 )s-NH- + H,0
The polymer can be converted into fibers by extruding it above its melting
point through spinnerettes, then cooling and drawing the resulting filaments.
It is also used to make molded articles. Nylon (66) is exceptionally strong and
abrasion resistant.
The starting materials for nylon (66) manufacture can be made in many
ways. Apparently, the best route to adipic acid is by air oxidation of cyclo-
hexane by way of cyclohexanone.
sec 28.4 condensation polymers 75 1
O
H 2 II
XL ,C^ C0 2 H
HX" "CH 2 ^^ H 2 C- -CH 2 ^o^ / 2
I I — — 77* I I » (<-H 2 ) 4
H 2 C^ c /CH 2 - H ^° H 2 C^ C /CH 2 \ CQ2H
Hexamethylenediamine is prepared from the addition product of chlorine to
butadiene (Section 6 • 2) by the following steps :
Ci 2 CH 2 -CH=CH-CH 2 + CH 2 =CH-CH-CH 2
CH 2 =CHCH=CH 2 <• I I -II
CI CI CI CI
2 NaCN H 2
► NCCH,CH=CHCH 2 CN ► H 2 N(CH 2 ) 6 NH 2
—2 Nad " metal
catalyst
Both the 1,2- and 1,4-chlorine addition products give the same dinitrile with
sodium cyanide.
Nylon (6) is obtained by the polymerization of £-caprolactam.
.C-c ° °
H 2 C \ A II II
2 | NH ^— -CH 2 -C-NH-CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -C-NH-
h >%Jh 2
H 2
Note that here the intramolecular interaction between amino and carboxyl
groups (lactam formation) is replaced by intermolecular interaction (poly-
amide formation). e-Caprolactam is prepared by the Beckmann rearrange-
ment (Section 16- 1E2) of cyclohexanone oxime, which can be made, in turn,
from cyclohexanone.
C. PHENOL-FORMALDEHYDE (BAKELITE) RESINS
One of the oldest-known thermosetting synthetic polymers is made by con-
densation of phenol with formaldehyde using basic catalysts. The resins that
are formed are known as Bakelites. The initial stage in the base-induced re-
action of phenol and formaldehyde yields a hydroxybenzyl alcohol. This part
chap 28 polymers 752
of the reaction closely resembles an aldol addition and can take place at either
an ortho or the para position.
0=0"
\=/CH 2 -O e
e / \
O-f VCH,OH
The next step in the condensation is formation of a dihydroxydiphenyl-
methane derivative which for convenience is here taken to be the 4,4' isomer.
ho-*;, ^-ch 2 oh + ^ /)~ OH H2Q> HO
\ /r CH2 ~x /
OH
This reaction is likely to be an addition to a base-induced dehydration
product of the hydroxybenzyl alcohol.
^)l CH ^ H ~ °
°J<q>
CH 2 + i ^O
H«=
-> o-
CH 2
CH, V = /
* HO-4 ,y-CH 2 -l >~OH
Continuation of these reactions to all of the available ortho and para posi-
tions of the phenol leads to a cross-linked three-dimensional polymer
(Figure 28-9).
Figure 28-9 Phenol-formaldehyde resin.
sec 28.5 addition polymers 753
28-5 addition polymers
We have already discussed the synthesis and properties of a considerable
number of addition polymers in this and earlier chapters. Our primary con-
cern here will be with some aspects of the mechanism of addition polymeriza-
tion that influence the character of the polymers formed.
A. VINYL POLYMERIZATION
The most important type of addition polymerization is that of the simple
vinyl monomers such as ethene, propene, styrene, and so on. In general, we
now recognize four basic kinds of polymerization of vinyl monomers — radical,
cationic, anionic, and coordination. The elements of the mechanisms of the
first three of these have been outlined earlier (Section 4-4H). The possibility,
in fact the reality, of a fourth mechanism is forced on us by the discovery of
the Ziegler and other (mostly heterogeneous) catalysts, which apparently do
not involve "free" radicals, cations or anions, and which can and usually
do lead to highly stereoregular polymers. Although a great deal of work has
been done on the mechanism of coordination polymerization, the details of
how each unit of monomer is added to the growing chains is mostly conjecture.
With titanium-aluminum catalysts, the growing chain probably has a C — Ti
bond; further monomer units are then added to the growing chain by co-
ordination with titanium, followed by an intramolecular rearrangement to
give a new growing-chain end and a new vacant site on titanium where a new
molecule of monomer can coordinate.
X -^^ /C H 2
— CH 2 — CH 2 — CH 2 — CH 2 '' ' HjCX"''
— CH 2 -CH 2 — CH 2 — CH 2
► — CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2
Ti''
In the coordination of the monomer with the titanium, the metal is probably
behaving as an electrophilic agent and the growing-chain end may well be
transferred to the monomer as an anion. Since this mechanism gives no ex-
plicit role to the aluminum, it is surely a considerable oversimplification.
Ziegler catalysts polymerize most monomers of the type RCH=CH 2 , pro-
vided the R group is one that does not react with the organometallic com-
pounds present in the catalyst.
B. RADICAL POLYMERIZATION
In contrast to coordination polymerization, formation of vinyl polymers by
radical chain mechanisms is reasonably well understood — at least for the
kinds of procedures used on a laboratory scale. The first step in the reaction
is the production of radicals; this can be achieved in a number of different
chap 28 polymers 754
ways, the most common being the thermal decomposition of an initiator,
usually a peroxide or an azo compound.
N — ' o— o ^-^ o
benzoyl peroxide
CHi CHi CHi
| | |
CH 3 -C— N=N— C— CH 3 4 °°' 80 °> 2 CH 3 -C- + N 2
CN CN CN
2,2'-azobis(2-methylpropanonitri!e)
Many polymerizations are carried out on aqueous emulsions of monomers.
For these, water-soluble inorganic peroxides, such as persulfuric acid, are
often employed.
Addition of the initiator radicals to monomer produces a growing-chain
radical which combines with successive molecules of monomer until, in some
way, the chain is terminated. It will be seen that addition to an unsymmetrical
monomer, such as styrene, can occur in two ways.
-* 2X- initiation
>-CH-CH 2 X
/ — > V_/
X ' + \ /-CH=CH,
\ /-CH-CH 2
All evidence on the addition of radicals to styrene indicates that the process
by which X- adds to the CH 2 end of the double bond is greatly favored over
addition at the CH end. This direction of addition is in accord with the con-
siderable stabilization of benzyl-type radicals relative to alkyl-type radicals
(see Section 24-2). Polymerization will then result in the addition of styrene
units to give phenyl groups only on alternate carbons ("head-to-tail"
addition).
CsHU CeHs C 6 Hs
I II
X-CH 2 -CH- ► X-CH 2 -CH-CH 2 -CH-
> X-CH 2 -CH-CH 2 -CH-CH 2 -CH-
I I I
C6H5 CeHs CeHs
In general, we predict that the direction of addition of an unsymmetrical
monomer will be such as to give always the most stable growing-chain radical.
The process of addition of monomer units to the growing chain can be
interrupted in different ways. One is chain termination by combination or dis-
proportionation of radicals. Explicitly, two growing-chain radicals can com-
sec 28. S addition polymers 755
bine with formation of a carbon-carbon bond, or disproportionation can
occur with a hydrogen atom being transferred from one chain to the other.
X-\-CH 2 -CH^CH 2 -CH- + -CH-CH^CH-CHj^X
/ C,,H 5 \ C 6 H 5 C„H 3 /C 6 H 5 \
4 r CH 2 -CH-/CH 2 -CH-CH-CH 2 -\CH-CH 27 [x
combination
. > X-r-CH
C„H 5 \ C„H 5 C 6 H 5 /c b H 5
H 5 \ C„H 5 C 6 H 5 /■
I-£cH = CH + CH 2 -CH 2 -\
-b"5
-* X-VCH 2 -CH-/CH = CH + CH 2 -CH 2 -VCH-CH 2 ^X
disproportionation
The disproportionation reaction is the radical equivalent of the E2 reaction.
: C>Vc— + ;C— ► c = c + h — c-
Which mode of termination occurs can be determined by measuring the
number of initiator fragments per polymer molecule. If there are two initiator
fragments in each molecule, termination must have occurred by combination.
One initiator fragment per molecule indicates disproportionation. Apparently
styrene terminates by combination; but, with methyl methacrylate, both
reactions take place, disproportionation being favored.
C. CATIONIC AND ANIONIC POLYMERIZATION
Polymerization of alkenes by the cationic mechanism is most important for
2-methylpropene and a-methylstyrene, which do not polymerize well by other
methods, and was discussed earlier in considerable detail (Section 4-4H).
In general, we expect that anionic polymerization (Section 4 -4H) will occur
when the monomer carries substituents that will tend to stabilize the anion
formed when a basic initiator, such as amide ion, adds to the double bond of
the monomer. Cyano and carbalkoxy groups are favorable in this respect and
R R
e / P./
H 2 N: + CH 2 =C ► H 2 N— CH 2 — C
X H H
it is reported that acrylonitrile and methyl methacrylate can be polymerized
with sodium amide in liquid ammonia. Styrene and isoprene undergo anionic
polymerization under the influence of powerful bases such as butyllithium
and phenylsodium.
Ethylene oxide reacts readily with aqueous hydroxide ion to give either
ethylene glycol or polymers of various chain length, depending on the quantity
of water present.
chap 28 polymers 756
H 2
HOCH 2 CH 2 OH
ethylene glycol
CH 2
I \)^
I /
CH 2
deficient
—^5 > HOCH 2 (CH 2 OCH 2 )„CH 2 OH
polyethylene glycol
Polyethylene glycol polymers can be viscous liquids or waxy solids (Carbo-
wax, Section 10-11) depending on the molecular weight, and all are water
soluble. This property makes them valuable for preserving archeological
relics. Water-logged wooden objects that would warp or disintegrate on being
dried can be repeatedly saturated with polyethylene glycol, thus removing the
water and adding a permanent filler simultaneously. The Swedish warship
Vasa recently raised from the bottom of Stockholm harbor, where it lay for
over three centuries, is being preserved in this way.
D. COPOLYMERS
When polymerization occurs in a mixture of monomers, there will be some
competition between the different kinds of monomers to add to the growing
chain and produce a copolymer. Such a polymer will be expected to have
quite different physical properties than a mixture of the separate homopoly-
mers. Many copolymers, such as butadiene-styrene, ethene-propene, Viton
rubbers, and vinyl chloride-vinyl acetate plastics are of considerable commer-
cial importance.
28-6 naturally occurring polymers
There are a number of naturally occurring polymeric substances that have a
high degree of technical or biological importance. Some of these, such as
natural rubber, cellulose, and starch have regular structures and can be re-
garded as being made up of single monomer units. Others such as wool, silk,
and deoxyribonucleic acid are copolymers. We have considered the chemistry
of most of these substances in some detail earlier and we shall confine our
attention here to silk, wool, and collagen.
A. SILK
Silk fibroin is a relatively simple polypeptide, the composition of which varies
according to the larva by which it is produced. The commercial product,
obtained from the cocoons of mulberry silk moths, contains glycine, L-ala-
nine, L-serine, and L-tyrosine as its principal amino acids. Silk fibroin has
an oriented-crystalline structure. The polypeptide chains occur in sheets, each
chain with an extended configuration parallel to the fiber axis (not the a helix,
Figure 17-7), and hydrogen bonded to two others in which the directions of
the peptide chain are reversed (Figure 28-10).
sec 28.6 naturally occurring polymers 757
/ \ / \
"0=C N-H -0=C N— H—
CHR RHC CHR RH^
/ \ / \
-H— N C=0-H-N C = 0-
\ / \ /
C=0-H-N C=0~-H-N
RHC CHR RHC 7 X CHR
\ / \ /
N-H— 0=C N-H— 0=C
/ \ / \
-0=C N-H-0=C N-H-
CHR RHC N CHR RHC X
/ \ / \
--H-N C=0-H— N C=0-
\ / \ /
^ C =0-H-N C =o-H-N
RHC CHR RHC X X CHR
\ / \ /
N— H— 0=C N-H — 0=C
/ \ / \
Figure 28-10 Hydrogen-bonded structure of silk fibroin. Note that the
peptides run in different directions in alternate chains.
B. WOOL
The structure of wool is more complicated than that of silk fibroin, because
wool, like insulin (Section 17-4), contains a considerable quantity of cystine
(Table 17 • 1), which provides disulfide cross links between the peptide chains.
These disulfide linkages play an important part in determining the mechanical
properties of wool fibers because, if the disulfide linkages are reduced, as with
ammonium thioglycolate solution, the fibers become much more pliable.
RCH 2 -S-S-CH 2 R + 2 HSCH 2 CC- 2 NH 4 ► RCH 2 SH + HSCH 2 R
(wool disulfide cross link)
+ NH 4 2 CCH 2 -S-S-CH 2 C0 2 NH 4
Advantage is taken of this in the curling of hair, thioglycolate reduction
being followed by restoration of the disulfide linkages through treatment with
a mild oxidizing agent while the hair is held in the desired, curled position.
C. COLLAGEN
The principal protein of skin and connective tissue is called collagen and is
primarily constituted of glycine, proline, and hydroxyproline. Collagen mole-
cules are very long and thin (14 A x 2900 A), and each appears to be made up
of three twisted polypeptide strands. When collagen is boiled with water, the
strands come apart and the product is ordinary cooking gelatin. Connective
tissue and skin are made up of fibrils, 200 to 1000 A wide, which are indicated
by X-ray diffraction photographs to be composed of collagen molecules
running parallel to the long axis. Electron micrographs show regular bands,
about 700 A apart, across the fibrils. It is believed that these correspond to
chap 28 polymers 758
700 A
| -*-l h«- 1 !— — 2900 A H
Figure 28-1 1 Schematic diagram of collagen molecules in a fibril so arranged
as to give the 700-A spacing visible in electron micrographs.
collagen molecules, all heading in the same direction but regularly staggered
by about a fourth of their length (Figure 28 • 1 1).
The conversion of collagen fibrils to leather presumably involves formation
of cross links between the collagen molecules. Various substances can be used
for the purpose, but chromium salts act particularly rapidly.
28-7 dyeing of Jibrous polymers
Many fibrous polymers from synthetic and natural sources are used in the
manufacture of fabrics, and the need for a variety of methods and a variety
of dyes should be clear from the chemical diversity of these polymers. At the
nonpolar extreme are substances such as polypropene, a long-chain hydro-
carbon; in the middle is cotton, a polyglucoside with ether and hydroxyl
linkages; at the polar end is wool, a polypeptide structure, cross-linked by
cystine and containing free acid and amino groups.
In virtually all dyeing processes the dye must do more than color the surface
of the fiber. It must also penetrate the fiber and not be removed during wash-
ing and cleaning operations. Thus, a water-soluble color applied directly to
medium- or non-polar fibers normally is poorly wash-fast, and some stratagem
has to be developed to keep it in the fiber. Some of the methods of producing
wash-fast dyes follow.
A. DYES WITH POLAR GROUPS
Substitution of polar groups such as amino and sulfonic acid groups into
colored molecules often improves wash-fastness by enabling the dye to com-
bine with polar sites in the fiber. This is a particularly useful technique with
wool and silk, both of which are polypeptides and contain many strongly
sec 28.7 dyeing of fibrous polymers 759
polar groups. Martius Yellow (Section 26-2), which is strongly acidic, is a
simple direct dye for wool and silk. For cotton, linen, and rayon, which are
cellulose fibers, it is more difficult to achieve wash-fast colors by direct dyeing.
Congo Red was the first reasonably satisfactory direct dye for cotton. It has
polar amine and sulfonate groups which, in the fiber, can form hydrogen
bonds to the cellulose ether and hydroxyl groups and to other dye molecules,
thus reducing its tendency to be leached out in washing.
Congo Red
B. DISPERSE DYES
The use of water-insoluble, fiber-soluble (" disperse ") dyes is helpful for many
of the medium- and less-polar fibers. Such dyes usually give true solutions in
the fiber — the absorption of the dye not being dependent on combination
with a limited number of polar sites. Disperse dyes are usually applied in the
form of a dispersion of finely divided dye in a soap solution in the presence
of some solubilizing agent such as phenol, cresol, or benzoic acid. The process
suffers from the fact that usually the absorption of dye in the fiber is slow and
is best carried out at elevated temperatures in pressure vessels.
l-Amino-4-hydroxyanthraquinone is a typical dye which can be used in
dispersed form to color Dacron (polyethylene glycol terephthalate). Absorp-
tion of this dye is a solution process, as indicated by the fact that, even up to
high dye concentrations in the fiber, the amount of dye in the fiber is directly
proportional to the equilibrium concentration of dye in the solution.
OH
l-arnino-4-hydroxyanthraquinone
(red-violet solid, used to dye fabrics pink)
C. MORDANT DYES
One of the oldest known methods of producing wash-fast colors is with the
aid of metallic hydroxides to form a link between the fabric and the dye. The
production of cloth dyed with "Turkey red," the coloring material of the
root of the madder plant, using aluminum hydroxide as a binder or " mordant,"
has been carried out for many centuries. The principal organic ingredient of
chap 28 polymers 760
Turkey red has been shown to be 1,2-dihydroxyanthraquinone ("alizarin")
and this substance is now prepared synthetically from anthraquinone.
1 ,2-dihydroxyanthraquinone
(alizarin)
Mordant dyes are useful on cotton, wool, or silk, and are applied in a
rather complicated sequence of operations whereby the cloth is treated with
a solution of a metallic salt in the presence of mild alkali and a wetting agent
for the purpose of forming a complex of the fiber with the metal cation. The
dye is then introduced and an insoluble complex salt (often called a "lake")
is formed in the fiber. With alizarin and aluminum hydroxide, it is probable
that the binding to the dye involves salt formation at the 1-hydroxyl and
coordination to aluminum at the adjacent carbonyl group.
fiber
X)H
Apparently, this chelated type of structure is important in contributing to
the excellent light-fastness of most mordant dyes.
A variety of metals can be used as mordants, but aluminum, iron, and
chromium are most commonly used. Mordant dyes normally have reasonably
acidic phenolic groups and some kind of an adjacent complexing group which
fills the function of the carbonyl group in alizarin.
D. VAT DYES
Another and very effective way of making fast colors is to introduce the dye
in a soluble form (which may itself be colorless) and then generate the dye in
an insoluble form within the fiber. Most commonly, the soluble form of the
dye is a reduced form, the dye being produced by oxidation. The overall
process is known as "vat dyeing," the name arising from the vats used in the
reduction step.
The famous dyes of the ancients, indigo and Tyrian purple (royal purple),
can be applied this way; reduced, soluble forms of these dyes occur naturally.
In the case of indigo, this is a glycoside, indican, which occurs in the indigo
sec 28.7 dyeing of fibrous polymers 761
plant. Enzymic or acid hydrolysis of indican gives 3-hydroxyindole (" in-
doxyl"), which exists in equilibrium with the corresponding keto form.
indoxyl
CH,
Air oxidation of indoxyl produces indigo probably by a radical mech-
anism (Figure 28-12).
Figure 28-12 Preparation of indigo from indoxyl.
leucoindigo (indigo white)
indigo
chap 28 polymers 762
The last stage of this reaction, the oxidation of leucoindigo, will be seen to
resemble conversion of hydroquinone to quinone. X-Ray studies have shown
that indigo has the trans configuration of the double bond. Indigo is very
insoluble in water and most organic solvents. It absorbs strongly at 5900 A.
In the ordinary dyeing process, indigo is reduced to the colorless leuco form
which, as an enol, is soluble in alkaline solution and is applied to fabric in
this form. That alkaline solutions are required for solubilization of the leuco
form of most vat dyes restricts the use of such dyes to fabrics such as cotton
and rayon which, unlike wool and silk, are reasonably stable under alkaline
conditions.
Oxidation of the leuco form to the dye in the fiber can be achieved simply
with oxygen of the air; but this is slow, and it is more common to regenerate
the dye by passing the fabric, which has absorbed the leuco form of the dye,
into a solution containing chromic acid or perboric acid.
summary
Polymers can be classified on the basis of their physical properties as elasto-
mers (elastic substances), thermoplastic polymers (substances that flow when
heated), or thermosetting polymers (rigid, insoluble, amorphous substances
possessing cross links between the polymer chains). Polymers that are not
cross-linked may be partly crystalline by virtue of van der Waals forces or
hydrogen bonds causing ordering of the chains. These substances become
glasslike at low temperatures (T g ) and begin to liquefy when heated above the
melting temperature (T m ).
Atactic polymers have a random orientation of groups along a chain
whereas isotactic polymers have the groups oriented in the same direction.
Syndiotactic polymers have a regular alternating orientation of the groups.
Synthetic polymers can be prepared by condensation reactions between:
(a) esters or anhydrides and alcohols
R0 2 C-Z-C0 2 R + HO-Y-OH
O + HO-Y— OH
O
O
O
II
-C-O-Y-O-C-Z-C-O-
O
II
-Y-O-C-Z-
(b) carboxylic acids and amines
H0 2 C-Z-C0 2 H + H 2 N-Y-NH 2
o o o
II II II
-> -C-NH-Y-NH-C-Z-C-NH-Y-
(c) phenols and formaldehyde
exercises 763
OH
.CH,-
Addition polymerization of a wide variety of vinyl compounds is brought
about by radical initiators (peroxides or azo compounds). Chain growth is
CH 2 =CHZ '—* -CH 2 -CH-CH 2 -CH-CH 2 -CH-
I I I
z z z
terminated by radical disproportionation or by radical combination.
Cationic and anionic polymerization is also possible with certain monomers.
Naturally occurring polymers include cellulose and starch (polymers of
glucose), rubber (a cis polymer of isoprene), nucleic acids (copolymers of
substituted pentoses and phosphoric acid), wool, silk, and collagen and pro-
teins in general (polypeptide copolymers).
Four general procedures for dyeing fibrous polymers are (a) direct dyeing —
useful with silk and wool, which are proteins and contain highly polar groups,
and sometimes with cellulose fibers such as cotton, linen, and rayon; (b) dis-
perse dyeing, direct solution of the dye in the fiber — useful with Dacron;
(c) mordant dyes, formation of a complex of a metal salt, dye, and fiber —
useful with cotton, wool, or silk; (d) vat dyeing, oxidation of a soluble form
of a dye to give an insoluble form within the fiber — useful with cotton and
rayon.
exercises
28-1 Write a reasonable mechanism for the thermal depolymerization of cyclo-
pentadiene tetramer. How could you chemically alter the tetramer to make
thermal breakdown more difficult ? Explain.
28-2 Suppose a bottle of cyclopentadiene were held at a temperature at which
polymerization is rapid, but depolymerization is insignificant. Would the
polymerization result in conversion of all of the cyclopentadiene into essen-
tially one gigantic molecule ? Why or why not ? How would you carry on the
polymerization so as to favor formation of polymer molecules with high
molecular weights ?
28-3 Show how each of the following polymer structures might be obtained from
suitable monomers by either addition or condensation. More than one step
may be involved.
a. -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -CH 2 -
b. -N-CH 2 -CH 2 -N-CH 2 -CH 2 -N-CH 2 -CH 2 -
I I I
CH3 CH3 CH3
chap 28 polymers 764
c. — CH— CH— CH— CH— CH— CH—
I II I I I
CH 3 CH 3 CH 3 CH 3 CH 3 CH 3
OOO
II II II
d. -0-CH 2 -CH 2 -C-0-CH 2 -CH 2 -C-0-CH 2 -CH 2 -C-
e. -CH 2 -CH — CH 2 — CH — CH 2 — CH-
II I
0-C-CH 3 O-C-CH3 O-C-CH3
II II II
o o o
/.
-CH 2 -CH-CH 2 -CH-CH 2 — CH-
1 1 1
OH OH OH
9-
-ch 2 ^^ch 2 -ch 2 h^~^ch 2 -ch 2 h^~^ch 2
1
h. -0-CH 2 -CH-CH 2 -0-C-0-CH 2 -CH-CH 2 -0-
O
I
c-o
I
o
1 II
-0-CH 2 -CH-CH 2 -0-C-0-CH 2 -CH-CH 2 -0-
O
28 -4 High-pressure polyethene (p. 1 02) differs from polyethene made with the aid of
Ziegler catalysts (p. 103) in having a lower density and lower T,„ . It has been
suggested that this is due to branches in the chains of the high-pressure mater-
ial. Explain how such branches might arise in the polymerization process
and how they would affect the density and T m .
28-5 Radical-induced chlorination of polyethene in the presence of sulfur
dioxide produces a polymer with many chlorine and a few sulfonyl chloride
(— S0 2 C1) groups, substituted more or less randomly along the chains.
Write suitable mechanisms for these substitution reactions. What kind of
physical properties would you expect the chlorosulfonated polymer to have
if substitution is carried to the point of having one substituent group to
every 25 to 100 CH 2 groups? How might this polymer be cross linked? (A
useful product of this general type is marketed under the name of Hypalon.)
28-6 When polyethene (and other polymers) are irradiated with X rays, cross
links are formed between the chains. What changes in physical properties
would you expect to accompany such cross linking? Would the polyethene
become more elastic? Explain.
Suppose polyethene were cross-linked by irradiation above T m ; what
would happen if it were then cooled ?
exercises 765
28-7 Answer the following questions in as much detail as you can, showing your
reasoning :
a. Why is atactic polymethyl methacrylate not an elastomer?
b. How might one make a polyamide which is an elastomer?
e. What kind of physical properties are to be expected for atactic poly-
propene ?
d. What would you expect to happen if a piece of high-molecular-weight
polyacrylic acid -f-CH,, — CH -)- were placed in a solution of sodium
hydroxide? '
COjH
e. What kind of properties would you expect for high-molecular-weight
poly-p-phenylene ?
H poly-p-phenylene
/ Are the properties, listed in Table 28-1, of polychloroprene as pro-
duced by radical polymerization of chloroprene (2-chlorobutadiene)
such as to make it likely that trans 1 ,4 addition occurs exclusively ?
28-8 The material popularly known as Silly Putty is a polymer having an
— O — Si(R) 2 — O — Si(R) 2 — O — backbone. It is elastic in that it bounces and
snaps back when given a quick jerk but rapidly loses any shape it is given
when allowed to stand. Which of the polymers listed in Table 28-1 is likely to
be the best candidate to have anything like comparable properties ? Explain.
What changes would you expect to take place in the properties of Silly Putty
as a function of time if it were irradiated with X rays (see Exercise 28-6)?
28-9 What kind of a polymer would you expect to be formed if />-cresol were
used in place of phenol in the Bakelite process ?
28-10 Polymerization of methyl methacrylate with benzoyl peroxide labeled with
14 C in the aromatic ring gives a polymer from which only 57% of the 14 C
can be removed by vigorous alkaline hydrolysis. Correlation of the 14 C
content of the original polymer with its molecular weight shows that, on the
average, there are 1.27 initiator fragments per polymer molecule. Write
mechanism(s) for this polymerization that are in accord with the experi-
mental data, and calculate the ratios of the different initiation and termina-
tion reactions.
28-11 The radical polymerization of styrene gives atactic polymer. Explain
what this means in terms of the mode of addition of monomer units to the
growing-chain radical.
28-12 Polyvinyl alcohol prepared by hydrolysis of vinyl acetate (Table 28-1) does
not consume measurable amounts of periodic acid or lead tetraacetate
(Section 1 1 -3). However, the molecular weight of a typical sample of the
polymer decreases from 25,000 to 5000. Explain what these results mean in
terms of the structure of polyvinyl alcohol and of polyvinyl acetate.
chap 28 polymers 766
28-13 Ozonizations of natural rubber and gutta percha, which are both polyiso-
prenes, give high yields of levulinic aldehyde (CH 3 COCH 2 CH 2 CHO) and
no 2,5-hexanedione (CH 3 COCH 2 CH 2 COCH 3 ). What are the structures of
these polymers ?
