CONTENTS ix 4 Stereochemistry 147 4.1 Preview 148 4.2 Chirality 149 4.3 The (R/S)Convention 152 4.4 Properties of Enantiomers:Physical Differences 155 4.5 The Physical Basis of Optical Activity 157 4.6 Properties of Enantiomers:Chemical Differences 159 4.7 Interconversion of Enantiomers by Rotation about a Single Bond: gauche-Butane 163 4.8 Diastereomers and Molecules Containing More than One Stereogenic Atom 164 4.9 Physical Properties of Diastereomers:Resolution,a Method of Separating Enantiomers from Each Other 169 4.10 Determination of Absolute Configuration(R or S)172 4.11 Stereochemical Analysis of Ring Compounds(a Beginning)173 4.12 Summary of Isomerism 176 4.13 Special Topic:Chirality without"Four Different Groups Attached to One Carbon”177 4.14 Special Topic:Stereochemistry in the Real World:Thalidomide,the Consequences of Being Wrong-Handed 180 4.15 Summary 181 4.16 Additional Problems 182 5 Rings 185 5.1 Preview 186 5.2 Rings and Strain 187 5.3 Quantitative Evaluation of Strain Energy 193 5.4 Stereochemistry of Cyclohexane:Conformational Analysis 197 5.5 Monosubstituted Cyclohexanes 199 5.6 Disubstituted Ring Compounds 204 5.7 Bicyclic Compounds 211 5.8 Special Topic:Polycyclic Systems 216 5.9 Special Topic:Adamantanes in Materials and Biology 217 5.10 Summary 219 5.11 Additional Problems 220
4 Stereochemistry 147 4.1 Preview 148 4.2 Chirality 149 4.3 The (R/S) Convention 152 4.4 Properties of Enantiomers: Physical Differences 155 4.5 The Physical Basis of Optical Activity 157 4.6 Properties of Enantiomers: Chemical Differences 159 4.7 Interconversion of Enantiomers by Rotation about a Single Bond: gauche-Butane 163 4.8 Diastereomers and Molecules Containing More than One Stereogenic Atom 164 4.9 Physical Properties of Diastereomers: Resolution, a Method of Separating Enantiomers from Each Other 169 4.10 Determination of Absolute Configuration (R or S) 172 4.11 Stereochemical Analysis of Ring Compounds (a Beginning) 173 4.12 Summary of Isomerism 176 4.13 Special Topic: Chirality without “Four Different Groups Attached to One Carbon” 177 4.14 Special Topic: Stereochemistry in the Real World: Thalidomide, the Consequences of Being Wrong-Handed 180 4.15 Summary 181 4.16 Additional Problems 182 5 Rings 185 5.1 Preview 186 5.2 Rings and Strain 187 5.3 Quantitative Evaluation of Strain Energy 193 5.4 Stereochemistry of Cyclohexane: Conformational Analysis 197 5.5 Monosubstituted Cyclohexanes 199 5.6 Disubstituted Ring Compounds 204 5.7 Bicyclic Compounds 211 5.8 Special Topic: Polycyclic Systems 216 5.9 Special Topic: Adamantanes in Materials and Biology 217 5.10 Summary 219 5.11 Additional Problems 220 CONTENTS ix
CONTENTS 6 Alkyl Halides,Alcohols,Amines,Ethers, and Their Sulfur-Containing Relatives 223 6.1 Preview 224 6.2 Alkyl Halides:Nomenclature and Structure 225 6.3 Alkyl Halides as Sources of Organometallic Reagents: A Synthesis of Hydrocarbons 227 6.4 Alcohols 230 6.5 Solvents in Organic Chemistry 238 6.6 Diols(Glycols)240 6.7 Amines 240 6.8 Ethers 249 6.9 Special Topic:Thiols(Mercaptans)and Thioethers(Sulfides)251 6.10 Special Topic:Crown Ethers 254 6.11 Special Topic:Complex Nitrogen-Containing Biomolecules-Alkaloids 255 6.12 Summary 256 6.13 Additional Problems 258 7 Substitution and Elimination Reactions: The SN2,SNI,El,and E2 Reactions 261 7.1 Preview 262 7.2 Review of Lewis Acids and Bases 263 7.3 Reactions of Alkyl Halides:The Substitution Reaction 267 7.4 Substitution,Nucleophilic,Bimolecular:The SN2 Reaction 268 7.5 The SN2 Reaction in Biochemistry 288 7.6 Substitution,Nucleophilic,Unimolecular:The SN1 Reaction 289 7.7 Summary and Overview of the SN2 and SN1 Reactions 296 7.8 The Unimolecular Elimination Reaction:E1 298 7.9 The Bimolecular Elimination Reaction:E2 301 7.10 What Can We Do with These Reactions? How to Do Organic Synthesis 312 7.11 Summary 320 7.12 Additional Problems 323 8 Equilibria 331 8.1 Preview 332 8.2 Equilibrium 334
