Stereochemistry of organic compounds

Stereochemistry of
Organic Compounds
ERNEST L. ELlEL
Department of Chemistry
The University of North Carolina at Chapel Hill
Chapel Hill, North Carolina

S A M U E L H. W l L E N
Department of Chemistry
The City College of the City University of New York
New York, New York
With a Chapter on Stereoselective Synthesis by

LEWIS N. MANDER
Research School of Chemistry
Australian National University
Canberra, Australia

A Wiley-lnterscience Publication

JOHN WlLEY & SONS, INC.
NewYork

Chichester

Brisbane

Toronto

Singapore

This text is printed on acid-free paper.
Copyright

01994 by John Wiley & Sons, Inc.

All rights reserved. Published simultaneously in Canada.
Reproduction or translation of any part of this work beyond
that permitted by Section 107 or 108 of-the 1976 United
States Copyright Act without the permission of the copyright
owner is unlawful. Requests for permission or further
information should be addressed to the Permissions Department,
John Wiley & Sons, Inc., 605 Third Avenue, New York, NY
10158-0012.
Library of Congress Cahloging in Publication Data:
Eliel, Ernest Ludwig, 1921Stereochemistry of organic compounds I Ernest L. Eliel, Samuel H.
Wilen, Lewis N. Mander.
p. cm.
"A Wiley-Interscience publication."
Includes index.
ISBN 0-471-01670-5
1. Stereochemistry. 2. Organic compounds. I. Wilen, Samuel H.
11. Mander, Lewis N. 111. Title.
QD481.E52115 1993
547.1'223--dc20
93-12476
Printed in the United States of America

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Contents

PREFACE

xiii

1. INTRODUCTION
1.1. Scope 1
1.2. History 2
1.3. Polarimetry and Optical Rotation 6
References 8

2. STRUCTURE
2.1. Meaning, Factorization, Internal Coordinates.
Isomers 11
2.2. Constitution 15
2.3. Configuration 18
2.4. Conformation 20
2.5. Determination of Structure 24
2.6. A Priori Calculation of Structure 32
2.7. Molecular Models 40
References 42
3. STEREOISOMERS
3.1. Nature of Stereoisomers 49
a. General 49
b. Barriers between Stereoisomers. Residual
Stereoisomers 54
3.2. Enantiomers 58
3.3. Diastereomers 62

a. General Cases 62
b. Degenerate Cases 65
References 69

4. SYMMETRY
4.1. Introduction 71
4.2. Symmetry Elements 71
4.3. Symmetry Operators. Symmetry Point Groups 74

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a. Point Groups Containing Chiral Molecules 76
b. Point Groups Containing Only Achiral Molecules 79
4.4. Desymmetrization 88
4.5. Averaged Symmetry 91
4.6. Symmetry and Molecular Properties 92
a. Rotation of Polarized Light 93
b. Dipole Moment 94
c. Symmetry Number 96
References 97
5. CONFIGURATION
5.1. Definitions: Relative and Absolute Configuration 101
5.2. Absolute Configuration and Notation 103
5.3. Determination of Absolute Configuration 113
a. Bijvoet Method 113
b. Theoretical Approaches 115
c. Modification of Crystal Morphology in the Presence

of Additives 116
5.4. Relative Configuration and Notation 117
5.5. Determination of Relative Configuration of Saturated
Aliphatic Compounds 124
a. X-Ray Structure Analysis 124
b. Chemical Interconversion Not Affecting Bonds to the
Stereogenic Atom 126
c. Methods Based on Symmetry Considerations 128
d. Correlation via Compounds with Chiral Centers of
Two Types 130
e. The Method of Quasi-racemates 132
f. Chemical Correlations Affecting Bonds to a Chiral
Atom in a "Known" Way. 134
g. Correlation by Stereoselective Synthesis of "Known"
Stereochemical Course 139
h. Chiroptical, Spectroscopic, and Other Physical
Methods 144
5.6. Conclusion: Network Arguments 147
References 147
6. PROPERTIES OF STEREOISOMERS. STEREOISOMER
DlSCRlMlNATION
6.1. Introduction 153
6.2. Stereoisomer Discrimination 153
6.3. The Nature of Racemates 159
6.4. Properties of Racemates and of Their Enantiomer
Components 162
a. Introduction 162
b. Optical Activity 163
c. Crystal Shape 164

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Contents

d. Density and Racemate Type 165
e. Melting Point 167
f. Solubility 173
g. Vapor Pressure 179
h. Infrared Spectra 183
i. Electronic Spectra 184
j. Nuclear Magnetic Resonance Spectra 185
k. X-Ray Spectra 186
1. Other Physical Properties 187
m. Liquid State and Interfacial Properties 189
n. Chromatography 194
o. Mass Spectrometry 197
p. Interaction with Other Chiral Substances 197
q. Biological Properties 201
r. Origins of Enantiomeric Homogeneity in Nature 209
6.5. Determination of Enantiomer and Diastereomer
Composition 214
a. Introduction 214
b. Chiroptical Methods 217
c. NMR Methods Based on Diastereotopicity 221
d. Chromatographic and Related Separation Methods
Based on Diastereomeric Interactions 240
e. Kinetic Methods 265

f. Calorimetric Methods 268
g. Isotope Dilution 269
h. Miscellaneous Methods 272
References 275

7. SEPARATION OF STEREOISOMERS. RESOLUTION.
RACEMIZATION
7.1. Introduction 297
7.2. Separation of Enantiomers by Crystallization 298
a. Crystal Picking. Triage 298
b. Conglomerates 299
c. Preferential Crystallization 304
d. Preferential Crystallization in the Presence of
Additives 311
e. Asymmetric Transformation of Racemates. Total
Spontaneous Resolution 315
7.3. Chemical Separation of Enantiomers via
Diastereomers 322
a. Formation and Separation of Diastereomers.
Resolving Agents 322
b. Resolution Principles and Practice 344
c. Separation via Complexes and Inclusion
Compounds 351
d. Chromatographic Resolution 359

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Contents

7.4.
7.5.

7.6.

7.7.
7.8.

e. Asymmetric Transformations of Diastereomers 364
f. General Methods for the Separation of
Diastereomers 374
Enantiomeric Enrichment. Resolution Strategy 381
Large Scale Resolution 388
a. Diastereomer-Mediated Resolution 389
b. Resolution by Preferential Crystallization 392
c. Kinetic Resolution 394
Kinetic Resolution 395
a. Theory. Stoichiometric and Abiotic Catalytic Kinetic
Resolution 395
b. Enzymatic Resolution 409
Miscellaneous Separation Methods 416
a. Partition in Heterogeneous Solvent Mixtures 416
b. Transport across Membranes 421
Racemization 424
a. Racemization Processes 426
b. Racemization of Amino Acids 436
References 440

