Organic Mechanisms: Reactions, Methodology, and Biological Applications

Instills a deeper understanding of how and why organicreactions happen

Integrating reaction mechanisms, synthetic methodology, andbiological applications, Organic Mechanisms gives organicchemists the tools needed to perform seamless organic reactions. Byexplaining the underlying mechanisms of organic reactions, authorXiaoping Sun makes it possible for readers to gain a deeperunderstanding of not only chemical phenomena, but also the abilityto develop new synthetic methods. Moreover, by emphasizingbiological applications, this book enables readers to master bothadvanced organic chemistry theory and practice.

Organic Mechanisms consists of ten chapters, beginningwith a review of fundamental physicochemical principles that areessential for understanding the nature of organic mechanisms. Eachone of the remaining chapters is devoted to a major class oforganic reactions, including:

Aliphatic C H bond functionalization Functionalization of the alkene C=C bond by cycloadditionreactions Nucleophilic substitutions on sp3–hybridized carbons Nucleophilic additions and substitutions on carbonylgroups Reactivity of the –hydrogen to carbonyl groups Rearrangements

A brief review of basic organic chemistry begins each chapter,helping readers move from fundamental concepts to an advancedunderstanding of reaction mechanisms. Key mechanisms areillustrated by expertly drawn figures highlighting microscopicdetails. End–of–chapter problems enable readers to put theirnewfound knowledge into practice by solving key problems in organicreactions with the use of mechanistic studies, and a SolutionsManual is available online for course instructors.

Thoroughly referenced and current with recent findings inorganic reaction mechanisms, Organic Mechanisms isrecommended for upper–level undergraduates and graduate students inadvanced organic chemistry, as well as for practicing chemists whowant to further explore the mechanistic aspects of organicreactions.