28-14 Devise a synthesis of polyvinylamine, remembering that vinylamine itself
is unstable.
28-15 How will the side chains on the L-amino acids of silk fibroin be oriented with
respect to the fiber sheets?
28-16 Apparently the economically important chain reaction wool + moths -►
holes + more moths has, as a key step, scission of the disulfide linkages of
cystine in the polypeptide chains by the digestive enzymes of the moth larva.
Devise a method of mothproofing wool which would involve chemically
altering the disulfide linkages (review Chapter 19).
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chap 29 some aspects of the chemistry of natural products 769
The area of organic chemistry that deals primarily with the structures and
chemistry of the compounds which are synthesized by living organisms is
extremely large and highly variegated. Many types of natural products, includ-
ing the carbohydrates, amino acids, proteins and peptides, and alkaloids
(discussed in earlier chapters), have been investigated in such detail that whole
volumes or series of volumes have been, or could be, devoted to their occur-
rence, isolation, analysis, structure proof, chemical reactions, synthesis,
biological function, and the biogenetic reactions by which they are produced.
The chemistry of many classes of natural products is of general interest
quite apart from their biochemical importance. Thus, the chemistry of the
bicyclic terpenes contributed much to the interesting and unusual chemistry
of such ring compounds long before satisfactory syntheses were available
by the Diels-Alder reaction (Chapter 27). Similarly, studies of the chemistry
of the steroids has added as much or more to our knowledge of conformations
in cyclohexane rings as studies of cyclohexane derivatives themselves. Many
other equally cogent examples could be cited.
Our plan in this chapter is to first consider in some detail how the structures
of natural products are established, both by classical procedures and by
modern instrumental methods. We shall then consider in an illustrative way
two rather closely related classes of natural products, terpenes and steroids.
Finally, we discuss some of the aspects and uses of biogenetic schemes for the
syntheses carried on by living systems. Throughout, we attempt to show how
much of the material covered earlier in this book is pertinent to the study of
natural products.
29-1 civetone
The active principle of civet, a substance collected from the scent gland of the
African civet cat, is called civetone. This compound and one of similar nature
called muscone, isolated from a scent gland of the Tibetan musk deer, are
used in preparation of perfumes. Although civetone and muscone do not
themselves have pleasant odors, they have the property of markedly enhancing
and increasing the persistence of the flower essences.
The structure of civetone was established in 1926 by the Swiss chemist
Ruzicka. The starting material for his work was commercial civet imported
from Abyssinia packed in buffalo horns — an inhomogeneous, yellow-brown
unctuous substance, containing 10 to 15% water, intermixed with civet-cat
hairs, and possessing a less-than-pleasant odor. Of several methods of
isolation of the active principle, the most useful involved destruction of the
glycerides present by hydrolysis with alcoholic potassium hydroxide, frac-
tional distillation of the unsaponifiable neutral material under reduced
pressure, and treatment of the distillate of bp 140° to 180° (3 mm) with
semicarbazide hydrochloride in the presence of acetate ion (Section 11-4D).
The crystalline product formed was the semicarbazone of civetone, and the
yield indicated that the starting material contained 1 to 1 5 % of the active
principle. Decomposition of the purified semicarbazone with boiling oxalic
acid solution gave, after reduced-pressure distillation, crystalline civetone
of mp 31°. The pure substance showed no optical activity.
chap 29 some aspects of the chemistry of natural products 770
Civetone is a ketone (an aldehyde would hardly have survived the alkaline
isolation procedure) which was shown by its elemental analysis and molec-
ular weight to be C 17 H 30 O. Saturated open-chain ketones have the general
formula C„H 2 „0 and civetone has four hydrogens less, which means that it
must have a triple bond, or two double bonds, or one double bond and one
ring, or two rings. Civetone reacts with permanganate, gives a dibromide, and
absorbs one mole of hydrogen in the presence of palladium. The presence of
one double bond and one ring is therefore indicated, and a partial structure
can be written as follows :
/
o=c x
C14H3
;c
Oxidation of civetone with cold potassium permanganate solution gave a
dibasic keto acid which was at first thought to be C 16 H 28 5 (loss of a carbon)
but later was shown to be C 17 H 30 O 5 . The formation of this acid confirms the
presence of a ring and shows that each of the double-bonded carbons carries
a hydrogen, because otherwise a dibasic acid with the same number of carbons
could not be formed.
/ f ] CH [O] / -co 2 H
O-C \ C 14 H 2 J II ►0 = C^C 14 H 28 [
A key step in the determination of the structure of civetone was to find out
how many carbon atoms separate the carbonyl group and the double bond.
This was done by oxidation of civetone under conditions such as to lead to
cleavage both at the double bond and at the carbonyl group. Different oxida-
tion procedures gave somewhat different results but in all cases mixtures of
dibasic acids were formed, the mildest conditions leading to formation of
pimelic acid, H0 2 C(CH 2 ) 5 C0 2 H; suberic acid, H0 2 C(CH 2 ) 6 C0 2 H; and
azelaic acid, H0 2 C(CH 2 ) 7 C0 2 H. The formation of azelaic acid indicates that
there is at least one continuous chain of seven CH 2 groups forming a bridge
between the carbonyl group and double bond.
(CH 2 ) 7
o=c . -i- ~^—
- A {c 7 H 14 r CH H °^ u ,/ c ° 2H
Since all the dicarboxylic acids isolated from the oxidation had continuous
chains, Ruzicka inferred that the other seven carbons were also linked up
in a continuous chain and that civetone is actually 9-cycIoheptadecenone.
/ CH ^CH
= C II
Vh 2 ) 7 - CH
9-cycloheptadecen- 1 -one
This was an exciting conclusion at a time when the largest known mono-
cyclic compounds were cyclooctane derivatives, and, along with the demon-
sec 29.1 civetone 771
stration in 1925 of the existence of cis- and trans-decalin (Section 29-4),
provided decisive evidence against the Baeyer theory of angle strain in large
carbocyclic rings (Section 3-4C).
The postulated presence of a cycloheptadecene ring in civetone was sup-
ported by oxidation of dihydrocivetone by chromic acid to heptadecanedioic
acid.
oo 3
/ V H 2 ,Pd / CH 2
° =C \ Jh^^ ° =C \ ^h ch 3 co 2 h,h 20
(CH 2 ) 7 (CH 2 ) 7 " 2
dihydrocivetone
H0 2 C(CH 2 ) 15 C0 2 H
heptadecanedioic
acid
Further evidence was obtained in confirmation of the structure of civetone,
one particularly interesting series of transformations being as follows:
0=C
(CH 2 ) 7 / CH ^^CH
_/ f H Zn(Hg) / CH
(CH 2 ) 7 (CH 2 ) 7
2H :
civetane
Pt
H (CH 2 ) 7 _
\/
C
HO / (CH 2 ) 7 '
dihydrocivetol
CH 2
I
CH,
KHSO 4> 180°
(-H 2 0)
/
HC
,(CH 2 ) 7 __ C
I
\ ^CH 2
CH-fCH 2 ) 6
civetane
The interest in these reactions is the demonstration that the symmetry of the
civetone ring is such that civetane (cycloheptadecene) produced by the Clem-
menson reduction (Section 11-4F) of civetone is identical with civetane
obtained by reduction of civetone to dihydrocivetol and dehydration over
an acidic catalyst.
In some quarters, the structure of a natural product is not regarded as
really confirmed until a synthesis is achieved by an unambiguous route, and
research aimed at such syntheses has been a fascinating and popular part of
organic chemistry for many years. Syntheses of naturally occurring sub-
stances often yield very considerable benefits in the development of new
synthetic reactions and furthermore may offer the possibility of preparing
modified forms of the natural products which are of biochemical or medical
interest.
In the case of civetone, a synthesis was not achieved until long after the
structure was established, but the finding of the cycloheptadecene ring in
civetone led Ruzicka to develop a method for the synthesis of large-ring
compounds which, although now largely superseded by other procedures,
gave the complete series of cyclic ketones from C 9 to C 21 and a number of
higher examples as well.
(CH 2 )„
heat
^ThbT
(CH 2 )„
O + CO, + H,0
chap 29 some aspects of the chemistry of natural products 772
Ruzicka showed that pyrolyzing the appropriate dicarboxylic acid with
thorium oxide gave 20 % of cyclooctanone and 1 to 5 % yields of the higher
ketones. The yields are in the 1 % range from C 9 to C 12 , where conformational
difficulties are to be expected during ring formation (Section 3-4C).
Musk-type odors are found to be associated with the C 14 to C 17 cycloalka-
nones, being particularly strong with cyclopentadecanone, which is available
commercially under the name Exaltone. Interestingly, the odors of civetone
and dihydrocivetone are the same. Further evidence for the presence of
the 17-membered ring in civetone is supplied by the identity of synthetic
cycloheptadecanone with dihydrocivetone. The synthesis of civetone was
reported by Stoll and co-workers in 1948.
29-2 spectroscopic methods in the determination
of the structures of natural products
The use of the types of spectroscopic methods described in Chapter 7 has
greatly reduced the difficulty in determining the structures of the natural
products of medium and low molecular weights. We have given many illustra-
tions of the kind of information which is obtained from ultraviolet, infrared,
and nmr spectroscopy in earlier chapters. Had these methods been available,
their application to the problem of determining the structure of civetone
would have been very helpful, but probably not decisive, for the reason that
civetone is mostly saturated hydrocarbon and distinction between some of the
possible isomers would be difficult if not impossible by spectroscopic methods.
Considerable difficulty can be expected in structure determinations of cyclic
compounds which have several saturated rings with no functional groups to
permit degradation by selective oxidation. A typical case is that of que-
brachamine, an indole alkaloid with a complex polycyclic ringsystem.
'\ J C2H?
H
quebrachamine
The ultraviolet spectrum of quebrachamine is typical of an indole and the nmr
spectrum shows that the indole system is substituted at the 2 and 3 positions.
Oxidation fails to open the saturated ring system, and the only very useful
degradative reaction found so far is distillation with zinc dust at 400°, which
yields a complex mixture of nitrogen compounds, including several pyridine
derivatives.
Fortunately, mass spectrometry is showing great promise in handling
structural problems of just this variety and, rather than try to review the
application of the other forms of spectroscopy to natural products, we shall
sec 29.2 spectroscopic methods and structures of natural products 773
concentrate here on mass spectrometry, which has hardly been mentioned
since Chapter 7.
One important use of mass spectrometry in the quebrachamine problem
was in the identification of the components of the mixture of pyridine bases
formed in the zinc-dust distillation. The mixture was separated by gas chro-
matography (Section 7T) and the fractions identified by their mass spectra
(Section 7-2B).
The procedure for identification of compounds by mass spectrometry is
first to determine mje for the intense peak of highest mass number. In most
cases this peak corresponds to the positive ion M® (a radical cation) formed
by removal of just one electron from the molecule M being bombarded, and
the mje value of M® is the molecular weight.
Removal of a nonbonding electron generally occurs more easily than
removal of an electron from a chemical bond. In the case of compounds such
as amines, ketones, and alcohols, all of which contain nonbonding electrons,
the radical cation M® can be expected to have the following structures:
:0
M RNH 2 R-C-R R-O-R
:6 ffi
M® RNH 2 R-C-R R-O-R
Incorrect molecular weights are obtained if the positive ion M® becomes
fragmented before it reaches the collector, or if two fragments combine to
give a fragment heavier than M®. The peak of M® is especially weak with
alcohols and branched-chain hydrocarbons, which readily undergo frag-
mentation by loss of water or side-chain groups. With such compounds the
peak corresponding to M® may be 0.1 % or less of the total ion intensity.
The pressure of the sample in the ion source of a mass spectrometer is
usually about 1CT 5 mm, and, under these conditions, buildup of fragments to
give significant peaks with mje greater than M® is rare. The only exception to
this is the formation of (M + 1) peaks resulting from transfer of a hydrogen
atom from M to M®. The relative intensities of such (M + 1) peaks are
usually sensitive to the sample pressure and may be identified this way.
With the molecular weight available from the M® peak with reasonable
certainty, the next step is to study the cracking pattern to determine whether
the mje values of the fragments give any clue to the structure. In the mixture
of pyridine derivatives obtained by zinc-dust distillation of quebrachamine,
the principal substance present showed M® at 107 and strong peaks at 106 and
92 (Figure 29T). Loss of one mje unit has to be loss of hydrogen, while loss of
fifteen corresponds to NH or CH 3 . Fragmentation of NH from a pyridine
derivative seems to be a drastic change, but loss of a methyl radical, CH 3 ,
is reasonable, particularly if it leads to a stabilized positive fragment. The mje
value of 107 corresponds to pyridine with one ethyl or two methyl groups.
Using 3-ethylpyridine and 3,5-dimethylpyridine as specific examples, we
could then have fragmentation reactions as follows :
chap 29 some aspects of the chemistry of natural products 774
100
50 I
100
50
100
50
j
, I, ,
1
III. .1,1. ...1
I AM',
1 I
1,
1
', ,1
1
it.. 1
ll. M, Jl
1 1
1 ;J
-
1,
1
1" ' "
ll 1
Li
i, Jl
M
llpllfl
i
1
15
I
M "
40
60
100 rn/e
m.w. 107
a
GH 2 CH 3
107
CrloCHa
m.w. 107
Figure 29-1 Mass spectra of 2-, 3-, and 4-ethyIpyridines. The vertical scale
is relative peak intensity. The spectrum of the C 7 H 9 N base from the zinc-
dust distillation of quebrachamine is the same as that of 3-ethylpyridine.
(By permission from K. Biemann, Mass Spectrometry, Organic Chemical Applications,
McGraw-Hill, New York, f%2.)
sec 29.2 spectroscopic methods and structures of natural products 775
cr CH '
(M)
107
"TO"
CH,
(M)
107
M ffi
107
-CH 3
CHCH,
CH,
H,C
106
H 3 C.
CH,
N 5
92
For both compounds, the fragment of mass 106 is a benzylic-type cation
which is expected to be stabilized by electron derealization, which will
distribute the positive charge over the ring. The fragment of mass 92 would be
a stabilized benzylic cation in the one case and a high-energy phenyl-type
cation in the other. The high intensity of the 92 peak suggests that the com-
pound of mass 107 is 3-ethylpyridine and the identity of their mass spectra and
other properties confirms this assignment.
Demonstration that the mixture of pyridines from zinc-dust distillation of
quebrachamine contains 75% of 3-ethylpyridine provided strong support
for the presence of a 3-ethylpiperidine grouping in the alkaloid.
3-ethylpiperidine
Further evidence on the structure of quebrachamine was obtained by
comparison of its mass spectrum with that of a transformation product [1] of
a related alkaloid of known structure, aspidospermine.
C 2 H 5
CH,0
[1]
chap 29 some aspects of the chemistry of natural products 776
It will be seen that formula [1] is actually that of a methoxyquebrachamine
and, if the methoxy group could be replaced by hydrogen, a synthesis of
quebrachamine would be achieved from aspidospermine, thus establishing the
structure of quebrachamine. Comparison of the mass spectra of [1] and
quebrachamine is much easier and no less definitive. The spectra (Figure 29-2)
at first glance look rather different, but careful examination shows that they
are actually very similar from m/e — 138 downward. Furthermore, virtually
all of the peaks that appear in quebrachamine from 143 up to that of M® (282)
have counterparts in the spectrum of the methoxy compound just 30 units
higher. This difference of 30 mass units is just the OCH 2 by which the molec-
ular weight of the methoxyquebrachamine exceeds the molecular weight of
quebrachamine itself.
Assuming the indole part of quebrachimine does not break up very easily,
we would expect the smallest abundant fragments from that part of the mole-
cule to have masses of 143 or 144.
CH,
C,H S
mol. wt. = 282
CH 2 + C 9 H 17 N
139
CH 3 + C 9 H 16 N-
138
It is significant that the largest fragment from the saturated part of que-
brachamine would then have m/e 138 or 139. From this we can see why
substitution of the methoxyl group affects all peaks of 143 and over, but not
those below this number.
CH,
CH,0
mol. wt. = 312
CH,0
H
=CH 2
+ C
»H, 7 N
73
139
CH,
H
-CH 3
+ c
»H 16 N
174
138
It would be a serious error to imagine that in mass spectra nothing is
observed but simple fragmentation of organic molecules on electron impact.
Actually, even though electron impact produces highly unstable molecular
110
282
125
nucbracharuinc
138
143
1/
96
115
.11.1. ■■■..■■11.
1 1.. ■■iiill. ..1 1 1 .
fe:
ii
157
..iiil.lii iJllil U
199 210
■I'l'- l.l-l
Ik
253
267
JL
90 110 m/e 130
150
170
190
210
i
230
i i i i i I t
250 270 290
110
125
AM
96
LMI
115
'".1 1.
138
M2*
I"'- -lll-'ll- .■»!'
173
V
■ I, llllil
187
CHC )
229 240
283
297
i
90
li i
110 m/e 130
1
150
170
190
210
230
250
270
290
310
Figure 29-2 Mass spectra of quebrachamine and a transformation product, formula [1], of aspidospermine. (By permission from K.
Biemann and J. Am. Chem. Soc.) The peaks at m/e 141 in quebrachamine and 1S6 in [1] correspond to parent ions which bear a double
positive charge, that is, M 2 ®,
chap 29 some aspects of the chemistry of natural products 778
ions, there is a strong tendency for breakdown to occur by chemically rea-
sonable processes (as with the ethylpyridines), and this may involve re-
arrangement of atoms from one part of the molecule to another. An excellent
example of such a rearrangement is provided by the M ffi ion of ethyl
butanoate, which breaks down to give ethene and a radical cation of the enol
form of ethyl acetate.
H 3 c :6 B
H 2 c x. JL
c c
(M e )
116
CH 2
CH 2
28
H 2 CT OC 2 H 5
The cyclic course of this fragmentation is revealed by studies of the mass
spectra of 2-, 3-, and 4-deuterated ethyl butanoate. The 2,2-dideuterio
compound gives the enol ion, now with mass 90; the 3,3-dideuterio isomer
gives the enol ion of mass 88 ; while the 4,4,4-trideuterated ester produces an
ion of mass 89.
D 2 C
I
II
2
(M®)
119
-OC,H 5
D 2 C' O
~C' OC 2 H 5
H 2
CD 2
II
CH 2
30
\ .®
I
H 2 C^ OC 2 H 5
89
29-3
terp<
•enes
The odor of a freshly crushed mint leaf, like many plant odors, is due to the
presence in the plant of volatile C 10 and C 15 compounds, which are called
rerpenes. Isolation of these substances from the various parts of plants, even
from the wood in some cases, by steam distillation or ether extraction gives
what are known as essential oils. These are widely used in perfumery, food
flavorings, and medicines, or as solvents. Among the typical essential oils are
those obtained from cloves, roses, lavender, citronella, eucalyptus, pep-
permint, camphor, sandalwood, cedar, and turpentine. Such substances are of
interest to us here because, as was pointed out by Wallach in 1887, the
components of the essential oils can be regarded as derived from isoprene.
sec 29.3 terpenes 779
CH 3
I
H 2 cr c
H
isoprene head tail
(2-methyl-l,3-
butadiene, C 5 H 8 )
^K^
Myrcene (C 10 H 16 ), a typical terpene, occurs in the oil of the West Indian
bay tree, whose leaves are used in the preparation of bay rum. The carbon
skeleton is clearly divisible into two isoprene units.
II '
H 2 CT ^CH
-\- II
H 2 C. CH 2
CH
II
/ c \
H 3 C CH 3
myrcene
The isoprene units in myrcene (and in almost all other terpenes as well) are
connected in a head-to-tail manner. Because it is time consuming to show all
the carbon and hydrogen atoms of such substances, we shall represent the
structures in a convenient short-hand notation in which the carbon-carbon
bonds are represented by lines, carbon atoms being understood at the junc-
tions or the ends of lines. By this notation, myrcene can be represented by
formulas like the following.
In the past the term terpene was reserved for C 10 hydrocarbons such as
myrcene. Current practice is to designate as terpenes (or isoprenoids or
terpenoids) all compounds that are multiples of the C 5 isoprene skeleton
including hydrocarbons, alcohols, aldehydes, and so on. The C 10 compounds
are monoterpenes, C 15 are sesquiterpenes, C 20 are diterpenes, C 30 are
triterpenes, and so on.
The empirical isoprene rule resulted from Ruzicka's observation that the
majority of the terpene families could be considered as arising from head-to-
tail combinations of isoprene units. Thus, the monoterpene (C 10 ) family
represents two such units, the sesquiterpenes (C 15 ) three, the diterpenes
(C 20 ) four, and so on. Some examples to illustrate this hypothesis are shown
with the head-to-tail isoprene junctions indicated by dashed lines. In the
cases of cyclic terpenes the thinner bonds indicate where subsequent cycli-
zation has taken place.
chap 29 some aspects of the chemistry of natural products 780
Monoterpenes (C 10 )
CH,OH
CH,OH
geraniol
(ginger grass)
CHO
citronellal
(oil of citronella)
nerol
(rose)
CH 2 OH
citronellol
(rose)
limonene
(lemon, orange)
menthol
(peppermint)
ascaridole
(chenopodium oil)
camphor
(camphor tree)
The terpene alcohols shown above have floral odors and are important
perfume ingredients. The aldehydes have much stronger, citruslike odors
and occur in many essential oils such as oil of citronella and oil of lemon.
Ascaridole is interesting in being a naturally occurring peroxide. Camphor
is a volatile solid substance which for centuries was believed to have medicinal
properties. It is now used chiefly as a plasticizer for cellulose nitrate (Section
15-7) and is synthesized commercially from a-pinene (see Exercise 29-12).
camphor
Camphor has a very large molal freezing point depression constant which
makes it useful for measuring molecular weights.
Camphor also produces large changes in the surface tension of water and a
chip of wood with a piece of camphor embedded in one end will be propelled
by the difference in surface pressure produced between the ends as the
camphor spreads on the surface of the water (camphor boat). This effect is
used in a defense mechanism of a tiny water beetle (Stenus bipunctatus), which
when threatened by birds, streaks across the surface of the water by expelling
a mixture of surface-active terpenes from the tip of its abdomen.
Sesquiterpenes (C 15 )
CH 2 OH
.
i
rH 'v
<>Np\
1^1^*1
w
Y^V
1 o —
farnesol
(lily of the valley)
/?-selinene
(oil of celery)
santonin
(Artemisia)
Farnesol, which occurs in lily of the valley and other plants, is a sex
attractant for male insects. Santonin, extracted from the plant Artemisia, has
sec 29.3 terpenes 781
been used for centuries in India as a medicinal because of its anthelmintic
property (ability to destroy intestinal worms).
Diterpenes (C 20 )
CH,OH
,CH 2 OH
phytol
(chlorophyll)
vitamin A
abietic acid
(pine rosin)
Whereas head-to-tail isoprene junctions can be readily picked out in phytol
and vitamin A the situation with abietic acid and mariy of the higher cyclic
isoprenoids is somewhat different because alkyl migrations have taken
place during their formation.
Phytol occurs as an ester of the propanoic side chain of chlorophyll
(Figure 15-1) and as a side chain in vitamin K t (Section 23-7). Abietic acid
is a major constituent of rosin, which is obtained as a nonvolatile residue in
the manufacture of turpentine by steam distillation of pine oleoresin or
shredded pine stumps. Abietic acid is the cheapest organic acid by the pound
and is used extensively in varnishes and as its sodium salt in laundry soaps).
Triterpenes (C 30 )
squalene
(shark liver oil)
lanosterol
(wool fat)
/?-amyrin
(manila elemi)
The cyclic structures of /?-amyrin and lanosterol and the folded conformation
shown for squalene resembles the ring system of the steroids, an extremely
important family of natural products to be discussed in the next section. The
chap 29 some aspects of the chemistry of natural products 782
resemblance has a fundamental basis, as we shall see when we examine the
biosynthesis of terpenes and steroids in Section 29-5.
Tetraterpenes (C 40 )
lycopene
(plant pigment, tomatoes, etc.)
'-carotene
(plant pigment, carrots, etc.)
The long conjugated chains in these compounds are responsible for their
color (Section 7-5).
29-4 steroids
In the discussion of the isoprenoid compounds it was our intention to show
how the occurrence, structures, and properties of a large and important class
of natural products can be correlated. In keeping the discussion within
reasonable bounds it was not possible to show how the various structures
were established, or give any one compound particular attention. With
steroids, we shall take the opposite approach of considering one member of
the class, cholesterol, in some detail and then show only the structures of
some other representative steroids.
The term steroid is generally applied to compounds containing a hydro-
genated cyclopentanophenanthrene carbon sketeton. Many of these com-
cyclopentanophenanthrene
pounds are alcohols, and sometimes the name sterol is used for the whole class.
However, sterol is better reserved for the substances that are actually alcohols.
A. CHOLESTEROL
Cholesterol is an unsaturated alcohol of formula C 27 H 45 OH which has long
been known to be the principal constituent of human gallstones. Cholesterol,
either free or in the form of esters, is actually widely distributed in the body,
sec 29.4 steroids 783
particularly in nerve and brain tissue, of which it makes up about one sixth
of the dry weight. The function of cholesterol in the body is not understood.
Experiments with labeled cholesterol indicate that cholesterol in nerve and
brain tissue is not rapidly equilibrated with cholesterol administered in the
diet. Two things are clear: Cholesterol is synthesized in the body and its
metabolism is regulated by a highly specific set of enzymes. The high specific-
ity of these enzymes may be judged from the fact that the very closely
related plant sterols, such as sitosterol, are not metabolized by the higher
animals, even though they have the same stereochemical configuration of all
groups in the ring and differ in structure only near the end of the side chain.
HO
HO'
cholesterol
sitosterol
The cholesterol level in the blood generally rises with a person's age and body
weight and is usually higher in populations whose diets are rich in animal fats.
Atherosclerosis (hardening of the arteries) in man is often associated with
high cholesterol levels in the blood and, indeed, it is possible to produce the
disease in certain animals by feeding them diets high in cholesterol.
Although cholesterol was recognized as an individual chemical substance
in 1812, all aspects of its structure and stereochemical configuration were not
settled until about 1955. The structural problem was a very difficult one,
because most of cholesterol is saturated and not easily degraded. Fortunately,
cholesterol is readily available, so that it was possible Jo use rather elaborate
degradative sequences which would have been quite out of the question with
some of the more difficultly obtainable natural products.
The first step in the elucidation of the structure of cholesterol was the deter-
mination of the molecular formula, first incorrectly as C 26 H 44 in 1859 and
then correctly as C 27 H 46 in 1888. The precision required to distinguish be-
tween these two formulas is quite high, since C 26 H 44 has 83.82% C and
11.90% H, whereas C 27 H 46 has 83.87 %C and 11.99% H. Cholesterol was
shown in 1859 to be an alcohol by formation of ester derivatives and in 1868
to possess a double bond by formation of a dibromide. By 1 903 the alcohol
function was indicated to be secondary by oxidation to a ketone rather than an
aldehyde. The presence of the hydroxyl group and double bond when com-
bined with the molecular formula showed the presence of four carbocyclic
rings. Further progress was only possible by oxidative degradation.
There is but one point of unsaturation in the cholesterol molecule and
oxidative reactions are not expected to proceed very well. However, chromic
acid has the property of attacking tertiary hydrogens, probably by removal of
H : e and formation of a carbonium ion. Under these conditions, El elimination
is expected, and this is likely to give the most highly substituted alkene which
would then be cleaved by the chromic acid. With the side chain of cholesterol,
chap 29 some aspects of the chemistry of natural products 784
two points of cleavage might be expected. Both processes occur, although the
CH 3 P
* X) +
cholesterol
(partial structure)
J~^y C0 2 H + (CH 3 ) 2 CO
yields are poor. The observation that methyl isohexyl ketone was formed by
cleavage of the side chain was important in that it gave the first identifiable
fragment of known structure. The discovery of a second point of cleavage was
even more significant, because it permitted correlation of cholesterol with
another series of compounds, known as the bile acids. The principal bile
acids are cholic acid [2] and desoxycholic acid [3].
