In Reaction Mechanisms in Organic Chemistry, eminent researcher Dr. Metin Balci delivers an excellent textbook for understanding organic reaction mechanisms. The book offers a way for undergraduate and graduate students to understand???rather than memorize???the principles of reaction mechanisms. It includes the most important reaction types, including substitution, elimination, addition, pericyclic, and C-C coupling reactions.
Each chapter contains problems and accompanying solutions that cover central concepts in organic chemistry. Students will learn to understand the foundational nature of ideas like Lewis acids and bases, electron density, the mesomeric effect, and the inductive effect via the use of detailed examples and an expansive discussion of the concept of hybridization.
Along with sections covering aromaticity and the chemistry of intermediates, the book includes:
- A thorough introduction to basic concepts in organic reactions, including covalent bonding, hybridization, electrophiles and nucleophiles, and inductive and mesomeric effects - Comprehensive explorations of nucleophilic substitution reactions, including optical activity and stereochemistry of SN2 reactions - Practical discussions of elimination reactions, including halogene elimination and Hofmann elimination - In-depth examinations of addition reactions, including the addition of water to alkenes and the epoxidation of alkenes
Perfect for students of chemistry, biochemistry, and pharmacy, Reaction Mechanisms in Organic Chemistry will also earn a place in the libraries of researchers and lecturers in these fields seeking a one-stop resource on organic reaction mechanisms.
Table of Contents
Preface xv
About the Author xvii
Abbreviations xix
1 Basic Concepts 1
1.1 Introduction to Reaction Mechanisms 1
1.2 Covalent Bonding and Hybridization 2
1.2.1 sp3-Hybridization of Carbon 4
1.2.2 sp2-Hybridization of Carbon 7
1.2.3 sp-Hybridization of Carbon 10
1.2.4 Bond Lengths 12
1.3 Electrophiles and Nucleophiles 13
1.3.1 Electrophiles (Electrophilic Compounds) 14
1.3.2 Nucleophiles (Nucleophilic Compounds) 15
1.4 Inductive and Mesomeric Effects 15
1.4.1 Inductive Effect 15
1.4.2 Mesomeric Effect (Resonance Structures) 18
1.5 Formal Charge and Oxidation Number 24
1.5.1 Formal Charge 24
1.5.2 Oxidation Number 25
1.6 Acids and Bases 28
1.6.1 Arrhenius Acid-Base Theory 29
1.6.2 Brønsted-Lowry Acid-Base Theory 29
1.6.3 Lewis Acid-Base Theory 30
1.6.4 Pearson Hard and Soft Acid-Base Theory 32
1.6.4.1 Hard Acids and Bases 32
1.6.4.2 Soft Acids and Bases 33
1.6.5 pKa Values of Acids 34
1.6.5.1 Factors Affecting the Acidity Strength of Organic Compounds 35
1.6.6 pKb Values of Bases 38
1.6.7 Factors Affecting the Strengths of Bases in Nitrogen-Containing Compounds 38
1.6.8 Heterocyclic Bases 40
1.7 Reaction Kinetics and Energy Diagrams 41
1.7.1 Thermodynamic vs. Kinetic Control of Reactions 43
1.7.2 Reaction rate 44
Problems 46
References 48
2 Nucleophilic Substitution Reaction 50
2.1 Types of Chemical Reactions 50
2.1.1 Polar Reactions 50
2.1.2 Radical Reactions 50
2.1.3 Pericyclic Reactions 50
2.1.3.1 Relationship Between Nucleophilicity and Basicity 51
2.1.3.2 Leaving Group 54
2.2 Unimolecular Nucleophilic Substitution Reactions, SN1 55
2.2.1 Stereochemistry in SN1 Reactions 58
2.2.2 Optical Activity 59
2.2.3 Other Factors Affecting SN1 Reactions: Steric Factors 61