8. HETEROTOPIC LIGANDS A N D FACES
(PROSTEREOISOMERISM, PROCH IRALITY)
8.1. Introduction. Terminology 465
8.2. Significance. History 467
8.3. Homotopic and Heterotopic Ligands and Faces 470
a. Homotopic Ligands and Faces 470
b. Enantiotopic Ligands and Faces 473
c. Diastereotopic Ligands and Faces 477
d. Concepts and Nomenclature 482
8.4. Heterotopicity and Nuclear Magnetic Resonance 488
a. General Principles. Anisochrony 488
b. NMR in Assignment of Configuration and of
Descriptors of Prostereoisomerism 492
c. Origin of Anisochrony 499
d. Conformationally Mobile Systems 502
e. Spin Coupling Nonequivalence (Anisogamy) 507
8.5. Heterotopic Ligands and Faces in Enzyme-Catalyzed
Reactions 508
a. Heterotopicity and Stereoelective Synthesis 508
b. Heterotopicity and Enzyme-Catalyzed Reactions 509
8.6. pro2-~hiralCenters: Chiral Methyl, Phosphate, and
Sulfate Groups 518
a. Chiral Methyl Groups 518
b. Chiral Phosphate Groups 526
c. Chiral Sulphate Groups 529
d. pro3-~hiralCenters: The Chiral Thiophosphate
Group 530
References 532

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Contents

9. STEREOCHEMISTRY OF ALKENES
9.1. Structure of Alkenes. Nature of cis-trans
Isomerism 539
a. General 539
b. Nomenclature 541
c. Cumulenes 543
d. Alkenes with Low Rotational Barriers; Nonplanar
Alkenes 544
e. The C=N and N=N Double Bonds 550
9.2. Determination of Configuration of cis-trans
Isomers 555
a. Chemical Methods 555
b. Physical Methods 562
9.3. Interconversion of cis-trans Isomers: Position of
Equilibrium and Methods of Isomerization 574
a. Position of cis-trans Equilibria 574
b. Methods of Equilibration 578
c. Directed cis-trans Interconversion 584
References 590

10. CONFORMATION OF ACYCLIC MOLECULES
10.1. Conformation of Ethane, Butane, and Other Simple
Saturated Acyclic Molecules 597
a. Alkanes 597
b. Saturated Acyclic Molecules with Polar Substituents
or Chains. The Anomeric Effect 606

10.2. Conformation of Unsaturated Acyclic and
Miscellaneous Compounds 615
a. Unsaturated Acyclic Compounds 615
b. Alkylbenzenes 624
c. Miscellaneous Compounds 627
10.3. Diastereomer Equilibria in Acyclic Systems 629
10.4. Physical and Spectral Properties of Diastereomers and
Conformers 634
a. General 634
b. Dipole Moments 635
c. Boiling Point, Refractive Index, and Density 638
d. Infrared Spectra 639
e. NMR Spectroscopy 641
10.5. Conformation and Reactivity: The Winstein-Holness
Equation and the Curtin-Hammett Principle 647
References 656

11. CONFIGURATION AND CONFORMATION OF CYCLIC
MOLECULES
11.1. Stereoisomerism and Configurational Nomenclature of
Ring Compounds 665

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11.2. Determination of Configuration of Substituted Ring
Compounds 669
a. Introduction 669

b. Symmetry-Based Methods 669
c. Methods Based on Physical and Chemical
Properties 671
d. Correlation Methods 675
11.3. Stability of Cyclic Molecules 675
a. Strain 675
b. Ease of Cyclization as a Function of Ring Size 678
c. Ease of Ring Closure as a Function of the Ring
Atoms and Substituents. The Thorpe-Ingold Effect 682
d. Baldwin's Rules 684
11.4. Conformational Aspects of the Chemistry of SixMembered Ring Compounds 686
a. Cyclohexane 686
b. Monosubstituted Cyclohexanes 690
c. Disubstituted and Polysubstituted
Cyclohexanes 700
d. Conformation and Physical Properties in
Cyclohexane Derivatives 709
e. Conformation and Reactivity in Cyclohexanes 720
f. sp2 Hybridized Cyclohexyl Systems 726
g. Six-Membered Saturated Heterocycles 740
11.5. Chemistry of Ring Compounds Other Than SixMembered Ones 754
a. Three-Membered Rings 754
b. Four-Membered Rings 755
c. Five-Membered Rings 758
d. Rings Larger Than Six-Membered 762
e. The Concept of I Strain 769
11.6. Stereochemistry of Fused, Bridged, and Caged Ring
Systems 771
a. Fused Rings 771
b. Bridged Rings 787

c. Paddlanes and Propellanes 794
d. Catenanes, Rotaxanes, Knots, and Mobius
Strips 800
e. Cubane, Tetrahedrane, Dodecahedrane,
Adamantane, and Buckminsterfullerene 806
References 811
12. STEREOSELECI'IVE SYN'THESIS
12.1. Introduction 835
a. Terminology 837
b. Stereoselective Synthesis 838
c. Categories of Stereoselective Synthesis 839
d. Convergent Syntheses 843

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Contents

12.2. Diastereoselective Synthesis of Achiral
Compounds 845
a. Cyclanes 845
b. Diastereoselective Syntheses of Alkenes 846
12.3. Diastereoselective Synthesis 858
a. Introduction 858
b. Strategies for Stereocontrol in Diastereoselective
Synthesis 859
c. Diastereoselective Syntheses Based on Chiral
Substrates of Natural Origin 872
d. Nucleophilic Additions 875
e. Electrophilic Reactions of Alkenes 894

f. The Aldol Reaction 913
g. Pericyclic Reactions 920
h. Catalytic Hydrogenations 932
i. Free R12.4. Enantioselective Syntheses 939
a. Introduction 939
b. Enantioselective Syntheses with Chiral Nonracemic
Reagents 941
c. Enantioselective Reactions with Chiral Nonracemic
Catalysts 947
d. Nonlinear Effects in Catalysis 959
e. Enzyme Based Processes 960
f. Enantioselective Synthesis Involving Discrimination
between Enantiotopic Groups 962
g. Enantioconvergent Syntheses 963
12.5. Double Stereodifferentiation 965
a. Introduction 965
b. Interactions between Principal Chiral
Reactants 967
c. Reagent Control 969
d. Kinetic Amplification 970
12.6. Conclusion 971
References 971
13. CHIROPTICAL PROPERTIES
13.1. Introduction 991
13.2. Optical Activity. Anisotropic Refraction 992
a. Origin. Theory 992
b. Optical Rotatory Dispersion 999
13.3. Circular Dichroism. Anisotropic Absorption 1003
13.4. Applications of Optical Rotary Dispersion and Circular

Dichroism 1007
a. Determination of Configuration and Conformation.
Theory 1007
b. Classification of Chromophores 1013
c. Sector and Helicity Rules 1019