CO,H
HO'
HO-
CO,H
desoxycholic acid
[3]
The presence of a number of substituents on the cycloalkane rings of
molecules such as cholic acid and cholesterol gives rise to various stereo-
chemical possibilities. The three hydroxyl groups in cholic acid are said to
occupy a positions ; that is, they are directed away from the viewer when the
skeleton of the molecule is oriented as shown above. On the other hand the
hydroxyl group in cholesterol and the angular methyl groups in both choles-
terol and cholic acid occupy fj positions. (See Section 15-3 for a similar use
of a and /? in the carbohydrate series).
Both cholic acid and desoxycholic acid occur in bile as sodium salts of
N-acyl derivatives of glycine (RCONHCH 2 C0 2 e Na e ) and taurine, j8-amino-
ethanesulfonic acid (RCONHCH 2 CH 2 S0 3 e Na®). The function of the salts in
bile is to aid in the solubilization and assimilation of fats and hydrocarbons,
such as carotene. The bile acids are obtained by alkaline hydrolysis of the
peptide bonds.
It will be seen that each of the six-membered rings in cholic acid carries a
sec 29.4 steroids 78S
hydroxyl group, and this is most important, because it provides an entry into
the rings by various kinds of oxidative processes. Furthermore, the side chain
is seen to be the same length as in one of the chromic acid- oxidation products
of cholesterol. The general similarity of the structures of the bile acids and
cholesterol, including the stereochemical relations of the rings, strongly
suggests that one is the precursor of the other in the body or that the two have
a common precursor. Tracer experiments have shown that cholic acid can, in
fact, be manufactured from dietary cholesterol.
HO ^
stereochemical configuration and
numbering system of cholesterol
[4]
Proof that cholesterol and the bile acids have the same general ring system
was achieved by reduction of cholesterol to two different hydrocarbons,
cholestane and coprostane, which differ only in the stereochemistry of the
junction between rings A and B.
cholestane
coprostane
The differing stereochemistry at the ring junction is shown in the following
conformational formulas in which the A and B rings are shown in the chair
conformations. (The symbol, — ' — , indicates the ring junction with ring C in
each case.)
CH,
CH
cholestane
[5]
coprostane
[6]
The A and B rings of these compounds can be regarded as derivatives of the
alicyclic compound decahydronaphthalene (decalin), C 10 H 18 , which exists in
stable cis and trans forms.
chap 29 some aspects of the chemistry of natural products 786
H
/ra«,s-decalin cw-decalin
Oxidation of coprostane, but not cholestane, gave an acid which turned out
to be identical with cholanic acid obtained by dehydration of cholic acid at
300° followed by hydrogenation.
CO,H
cholanic acid
Determination of the sizes of the rings in cholesterol and the bile acids was
achieved in part by use of the so-called Blanc rule, which states that a six-
carbon dicarboxylic acid on heating will give a ketone, whereas a five-carbon
dicarboxylic acid will give an anhydride (Section 13-1 IB). Reduction of
cholesterol to cholestanol followed by oxidation yielded a dibasic acid, which
on heating formed a ketone. This indicated the ring on which the hydroxyl
was located to be a six-membered ring.
jS?
H
cholestanol
H 3 C I^S
-H 2 0, -C0 2
-* o
Application of the Blanc rule to dicarboxylic acids obtained by opening the
B ring indicated this ring to be six-membered but gave the wrong answer on
ring C, an anhydride being formed in place of a ketone. The correct ring size
was obtained for ring D by removing the side chain from cholanic acid,
opening the ring by oxidation, and showing that an anhydride was formed on
pyrolysis.
Location of the methyl groups was achieved by extended degradations — the
methyl at C-10 being located by degradation of desoxycholic acid [7] to
a-methyl-a-carboxyglutaric acid [8].
sec 29.4 steroids 787
CO,H
[7]
H 3 C
H0 2 C C0 2 H
[8]
With the wrong size for ring C, it was inevitable that at some stage incorrect
structures would be proposed for cholesterol and the bile acids. Tentative
structures [9] and [10] proposed in 1928 for desoxycholic acid and cholesterol,
respectively, show a resemblance to the structures now known to be correct,
but have a five-membered ring fused to ring A.
HO
HO
[10]
Shortly thereafter, X-ray diffraction measurements indicated sterols to be
extended rather than compact molecules. This evidence combined with the
formation of chrysene and methylcyclopentanophenanthrene [11] from
selenium dehydrogenation of cholesterol led to postulation of the correct ring
structure in 1932.
Figure 29-3 Proton nmr spectrum of cholesterol at 100 MHz as a 10%
solution in deuteriochloroform with reference to TMS at 0.00. At 60 MHz
the chemical shifts are smaller and many of the features of the spectrum
between 0.7 and 2.4 ppm are run together and less distinct. (Spectrum
kindly furnished by Varian Associates.)
!'il)0
~T~
400
.'in i
CH,
groups i
il llz
H
II
-( )
I
_1
4
-OH
I
\ -* **■' I . :
TMS |
■V— |
ppm
chap 29 some aspects of the chemistry of natural products 788
CH,
cholesterol
Se
300°
chrysene
[11]
The absolute configuration of the sterols and bile acids was established in
1955. Cholesterol has eight asymmetric centers and therefore there are 256
possible stereoisomers, but only cholesterol itself occurs naturally.
The proton nmr spectrum of cholesterol at 100 MHz is shown in Figure
29-3. Such spectra are obviously of considerable value in the determination of
the structures of even quite complex natural products. With cholesterol, many
of the protons at or near the functional groups stand out quite clearly.
B. REPRESENTATIVE STEROIDS
The structures and physiological functions of a number of important steroids
are shown in Table 29 T . Total syntheses have been achieved for the important
sterols, sex hormones, and adrenal cortical hormones. The need for large
quantities of cortisone and related substances for therapeutic use in treatment
of arthritis and similar metabolic diseases has led to intensive research on
synthetic approaches for methods of producing steriods with oxygen functions
at C-ll, which is not a particularly common point of substitution in steroids.
The most efficient way of doing this is by microbiological oxidation, and
cortisone can be manufactured on a relatively large scale from the saponin
diosgenin, which is isolated from tubers of a Mexican yam of the genus
Dioscorea. Diosgenin is converted to progesterone, then by a high-yield (80 to
90 %) oxidation with the mold Rhizopus nigricans to 1 1-hydroxyprogesterone,
and finally to cortisone.
CO CH,
COCH,OH
cortisone
sec 29.S biogenesis of terpenes and steroids 789
Two synthetic steroids whose use has implications in the areas of phys-
iology, economics, sociology, and religion are the compounds norethindrone
[12] and mestranol [13]. These and a number of other compounds which are
structurally related to the sex hormones (Table 29-1) can be used to control
ovulation. Mixtures of such compounds are marketed as oral contraceptives
under various names, Enovid, Ortho-Novum, and so on.
H 3 C t"?c»CH
CH 3
[13]
Vitamin D is of special interest as a photochemical transformation product
of ergosterol.
hv
2820 A
ergosterol
HO
vitamin D 2
(X-ray diffraction studies indicate the
transoid configuration of the 6,7 bond
in the crystal)
29 -S biogenesis of terpenes and steroids
Inspection of the structures for the pentacyclic triterpene, jS-amyrin, and
cholesterol shows such a striking resemblance between the carbon skeletons
that it is not hard to imagine that the way in which these substances are
synthesized, their biogenesis, may be closely related.
amynn
cholesterol
chap 29 some aspects of the chemistry of natural products 790
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sec 29.5 biogenesis of terpenes and steroids 791
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chap 29 some aspects of the chemistry of natural products 792
This idea is heightened by the structure of lanosterol, the tetracylic triter-
pene alcohol which occurs alongwith cholesterol in wool fat and has properties
so typical of the sterols that it is better known as a sterol than a triterpene.
CH 3
lanosterol
Positive evidence that terpene and steroid biogenesis are related has been
provided by experiments with carbon-14 labels which show that acetic acid is
their common biological precursor. The general biosynthetic pathway in-
volving polymerization of C 5 units is shown in Figure 29-4.
Acetate is converted to 3,5-dihydroxy-3-methylpentanoic acid (mevalonic
acid) by coenzyme A. Further enzymic action leads to the diphosphate,
isopentenyl pyrophospate (IPP), the phosphoryl donor being ATP. IPP is the
biological equivalent of isoprene which is not itself found in nature.
CH,
o
o
CH, = C
-CH 2 — CH,— O— P— O-P— O e =
I I
o o
e e
isopentenyl pyrophosphate (IPP)
The formation of C 10 compounds occurs by the condensation of one
molecule of IPP with one molecule of its structural isomer, 3,3-dimethyl-
allyl pyrophosphate (3,3-D). This reaction involves a displacement of pyro-
phosphate from 3,3-D by the methylene carbon of IPP and the loss of a proton
from the C-2 position. The compound thus formed is a pyrophosphate
derivative of geraniol and is the precursor of the whole set of monoterpenes.
"o-p 2 o 6 3e + hp 2 o, 3£
geranyl pyrophosphate
Further condensation with another molecule of IPP produces a C 15
pyrophosphate, which turns out to be the precursor not only of the sesquiter-
penes (C 15 ) but also squalene and lanosterol (C 30 ) and the steroids, as shown
in Figure 29-4.
The conversion of squalene to lanosterol is particularly interesting because,
sec 29.5 biogenesis of terpenes and steroids 793
3CH,CO,H
CH 3 OH
coenzyme A CH 2 CH 2
C0 2 H CH 2 — OH
mevalonic acid
enzymic
~„ „ 3G equilibration
0-P 2 0e .
IPP
monoterpenes <-
(C, )
Ci o-pyrophosphate
(geranyl pyrophosphate)
IPP
sesquiterpenes <-
(C 15 )
diterpenes
(C 20 )
C ^-pyrophosphate
IPP
C 20 -pyrophosphate
tetraterpenes
(C 40 )
3,3-D
squalene
(C 30 )
lanosterol
(C 30 )
cholesterol
(C 27 )
Figure 29-4 General biogenetic route to terpenes and steroids starting from
acetic acid.
although squalene is divisible into isoprene units, lanosterol is not, a methyl
being required at C-8 and not C-l 3.
HO
lanosterol
chap 29 some aspects of the chemistry of natural products 794
Some kind of rearrangement is therefore required to get from squalene to
lanosterol. The nature of this rearrangement becomes clearer if we write the
squalene formula in the shape of lanosterol.
squalene
When written in this form, we see that squalene is beautifully constructed
for cyclization to the ring system of lanosterol and this conversion has
recently been shown to occur in both plants and animals via [14], the 2,3-
epoxide of squalene. Acid-catalyzed opening of the epoxide ring and ring
closure in the remainder of the molecule are essentially synchronous and
HO
HO
[16]
produce a carbonium ion [15] which eliminates a proton to give [16], an
isomer of lanosterol. Now if a sequence of carbonium ion-type rearrange-
ments occurs we can see how [16] could be readily converted to lanosterol.
summary 795
HO
HO
ofH 9 ,CH 3 e ,CH 3 s
HO
ianosterol
The evidence is strong that the biogenesis of Ianosterol actually proceeds
by a route of this type. With squalene made from either methyl- or carboxyl-
labeled acetate, all the carbons of Ianosterol and cholesterol are labeled as
predicted. Furthermore, ingenious double-labeling experiments have shown
that the methyl at £-13 of Ianosterol is the one that was originally located at
C-14, whereas the one at C-14 is one that came from C-8.
The conversion of Ianosterol to cholesterol involves removal of the three
methyl groups at the 4, 4, and 14 positions, shift of the double bond at the
B/C junction to between C-5 and C-6, and reduction of the C-24 to C-25
double bond. The methyl groups are indicated by tracer experiments to be
eliminated by oxidation to carbon dioxide.
summary
Elucidation of the structure of a natural product usually involves degradation
to smaller fragments that can be identified with known compounds. Mass
spectrometry can be used to advantage both for producing fragments and for
identifying them, and for determining molecular weights. Fragmentation
patterns in the mass spectrometer are best interpreted by postulating that
stabilized cations will tend to be produced either directly or by rearrangement.
Terpenes (isoprenoid compounds) contain carbon skeletons made by head-
to-tail unions of C 5 isoprene units, for example.
(isoprene)
(myrcene)
head
tail
chap 29 some aspects of the chemistry of natural products 796
Many terpenes contain oxygen, for example, camphor and vitamin A.
The junctions of the isoprene units in these compounds are shown here by
dashed lines and ring-closure positions with arrows.
(camphor)
CH,OH
(vitamin A)
Steroids, which are derivatives of cyclopentanophenanthrene, include
cholesterol (a sterol) and cholic acid (a bile acid). They have the same carbon
HO
HO-
CO,H
(cholesterol)
H
(cholic acid)
skeleton in the rings but differ in configuration as shown.
Studies using carbon- 14 labels have shown that the biogenesis of cholesterol
follows the sequence: acetic acid, mevalonic acid, several isoprenoid pyro-
phosphates, squalene, lanosterol, and cholesterol.
exercises
29-1 Muscone, the active principal of Tibetan musk, is an optically active ketone
of formula Ci 6 H 3 oO. On oxidation it gives a mixture of dicarboxylic acids.
At least two acids of formula C16H30O4 are formed, along with some
dodecanedicarboxylic acid and suberic acid.
Clemmenson reduction of muscone gives an optically inactive hydro-
carbon shown by synthesis to be methylcyclopentadecane. Muscone is not
racemized by strong acids or strong bases, although it does form a benzyli-
dene (=CHC 6 H 5 ) derivative with benzaldehyde and sodium methoxide.
What structure(s) for muscone are consistent with the above experimental
evidence ? Give your reasoning. What additional evidence would be helpful ?
29-2 Explain how use of ultraviolet, infrared, or nmr spectroscopy could be used
to distinguish between the following possible structures for civetone.
a. 9-cycloheptadecenone and 2-cycloheptadecenone
b. m-9-cycloheptadecenone and fraw.s-9-cycloheptadecenone
c. 8-methyl-8-cyclohexadecenone and 9-cycloheptadecenone
d. 8-cycloheptadecenone and 9-cycloheptadecenone
29-3 How could you use deuterium labeling to show that the fragmentation of
3-ethylpyridine which occurs in the mass spectrometer results in loss of the
CH 3 group and not an NH fragment ? Be as specific as possible.
exercises 797
29-4 The relative intensities of (M — 15) peaks for the 2- and 4-ethylpyridines are
much less than for 3-ethylpyridine (see Figure 29-1). Suggest a reason for this.
Can your explanation also account for the fact that intensity ratios (M — 15)/
(M — 1) for the different isomers fall in the ratio 3 > 4 > 2? Explain.
29-5 a. Identify the fragments in the mass spectrum of quebrachamine with m/e
values of 267, 253, 157, and 125. Show your reasoning.
b. The very strong peak at 1 10 in the mass spectrum of quebrachamine has
no counterpart at 172. How might a fragment of 110 mass units be
reasonably formed by breakdown of the primary dissociation products ?
29-6 The mass spectrum of 1-phenylpropane has a prominent peak at mass 92.
With 3,3,3-trideuterio-l-phenylpropane, the peak shifts to 93. Write a
likely mechanism for breakdown of 1-phenylpropane to give a fragment of
mass 92.
29-7 The mass spectra of alcohols usually show peaks of (M — 18), which
correspond to loss of water. What kind of mechanisms can explain the
formation of (M —18) peaks, and no (M — 19) peaks, from 1,1-dideuterio-
ethanol and l,l,l,3,3-pentadeuterio-2-butanol?
29-8 a. Write out all of the possible carbon skeletons for acyclic terpene and
sesquiterpene hydrocarbons that follow the isoprene rule. Do not con-
sider double-bond position isomers.
b. Do the same for monocyclic terpene hydrocarbons with a six-membered
ring.
29-9 The terpene known as alloocimene (Ci Hi 6 ) shows A max at 2880 A and gives
among other products 1 mole of acetone and 1 mole of acetaldehyde on
ozonization. What is a likely structure for alloocimene ? Show your reasoning.
29-10 Write structures for each of the optical and cis-trans isomers that are
possible of the following isoprenoid compounds :
a. myrcene e. /3-selinene
b. farnesol /. oc-pinene
c. limonene g. camphor
d. phytol
29-11 Nerol and geraniol cyclize under the influence of acid to yield a-terpineol.
How could the relative ease of cylization of these alcohols, coupled with
other reactions, be used to establish the configurations at the double bond of
geraniol, nerol, and the corresponding aldehydes, geranial and neral ? Write
a mechanism for the cyclizations.
-OH
a-terpineol
29-12 Camphor can be made on an industrial scale from a-pinene (turpentine) by
chap 29 some aspects of the chemistry of natural products 798
the following reactions, some of which involve carbonium ion rearrange-
ments of a type particularly prevalent in the bicyclic terpenes and the
scourge of the earlier workers in the field trying to determine terpene
structures.
Ti0 2 -H 2
CH 3 CQ 2 H
180° k\ J H®
a-pinene camphene isobornyl acetate
H 2
isoborneol
[O]
camphor
Write mechanisms for the rearrangement reactions noting that hydrated
titanium oxide is an acidic catalyst.
29-13 How many optical isomers of cholic acid are possible?
29-14 Assuming cholesterol has the stereochemical configuration shown below
draw a similar configurational structure for cholic acid (including the
hydroxyl groups).
HO
29-15 When the sodium salt of 12-ketocholanic acid is heated to 330°, 1 mole of
water and 1 mole of carbon dioxide are evolved and a hydrocarbon
" dehydronorcholene " is formed. Selenium dehydrogenation of this sub-
stance gives methylcholanthrene.
CH,
methylcholanthrene
12-ketocholanic acid
What is a likely structure for "dehydronorcholene" and how does the
formation of methylcholanthrene help establish the location of the sterol
side chain on ring D ?
exercises 799
29-16 Using the stereochemical information shown in formulas [2], [4], and [5]
decide whether the following substituents occupy equatorial or axial
positions.
a. the C-19 methyl in cholestane
b. the C-5 hydrogen in cholestane
c. the C-3 hydroxyl in cholesterol
d. the C-3 hydroxyl in cholic acid
e. the C-7 hydroxyl in cholic acid
general index
Abietic acid, 781
Absolute configuration, of alanine, 383
of glyceraldehyde, 382
of lactic acid, 382
of natural amino acids, 383
of optical isomers, 381-384
of tartaric acid, 382
X-ray determination of, 382
Acetaldehyde, acetal from, 288
from ethyne, 279
with hydrogen chloride, 289
infrared spectrum of, 334-335
with methanol, 284
physical properties of, 277
Acetaldol, from acetaldehyde, 306
dehydration of, 306
Acetals, from carbohydrates, 404
formation of, 283-287
hydrolysis of, 287
Acetamide, physical properties of, 435
Acetanilide, infrared spectrum of, 436
nitration of, 606
Acetate radicals, 618
Acetic acid, 190
acid dissociation constant of, 315,
331
in biogenesis, 792
conjugate acid of, 339
with ethanol, 254
infrared spectrum of, 334-335
with methanol, 253-254
physical properties of, 331
Acetoacetic acid, decarboxylation of,
341
Acetoacetic ester condensation (see
Claisen condensation)
Acetoacetic ester synthesis, 361
Acetone, cyanohydrin of, 282-283, 285
diacetone alcohol from, 307-308
halogenation of, 303-304
from isopropyl alcohol, 259
photodissociation, 703
physical properties of, 277
from propyne, 121
Acetonitrile, hydrolysis of, 344
Acetophenone, formation, 565
Acetoxy radicals, 618
Acetyl chloride, with methanol, 252-
253
Acetyl pernitrite, in air pollution, 58
Acetyl radicals, from acetone, 703
Acetylacetone (see 2,4-Pentanedione)
Acetylcholine, 506
Acetylcholinesterase, 506
Acetylene (see Ethyne)
N-Acetyl-D-glucosamine, 412
N-Acetylimidazole, 500
Acid anhydrides (see Carboxylic acid
anhydrides)
Acid catalysis, in organic systems,
497-498
Acid chlorides (see Acyl chlorides)
Acid dissociation constants, definition
of, 13
Acid halides (see Acyl halides)
Acid strengths, and reactivity in S N
reactions, 202
Acrolein, with hydrogen chloride, 312
Acrylic acid, hydration of, 355
with hydrogen bromide, 355
Acrylonitrile, polymer from, 747
polymerization, 755
Acyl cations, 565
Acyl chlorides, amides from, 345, 431-
432, 438
with amines, 345, 431-432, 438
from carboxylic acids, 340
esters from, 345
801
general index 802
formation of, 340
hydrolysis of, 344-345
with lithium aluminum hydride,
349
with organometallic compounds,
232-233
reduction of, 279
from thionyl chloride, 280
Acyl halides, in acylation of arenes,
565
with alcohols, 252-253
Acylation, of amines, 431-432
of arenes, 565-566
of benzene, 651
of heterocyclic compounds, 674-
677
of naphthalene, 575-576
of pyridine, 679
Acyloin condensation, 717
1,4 Addition (see Conjugate addition)
Addition polymers, 753-756
Adenine, in DNA, 480
prebiotic synthesis of, 486
Adenine deoxyriboside, 480
Adenosine, in ATP, 408
in NAD®, 506
structure of, 407-408
Adenosine diphosphate (ADP), from
ATP, 529
ATP from, 509
Adenosine triphosphate (ATP), in bio-
genesis, 792
hydrolysis of, 509, 529
in oxidative phosphorylation, 509
structure of, 408
synthesis from ADP, 509
Adipic acid, acid dissociation constant
of, 357
cyclopentanone from, 358
nylon from, 747, 750
physical properties of, 357
preparation, 750
Adrenal cortical hormones, 788
Adrenaline, 658-659
Aglycone groups, 407, 415
AIBN (see 2,2'-Azobis [2-methylpro-
panonitrile])
Alanine, formation of, 343
physical properties of, 459
prebiotic synthesis, 486
Alanylcysteinylserine, 469
Alcohols, acidic and basic properties,
13, 251-255
with acyl halides, 252-253
from alkenes, 249
from alkyl halides, 249
from carbonyl compounds, 250
with carboxylic acids, 252-255
from cyclic ethers, 234
dehydration of, 256-258
as derivatives of water, 9
by haloform reaction, 306
hydration of, 249
hydroboration of, 249
hydrogen bonding in, 246-249
with hydrogen halides, 255
with Lucas reagent, 255
nomenclature of, 187-190
from organomagnesium com-
pounds, 230-233, 250
oxidation of, 259-260, 278, 306,
336
physical properties of, 245-247,
331
polyhydroxy, 260-262
preparation of, 249-251
reactions involving the C— O
bond, 255-258
reactions involving the O— H
bond, 251-255
reactions of, 251-262
resolution of, 385
spectroscopic properties of, 247-
249
with sulfuric acid, 256
unsaturated, 262
water solubility of, 246
Alcohol :NAD oxidoreductase, 506
Aldehydes, 282-284
from alcohols, 259, 279
with alcohols, 283-287
aldol addition to, 306-309
from alkenes, 279
with amines, 288-289, 433
aromatic, 656-657
Cannizzaro reaction, 293
from carboxylic acids, 279-280
C— H stretching frequency, 294
with Fehling's solution, 293
by formylation, 652-653
from 1,2-glycols, 279, 280-281
halogenation of, 303-306
hydration of, 285
hydrogenation of, 290
general index 803
from nitriles, 280, 349
nmr spectra of, 278, 294
nomenclature of, 275-276
with organomagnesium com-
pounds, 232
oxidation of, 292, 336
physical properties of, 277
polymerization of, 287-288
preparation of, 278-281, 294
purification of, 294
reactions of, 281-294
with sodium bisulfite, 294, 527
spectroscopic properties of, 277-
278
tests for, 294-295
a,/3-unsaturated, 311-312
uv spectra of, 334
Aldol addition, 306-309, 499
to formaldehyde, 752
Aldols, dehydration of, 309
Alizarin (see 1 ,2-Dihydroxyanthra-
quinone)
Alkadienes, complexes with metals,
235
naming of, 82
Alkaloids, 682-684
Alkanes, 46-74
from alkylboranes, 97
bromination of, 119-120
from carbonyl compounds, 291
chemical reactions of, 56-61
combustion of, 56-58
isomers of, 48
nitration of, 61, 442
nomenclature of, 47
in petroleum, 56
physical properties of, 53-56
structure of, 19
substitution of, 59-61
Alkenes, in alkylation of benzene, 564
from ammonium hydroxides, 428
chemical reactions of, 86-103
cis-trans isomerism of, 84
complexes with metals, 235
configuration of, 84
conjugated, bonding in, 127-147
electrophilic addition to, 87-96
hydration of, 497
hydroboration of, 96-97
hydroxy lation of, 286
nomenclature of, 81-83
oxidation of, 96-99, 279, 336, 562
photorearrangement of cis-trans
isomers, 707
polymerization of, 99-103
radical addition to, 94-96
with singlet oxygen, 706
structure of, 19
from vinylboranes, 115
Alkenyl groups, naming of, 82
Alkoxide ions, 251
oxidation of, 260
Alkoxysilanes, 532
Alkyl bromides, from alcohols, 255
from carboxylic acids, 342
from phosphorus tribromide, 256
Alkyl cations (see Carbonium ions)
Alkyl chlorides, physical properties of,
331
from thionyl chloride, 255-256
Alkyl chlorosulfite, from thionyl-
chloride, 256
Alkyl groups, naming of, 49-51
reactivity in El reactions, 208
reactivity in E2 reactions, 206-
207
rearrangement of, 258, 280-281
in S N reactions, 202
Alkyl halides, 217-226
from alcohols, 255-256
with alkoxides, 252
in alkylation of benzene, 564
displacement reactions of, 193-
194
with enolate anions, 310
hydrolyses of, 249
with metals, 228
nomenclature of, 187-190
from organomagnesium com-
pounds, 230-231
physical properties of, 217
preparation of, 218-219
reactions of, 219
solubility of with silver, 203
spectra of, 217-218
uv spectra of, 217-218
Alkyl hydrogen sulfates, alkenes from,
256
displacement of, 256
formation of, 256
Alkyl sulfates, with alkoxides, 252
Alkyl sulfides (see Thioethers)
Alkylation, of amines, 428
of arenes, 564-565
general index 804
of benzene, 651
of carbonyl compounds, 315
of esters, 354
of ketones, 499
of nitrites, 440
of phenols, 631-632
of pyridine, 679
Alkylbenzenes, oxidation, 649
radical halogenation, 650
synthesis, 564-566
Alkylidenephosphoranes, formation,
530
reactions, 531
Alkynes, 111-121
acidity of, 116-117
addition reactions of, 1 1 3-1 1 5
hydration of, 114, 279
hydroboration of, 115
hydrogenation of, 726
naming of, 111
nucleophilic addition to, 115
oxidation of, 114
oxidative coupling, 726
physical properties of, 112
with silver ammonia solution,
116-117
structure of, 19
Alkynide salts, 116-117
Alkynyl groups, naming of, 111
Allene, 83
Allenes, optical isomerism of, 379
Ally] alcohol, reactivity of, 262
Allyl anion, resonance structures of,
139
Allyl bromide (see 3-Bromopropene)
Allyl cation, resonance structures of,
138
Allyl chloride 189, 220-221
Allyl halides, preparation of, 220
reactivity in S N reactions, 221-222
o-Allylphenol, by Claisen rearrange-
ment, 632
from phenol, 631
Aluminum chloride, in alkylation of
arenes, 564
Aluminum oxide, in alcohol dehydra-
tion, 257
American Chemical Society, 52
Amide group, resonance in, 434
Amides, 434-440
acidic properties of, 437
from acyl chlorides, 345
amines from, 439
from anhydrides, 345
basic properties of, 438
dehydration of, 280
from esters, 345
hydrogen bonding in, 435
hydrolysis of, 344-345, 497
infrared spectra of, 435
with lithium aluminum hydride,
349
nmr spectra of, 435
with organomagnesium com-
pounds, 232
physical properties of, 435
preparation of, 438-439, 468
protonation of, 438
reactions of, 439
reduction of, 430, 439
spectral properties of, 435
uv spectra of, 437
Amination, of pyridine, 679
Amine oxides, formation of, 433, 523
optical activity of, 434
rearrangement of, 434
Amines, 421-434
with acid derivatives, 438
with acids, 431
as acids and bases, 13, 426-427,
614-615
acylation of, 431^432
aromatic, 614-620
basic properties, 614-615
in cancer therapy, 429
carcinogenic properties, 620
as derivatives of ammonia, 9
diazonium salts from, 591
halogenation of, 432
hydrogen bonding in, 423-425
infrared spectra of, 424-425
naming of, 190
from nitriles, 280
with nitrous acid, 432, 616-617
nmr spectra of, 425
nomenclature of, 421-423
oxidation of, 432-433
physical properties of, 423-425,
614
preparation of, 428—43 1
reactions of, 431-434
by reduction, 430
spectroscopic properties of, 423-
425
general index 80S
stereochemistry of, 425-426
Amino acid sequence, in peptides, 470
Amino acids, 457-467
acid-base properties of, 458-460
acidic and basic types, 457
analysis of, 463-467
configuration of, 457
essential, 458
lactams from, 715
ninhydrin test, 463-464
with nitrous acid, 463
synthesis of, 458
Amino sugars, 401-402
m-Aminoanisole, formation, 595
4-Aminobiphenyl, carcinogenic pro-
perties, 620
,/3-Aminoethanesulfonic acid, 784
2-Aminoethanol, 421
l-Amino-4-hydroxyanthraquinone,759
Aminomalorionitrile, from hydrogen
cyanide, 486
2-Aminonaphthalene, carcinogenic
properties, 620
p-Aminophenol, acid dissociation con-
stant, 629
diazotization, 618
uv spectrum, 629
2-Aminopyridine, from pyridine, 678
Ammonia, acid dissociation constant
of, 13, 251
base dissociation constant of, 13,
423
bond angles in, 8
derivatives of, 9
physical properties of, 10, 423
Ammonium cyanate, 3
Ammonium hydroxides, formation of,
428
thermal decomposition of, 428
Ammonium salts, nomenclature of,
421-423
in S N reactions, 194
Ammonium sulfide, in reduction of
nitro compounds, 609
Ammonium thioglycolate, 747
Amygdalin, structure and occurrence,
657
Amylopectin, 412
Amylose, 412
^-Amyrin, 781, 789
Analysis, of amino acids, 463-467
of peptides, 469^*70
Anchimeric assistance, 502
Androsterone, 791
Angle strain, in cycloalkanes, 67-68
Anhydrides (see Carboxylic acid an-
hydrides)
Aniline, acid dissociation constant, 614
base dissociation constant of, 423,
427, 614
bromination, 616
from bromobenzene, 595
derealization in, 427
from nitrobenzene, 609
physical properties of, 423
resonance hybrid of, 615
stabilization energy of, 605
tautomer of, 427, 605
uv spectrum, 556, 614
Anilinium ion, resonance hybrid of,
614
Anisaldehyde, in benzoin condensa-
tion, 656
Anisole, cleavage of, 632
formation of, 630
physical properties of, 263
[10] Annulene, structure of, 725
[18] Annulene, synthesis of, 726
Annulenes, 725-726
Anomeric effect, 407
Anomers, of glucose, 404-405
Anthocyanidins, 687
Anthocyanins, 687
Anthracene, bond lengths in, 574
monosubstitution products, 551
physical properties, 553
reactions, 577
resonance hybrid of, 575
uv spectrum of, 557
Antibiotics, 4, 527
streptomycin, 402
Antigen, composition of, 413
Antimony pentafluoride, in super
acids, 13
Antipellagra factor, 684
Antipernicious anemia factor, 681-682
L-Arabinose, structure of, 400-401
Arenes, 549-578
acylation of, 565-566
alkylation of, 564-565
complexes with halogens, 562-563
deuteration of, 567
halogenation of, 562-563,
nitration of, 561-562
general index 806
nmr spectra of, 558
nomenclature of, 549-552
physical properties of, 553
reactions of, 559-577
spectroscopic properties of, 554-
558
sulfonation of, 566
Arginine, physical properties, 461
Aromatic amines {see Arylamines)
Aromatic halides {see Aryl halides)
Aromatic hydrocarbons {see Arenes)
Aromatic side-chain derivatives, 648-
665
Aromatic substitution {see Electro-
philic aromatic substitution, Nucleo-
philic aromatic substitution, etc.)