2.3 Bimolecular Substitution Reactions, SN2 62
2.3.1 Stereochemistry of SN2 Reactions 64
2.3.2 Factors Affecting the SN2 Reaction Mechanism 66
2.3.2.1 The Structure of the Substrate 66
2.3.2.2 Solvent Effect 68
2.3.2.3 Leaving Group Effect 69
2.3.2.4 Structure of the Nucleophile 70
2.3.3 Nucleophilic Substitution in Allylic Systems: Allylic Rearrangement 71
2.3.3.1 Stereochemistry in Allylic Substitution Reactions 73
2.3.4 Internal Nucleophilic Substitution Reaction, SNi 74
2.3.5 Neighboring Group Participation in Nucleophilic Substitution Reactions 75
2.3.5.1 Reaction Rate 76
2.3.5.2 Configuration Retention 77
2.3.5.3 Molecular Rearrangement 78
2.3.6 Ambident Nucleophiles 78
2.3.7 Various Nucleophilic Substitution Reactions 80
2.3.7.1 Williamson Ether Synthesis 80
2.3.7.2 Ether Cleavage 81
2.3.7.3 Reactions of Epoxides 82
2.3.7.4 Substitution in Unsaturated Systems 83
Problems 83
References 85
3 Elimination Reactions 87
3.1 Unimolecular Elimination Reactions, E1 88
3.1.1 E1 Reaction Mechanism 88
3.1.1.1 Dehydration of Alcohols 91
3.1.2 Factors Affecting the Ratio of E1 and SN1 92
3.2 Bimolecular Elimination Reactions, E2 94
3.2.1 Kinetic Isotope Effect 98
3.2.2 Stereochemistry in E2 Elimination Reactions 98
3.2.2.1 Erythro- and Threo-Configurations 100
3.2.3 E2 Elimination in the Cyclohexane System 105
3.2.3.1 Conformation and Configuration in Cyclohexane 105
3.2.3.2 syn-Elimination (cis-Elimination) 112
3.3 Unimolecular Conjugate Base Elimination, E1cb 112
3.4 Elimination Reaction in Synthesis 114
3.4.1 Halogen Elimination 114
3.4.2 Hofmann Elimination: Quaternary Ammonium Salts 116
3.4.3 Pyrolytic Elimination: Intramolecular cis-Elimination Reactions 119
3.4.4 Elimination at the Bridgehead: Bredt’s Rule 123
3.4.5 Grob Fragmentation 126
Problems 129
References 131
4 Addition Reactions to Alkenes 133
4.1 Halogen Addition to Alkenes: Halogenation 133
4.1.1 Stereochemistry of Halogen Addition 136
4.2 Addition of Hydrogen Halides to Alkenes: Markovnikov’s Rule 138
4.2.1 Anti-Markovnikov Addition of Hydrogen Halides to Alkenes 141
4.3 Addition of Water and Alcohols to Alkenes 143
4.3.1 Hydration 143
4.3.2 Alkoxylation 144
4.3.3 Formation of Halohydrins 145
4.4 Hydration Alkenes: Oxymercuration and Demercuration 146
4.5 Hydroboration of Alkenes: anti-Markovnikov Hydration 148
4.6 Oxidation of Alkenes 152
4.6.1 Epoxidation 152
4.6.2 Dioxirane 156
4.6.3 Epoxide Ring-Opening Reactions 157
4.6.4 Vicinal cis-Dihydroxylation 159
4.6.5 Dihydroxylation via PIFA 161
4.6.6 Enzymatic Dihydroxylation 162
4.6.7 Ozonolysis: Oxidative Cleavage of Alkenes 162
4.7 Reduction of Alkenes 165
4.7.1 Heterogeneous Catalytic Reduction 166
4.7.2 Homogeneous Catalytic Reduction 168
4.8 Addition to Conjugated Dienes 171
Problems 176
References 177
5 Carbonyl Compounds 181
5.1 Reactivity of the Carbonyl Group 181
5.1.1 Structure-Reactivity Relationships 183
5.2 Reactions of Carbonyl Compounds: Addition Reactions 186
5.2.1 Hydration: Addition ofWater to Carbonyl Groups 187
5.2.2 Hemiacetal Formation: Addition of Alcohols to Carbonyl Groups 190
5.2.2.1 Cyclic Acetals and Their Synthetic Application 191
5.2.2.2 What is the Protecting Group? 192
5.2.2.3 Protection of Diols 193
5.2.2.4 Formation of Thioacetals and Their Synthetic Application 193
5.2.2.5 Umpolung: Polarity Inversion of the Aldehyde Carbonyl Group 195