Preface xiii

1 Fundamental Principles 1

1.1 Reaction Mechanisms and their Importance 1

1.2 Elementary (Concerted) and Stepwise Reactions 2

1.3 Molecularity 4

1.3.1 Unimolecular Reactions 4

1.3.2 Bimolecular Reactions 4

1.4 Kinetics 5

1.4.1 Rate Laws for Elementary (Concerted) Reactions 5

1.4.2 Reactive Intermediates and the Steady–State Assumption9

1.4.3 Rate Laws for Stepwise Reactions 12

1.5 Thermodynamics 13

1.5.1 Enthalpy, Entropy, and Free Energy 13

1.5.2 Reversible and Irreversible Reactions 14

1.5.3 Chemical Equilibrium 15

1.6 The Transition State 17

1.7 The Molecular Orbital Theory 19

1.7.1 Formation of Molecular Orbitals from Atomic Orbitals19

1.7.2 Molecular Orbital Diagrams 25

1.7.3 Resonance Stabilization 25

1.7.4 Frontier Molecular Orbitals 28

1.8 Electrophiles/Nucleophiles versus Acids/Bases 29

1.8.1 Common Electrophiles 29

1.8.2 Common Nucleophiles 33

1.9 Isotope Labeling 35

Problems 38

References 40

2 The Aliphatic C H Bond Functionalization 41

2.1 Alkyl Radicals: Bonding and their Relative Stability 42

2.2 Radical Halogenations of the C H Bonds on sp3–HybridizedCarbons: Mechanism and Nature of the Transition States 47

2.3 Energetics of the Radical Halogenations of Alkanes and theirRegioselectivity 51

2.3.1 Energy Profiles for Radical Halogenation Reactions ofAlkanes 51

2.3.2 Regioselectivity for Radical Halogenation Reactions 52

2.4 Kinetics of Radical Halogenations of Alkanes 56

2.5 Radical Initiators 61

2.6 Transition–Metal–Compounds–Catalyzed Alkane C H BondActivation and Functionalization 64

2.6.1 The C H Bond Activation via Agostic Bond 64

2.6.2 Mechanisms for the C H Bond Oxidative Functionalization65

2.7 Superacids–Catalyzed Alkane C H Bond Activation andFunctionalization 68

2.8 Nitration of Aliphatic C H Bonds via the Nitronium NO2 + Ion69

2.9 Enzyme–Catalyzed Alkane C H Bond Activation andFunctionalization: Biochemical Methods 71

Problems 75

References 77

3 Functionalization of the Alkene C C Bond by ElectrophilicAdditions 78

3.1 Markovnikov Additions via Intermediate Carbocations 79

3.1.1 Additions of Alkenes to Hydrogen Halides (HCl, HBr, andHI): Mechanism, Regiochemistry, and Stereochemistry 79

3.1.2 Acid– and Transition–Metal–Catalyzed Hydration of Alkenesand Its Applications 84

3.1.3 Acid–Catalyzed Additions of Alcohols to Alkenes 89

3.1.4 Special Electrophilic Additions of the Alkene C C Bond:Mechanistic and Synthetic Aspects 89

3.1.5 Electrophilic Addition to the C C Triple Bond via a VinylCation Intermediate 94

3.2 Electrophilic Addition of Hydrogen Halides to ConjugatedDienes 95

3.3 Non–Markovnikov Radical Addition 96

3.4 Hydroboration: Concerted, Non–Markovnikov syn–Addition97

3.4.1 Diborane (B2H6): Structure and Properties 97

3.4.2 Concerted, Non–Markovnikov syn–Addition of Borane (BH3) tothe Alkene C C Bond: Mechanism, Regiochemistry, and Stereochemistry98

3.4.3 Synthesis of Special Hydroborating Reagents 102

3.4.4 Reactions of Alkenes with Special Hydroborating Reagents:Regiochemistry, Stereochemistry, and their Applications in ChemicalSynthesis 103

3.5 Transition–Metal–Catalyzed Hydrogenation of the Alkene C CBond (syn–Addition) 107

3.5.1 Mechanism and Stereochemistry 107

3.5.2 Synthetic Applications 110

3.5.3 Biochemically–Related Applications: Hydrogenated Fats(Oils) 111

3.6 Halogenation of the Alkene C C Bond (Anti–Addition):Mechanism and Its Stereochemistry 113

Problems 117

References 120

4 Functionalization of the Alkene C C Bond by CycloadditionReactions 121

4.1 Cycloadditions of the Alkene C C Bond to Form Three–MemberedRings 122

4.1.1 Epoxidation 122

4.1.2 Cycloadditions via Carbenes and Related Species 124

4.2 Cycloadditions to Form Four–Membered Rings 128

4.3 Diels Alder Cycloadditions of the Alkene C C Bond toForm Six–Membered Rings 131

4.3.1 Frontier Molecular Orbital Interactions 132

4.3.2 Substituent Effects 135

4.3.3 Other Diels Alder Reactions 138

4.4 1,3–Dipolar Cycloadditions of the C C and other MultipleBonds to Form Five–Membered Rings 142

4.4.1 Oxidation of Alkenes by Ozone (O3) and Osmium Tetraoxide(OsO4) via Cycloadditions 142

4.4.2 Cycloadditions of Nitrogen–Containing 1,3–Dipoles toAlkenes 145

4.4.3 Cycloadditions of Alkenes, Alkynes, and Nitriles to theDithionitronium (NS2+) Ion: Making CNS–Containing AromaticHeterocycles 147

4.5 Pericyclic Reactions 154

Problems 158

References 161

5 The Aromatic C H Bond Functionalization and RelatedReactions 162

5.1 Aromatic Nitration: All Reaction Intermediates and FullMechanism for the Aromatic C H Bond Substitution by Nitronium (NO2+) and Related Electrophiles 163

5.1.1 Charge–Transfer Complex [ArH, NO2+] between Arene andNitronium 164

5.1.2 Ion–Radical Pair [ArH+ , NO2] 164

5.1.3 Arenium [Ar(H)NO2]+ Ion 165

5.1.4 Full Mechanism for Aromatic Nitration 166

5.2 Mechanisms and Synthetic Utility for Aromatic C H BondSubstitutions by Other Related Electrophiles 167

5.3 The Electrophilic Aromatic C H Bond Substitution Reactionsvia SN1 and SN2 Mechanisms 174

5.3.1 Reactions Involving SN1 Steps 175

5.3.2 Reactions Involving SN2 Steps 179

5.4 Substituent Effects on the Electrophilic AromaticSubstitution Reactions 181

5.4.1 Ortho– and Para–Directors 183

5.4.2 Meta–Directors 185

5.5 Isomerizations Effected by the Electrophilic AromaticSubstitution Reactions 187

5.6 Electrophilic Substitution Reactions on the AromaticCarbon Metal Bonds: Mechanisms and Synthetic Applications191

5.7 Nucleophilic Aromatic Substitution via a Benzyne (aryne)Intermediate: Functional Group Transformations on Aromatic Rings193