Aryl cations, from diazonium com-
pounds, 619
Aryl groups, naming of, 550
Aryl halides, 589-598
from diazonium salts, 591
infrared spectra, 590
physical properties of, 590
preparation of, 590-592, 618-619
reactions of, 592-596
reactivity of, 589
Aryl halogen compounds {see Aryl
halides)
Aryl nitrogen compounds, 605-620
Aryl oxygen compounds, 627-643
Arylamines, from nitro compounds,
592
Arylhydrazines, from diazonium salts,
619
Arylmethyl halides, physical proper-
ties, 652
Ascaridole, 780
Ascorbic acid, pK H A of, 418
structure of, 413
Asparagine, physical properties, 461
Aspartic acid, physical properties,
461
Asphalt, from petroleum, 58
Aspidospermine, mass spectrum, 776
structure of, 775
Aspirin, 658
Asymmetric induction, 386-387
Asymmetric synthesis, 386-387
in biochemical systems, 387
Asymmetry, and optical activity, 372-
374
Atherosclerosis, 783
Atomic orbital models, of 1,3-buta-
diene, 142
of pyrrole, 672-673
of trimethylenemethyl, 142
ATP {see Adenosine triphosphate)
Atropa belladonna, atropine from, 684
Atropine, 684
Autoxidation, of ethers, 265
nitroarene catalysis in, 613
Avogadro, A., 3
Axial positions and substituents {see
Cyclohexane)
Azelaic acid, from civetone, 770
Azides, as 1,3-dipoles, 721-723, 731
reduction of, 430
Azines, formation of, 289
Azo compounds, from diazonium
compounds, 443
from hydrazines, 443
Azobenzene, 443
from nitrobenzene, 61 1
2,2'-Azobis(2-methylpropanonitrile)
(AIBN), 443
initiator in radical polymerization,
754
Azomethane, 422, 443
Azoxybenzene, 610
Azulene, rearrangement, 578
resonance hybrid of, 578
Bacteriophage DNA, 484
Bakelites, 751-752
Barbaralane, valence tautomers, 724
Barbituric acid, 685
tautomers of, 723
Barbituric acids, synthesis of, 686
Base catalysis, in organic systems, 499
Base ionization constant, definition of,
13
Beckmann rearrangement, 429-430,439
Benzal chloride, 651
physical properties, 653
radical chlorination, 650
Benzaldehyde, acetals from, 287
in benzoin condensation, 656
benzoin from, 656
phenylalanine from, 458
uv spectrum, 556
Benzedrine, 659
Benzene, acylation, 565-566
alkylation, 564
general index 807
bonding in, 129-133
bromination, 128, 563
deuteration, 567
excited singlet state, 701
heat of combustion of, 129
nitration, 592
physical properties, 553
resonance in, 549
resonance structures of, 132
shape of, 127
stabilization energy of, 128-129
structure, 549
substitution reactions of, 560
sulfonation, 566
thiophene in, 678
uv spectrum, 556-557
Benzene-de , formation of, 567
Benzenediazocyanide, 618
Benzenediazonium chloride, 617
diazo coupling of, 620
Benzenediazonium cyanide, 618
isomers of, 618
Benzenesulfonic acid, formation of, 566
phenol from, 627
Benzhydrol, in photoreduction, 705
Benzhydrol radicals, formation and
dimerization, 704
Benzhydryl chloride, physical proper-
ties, 653
Benzidine, basicity of, 614
carcinogenic properties, 620
from hydrazobenzene, 611
uv spectrum, 614
Benzidine rearrangement, 61 1
Benzilic acid, from benzil, 313
rearrangement of, 313, 321
Benzocaine, 659
Benzofuran, 679
Benzoic acid, acid dissociation con-
stant of, 331
formation of, 649
physical properties of, 331
Benzoic acids, acid dissociation con-
stants of, 661
Benzoin condensation, 656-657
Benzoin, formation of, 656-657
Benzophenone, photoreduction of,
704-705
as photosensitizer, 706
triplet state of, 705
Benzopinacol, by photoreduction,
704-705
/>-Benzoquinone, additions to, 639-640
stabilization energy of, 636
Benzoquinuclidine, basicity of, 622
Benzotrichloride, physical properties
of, 653
reactions of, 651
from toluene, 650
Benzotrifluoride, physical properties
of, 653
Benzoyl peroxide, initiator in radical
polymerization, 754
Benzyl bromide, 589
physical properties of, 653
Benzyl cation, resonance stabilization
of, 653
resonance structures of, 589
Benzyl chloride,
nitration of, 568
physical properties of, 653
radical chlorination of, 650
reactions of, 651
Benzyl fluoride, physical properties of,
653
Benzyl halides, reactivity of,
589
Benzyl iodide, physical properties of,
653
Benzyl radical, resonance hybrid of,
650
Benzyloxycarbonyl group, 471
Benzyne, 596, 627
Betaines, definition of, 531
Biacetyl, formation of, 703
Bicarbonate ion, resonance structures
of, 138
Bile acids, 784
Bile pigments, 681
Biogenesis, of cholesterol, 792-795
of lanosterol, 792-795
of squalene, 792-795
of terpenes and steroids, 789-794
Biphenyl, 550
formylation of, 652
uv spectrum of, 556
Biphenyls, optical isomerism of, 380
structure of, 380
Blanc rule, 786
Boat form, of cyclohexane, 64
Bond angles, in dimethyl ether, 10
in methanol, 10
strain in cycloalkanes, 67-68
in water, 7-8
general index 808
Bond energies, conjugation effects on,
24
relative order of C— H, 60
of silicon compounds, 532
table of, 24-25
Bond lengths, in anthracene, 574
in benzene, 549
boron-nitrogen, 537
in ethane, 35
in ethene, 35
in ethyne, 35
in naphthalene, 574
Bonding, in boron hydrides, 537
in conjugated unsaturated sys-
tems, 127-147
the covalent bond, 5
d orbitals in, 517-520
delocalized, 131
in double bonds, 1 30
electron-deficient, 92
in ethene, 131
in ferrocene, 235
the ionic bond, 5
in organic compounds, 5
in organometallic compounds,
227, 230
polarity of, 6
three-center, 538
Bonds, ir-type, 34
Bonds, cr-type, 34
Borazines, structure of, 537
Boric acid, 536
Boron, organic compounds of, 536-
540
Boron hydrides, addition to alkenes,
96-97
bonding in, 538
Boron trifiuoride, 536
diborane from, 97
etherate of, 264
Bromination, of anthracene, 577
of benzene, 128, 563
of phenanthrene, 577
Bromine, addition to alkynes, 113, 114
addition to cyclohexene, 89
addition to 4-methyl-2-hexene, 86
addition to multiple bonds, 37
with benzene, 128, 563
with 1,5-hexadiene, 127
with 2,4-hexadiene, 127
reaction with alkanes, 60-61
Bromobenzene, 589
from benzene, 128
chlorination of, 590
nitration of, 568
physical properties of, 590
with potassium amide, 595
o-Bromochlorobenzene, preparation
of, 590
/»-Bromochlorobenzene, preparation
of, 590
Bromocyclohexane, conformations of,
67
2-Bromocyclohexanone, formation of,
303
Bromoethane (see Ethyl bromide)
Bromoform, from methyl ketones,
305-306
1-Bromohexane, with ethylene oxide,
265
Bromomethane (see Methyl bromide)
l-Bromo-3-methylbutane, from 3-
methyl-1-butyne, 119
2-Bromo-2-methylbutane, from 2-
methylbutane, 61
solvolysis of, 208
2-Bromo-3-methyl-l-butene, from 3-
methyl-1-butyne, 119
l-Bromo-2-methylpropane (see Iso-
butyl bromide)
4-Bromo- 1 -naphthylamine, diazotiza-
tion of, 591
p-Bromonitrobenzene, with methoxide,
594
Bromonium ions, 91, 134
l-Bromo-2-phenyl-l-propene, by E2
elimination, 707
photoisomerization of, 707
1-Bromopropane (see Propyl bromide)
2-Bromopropane (see Isopropyl bro-
mide)
2-Bromopropanoic acid, substitution
of, 343-344
3-Bromopropanoic acid, from acrylic
acid, 355
3-Bromopropene, 589
with sodium phenoxide, 631
Bromotoluenes, 550
Brucine, 683
as resolving agent, 385
Bullvalene, valence tautomers of, 725
1,2-Butadiene, 82
1,3-Butadiene, 82
conformations of, 133, 719
general index 809
conjugate addition to, 134, 221,
' 719
cycloaddition to, 729
with diethyl maleate, 720
dimerization of, 720
7r-electron systems of, 141-142
excited state of, 1 68, 701
hexamethylenediamine from, 751
with hydrogen chloride, 221
molecular orbitals of, 698, 727-
729
nylon from, 75 1
resonance structures of, 136
Butadiyne, 111
with methanol, 115
Butane, from ethyne, 119
isomers of, 48
in natural gas, 57
physical properties of, 55, 63, 83
1,4-Butanediol, physical properties of,
261
2,3-Butanediol, optical isomers of, 392
2,3-Butanedione, 313, 703
Butanethiol, occurrence, 522
Butanoic acid, 190
acid dissociation constant of, 331
physical properties of, 331
synthesis of, 354
1-Butanol (see w-Butyl alcohol)
2-Butanol (see i-Butyl alcohol)
2-Butanone (see Methyl ethyl ketone)
1,2,3-Butatriene, 82
2-Butenal, 306
1-Butene, infrared spectrum of, 163
naming of, 81
physical properties of, 84
2-Butene, geometric isomers of, 84
c/.y-2-Butene, heat of combustion of, 85
physical properties of, 84-85
trans-2-Butene, heat of combustion of,
85
physical properties of, 84-85
2-Butene ozonide, 97
cw-Butenedioic acid (see Maleic acid)
/raay-Butenedioic acid (see Fumaric
acid)
2-Butenoic acid, from 3-hydroxybu-
tanoic acid, 356
3-Butenoic acid, acid dissociation con-
stant of, 331
physical properties of, 331
reduction of, 340
3-Buten-l-ol, formation of, 340
Butenyne, 111
from ethyne, 115
hydrogenation of, 119
f-Butoxy carbonyl group, 472
n-Butyl alcohol, physical properties of,
247
.y-Butyl alcohol, asymmetry of, 372
from 2-butanone, 373
physical properties of, 247
projection formulas of, 374
/-Butyl alcohol, in acetal formation,
287
from /-butyl chloride, 197, 199,
206-207
manufacture of, 251
from 2-methylpropene, 88
physical properties of, 247, 535
Butyl alcohols, vapor-phase chromato-
gram of, 155
/-Butyl bromide, equilibration with
isobutyl bromide, 94
from propene, 93
Butyl carbitol, physical properties of,
264
n-Butyl chloride, 53
/-Butyl chloride, with aqueous base,
197
/-Butyl compounds (see Isobutyl com-
pounds)
/-Butylamine, base dissociation con-
stant of, 423
oxidation of, 433
physical properties of, 423
/-Butylbenzene, nitration of, 568
physical properties of, 553
/-Butylcarboxaldehyde, acetals from,
287
r-Butylcyclohexane, formation of, 635
4-/-Butylcyclohexyl chloride, confor-
mations of, 71
cis-trans isomers of, 71
4-/-Butyl-4-isopropyldecane, naming
of, 52
/-Butylphenol, hydrogenation of, 635
2-Butylpyridine, from pyridine, 678
2-Butyne, naming of, 111
Butyric acid (see Butanoic acid)
y-Butyrolactam, 467
from ethyl 4-aminobutanoate, 468
formation of, 715
y-Butyrolactone, 467
general index 810
formation of, 715
from 3-hydroxybutanoic acid, 356
Cahn-Ingold-Prelog system, for con-
figuration, 382
Calcium carbide, as a salt of ethyne, 1 1 6
Camphene, from a-pinene, 798
Camphor, 780
in molecular-weight determina-
tion, 157, 780
from a-pinene, 798
as plasticizer, 780
synthesis of, 780
Camphor- 10-sulfonic acid, as resolving
agent, 385
Cancer therapy, drugs in, 429
Cannizzaro, S., 3
Cannizzaro reaction, 294
acids and alcohols from, 650
ofglyoxal, 313, 321
Capell, L. T., 552
e-Caprolactam, polymerization of, 751
Carbanions, in autoxidation, 613
methyl, 32
in nucleophilic addition, 115
in polymerization, 100
stable triarylmethyl, 654
Carbene, from chloroform, 223
from diazomethane, 224
insertion reactions of, 224
from iodomethylzinc iodide, 224
Carbenes, methylene, 32-33
Carbitols, definition of, 264
from ethylene oxide, 266
Carbohydrates, 399-415
classification of, 400^02
with immunological specificity,
413^114
Carbon- 14, in biogenesis experiments,
792
Carbon dioxide, with organomag-
nesium compounds, 232
Carbon monoxide, air pollution from,
58
in methanol formation, 251
poisoning, 681
Carbon tetrachloride, dipole moment
of, 8
as a fire extinguishing fluid, 222
fluorination of, 224
as an infrared solvent, 217
infrared spectrum of, 217-218
from methane chlorination, 28,
60, 222
phosgene from, 222
physical properties of, 222, 535
reactivity in S N reactions, 223
with sodium, 222
toxicity of, 222
Carbonium ions, in alkylation of
arenes, 564
methyl, 32
in polymerization, 101
rearrangements of, 208, 258, 280-
281, 565
relative stability of, 94
stable triarylmethyl, 653-654
Carbonyl compounds, from alkenes
by ozonization, 98
with amines, 288-289
with organometallic compounds,
231-233, 250
oxidation of, 293
reduction of, 250, 290-292
structures of, 252
unsaturated, 310-313
Carbonyl groups, bond energy of, 275
effect of chemical shift, 278
electronic transitions in, 277-278
equilibrium in additions to, 275,
277, 282
with hydrogen cyanide, 282-283
infrared stretching frequencies for,
278
polarity of, 277, 278
reactivity of, 275-277, 281
Carbowax (see Polyethylene glycol)
Carboxyl group, inductive effect of,
356-357
Carboxylate radicals, decarboxylation
of, 342
from diacyl peroxides, 342
in Hunsdieker reaction, 342
in Kolbe electrolysis, 342
Carboxylate salts, solubility of, 332
Carboxylic acid anhydrides, in acyla-
tion of arenes, 565
amides from, 345
with amines, 431-432, 438
esterification of, 345
hydrolysis of, 344-345
with lithium aluminum hydride,
349
general index 811
Carboxylic acids (see also Dicarboxylic
acids), 329-343
acid ionization constants of, 329,
336-337
acidity of, 336-339
from alcohols, 259, 336
from aldehydes, 292, 336
from alkenes, 336
from alkylmalonic esters, 354
basic properties of, 338-339
decarboxylation of, 341-342, 354
derivatives of, 344
from 1,2-glycols, 336
by haloform reaction, 306
halogenation of, 342-343
from hydrocarbons, 336
hydrogen bonding in, 330
hydroxy, 356
by malonic ester synthesis, 336
from methyl ketones, 292
from nitriles, 336
nmr spectra of, 334
nomenclature of, 190-191, 329
odors of, 333
from organomagnesium com-
pounds, 232-233, 336
with phosphorus halides, 340
physical properties of, 330-334
preparation of, 336, 649
reactions of, 339-343
reduction of, 279-280, 340
solubility of, 331-332
spectra of, 334-335
with thionyl chloride, 340
unsaturated, 355-356
uv spectra of, 334
Carboxylic ester formation, 252-255
acid catalysts in, 253-254
equilibrium in, 254-255
mechanism of, 252-255
steric hindrance in, 255
Carboxylic ester interchange, 345
acid-catalyzed, 348-349
base-catalyzed, 348
in condensation polymerization,
749
Carboxylic esters, from acid chlorides,
345
acidic properties of, 350-351
from alcohols, 252-255
alkylation of, 354
amides from, 345, 438
with amines, 345, 438
from anhydrides, 345
anions from, 350-351
condensation of, 352-354
formation and hydrolysis of, 497-
498
hydrolysis of, 344-345, 497, 500
with lithium aluminum hydride,
349
naming of, 191
with organomagnesium com-
pounds, 232-233
reduction of, 349
Carcinogenic compounds, aromatic
amines, 620
polynucleaf hydrocarbons, 553
j3-Carotene, 699-700, 782
Catalase, properties and function of,
478
Catalysis, in acetal formation, 286
in alcohol dehydration, 257
in alkyl chloride formation, 255
in condensation reactions, 288
in cyanohydrin formation, 283
definition of, 495
in dehydration of alcohols, 258
in ester formation, 253-254
in ester interchange, 345
general acid and base, 500-501
in halogenation of carbonyl com-
pounds, 303-304
in hemiacetal formation, 284
heterogeneous and homogeneous,
36, 497
in hydrogenation, 290
intramolecular, 502
in methanol formation, 251
micelles in, 333
nucleophilic, 499-500
in organic systems, 495-503
poisoning of, 279
in reduction of acyl chlorides, 279
specific-acid, 501
Catechol, acid dissociation constant of,
629
structure of, 635
uv spectrum of, 629
Catenane, 718
Celcon, 288
Cellobiose, hydrolysis of, 410
structure of, 408-409
Cellosolves, definition of, 264
general index 812
from ethylene oxide, 266
Cellulose, fibers from, 410
hydrolysis of, 408
structure of, 410
Cellulose acetate, 410
Cellulose nitrate, 410
Cellulose xanthate, 410
Cetane, heat of combustion, 510
Chain reaction, in methane chlorina-
tion, 31
Chain termination, in radical poly-
merization, 754-755
Chair form, of cyclohexane, 64-67
Charge-transfer complexes, of halo-
gens with arenes, 562-563
of polynitro compounds, 612-613
quinhydrones, 638
Chelate ring, in phenols, 634
Chemical Abstracts, 52
Chemical evolution, 486-487
Chemical shift {see also Nuclear mag-
netic resonance spectroscopy)
of enol-OH groups, 315
Chirality, 382
definition of, 372
Chitin, 412
Chloral hydrate, 261
Chlorambucil, 429
Chlorination, of chloromethane, 28-30
of methane, 28-32
photochemical, 28-32, 703
Chlorine, absorption of light by, 30
with alkanes, 59-61
with methane, 28
a-Chloro ethers, from aldehydes, 289
Chloroacetic acid, acid dissociation
constant of, 331, 338
glycine from, 458
physical properties of, 331
Chloroacetone, formation of, 303
o-Chloroanisole, amination, 595
Chlorobenzene, nitration of, 568-569,
571, 606
phenol from, 595, 627
physical properties of, 590
2-Chloro- 1,3 -butadiene, polymer from,
746
1-Chlorobutane {see w-Butyl chloride)
2-Chlorobutanoic acid, acid dissocia-
tion constant of, 331
physical properties of, 331
3-Chlorobutanoic acid, acid dissocia-
tion constant of, 331
physical properties of, 331
4-Chlorobutanoic acid, acid dissocia-
tion constant of, 331
physical properties of, 331
l-Chloro-2-butene, from 1,3-buta-
diene, 221
3-Chloro-l-butene, from 1,3-buta-
diene, 221
Chlorocyclohexane, conformations of,
67
rra/K-2-ChlorocyclohexanoI, from
cyclohexane, 88
Chlorocyclopentane, 62
l-Chloro-2,4-dinitrobenzene, with di-
ethylamine, 593
4-Chloro-2-ethyl-2-buten-l-ol, 187
l-Chloro-2-fluoro-l , 1 ,2,2-tetrabromo-
ethane, nmr spectrum of, 177-178
Chloroform, 60
as an anesthetic, 222
ethanol in, 222
fluorination of, 225
with hydroxide ion, 223
as an infrared solvent, 217
infrared spectrum of, 217-218
from methane chlorination, 60,
222
from methyl ketones, 305-306
phosgene from, 222
physical properties of, 222, 535
solvent properties of, 222
Chloromethane {see Methyl chloride)
Chloromethyl cation, 652
Chloromethylation, of benzene, 652
of heterocyclic compounds, 674—
677
l-Chloro-2-methylbutane, from 2-
methylbutane, 61
l-Chloro-3-methylbutane, from 2-
methylbutane, 61
2-Chloro-2-methylbutane, from 2-
methylbutane, 61
solvolysis of, 208
3-Chloro-2-methylbutane, from 2-
methylbutane, 61
4-Chloro-2-methylbutane-2-sulfonic
acid, preparation of, 527
4-Chloro-2-methyl-2-butanethiol, oxi-
dation of, 527
cw-3-Chloro-l-methylcyclopentane,
with hydroxide ion, 201
general index 813
2-Chloro-2-methylpropane, from 2-
methylpropene, 93
1-Chloronaphthalene, physical proper-
ties of, 590
2-Chloronaphthalene, physical proper-
ties of, 590
3-Chloro-l-nitrobutane, 53
Chloronium ions, 92
2-Chloropentanoic acid, 190
5-Chloropentanoic acid, acid dissocia-
tion constant of, 331
physical properties of, 331
Chlorophyll, in photosynthesis, 399
phytol in, 781
as pyrrole derivative, 681
structure of, 399
Chloroprene (see 2-Chloro-l,3-buta-
diene)
1-Chloropropane (see Propyl chloride)
2-Chloropropane (see Isopropyl chlo-
ride)
2-Chloropropanoic acid, from pro-
panoic acid, 343
3-Chloropropanoic acid, from pro-
panoic acid, 343
2-Chloro-l-propene, from propyne,
121
/3-Chloropropionaldehyde, from acro-
lein, 286
3-Chloro-l -propyne, in S N reactions,
221
m-Chlorotoluene, physical properties
of, 590
o-Chlorotoluene, formation of, 591
physical properties of, 590
p-Chlorotoluene, hydrolysis of, 595
physical properties of, 590
Chlorotrifiuoroethene, polymer from,
745
Cholanic acid, 786
Cholestane, 785
Cholesterol, 782-788
Cholesterol, absolute configuration,
788, 798
dehydrogenation of, 787
from lanosterol, 795
metabolism of, 783
methyl groups, in 786-787
molecular formula of, 783
nmr spectrum of, 787
numbering system of, 785
oxidative degradation, 783-784
reduction of, 785
ring sizes of, 786
X-ray diffraction of, 787
Cholic acid, 784
Cholic acids (see Bile acids)
Chromatography, in amino acid anal-
ysis, 465-466
gas-liquid, 153, 155-156
liquid-liquid, 153
liquid-solid, 153-154
Chromic acid, in oxidation of alcohols,
259
Chromic oxide, in oxidation of al-
cohols, 259
Chromone, 687
Chromosomes, composition of, 477
Chymotrypsin, in ester hydrolysis, 504
properties and function of, 478
Cinchona alkaloids, 684
Citronellal, 780
Citronellol, 780
Civetone, 769-772
Claisen condensation, 716
of esters, 352-354
Claisen rearrangement, 632
Claus, structure of benzene, 128
Clemmensen reduction, 291-292, 718
of civetone, 771
Cocaine, 684
Codeine, 684
Codon, for phenylalanine, 485
Codons, 483, 485
Coenzyme A, in biogenesis, 792
Coenzyme Q, 640
Coenzymes, 503
Collagen, leather from, 757-758
Colors, complementary, 701
Combustion, calculation of heat of, 24
definition of, 23
and elemental analysis, 156-157
Complexes (see also Charge-transfer
complexes)
in acylation of arenes, 566
halogens with arenes, 562-563
7r-type, 612-613
Conant, J. B., 681
Condensation polymers, 748-752
Condensation reactions, acyloin, 717
benzoin, 656-657
of carbonyl compounds, 288-290
definition of, 288
polymerization, 748-752
general index 814
of silanols, 535
Conessine, 791
Configuration, Cahn-Ingold-Prelog
system, 382
of cis-trans isomers, 86
definition of, 84
determination of, 38, 86
dl designation of, 382
of glucose, 402
inversion of, 389
at nitrogen, 425-426
of optical isomers, 381-384
rs designation of, 382
Conformational analysis, and nmr
spectroscopy, 177
Conformations, asymmetric, 376
of bromocyclohexane, 67
of 4-?-butylcyclohexyl chloride, 71
of chlorocyclohexane, 67
of cyclohexanes, 63-67
of decalins, 785-786
definition of, 21, 84
of cis- 1 ,4-di-?-butylcyclobutane,
72
eclipsed, 21
of glucose, 405
of methylcyclohexane, 65-66
Newman convention, 22
saw-horse convention, 22
staggered, 21
Conformers, definition of, 315, 369
Congo Red, 759
Coniine, 684
Conjugate addition, 127, 133-135,
718-721
to 1,3 -butadiene, 221
to quinones, 639-640
to a,/3-unsaturated carbonyl com-
pounds, 311, 355
Conjugated dienes, electronic spectrum
of, 166
with singlet oxygen, 706
stabilization of, 135-137
Conjugated double bonds, bonding in,
127-147
definition of, 83
Conjugation, and light absorption,
699-703
Conjugation, and spectra of carbonyl
compounds, 277
Conjugation, and structures for excised
states, 168
Conjugation, in a,/3-unsaturated car-
bonyl compounds, 311
Conjugation effects, in electrophilic
aromatic substitution, 572
Cope rearrangements, 723-724
Copolymers, butadiene-styrene, 756
definition of, 103
ethene-propene, 748, 756
vinyl chloride- vinyl acetate, 748,
756
Coprostane, 785
oxidation, 786
Corpus luteum, hormones from, 790
Cortisone, 791
synthesis, 788
therapeutic uses, 788
Cotton, cellulose in, 410
dyeing of, 759, 760
Cotton effect, 390
Coumarin, 687
Coumarins, occurrence and synthesis,
687
Couper, A. S., 3
Covalent bonding (see also Bonding), 5
and polarity, 6
Covalent catalysis, 500
Cracking, of kerosene, 58
p-Cresol, acid dissociation constant,
629
uv spectrum, 629
Cresols, from />-chlorotoluene, 595
physical properties of, 634-635
Crick, F. H. C, 428
Crotonaldehyde, from acetaldehyde,
306
Crotonic acid (see 2-Butenoic acid)
Crotyl chloride (see l-Chloro-2-bu-
tene)
Crystal Violet, resonance hybrid, 702
Crystallites, of polymers, 739-741
Crystallization, solvents for, 153
Cumene (see Isopropylbenzene)