6 Alkyl Halides, Alcohols, Amines, Ethers, and Their Sulfur-Containing Relatives 223 6.1 Preview 224 6.2 Alkyl Halides: Nomenclature and Structure 225 6.3 Alkyl Halides as Sources of Organometallic Reagents: A Synthesis of Hydrocarbons 227 6.4 Alcohols 230 6.5 Solvents in Organic Chemistry 238 6.6 Diols (Glycols) 240 6.7 Amines 240 6.8 Ethers 249 6.9 Special Topic: Thiols (Mercaptans) and Thioethers (Sulfides) 251 6.10 Special Topic: Crown Ethers 254 6.11 Special Topic: Complex Nitrogen-Containing Biomolecules—Alkaloids 255 6.12 Summary 256 6.13 Additional Problems 258 7 Substitution and Elimination Reactions: The SN2, SN1, E1, and E2 Reactions 261 7.1 Preview 262 7.2 Review of Lewis Acids and Bases 263 7.3 Reactions of Alkyl Halides: The Substitution Reaction 267 7.4 Substitution, Nucleophilic, Bimolecular: The SN2 Reaction 268 7.5 The SN2 Reaction in Biochemistry 288 7.6 Substitution, Nucleophilic, Unimolecular: The SN1 Reaction 289 7.7 Summary and Overview of the SN2 and SN1 Reactions 296 7.8 The Unimolecular Elimination Reaction: E1 298 7.9 The Bimolecular Elimination Reaction: E2 301 7.10 What Can We Do with These Reactions? How to Do Organic Synthesis 312 7.11 Summary 320 7.12 Additional Problems 323 8 Equilibria 331 8.1 Preview 332 8.2 Equilibrium 334 x CONTENTS
CONTENTS xi 8.3 Entropy in Organic Reactions 337 8.4 Rates of Chemical Reactions 339 8.5 Rate Constant 341 8.6 Energy Barriers in Chemical Reactions: The Transition State and Activation Energy 342 8.7 Reaction Mechanism 349 8.8 The Hammond Postulate:Thermodynamics versus Kinetics 351 8.9 Special Topic:Enzymes and Reaction Rates 357 8.10 Summary 358 8.11 Additional Problems 360 9 Additions to Alkenes 1 363 9.1 Preview 364 9.2 Mechanism of the Addition of Hydrogen Halides to Alkenes 365 9.3 Effects of Resonance on Regiochemistry 366 9.4 Brief Review of Resonance 372 9.5 Resonance and the Stability of Carbocations 374 9.6 Inductive Effects on Addition Reactions 378 9.7 HX Addition Reactions:Hydration 380 9.8 Dimerization and Polymerization of Alkenes 384 9.9 Rearrangements during HX Addition to Alkenes 386 9.10 Hydroboration 390 9.11 Hydroboration in Synthesis:Alcohol Formation 398 9.12 Special Topic:Rearrangements in Biological Processes 401 9.13 Summary 402 9.14 Additional Problems 404 10 Additions to Alkenes 2 and Additions to Alkynes 409 10.1 Preview 410 10.2 Addition of H2 and X2 Reagents 410 10.3 Hydration through Mercury Compounds:Oxymercuration 421 10.4 Other Addition Reactions Involving Three-Membered Rings:Oxiranes and Cyclopropanes 423 10.5 Dipolar Addition Reactions:Ozonolysis and the Synthesis of Carbonyl(R2C=O)Compounds 436 10.6 Addition Reactions of Alkynes:HX Addition 444 10.7 Addition of X2 Reagents to Alkynes 447