5.8 Nucleophilic Aromatic Substitution via an AnionicMeisenheimer Complex 197

5.9 Biological Applications of Functionalized Aromatic Compounds200

Problems 204

References 207

6 Nucleophilic Substitutions on sp3–Hybridized Carbons:Functional Group Transformations 209

6.1 Nucleophilic Substitution on Mono–Functionalizedsp3–Hybridized Carbon 209

6.2 Functional Groups which are Good and Poor Leaving Groups211

6.3 Good and Poor Nucleophiles 213

6.4 SN2 Reactions: Kinetics, Mechanism, and Stereochemistry215

6.4.1 Mechanism and Stereochemistry for SN2 Reactions 215

6.4.2 Steric Effect on SN2 Reactions 218

6.4.3 Effect of Nucleophiles 220

6.4.4 Solvent Effect 222

6.4.5 Effect of Unsaturated Groups Attached to theFunctionalized Electrophilic Carbon 224

6.5 Analysis of the SN2 Mechanism Using Symmetry Rules andMolecular Orbital Theory 225

6.5.1 The SN2 Reactions of Methyl and Primary Haloalkanes RCH2X(X = Cl, Br, or I; R = H or an Alkyl Group) 225

6.5.2 Reactivity of Dichloromethane CH2Cl2 228

6.6 SN1 Reactions: Kinetics, Mechanism, and Product Development229

6.6.1 The SN1 Mechanism and Rate Law 229

6.6.2 Solvent Effect 231

6.6.3 Effects of Carbocation Stability and Quality of LeavingGroup on the SN1 Rates 231

6.6.4 Product Development for SN1 Reactions 235

6.7 Competition between SN1 and SN2 Reactions 237

6.8 Some Useful SN1 and SN2 Reactions: Mechanisms and SyntheticPerspectives 241

6.8.1 Nucleophilic Substitution Reactions Effected by CarbonNucleophiles 241

6.8.2 Synthesis of Primary Amines 246

6.8.3 Synthetic Utility of Triphenylphosphine: A StrongPhosphorus Nucleophile 247

6.8.4 Neighboring Group–Assisted SN1 Reactions 247

6.9 Biological Applications of Nucleophilic SubstitutionReactions 251

6.9.1 Biomedical Applications 251

6.9.2 Biosynthesis Involving Nucleophilic Substitution Reactions253

6.9.3 An Enzyme–Catalyzed Nucleophilic Substitution of aHaloalkane 255

Problems 256

References 259

7 Eliminations 260

7.1 E2 Elimination: Bimolecular –Elimination of H/LG and ItsRegiochemistry and Stereochemistry 261

7.1.1 Mechanism and Regiochemistry 261

7.1.2 E2 Eliminations of Functionalized Cycloalkanes 264

7.1.3 Stereochemistry 267

7.2 Analysis of the E2 Mechanism Using Symmetry Rules andMolecular Orbital Theory 268

7.3 Basicity versus Nucleophilicity for Various Anions 271

7.4 Competition of E2 and SN2 Reactions 274

7.5 E1 Elimination: Stepwise –Elimination of H/LG via anIntermediate Carbocation and Its Rate Law 276

7.5.1 Mechanism and Rate Law 276

7.5.2 E1 Dehydration of Alcohols 278

7.5.3 E1 Elimination of Functionalized Alkanes 281

7.6 Special –Elimination Reactions 283

7.7 Elimination of LG1/LG2 in the Compounds that Contain TwoFunctional Groups 286

7.8 –Elimination Giving a Carbene: A Mechanistic Analysis UsingSymmetry Rules and Molecular Orbital Theory 288

