Preface ......................................................... v
Acknowledgment and Personal Statement ......................... vii
Introduction ................................................... ix
Chapter 1. Chemical Bonding and Molecular Structure ............ 1
Introduction .................................................... 1
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 Equalization ................... 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
1.2.1. 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. Mulliken Population Analysis ..................... 60
1.4.2. Natural Bond Orbitals and Natural Population
Analysis ......................................... 61
1.4.3. Atoms in 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
Т.1.5.1. DFT Formulation of Chemical
Potential, Electronegativity,
Hardness and Softness, and Covalent
and van der Waal Radii ................. 95
T.l.5.2. DFT Formulation of Reactivity-The
Fukui Function ......................... 97
Т.1.5.З. 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
2.2.1. 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 Reactions .............................. 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 Stereoselectivity ............................. 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. Lipases and Esterases ................. 216
T.2.2.2. Proteases and Acylases ................ 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 in
Reactions ....................................... 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. Curtin-Hammett Principle ........................ 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
Relationships ................................... 335
3.6.2. Application of Linear Free-Energy
Relationships to Characterization of Reaction
Mechanisms ...................................... 342
3.7. Catalysis ............................................... 345
3.7.1. 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
4.1.1. Substitution by the Ionization (SNl)
Mechanism ....................................... 391
4.1.2. Substitution by the Direct Displacement (SN2)
Mechanism ....................................... 393
4.1.3. Detailed Mechanistic Description and
Borderline 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
4.2.1. 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
Ionization 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. Selenenylation .................................. 500
5.5. Addition Reactions Involving Epoxides ................... 503
5.5.1. Epoxides from Alkenes 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. Hydroboration ................................... 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. Additions to Allenes ............................ 545
5.10. Elimination Reactions ................................... 546
5.10.1. The E2, El and E1cb 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 С-Н
Bonds ........................................... 564
General References ............................................ 569
Problems ...................................................... 569
Chapter 6. Carbanions and Other Carbon Nucleophiles .......... 579
Introduction .................................................. 559
6.1. Acidity 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 5N2 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. Amide Hydrolysis ................................ 662
7.4.4. Acylation of Nucleophilic Oxygen and Nitrogen
Groups .......................................... 664
7.4.1. Intramolecular Catalysis of Carbonyl
Substitution Reactions .......................... 668
7.5. Intramolecular 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 Ketones ................... 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 Annulenes ............... 733
8.2.7. Other Related Structures ........................ 735
8.3. Aromaticity in Charged Rings ............................ 738
8.4. Homoaromaticity ......................................... 743
8.5. Fused-Ring 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
Elimination-Addition Mechanism .................. 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 Diels-Alder Reaction ..... 839
10.2.2. Substituent 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 [l,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 DFT Concepts to Reactivity
and Regiochemistry of Cycloaddition Reactions ... 945
Problems ...................................................... 951
Chapter 11. Free Radical Reactions ............................ 965
Introduction .................................................. 965
11.1. Generation and Characterization of Free Radicals ........ 967
11.1.1. Background ...................................... 967
11.1.2. Long-Lived Free Radicals ........................ 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 Radicals ................................ 988
11.2. Characteristics of Reactions Involving Radical
Intermediates ........................................... 992
11.2.1. Kinetic Characteristics of Chain Reactions ...... 992
11.2.2. Determination of Reaction Rates ................. 995
11.2.3. Structure-Reactivity Relationships ............. 1000
11.3. Free Radical Substitution Reactions .................... 1018
11.3.1. Halogenation ................................... 1018
11.3.2. Oxygenation .................................... 1024
11.4. Free Radical Addition Reactions ........................ 1026
11.4.1. 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. 5RN1 Substitution Processes ............................ 1044
11.6.1. SRN1 Substitution Reactions of Alkyl Nitro
Compounds ...................................... 1045
11.6.2. SRN1 Substitution Reactions of Aryl and Alkyl
Halides ........................................ 1048
Topic 11.1. Relationships between Bond and Radical
Stabilization Energies ......................... 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 ..................................... 1073
12.2. Photochemistry of Alkenes, Dienes, and Polyenes ........ 1081
12.2.1. cis-trans Isomerization ........................ 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 ................... 1116
12.3.1. 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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