BASIC ORGANICSTEREOCHEMISTRY

ERNEST L. ELIEL

SAMUEL H. WILEN

MICHAEL P. DOYLE

Preface

xii i

1 Introduction

1

1-1 . Scope, 11-2 . History, 11-3 . Polarimetry and Optical Rotation, 5

References, 7

2 Structure

8

2-1 . Meaning, Factorization, Internal Coordinates, Isomers, 82-2. Constitution, 1 12-3. Configuration, 1 32-4. Conformation, 1 52-5 . Determination of Structure, 1 72-6. A Priori Calculation of Structure, 202-7 . Molecular Models, 25

References, 26

3 Stereoisomers

30

3-1 . Nature of Stereoisomers, 3 0a. General, 30b. Barriers Between Stereoisomers and Residual Stereoisomers, 3 4

3-2 . Enantiomers, 3 63-3 . Diastereomers, 3 9

a. General Cases, 39

b . Degenerate Cases, 42References, 44

4 Symmetry

4 5

4-1 . Introduction, 4 54-2. Symmetry Elements, 454-3. Symmetry Operators and Symmetry Point Groups, 48

a. Point Groups Containing Chiral Molecules, 4 9b. Point Groups Containing Only Achiral Molecules, 5 1

4-4. Averaged Symmetry, 5 84-5. Symmetry and Molecular Properties, 5 9

a. Rotation of Polarized Light, 5 9b. Dipole Moment, 6 1c. Symmetry Number, 6 2References, 63

5 Configuration

65

5-1 . Definitions : Relative and Absolute Configuration, 6 55-2. Absolute Configuration and Notation, 675-3. Determination of Absolute Configuration, 7 5

a. Bijvoet Method, 75b. Theoretical Approaches, 77c. Modification of Crystal Morphology in the Presence of Additives, 7 7

5-4. Relative Configuration and Notation, 7 95-5. Determination of Relative Configuration of Saturated Aliphati c

Compounds, 8 4a. X-Ray Structure Analysis, 8 5b. Chemical Interconversion Not Affecting Bonds to the Stereogeni c

Atom, 86c. Methods Based on Symmetry Considerations, 8 6d. Correlation Via Compounds with Chiral Centers of Two Types, 8 9e. The Method of Quasi-Racemates, 9 0f. Chemical Correlations Affecting Bonds to a Chiral Atom in a

"Known" Way (For an overview, see ref. 32 .), 90g. Correlation by Stereoselective Synthesis of "Known" Stereochemical

Course, 9 5h. Chiroptical, Spectroscopic, and Other Physical Methods, 9 8

5-6. Conclusion : Network Arguments, 9 8References, 98

6 Properties of Stereoisomers and Stereoisomer Discrimination

10 2

6-1 . Introduction, 1026-2. Stereoisomer Discrimination, 10 26-3. The Nature of Racemates, 106

6-4. Properties of Racemates and of Their Enantiomer Components, 10 8a. Introduction, 108b. Optical Activity, 109c. Crystal Shape, 10 9d. Density and Racemate Type, 11 0e. Melting Point, 11 1f. Solubility, 115g. Vapor Pressure, 11 9h. Infrared Spectra, 12 0i. Electronic Spectra, 12 1j. Nuclear Magnetic Resonance Spectra, 12 2k. X-Ray Spectra, 12 31 . Liquid State and Interfacial Properties, 124m. Chromatography, 128n. Mass Spectrometry, 129o. Interaction with Other Chiral Substances, 13 0p. Biological Properties, 13 2q. Origins of Enantiomeric Homogeneity in Nature, 13 8

6-5 . Determination of Enantiomer and Diastereomer Composition, 14 2a. Introduction, 142b. Chiroptical Methods, 14 5c. NMR Methods Based on Diastereotopicity, 147d. Chromatographic and Related Separation Methods Based on

Diastereomeric Interactions, 160e. Kinetic Methods, 176f. Miscellaneous Methods, 17 8References, 180

