Metin Balc¿, PhD, is Professor Emeritus of the Middle East Technical University in Ankara. He received his doctorate in 1976 from the University of Cologne. His research is focused on the synthesis of cyclitols, endoperoxides, cyclic strained compounds, bromine chemistry, and heterocyclic compounds.

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 ¿-Carbon Atoms 228

5.6.1 Acidity of ¿-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, ¿-Epimerization 235

5.6.6.2 ¿-Halogenation of Aldehydes and Ketones 237

5.6.7 ¿-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...