8.3 Entropy in Organic Reactions 337 8.4 Rates of Chemical Reactions 339 8.5 Rate Constant 341 8.6 Energy Barriers in Chemical Reactions: The Transition State and Activation Energy 342 8.7 Reaction Mechanism 349 8.8 The Hammond Postulate: Thermodynamics versus Kinetics 351 8.9 Special Topic: Enzymes and Reaction Rates 357 8.10 Summary 358 8.11 Additional Problems 360 9 Additions to Alkenes 1 363 9.1 Preview 364 9.2 Mechanism of the Addition of Hydrogen Halides to Alkenes 365 9.3 Effects of Resonance on Regiochemistry 366 9.4 Brief Review of Resonance 372 9.5 Resonance and the Stability of Carbocations 374 9.6 Inductive Effects on Addition Reactions 378 9.7 HX Addition Reactions: Hydration 380 9.8 Dimerization and Polymerization of Alkenes 384 9.9 Rearrangements during HX Addition to Alkenes 386 9.10 Hydroboration 390 9.11 Hydroboration in Synthesis: Alcohol Formation 398 9.12 Special Topic: Rearrangements in Biological Processes 401 9.13 Summary 402 9.14 Additional Problems 404 10 Additions to Alkenes 2 and Additions to Alkynes 409 10.1 Preview 410 10.2 Addition of H2 and X2 Reagents 410 10.3 Hydration through Mercury Compounds: Oxymercuration 421 10.4 Other Addition Reactions Involving Three-Membered Rings: Oxiranes and Cyclopropanes 423 10.5 Dipolar Addition Reactions: Ozonolysis and the Synthesis of Carbonyl (R2C O) Compounds 436 10.6 Addition Reactions of Alkynes: HX Addition 444 10.7 Addition of X2 Reagents to Alkynes 447 P CONTENTS xi
xii CONTENTS 10.8 Hydration of Alkynes 448 10.9 Hydroboration of Alkynes 450 10.10 Hydrogenation of Alkynes:Alkene Synthesis through syn Hydrogenation 452 10.11 Reduction by Sodium in Ammonia:Alkene Synthesis through anti Hydrogenation 452 10.12 Special Topic:Three-Membered Rings in Biochemistry 455 10.13 Summary 456 10.14 Additional Problems 460 11 Radical Reactions 467 11.1 Preview 468 11.2 Formation and Simple Reactions of Radicals 469 11.3 Structure and Stability of Radicals 477 11.4 Radical Addition to Alkenes 481 11.5 Other Radical Addition Reactions 487 11.6 Radical-Initiated Addition of HBr to Alkynes 489 11.7 Photohalogenation 490 11.8 Allylic Halogenation:Synthetically Useful Reactions 497 11.9 Special Topic:Rearrangements(and Nonrearrangements) of Radicals 501 11.10 Special Topic:Radicals in Our Bodies;Do Free Radicals Age Us?504 11.11 Summary 505 11.12 Additional Problems 507 12 Dienes and the Allyl System:2p Orbitals in Conjugation 511 12.1 Preview 512 12.2 Allenes 513 12.3 Related Systems:Ketenes and Cumulenes 515 12.4 Allenes as Intermediates in the Isomerization of Alkynes 516 12.5 Conjugated Dienes 519 12.6 The Physical Consequences of Conjugation 521 12.7 Molecular Orbitals and Ultraviolet Spectroscopy 525 12.8 Polyenes and Vision 533 12.9 The Chemical Consequences of Conjugation: Addition Reactions of Conjugated Dienes 534 12.10 Thermodynamic and Kinetic Control of Addition Reactions 537
10.8 Hydration of Alkynes 448 10.9 Hydroboration of Alkynes 450 10.10 Hydrogenation of Alkynes: Alkene Synthesis through syn Hydrogenation 452 10.11 Reduction by Sodium in Ammonia: Alkene Synthesis through anti Hydrogenation 452 10.12 Special Topic: Three-Membered Rings in Biochemistry 455 10.13 Summary 456 10.14 Additional Problems 460 11 Radical Reactions 467 11.1 Preview 468 11.2 Formation and Simple Reactions of Radicals 469 11.3 Structure and Stability of Radicals 477 11.4 Radical Addition to Alkenes 481 11.5 Other Radical Addition Reactions 487 11.6 Radical-Initiated Addition of HBr to Alkynes 489 11.7 Photohalogenation 490 11.8 Allylic Halogenation: Synthetically Useful Reactions 497 11.9 Special Topic: Rearrangements (and Nonrearrangements) of Radicals 501 11.10 Special Topic: Radicals in Our Bodies; Do Free Radicals Age Us? 504 11.11 Summary 505 11.12 Additional Problems 507 12 Dienes and the Allyl System: 2pOrbitals in Conjugation 511 12.1 Preview 512 12.2 Allenes 513 12.3 Related Systems: Ketenes and Cumulenes 515 12.4 Allenes as Intermediates in the Isomerization of Alkynes 516 12.5 Conjugated Dienes 519 12.6 The Physical Consequences of Conjugation 521 12.7 Molecular Orbitals and Ultraviolet Spectroscopy 525 12.8 Polyenes and Vision 533 12.9 The Chemical Consequences of Conjugation: Addition Reactions of Conjugated Dienes 534 12.10 Thermodynamic and Kinetic Control of Addition Reactions 537 xii CONTENTS