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Contents

d. Exciton Chirality 1043
e. Other Applications. Induced ORD and CD 1050
f. Fluorescence Detected Circular Dichroism 1059
g. Circular Dichroism of Chiral Polymers 1060
13.5. Applications of Optical Activity 1071
a. Polarimetry 1071
b. Empirical Rules and Correlations. Calculation of
Optical Rotation 1080
13.6. Vibrational Optical Activity 1093
13.7. Circular Polarization of Emission. Anisotropic
Emission 1100
References 1105
14. CHIRALITY IN MOLECULES DEVOID OF CHIRAL CENTERS
14.1. Introduction. Nomenclature 1119
14.2. Allenes 1122
a. Historical. Natural Occurrence 1122
b. Synthesis of Optically Active Allenes 1124
c. Determination of Configuration and Enantiomeric
Purity of Allenes 1125

d. Cyclic Allenes, Cumulenes, Ketene Imines 1132
14.3. Alkylidenecycloalkanes 1133
14.4. Spiranes 1138
14.5. Biphenyls. Atropisomerism 1142
a. Introduction 1142
b. Biphenyls and Other Atropisomers of the sp2-sp2
Single-Bond Type 1143
c. Atropisomerism about sp2-sp3Single Bonds 1150
d. Atropisomerism about sp3-sp3Bonds 1153
14.6. Molecular Propellers and Gears 1156
a. Molecular Propellers 1156
b. Gears 1160
14.7. Helicenes 1163
14.8. Molecules with Planar Chirality 1166
a. Introduction 1166
b. Cyclophanes 1166
c. Annulenes 1170
d. trans-Cycloalkenes 1172
e. Metallocenes and Related Compounds 1175
14.9. Cyclostereoisomerism 1176
References 1181

GLOSSARY
INDEX

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1119

Preface

It is now over 30 years since the last comprehensive text on organic stereochemistry (Stereochemistry of Carbon Compounds, McGraw-Hill, 1962) was
published by one of us. Since then there has been enormous interest and activity
in the field and entirely new concepts have sprung up. To give just a few
examples: Conformational analysis has come of age. Nuclear magnetic resonance
has become ubiquitous in chemistry and NMR spectra very often require consideration of configuration and conformation before they can be interpreted and, in
turn, permit inferences about the configuration and conformation of the compounds whose spectra are recorded. Molecular mechanics, in its infancy in 1962,
is now a widely used tool. The concepts of prostereoisomerism (commonly known
under the more restrictive term prochirality), which were barely understood in
1962 are now broadly disseminated and utilized. The preparation of pure enantiomers has become of consuming interest in the pharmaceutical, flavor, and
agricultural industries, not to speak of university laboratories. As a result, there
has been enormous progress in the area of enantioselective synthesis, in the
techniques for separating enantiomers, and in the methods for analysis of
enantiomeric purity, the latter spurred by instrumental developments in spectroscopy and in chromatography. There has also been significant development in
the conceptual and mathematical foundations of stereochemistry, especially in the
application of symmetry concepts.
Contemporary elementary textbooks in organic chemistry have taken cognizance of these developments by increasingly incorporating stereochemical principles with the result that stereochemical ideas and concepts are introduced to
undergraduate students to a greater extent than was the case 30 years ago. Within
the last 15 years a number of briefer stereochemistry books have appeared. While
these books elaborate on this greater awareness of stereochemistry, we felt that
the time had come for the preparation of an up-to-date comprehensive text. This
book is intended to serve as a textbook for graduate students and advanced
undergraduate students for whom it may serve as a guide to subsequent studies
and research. We have endeavored to prepare a book that may also serve as a
comprehensive guide for research workers who might wish to have stereochemical
principles explained and illustrated under one cover.
The task of writing such a text has been rather daunting, and, as a result, has
extended over more years than we would have liked. As implied in the first
paragraph, the field has grown enormously since the last comprehensive text was

xiii

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xiv

Preface

put together; the fact that this book has three authors rather than a single one is
only one token of this development. Even three authors cannot be conversant
with all the ramifications of the subject as it exists in 1994. We must therefore ask
the reader's forbearance if, on occasions, discussion of a given subject is not as
authoritative or as detailed as one might wish. As with the 1962 book, this one is
limited to the stereochemistry of organic compounds, but unlike in the earlier
work, we were forced to exclude certain subjects even though they are parts of
organic stereochemistry. Thus limitations of space and time have forced us to
exclude polymer stereochemistry. The stereochemistry of reaction mechanism has
been touched on but peripherally and this has led to the exclusion of discussion of
the Woodward-Hoffmann rules. The enormously large area of stereoselective
synthesis could only be covered in overview form; we are greatly indebted to
Professor Lewis N. Mander of the Australian National University for contributing
the chapter on this topic.
Even with these omissions, the book is more extensive than we would have
liked. In order to make it somewhat easier for the reader to cover the essential
material, we have used smaller print for subject matter that may not be in the
mainstream of the argument, but may be of interest to some of our readers.
Along with the burgeoning literature on stereochemistry has come a proliferation of new and modified terminology that befuddles novices and sometimes
experienced scientists as well. We have been conservative in our usage of new
terms by limiting ourselves, as much as possible, to established terminology. In

addition to defining terms at appropriate places in the text, we have gathered the
more important definitions in a glossary appearing at the end of the book. The
glossary anticipates, but does not duplicate, a listing of IUPAC terminology on
stereochemistry that has been in gestation for quite a few years.
Stereochemistry is an old subject and we have tried to pay some attention to its
historical development. One important ingredient in understanding the history of
any subject is to know who did what when. This cannot be accomplished solely by
listing references at the ends of chapters, since readers are apt to turn to such
references only when they have an interest in a specific topic. Listing the
references at the bottom of each page would unfortunately have added appreciably to the production cost, and hence to the price of this book. We have,
therefore, included authors' names and the year of publication of the work as the
reference citation within the text with the name of the senior author included
even if not the first of several listed in the ordinary style of citations as "et al." In
addition, to facilitate entry into the literature of sterochemistry, we have included
the titles of review articles in the reference list at the end of each chapter.
One of the authors (ELE) is grateful to the John Simon Guggenheim
Foundation for fellowships during the academic years 1975-1976 and 1983-1984.
Without this help, supplemented by academic leaves provided by the University
of North Carolina at Chapel Hill, this book could not have been launched. ELE
also acknowledges the hospitality of Stanford, Princeton, and Duke Universities
during these leaves, as well as many stimulating conversations with Harry S.
Mosher, Hans Gerlach, Kurt Mislow, James G. Nourse, and Jack D. Dunitz.
Another author (SHW) is pleased to acknowledge a Fellowship leave granted in
1983-1984 by the City College, City University of New York, and the hospitality
of the Chemistry Department of the University of North Carolina at Chapel Hill

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Preface

XV

during several visits occasioned by the preparation of this book as weil as for a
visiting professorship in the Spring of 1984.
A number of colleagues have read and made suggestions for the improvement
of various versions of the manuscript of this book. Professors James H. Brewster
and Michael P. Doyle read the entire text and Professors William A. Bonner,
Andre Collet, Jack D. Dunitz, Mark M. Green, Jean Jacques, Henri B. Kagan,
Meir Lahav, Kurt Mislow, Laurence A. Nafie, Vladimir Prelog, Hans-Jurg
Schneider, George Severne, Roger A. Sheldon, Grant Gill Smith, Dr. Jeffrey I.
Seeman, and the late Gunther Snatzke commented on entire chapters or sections.
To all these colleagues we are grateful. Nevertheless we ourselves take full
responsibility for the contents. We also wish to express our gratitude to Eva Eliel
and to Rosamond Wilen for assistance in the checking of proof.
We appreciate the release, on the part of McGraw-Hill, Inc., of the rights to
Stereochemistry of Carbon Compounds (Eliel, 1962), which has enabled us to use
several figures from that book. We are also grateful to Springer-Verlag GmbH &
Co., Heidelberg, for permission to use the text and figures of the chapter
"Prostereoisomerism (Prochirality)" by E.L. Eliel, which appeared in Topics in
Current Chemistry, Vol. 105. A substantial amount of material in Chapter 8 has
been taken from this earlier work.