7.9 E1cb Elimination and its Biological Applications 288

7.9.1 The E1cb Mechanism 288

7.9.2 Biological Applications 291

Problems 294

References 297

8 Nucleophilic Additions and Substitutions on Carbonyl Groups298

8.1 Nucleophilic Additions and Substitutions of CarbonylCompounds 298

8.2 Nucleophilic Additions of Aldehydes and Ketones and theirBiological Applications 301

8.2.1 Acid– and Base–Catalyzed Hydration of Aldehydes andKetones 301

8.2.2 Acid–Catalyzed Nucleophilic Additions of Aldehydes andKetones to Alcohols 303

8.2.3 Biological Applications: Cyclic Structures ofCarbohydrates 307

8.2.4 Addition of Sulfur Nucleophile to Aldehydes 311

8.2.5 Nucleophilic Addition of Amines to Ketones and Aldehydes311

8.2.6 Nucleophilic Additions of Aldehydes and Ketones to HydrideDonors: Organic Reductions 315

8.3 Biological Hydride Donors NAD(P)H and FADH2 316

8.4 Activation of Carboxylic Acids via NucleophilicSubstitutions on the Carbonyl Carbons 320

8.4.1 Reactions of Carboxylic Acids with Thionyl Chloride320

8.4.2 Esterification Reactions and Synthetic Applications321

8.4.3 Formation of Anhydrides 325

8.4.4 Nucleophilic Addition to Alkyllithium 326

8.5 Nucleophilic Substitutions of Acyl Derivatives and theirBiological Applications 327

8.5.1 Nucleophilic Substitutions of Acyl Chlorides andAnhydrides 327

8.5.2 Hydrolysis and Other Nucleophilic Substitutions of Esters329

8.5.3 Biodiesel Synthesis and Reaction Mechanism 331

8.5.4 Biological Applications 332

8.6 Reduction of Acyl Derivatives by Hydride Donors 335

8.7 Kinetics of the Nucleophilic Addition and Substitution ofAcyl Derivatives 337

Problems 340

References 342

9 Reactivity of the –Hydrogen to Carbonyl Groups 344

9.1 Formation of Enolates and their Nucleophilicity 344

9.1.1 Formation of Enolates 344

9.1.2 Molecular Orbitals and Nucleophilicity of Enolates 348

9.2 Alkylation of Carbonyl Compounds (Aldehydes, Ketones, andEsters) via Enolates and Hydrazones 349

9.2.1 Alkylation via Enolates 349

9.2.2 Alkylation via Hydrazones and Enamines 351

9.3 Aldol Reactions 354

9.3.1 Mechanism and Synthetic Utility 354

9.3.2 Stereoselectivity 361

9.3.3 Other Synthetic Applications 364

9.4 Acylation Reactions of Esters via Enolates: Mechanism andSynthetic Utility 367

9.5 Roles of Enolates in Metabolic Processes in Living Organisms373

Problems 376

References 378

10 Rearrangements 380

10.1 Major Types of Rearrangements 380

10.2 Rearrangement of Carbocations: 1,2–Shift 381

10.2.1 1,2–Shifts in Carbocations Produced from AcyclicMolecules 382

10.2.2 1,2–Shifts in Carbocations Produced from CyclicMolecules Ring Expansion 383

10.2.3 Resonance Stabilization of Carbocation PinacolRearrangement 385

10.2.4 In vivo Cascade Carbocation Rearrangements: BiologicalSignificance 387

10.2.5 Acid–Catalyzed 1,2–Shift in Epoxides 388

10.2.6 Anion–Initiated 1,2–Shift 389

10.3 Neighboring Leaving Group–Facilitated 1,2–Rearrangement390

10.3.1 Beckmann Rearrangement 391

10.3.2 Hofmann Rearrangement 393

10.3.3 Baeyer Villiger Oxidation (Rearrangement) 394

10.3.4 Acid–Catalyzed Rearrangement of Organic Peroxides 396

10.4 Carbene Rearrangement: 1,2–Rearrangement of HydrogenFacilitated by a Lone Pair of Electrons 399

10.5 Claisen Rearrangement 401

10.6 Photochemical Isomerization of Alkenes and its BiologicalApplications 403

10.6.1 Photochemical Isomerization 403

10.6.2 Biological Relevance 404

10.7 Rearrangement ofCarbon Nitrogen Sulfur–Containing Heterocycles 405

Problems 409

References 411

Index 413

XIAOPING SUN, PhD, is Professor of Chemistry at the University of Charleston. Dr. Sun has more than ten years of experience teaching advanced organic chemistry and biochemistry. His research focuses on studying the mechanisms of chemical reactions. Dr. Sun is the recipient of a research grant from the National Science Foundation.

"Summing Up: Recommended.  Highly recommended. Upper–division undergraduates and above."  (Choice, 1May 2014)