CONTENTS xili 12.11 The Allyl System:Three Overlapping 2 Orbitals 541 12.12 The Diels-Alder Reaction of Conjugated Dienes 544 12.13 Special Topic:Biosynthesis of Terpenes 554 12.14 Special Topic:Steroid Biosynthesis 559 12.15 Summary 563 12.16 Additional Problems 564 13 Conjugation and Aromaticity 57 13.1 Preview 572 13.2 The Structure of Benzene 573 13.3 A Resonance Picture of Benzene 575 13.4 The Molecular Orbital Picture of Benzene 578 13.5 Quantitative Evaluations of Resonance Stabilization in Benzene 580 13.6 A Generalization of Aromaticity:Huickel's 4n+2 Rule 582 13.7 Substituted Benzenes 595 13.8 Physical Properties of Substituted Benzenes 598 13.9 Heterobenzenes and Other Heterocyclic Aromatic Compounds 598 13.10 Polynuclear Aromatic Compounds 602 13.11 Introduction to the Chemistry of Benzene 606 13.12 The Benzyl Group and Its Reactivity 610 13.13 Special Topic:The Bio-Downside,the Mechanism of Carcinogenesis by Polycyclic Aromatic Compounds 614 13.14 Summary 617 13.15 Additional Problems 619 14 Substitution Reactions of Aromatic Compounds 623 14.1 Preview 624 14.2 Hydrogenation of Aromatic Compounds 626 14.3 Diels-Alder Reactions 628 14.4 Substitution Reactions of Aromatic Compounds 631 14.5 Carbon-Carbon Bond Formation:Friedel-Crafts Alkylation 639 14.6 Friedel-Crafts Acylation 643 14.7 Synthetic Reactions We Can Do So Far 646 14.8 Electrophilic Aromatic Substitution of Heteroaromatic Compounds 652 14.9 Disubstituted Benzenes:Ortho,Meta,and Para Substitution 655 14.10 Inductive Effects in Aromatic Substitution 666
12.11 The Allyl System: Three Overlapping 2p Orbitals 541 12.12 The Diels–Alder Reaction of Conjugated Dienes 544 12.13 Special Topic: Biosynthesis of Terpenes 554 12.14 Special Topic: Steroid Biosynthesis 559 12.15 Summary 563 12.16 Additional Problems 564 13 Conjugation and Aromaticity 571 13.1 Preview 572 13.2 The Structure of Benzene 573 13.3 A Resonance Picture of Benzene 575 13.4 The Molecular Orbital Picture of Benzene 578 13.5 Quantitative Evaluations of Resonance Stabilization in Benzene 580 13.6 A Generalization of Aromaticity: Hückel’s 4n + 2 Rule 582 13.7 Substituted Benzenes 595 13.8 Physical Properties of Substituted Benzenes 598 13.9 Heterobenzenes and Other Heterocyclic Aromatic Compounds 598 13.10 Polynuclear Aromatic Compounds 602 13.11 Introduction to the Chemistry of Benzene 606 13.12 The Benzyl Group and Its Reactivity 610 13.13 Special Topic: The Bio-Downside, the Mechanism of Carcinogenesis by Polycyclic Aromatic Compounds 614 13.14 Summary 617 13.15 Additional Problems 619 14 Substitution Reactions of Aromatic Compounds 623 14.1 Preview 624 14.2 Hydrogenation of Aromatic Compounds 626 14.3 Diels–Alder Reactions 628 14.4 Substitution Reactions of Aromatic Compounds 631 14.5 Carbon–Carbon Bond Formation: Friedel–Crafts Alkylation 639 14.6 Friedel–Crafts Acylation 643 14.7 Synthetic Reactions We Can Do So Far 646 14.8 Electrophilic Aromatic Substitution of Heteroaromatic Compounds 652 14.9 Disubstituted Benzenes: Ortho, Meta, and Para Substitution 655 14.10 Inductive Effects in Aromatic Substitution 666 CONTENTS xiii