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Introduction

1-1. SCOPE
Stereochemistry (from the Greek stereos, meaning solid) refers to chemistry in

three dimensions. Since most molecules are three-dimensional (3D), stereochemistry, in fact, pervades all of chemistry. It is not so much a branch of the
subject as a point of view, and whether one chooses to take this point of view in
any given situation depends on the problem one wants to solve and on the tools
one has available to solve it.
In the evolution of chemical thought, the stereochemical point of view came
relatively late; much of the often excellent chemistry of the nineteenth century
ignores it. By the same token, some important contemporaneous developments,
such as the computer design of synthesis (Wipke, 1974; Wipke et al., 1977) and
the computer-assisted elucidation of chemical structure (Carhart, Djerassi, et al.,
1975), legitimately started out by disregarding the third dimension; however, this
shortcoming has since been remedied (e.g., Djerassi et al., 1982; Corey et al.,
1985).
Nevertheless, there is little question that, at least in the last 25 years, the third
dimension has become all-important in the understanding of problems not only in
organic, but in physical, inorganic, and analytical chemistry as well as biochemistry, so that no chemist can afford to be without a reasonably detailed knowledge
of the subject.
It has become customary to factorize stereochemistry into its static and
dynamic aspects. Static stereochemistry (perhaps better called stereochemistry of
molecules) deals with the counting of stereoisomers, with their structure (i.e.,
molecular architecture), with their energy, and with their physical and most of
their spectral properties. Dynamic stereochemistry (or stereochemistry of reactions) deals with the stereochemical requirements and the stereochemical
outcome of chemical reactions, including interconversion of conformational isomers or topomers (cf. Chapter 2); this topic is deeply interwoven with the study
and understanding of reaction mechanisms. Like most categorizations, this one is

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Introduction

not truly dichotomous and some subjects fall in between; for example, quantum
mechanical treatments of stereochemistry may deal with either its structural or its
mechanistic aspects; spectroscopic measurements may fathom reaction rate as
well as molecular structure.
Limitations of space, plus the sheer vastness to which the subject of stereochemistry has grown, force us to make choices in what will be discussed in this
book. Static aspects, including spectroscopic ones, will be covered in detail.
Dynamic stereochemistry and reference to calculations will be woven into the
text, but reaction mechanisms will not be described in a systematic fashion. In
particular, there will be no specific coverage of electrocyclic reactions and orbital
symmetry. While we regret these omissions, we take note of the fact that there
are a number of excellent books on reaction mechanism that include stereochemical aspects (Ingold, 1969; Deslongchamps, 1983; Lowry and Richardson, 1987;
Carey and Sundberg, 1991; March, 1992) and several detailed treatments of
the Woodward-Hoffmann rules (Woodward and Hoffmann, 1969, 1970;
Anh, 1970; Lehr and Marchand, 1972; Fleming, 1976; Marchand and Lehr, 1977;
Gilchrist and Storr, 1979). With equal regret (because we consider the division
between inorganic and organic chemistry to be artificial) we had to omit inorganic
compounds (cf. Geoffroy, 1981; Kepert, 1982), both coordination compounds (cf.
Sokolov, 1990) and compounds of the main group elements, such as silicon (cf.
Corriu, 1984), sulfur (Mikolajczyk and Drabowicz, 1982; Mikolajczyk, 1987), and
phosphorus (Gallagher and Jenkins, 1968; Quin, 1981; Verkade and Quin, 1987).
Only the stereochemistry of nitrogen will be marginally touched on. We have also
had to forgo a treatment of the stereochemistry of polymers (Bovey, 1969, 1982;
Farina, 1987). Nor will we deal, in this book, with the mathematical foundations
of stereochemistry, but we draw attention to a recent book (Mezey, 1991) and
review article (Buda, Mislow, et al., 1992) in this area.

1-2.

HISTORY

Only a very abbreviated history of stereochemistry will be given here, since two
authoritative books (Bykov, 1966; Ramsay, 1981) plus a collection of pertinent
essays (Ramsay, 1975) are available (see also Mason, 1976).
Historically, the origins of sterochemistry stem from the discovery of planepolarized light by the French physicist Malus (1809). In 1812 another French
scientist, Biot (q.v.), following an earlier observation of his colleague Arago
(1811), discovered that a quartz plate, cut at right angles to its crystal axis, rotates
the plane of polarized light through an angle proportional to the thickness of the
plate; this constitutes the phenomenon of optical rotation. Some quartz crystals
turn the plane of polarization to the right, while others turn it to the left. Three
years later, Biot (1815) extended these observations to organic substances-both
liquids (such as turpentine) and solutions of solids (such as sucrose, camphor, and
tartaric acid). Biot recognized the difference between the rotation produced by
quartz and that produced by the organic substances he studied: The former is a
property of the crystal; it is observed only in the solid state and depends on the
direction in which the crystal is viewed, whereas the latter is a property of the

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3

History

individual molecules, and may therefore be observed not only in the solid, but in
the liquid and gaseous states, as well as in solution.
With respect to the question of the cause of optical rotation, the French
mineralogist Haiiy (q.v.) had already noticed in 1801 that quartz crystals exhibit
the phenomenon of hemihedrism. Hemihedrism (cf. Section 6-4.c) implies inter
alia that certain facets of the crystal are so disposed as to produce nonsuperposable species (Fig. 1.1, A and B), which are related as an object to its mirror

image. (Such mirror-image crystals are called "enantiomorphous," from the
Greek enantios meaning opposite and morphe form.) In 1822, Sir John Herschel
(q.v.), a British astronomer, observed that there was a relation between hemihedrism and optical rotation: All the quartz crystals having the odd faces inclined in
one direction rotate the plane of polarized light in one and the same sense,
whereas the enantiomorphous crystals rotate polarized light in the opposite sense.
It was, however, left to the genius of Pasteur to extend this correlation from
the realm of crystals, such as quartz, which rotate polarized light only in the solid
state, to the realm of molecules, such as dextro-tartaric acid, which rotate both as
the solid and in solution. [dextro-Tartaric acid, henceforth denoted as (+)-tartaric
acid, rotates the plane of polarized light to the right, see Section 1-3.1 In 1848
Pasteur (q.v.) had succeeded in separating crystals of the sodium ammonium salts
of (+)- and (-)-tartaric acid from the racemic (nonrotating) mixture. When the
salt of the mixed (racemic) acid, which is found in wine caskets, was crystallized
by slow evaporation of its aqueous solution, large crystals formed which, to
Pasteur's surprise and delight, displayed hemihedric crystals similar to those
found in quartz (Fig. 1.1). By looking at these crystals with a lens, Pasteur was
able to separate the two types (with their dissymmetric facets inclined to the right
or left) by means of a pair of tweezers. When he then separately redissolved the
two kinds of crystals, he found that one solution rotated polarized light to the
right [the crystals being identical with those of the salt of the natural (+)-acid],
whereas the other rotated to the left. [(-)-Tartaric acid had never been encountered up to that time.]
The relationship between crystal morphology and molecular structure (in particular, molecular configuration) has presented a challenge to chemists and crystallographers ever since. However, it was only in 1982 (cf. Addadi et al., 1986) that
a definite relationship was established, allowing one to deduce configuration from
crystal habit (cf. Chapter 5).