Cumulated double bonds, definition
of, 83
in ketenes, 312
Cupric acetylacetonate, 316
Cuprous salts, in ethyne dimerization,
114, 115, 119
Curtius reaction, 430
Cyanic acid, 422
Cyanide ion, in cyanohydrin forma-
tion, 283
general index 815
Cyano compounds, synthesis of, 618-
619
Cyanoacetic acid, 440
acid dissociation constant of, 331
decarboxylation of, 341
physical properties of, 331
Cyanocobalamin (see Vitamin Bi 2 )
Cyanohydrin formation, 282-283
by 1,4-addition, 311
equilibrium in, 284
2-Cyanopropanoic acid, formation of,
343
p-Cyanotoluene, synthesis of, 619
Cyclization reactions, 715-730
of alkynes, 721
of carbonyl compounds, 715-718
Cycloaddition reactions, 718-723
of 1,3-butadiene, 729
cis-1,1, 224
of ethene, 729
and orbital symmetry, 726-730
photochemical, 707-708
Cycloalkanes, 62-74
angle strain in, 67-68
chemical properties of, 68-70
heats of combustion of, 68
cis-trans isomerism of, 69-71
naming of, 62
physical properties of, 63
Cyclobutane, from cyclobutyl bro-
mide, 230
heat of combustion of, 68
physical properties of, 63, 83, 226
Cyclodecane, heat of combustion of,
68
Cycloheptane, heat of combustion of,
68
physical properties of, 63
1,3,5-Cycloheptatriene, oxidation of,
641
X-irradiation of, 668
Cycloheptatrienyl cation, resonance
structures of, 144
Cycloheptatrienyl radical, epr spec-
trum, 668
1,3-Cyclohexadiene, with tetracyano-
ethylene, 719
1,4-Cyclohexadiene, formation of, 721
Cyclohexane, axial positions in, 65-67
boat form of, 64
chair form of, 64-67
conformations of, 63-67
equatorial positions in, 65-67
heat of combustion of, 68
nmr spectrum of, 178-179
oxidation of, 750
physical properties of, 63
twist-boat form of, 65-66
Cyclohexane-l,2-dicarboxylic acid, 377
Cyelohexanethiol, synthesis of, 522
Cyclohexanol, in acetal formation, 288
physical properties of, 628
Cyclohexanols, from phenols, 635
Cyclohexanone, bromination of, 303
cyanohydrin of, 284
from pimelic acid, 358
preparation of, 750
Cyclohexene, with bromine, 128
with dichloromethylene, 224
electrophilic additions to, 89
heat of combustion of, 129
with iodomethylzinc iodide, 224
Cyelohexyl bromide, with magnesium,
522
Cyclohexylamine, base dissociation
constant of, 423
infrared spectrum of, 424
physical properties of, 423
Cyclohexylcarbinyl chloride, 190
Cyclononane, heat of combustion of,
68
physical properties of, 63
Cyclooctane, 63
heat of combustion of, 68, 148
physical properties of, 63
Cyclooctanone, synthesis 1 of, 772
Cyclooctatetraene, additions to, 724
from ethyne, 721
heat of combustion of, 148
structure of, 578
valence tautomers of, 723-724
1,3,5-Cyclooctatriene, valence tauto-
mers of, 723
Cyclopentadecane, heat of combustion
of, 68
Cyclopentadiene, polymerization of,
737
Cyclopentadienyl radical, cation,
anion, relative stabilities of, 145
resonance structures of, 144
7T-Cyclopentadienyldiethenerhodium,
235
Cyclopentane, heat of combustion of,
68
general index 816
physical properties of, 63
c«-l,2-Cyclopentanediol, from cyclo-
pentene, 99
?ra«.y-l,2-Cyclopentanediol, from cy-
clopentene, 99
Cyclopentanone, from adipic acid, 358
cyanohydrirt of, 284
with phosphorus pen-tachloride,
290
with sulfur tetrafiuoride, 290
Cyclopentene, oxidation of, 99
Cyclopentyl chloride (see Chlorocyclo-
pentane)
Cyclopropane, heat of combustion of,
68
physical properties of, 63
Cyclopropanecarbonitrile, reduction
of, 280
Cyclopropanecarboxaldehyde, prep-
aration of, 280
Cyclopropanecarboxylic acid, forma-
tion of, 306
Cyclopropyl methyl ketone, bromina-
tion of, 306
Cyclopropyne, 117
Cysteine, 457, 522
physical properties of, 461
Cystine, 457
from cysteine, 523
physical properties of, 461
in wool, 757
Cytochromes, 508, 641
Cytosine, in DNA, 480
Cytosine deoxyribonucleotide, 481
Cytosine deoxyriboside, 481
2,4-D, ecological effect, 598
Dacron, preparation of, 749
DDE (see DDT)
DDT, 4
DDE from, 597
ecological effects of, 596-597
DDT dehydrochlorinase, in conversion
of DDT to DDE, 602
Decaborane, 537
Decalin, 551
conformations of, 785-786
Decane, isomers of, 48
physical properties of, 55
Decarboxylation, of carboxylate rad-
icals, 342
of carboxylic acids, 341-342, 354
Dehydration, of alcohols, 256-258
Dehydrobenzene (see Benzyne)
Derealization, in benzene, 549
of electrons in conjugated systems,
127-147
in excited states, 556
Derealization energy (see also Stabi-
lization energy and Resonance
energy), 132
Delphinidin chloride, 687-688
Delrin, 288
Denaturation, of proteins, 469
2-Deoxyribofuranose, in DNA, 479
Deoxyribonucleic acid (DNA), in
chromosomes, 477
2-deoxy-2-ribose in, 400
double-stranded helix of, 479
equivalence of base pairs in, 483
in genetic control, 483^486
hydrolysis of, 482
molecular weights of, 479
nucleotides in, 482
replication of, 483-486
structure of, 477^183
thermal dissociation of, 479
Watson-Crick model of, 483
Deoxyribonucleosides, as glycosides,
407
2-Deoxy- D-ribose, structure of, 400-
401
Desoxycholic acid, 784
degradation of, 786
Detergents, phosphates in, 528
from sulfonic acids, 526
Deuteration of arenes, 567
Dewar, J., 128, 708
Dewar benzene, 708
Dextrose, 410
Diacetone alcohol, dehydration of, 309
formation of, 307-308
Diamines, tetrazotization of, 618
4,4'-Diaminobiphenyl (see Benzidine)
Diastase, 412
Diastereomers, 375-379
definition of, 378
physical properties of, 378
Diatomic molecules, potential energy
diagram, 697
Diazirine, preparation and properties
of, 444
Diazo compounds, 443-444
general index 817
Diazo coupling, 619-620
of heterocyclic compounds, 674-
677
of tropolones, 642
Diazoalkanes, as 1,3-dipoles, 721-723,
731
Diazomethane, 422
esters from, 444
as methylating agent, 444
methylene from, 224
from N-nitroso-N-methyl amide,
444
with phenols, 631
physical properties of, 444
properties of, 443
Diazonium salts, 617-620
coupling of, 619-620
covalent forms of, 618
decomposition of, 591
with hypophosphorous acid, 608
radicals from, 618
reduction of, 619
replacement reactions, 618-619
in Sn reactions, 194
stability of, 618
Diazotization, of/>-aminophenols, 618
of arylamines, 591-592, 616-617
Diborane, with alkenes, 96-97, 539-540
structure of, 92, 537-538
2,3-Dibromobutane, 377
trans-1 ,2-Dibromocyclohexane, from
cyclohexene, 88, 128
1,2-Dibromoethane, from ethene, 37,
90
in formation of organomagnesium
compounds, 592
in gasoline, 58, 234
naming of, 37
1,1-Dibromoethene, 39
1 ,2-Dibromoethene, cis and trans iso-
mers, 38
from ethyne, 38
physical properties of, 38
2,5-Dibromo-3-hexene, from 2,4-hexa-
diene, 127
4,5-Dibromo-2-hexene, from 2,4-hexa-
diene, 127
5,6-Dibromo-l-hexene, from 1,5-hexa-
diene, 127
2,3-Dibromo-4-methylhexane, from 4-
methyl-2-hexene, 86
frfl«j-l,2-Dibromo-l-propene, from
propyne, 121
Di-?-butyl ether, stability of, 257
Di-n-butyl phthalate, as plasticizer, 748
c«-.s)w-Di-?-butylethylene, repulsive
interactions in, 85
1,3-Dicarbonyl compounds, 314
Dicarboxylic acids, 356-359
acidic properties of, 356-358
and Blanc rule, 786
in ketone synthesis, 772
thermal behavior of, 358
Dichloroacetic acid, acid dissociation
constant of, 331
physical properties of, 331
w-Dichlorobenzene, preparation of,
592
1 , 1 -Dichloro-2,2-bis(p-chlorophenyl)
ethene (see DDT, from DDE)
Dichlorocarbene, from chloroform,
223
electrophic nature of, 223
Dichlorodiphenyltrichloroethane (see
DDT)
Dichloromethane, with hydroxide ion,
223
from methane chlorination, 28, 60,
222
Dichloromethane, physical properties
of, 222, 535
Dichloromethylene (see Dichlorocar-
bene)
1 ,5-Dichloro-2,6-naphthoquinone, 638
Dichlorosilane, physical properties of,
535
Dicyclohexylcarbodiimide, in oxida-
tion of alcohols, 526
in peptide synthesis, 472-473
Dieckmann reaction, 716
Dielectric constant, of solvents in S N
reactions, 204
Diels-Alder reaction, 719-721
of cyclooctatetraene, 724
of cyclopentadiene, 737
Dienes, conformations of, 719
Dienophile, definition of, 719
Diesel oil, composition of, 58
Diethyl ether, from ethanol, 256
from ethyl hydrogen sulfate, 256
with methylsodium, 264
peroxides from, 265
physical properties of, 263
as a solvent, 264
general index 818
as solvent for organomagnesium
compounds, 230
uses of, 263
Diethyl maleate, with 1,3-butadiene,
720
Diethyl malonate, alkylation of, 354
Diethyl phenylphosphonate, 530
Diethyl sulfide, 521
Diethylamine, base dissociation con-
stant of, 423
with 1 -chloro-2,4-dinitrobenzene,
593
nmr spectrum of, 425
physical properties of, 423-424
Diethyldiketopiperazine, from ethyl
2-aminobutanoate, 468
Diethylene glycol, 264
from ethylene oxide, 266
physical properties of, 263
Diethyloxonium bromide, 264
Difluorodichloromethane, formation
of, 224
reactivity of, 224-225
utility of, 224
o,o'-Difiuorodiphenic acid, optical iso-
mers of, 381
1,1-Difluoroethane, from ethyne, 114
Digitogenin, 791
Digitoxigenin, 791
Diglyme, 264
physical properties of, 264
9,10-Dihydroanthracene, 551
Dihydropentaborane, 537
1,2-Dihydroxyanthraquinone, 760
m-Dihydroxybenzene (see Resorcinol)
o-Dihydroxybenzene (see Catechol)
p-Dihydroxybenzene (see Hydroquin-
one)
Dihydroxymethane (see Formalde-
hyde)
2,4-Dihydroxypyrimidine (see Uracil)
Diisobutylene, from 2-methylpropene,
102
Diisopropyl ether, peroxides from, 265
as a solvent, 264
Diisopropyl fluorophosphate, 506
Diketene, structure of, 313, 321
1,1-Dimethoxyethane, from acetalde-
hyde, 284
nmr spectrum of, 175
Dimethyl acetal (see 1,1-dimethoxy-
ethane)
Dimethyl ether, bond angles in, 10
physical properties of, 12
solubility in water, 1 2
Dimethyl sulfate, 521
properties of, 528
Dimethyl sulfoxide, acid strength of,
526
dielectric constant of, 205, 525
double bonds in, 519
oxidizing properties of, 526
physical properties of, 525
shape of, 519
solvent properties of, 525
N,N-Dimethylacetamide, physical
properties of, 435
Dimethylallylcarbinol, 191
Dimethylamine, physical properties of,
12
/;-Dimethylaminoazobenzene, forma-
tion of, 620
carcinogenic properties of, 620
Dimethylaminoborane, 539
N,N-Dimethylaniline, basicity of, 614
diazo coupling of, 620
uv spectrum of, 614
Dimethylbenzenes (see Xylenes)
2,2-Dimethylbutane, 49, 55
2,3-Dimethylbutane, 49, 55
2,3-Dimethyl-2,3-butanediol (see Pin-
acol)
3,3-Dimethyl-2-butanol, dehydration
of, 258
3,3-Dimethyl-2-butanone (see Pina-
colone)
l,3-Dimethyl-5-f-butyl-2,4,6-trinitro-
benzene, in perfumes, 612
Dimethylchloroborane, 539
1 ,4-Dimethylcyclohexane, naming of,
62
1,3-Dimethylcyclohexene, 82
1 ,2-Dimethylcyclopropane, cis-trans
isomers of, 69
4,4-Dimethyl-l,2-dibromo-l-pentene,
from 4,4-dimethyl-l-pentyne, 113
N,N-Dimethylformamide, dielectric
constant of, 205
infrared spectrum of, 436
solvent properties of, 437
Dimethylglycolic acid, from acetone,
282
1,2-Dimethylhydrazine, 422
N,N-Dimethylhydroxylamine, 422
general index 819
Dimethylmercury, formation of, 228-
229
2,2-Dimethylpentane, from 4,4-di-
methyl-1-pentyne, 113
2,3-Dimethylpentane, naming of, 51
4,4-Dimethyl-l-pentene, from 4,4-di-
methyl-1-pentyne, 113
4,4-Dimethyl-l-pentyne, bromine ad-
dition to, 113
hydrogenation of, 113
2,2-Dimethylpropane, 49
physical properties of, 11, 535
3,5-Dimethylpyridine, mass spectrum
of, 773-775
Dimethylsilanediol, physical proper-
ties, 535
Dimsyl ion, 526
2,4-Dinitroaniline, reduction of, 609-
610
p-Dinitrobenzene, synthesis of, 606-
607
2,4-Dinitrobenzenesulfenyl chloride,
521
2,4-Dinitrochlorobenzene, formation
of, 632
o,o'-Dinitrodiphenic acid, optical iso-
mers of, 380
2,4-Dinitrofluorobenzene, with pep-
tides, 593
in N-terminal amino acid analysis,
470
2,4-Dinitro-l-naphthol (see Martius
Yellow)
2,4-Dinitrophenol, with phosphorus
pentachloride, 632
2,4-Dinitrotoluene, nitration of, 562
reduction of, 609-610
Diols (see Glycols)
Diosgenin, cortisone from, 788
1,4-Dioxane, from ethylene oxide,
266
peroxides from, 265
physical properties of, 263
solubility in water, 264
as a solvent, 264
Diphenyl disulfide, 521
Diphenyl ether, 190
Diphenyl sulfone, 521
Diphenylamine, basicity of, 614
uv spectrum of, 614
l,10-Diphenyl-l,3,5,7,9-decapen-
taene, light absorption of, 699
1,2-Diphenylethene, light absorption
of, 699
Diphenylmethane, 550
Diphenylmethyl cation, resonance
stabilization of, 653
Diphosphopyridine nucleotide
(DPN ffi ) (see Nicotinamide-adenine
dinucleotide NAD®)
Diphosphoric acid, derivatives of, 528
1,3-Dipolar additions, 721-723
1,3-Dipolar reagents, 722
Dipole moments, demonstration of, 7
1,2-dibromoethene, cis and trans,
39
and molecular shape, 7
of water, 7
Disaccharides, 400, 407, 408-410
Disilane, physical properties of, 535
Dispersion forces (see van der Waals
forces)
Disproportionation, in alkene polym-
erization, 102
Disulfides, preparation of, 523
in proteins, 457-458
reduction of, 747
Diterpenes, 779-781
Dithioacetals, from thiols, 523
Dithioacetic acid, 520
Dithioketals, from thiols, 523
DMSO (see Dimethyl sulfoxide)
DNA (see Deoxyribonucleic acid)
DNA-polymerase, 484
Dodecane, physical properties of, 55
Double bonds, with 3d orbitals, 519
Double bonds, with 3p orbitals, 519
Double bonds, in silicon compounds,
534, 535
Drugs, 4
antibiotic, 527
barbiturates, 685
examples of, 658-659
Durene, physical properties, 553
Dyes, azo compounds, 620
for cotton, 759, 760
Crystal Violet, 702
for Dacron, 759
disperse, 759
fading of, 160
Martius Yellow, 700
mordant, 759-760
for polymers, 758-762
for rayon and cotton, 762
general index 820
sulfonic acids in, 527
vat, 760-762
for wool and silk, 758-759
Dynamite, 262
E2 reaction (see Elimination reactions)
Eicosane, isomers of, 48
physical properties of, 55
Einstein units, definition of, 703
Elastomers, configuration, 742
Electromagnetic radiation, absorption
of, 159-161
electric and magnetic forces in,
369
Electromagnetic spectrum, regions of,
695
Electron diffraction, of boron hy-
drides, 538
Electron paramagnetic resonance spec-
troscopy, 659-661
Electron paramagnetic resonance spec-
trum, of cycloheptatrienyl, 668
Electron repulsion, and acidity of
alkynes, 116
between bonding electron pairs, 9
between nonbonding electron
pairs, 9
and electrophilic addition, 87
and molecular shape, 8
in singlet and triplet states, 698
and tetrahedral methane, 130
Electron spin, 130, 131
Electron spin resonance spectroscopy
(see Electron paramagnetic reso-
nance spectroscopy)
Electron transport chain, 641
Electronegativity, and acid strength,
116,338
of carbon, 6
of elements, 6
of fluorine, 6
of hydrogen, 6
and hydrogen bonding, 11, 423
of nitrogen, 6
of oxygen, 6
and polarity, 6
scale of, 6
Electronic absorption spectra, of
arenes, 554-557
of aldehydes, 334
of amides, 437
benzenoid bands, 557
of carboxylic acids, 334
of ketones, 334
of polyenes, 699
and rotatory dispersion, 391
of a,/3-unsaturated carbonyl com-
pounds, 311
Electronic absorption spectroscopy,
165-168
Electron absorption spectrum, of an-
iline, 556
of anthracene, 557
of benzaldehyde, 556
of benzene, 556
of biphenyl, 556
of iodobenzene, 556
of methyl ethyl ketone, 277-278
of methyl vinyl ketone, 277-278
of naphthacene, 557
of naphthalene, 557
of />-nitrophenol, 700
of pentacene, 557
of phenol, 556
of stilbene, 556
of styrene, 556
Electronic configuration, of oxygen
and sulfur, 518
Electronic states, singlet, 697-699
triplet, 697-699
Electronic transitions, «->w*, 277,
391, 704
77->77*, 278, 311, 554
Electrophile, definition of, 87
Electrophilic addition, 87-92
to alkenes, mechanism of, 87-92
Electrophilic aromatic substitution,
559-577
acylation, 565-566
alkylation, 564-565
by aryl cations, 619
catalysts in, 561, 563, 564
chloromethylation, 652
deuteration, 567
diazo coupling, 619-620
of disubstituted benzenes, 573-
574
examples of, 560
formylation, 642
of furan, 674-678
halogenation, 562-563
kinetic control in, 569
mechanism of, 559-561
general index 821
nitration, 561-562
orientation in, 567-574
of phenoxide ion, 633
of polynuclear aromatic hydro-
carbons, 574-577
of pyridine, 674-678
of pyrrole, 674-678
reactivity effects in, 570-573
substituting agents in, 561
sulfonation, 566
of thiophene, 674-678
of tropolones, 642
Elemental analysis, 156-157
from mass spectrometry, 159
Elimination reactions, 205-208
of alkyl hydrogen sulfate, 256
1,1 or alpha, 223
of aryl halides, 595-596
the El reaction, 207-208
the E2 reaction, 206-207
in ether synthesis, 252
Emulsin, 410
Enamines, rearrangement of, 427
Enantiomers, definition of, 373
physical properties of, 374
separation of, 384
End-capping, of polymers, 288
Endocyclic, definition of, 82
Enolate anions, alkylation of, 310
formation of, 304-306
reactions of, 306-310
in S N reactions, 310
Enolization, acid-catalyzed, 304-305,
501
base-catalyzed, 304-306
Enols, hydrogen bonding in, 315
oxidation of, 293
Enovid, 789
Enthalpy, definition of, 23
Entropy of activation, 496
definition of, 199
Enzymes, active sites of, 504
alcohol :NAD® oxidoreductase,
508
and asymmetric synthesis, 387
cytochromes, 476, 508
epr spectra of, 661
flavins, 508
in hydrolysis of DNA, 482
in hydrolysis of saccharides, 410
hydrolytic, 504-506
in mitochondria, 509
oxidative, 506-509
Enzymic processes, 495-513
Epimers, 403
Epinephrine, 659
Equatorial positions and substituents
(see Cyclohexane)
Equilenin, 790
Equilibrium constants, 26
Ergosterol, 790
vitamin D from, 789
Ergot alkaloids, 683
Erythrose, oxidation of, 379
projection formulas of, 378
Escherichia coli, DNA from, 483
Esr or epr (see Electron paramagnetic
resonance spectroscopy)
Essential oils, 778-782
Esterification (see Carboxylic esters,
formation of)
Esters (see Carboxylic esters)
Estradiol, 790
Estrone, 790
Ethane, bond lengths in, 35
heat of combustion of, 24, 113,
510
molecular shape of, 20
in natural gas, 57
physical properties of, 11, 55, 112,
246, 535
rotational conformations of, 21
structure of, 19
1,2-Ethanediol (see Ethylene glycol)
Ethanesulfinic acid, 521
Ethanethiol, 520
acid dissociation constant, 522
formation of, 522
physical properties of, 522
Ethanol (see Ethyl alcohol)
Ethan- l-ol-2-thiol, 524
Ethene, additions to, 34
bent bonds in, 20, 34
bond lengths in, 35
bonding in, 34
with chlorine, 223
cycloaddition of, 729
from ethyl alcohol, 256-257
from ethyl chloride, 206
geometry of, 35
halogen addition to, 37
heat of combustion of, 68, 113
hydration of, 88, 250, 275
hydroboration of, 96
general index 822
hydrogenation of, 35
model of, 20, 34
molecular orbitals of, 727-729
molecular shape of, 20
oxidation of, 261
physical properties of, 112
polymer from, 745
polymerization of, 100-103
structure of, 19
Ethers, 262-266
acid cleavage of, 264
from alcohols, 252, 256-257, 263
from alkyl halides, 263
basic cleavage of, 264
basic properties of, 264
cyclic, 265-266
as derivatives of water, 9
naming of, 190
peroxides from, 265
physical properties of, 263
preparation of, 263
reactions of, 264-265
as solvents, 264
Ethyl acetate, in Claisen condensation,
352-353
Ethyl acetoacetate (see also Claisen
condensation)
acid dissociation constant of, 351
alkylation of, 354
nmr spectrum of, 350-352
synthesis of, 352-353
tautomers of, 351-352
Ethyl alcohol, absolute, 250
in acetal formation, 287
with acetic acid, 254
acid dissociation constant of, 251,
315, 522
acidity of, 337
dehydration of, 256-257
from ethene, 88, 250
in ether formation, 256-257
from ethyl chloride, 206
by fermentation, 245, 250
from formaldehyde, 231
heat of combustion of, 510
infrared spectrum of, 247-248
manufacture of, 250
NAD® oxidation, 506-507
nmr spectrum of, 169
physical propert ies of, 522
salt of, 251
with sodium amide, 251
with sodium hydride, 251
toxicity of, 245
Ethyl 2-aminobutanoate, thermal de-
composition of, 468
Ethyl 4-aminobutanoate, thermal de-
composition of, 468
Ethyl benzoate, alkaline hydrolysis of,
661
nitration of, 568
Ethyl benzoylacetate, synthesis of, 353
Ethyl bromide, physical properties of,
217
Ethyl butanoate, mass spectrum of,
778
Ethyl chloride, with sodium hydroxide,
206
Ethyl 2-chloro-3-butenoate, 191
Ethyl ether (see Diethyl ether)
Ethyl formylphenylacetate, synthesis
of, 353
Ethyl hydrogen sulfate, ethene from,
256
Ethyl iodide, nmr spectrum of, 171
Ethyl methyl sulfoxide, 521
2-(Ethyl oxalyl)-cyclohexanone, syn-
thesis of, 353
Ethyl phenylacetate, 191
Ethyl thioacetate, formation of, 523
Ethylamine, base dissociation constant
of, 423
physical properties of, 423
Ethylbenzene, 550
formation of, 564
physical properties of, 553
Ethylene (see Ethene)
Ethylene chlorohydrin, from ethylene
oxide, 266
Ethylene dibromide (see 1,2-Dibromo-
ethane)
Ethylene glycol, from ethylene oxide,
261, 266
physical properties of, 261
polymer from, 747
uses of, 261
Ethylene oxide, with 1-bromohexane,
265
commercial importance of, 266
from ethane, 261
with organomagnesium com-
pounds, 234, 265
physical properties of, 263
polymerization of, 755
general index 823
reactivity of, 265
strain in, 265
Ethylenediamine, base dissociation
constant of, 423
physical properties of, 423
Ethylmagnesium bromide, formation
of, 228
Ethylmercuric chloride, fungicidal
properties, 234
l-Ethyl-3-methylcyclopentane, 62
4-Ethyl-3-methylheptane, 52
4-Ethyl-3-methyl-;ra«^-3-heptene, 84
3-Ethylpentane, physical properties of,
424
Ethylphenylcarbinylamine, 190
Ethylpyridines, mass spectra of, 773-
775
Ethyne, acid ionization constant of,
122
additions to, 34, 38
bond lengths in, 35
from calcium carbide, 112
with chlorine, 223
dimerization of, 114, 115, 119
heat of combustion of, 24, 113
hydration of, 114
hydrogenation of, 35
model of, 20
molecular shape of, 20
from petroleum gases, 112
physical properties of, 112
stability of, 112
structure of, 19
for welding, 112
Euclid, 3
Eugenol, oxidation of, 658
Evolution, chemical, 486-487
Excited states, of ferric phenoxide, 631
Exocyclic, definition of, 82
Explosives, 4, 611-612
from cellulose, 410
dynamite, 262
nitro compounds, 442
nitrocellulose, 262
nitroglycerin, 262
peroxides, 265
Farnesol, 780
Fats, glycerol from, 262
hydrolysis of, 330
Fatty acids, 330
Fehling's solution, 293 , 404
Ferric chloride, complexes with tropo-
lones, 642
with phenols, 631
Ferrocene, bonding in, 235
from cyclopentadiene, 235
physical properties of, 235
Fibers, from cellulose, 410
dyeing of, 758-762
Fibrogenin, properties and function of,
478
Fischer, E., 402-403
Fischer, H., 681
Flavins, 508, 641
Flavones, 687
Flavorings, examples of, 658-659
Flax, cellulose in, 410
Fluorescence, 696-699
Fluorine, heat of reaction with meth-
