Contents Preface v Acknowledgment and Personal Statement vii Introduction ix Chapter 1 Chemical Bonding and Molecular Structure 1 Introduction ix 1.1 Description of Molecular Structure Using Valence Bond Concepts 2 1 1.1 Hybridization 4 1.1.2 The Origin of Electron-Electron Repulsion 7 1.1.3 Electronegativity and Polarity 8 1.1.4 Electronegativity Equahzat10n 11 1.1.5 Differential Electronegativity of Carbon Atoms 12 1.1.6 Polarizability, Hardness, and Softness 14 1.1.7 Resonance and Conjugation 18 1.1.8 Hyperconjugation 22 1.1.9 Covalent and van der Waals Radii of Atoms 24 1.2 Molecular Orbital Theory and Methods 26 I 2.1 The Huckel MO Method 27 1.2.2 Semiempirical MO Methods 32 1.2.3 Ab Initio Methods 32 1.2.4 Pictorial Representation of MOs for Molecules 35 1.2.5 Qualitative Application of MO Theory to Reactivity: Perturbational MO Theory and Frontier Orbitals 41 1.2.6 Numerical Application of MO Theory 50 1.3 Electron Density Functionals 54 1.4 Representation of Electron Density Distribution 57 1.4 1 Mululliken Populat10n Analysis 60 1.4.2 Natural Bond Orbitals and Natural Population Analysis 61 1.4.3 Atoms m Molecules 63 1.4.4 Comparison and Interpretation of Atomic Charge Calculations 70 1.4.5 Electrostatic Potential Surfaces 73 1.4.6 Relationships between Electron Density and Bond Order 76 Topic 1.1 The Origin of the Rotational (Torsional) Barrier in Ethane and Other Small Molecules 78 Topic 1.2 Heteroatom Hyperconjugation (Anomeric Effect) in Acyclic Molecules 81 Topic 1.3 Bonding in Cyclopropane and Other Small Ring Compounds 85 Topic 1.4 Representation of Electron Density by the Laplacian Function 92 Topic 1.5 Application of Density Functional Theory to Chemical Properties and Reactivity 94 T.1.5.1 DFT Formulation of Chemical Potential, Electronegativity, Hardness and Softness, and Covalent and van der Waal Radii 95 T.1.5.2 DFT Formulation of Reactivity-The Fukui Function 97 T.1.5.3 DFT Concepts of Substituent Groups Effects 100 General References 106 Problems 106 Chapter 2 Stereochemistry, Conformation, and Stereoselectivity 119 Introduction 119 2.1 Configuration 119 2.1.1 Configuration at Double Bonds 119 2.1.2 Configuration of Cyclic Compounds 121 2.1.3 Configuration at Tetrahedral Atoms 122 2.1.4 Molecules with Multiple Stereogenic Centers 126 2.1.5 Other Types of Stereogenic Centers 128 2.1.6 The Relationship between Chirality and Symmetry 131 2.1 7 Configuration at Prochiral Centers 133 2.1.8 Resolution—The Separation of Enantiomers 136 2.2 Conformation 142 2.2 l Conformation of Acyclic Compounds 142 2.2.2 Conformations of Cyclohexane Derivatives 152 2.2.3 Conformations of Carbocyclic Rings of Other Sizes 161 2.3 Molecular Mechanics 167 2.4 Stereoselective and Stereospecific Reactions 169 2.4.1 Examples of Stereoselective Reactions 170 2.4.2 Examples of Stereospecific Reactions 182 2.5 Enantioselective React10ns 189 2.5.1 Enantioselective Hydrogenation 189 2.5.2 Enantioselective Reduction of Ketones 193 2.5.3 Enantioselective Epoxidation of Allylic Alcohols 196 2.5.4 Enantioselective Dihydroxylation of Alkenes 200 2.6 Double Stereodifferentiation: Reinforcing and Competing Stereoselect1v1ty 204 Topic 2.1 Analysis and Separation of Enantiomeric Mixtures 208 T.2.1.1 Chiral Shift Reagents and Chiral Solvating Agents 208 T.2.1.2 Separation of Enantiomers 211 Topic 2.2 Enzymatic Resolution and Desymmetrization 215 T.2.2.1 Li pases and Esterases 216 T.2.2.2 Proteases and Acy lases 222 T.2.2.3 Epoxide Hydrolases 224 Topic 2.3 The Anomeric Effect in Cyclic Compounds 227 Topic 2.4 Polar Substituent Effects in Reduction of Carbonyl Compounds 234 General References 239 Problems 240 Chapter 3 Structural Effects on Stability and Reactivity 253 Introduction 253 3.1 Thermodynamic Stability 254 3.1.1 Relationship between