Figure 1.1. Hemihedrism of quartz crystals. [Reprinted with permission from L. F. Fieser and M.
Fieser (1956), Organic Chemistry, 3rd ed., Heath, Lexington, MA.]

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4

Introduction

Pasteur (1860) soon came to realize the analogy between crystals and
molecules: In both cases the power to rotate polarized light was caused by
dissymmetry, that is the nonidentity of the crystal or molecule with its mirror
image, expressed in the case of the ammonium sodium tartrate crystal by the
presence of the hemihedric faces. Similarly, Pasteur postulated, the molecular
structures of (+)- and (-)-tartaric acids must be related as an object to its mirror
image. The two acids are thus enantiomorphous at the molecular level; we call
them enantiomers. [The ending -mer (as in isomer, polymer, and oligomer from
the Greek meros meaning part) usually refers to a molecular species.]
By the time Pasteur had arrived at this insight, his interests had shifted from
chemistry to microbiology, and he never couched the mirror-image relationship in
unequivocal geometric terms, even though the structural theory of organic
chemistry, which must form the basis of any such precise specification, was
beginning to unfold at that time thanks to the publications of Kekule (1858),
Couper (1858) and Butlerov (1861). It was not until 1874 that van't Hoff (1874,
1875) in Utrecht, the Netherlands and Le Be1 (1874) in Paris, France independently and almost simultaneously proposed the case for enantiomerism in a
substance of the type Cabcd: the four substituents are arranged tetrahedrally
around the central carbon atom to which they are linked. van't Hoff, who had
worked with Kekule and whose views were based on structural theory, specified
the 3D arrangement quite precisely: The four linkages to a carbon atom point
toward the corners of a regular tetrahedron (Fig. 1.2) and two nonsuperposable
arrangements (enantiomers) are thus possible.
We call the model corresponding to a given enantiomer (e.g., Fig. 1.2, A) and
the molecule that it represents "chiral"' (meaning handed, from Greek cheir,
hand) because, like hands, the molecules are not superposable with their mirror

images. The term chiral was first used by Thomson (later elevated to the peerage
as Lord Kelvin) in 1884 (Kelvin, 1904), was rediscovered by Whyte (1957, 1958),
and was firmly reintroduced into the stereochemical literature by Mislow (1965)
and by Cahn, Ingold, and Prelog (1966) who define a model as chiral when it has
no element of symmetry (plane, center, alternating axis; cf. Chapter 4) except at
most an axis of rotation.
A certain amount of confusion or ambiguity has arisen in the use of the term.
When a molecule is chiral, it must be either "right-handed" or "left-handed." But
if a substance or sample is said to be chiral, this merely means that it is made up of

Figure 1.2. Tetrahedral carbon.

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5

History

chiral molecules; it does not necessarily imply that all the constituent molecules
have the same "sense of chirality" (R or S, or M or P; cf. Chapter 5). We may
distinguish two extreme situations (plus an infinite number of intermediate ones):
(a) The sample is made up of molecules that all have the same sense of chirality
(homochiral molecules). In that case the sample is said to be chiral and "nonracemic." This serves to distinguish this case from the opposite situation where
(b) the sample is made up of equal (or very nearly equal) numbers of molecules
of opposite sense of chirality (heterochiral molecules), in which case the sample is
chiral but racemic. Thus the statement that a macroscopic sample (as distinct from
an individual molecule) is chiral is ambiguous and therefore sometimes insufficient; it may need to be further stated if the sample is racemic or nonracemic.
Lack of precision on this point has led to some confusion, for example, in the
titles of articles where the synthesis of a chiral natural product is claimed, but it is

not clear whether the investigator simply wishes to draw attention to the chirality
of the pertinent structure or whether the product has actually been synthesized as
a single enantiomer (i.e., an assembly of homochiral molecules, which should not,
however, be called a homochiral sample).
The situation is even slightly more complex than so far implied. There is little
ambiguity about the meaning of "chiral, racemic": Chiral, racemic means that
(within the limits of normal stochastic fluctuations) the sample is made up of equal
numbers of molecules of opposite sense of chirality. But in a "chiral, nonracemic"
sample there can be some molecules of a sense of chirality opposite to that of the
majority; that is, the sample may not be enantiomerically pure (or enantiopure).
Experimental tests as to whether a sample is enantiopure or merely enantioenriched will be discussed in Section 6-5.
In consequence of these definitions, use of the word "chiral" should be restricted to
molecules (or models thereof) and substances as in chiral substrate, chiral catalyst,
chiral stationary phase, and so on. However, we strongly discourage the application
of the word to processes, as in chiral synthesis, chiral catalysis, chiral recognition,
chiral chromatography, and so on.

It immediately follows from van't Hoff's hypothesis that in an alkene, where
the tetrahedra are linked along one edge, cis-trans isomerism is possible (see
Chapter 9) and already in 1875 van't Hoff (q.v.) predicted the stereoisomerism of
allenes, not actually observed in the laboratory until 1935 (cf. Chapter 14; Fig.
1.3).
In contrast, Le Bel, whose ideas were based on Pasteur's analogy between
crystals and molecules, admitted the possibility of asymmetric (or, as we would
now say, chiral) arrangements other than tetrahedral in Cabcd (cf. Snelders,
1975). As a consequence he left open the question as to whether alkenes were
planar and he actually looked for enantiomeric alkenes, a search that he
abandoned only 20 years later (Le Bel, 1894).

Figure 1.3.

Tetrahedral representation of alkenes and allenes.

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6

Introduction

The hypothesis of van't Hoff and Le Be1 has stood with but minor modifications until today (cf. Eliel, 1974 for an account of the centennial of the
theory). Both the visualization of molecules by X-ray and electron diffraction and
the interpretation of vibrational [infrared (IR) and Raman] spectra have confirmed that carbon is, indeed, tetrahedral. Quantum mechanical calculations
concur in predicting a much lower energy for tetrahedral methane than for
(hypothetical) methane of planar geometry (Monkhorst, 1968; Hoffmann et al.,
1970).
van't Hoff (1874) had already pointed out that if CX,Y, were planar (or, for that
matter, square pyramidal), two isomers should exist but only one is found. For a
detailed discussion see Wheland (1960).