ane, 75
reaction with alkanes, 60
Fluorine oxide, dipole moment of, 7
shape of, 7
Fluorobenzene, formation of, 619
physical properties of, 590
l-Fluoro-4-bromonaphthalene, forma-
tion of, 591
Fluorocarbons, 225-226
physical properties of, 225-226
Fluorochloromethane, formation of,
224
2-Fluoroethanol, toxicity of, 226
Fluorosulfonic acid, super acid, 13
Fluxional systems, 723-725
Formal bonds, 136
Formaldehyde, with acetaldehyde, 325
with acetone, 308-309
in aldol addition, 308-309
carbonyl bond strength of, 308
in chloromethylation, 652
from dichloromethane, 223
hydration of, 261, 275
with lithium aluminum hydride,
291
with organomagnesium com-
pounds, 231-232
physical properties of, 277
polymerization of, 287-288
polymers from, 747, 751-752
with sodium borohydride, 291
Formaldoxime, 289
Formamide, physical properties of, 435
general index 824
Formamidine, in adenine synthesis, 487
Formic acid, 190
acid dissociation constant of, 331
physical properties of, 331
Formyl chloride, 340
Formylation, of arenes, 652
of heterocyclic compounds, 674-
677
Franck-Condon principle, 696-697
Free energy of activation, 496
Free energy of reaction, 26-28
Friedel-Crafts acylation (see also Acyl-
ation), 565-566
of benzene, 651
Friedel-Crafts alkylation (see also
Alkylation), 564-565
of benzene, 651
Fructose, phenylosazone from, 403
structure of, 401
Fumaric acid, 86
acid dissociation constant of, 357
physical properties of, 357
Fungicides, natural, 641
Fukui, K., 726
Furan, aromatic character of, 672-673
chemical properties of, 673-679
physical properties of, 671
Furanoses, 406
Fusel oil, 245
D-Galactose, structure of, 401
Gallstones, 782
Gas constant, 27
Gasoline, composition of, 57-58
Gelatin, 757
Gentiobiose, in amygdalin, 657
Geometrical isomerism, 39-41
Geraniol, 780
Geranyl pyrophosphate, in biogenesis,
792
D-Glucaric acid, from glucose, 404
Gluconic acid, from glucose, 404
D-Glucosamine, from chitin, 412
Glucose, 402-404
anomers of, 404^405
configuration of, 383
conformations of, 405
heat of combustion of, 24, 510
mutarotation of, 406
phenylosazone from, 403
photosynthesis of, 387
properties of, 403^-04
stereoisomers of, 383
structure of, 401-402
Glucovanillin, 658
Glutamic acid, isoelectric point, 463
physical properties of, 461
Glutamine, physical properties of, 461
Glutaric acid, acid dissociation con-
stant of, 357
anhydride from, 358
physical properties of, 357
Glutaric anhydride, formation of, 358
Glyceraldehyde, absolute configuration
of, 382
from acrolein, 286
Glyceric acid, in photosynthesis, 399
Glycerides, hydrolysis of, 330
Glycerol, esters of, 330
from fats, 262
physical properties of, 261
polymer from, 750
from propene, 220, 262
uses of, 261
Glyceryl tristearate, heat of combus-
tion of, 510
Glycine, acid-base properties of, 462
N-acyl derivatives, 784
heat of combustion of, 510
isoelectric point, 463
physical properties of, 459
Glycogens, 412
Glycolic acid, from glyoxal, 313, 321
1,2-Glycols, from alkenes, 261
definition of, 260-261
oxidation of, 279, 336
rearrangements of, 280-281
1,1-Glycols, dehydration of, 261
Glycosides, 407-408
N-Glycosides, in DNA, 480
Glycylalanine, 469
Glyoxal, 313, 321
Glyptal resin, 750
Gomberg, M., 654
Grignard, V., 229
Grignard reagents (see Organomag-
nesium compounds)
Guanidine, base strength of, 444
Guanine, in DNA, 480
2-Halo acids (see 2-Halocarboxylic
acids)
general index 825
Haloalkanes, naming of, 53
Haloalkynes, in S N reactions, 220
Haloamines, formation of, 432
properties of, 432
2-Halocarboxylic acids, preparation of,
343-344
substitution of, 343-344
Haloform reaction, 292, 305-306
with />-tolyl methyl ketone, 650
Halogenation {see also Electrophilic
aromatic substitution and Radical,
halogenation)
of arenes, 562-563
of carbonyl compounds, 303-306
of carboxylic acids, 342, 343
of heterocyclic compounds, 674-
677
Halogens, addition to alkenes, 87-91
additions to multiple bonds, 37
charge-transfer complexes of, 562-
563
reactivity in aromatic substitution,
563
Halonium ions, 92
Halosilanes, examples of, 532
Hammett equation, 663
Heat of activation, 496
definition of, 199
Heats of combustion, of various
substances, 510
a-Helix, hydrogen bonding in, 475
Hemiacetals, of carbohydrates, 404
cyclic, 287
formation of, 283-287, 497, 499
hydrolysis of, 497
from hydroxyaldehydes, 716
Hemin, structure of, 680
Hemlock, coniine in, 684
Hemoglobin, 680
properties and function of, 478
quaternary structure of, 475
Hemp, cellulose in, 410
Heptane, isomers of, 48
octane rating of, 58
physical properties of, 53-55, 63
Herbicides, 4
Heterocycle, definition of, 427
Heterocyclic compounds {see also
individual types such as Pyrrole,
Furan, etc.), 671-689
by 1,3-dipolar addition, 722
naming of, 671
natural products, 680-689
nucleophilic substitution reactions
of, 678-679
saturated types, 671
unsaturated types, 672
Heterolytic bond breaking, definition
of, 88
Hexaborane, 537
1,5-Hexadiene, with bromine, 127
Cope rearrangement of, 724
2,4-Hexadiene, with bromine, 127
conjugate addition of, 720
l,3-Hexadien-5-yne, 111
Hexafluoroacetone hydrate, 261
Hexafiuoropropene, polymers from,
745
Hexamethylenediamine, nylon from,
747, 750
preparation of, 751
Hexamethylethane, 51
Hexamethylphosphoramide, dielectric
constant of, 205
Hexane, isomers of, 48-49, 55
physical properties of, 53-55, 63,
112,424
Hexanedioic acid (see Adipic acid)
Hexaphenylethane, formation and dis-
sociation, 654
1 -Hexene, physical properties of, 1 1 2
cw-3-Hexene, heat of combustion of, 85
from 3-hexyne, 115
physical properties of, 85
trans-3-Hexem, heat of combustion of
85
physical properties of, 85
l-Hexene-3,5-diyne, 111
1-Hexyne, physical properties of, 112
3-Hexyne, hydroboration of, 115
Hinokitiol, 641
Histidine, in ester hydrolysis, 505
in hydrolytic enzymes, 500
physical properties of, 461
HMP {see Hexamethylphosphoramide)
Hodgkin, D. C, 476
Hoffmann, R., 726
Hofmann reaction, 430
Homology, concept of, 53-56
Homolytic bond breaking, definition
of, 88
Hormones, 4
adrenal cortex, 791
sex, 790-791
general index 826
Hiickel, E., 141
Hiickel's (An + 2) rule, 145, 578
Hund's rule, 142, 698
Hunsdiecker reaction, 342
Hydrazine, 289
in reduction of carbonyl com-
pounds, 292
Hydrazines, formation and properties
of, 442^143
Hydrazobenzene, from nitrobenzene,
611
rearrangement of, 61 1
Hydrazoic acid, 422
Hydrazones, formation of, 289
Hydroboration of alkenes, 96-97,
539-540
of propene, 97
Hydrocarbons (see also individual types
such as Alkanes, Alkenes, etc.)
C-l and C-2 compounds, 19-42
chemical reactions of, 23
definition of, 9, 19
nomenclature of, 47-52
substitution of, 26
solubility in water, 12
Hydrogen, addition to 4-methyl-2-
hexene, 86
addition to muliple bonds, 35,
113, 115
Hydrogen bonding, in adenine-thy-
mine, 482
in alcohols, 246-249, 334
in amides, 435
in amines, 423^425
in carboxylic acids, 330, 334
and decarboxylation, 341
in dicarboxylic acids, 356-357
in DNA, 479
in enols, 315
in guanine-cytosine, 482
intramolecular, 634-635
in N-methylamine, 12
N-H---N, 12
O-H-O, 11-12
in peptides, 475
in phenols, 628
and physical properties, 10
in polyamides, 739
in pyrrole, 671
in silanols, 535
in silk, 757
and spectroscopic properties of
alcohols, 247-249
strength of, 1 1
in thiols, 522
in tropolone, 642
Hydrogen bromide, addition to 3-
methyl-1-butene, 119
addition to 3-methyl-l-butyne,
119
electrophilic addition to propene,
94
with methanol, 251
radical addition to propene,
94
Hydrogen cyanide, in adenine synthe-
sis, 486^-87
with aldehydes and ketones, 282-
284
conjugate addition of, 31 1
Hydrogen fluoride, acid dissociation
constant of, 13
addition to ethyne, 1 14
base ionization constant of, 13
physical properties of, 10
Hydrogen halides, in alkyl halide
formation, 255
with carbonyl groups, 288
conjugate addition of, 311
Hydrogen molecule ion, 92
Hydrogen peroxide, in alkene oxida-
tion, 261
singlet oxygen from, 706
Hydrogen sulfide, acid dissociation
constant of, 522
Hydrogenation, of acyl halides, 279
in analysis, 36
of carbon monoxide, 251
catalytic, 35
with diborane, 96-97
of diisobutylene, 102
of ethene, heat of, 35
of ethyne, heat of, 35
mechanism of catalytic, 36
Hydrolysis, of acetals, 287
of acid derivatives, 336, 344, 439
of alkyl halides, 249
of amides, 336, 439
of ATP, 509, 529
of carboxylate salts, 329
of esters, 336
of nitriles, 336, 439
of organosilicon compounds, 534
of peptides, 469
general index 827
Hydroperoxides, from organomagne-
sium compounds, 231
Hydroquinone, acid dissociation con-
stant of, 629
structure of, 635
uv spectrum of, 629
Hydroxyaldehydes, hemiacetals from,
716
Hydroxycarboxylic acids, lactones
from, 715
jj-Hydroxybenzaldehyde, acid disso-
ciation constant of, 629
uv spectrum of, 629
Hydroxybenzaldehydes, physical prop-
erties of, 634-635
o-Hydroxybenzoic acid {see Salicyclic
acid)
jS-Hydroxybutyraldehyde {see Acetal-
dol)
3-Hydroxyindole, indigo from, 760-761
Hydroxyl groups {see also Alcohols,
Carboxylic acids, etc.)
chemical shift of, 247-249
hydrogen bonding in, 11, 245-249
infrared bands of, 247
and solubility, 12
Hydroxylamines, 289, 422
from secondary amines, 434
tautomers of, 434
5-Hydroxylysine, physical properties
of, 459
2-Hydroxy-5-methyl-3-hexenoic acid,
190
2-Hydroxy-l -naphthaldehyde, forma-
tion of, 653
1 1 -Hydroxyprogesterone, cortisone
from, 788
Hydroxyproline, in ninhydrin test, 465
physical properties of, 461
3-Hydroxypropanoic acid, from acry-
lic acid, 355
2-Hydroxypyridine, tautomers of, 723
2-Hydroxypyrimidine, derivatives of
•in DNA, 480
a-Hydroxysulfonate salts, from alde-
hydes, 527
5-Hydroxytryptamine, in the brain,
682-683
Hypochlorous acid, addition to cyclo-
hexene, 89
Hypohalous acids, addition to alkenes,
249
I effect {see Inductive effects)
Identification, of organic compounds,
156-159
Imidazole, 679
basicity of, 500
in ester hydrolysis, 500
Imides, acid strengths of, 439
Imines, from enamines, 427
from nitriles, 349
Indican, 760
Indigo, configuration of, 762
preparation and occurrence, 760-
762
properties, 762
• Indole, natural products related to,
682-683
structure of, 679
Indole alkaloids, 682-683
quebrachamine, 772
Indoxyl {see 3-Hydroxyindole)
Inductive effects, and acid strengths,
337-338
of carboxyl groups, 356-357
and decarboxylation, 341
in electrophilic aromatic substitu-
tion, 570-573
of ester groups, 350-351
Infrared spectra, of alcohols, 247-
248
of alkyl halides, 217-218
of amides, 435
of amines, 424-425
of arenes, 554-555
of aryl halides, 590
of carboxylic acids, 334-335
Infrared spectroscopy, 161-165
absorption frequencies in, 166-167
of C-H bonds, 164-165
fingerprint region, 162, 164
of multiple bonds, 164-165
Infrared spectrum, of acetaldehyde,
334-335
of acetanilide, 436
of acetic acid, 334-335
of 1-butene, 163
of carbon tetrachloride, 217-218
of chloroform, 217-218
of cyclohexylamine, 424
of N,N-dimethylformamide, 436
of ethanol, 247-248, 334-335
of N-methylaniline, 424
of octane, 163
general index 828
of phenylacetylene, 164
of propanamide, 436
of toluene, 554-555
of w-xylene, 554-555
of o-xylene, 554-558
of p-xylene, 554-555
Inhibitors, in chain reactions, 32
Initiation, of chain reactions, 31
Initiators, in radical polymerization,
754
Inositol, 418
Insecticides, 4
Insulin, amino acids in, 475
primary structure of, 475
properties and function of, 478
quaternary structure of, 475
X-ray diffraction of, 476
Intermediates, in electrophilic aromatic
substitution, 559, 675
in nucleophilic aromatic substitu-
tion, 593
Intermolecular forces, and physical
properties, 10
Intersystem crossing, 698
in benzophenone, 704
Invert sugar, 410
Invertase, 410
Iodide ion, catalysis by, 496
Iodine monochloride, in aromatic
substitution, 563
Iodobenzene, physical properties of,
590
uv spectrum of, 556
Iodoethane (see Ethyl iodide)
Iodoform, from methyl ketones, 305-
306
2-Iodo-3-hydroxybenzaldehyde, Can-
nizzaro reaction of, 650
2-Iodo-3-hydroxybenzoic acid, forma-
tion of, 650
2-Iodo-3-hydroxybenzyl alcohol, form-
ation of, 650
Iodomethane (see Methyl iodide)
Iodonium ions, in S N reactions, 194
1-Iodophenanthrene, formation of,
591
2-Iodopropanoic acid, formation of,
343
Iodotoluenes, formation of, 563
Ion-exchange resins, in amino acid
analysis, 466
Ionic bonding, 5
Ionic polymerization, 755-756
IPP (see Isopentenyl pyrophosphate)
Iso, definition of, 49
Isobutane (see 2-Methylpropane)
Isobutyl alcohol, physical properties
of, 247
Isobutyl bromide, 53
equilibration with f-butyl bro-
mide, 94
Isobutylene (see 2-Methylpropene)
Isobutyraldehyde, acetals from, 287
from 2-methylpropene, 281
Isobutyric acid (see 2-Methylpropanoic
acid)
Isoelectric points, of amino acids, 459-
461
definition of, 463
of proteins, 476, 478
Isoelectronic, definition of, 8
Isohexane (see 2-Methylpentane)
Isoleucine, physical properties of, 459
Isomerism (see also individual types
such as Optical, Geometric, etc.) in
alkenes, 84
in arenes, 550
conformational, 38, 84
in cycloalkanes, 69
geometrical, 39, 69, 84
structural, 38, 84
Isomers, configurational, 38
conformational, 38
definition of, 369
ortho, meta, and para, 550
structural, 38
Isooctane (see 2,2,4-Trimethylpentane)
Isopentenyl pyrophosphate (IPP), in
biogenesis, 792
Isoprene, 83
polymer from, 742-743, 746
polymerization of, 755
Isoprene units, in naturally occurring
quinones, 641
in terpenes, 779
Isopropyl alcohol, in acetal formation,
287
manufacture of, 251
oxidation of, 259
in photoreduction of ketones, 704
Isopropyl bromide, from propane,
219
from 2-propanol, 219
from propene, 94, 219
general index 829
Isopropyl chloride, physical proper-
ties of, 217
from propene, 93
Isopropyl hydrogen chromate, 259
Isopropyl methyl ether, formation of,
252
/j-Isopropylbenzaldehyde, formation
of, 652
Isopropylbenzene, 550
acetone from, 627
formation of, 564
formylation, 652
hydroperoxide, 627-628
oxidation of, 627
phenol from, 627
physical properties of, 553
Isopropyllithium, triisopropylcarbinol
from, 234
Isoquinoline, 679-680
natural products related to, 684
Isovaleryl chloride {see 3-Methyl bu-
tanoyl chloride)
IUPAC {see also Nomenclature), 19
Jute, cellulose in, 410
Kekule,A,3, 127
Kel-F, from chlorotrifluoroethene, 225
Kerosene, composition of, 58
Ketene, from acetone, 312, 703
as an acetylating agent, 313
with amines, 312
cumulated double bonds in, 312—
313
dimers of, 313, 321
with hydroxylic compounds, 312
physical properties of, 312
Ketimmes, hydrolysis of, 233
/3-Keto esters, hydrolysis of, 354
synthesis of, 352-354
12-Ketocholanic acid, 798
Ketones, with acid halides, 289-290
from acyl chlorides, 279
by acylation of arenes, 565
from alcohols, 259, 279
aldol addition to, 307-309
from alkenes, 279
from alkylacetoacetic esters, 354
from alkynes, 279
with amines, 288-289, 433
Clemmensen reduction of, 291-
292
in condensation reactions, 354
from dicarboxylic acids, 716
from 1,2-glycols, 279, 280
halogenation of, 303-306
with hydrogen cyanide, 283
hydrogenation of, 290
nomenclature of, 275-276
from organocadmium compounds,
279
from organomagnesium com-
pounds, 232-233
physical properties of, 277
preparation of, 278-281, 294
reactions of, 281-294
reduction of, 290, 291-292, 566
spectroscopic properties of, 277-
278
synthesis of large ring, 771
a,j3-unsaturated, 311-312
uv spectra of, 334
Wolff-Kishner reduction of, 292
Kharasch, M. S., 94
Kiliani-Fischer cyanohydrin synthesis,
417
Kinetic control, 94
in electrophilic aromatic substitu-
tion, 569
Kinetics, of S N reactions, 196-197
Kolbe electrolysis, 342
Kolbe reaction, 633
Korners absolute method, 567
Kraft process, in paper manufacture,
411
Kiirster, W., 681
Lactams, 467-468
from amino acids, 715
nylon (6) from, 751
^-Lactams, in penicillin G, 468
Lactic acid, from 2-bromopropanoic
acid, 502
configuration of, 381-382
formation of, 343
Lactides, from hydroxy acids, 356
Lactones, from hydroxy acids, 356, 715
from unsaturated acids, 355
/3-Lactones, from ketenes, 313
Lactose, structure of, 408-409
Ladenburg, A., 128, 708
general index 830
Ladenburg benzene, 707
Lanosterol, 781
biogenesis of, 792-795
isomer of, 794-795
from squalene, 792-795
in wool fat, 792
LeBel, J. A., 3
and tetrahedral carbon atom, 385
Lead fluoride, physical properties of, 14
Lead oxide, as antiknock agent, 58
Leaving groups, in S N reactions, 202
Leucine, physical properties of, 459
Lewis acids, in aromatic halogenation,
563
organoboranes, 536
Lexan, preparation of, 749
Light absorption {see also Electronic
absorption spectra), 696-699
and chemical structure, 699-703
Lignin, 411
Limonene, 780
Lindlar catalyst, 726
Linear free-energy relations, 661-664
Linoleic acid, 330
Lipids, 262, 413
Lithium aluminum hydride, with 3-
butenoic acid, 340
with carboxylic acids, 340
decomposition of, 292
with formaldehyde, 291
with ketones, 291
with nitriles, 280
reduction of acid derivatives by,
349
Lithium hydride, 291
Lithium nitride, formation of, 511
Longuet-Higgins, H. C, 726
LSD {see Lysergic acid diethylamide)
Lucas reagent, 255
Luciferin, 688
Lycopene, 782
uv spectrum of, 166
Lysergic acid, 683
Lysergic acid diethylamide (LSD), 683
Lysine, isoelectric point of, 463
physical properties of, 459
Lysozyme, properties and function of,
478
Magnesium, as inorganic coenzyme,
484
Maleic acid, acid dissociation con-
stant of, 357
anhydride from, 358
dehydration of, 86
physical properties of, 357
Maleic anhydride, formation of, 358
from maleic acid, 86
Malic acid, as resolving agent, 385
Malonic acid, acid dissociation con-
stant of, 357
decarboxylation of, 341, 359
physical properties of, 357
Malonic ester synthesis, of carboxylic
acids, 336, 361
Malonic esters, barbituric acids from,
686
Malonic esters, in synthesis of carbox-
ylic acids, 336, 361
Maltase, 410
Maltose, hydrolysis of, 410
structure of, 408-409
Mandelic acid, as resolving agent, 385
D-Mannose, phenylosazone from, 403
structure of, 401
Markownikoff 's rule, 92-96
in additions to alkynes, 114
Martius Yellow, 700, 759
Mass spectrometry, 158-159
molecular weights from, 773
rearrangements in, 778
in structure determination, 772-
778
Mass spectrum, of aspidospermine,
776
and CH 5 ®, 13
of 3,5-dimethylpyridine, 773-775
of ethyl butanoate, 778
of 2-, 3-, and 4-ethylpyridine, 773-
775
of quebrachamine, 772-778
Mayo, F. R., 94
Menadione {see 2-Methyl-l,4-naphtho-
quinone)
Menthol, 780
Menthone, cyanohydrin of, 284
Mercaptans {see Thiols)
Mercaptoethanol {see Ethan- l-ol-2-
thiol)
Mercuric salts, in alkyne hydration,
114
Merophan, 429
Merrifield, R. B., 472
general index 831
Mescaline, 659
Mesityl oxide, formation of, 309
Mesitylene (see 1,3,5-Trimethylben-
zene)
Messenger RNA, 485
Mestranol, 789
Metabolism, 495-513
Metal chelates, of carbonyl com-
pounds, 315
Metal hydrides, in reduction of car-
bonyl compounds, 291
Metallocenes, 235
Metals, as prosthetic groups, 476
Methacrolein, 276
Methacrylic acid, 276
Methanal (see Formaldehyde)
Methane, acid dissociation constant of,
13, 229
base ionization constant of, 13
bond angles in, 8
bonding in, 6
calculation of heat of combustion
of, 24
chlorination of, 222
derivatives of, 9
heat of combustion of, 24
heat of monofluorination, 75
from methylmagnesium iodide,
230
model of, 20
molecular shape of, 20
in natural gas, 56-57
physical properties of, 10, 55, 535
thermodynamic values for the
chlorination of, 27
Methanesulfonic acid, 521, 528
Methanesulfonyl chloride, 521
Methanethiol, 521
Methanol (see Methyl alcohol)
Methionine, 457
oxidation of, 525
physical properties of, 461
2-Methoxyacetanilide, nitration of,
574
Methoxyacetic acid, acid dissociation
constant of, 331
physical properties of, 331
Methoxybenzaldehydes, physical prop-
erties of, 634-635
4-Methoxybenzoin, formation of, 656
l-Methoxy-l-buten-3-yne, from 1,3-
butadiyne, 115
1-Methoxyethanol, from acetaldehyde,
284
Methyl alcohol, with acetic acid, 253-
254
bond angles in, 10
with hydrogen bromide, 251
from methyl chloride, 196-198,
200
physical properties of, 12, 246
preparation of, 245
solubility in water, 12
toxicity of, 245
Methyl-2-aminobenzoate, 659
Methyl anion, 33
Methyl azide, 422
Methyl bromide, reactivity toward
nucleophiles, 204
Methyl f-butyl ketone, cyanohydrin of,
284
Methyl cation, 32
Methyl cellosolve, physical properties
of, 264
Methyl chloride, with chloride ion, 205
with hydroxide, 195-198, 200, 496
mechanism of formation from
methane chlorination, 28
from methane chlorination, 27, 60
Methyl ethyl ether, formation of, 252
Methyl ethyl ketone, cyanohydrin of,
284
with lithium aluminum hydride,
373
synthesis of, 354
uv spectrum of, 277-278
Methyl glucoside, formation of, 404
Methyl iodide, physical properties of,
217
radicals from, 661
Methyl isocyanate, 422
Methyl isohexyl ketone, from choles-
terol, 784
Methyl isopropyl ketone, cyanohydrin
of, 284
Methyl methacrylate, 747
polymerization of, 755
Methyl nitrate, 422
Methyl nitrite, 422
Methyl propionate, 191
Methyl radicals, from acetone, 703
epr spectrum of, 661
Methyl vinyl ether, physical properties
of, 263
general index 832
Methyl vinyl ketone, with hydrogen
cyanide, 311
uv spectrum of, 278
a-Methylallyl chloride (see 3-Chloro-l-
butene)
Methylamine, base dissociation con-
stant of, 423
from nitromethane, 431 •
physical properties of, 12, 423
N-Methylaniline, base dissociation con-
stant of, 614
infrared spectrum of, 424
uv spectrum of, 614
1-Methylanthracene, 551
2-Methyl-l,3-butadiene (see Isoprene)
2-Methylbutane, 49
bromination of, 61
chlorination of, 60
2-Methyl-2-butanol, nmr spectrum of,
173
3-Methylbutanoyl chloride, forma-
tion of, 340
2-Methyl-l-butene, from /-pentyl
chloride, 208
2-Methyl-2-butene, formation of, 258
from neopentyl iodide, 208
from ?-pentyl chloride, 208
2-Methyl-3-buten-2-ol, 191
Methyl-7-butylcarbinol, dehydration
of, 258
l-Methyl-3-f-butyl-2,4,6-trinitroben-
zene, in perfumes, 612
3-Methyl-l-butyne, hydrogen bro-
mide addition to, 1 19
hydrogenation of, 1 19
a-Methyl-a-carboxyglutaric acid, 786-
787
Methylchlorosilane, preparation of,
534
Methylcholanthrene, 798
Methylcyclohexane, chair forms of,
65
frww-3-MethylcyclopentanoI, from 3-
chloro-l-methylcyclopentane, 201
Methylcyclopentanophenanthrene, 787
Methylcyclopropane, physical proper-
ties of, 83
10-Methyl-2-decalone, optical rotatory
dispersion curves for, 390