5.2.3 Reactions of Aldehydes and Ketones with Amines 196
5.2.3.1 Oximes 199
5.2.3.2 Hydrazones 199
5.3 Reduction of Carbonyl Groups 200
5.3.1 Wolff-Kishner Reduction (Under Basic Conditions) 200
5.3.2 Clemmensen Reduction (Under Acidic Conditions) 201
5.3.3 Metal Hydride Reduction of the Carbonyl Groups 201
5.3.3.1 Diisobutyl Aluminum Hydride (DIBAL) Reduction 203
5.3.3.2 Sodium Borohydride (NaBH4) Reduction 203
5.3.3.3 Reduction of Carboxylic Acids 205
5.3.3.4 Meerwein-Ponndorf-Verley Reduction and Oppenauer Oxidation 209
5.4 Reaction of Carbonyl Groups with Organometallic Compounds 210
5.4.1 Grignard Reagents 210
5.4.2 Reactions with Active Hydrogen-Containing Compounds 213
5.4.3 Reactions with Carbonyl Compounds 213
5.4.4 Stereochemistry 214
5.4.5 Reaction with Esters 215
5.4.6 Reactions with Different Functional Groups 215
5.5 Reaction of Carbonyl Groups with Ylides 218
5.5.1 Phosphonium Ylides and Wittig Reactions 219
5.5.2 Reaction Mechanism 219
5.5.3 Stable Ylides 220
5.5.4 Unstable Ylides 220
5.5.5 Wittig-Schlosser Reaction 221
5.5.6 Wittig-Horner Reaction 222
5.5.7 Horner-Wadsworth-Emmons Reaction (HWE Reaction) 223
5.5.8 Sulfur Ylides 224
5.5.9 Julia Olefination 226
5.5.10 Peterson Olefination 227
5.6 Reactivity of α-Carbon Atoms 228
5.6.1 Acidity of α-Hydrogens 228
5.6.2 Keto-Enol Tautomerism 229
5.6.3 Acid-Catalyzed Enolization 232
5.6.4 Base-Catalyzed Enolization 233
5.6.5 Kinetic and Thermodynamic Enolates 234
5.6.6 Enol and Enolate Reactions 235
5.6.6.1 Racemization of Chiral Ketones, α-Epimerization 235
5.6.6.2 α-Halogenation of Aldehydes and Ketones 237
5.6.7 α-Alkylation of Carbonyl Compounds 241
5.6.7.1 Stork Enamine Reaction 243
5.6.7.2 Enolates Derived from 1, 3-Dicarbonyl Compounds 245
5.6.7.3 Enolates, Ambident Nucleophiles: C vs. O Alkylation 249
5.7 Condensation Reactions of Carbonyl Compounds 251
5.7.1 Aldol Condensation 252
5.7.2 Crossed Aldol Condensation 254
5.7.3 Robinson Annulation 256
5.7.4 Claisen Ester Condensation 257
5.7.5 Crossed Claisen Ester Condensation 259
5.7.6 Dieckmann Condensation 260
5.7.7 Knoevenagel Condensation 261
5.7.8 Perkin Condensation 264
5.7.9 Stobbe Condensation 265
5.7.10 Role of Condensation Reactions in Synthetic Chemistry 266
5.8 Ester Hydrolysis Reactions 268
5.8.1 Ester Hydrolysis 269
5.8.2 Ester Hydrolysis under Basic Conditions 270
5.8.3 BAL2 Mechanism 271
5.8.4 Ester Hydrolysis under Acidic Conditions 272
5.8.5 Asymmetric Ester Hydrolysis 273
5.8.6 Transesterification 273
Problems 275
References 278
6 Aromaticity 281
6.1 Aromatic Compounds 281
6.1.1 Discovery and Structure of Benzene 281
6.1.2 Aromatic, Antiaromatic, and Nonaromatic Compounds 284
6.1.2.1 Aromatic Compounds 284
6.1.2.2 Antiaromatic Compounds 285
6.1.2.3 Nonaromatic Compounds 286
6.1.3 Determination of the Molecular Orbitals of Aromatic Compounds 287
6.1.4 What Are the Criteria for Aromaticity? How Does One Quantify Aromaticity? 288
6.1.4.1 Thermodynamic and Aromatic Resonance Stabilization Energy 288
6.1.4.2 Structural Evidence for Aromaticity 289
6.1.4.3 Magnetic Evidence for Aromaticity 289
6.1.5 Homoaromaticity 291
6.1.6 Möbius Aromaticity 293
6.2 Aromatic Ions 294
6.3 Annulenes 303
6.3.1 Cyclobutadiene 303
6.3.2 [10]Annulene 305
6.3.3 [12]Annulenes 307
6.3.4 [14] and Higher Annulenes 308
6.4 Aromaticity in Fused Systems 311
6.5 Aromaticity in Heterocyclic Compounds 314
