Arrow-Pushing in Organic Chemistry

DANIEL E. LEVY, PhD, is the owner of DEL BioPharma LLC, USA. He previously worked at Glycomed, COR Therapeutics, Scios, and Intradigm. Dr. Levy developed, with Dr. Péter Fügedi, short courses entitled "Modern Synthetic Carbohydrate Chemistry" and "The Organic Chemistry of Sugars." He has three books to his credit, including the rst edition of Arrow-Pushing in Organic Chemistry (Wiley, 2008). He received his bachelors in chemistry from the University of California– Berkeley and his doctorate in organic chemistry from the Massachusetts Institute of Technology.

PREFACE xi

ACKNOWLEDGEMENTS xiii

ABOUT THE AUTHOR xv

1. Introduction 1

1.1 Definition of Arrow-Pushing 1

1.2 Functional Groups 5

1.3 Nucleophiles and Leaving Groups 7

1.4 Summary 8

Problems 9

2. Free Radicals 19

2.1 What Are Free Radicals? 19

2.2 How Are Free Radicals Formed? 21

2.2.1 Free Radical Initiators 22

2.2.2 Electron Transfer 23

2.3 Free Radical Stability 23

2.4 What Types of Reactions Involve Free Radicals? 25

2.4.1 Halogenation Reactions 26

2.4.2 Polymerization Reactions 28

2.4.3 Oxidation Reactions 30

2.5 Summary 31

Problems 32

3. Acids 37

3.1 What Are Acids? 37

3.2 What Is Resonance? 38

3.3 How Is Acidity Measured? 41

3.4 Relative Acidities 42

3.5 Inductive Effects 47

3.6 Inductive Effects and Relative Acidities 49

3.7 Relative Acidities of Hydrocarbons 50

3.8 Summary 51

Problems 52

4. Bases and Nucleophiles 61

4.1 What Are Bases? 61

4.2 What Are Nucleophiles? 66

4.3 Leaving Groups 70

4.4 Summary 70

Problems 71

5. SN2 Substitution Reactions 81

5.1 What Is An SN2 Reaction? 81

5.2 What Are Leaving Groups? 83

5.3 Where Can SN2 Reactions Occur? 84

5.4 SN2′ Reactions 85

5.5 Summary 88

Problems 89

6. SN1 Substitution Reactions 97

6.1 What Is An SN1 Reaction? 97

6.2 How Are SN1 Reactions Initiated? 98

6.3 The Carbocation 99

6.3.1 Molecular Structure and Orbitals 100

6.3.2 Stability of Carbocations 103

6.4 Carbocation Rearrangements 105

6.4.1 1,2-Hydride Shifts 105

6.4.2 1,2-Alkyl Shifts 106

6.4.3 Preventing Side Reactions 109

6.5 Summary 109

Problems 110

7. Elimination Reactions 115

7.1 E1 Eliminations 115

7.2 E1cB Eliminations 118

7.3 E2 Eliminations 120

7.4 How Do Elimination Reactions Work? 121

7.5 E1cB Eliminations Versus E2 Eliminations 124

7.6 Summary 124

Problems 126

8. Addition Reactions 133

8.1 Addition of Halogens to Double Bonds 133

8.2 Markovnikov’s Rule 135

8.3 Additions to Carbonyls 137

8.3.1 1,2-Additions 137

8.3.2 1,4-Additions 138

8.3.3 Addition–Elimination Reactions 141

8.4 Summary 143

Problems 144

9. Carbenes 153

9.1 What Are Carbenes? 153

9.2 How Are Carbenes Formed? 154

9.3 Reactions with Carbenes 156

9.3.1 Carbene Dimerization 156

9.3.2 Cyclopropanation Reactions 157

9.3.3 O-H Insertion Reactions 161

9.4 Carbenes Versus Carbenoids 162

9.5 Summary 163

Problems 164

10. Pericyclic Reactions 171

10.1 What Are Pericyclic Reactions? 171

10.2 Electrocyclic Reactions 172

10.3 Cycloaddition Reactions 175

10.3.1 The Diels–Alder Reaction 175

10.3.2 The Ene Reaction 178

10.3.3 Dipolar Cycloaddition Reactions 180

10.4 Sigmatropic Reactions 182

10.4.1 The Cope Rearrangement 183

10.4.2 The Claisen Rearrangement 184

10.5 Summary 187

Problems 189

11. Moving Forward 195

11.1 Functional Group Manipulations 195

11.2 Name Reactions 196

11.3 Reagents 208

11.4 Final Comments 208

Problems 209

Appendix 1. pKa Values of Protons Associated with Common Functional Groups 219

Appendix 2. Answers and Explanations to Problems 223

Chapter 1 Solutions 224

Chapter 2 Solutions 234

Chapter 3 Solutions 241

Chapter 4 Solutions 258

Chapter 5 Solutions 270

Chapter 6 Solutions 285

Chapter 7 Solutions 293

Chapter 8 Solutions 303

Chapter 9 Solutions 318

Chapter 10 Solutions 334

Chapter 11 Solutions 347

Appendix 3. Student Reaction Glossary 369

Index 373

Periodic Table of Elements 401