Structure and Thermodynamic Stability for Hydrocarbons 256 3.1.2 Calculation of Enthalpy of Formation and Enthalpy of Reaction 257 3.2 Chemical Kinetics 270 3.2.1 Fundamental Principles of Chemical Kinetics 270 3.2.2 Representation of Potential Energy Changes m Reacllons 273 3.2.3 Reaction Rate Expressions 280 3.2.4 Examples of Rate Expressions 283 3.3 General Relationships between Thermodynamic Stability and Reaction Rates 285 3.3.1 Kinetic versus Thermodynamic Control of Product Composition 285 3.3.2 Correlations between Thermodynamic and Kinetic Aspects of Reactions 287 3.3.3 Curtm-Hammett Prmciple 296 3.4 Electronic Substituent Effects on Reaction Intermediates 297 3 4.1 Carbocations 300 3.4.2 Carbanions 307 3.4 3 Radical Intermediates 311 3.4.4 Carbonyl Addition Intermediates 319 3.5 Kinetic Isotope Effects 332 3.6 Linear Free－ Energy Relationships for Substituent Effects 335 3.6.1 Numerical Expression of Linear Free-Energy Relat10n ships 335 3.6.2 Application of Linear Free-Energy Relationships to Characterization of Reaction Mechanisms 342 3.7 Catalysis 345 3.7.l Catalysis by Acids and Bases 345 3.7 2 Lewis Acid Catalysis 354 3.8 Solvent Effects 359 3 8.1 Bulk Solvent Effects 359 3.8.2 Examples of Specific Solvent Effects 362 Topic 3.1 Acidity of Hydrocarbons 368 General References 376 Problems 376 Chapter 4 Nucleophilic Substitution 389 Introduction 389 4.1 Mechanisms for Nucleophilic Substitution 389 4.1.l Substitution by the Ionization (SNI) Mechanism 391 4.1.2 Substitution by the Direct Displacement (SN2) Mechanism 393 4.1.3 Detailed Mechanistic Description and Borderlme Mechanisms 395 4.1.4 Relationship between Stereochemistry and Mechanism of Substitution 402 4.1.5 Substitution Reactions of Alkyldiazonium Ions 405 4.2 Structural and Solvation Effects on Reactivity 407 4.2 l Characteristics of Nucleophilicity 407 4.2.2 Effect of Solvation on Nucleophilicity 411 4.2.3 Leaving-Group Effects 413 4.2.4 Steric and Strain Effects on Substitution and Iomzation Rates 415 4.2.5 Effects of Conjugation on Reactivity 417 4 3 Neighboring-Group Participation 419 4.4 Structure and Reactions of Carbocation Intermediates 425 4.4.1 Structure and Stability of Carbocations 425 4.4.2 Direct Observation of Carbocations 436 4.4.3 Competing Reactions of Carbocations 438 4.4.4 Mechanisms of Rearrangement of Carbocations 440 4.4.5 Bridged (Nonclassical) Carbocations 447 Topic 4.1 The Role Carbocations and Carbonium Ions in Petroleum Processing 454 General References 459 Problems 459 Chapter 5 Polar Addition and Elimination Reactions 473 Introduction 475 5.1 Addition of Hydrogen Halides to Alkenes 476 5.2 Acid-Catalyzed Hydration and Related Addition Reactions 482 5.3 Addition of Halogens 485 5.4 Sulfenylation and Selenenylation 497 5.4.1 Sulfenylation 498 5.4.2 Selenenylatlon 500 5.5 Addition Reactions Involving Epoxides 503 5.5.1 Epoxides from Alken es and Peroxidic Reagents 503 5.5.2 Subsequent Transformations of Epoxides 511 5.6 Electrophilic Additions Involving Metal Ions 515 5.6.1 Solvomercuration 515 5.6.2 Argentation the Formation of Silver Complexes 520 5.7 Synthesis and Reactions of Alkylboranes 521 5.7 1 Hydroborat10n 522 5.7 2 Reactions of Organoboranes 526 5.7.3 Enantioselective Hydroboration 529 5.8 Comparison of Electrophilic Addition Reactions 531 5.9 Additions to Alkynes and Allenes 536 5.9.1 Hydrohalogenation and Hydration of Alkynes 538 5.9.2 Halogenation of Alkynes 540 5.9.3 Mercuration of Alkynes 544 5.9.4 Overview of Alkyne Additions 544 5.9.5 Add1t1ons to Allenes 545 5.10 Ehminat10n React10ns 546 5.10.1 The E2, El and Elcb Mechanisms 548 5.10.2 Regiochemistry of Elimination Reactions 554 5.10.3 Stereochemistry of E2 Elimination Reactions 558 5.10.4 Dehydration of Alcohols 563 5.10.5 Eliminations Reactions Not Involving