7 Separation of Stereoisomers, Resolution, and Racemization

197

7-1 . Introduction, 1977-2 . Separation of Enantiomers by Crystallization, 19 8

a. Crystal Picking and Triage, 198b. Conglomerates, 19 8c. Preferential Crystallization, 20 1d. Asymmetric Transformation of Racemates and Total Spontaneou s

Resolution, 2047-3. Chemical Separation of Enantiomers via Diastereomers, 209

a. Formation and Separation of Diastereomers ; Resolving Agents, 20 9b. Resolution Principles and Practice, 22 7c. Separation Via Complexes and Inclusion Compounds, 23 1d. Chromatographic Resolution, 23 6e. Asymmetric Transformations of Diastereomers, 24 0f. General Methods for the Separation of Diastereomers, 24 6

7-4. Enantiomeric Enrichment and Resolution Strategy, 253

7-5. Kinetic Resolution, 25 7a. Theory and Stoichiometric and Abiotic Catalytic Kineti c

Resolution, 25 8b. Enzymatic Resolution, 268

7-6 . Miscellaneous Separation Methods, 2747-7. Racemization, 27 7

a. Racemization Processes, 278b. Racemization of Amino Acids, 284References, 287

8 Heterotopic Ligands and Faces : Prostereoisomerism andProchirality

303

8-1 . Introduction and Terminology, 30 38-2. Significance and History, 3058-3 . Homotopic and Heterotopic Ligands and Faces, 307

a. Homotopic Ligands and Faces, 307b. Enantiotopic Ligands and Faces, 31 0c. Diastereotopic Ligands and Faces, 31 2d. Concepts and Nomenclature, 31 5

8-4. Heterotopicity and Nuclear Magnetic Resonance, 31 8a. General Principles, Anisochrony, 31 8b. NMR in Assignment of Configuration and of Descriptors o f

Prostereoisomerism, 320c. Origin of Anisochrony, 32 3d. Conformationally Mobile Systems, 32 5

8-5. Heterotopic Ligands and Faces in Enzyme-Catalyzed Reactions, 32 9a. Heterotopicity and Stereoelective Synthesis, 32 9b. Heterotopicity and Enzyme-Catalyzed Reactions, 33 0References, 33 5

9 Stereochemistry of Alkenes

33 9

9-1 . Structure of Alkenes and Nature of cis-trans Isomerism, 33 9a. General, 33 9b. Nomenclature, 34 0c. Cumulenes, 342d. Alkenes with Low Rotational Barriers and Nonplanar Alkenes, 34 2e. The C=N and N=N Double Bonds, 34 6

9-2. Determination of Configuration of cis-trans Isomers, 34 8a. Chemical Methods, 34 8b. Physical Methods, 35 3

9-3. Interconversion of cis-trans Isomers : Position of Equilibrium andMethods of Isomerization, 36 2a. Position of cis-trans Equilibria, 362b. Methods of Equilibration, 366

c . Directed cis-trans Interconversion, 36 8References, 37 1

10 Conformation of Acyclic Molecules

376

10-1 . Conformation of Ethane, Butane, and Other Simple Saturated Acycli cMolecules, 37 6a . Alkanes, 37 6b. Saturated Acyclic Molecules with Polar Substituents or Chains

and the Anomeric Effect, 38310-2 . Conformation of Unsaturated Acyclic and Miscellaneou s

Compounds, 38 8a. Unsaturated Acyclic Compounds, 38 8b. Alkylbenzenes, 395c. Miscellaneous Compounds, 39 7

10-3 . Physical and Spectral Properties of Diastereomers and Conformers, 39 8a. General, 39 8b. Dipole Moments, 39 9c. Infrared Spectra, 400d. NMR Spectroscopy, 40 1

10-4 . Conformation and Reactivity : The Winstein-Holness Equation and th eCurtin-Hammett Principle, 40 7References, 41 5