6.5.1 Heteroaromatic Compounds with Three-Membered Ring 314
6.5.2 Heteroaromatic Compounds with a Five-Membered Ring 315
6.5.3 Heteroaromatic Compounds with Six-Membered Ring 323
6.5.3.1 Electrophilic Aromatic Substitution 324
6.5.3.2 Nucleophilic Aromatic Substitution 326
6.5.3.3 Pyridine N-Oxides 327
6.5.3.4 Electrophilic Substitution 328
6.5.3.5 Nucleophilic Substitution 328
6.5.3.6 Six-Membered Ring Heteroaromatic Compounds with Two Nitrogen Atoms 329
6.5.4 Heteroaromatic Compounds with a Seven-Membered Ring 330
6.5.4.1 Oxepine 330
6.5.4.2 1H-Azepine 331
6.5.4.3 Thiepine 332
6.6 Electrophilic Aromatic Substitution: Chemistry of Benzene 333
6.6.1 Halogenation of Benzene 335
6.6.2 Nitration 336
6.6.3 Sulfonation 337
6.6.4 Friedel-Crafts Acylation 338
6.6.5 Friedel-Crafts Alkylation 339
6.6.6 Clemmensen Reduction 341
6.6.7 Reactivity of Monosubstituted Benzene Derivatives 341
6.6.8 Directing Effects of Substituents: Activating Groups 344
6.6.9 Directing Effects of Substituents: Deactivating Groups 349
6.6.10 Electrophilic Aromatic Substitution on Disubstituted Benzenes 352
6.7 Functionalization of the Side-Chain Substituents of Benzene 354
6.7.1 Oxidation of the Side Chain of Alkylbenzenes 354
6.7.2 Halogenation of Side Chains of Alkylbenzenes 355
6.7.3 Arenediazonium Ion as an Electrophile 356
6.8 Nucleophilic Aromatic Substitution Reactions 357
6.8.1 Addition-Elimination Mechanism (SNAr Mechanism) 358
6.8.2 Reaction of Arenediazonium Salts with Nucleophiles 360
6.8.2.1 Reductive Dediazonization 360
6.8.3 Elimination-Addition Mechanism 363
6.9 Polycyclic Aromatic Compounds 365
6.9.1 Naphthalene 365
6.9.2 Benzenoid Aromatic Compounds 368
Problems 373
References 375
7 Reactive Intermediates: Carbocations 381
7.1 Structure and Stability of Carbocations 384
7.2 Generation of Carbocations 387
7.2.1 Ionization Mechanism 387
7.2.2 Electrophilic Addition to π Bonds 388
7.3 Detection of Carbocations 388
7.4 Reactions of Carbocations: Rearrangements 389
7.4.1 Reactions with Nucleophiles 389
7.4.2 Double-bond Formation by Proton Elimination 389
7.4.3 Rearrangement 389
7.4.4 Carbocation Rearrangement 390
7.4.5 Ethyl Carbocation 390
7.4.6 Isopropyl Carbocation 390
7.4.7 Cyclopentyl Carbocation 391
7.4.8 TheWagner-Meerwein Rearrangement 391
7.4.9 Pinacol Rearrangement 393
7.4.10 Tiffeneau-Demjanov Rearrangement 395
7.4.11 Dienone-Phenol Rearrangement 398
7.4.12 Neighboring Group Participation in Molecular Rearrangement (Anchimeric Assistance) 398
7.4.13 Nonclassical Carbocations 401
7.4.14 Nametkin Rearrangement 406
7.4.15 Hydride Shift 406
7.4.16 Base-induced Nucleophilic Rearrangements 408
7.4.17 Favorskii Rearrangement 408
7.4.18 Ramberg-Bäcklund Rearrangement 411
7.4.19 Benzil-Benzilic Acid Rearrangement 412
7.5 Rearrangement to Electron-deficient Nitrogen 412
7.5.1 Beckmann Rearrangement 413
7.5.2 Neber Rearrangement 415
7.5.3 Stieglitz Rearrangement 416
7.6 Rearrangement to Electron-deficient Oxygen 416
7.6.1 Baeyer-Villiger Rearrangement (or Oxidation) 417
Problems 419
References 421
8 Reactive Intermediates Carbanions, Carbenes, and Nitrenes 424
8.1 Carbanions: Electrophilic Rearrangements 424
8.1.1 Stevens Rearrangement 425
8.1.2 Sommelet-Hauser Rearrangement 427
8.1.3 Wittig Rearrangement 429
8.2 Carbenes 429
8.2.1 Naming Carbenes 430
8.2.2 Structure and Reactivity of Carbenes 430
8.2.3 Inductive Effect 430