1-3. POLARIMETRY A N D OPTICAL ROTATION
It was mentioned in Section 1-2 that the discoveries of polarized light and optical
rotation led to the concept of molecular chirality which, in turn, is basic to the
field of stereochemistry. Polarized light and optical rotation are therefore usually
given considerable play in elementary treatments of stereochemistry. In the
present text we take the view that the central theme of stereochemistry is
molecular architecture, notably including chirality, and the resultant fits (as of a
right hand with a right glove or of an enzyme with its natural substrate) or misfits
(as of a right hand with a left glove or of an enzyme with the enantiomer of its
natural substrate). In this theme, polarimetry and optical rotation are but

epiphenomena (side issues), which are important, indeed, as diagnostic tools for
chirality but not central to its existence. 'We shall therefore treat polarimetry only
briefly at this point, assuming that the nature of polarized light and the workings
of a polarimeter are already familiar to the reader.
Methods of palpating chirality by optical tools [polarimetry, optical rotatory
dispersion (ORD), and circular dichroism (CD)] have been called "chiral-optical"
methods by Weiss and Dreiding (Weiss, 1968) later contracted to "chiroptical"
methods (Prelog, 1968; Henson and Mislow, 1969; see also Kelvin, 1904, p. 461), a
term that will be used in this book. These methods will be discussed in detail in
Chapter 13.

The observed angle of rotation of the plane of polarization by an optically
active liquid, solution, or (more rarely) gas or solid is usually denoted by the
symbol a. The angle may be either positive (+) or negative (-) depending on
whether the rotation is clockwise, that is, to the right (dextro) or counterclockwise, that is, to the left (levo) as seen by an observer towards whom the
beam of polarized light travels. (This is opposite from the direction of rotation
viewed along the light beam.) It may be noted that no immediate distinction can
be made between rotations of a + 180 no (n =integer), for if the plane of
polarization is rotated in the field of the polarimeter by +180", the new plane will
coincide with the old one. In fact a, as measured, is always recorded as being
between -90" and +90". Thus, for example, no difference appears between

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7

Polarirnetry and Optical Rotation

rotations of +50", +230", +410", or -130". To make the distinction, one must

measure the rotation at least at one other concentration. Since optical rotation is
proportional to concentration (see below), if solutions of the above rotations were
diluted to one-tenth of their original concentrations, their rotations would become
+5", +23", +41°, and -13", values that are all clearly distinct. Readings taken at
two different concentrations almost always determine a unequivocally. An alternative for solutions and the method of choice for pure liquids is to measure the
rotation in a shorter tube. In the above cases, if a tube of a quarter of the original
length [e.g., 0.25 decimeters (dm) instead of 1dm] is used, the rotations as
recorded become + 12.5", +57.5", -77.5" (equivalent to + 102S0), and -32.5",
again all clearly distinguishable. [Note that halving the tube length (e.g., from 1
to 0.5 dm) would have left the ambiguity between the first and third observation
(+25" vs. +205" = 180" + 25") and between the fourth and second (-65" and
+115" = 180" - 65").]
Biot discovered that the observed rotation is proportional to the length 8 of
the cell or tube containing the optically active liquid or solution and the
concentration c (or density in the case of a pure liquid): a = [ a ] c 8 (Biot's law).
The value of the proportionality constant [ a ] depends on the units chosen; in
polarimetry it is customary to express [ in decimeters, because the cells are
usually 0.25, 0.5, 1, or 2 dm in length, and c in grams per milliliter (g mL-l) or
(and this is preferred for solutions) in g 100 mL-'. Thus,
a
= [(dm)

100 a
m ~ - l ) [(dm) cl(g 100 m ~ - ' )
-

(1.1)

The value of [ a ] , the so-called specific rotation, depends on wavelength and
temperature which are usually indicated as subscripts and superscripts, respectively; thus [a]: denotes the specific rotation for light of the wavelength of the

sodium D-line (589 nm) at 25°C. (Evidently, a polarimeter requires a source of
monochromatic light as well as a thermostatted cell; moreover, the solution must
be made up in a thermostatted volumetric flask at the same temperature as that of
the measurement, o r else the volume correction must be applied.) In addition, [ a ]
also depends on the solvent and to some extent on the concentration (in a fashion
not taken into account by the concentration term in Biot's law), which must thus
also be specified. This is usually done by adding such information in parentheses,
thus [a]::, - 10.8 +- 0.1 (c 5.77, 95% ethanol) denotes the specific rotation at
20°C for light of wavelength 546 nm in 95% ethanol solution at a concentration of
5.77 g 100 mL-'. The importance of solvent and concentration is occasioned by
association phenomena, which will be discussed in more detail below and in
Chapter 13.
The dimensions of [a]are degcm2g-Lnot degrees (Snatzke, 1989190). In this
book [a] will always be given without the units (understood to be
lo-' deg cm2 g-l) and (in contrast to the observed rotation a) will not be given in
degrees.

For pure liquids, since the density is fixed at a given temperature, one may
simply state the observed rotation, along with the cell length, such as a: + 44'

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8

Introduction

(neat, 8 = 1dm), the word "neat" (or sometimes "homog" for homogeneous)
denoting that the rotation refers to the undiluted (pure) liquid. However, even
here it is preferable to give the specific rotation. Thus, if the density of the liquid

in question at 25°C is 1.1, the specific rotation is [a]: + 40 (neat) (4411 x 1.1).
Since optical rotation is proportional to the number of molecules encountered
by the beam of polarized light, if two substances have unequal molecular weights
but are alike with respect to their power of rotating polarized light, the substance
of smaller molecular weight will have the larger specific rotation simply by virtue
of having more molecules per unit weight. In order to compensate for this effect
and to put rotation on a per-mole basis, one defines the term "molar rotation" as
the product of specific rotation and molecular weight divided by 100. (The divisor
serves to keep the numerical value of molar rotation on the same approximate
scale as that of specific rotation. For a substance of molecular weight (MW) 100,
molar and specific rotation are the same.) Thus, denoting molar rotation by [MI
or [@I, the latter symbol being preferred

[MI= [@I

=

[a].MW -

100

-

a

[(dm). c"(mol100 m ~ - ' )

The choice of solvent particularly affects the rotation of polar compounds
because of its intervention in solvation and association phenomena (cf. Chapter
13). Substantial changes of specific rotation with solvent are not uncommon;

reversals of sign are less frequent but have been explicitly reported in a number of
instances (Chapter 13). A pH dependence of rotation is also common in the case
of acids and bases and reversals are recorded, for example, for (S)-(+)-lactic
acid, dextrorotatory in water, whose sodium salt is levorotatory (Borsook et al.,
1933) and for L-leucine, which is levorotatory in water but dextrorotatory in
aqueous hydrochloric acid (Stoddard and Dunn, 1942).
An even more remarkable change in rotation, from positive to negative, is
seen in 2-methyl-2-ethylsuccinic acid (Krow and Hill, 1968) as its solution in
chloroform (containing 0.7% ethanol) is diluted, with a reversal of sign (corresponding to null rotation) occurring at a concentration of 6.3%. The phenomenon
(presumably due to association) is confined to solvents of low polarity (CHCl, or
CH,Cl,); no reversal is seen in alcohol solvents, pyridine, diglyme, or acetonitrile. 2-Methyl-2-ethylsuccinic acid is also a case where the presence of one
enantiomer affects the rotation of the other beyond the obvious way of partially
canceling it (Horeau, 1969; Horeau and Guette, 1974). These points will be
returned to later (Chapter 13).