11 Configuration and Conformation of Cyclic Molecules

421

11-1 . Stereoisomerism and Configurational Nomenclature of Rin gCompounds, 42 1

11-2 . Determination of Configuration of Substituted Ring Compounds, 42 3a. Introduction, 423b. Symmetry-Based Methods, 42 4c. Methods Based on Physical and Chemical Properties, 42 5d. Correlation Methods, 427

11-3 . Stability of Cyclic Molecules, 42 9a. Strain, 429b. Ease of Cyclization as a Function of Ring Size, 43 2c. Ease of Ring Closure as a Function of the Ring Atoms and

Substituents : The Thorpe-Ingold Effect, 43 3d. Baldwin's Rules, 43 4

11-4 . Conformational Aspects of the Chemistry of Six-Membered Rin gCompounds, 436a. Cyclohexane, 43 6b. Monosubstituted Cyclohexanes, 43 9c. Disubstituted and Poly substituted Cyclohexanes, 44 7d. Conformation and Physical Properties in Cyclohexan e

Derivatives, 453

e. Conformation and Reactivity in Cyclohexanes, 45 7f. sp2 Hybridized Cyclohexyl Systems, 46 3g. Six-Membered Saturated Heterocycles, 472

11-5 . Chemistry of Ring Compounds Other than Six-Membered Ones, 48 0a. Three-Membered Rings, 48 0b. Four-Membered Rings, 48 1c. Five-Membered Rings, 482d. Rings Larger Than Six-Membered, 48 5

11-6. Stereochemistry of Fused, Bridged, and Caged Ring Systems, 49 1a. Fused Rings, 492b. Bridged Rings, 50 1c. Propellanes, 505d. Catenanes, Rotaxanes, Knots, and Möhius Strips, 50 5e. Cubane, Tetrahedrane, Dödecahedrane, Adamantane, an d

Buckminsterfullerene, 51 3References, 51 7

12 Chiroptical Properties

534

12-1 . Introduction, 53 412-2. Optical Activity and Anisotropic Refraction, 535

a. Origin and Theory, 53 5b. Optical Rotatory Dispersion, 54 1

12-3 . Circular Dichroism and Anisotropic Absorption, 54 412-4 . Applications of Optical Rotary Dispersion and Circular Dichroism, 54 8

a. Determination of Configuration and Conformation : Theory, 54 8b. Classification of Chromophores, 55 0c. Sector and Helicity Rules, 55 3d. Exciton Chirality, 567e. Other Applications : Induced ORD and CD, 57 0f. Circular Dichroism of Chiral Polymers, 57 6

12-5 . Applications of Optical Activity, 58 5a. Polarimetry, 58 5b. Empirical Rules and Correlations : Calculation of Optical

Rotation, 59 312-6 . Vibrational Optical Activity, 597

References, 59 8

13 Chirality in Molecules Devoid of Chiral Centers

60 8

13-1 . Introduction and Nomenclature, 60 813-2 . Allenes, 61 1

a. Historical Overview and Natural Occurrence, 61 1b. Synthesis of Optically Active Allenes, 61 2c. Determination of Configuration and Enantiomeric Purity o f

Allenes, 613

d . Cyclic Allenes, Cumulenes, and Ketene Imines, 61 613 .3 . Alkylidenecycloalkanes, 61 713-4 . Spiranes, 62013-5 . Biphenyls and Atropisomerism, 62 2

a. Introduction, 622b. Biphenyls and Other Atropisomers of the sp2-sp2 Single-Bon d

Type, 623c. Atropisomerism About sp 2-sp3 Single Bonds, 62 9d. Atropisomerism About sp 3-sp3 Bonds, 630

13-6 . Molecular Propellers, 63 213-7 . Helicenes, 63 613-8 . Molecules with Planar Chirality, 63 8

a. Introduction, 638b. Cyclophanes, 639c. trans-Cycloalkenes, 64 0d. Metallocenes and Related Compounds, 64 2References, 64 2

Index

649