Methylene (see Carbene)
Methylene dichloride (see Dichloro-
methane)
Methylene glycol, dehydration of, 261
from formaldehyde, 261
Methylenecyclobutane, 82
Methylenecyclobutene, formation of,
428
Methylenecyclohexane, synthesis of,
531
Methylenetriphenylphosphorane, with
cyclohexanone, 531
Methylethylamine, 191
3-Methylhexane, from 4-methyl-2-
hexene, 86
4-Methyl-2-hexene, bromine addition
to, 86
hydrogenation of, 86
5-Methyl-2-hexene, 103
Methyllithium, formation of, 228
Methylmagnesium iodide, bonding in,
230
with ethanol, 230
with formaldehyde, 231
from methyl iodide, 229
Methylmalonic acid, formation of, 343
a-Methylnaphthalene, 551
/S-Methylnaphthalene, 551
2-Methyl-l ,4-naphthoquinone, 640
Methyloxonium bisulfate, formation
of, 254
Methyloxonium bromide, formation
of, 251
2-Methylpentane, 49, 55
3-Methylpentane, 49, 55
4-Methyl-3-penten-2-one (see Mesityl
oxide)
2-Methylpropane, in natural gas, 57
naming of, 48
physical properties of, 11, 83
shape of, 49
3-Methylpropanoic acid, 190
acid dissociation constant of, 331
physical properties of, 331
2-Methyl-l -propanol (see Isobutyl
alcohol)
2-Methyl-2-propanol (see /-Butyl alco-
hol)
2-Methylpropanal (see Isobutyralde-
hyde)
2-Methylpropenal (see Methacrolein)
2-Methylpropene, from ?-butyl alcohol,
257
from ?-butyl chloride, 206-207
dimerization of, 101
general index 833
hydration of, 88
isobutyraldehyde from, 281
physical properties of, 84
polymerization of, 101, 755
polymers from, 746
2-Methylpropenoic acid (see Metha-
crylic acid)
2-Methyl-2-propenonitrile, from ace-
tone, 282
5-(l-Methylpropyl)decane, naming of,
52
N-Methylpyrrolidone, solvent proper-
ties of, 437
Methylsilane, physical properties of,
535
Methylsodium, ether cleavage with, 264
a-Methylstyrene, polymerization of,
755
2-(Methylthio)ethanol, 524
Methyltrichlorosilane, physical prop-
erties of, 535
Mevalonic acid, in biogenesis, 792
Micelles, 332-333
catalysis by, 333
Michaelis-Menten effect, 504
Microwave spectroscopy, bond lengths
and bond angles from, 160
Mitochondria, 509, 640
Models, ball-and-stick, 20, 22
of cyclohexanes, 64-67
space-filling, 22
Molecular orbital energies, of 1,3-
butadiene, 142
of conjugated cyclic systems, 143
of ethene, 142
of trimethylenemethyl, 143
Molecular orbital theory, 140-145
and concerted reactions, 726-730
LCAO approach, 727
Molecular orbitals, antibonding, 727
bonding, 727
of 1,3-butadiene, 698, 727-729
energies of, 160
of ethene, 727-729
in methane, 1 30
Molecular rotation, definition of, 372
Molecular shapes, importance of, 8
Molecular weights, from boiling point
elevations, 157
by end group analysis, 157
from freezing-point depressions,
157
from light scattering, 157
by mass spectrometry, 157-158
osmotic pressure, 1 57
of proteins, 476
from sedimentation rates, 157
from vapor density measurements,
157
from viscosity measurements, 1 57
Molozonide, 98
Monosaccharides, 400-408
Monoterpenes, 779-780
Morphine, 684
Muscone, 769
Mustard gas, toxicity of, 429
Mutarotation, of glucose, 406
Myoglobin, properties and function of,
478
Myrcene, 779
NAD (see Nicotinamide-adenine di-
nucleotide)
NADH (see Nicotinamide-adenine di-
nucleotide)
Naphthacene, 552
uv spectrum of, 557
Naphthalene, acylation of, 575-576
from azulene, 578
bond lengths in, 574
monosubstitution products of, 551
physical properties of, 553
reactions of, 575-576
resonance hybrid of, 575
sulfonation of, 575-576
uv spectrum of, 557
1-Naphthalenesulfonic acid, from
naphthalene, 575-576
1-Naphthol, acid dissociation con-
stant of, 629
uv spectrum of, 629
2-Naphthol, acid dissociation constant
of, 629
formylation of, 653
2-Naphthyl methyl ketone, as photo-
sensitizer, 707
1-Naphthylamine, basicity of, 614
uv spectrum of, 614
2-Naphthylamine, basicity of, 614
uv spectrum of, 614
1 -Naphthylphenylmethylsilane, enan-
tiomers of, 533
Narcotine, 684
general index 834
Natta, G., 103
Natural gas, composition of, 56-57
Natural products, 769-796
polyhetero, 688
related to indole, 682-683
related to isoquinoline, 684
related to pteridine, 686
related to purine, 686
related to pyran, 686-688
related to pyridine, 684
related to pyrimidine, 685-686
related to pyrrole, 680-682
related to quinoline, 684
Natural rubber, 742
with ozone, 98
Neo, definition of, 49
Neohexane (see 2,2-Dimethylbutane)
Neopentane (see 2,2-Dimethylpropane)
Neopentyl halides, in S N 2 reactions,
202
Neopentyl iodide, formation of, 231
solvolysis of, 208
Neoprene, 746
Nerol, 780
Newton, I., 3
Niacin (see Nicotinic acid)
Nickel, in catalytic hydrogenation, 35
Nicol prism, and polarized light, 369
Nicotinamide, in NAD®, 506
Nicotinamide-adenine dinucleotide
(NAD®), 506, 684
Nicotine, 684
Nicotinic acid, 684
Ninhydrin, color test for a-amino
acids, 463^64
structure of, 464
Nitration (see also Electrophilic aro-
matic substitution)
of alkanes, 61
of arenes, 561-562
of heterocyclic compounds, 674-
677
of 2-methoxyacetanilide, 574
of monosubstituted benzenes, 568
of p-nitrotoluene, 573
of phenanthrene, 577
of trifluoromethylbenzene, 568
Nitric acid, 422
Nitric oxide, 422
Nitrile oxide, as 1,3-dipole, 721-723,
731
Nitriles, alkylation of, 440
hydrolysis of, 336, 439
with lithium aluminum hydride,
280, 349
with organomagnesium com-
pounds, 233
properties of, 440
reduction of, 280, 349, 430
Nitrite esters, 442
Nitro compounds (see also Nitro-
alkanes), 441-442
from alkyl halides, 442
from amines, 433, 442
aromatic, 606-613
reduction of, 430, 591, 608-611
synthesis of, 606-608, 618-619
Nitro groups, effects of, 608
resonance in, 441
Nitroacetic acid, decarboxylation of,
341
Nitroalkanes (see also Nitro com-
pounds), from alkanes, 61
electronic spectra of, 441
infrared spectra of, 441
naming of, 53
m-Nitroaniline, basicity of, 614
uv spectrum of, 614
p-Nitroaniline, basicity of, 614
formation and diazotization of,
606
oxidation of, 606
resonance in, 616
uv spectrum of, 614
Nitrobenzene, 568
chlorination of, 569, 571
nmr spectrum of, 558
physical properties of, 608
radical anion from, 613
reduction of, 609
m-Nitrobenzoic acid, 568
/j-Nitrobenzoic acid, synthesis of, 606
3-Nitrobiphenyl, 619
3-Nitro-4'-chlorobenzoin, 656
Nitroethane, 61
Nitrogen, fixation of, 511
Nitrogen dioxide, 422
Nitrogen mustards, in cancer therapy,
429
with DNA, 429
Nitroglycerin, from glycerol, 262
5-Nitro-2-indanone, oxidation of, 649
Nitromethane, 61, 422
reduction of, 431
general index 835
3-Nitro-2-methylpentane, 53
2-Nitro-2-methylpropane, formation
of, 433
o-Nitrophenol, physical properties of,
633
p-Nitrophenol, acid dissociation con-
stant of, 629
resonance, in 700
uv spectrum , 629, 700
jP-Nitrophenolate, resonance in, 700
uv spectrum of, 700
Nitrophenols, nmr spectra of, 635, 637
physical properties of, 634-635
4-Nitrophthalic acid, formation of, 649
Nitropropanes, 61
Nitroso compounds, 440-441
from aromatic amines, 617
rearrangement of, 617
Nitrosobenzene, 609
dimer of, 610
formation of, 610
with N-phenylhydroxylamine,
610-611
/7-Nitroso-N,N-dimethylaniline, 617
Nitrosomethane, 422
2-Nitrosopropane, rearrangement of,
441
m-Nitrotoluene, preparation of, 608
p-Nitrotoluene, nitration of, 562, 573
oxidation of, 606
Nitrotoluenes, formation of, 562
Nitrous acid, 422
with amines, 432
with aromatic amines, 616-617
Nitrous oxide, 422
Nmr (see Nuclear magnetic resonance
spectroscopy)
Nomenclature, of alcohols, 187-190
of alkenes, 81-83
of alkyl halides, 187-190
of alkynes, 111
of amines, 421^423
of ammonium salts, 421-423
of annulenes, 725
of benzene derivatives, 549-552
of benzoins, 656
Nomenclature, of carboxylic acids,
190, 329
of carboxylic esters, 191
of ethers, 190
of halogenated hydrocarbons, 37
of heterocyclic compounds, 671
IUPAC rules for, 19
of organoboron compounds, 539
of organosulfur compounds, 520-
521
single- or multiple-word names,
191-192
use of Greek letters, 191
Nonane, isomers of, 48
physical properties of, 55, 63
Nonbenzenoid compounds, 578
Norbornene, with phenyl azide, 722
Norethindrone, 789
Nuclear magnetic resonance spectra
(nmr), of alcohols, 247-249
of amides, 435
of amines, 425
of arenes, 558
of carboxylic acids, 334
of fiuxional systems, 723-724
and hydrogen bonding, 635
of a, /J-unsaturated carbonyl com-
pounds, 311
Nuclear magnetic resonance spectros-
copy, 168-179
the chemical shift, 170-171
in qualitative analysis, 174-176
and rate processes, 176-178, 696
spin-spin splitting, 171-174
Nuclear magnetic resonance spectrum,
of l-chloro-2-fluoro-l ,1,2,2-tetra-
bromoethane, 178
of cholesterol, 787
of dietbylamine, 425
of 1,1-dimethoxyethane, 175
of ethyl acetoacetate, 350-352
of ethyl alcohol, 169
of ethyl iodide, 171
of 2-methyl-2-butanol, 173
of nitrobenzene, 558
o-, m-, p-nitrophenols, 635, 637
of 2,4-pentanedione, 314-315
of propanamide, 437
Nucleic acids (see Ribonucleic acid and
Deoxyribonucleic acid)
Nucleophiles, base dissociation con-
stants, of, 204
definition of, 87, 192
in electrophilic addition, 89
Nucleophilic addition, to alkynes, 115
Nucleophilic aromatic substitution, of
activated aryl halides, 593-594
elimination-addition mechanism,
general index 836
594-596
rearrangements in, 595
Nucleophilic catalysis, 496-497, 499-500
Nucleophilic displacement reactions
(see also Nucleophilic aromatic sub-
stitution), 192-205
of activated aryl halides, 593-594
of alkyl derivatives, 193-195
of alkyl halides, 193-195
catalysis by heavy metal salts, 203
energetics of, 197-200
of heterocyclic compounds, 678-
679
kinetics of, 196-197
the leaving group in, 202-203
mechanisms of, 195-197
nature of solvent, 204-205
reagents for, 193-195
S N /, 502
solvents for, 193-195
stereochemistry of, 200-201, 389
structural effects in, 201-204
synthetic utility of, 193-195
Nucleophilic reagents, and basicity,
203-204
list of, 193-194
Nucleosides, 480-481
Nucleotides, 481
Nylon, 750-751
hydrogen bonding in, 739
Octafluorocyclobutane, physical prop-
erties of, 226
as a propellant, 226
Octane, heat of combustion of, 24, 57,
510
infrared spectrum of, 163
isomers of, 48
octane rating of, 58
physical properties of, 53-55, 63
Octane rating, 57-58
1-Octanol, from 1-hexanol, 265
Oil of wintergreen, 658
Olefins (see also Alkenes), 81
Oleic acid, 330
Opium alkaloids, 684
Optical activity, origin of, 369-371
Optical isomerism, 369-392
and absolute and relative con-
figuration, 381-384
of allenes, 379-380
of amine oxides, 434
of amines, 426
asymmetric induction, 386-387
of biphenyls, 380-381
in 2-butanol, 369
conventions for, 374-375, 381-384
and optical rotatory dispersion,
389-391
of organophosphorus compounds,
525
of organosilicon compounds,
533
of organosulfur compounds, 524-
525
projection formulas, 374-375
resolution (see Resolution)
and restricted rotation, 379-381
of spiranes, 379-380
Optical isomers, definition of, 369
diastereomers, 378
enantiomers, 384
meso forms, 377
resolution of, 384
threo and erythro forms, 377
Optical rotatory dispersion, 389-391
of 10-methyl-2-decalone, 390
Oral contraceptives, 789
Orbital symmetry, and cycloaddition
reactions, 726-730
Orbitals, antibonding, 141, 277
bonding, 145
definition of, 7, 129
in ethene, 34
nonbonding, 141
shapes of, 129, 517-518
d Orbitals, and chemical bonds, 517-
520
in organosilicon compounds, 533-
534
p Orbitals, 129
s Orbitals, 129
d 2 sp 3 Orbitals, 519
sp 2 Orbitals, 131
sp 3 Orbitals, 130, 519
ORD (see optical rotatory dispersion)
Organic chemistry, definition of, 3
Organic nitrogen compounds, 421-
426
Organic synthesis (see Synthesis)
Organoboranes, as Lewis acids, 536
Organoboron compounds, 536-540
nomenclature of, 539
general index 837
Organocadmium compounds, with
acyl chlorides, 233, 279
ketones from, 233
Organofluorine compounds, physio-
logical properties of, 226
Organolithium compounds, 234
Organomagnesium compounds, with
acids, 230
with 1-alkynes, 229
with carbonyl compounds, 231-
233, 250
carboxylic acids from, 336
with cyclopentadiene, 229
with halogens, 230-231
with metallic halides, 229
with nitriles, 233
with oxygen, 230-231
with sulfur, 230-231
thiols from, 522
Organomercury compounds, from
Grignard reagents, 229
from methyl iodide, 228
as seed fungicides, 234
Organometallic compounds {see also
individual types such as Organomag-
nesium compounds), 226-235
from aryl halides, 592-593
bonding in, 227, 230
preparation of, 228-229
toxicity of, 229
use of, 234
Organonitrogen compounds {see Or-
ganic nitrogen compounds)
Organophosphorus compounds, 528-
531
asymmetry of, 525
Organosilicon compounds {see also
individual types such as Silanes, Sil-
anols, etc.), 531-536
asymmetry of, 533
preparation and properties, 534-
535
types of, 532 .
Organosodium compounds, 234
Wurtz coupling of, 228
Organosulfur compounds, 520-528
nomenclature of, 520-521
Orientation, in addition polymeriza-
tion, 754
in electrophilic aromatic subsitu-
tion, 567-574
in nitration of arenes, 568
Orion {see Polyacrylonitrile)
Ortho-Novum, 789
Osazones, formation of, 403
Osmium tetroxide, in alkene oxidation,
261
Oxalic acid, acid dissociation constant
of, 357
decarboxylation of, 359
physical properties of, 357
Oxidation, of alcohols, 259-260, 523,
526
of alkenes with osmium tetroxide,
98-99
of alkenes with ozone, 97
of alkenes with permanganate,
98-99
of alkylboranes, 97
of amines, 432-433, 523
of cholesterol, 784
of civetone, 770-771
of cumene, 627
of cyclohexane, 750
of enols, 292
of ethanol by NAD®, 506-508
of eugenol, 658
of glucose, 509
of hydroquinones, 638
and metabolic processes, 510
microbiological, 788
photochemical, 705-706
of sulfides, 525
of thiols, 523-524
Oxidation levels, of nitrogen, 421
Oxidative phosphorylation, 509
Oximes, formation of, 289
reduction of, 430
rearrangement of, 429^130, 439
Oxomalonic acid, 282
Oxonium ions, from carbonyl com-
pounds, 285-286
in enol formation, 304
from ethers, 264
in hemiacetal and acetal forma-
tion, 285-286
Oxygen, excited singlet state of, 705-
706
as inhibitor in chain reactions, 32
triplet state of, 705
Ozone, air pollution from, 58
as 1,3-dipole, 721-723, 731
Ozonides, 97
Ozonization, 97-98, 279
general index 838
Palladium, in catalytic hydrogenation,
35
in reduction of acyl chlorides, 279
Palmitic acid, 330
acid dissociation constant of, 331
physical properties of, 331
Papain, properties and function of,
478
Papaverine, 684
Paper chromatography, in amino acid
analysis, 466
Paraffin, 56
Paraformaldehyde, from formalde-
hyde, 287-288
Partial rate factors, in nitration of
arenes, 569
Pasteur, L., 385
Patterson, A. M., 552
Pauli exclusion principle, 1 30
Pelargonidin chloride, 687-688
Pencillin, in resolution of enantiomers,
385
Penicillin G., /3-lactam structure of, 468
X-ray diffraction analysis of, 468
Pentaborane, structure of, 537-538
Pentacene, uv spectrum of, 557
Pentadecane, physical properties of, 55
1,3-Pentadiene, 83
1,4-Pentadiene, 83
Pentaerythritol, preparation of, 324
Pentane, isomers of, 48-49
physical properties of, 55, 63, 424
2,3-Pentanediol, optical isomers of,
392
2,4-Pentanedione, acid dissociation
constant of, 315
Be" salt of, 316
Cu" salt of, 316
enol form of, 314
nmr spectrum of, 314-315
tautomerization of, 315, 723
Pentanoic acid, acid dissociation con-
stant of, 331
physical properties of, 331
m-2-Pentene, heat of combustion of,
85
physical properties of, 85
?ra«.s-2-Pentene, heat of combustion of,
85
physical properties of, 85
4-Pentenoic acid, y-valerolactone
from, 355
f-Pentyl chloride (see 2-Chloro-2-
methylbutane)
n-Pentylamine, physical properties of,
424
Peptide synthesis, coupling reagents
in, 472
protecting groups in, 471
solid-phase, 472
yields in, 471
Peptides, 468-474
amino acid sequence in, 470
analysis of, 469-470
with 2,4-dinitrofluorobenzene, 593
naturally occurring polymers,
756-757
synthesis of, 470-474
Peracids, with amines, 433
in radical polymerization, 754
Perfluoro-2-methylpropene, toxicity of,
226
Perfumes, 4
civetone in, 769
coumarins in, 687
cyclopentadecanone in, 772
exaltone in, 772
examples of, 658-659
ingredients in, 612
muscone in, 769
terpene alcohols in, 780
Perhydrophenanthrene, 551
Periodic table, 517
Permanganate oxidation, of alco-
hols, 260
of alkenes, 261, 287
of amines, 432
Peroxides, as radical initiators,
95
Peroxy radicals, 32
Persulfuric acid, in radical polym-
erization, 754
Pesticides, 4
analysis for, 156
organochlorine derivatives, .596-
598
Petroleum, 56-58
Phenacetin, 659
Phenalenyl, 552
Phenanthrene, monosubstitution prod-
ucts of, 551
physical properties of, 553
reactions of, 577
resonance hybrid of, 575
general index 839
1-Phenanthrylamine, diazotization of,
591
Phenobarbital, 659, 685
Phenol, acid dissociation constant of,
629
from chlorobenzene, 595
commercial synthesis of, 627
physical properties of, 628-629
polymers from, 751-752
resonance hybrid of, 630
stabilization energy of, 605
tautomer of, 605
uv spectrum of, 556, 629
Phenol-formaldehyde resins, 751-752
Phenolphthalein, structure of, 710
Phenols, acidity of, 630
alkylation of, 631-632
from aromatic amines, 617
bromination of, 632-633
chemical properties of, 630-635
with ferric chloride, 631
hydrogen bonding in, 634
nmr spectra of, 635, 637
oxidation of, 635-636
physical properties of, 627-629,
633
polyhydric, 635-636
quinones from, 635-636
reduction of, 635
separation from carboxylic acids,
631
synthesis of, 627-629
Phenoxide anion, resonance hybrid
of, 630
Phenyl acetate, formation of, 630
Phenyl allyl ether, from phenol, 631
rearrangement of, 632
Phenyl azide, addition reactions of, 722
Phenyl halides, in S N reactions, 220
Phenyl radicals, from diazonium salts,
618
Phenylacetic acid, acid dissociation
constant of, 331
physical properties of, 331
Phenylacetylene, 550
infrared spectrum of, 164
Phenylalanine, physical properties of,
459
synthesis of, 458
Phenylamine {see Aniline)
/i-Phenylbenzaldehyde, formation of,
652
l-Phenyl-2-butanol, 187
l-Phenyl-3-buten-l-ol, 189
Phenyldichloroborane, 539
^-Phenylenediamine, uv spectrum of,
614
Phenylethanone {see Acetophenone)
Phenylethene {see Styrene)
2-Phenylethyl bromide, 589
Phenylhydrazine, osazones from, 403
N-Phenylhydroxylamine, 609
from nitrobenzene, 610
Phenyllithium, 191
preparation of, 593
Phenylmagnesium bromide, prepara-
tion of, 592
Phenylmagnesium iodide, 191
2-Phenylpyridine, from pyridine, 678
Phenyltrichloromethane, physical
properties of, 535
Phenyltrichlorosilane, physical prop-
erties of, 535
Phenyl trimethylammonium salts, ni-
tration of, 568
Phenyltrimethylmethane, physical
properties of, 535
Phenyltrimethylsilane, physical prop-
erties of, 535
Phillips process, in coordination poly-
merization, 103
Phloroglucinol, reactivity of, 636
structure of, 635
Phosphate groups, in DNA, 479
Phosphines, asymmetric, 525
Phosphonate esters, hydrolysis of, 502
Phosphonium salts, with basic re-
agents, 530
formation of, 530
reactions of, 530
Phosphorescence, 696-699
Phosphoric acid, derivatives of, 528-
530
Phosphorous acid, structure of,
529
Phosphorus, in halogenation of acids,
343
organic compounds of, 528-531
Phosphorus halides, with carboxylic
acids, 340
Phosphorus pentachloride, in Beck-
mann rearrangement, 430
with cyclopentanone, 290
Phosphorus pentafluoride, 517
general index 840
Phosphorus tribromide, in alkyl bro-
mide formation, 256
Photochemistry, 695-709
Photodissociation, 703-704
Photographic developers, 639
Photosensitizers, benzophenone, 706
definition of, 706
2-naphthyl methyl ketone, 707
in photoisomerization, 707
Photosynthesis, of carbohydrates, 399
of glucose, 387
radicals in, 661
study of, 466
Phthalic acid, acid dissociation con-
stant of, 357
anhydride from, 358, 715
physical properties of, 357
Phthalic anhydride, formation of, 358,
715
polymer from, 750
Phytol, 781
in chlorophyll, 781
in vitamin K, 781
Picric acid, 611-612
acid dissociation constant of, 629
charge- transfer complexes of, 612
uv spectrum of, 629
Pimelic acid, acid dissociation constant
of, 357
from civetone, 770
cyclohexanone from, 358
physical properties of, 357
Pinacol, rearrangement of, 280
Pinacolone, from pinacol rearrange-
ment, 280
a-Pinene, camphor from, 780
Piperidine, base dissociation constant
of, 423
physical properties of, 423
Piperonal, 659
Plane-polarized light (see also Optical
Isomerism), and origin of optical
rotation, 369-371
Plasticizers, 748
camphor, 780
Plastics (see also Polymers), from cellu-
lose, 410
from formaldehyde, 288
thermal moulding of, 740
Platinum, in catalytic hydrogenation,
35
Polarimeter, description of, 370-371
Polarizability, and S N reactions, 203
Pollution, atmospheric, 58
by detergents, 526
from paper pulping, 41 1
from petroleum, 58
by phosphates, 528
trace analysis for, 156
Polyacrylonitrile, 740
Polyamides, definition of, 469
nylons, 750-751
Polycyclopentadiene, 737
Polyesters, preparation of, 749-750
Polyethylene (see also Polythene), 102
Polyethylene glycol, from ethylene
oxide, 266
uses of, 756
Polyhalogen compounds, 222-226
Polyhetero systems, examples of, 679-
680
Polyisobutylene, 101
Polyisoprene (see also Natural rubber),
98, 742-743
Polymerization, by addition, 753-756
anionic, 100
azo initiators in, 443
cationic, 101, 755-756
by condensation, 748-752
coordination, 103, 753
of cyclopentadiene, 737
ionic, 755-756
of isopentenyl pyrophosphate, 792
of isoprene, 743
radical, 102, 743, 753-755
of tetrafluoroethene, 225
vinyl, 753
Ziegler, 743
Polymers, 737-766
from aldehydes, 287-288
atactic, 744
cold-drawing, 740
cross linking, 738
crystalline state of, 740
definition of, 99
DNA, 479
dyeing of, 758-762
elastomers, 738, 741
glass temperature of, 740
glyptal resin, 750
isotactic, 744
melting temperature, 740
naturally occurring, 756-758
nylons, 750
general index 841
in peptide synthesis, 472
phenol-formaldehyde resins, 751—
752
physical properties of, 738-748
preparation, 748-756
representative, 745-747
silicones, 533, 536
stereoregular, 753
syndiotactic, 744
thermoplastic, 738
thermosetting, 738
types of, 737-738
vulcanization of, 743
Polynitro compounds, 611-612
charge-transfer complexes of, 612-
613
Polynuclear aromatic hydrocarbons,
double bond character in, 574
naming of, 551-552
substitution reactions of, 574
Polyoxymethylene {see Formaldehyde,
polymers from)
Polypeptides {see Peptides)
Polypropene, 100
isotactic, 744
Polypropylene {see Polypropene)
Polysaccharides {see Cellulose, Starch,
etc.)