REFERENCES
Addadi, L., Berkovitch-Yellin, Z., Weissbuch, I . , Lahav, M., and Leiserowitz, L. (1986), "A Link
between Macroscopic Phenomena and Molecular Chirality: Crystals as Probes for the Direct
Assignment of Absolute Configuration of Chiral Molecules," Top. Stereochem., 16, 1.
Alembic Club Reprint (Engl. Transl.) No. 14, Edinburgh, UK, 1905.
Anh, N . T. (1970), Les R2gles de Woodward-Hoffmann, Ediscience, Paris.
Arago, D . F. (1811), Mem. Cl. Sci. Math. Phys. Inst. Imp. Fr., 12, 93, 115.
Benfey, 0. T . , Ed. (1963), "Classics in the Theory of Chemical Combination," Classics of Science,
Vol. 1, Dover Publications, New York; reprinted by Krieger, Malabar, FL, 1981.

www.pdfgrip.com


References

Biot, J.B. (1812), Mem. C1. Sci. Math. Phys. Inst. Imp. Fr., 13, 1.
Biot, J. B. (1815), Bull. Soc. Philomath. Paris, 190.
Borsook, H., Huffman, H. M., and Liu, Y.-P. (1933), J. Biol. Chem., 102, 449.
Bovey, F.A. (1969), Polymer Conformation and Configuration, Academic, New York.
Bovey, F.A. (1982), Chain Structure and Conformation of Macromolecules, Academic, New York.
Buda, A. B., Auf der Heyde, T., and Mislow, K. (1992), "On Quantifying Chirality," Angew. Chem.
Int. Ed. Engl., 31, 989.
Butlerov, A. M. (1861), Z. Chem. Pharm., 4 , 546. Translation by Kluge, F. F. and Larder, D. F.
(1971), J. Chem. Educ., 48, 289.
Cahn, R. S., Ingold, Sir C., and Prelog, V. (1966), "Specification of Molecular Chirality," Angew.
Chem. Int. Ed. Engl., 5, 385.
Carey, F.A. and Sundberg, R. J. (1990), Advanced Organic Chemistry. Part A: Structure and
Mechanism, 3rd ed., Plenum, New York.
Carhart, R. E., Smith, D. H., Brown, H., and Djerassi, C. (1975), J. Am. Chem. Soc., 97, 5755.
Corey, E. J., Long, A. K., and Rubenstein, S. D. (1985), Science, 228, 408.
Corriu, R. J. P., GuCrin, C., and Moreau, J. J. E . (1984), "Stereochemistry at Silicon," Top.
Stereochem., 15, 43.
Couper, A. S. (1858), Philos. Mag., [4], 16, 104; C. R. Acad. Sci., 46, 1157; see also Benfey (1963),
p. 132.
Deslongchamps, P. (1983), Stereoelectronic Effects in Organic Chemistry, Pergamon, New York
Djerassi, C., Smith, D. H., Crandell, C. W., Gray, N. A. B., Nourse, J. G., and Lindley, M. R.
(1982), "The Dendral Project: Computational Aids to Natural Products Structure Elucidation,"
Pure Appl. Chem., 54, 2425.
Eliel, E. L. (1974), CHEMTECH, 758.
Farina, M. (1987), "The Stereochemistry of Linear Macromolecules," Top. Stereochem., 17, 1.
Fleming, I. (1976), Frontier Orbitals and Organic Chemical Reactions, Wiley, New York.
Gallagher, M. J. and Jenkins, I. D. (1968), "Stereochemical Aspects of Phosphorus Chemistry," Top.
Stereochem., 3, 1.
Geoffroy, G. L., Ed. (1981), "Inorganic and Organometalic Stereochemistry," in Top. Stereochemistry, Vol. 12, contains several pertinent chapters. Wiley, New York.
Gilchrist, T. L. and Storr, R. C. (1979), Organic Reactions and Orbital Symmetry, 2nd ed.,

Cambridge University Press, New York.
Haiiy, R. J. (1801), Traiti de Mineralogie, Chez Louis, Paris.
Henson, P. D. and Mislow, K. (1969), J. Chem. Soc. D, 413.
Herschel, J . F. W. (1822), Trans. Cambridge Philos. Soc., 1, 43.
Hoffmann, R., Alder, R. W., and Wilcox, C. F. (1970), J. Am. Chem. Soc., 92, 4992.
Horeau, A. (1969), Tetrahedron Lett., 3121.
Horeau, A. and GuettC, J. P. (1974), Tetrahedron, 30, 1923.
Ingold, C. K. (1969), Structure and Mechanism in Organic Chemistry, 2nd ed., G. Bell and Sons,
London and Cornell University Press, Ithaca, NY.
Jacques, J. (1986), Sur la Dissymktrie Molkculaire, Christian Bourgeois, Paris.
KekulC, A. (1858), Justus Liebigs Ann. Chem., 106, 129; cf. Benfey (1963) 109 (Engl. transl.).
Kelvin, Lord (W. Thomson) (1904), Baltimore Lectures on Molecular Dynamics and the Wave Theory
of Light, C. J. Clay & Sons, London. The lectures were given in 1884 and 1893.
Kepert, D.L. (1982), Inorganic Stereochemistry, Springer-Verlag, New York.
Krow, G. and Hill, R. K. (1968), Chem. Commun., 430.
Le Bel, J. A. (1874), Bull. Soc. Chim. Fr., [2], 22, 337; see also Richardson, G. M. (1901).
Le Bel, J. A. (1894), BUN. Soc. Chim. Fr., [3], 11, 295.
Lehr, R. and Marchand, A. (1971), Orbital Symmetry: A Problem Solving Approach, Academic, New
York.
Lowry, T. H. and Richardson, K. S. (1987), Mechanism and Theory in Organic Chemistry, 3rd ed.,
Harper & Row, New York.

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10

Introduction

Malus, E. L. (1809) Mem. Soc. d'Arcuei1, 2, 143.

March, J. (1992), Advanced Organic Chemistry. Reactions, Mechanisms and Structure, 4th ed. Wiley,
New York.
Marchand, A. P. and Lehr, R. E., Eds. (1977), Pericyclic Reactions ( 2 vols.), Academic, New York.
Mason, S. F. (1976), "The Foundations of Classical Stereochemistry," Top. Stereochem., 9, 1.
Mezey, P. G., Ed. (1991), New Developments in Molecular Chirality, Kluwer Academic, Boston, MA.
Mikoiajczyk, M. and Drabowitz, J. (1982), "Chiral Organosulfur Compounds," Top. Stereochem., 13,
333.
Mikoiajczyk, M. (1987), "Sulfur Stereochemistry-Old Problems and New Results," Zwanenburg, B.
and Klunder, A. J. H., Eds., Perspectives in the Organic Chemistry of Sulfur, Elsevier, New
York, p. 23.
Mislow, K. (1965), Introduction to Stereochemistry, Benjamin, New York, p. 52.
Monkhorst, H. J. (1968), Chem. Commun., 1111 has calculated that planar methane would be
250 kcal mol-' (1046 kJ mol-') less stable than tetrahedral.
Pasteur, L. (1860), Two lectures delivered before the Societt Chimique de France, Jan. 20 and Feb. 3.
cf. Jacques, 1986. For English translation see references to Richardson, 1901 and Alembic Club
Reprint, No. 14.
Prelog, V. (1968), Proc. Koninkl. Ned. Akad. Wetenschap., B71, 108.
Quin, L. D. (1981), The Hetereocyclic Chemistry of Phosphorus, Wiley-Interscience, New York.
Ramsay, O.B., Ed. (1975), van't Hoff-Le Be1 Centennial, ACS Symposium Series 12, American
Chemical Society, Washington, DC.
Ramsay, 0. B. (1981), Stereochemistry, Heyden & Son, Philadelphia.
Richardson, G. M., Ed. (1901), The Foundations of Stereochemistry, American Book Co., New York.
Snatzke, G. (1989/90), personal communication to SHW; see also Section 13-5.a.
Snelders, H. A. M. (1975), "J. A. Le Bel's Stereochemical Ideas Compared with those of J. H. van't
Hoff (1974)" in van't Hoff-Le Be1 Centennial, Ramsay, 0 . B., Ed., ACS Symposium Series 12,
American Chemical Society, Washington, DC., p. 66.
Sokolov, V. I. (1990), Chirality and Optical Activity in Organometallic Compounds, Gordon and
Breach, New York.
Stoddard, M. P. and Dunn, M. S. (1942), J. Biol. Chem., 142, 329.
Thomson, W. - see Kelvin.