C-H Bonds 564 General References 569 Problems 569 Chapter 6 Carbanions and Other Carbon Nucleophiles 579 Introduction 559 6.1 Ac1d1ty of Hydrocarbons 579 6.2 Carbanion Character of Organometallic Compounds 588 6.3 Carbanions Stabilized by Functional Groups 591 6.4 Enols and Enamines 601 6.5 Carbanions as Nucleophiles in SN2 Reactions 609 6.5.1 Substitution Reactions of Organometallic Reagents 609 6.5.2 Substitution Reactions of Enolates 611 General References 619 Problems 619 Chapter 7 Addition, Condensation and Substitution Reactions of Carbonyl Compounds 629 Introduction 629 7.1 Reactivity of Carbonyl Compounds toward Addition 632 7.2 Hydration and Addition of Alcohols to Aldehydes and Ketones 638 7.3 Condensation Reactions of Aldehydes and Ketones with Nitrogen Nucleophiles 645 7.4 Substitution Reactions of Carboxylic Acid Derivatives 654 7.4.1 Ester Hydrolysis and Exchange 654 7.4 2 Aminolysis of Esters 659 7.4.3 AmideHydrolysis 662 7.4.4 Acylation of Nucleophilic Oxygen and Nitrogen Groups 664 7.5 lntramolecular Catalysis of Carbonyl Substitution Reactions 668 7.6 Addition of Organometallic Reagents to Carbonyl Groups 676 7.6.1 Kinetics of Organometallic Addition Reactions 677 7.6.2 Stereoselectivity of Organometallic Addition Reactions 680 7.7 Addition of Enolates and Enols to Carbonyl Compounds: The Aldol Addition and Condensation Reactions 682 7 7.1 The General Mechanisms 682 7.7.2 Mixed Aldol Condensations with Aromatic Aldehydes 685 7.7.3 Control of Regiochemistry and Stereochemistry of Aldol Reactions of Ke tones 687 7.7.4 Aldol Reactions of Other Carbonyl Compounds 692 General References 698 Problems 698 Chapter 8 Aromaticity 713 Introduction 713 8.1 Criteria of Aromaticity 715 8.1.1 The Energy Criterion for Aromaticity 715 8.1.2 Structural Criteria for Aromaticity 718 8.1.3 Electronic Criteria for Aromaticity 720 8.1.4 Relationship among the Energetic, Structural, and Electronic Criteria of Aromaticity 724 8.2 The Annulenes 725 8 2.1 Cyclobutadiene 725 8 2.2 Benzene 727 8 2.3 1,3,5,7-Cyclooctatetraene 727 8.2.4 [10]Annulenes-1,3,5,7,9-Cyclodecapentaene Isomers 728 8.2.5 [12], [14] and [16]Annulenes 730 8.2.6 [18]Annulene and Larger Ann 8.2.7 Other Related Structures 735 8.3 Aromaticity in Charged Rings 738 8.4 Homoaromaticity 743 8.5 Fused-Rmg Systems 745 8.6 Heteroaromatic Systems 758 General References 760 Problems 760 Chapter 9 Aromatic Substitution 771 Introduction 771 9.1 Electrophilic Aromatic Substitution Reactions 771 9.2 Structure-Reactivity Relationships for Substituted Benzenes 779 9.2.1 Substituent Effects on Reactivity 779 9.2.2 Mechanistic Interpretation of the Relationship between Reactivity and Selectivity 787 9.3 Reactivity of Polycyclic and Heteroaromatic Compounds 791 9.4 Specific Electrophilic Substitution Reactions 796 9.4.1 Nitration 796 9.4.2 Halogenation 800 9.4.3 Protonation and Hydrogen Exchange 804 9.4.4 Friedel-Crafts Alkylation and Related Reactions 805 9.4.5 Friedel-Crafts Acylation and Related Reactions 809 9.4.6 Aromatic Substitution by Diazonium Ions 813 9.4.7 Substitution of Groups Other than Hydrogen 814 9.5 Nucleophilic Aromatic Substitution 816 9.5.1 Nucleophilic Aromatic Substitution by the Addition-Elimination Mechanism 817 9.5.2 Nucleophilic Aromatic Substitution by the Ehmmat10n-Add1tion Mechamsm 821 General References 824 Problems 824 Chapter 10 Concerted Pericyclic Reactions 833 Introduction 833 10.1 Cycloaddition Reactions 834 10.2 The Diels-Alder Reaction 839 10.2.1 Stereochemistry of the Diets-Alder Reaction 839 10.2.2 Substitu ent Effects on Reactivity, Regioselectivity and Stereochemistry 843 10.2.3 Catalysis of Diels-Alder Reactions by Lewis Acids 848 10.2.4 Computational Characterization of Diels-Alder Transition Structures 851 10.2.5 Scope and Synthetic