Polystyrene, configurations of, 744
Polystyrene resin, in peptide synthesis,
472
Polytetrafluoroethene {see Teflon)
Polythene, 745
from ethene, 102, 745
crystalline character of, 739
Polyvinyl chloride, 745
"Polywater", 11
Potassium bromide, in infrared spec-
troscopy, 161
Potassium f-butoxide, in E2 elimina-
tion, 252
Potassium permanganate {see Perman-
ganate oxidation)
Potential energy, of diatomic mole-
cules, 697
Progesterone, 790
cortisone from, 788
Projection formulas {see also Optical
isomerism), of 2-butanol, 374
conventions for, 375, 383
Fischer type, 405
Haworth type, 405
Proline, in ninhydrin test, 465
physical properties of, 461
Propadiene {see Allene)
Propanamide, infrared spectrum of,
436
nmr spectrum of, 437
Propane, with bromine, 219
in natural gas, 57
nitration of, 61
physical properties of, 11, 55, 63
1,3-Propanedithiol, with acetone, 523
Propanethiol, occurrence, 522
Propanoic acid, 190
acid dissociation constant of, 331
cleavage of alkyl boranes, 97
physical properties of, 331
Propanone {see Acetone)
Propanoyl chloride, with benzene, 566
Propargyl chloride {see 3-Chloro-l-
propyne)
Propenal {see Acrolein)
Propene, addition reactions of, 104
with chlorine, 220
hydroboration of, 539
with hydrogen halides, 219
from isopropyl iodide, 252
polymer from, 745
from propyne, 121
Propanoic acid {see Acrylic acid)
2-Propen-l-ol {see also Allyl alcohol),
262
Propionamide {see Propanamide)
Propionic acid {see Propanoic acid)
n-Propyl alcohol, from tri-«-propyl-
borane, 97
Propyl bromide, from propane, 219
from 1-propanol, 219
from propene, 95
re-Propyl chloride, physical properties
of, 217
ra-Propylbenzene, formation of, 566
physical properties of, 553
Propylene {see also Propene), 82
3-Propyl-l-heptene, naming of, 81
Propyne, acid dissociation constant of,
229
addition reactions of, 121
hydration of, 114
Prosthetic groups, 503
in hemoglobin, 680
metals as, 476
in proteins, 469
general index 842
Protecting groups, benzyloxycarbonyl,
471
f-butoxycarbonyl, 472
in peptide synthesis, 471
removal of, 471, 473
Proteins, 4
biological functions of, 477
biosynthesis of, 477
conformations of, 474
denaturation of, 469
heat of combustion of, 510
in hemoglobin, 680
isoelectric points of, 476, 478
as peptides, 469
structures of, 474-477
Proton magnetic resonance spectros-
copy (see Nuclear magnetic reson-
ance spectroscopy)
Protonium ions, 91-92
Prototropic change, 315
Pteridine, 679, 686
Purification, by chromatography, 156
by crystallization, 153
by distillation, 153
by extraction, 153
Purine, 679
derivatives of, 407, 480
natural products related to, 686
Pyran, natural products related to,
686-688
structure of, 406
Pyranose, definition of, 406
Pyrene, 552
3,10-Pyrenequinone, 638
Pyridine, base strength of, 423, 427,
431, 674
chemical properties of, 673-679
natural products related to, 684
nucleophilic substitution reactions
of, 678-679
physical properties of, 423, 431,
671
Pyridinium salts, formation of, 674
a-Pyridone, catalysis by, 503
from pyridine, 678
tautomers of, 503, 723
Pyridoxine, 684
Pyrimidine, 679
derivatives of, 407
natural products related to, 685-
686
Pyrogallol, structure of, 635
a-Pyrone, 686
y-Pyrone, resonance hybrid of, 686-687
Pyrrole, acid dissociation constant of,
674
aromatic character of, 672-673
atomic orbital description of, 672-
673
chemical properties of, 673-679
hydrogen bonding in, 671
physical properties of, 671
natural products related to, 680-
682
resonance hybrid of, 672
Pyrrylmagnesium bromide, formation
of, 674
Pyrrylpotassium, 674
Pyrryl anion, resonance hybrid of, 674
Quantum yield, definition of, 703
Quartz, in separation of tautomers, 352
Quebrachamine, mass spectrum of,
772-777
pyridines from, 773-775
structure determination of, 772-
777
Quercitin, 687
Quinhydrone, 638
Quinine, as resolving agent, 385
Quinoline, 679-680
natural products related to, 684
Quinone-hydroquinone equilibrium,
638
Quinones, 636-641
addition reactions of, 639-640
naturally occurring, 640
from phenols, 635-636
reduction of, 638
Quinuclidine, basicity of, 622
Racemization, by acid-catalyzed enol-
ization, 388
by base-catalyzed enolization, 388
definition of, 373
mechanisms of, 388
by an S N 1 process, 388
Radiation, effects of, 695
Radical addition, to alkenes, 94-96
Radical halogenation, of alkanes, 28-
32, 59-61
of alkylbenzenes, 650
general index 843
Radical polymerization, 753-755
Radicals, acetyl, 703
anion, 613
alkoxy, 95
benzhydrol, 704
coupling of, 655
methyl, 32, 703
in photosynthesis, 661
semiquinone, 638-639
stabilities of, 96
stable triarylmethyl, 654
Raney nickel, 36
Rayon acetate, 410
Reaction (p) constants, of Hammett
equation, 663-664
Reaction intermediates, types of (see
also Intermediates), 32
Reaction rates, diffusion controlled, 495
and entropy of activation, 30
and heat of activation, 30
and mechanism, 28
and rate-determining step, 29
and S N reactions, 196-197
Reactions (see also individual types
such as Hydrogenation, Nucleo-
philic displacement, etc.)
addition of unsaturated hydro-
carbons, 34
additions to alkynes, 113-115
alkylation of esters, 354
chain-termination in radical types,
31
Claisen condensation, 352-354
combustion, 23
condensation of carbonyl com-
pounds with amines, 288-289
conjugate addition, 127, 133-135
cyclization, 715-730
cycloaddition, 718-723
electrophilic addition to alkenes,
87-96
electrophilic aromatic substitu-
tion, 559-577
elimination, 205-208, 252, 256
endothermic, 23
esterification, 252-255
of excited states, 695-709
exothermic, 23
heat of, 23
hydrogenation, 35
nucleophilic addition to alkynes,
115
nucleophilic displacement, 192-
205
oxidation of alcohols, 259-260
polymerization of alkenes, 99-103
propagation, 31
solvolysis, 197
substitution, 26, 252
thermodynamics of, 26
Rearrangement, of benzilic acid, 313,
321
of cumene hydroperoxide, 627-
628
of glyoxal, 313, 321
of hydrazobenzene, 611
of a-pinene, 798
of squalene, 795
Rearrangements, of alkyl groups, 258,
565
in alkylation of arenes, 565
Beckmann, 429^130
Claisen, 632
Cope, 723-724
of dienes, 723-724
of 1,2-glycols, 280
in mass spectrometry, 778
of N-nitroso compounds, 617
of oximes, 429^130
of phenyl allyl ethers, 632
photochemical, 707
of terpenes, 798
of /3,y-unsaturated carbonyl com-
pounds, 312
Reducing sugars, definition of, 406
Reduction, of carboxylic acids, 279-
280, 340
of civetone, 771
of diazonium salts, 619
of nitriles, 280
of nitro compounds, 608-61 1
photochemical, 704-705
of quinones, 638
Relative configuration, of optical iso-
mers, 381-384
Reserpine, 683
Resolution, crystallization procedure
for, 385
definition of, 373
of enantiomers, 384
of optically active acids, 385
of optically active alcohols, 385
of optically active bases, 385
Pasteur method for, 385
general index 844
Resonance, in carboxylate anions, 337
in excited state of 1,3 -butadiene,
168
Resonance energy (see also Dereal-
ization energy and Stabilization
energy), 132
of benzene, 549
Resonance method, 13
rules for, 140
Resorcinol, acid dissociation constant
of, 629
reactivity of, 636
structure of, 635
uv spectrum of, 629
Restricted rotation, and optical activ-
ity, 379-381
Rf value, definition of, 466
Ribofuranose, in vitamin B 12 , 681- 682
Ribonuclease, properties and function
of, 478
synthesis of, 474
Ribonucleic acid (RNA), 484
bases in, 485
classes of, 485
differences from DNA, 489
D-ribose in, 400
Ribonucleosides, as glycosides, 407
D-Ribose, in NAD®, 506
in RNA, 400, 484
structure of, 400-401
in vitamin B 12 400
Ribosomal RNA, 485
Ribosomes, 484
RNA (see Ribonucleic acid)
Robinson, R., 683
Rosenmund reduction, 279-280
Ruff degradation, 416
Ruzicka, L., 769, 779
S N reactions (see Nucleophilic dis-
placement reactions)
S— S linkages, in proteins, 457^158
Saccharides, classification of, 400-402
Salicylaldehyde, acid dissociation con-
stant, 629
coumarin from, 687
uv spectrum of, 629
Salicylic acid, acetyl derivative of, 658
formation of, 633
methyl ester of, 658
physical properties of, 633
Salmonella bacteria, 413
Sandmeyer reaction, 591, 618-619
Sanger, F., 475
Santonin, 780
Saponification, 345
Schiemann reaction, 591, 619
Schiff 's base, formation of, 289
Schmidt reaction, 430
Selection rules, spectroscopic, 698
^-Selinene, 780
Semicarbazide, 289
Semicarbazones, formation of, 289
Semiquinone radicals, 638-639
epr spectra of, 661
Sensitizers (see Photosensitizers)
Serine, in ester hydrolysis, 505
in hydrolytic enzymes, 500
physical properties of, 459
Serotonin (see 5-Hydroxytryptamine)
Sesquiterpenes, 779-780
Sex attractants, farnesol, 780
Sex hormones, 788-789
Silane, physical properties of, 535
Silanes, examples of, 532
physical properties of, 535
Silanols, examples of, 532
preparation and properties of,
534-535
Silica gel, in alcohol dehydration, 257
in thin-layer chromatography,
467
Silicon compounds, bond strengths of,
532
organic compounds of, 531-536
resolution of, 533
tetrahedral structure of, 533
Silicones, 536
Silk, 756-757
Siloxanes, examples of, 532
preparation and properties of,
534-535
Silver, as catalyst in ethene oxidation,
261
Silver bromide, in photography, 639
Silver ion, complexes with alkenes, 235
Singlet state, nature of, 697
of oxygen, 705
Sitosterol, 783
Skew-boat (see Twist-boat)
Smog (see Pollution, atmospheric), 58
Soap, cleansing action of, 332
formation of, 330
general index 845
Sodium bisulfite, with aldehydes, 294,
527
Sodium borohydride, decomposition
of, 291
diborane from, 97
with formaldehyde, 291
with ketones, 291
in reduction of metal salts, 36
Sodium chloride, bonding in, 5
in infrared spectroscopy, 161
physical properties of, 5
Sodium dichromate, in oxidation of
alcohols, 259
Sodium ethoxide, formation of, 251
Sodium fluoroacetate, toxicity of, 226
Sodium phenoxide, with carbon diox-
ide, 633
Sodium phenyl carbonate, rearrange-
ment of, 633
Sodium sulfide, in Kraft process, 41 1
Sodium sulfonates, as detergents, 526
Sodium triphenylmethide, formation
of, 654
Soluble RNA, 485
Solvents, polar aprotic in S N reactions,
205
for S N reactions, 194-195
Sorbitol, from glucose, 404
Specific rotation, definition of, 371
Spectroscopy, 159-178
electronic absorption, 165-168
elucidating structures with, 4
infrared, 161-165
methods in structure determina-
tion, 772-778
microwave, 160
nuclear magnetic resonance, 168—
178
X-ray diffraction, 159
Spiranes, examples of, 380
optical isomerism of, 379
Spiro[2.2]pentane, structure of, 380
Squalene, 781
biogenesis of, 792-795
conversion to lanosterol, 792-795
epoxide, 794
Stabilization energy (see also Dereal-
ization energy a/w/Resonance energy)
of benzene, 128-129,549
of iJ-benzoquinone, 636
of 1,3-butadiene, 135
of heterocyclic compounds, 673
Staggered conformations (see Con-
formations, staggered)
Starch, heat of combustion of, 510
hydrolysis of, 408
structure of, 412
Stearic acid, 330
acid dissociation constant of, 331
physical properties of, 331
Stereochemistry {see also individual
types such as Optical isomerism and
Geometrical isomerism)
of allenes, 379-380
of amines, 425-426
of biphenyls, 380-381
definition of, 369
of electrophilic addition to al-
kenes, 89
geometric isomerism or cis- trans,
69-71, 84
of nucleophilic displacement re-
actions, 200-201, 389
and optical isomerism, 369-392
of organophosphorus compounds,
525
of organosilicon compounds, 533
of spiranes, 379-380
Stereoisomers, definition of, 39
Stereospecificity, of biochemical re-
actions, 387
Steric acceleration, in S N reactions,
202
Steric hindrance, in acetal formation,
287
in additions to a,/3-unsaturated
carbonyl compounds, 311
in alkylation of phenols, 631
in biphenyls, 381
in boat cyclohexane, 65
in carbonyl additions, 281-282
in ds-alkenes, 85
in hemiacetal formation, 287
relief of, 10
Steroids, 782-789
biogenesis of, 789-794
representative types, 788-791
Stigmasterol, 790
Stilbene, photoisomerization of cis-
trans isomers of, 707
uv spectrum of, 556
Stoll, synthesis of civetone, 772
Strecker synthesis, 458
Streptomycin, 402
general index 846
Structural isomers, 83, 369
Structure, definition of, 21, 84
Structure determination, 156-178
Strychnine, 683
as resolving agent, 385
Styrene, 128, 550
polymerization of, 754-755
polymers from, 746
uv spectrum of, 556
Suberic acid, from civetone, 770
Substituent (a) constants, of Hammett
equation, 662-663
Substituent effects, in base strengths
of amines, 616
in electrophilic aromatic substi-
tution, 567-574
in light absorption, 701-702
in nucleophilic aromatic substitu-
tion, 594
Substitution reactions (see also Nucle-
ophilic displacement reactions, Nu-
cleophilic aromatic substitution,
etc.)
electrophilic aromatic, 559-577
of 2-halo acids, 343-344
radical mechanisms of 28-32
S N 1 with aryl compounds, 617
of saturated hydrocarbons, 26
Succinic acid, acid dissociation con-
stant of, 357
anhydride from, 358, 715
catalyst in aldol addition, 309
formation of, 358, 715
physical properties of, 357
Succinimide, 439
Sucrose, structure of, 408-409
Sugars (see also Monosaccharides, Di-
saccharides, Carbohydrates, etc.), 4
Sulfa drugs, 527
Sulfadiazine, 527, 685
Sulfaguanidine, 527
Sulfate esters, 528
Sulfenic acids, and derivatives, 526
Sulfinic acids, and derivatives, 526
Sulfonation, of arenes, 566
of heterocyclic compounds, 674-
677
of naphthalene, 575-576
of phenanthrene, 577
Sulfones, 525-526
from thioethers, 524-526
Sulfonic acids, acid strengths of, 527
and derivatives, 526
preparation of, 527
Sulfonium salts, formation of, 524
resolution of, 524-525
Sulfonyl chlorides, 527
Sulfoxides, 525-526
from thioethers, 524-526
Sulfur, in catalyst poisoning, 279
electronegativity of, 522
elemental, 519
organic compounds of, 520-528
Sulfur hexafluoride, 517
Sulfur-sulfur bonds, in proteins, 457-
458
Sulfur tetrafluoride, with cyclopenta-
none, 290
Sulfur trioxide, in aromatic sulfona-
tion, 567
Sulfuric acid, in ester formation, 253-
254
esters of, 256-258
Super acids, 1 3
and carbonium salts, 200
Synthesis, of cyclic ketones, 771
of organic compounds, general
considerations, 117-120
overall yields in, 471
of peptides, 470-474
prebiotic, 486
Synthetic fibers (see also Polymers,
types of), 4
2,4,5-T, ecological effect of, 598
Tartaric acid, absolute configuration
of, 382
optical isomers of, 377-378
physical properties of, 374
resolution of, 385
as resolving agent, 385
from threose, 379
meso-Tartaric acid, from ( — )-erythrose,
379
Taurine, 784
Tautomer, definition of, 315 '
Tautomers, of aniline, 427, 605
of barbaralane, 724
of barbituric acid, 723
of bullvalene, 725
of 1,3,5-cyclooctatriene, 723
of ethyl acetoacetate, 351-352
of hydroxypyridine, 503, 723
of hydroxypyrimidines, 480-481
general index 847
of 2,4-pentanedione, 723
of phenol, 605
valence bond, 723
of vinyl alcohols, 605
of vinylamines, 605
Teflon, 743, 745
properties of, 225
from tetrafluoroethene, 225
Terephthalic esters, polymers from,
747
Terpenes, 778-782
biogenesis of, 789-794
in wood, 411
Testosterone, 791
Tetraborane, 537
1 , 1 ,2,2-Tetrabromo-4,4-dimethylpen-
tane, from 4,4-dimethyl-l-pentyne,
113
1,2,5,6-Tetrabromohexane, from 1,5-
hexadiene, 127
Tetra-r-butylmethane, 1 17
2,3,7,8-Tetrachlorobenzodioxin, tera-
togenic agent, 598
Tetrachloromethane (see also Carbon
tetrachloride), 28
Tetrachlorosilane, physical properties
of, 535
Tetracyanoethene, charge-transfer
complexes of, 613
as a dienophile, 719
Tetracyanomethane, 117
Tetraethyllead, from ethyl chloride, 234
in gasoline, 58, 234
physical properties of, 234
Tetrafluoroethene, from chloroform,
225
dimerization of, 726
polymer from, 745
polymerization of, 225
Tetrafluoromethane, bond angles in, 8
bonding in, 6
Tetrahedrane, 117
Tetrahydrofuran, peroxides from, 265
properties of, 266
physical properties of, 263
solubility in water, 264
as a solvent, 264
Tetralin, 551
Tetramethylene glycol (see 1,4-Butane-
diol)
Tetramethylene oxide (see Tetrahy-
drofuran)
Tetramethylene sulfone, dielectric con-
stant of, 205
Tetramethylefhylene, 81
formation of, 258
2,2,5,5-Tetramethyl-cw-3-hexene (see
cw-.syw-Di-r-butylethylene)
Tetramethyllead, physical properties
of, 14
2,2,4,4-Tetramethyl-3-pentanol, 1 89
Tetramethylsilane, in nmr spectros-
copy, 170
physical properties of, 535
Tetranitromethane, 442
N,2,4,6-Tetranitro-N-methylaniline,
611-612
Tetraphenylmethane, physical proper-
ties of, 535
Tetraphenylsilane, physical properties
of, 535
1 ,2,4,6- Tetraphenylthiabenzene, 520
Tetraterpenes, 782
Tetrazotization, of diamines, 618
Tetryl (see N,2,4,6-Tetranitro-N-meth-
ylaniline)
Thalidomide, 440
Thermodynamics, equilibrium con-
stants, 26-28, 93
free energy of reaction, 26-28
entropy of reaction, 26-28
heat of reaction, 26-28
Thiamine, 685
pyrophosphate, 685
Thiazole, 679
Thietane, 520
Thin-layer chromatography, in amino
acid analysis, 467
Thiobenzophenone, 521
Thioesters, from thiols, 523
Thioethers, nucleophilic properties of,
524
preparation of, 524-525
from thiols, 523
Thiols, 521-524
acid strength of, 522
hydrogen bonding in, 522
infrared spectra of, 522
mercury salts of, 522
from organomagnesium com-
pounds, 230-231
oxidation of, 523-524, 527
in paper manufacture, 522
in petroleum, 522
general index 848
preparation, 522
Thionyl chloride, with carboxylic
acids, 340
in preparation of alkyl chlorides,
255-256
Thiophene, aromatic character of, 672-
673
chemical properties of, 673-679
physical properties of, 671
Thiophenol, 520
Thorium oxide, in ketone synthesis, 772
Threonine, configuration of, 384
physical properties of, 459
Threose, oxidation of, 379
projection formulas of, 378
jS-Thujaplicin, 641
Thymine, in DNA, 480
Thyroxine, physical properties of, 461
Titanocene, with nitrogen, 511
TMS {see Tetramethylsilane)
Tobacco mosaic virus, properties and
function of, 478
Tollen's reagent, 404
Toluene, 550
infrared spectrum of, 554-555
iodination of, 563
nitration of, 562, 568, 606
physical properties of, 553
radical chlorination of, 650
sulfonation of, 566
p-Toluenesulfonic acid, formation of,
566
/>-Toluenesulfonyl chloride, in sulfon-
ate ester synthesis, 527
/i-Toluic acid, preparation of, 650
o-Toluidine, diazotization of, 591
j?-Toluidine, basicity of, 614
nitration of, 608
uv spectrum of, 614
/)-Tolyl methyl ketone, oxidation of,
650
Transfer RNA, 485
Transition states, in electrophilic aro-
matic substitution, 569-571
in S N reactions, 198-200
Triacontane, isomers of, 48
physical properties of, 55
2,4,6-Tribromoaniline, formation of,
616
2,3,3-Tribromo-2-methylpropanoic
acid, 191
2,4, 6-Tribromophenol formation of, 633
Tri-«-butylamine, base dissociation
constant of, 423
physical properties of, 423
Trichloroacetaldehyde, 282
Trichloroacetic acid, acid dissociation
constant of, 331, 338
decarboxylation of, 341
physical properties of, 331
Trichloroethane, physical properties
of, 535
Trichloroethene, 81
from ethene and ethyne, 223
Trichloromethane {see Chloroform)
Trichlorosilane, physical properties of,
535
Triclene, 223
Tricresyl phosphate, as plasticizer, 748
Triethyl phosphate, 530
Triethylamine, base dissociation con-
stant of, 423
physical properties of, 423-424
Triethylborane, from ethene, 96
Triethylene glycol, 264
Trifiuoroacetic acid, acid strength of,
331, 337
physical properties of, 331
Trifluoromethylbenzene, nitration of,
568
Triglyme, 264
2,3,4-Trihydroxybutanal, disastereo-
mers of, 378
Triisopropylcarbinol, from isopropyl-
lithium, 234
Triisopropylmethane, 51
Trimethylaluminum, 228
Trimethylamine, physical properties
of, 12
Trimethylamine borane, 539
1 ,3,5-Trimethylbenzene, charge-trans-
fer complexes of, 613
physical properties of, 553
Trimethylborane, 536
2,2,3-Trimethylbutane, naming of, 52
Trimethylene oxide, 266
with organomagnesium com-
pounds, 234
Trimethylenemethyl, 77-electron sys-
tems of, 141-143
resonance structures of, 142
2,2,5-Trimethyl-3-hexyne, naming of,
111
2,2,4-Trimethylpentane, heat of
general index 849
combustion of, 57
in gasoline, 57
octane rating of, 58
Trimethylphosphine, basic properties
of, 530
Trimethylsilanol, physical properties
of, 535
Trimethylsulfonium bromide, 521
1,3,5-Trinitrobenzene, charge-transfer
complexes of, 613
preparation of, 606-607
1,3,5-Trinitrobenzoic acid, decarboxyl-
ation of, 606-607
2,4,6-Trinitrophenol (see Picric acid)
2,4,6-Trinitrotoluene (TNT), 442, 611-
612
formation of, 562
Trioxymethylene, 288
Triphenylamine, uv spectrum of, 614
Triphenylborane, 539
Triphenylcarbinol, with sulfuric acid,
654
Triphenylmethane, 191
with sodium amide, 654
Triphenylmethyl chloride, physical
properties of, 653
Triphenylmethyl peroxide, 655
Triphenylmethyl radical, coupling of,
655
epr spectrum of, 661
resonance hybrid of, 655
Triphosphoric acid, derivatives of, 528
Triplet state, of benzophenone, 705
of oxygen, 705
nature of, 697
Tri-w-propylborane, from propene,
97
Triterpenes, 781-782
Trityl chloride (see Triphenylmethyl
chloride)
Tropane alkaloids, 684
Tropilidene (see 1,3,5-Cycloheptatri-
ene)
Tropolone, acid dissociation constant
of, 641
hydrogen bonding in, 642
preparation of, 641
resonance hybrid of, 642
Tropolones, 641-642
complexes with ferric chloride, 642
electrophilic substitution reac-
tions of, 642
Tropylium cation, formation of, 642
hybrid structure of, 642
Tryptophan, 682
physical properties of, 461
Tschitchibabin reaction, 678
Twist-boat form, of cyclohexane, 65
of c«-l,4-di-?-butylcyclohexane,
72
Tyrian purple, 760
Tyrosine, physical properties of, 461
Ultraviolet light, absorption of, 160
Ultraviolet spectra (see Electronic
absorption spectra)
Undecane, physical properties of, 55
<x,/3-Unsaturated carbonyl compounds
(see also Carboxylic acids, unsat-
urated, Aldehydes, a^-unsaturated,
etc.), conjugate addition to, 311, 355
Unsaturated compounds (see Alkenes,
Alkynes, Aldehydes, Carboxylic
acids, etc.)
Uracil, in RNA, 485
Urea, 3
barbituric acid from, 686
heat of combustion of, 511
hydrolysis of, 504
Urease, 504
Valence tautomerization, 723
n- Valeric acid (see Pentanoic acid)
y-Valerolactone, formation of, 355
Valine, physical properties of, 459
van der Waals forces, 36, 39, 475, 739
and physical properties, 10
Van Slyke aminonitrogen determina-
tion, 463
Vanillin, structure, occurrence and
synthesis, 658
van't Hoff, J. H., 3
and tetrahedral carbon, 386
Vaseline, from petroleum, 58
Veronal, 685
Vibrational and rotational states, 695
Vinyl acetate, polymer from 746
Vinyl alcohol, acetaldehyde from, 262
polymer from, 746
Vinyl alcohols, derivatives of, in poly-
merization, 262
tautomers of, 605
general index 850
Vinyl amines, resonance in, 140
tautomers of, 605
Vinyl bromide, 589
Vinyl butyral, polymer from, 746
Vinyl chloride, from ethene, 220
from ethyne, 220
polymers from, 745
Vinyl ethers, bromine addition to, 139
resonance structures in, 139
Vinyl fluoride, from ethyne, 114
polymer from, 745
Vinyl halides, preparation of, 219-220
resonance structures in, 139
in S N reactions, 220
Vinyl polymerization, 753
Vinylacetic acid (see 3-Butenoic acid)
Vinylacetylene (see Butenyne)
Vinylboranes, alkenes from, 115
from alkynes, 115
Vinylidene halides, polymers from, 743
Viscose rayon, 410
Visible light, absorption of, 160
Vitamin A, 781
Vitamin Bi (see Thiamine)
Vitamin B 6 (see Pyridoxine)
Vitamin B 12 , D-ribose in, 400
structure of, 681-682
Vitamin C (see Ascorbic acid)
Vitamin D 2 , 790
from ergosterol, 789
Vitamin K 1; 640
phytol in, 781
Vitamins, 4
Viton, 225
Vulcanization, 743
Waxes, from petroleum, 58
Whiskey, proof of, 245
Whisky (see Whiskey)
Williamson synthesis, 252, 263, 267
Willstatter, R., 681
Wittig reaction, 531
Wohl degradation, 417
Wohler, A., 3
Wolff-Kishner reduction, 292
Wood, cellulose in, 410
composition of, 411
Wood alcohol (see Methanol), 245
Woodward, R. B., 681, 683, 726
Wool, 757
Wurtz coupling, 654
X-ray diffraction, of boron hydrides,
538
of cholesterol, 787
of glucose, 405
of insulin, 476
of naphthalene, 574
of penicillin G, 468
and structure determination, 4,
159
of vitamin D 2 , 789
m-Xylene, infrared spectrum, 554-555
physical properties of, 553
o-Xylene, infrared spectrum, 554-555
physical properties of, 553
p-Xylene, infrared spectrum of, 554-
555
physical properties of, 553
Xylenes, 550
D-Xylose, structure of, 400-401
Walker, D. F., 552
Wallach, O., 778
Water, acid dissociation constant of,
- 13, 122
base ionization constant of, 1 3
bond angles of, 7-8
derivatives of, 9
dielectric constant of, 204
dipole moment of, 7
physical properties of, 10
shape of, 7
Watson, J. D., 483
Wave equations, 130
Yields, in organic synthesis, 471
Ylids (see Alkylidene phosphoranes)
Ziegler, K., 103
Ziegler catalysts, in polymerization,
744, 753
Ziegler process, in coordination poly-
merization, 103
Zinc chloride, in alkyl chloride forma-
tion, 255
Zwitterions, 462
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