van't Hoff, J. H. (1874), Arch. Neerl. Sci. Exactes Nat., 9 , 445. The Dutch version of this seminal
article was published simultaneously in the form of a pamphlet in September, 1874 and has been
reprinted in the Netherlands on the occasion of the van't Hoff Centennial in 1974. The French
version was republished in abbreviated and revised form in Bull. Soc. Chim. Fr., [2], 23, 295
(1875). English translations are available in Richardson (1901), p. 37 and in Benfey (1963), p.
151.
van't Hoff, J. H. (1875), La Chimie dans L'Espace, Bazendijk, Rotterdam, The Netherlands, pp.
13-14.
Verkade, J. G. and Quin, L. D., Eds. (1987), Phosphorus-31 NMR Spectroscopy in Stereochemical
Analysis, VCH Publishers, New York.
Wheland, G. A. (1960), Advanced Organic Chemistry, 3rd ed., Wiley, New York.
Whyte, L. L. (1957), Nature (London), 180, 513.
Whyte, L. L. (1958), Nature (London), 182, 198.
Weiss, U. (1968), Experientia, 24, 1088.
Wipke, W. T. (1974), "Computer-Assisted Three-Dimensional Synthetic Analysis" in Wipke, W. T.,
Heller, S. R., Feldman, R. J., and Hyde, E., Eds., Computer Representation and Manipulation
of Chemical Information, Wiley, New York, p. 147.
Wipke, W. T. and Howe, W. J., Eds. (1977), Computer Assisted Organic Synthesis, ACS Symposium
Series 61, American Chemical Society, Washington, DC.
Woodward, R. B. and Hoffmann, R. (1969), The Conservation of Orbital Symmetry, Angew. Chem.
Int. Ed. Engl., 8, 781; id. (1970) Academic, New York.

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Structure

2-1. MEANING, FACTORIZATION. INTERNAL COORDINATES.
ISOMERS
We have seen (Section 1-1) that static stereochemistry deals with the shape of

molecules (molecular architecture or molecular structure). The nomenclature
rules of IUPAC (International Union of Pure and Applied Chemistry) (Cross and
Klyne, 1976) do not provide an unequivocal definition of "structure"; we shall use
the term in the sense of the crystallographer as denoting the position in space of
all the atoms constituting a molecule. Molecular structure may thus be defined in
terms of the Cartesian coordinates of the atoms, or the oblique coordinates that
crystallographers often use for crystals belonging to the monoclinic, triclinic, and
trigonal hexagonal systems.
For many purposes (cf. Section 2-7), it is more convenient to employ so-called
"internal coordinates": bond lengths (or distances) r, bond angles 6, and torsion
angles o or 7 [polymer chemists, unfortunately, use 7 for the bond angle and 6 for
the torsion angle (cf. Jenkins, 1981)l. Since the absolute position and orientation
of a molecule is of no structural significance, only relative positions of atoms
within the molecule need to be specified. For a diatomic molecule A-B (Fig.
2.1), structure is thus completely defined by the nature of the nuclei A and B and
the bond distance r between their centers. For a triatomic molecule ABC (Fig.
2.1), besides the nature of A, B, and C, their connectivity (i.e., which atom is
connected to which) and the bond lengths A-B (r,) and B-C (r,), we must
specify the bond angle 6. With a tetratomic molecule ABCD the situation is
slightly more complicated: In addition to the nature and connectivity of the atoms
and the bond distances r,, r,, and r, and bond angles 6, and O,, one must now
specify the torsion angle o (Fig. 2.1) in order to fix the position of all four atoms
A , B, C, and D. The torsion angle o is defined as the angle between the planes
ABC and BCD (Fig. 2.2); this angle has sign as well as magnitude. If the turn
from the ABC to the BCD plane (front to back) is clockwise (Fig. 2.2), w is

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12

Structure

'a
AB
-

r

r2

C

A

Figure 2.1.

r3

r2

C

A

g2 r3

C

A

E

Internal coordinates.

positive, if it is counterclockwise (Fig. 2.2), o is negative. In determining the sign
of o it is immaterial whether one views the ABCD array from AB looking toward
CD or from CD looking toward AB.
For each additional atom (e.g., E in ABCD-E) three more coordinates need
to be specified: the bond length D-E, the bond angle B(CDE), and the torsion
angle o(BCDE). Thus the total number of independent coordinates for a
nonlinear n-atomic molecule is 3n - 6; for a chain of n atoms these may be taken
as n - 1 bond distances (the first atom defines no such distance), n - 2 bond
angles (not defined for the first two atoms), and n - 3 torsion angles (defined only
for atoms after the third). Figure 2.1 (right) displays an example (5 atoms, 9
coordinates).
The situation is more complicated for branched molecules, rings, or molecules with
three or more collinear atoms. For example, the nine independent coordinates for
CHFClBr (Fig. 2.8) are four bond distances, five bond angles, and no torsion
angle. Actually, the four bonds form six bond angles which, however, are not
independent but are interrelated by an equation of constraint. For the five-atom
carbon skeleton of 2-methylbutane (isopentane) we can choose four bond distances, four bond angles, and one torsion angle. In these cases, the total number of
independent coordinates remains 3n -6; but when three or more atoms are
collinear, as in methylallene (H,C-CH=C=CH,) or butatriene (H,C=C=C=CH,)
this number is less (five instead of six for the carbon skeleton in these two cases:
three bond distances and two bond angles.)

Whereas torsion angles change widely from one molecule to another and even
bond angles can vary appreciably from their standard magnitudes (e.g., the
normal CCC angle of 112" in propane is reduced to 88" in cyclobutane), bond

distances are usually quite constant (see, however, Sections 2-2 and 2-7). Standard bond distances (Sutton, 1958, 1965) for common bonds to carbon are given
in Table 2.1.

o (positive)

o (negative)
(b)

(a)
Figure 2.2.

Torsion angle.

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