Applications of the Diels-Alder Reaction 860 10.2.6 Enantioselective Diels-Alder Reactions 865 10.2.7 Intramolecular Diels-Alder Reactions 868 10.3 1,3-Dipolar Cycloaddition Reactions 873 10.3.1 Relative Reactivity, Regioselectivity, Stereoselectivity, and Transition Structures 874 10.3.2 Scope and Applications of 1,3-Dipolar Cycloadditions 884 10.3.3 Catalysis of 1,3-Dipolar Cycloaddition Reactions 886 10.4 [2+2] Cycloaddition Reactions 888 10.5 Electrocyclic Reactions 892 10.5.1 Overview of Electrocyclic Reactions 892 10.5.2 Orbital Symmetry Basis for the Stereospecificity of Electrocyclic Reactions 894 10.5.3 Examples of Electrocyclic Reactions 903 10.5.4 Electrocyclic Reactions of Charged Species 906 10.5.5 Electrocyclization of Heteroatomic Trienes 910 10.6 Sigmatropic Rearrangements 911 10.6.1 Overview of Sigmatropic Rearrangements 911 10.6.2 [1,3]-, [1,5]~ and [1,7]-Sigmatropic Shifts of Hydrogen and Alkyl Groups 912 10.6.3 Overview of [3,3]-Sigmatropic Rearrangements 919 10.6.4 [2,3]-Sigmatropic Rearrangements 939 Topic 10.1 Application of DFf Concepts to Reactivity and Regiochemistry of Cycloaddition Reaction s 945 Problems 951 Chapter 11 Free Radical Reactions 965 Introduction 965 11.1 Generation and Characterization of Free Radical s 967 11.1.1 Background 96 7 11.1.2 Long-Lived FreeRadical s 968 11.1.3 Direct Detection of Radical Intermediates 970 11.1.4 Generation of Free Radicals 976 11.1.5 Structural and Stereochemical Properties of Free Radicals 980 11.1.6 Substituent Effects on Radical Stability 986 11.1.7 Charged R adicals 988 11.2 Characteristic s of Reactions Involving Radical Inte rmediates 992 11.2.1 Kinetic Characteristics of Chain Reactions 992 11.2.2 Determination of Reaction Rates 995 11.2.3 Structure-Reactivity Relationships 100。 11.3 Free Radical Substitution Reactions 1018 11.3.1 Halogenation 1018 11.3.2 Oxygenation 1024 11.4 Free Radical Addition Reaction s 1026 11.4 I Addition of Hydrogen Halides 1026 11.4.2 Addition of Halomethanes 1029 11.4.3 Addition of Other Carbon Radicals 1031 11.4.4 Addition of Thiols and Thiocarboxylic Acids 1033 11.4.5 Examples of Radical Addition Reactions 1033 11.5 Other Types of Free Radical Reactions 1037 11.5.1 Halogen, Sulfur, and Selenium Group Transfer Reactions 1037 11.5.2 Intramolecular Hydrogen Atom Transfer Reactions 1040 11.5.3 Rearrangement Reactions of Free Radicals 1041 11.6 SRN 1 Substitution Proces ses 1044 11.6.1 SRN 1 Substitution Reacti ons of Alkyl Nitro Co mpounds 1045 11.6.2 S RN 1 Substitution Reactions of Aryl and Alkyl Halides 1048 Topic 11.1 Relationships betw een Bond and Radical Stabilization Energ1es 1052 Topic 11.2 Structure-Reactivity Relationships in Hydrogen Abstraction Reactions 1056 General References 1062 Problems 1063 Chapter 12 Photochemistry 1073 Introduction 1073 12.1 General Principles 10 73 12.2 Photochemistry of Alkenes, Dienes, and Polyenes 1081 12.2 1 cis-trans Isomerizat10n 1081 12.2 2 Photoreactions of Other Alkenes 1091 12.2.3 Photoisomerization of 1,3-Butadiene 1096 12.2.4 Orbital Symmetry Considerations for Photochemical Reactions of Alkenes and Dienes 1097 12.2.5 Photochemical Electrocyclic Reactions 1100 12.2.6 Photochemical Cycloaddition Reactions 1109 12.2.7 Photochemical Rearrangements Reactions of 1,4-Dienes 1112 12.3 Photochemistry of Carbonyl Compounds l 116 12.3 l Hydrogen Abstraction and Fragmentation Reactions 1118 12.3.2 Cycloaddition and Rearrangement Reactions of Cyclic Unsaturated Ketones 1125 12.3.3 Cycloaddition of Carbonyl Compounds and Alkenes 1132 12.4 Photochemistry of Aromatic Compounds 1134 Topic 12.1 Computational Interpretation of Diene and Polyene Photochemistry 1137 General References 1145 Problems 1146 References to Problems 1155 Index 1171
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