8.2.4 Mesomeric Effect 430
8.2.5 Carbene Generation 431
8.2.5.1 Carbene Precursors: Synthesis of Diazo Compounds 432
8.2.5.2 Bamford-Stevens Reaction 432
8.2.5.3 N-Nitrosoalkyl Urea Compounds 433
8.2.5.4 Diazirines 434
8.2.5.5 α-Elimination Method 435
8.2.5.6 Simmons-Smith Reaction 437
8.2.6 Carbene Reactions 438
8.2.6.1 Carbene Cycloaddition Reactions 439
8.2.6.2 Carbene Insertion Reactions 445
8.2.6.3 Carbene Rearrangements 446
8.3 Azides and Nitrenes 453
8.3.1 Nitrene Synthesis 454
8.3.1.1 Synthesis of Acyl Azides 455
8.3.2 Nitrene Rearrangements 455
8.3.2.1 Curtius Rearrangement 455
8.3.2.2 Schmidt Rearrangement 457
8.3.2.3 Lossen Rearrangement 457
8.3.2.4 Hofmann Rearrangement 458
8.3.3 Nitrene Cycloaddition Reactions 458
8.3.4 Nitrene Insertion Reactions 460
Problems 461
References 465
9 Reactive Intermediates: Radicals and Singlet Oxygen 468
9.1 Structure of Radicals and Their Stability 468
9.1.1 Generation of Radicals 471
9.1.2 Radical Reactions 472
9.1.2.1 Atom-Abstraction Reaction 472
9.1.2.2 Radical Combination and Disproportionation 475
9.1.2.3 Kolbe Electrolysis (Kolbe Reaction) 476
9.1.2.4 Hunsdiecker Reaction 477
9.1.2.5 Radical Addition to Alkenes 478
9.1.2.6 Manganese(III)-Mediated Oxidative Radical Additions to Alkenes 480
9.1.2.7 Birch Reduction 481
9.1.2.8 Di-π-methane Rearrangement 483
9.1.2.9 Diradicals Derived from Diazo Compounds 486
9.2 Singlet Oxygen 487
9.2.1 The Electronic Configuration of the Oxygen Molecule 487
9.2.2 Singlet Oxygen Generation 489
9.2.2.1 Generation of Photosensitized Singlet Oxygen 489
9.2.2.2 Chemical Sources for Singlet Oxygen 490
9.2.3 Reactions of Singlet Oxygen 492
9.2.3.1 Ene Reactions 492
9.2.3.2 [2+2] Cycloaddition Reactions 493
9.2.3.3 [4+2] Cycloaddition Reactions 495
9.2.3.4 Bicyclic Endoperoxides in Synthesis 496
References 497
10 Pericyclic Reactions 500
10.1 Frontier Molecular Orbitals 502
10.2 Electrocyclic Reactions 505
10.2.1 Thermal Electrocyclic Reactions 505
10.2.2 Photochemical Electrocyclic Reactions 506
10.2.3 Application of the Woodward-Hoffman Rules to Electrocyclic Reactions 508
10.2.3.1 Neutral Compounds 508
10.2.3.2 Ionic Compounds 510
10.3 Correlation Diagrams 512
10.3.1 Symmetry Elements 512
10.4 Cycloaddition Reactions 515
10.4.1 Stereoselectivity in Cycloaddition Reactions: Secondary Orbital Interactions 520
10.4.2 Factors Affecting the Rates of Cycloadditions 521
10.4.3 Coefficients of the Frontier Orbitals: Application to Regioselectivity in Diels-Alder Reactions 522
10.5 Sigmatropic Reactions 526
10.6 Cope and Claisen Rearrangements 530
10.6.1 Oxy-Cope Rearrangement 531
10.6.2 Claisen Rearrangement 532
Problems 533
References 535
11 Carbon-Carbon Coupling Reactions 537
11.1 History 537
11.2 Mizoroki-Heck Coupling Reaction 539
11.2.1 Regioselectivity 542
11.3 Stille Coupling Reaction 547
11.3.1 Synthesis of Organotin Compounds 550
11.4 Suzuki-Miyaura Coupling Reaction 552
11.5 Negishi Coupling Reaction 558
11.6 Sonogashira Coupling Reaction 562
11.7 Kumada Coupling Reaction 566
11.8 Hiyama Coupling Reaction 567
11.8.1 Hiyama-Denmark Coupling 569
11.9 Buchwald-Hartwig Coupling Reaction 570
11.10 Tsuji-Trost Coupling Reaction 571
11.11 Palladium-Catalyzed Carbonylation Reactions 573
11.11.1 Carbonylative Coupling Reactions with Organometallic Reagents 576
11.11.2 Mo(CO)6-Mediated Carbonylation 577
References 578
Solutions 583
Index 605
