CONTENTS
xi
Preface xxv
INTRODUCTION 1
The Origins of Organic Chemistry 1
Berzelius, W?hler, and Vitalism 1
The Structural Theory 3
Electronic Theories of Structure and Reactivity 3
The Influence of Organic Chemistry 4
Computers and Organic Chemistry 4
Challenges and Opportunities 5
Where Did the Carbon Come From? 6
CHAPTER 1
CHEMICAL BONDING 7
1.1 Atoms, Electrons, and Orbitals 7
1.2 Ionic Bonds 11
1.3 Covalent Bonds 12
1.4 Double Bonds and Triple Bonds 14
1.5 Polar Covalent Bonds and Electronegativity 15
1.6 Formal Charge 16
1.7 Structural Formulas of Organic Molecules 19
1.8 Constitutional Isomers 22
1.9 Resonance 23
1.10 The Shapes of Some Simple Molecules 26
Learning By Modeling 27
1.11 Molecular Dipole Moments 30
1.12 Electron Waves and Chemical Bonds 31
1.13 Bonding in H
2
: The Valence Bond Model 32
1.14 Bonding in H
2
: The Molecular Orbital Model 34
1.15 Bonding in Methane and Orbital Hybridization 35
1.16 sp
3
Hybridization and Bonding in Ethane 37
1.17 sp
2
Hybridization and Bonding in Ethylene 38
1.18 sp Hybridization and Bonding in Acetylene 40
1.19 Which Theory of Chemical Bonding Is Best? 42
1.20 SUMMARY 43
PROBLEMS 47
CHAPTER 2
ALKANES 53
2.1 Classes of Hydrocarbons 53
2.2 Reactive Sites in Hydrocarbons 54
2.3 The Key Functional Groups 55
2.4 Introduction to Alkanes: Methane, Ethane, and Propane 56
2.5 Isomeric Alkanes: The Butanes 57
Methane and the Biosphere 58
xii CONTENTS
2.6 Higher n-Alkanes 59
2.7 The C
5
H
12
Isomers 59
2.8 IUPAC Nomenclature of Unbranched Alkanes 61
2.9 Applying the IUPAC Rules: The Names of the C
6
H
14
Isomers 62
A Brief History of Systematic Organic Nomenclature 63
2.10 Alkyl Groups 65
2.11 IUPAC Names of Highly Branched Alkanes 66
2.12 Cycloalkane Nomenclature 68
2.13 Sources of Alkanes and Cycloalkanes 69
2.14 Physical Properties of Alkanes and Cycloalkanes 71
2.15 Chemical Properties. Combustion of Alkanes 74
Thermochemistry 77
2.16 Oxidation–Reduction in Organic Chemistry 78
2.17 SUMMARY 80
PROBLEMS 83
CHAPTER 3
CONFORMATIONS OF ALKANES AND CYCLOALKANES 89
3.1 Conformational Analysis of Ethane 90
3.2 Conformational Analysis of Butane 94
Molecular Mechanics Applied to Alkanes and Cycloalkanes 96
3.3 Conformations of Higher Alkanes 97
3.4 The Shapes of Cycloalkanes: Planar or Nonplanar? 98
3.5 Conformations of Cyclohexane 99
3.6 Axial and Equatorial Bonds in Cyclohexane 100
3.7 Conformational Inversion (Ring Flipping) in Cyclohexane 103
3.8 Conformational Analysis of Monosubstituted Cyclohexanes 104
Enthalpy, Free Energy, and Equilibrium Constant 106
3.9 Small Rings: Cyclopropane and Cyclobutane 106
3.10 Cyclopentane 108
3.11 Medium and Large Rings 108
3.12 Disubstituted Cycloalkanes: Stereoisomers 108
3.13 Conformational Analysis of Disubstituted Cyclohexanes 110
3.14 Polycyclic Ring Systems 114
3.15 Heterocyclic Compounds 116
3.16 SUMMARY 117
PROBLEMS 120
CHAPTER 4
ALCOHOLS AND ALKYL HALIDES 126
4.1 IUPAC Nomenclature of Alkyl Halides 127
4.2 IUPAC Nomenclature of Alcohols 127
4.3 Classes of Alcohols and Alkyl Halides 128
4.4 Bonding in Alcohols and Alkyl Halides 129
4.5 Physical Properties of Alcohols and Alkyl Halides: Intermolecular Forces 130
4.6 Acids and Bases: General Principles 133
4.7 Acid–Base Reactions: A Mechanism for Proton Transfer 136
4.8 Preparation of Alkyl Halides from Alcohols and Hydrogen Halides 137
4.9 Mechanism of the Reaction of Alcohols with Hydrogen Halides 139
4.10 Structure, Bonding, and Stability of Carbocations 140
CONTENTS xiii
4.11 Potential Energy Diagrams for Multistep Reactions: The S
N
1
Mechanism 143
4.12 Effect of Alcohol Structure on Reaction Rate 145
4.13 Reaction of Primary Alcohols with Hydrogen Halides: The S
N
2
Mechanism 146
4.14 Other Methods for Converting Alcohols to Alkyl Halides 147
4.15 Halogenation of Alkanes 148
4.16 Chlorination of Methane 148
4.17 Structure and Stability of Free Radicals 149
4.18 Mechanism of Methane Chlorination 153
From Bond Energies to Heats of Reaction 155
4.19 Halogenation of Higher Alkanes 156
4.20 SUMMARY 159
PROBLEMS 163
CHAPTER 5
STRUCTURE AND PREPARATION OF ALKENES: ELIMINATION
REACTIONS 167
5.1 Alkene Nomenclature 167
Ethylene 168
5.2 Structure and Bonding in Alkenes 170
5.3 Isomerism in Alkenes 172
5.4 Naming Stereoisomeric Alkenes by the E–Z Notational System 173
5.5 Physical Properties of Alkenes 174
5.6 Relative Stabilities of Alkenes 176
5.7 Cycloalkenes 180
5.8 Preparation of Alkenes: Elimination Reactions 181
5.9 Dehydration of Alcohols 182
5.10 Regioselectivity in Alcohol Dehydration: The Zaitsev Rule 183
5.11 Stereoselectivity in Alcohol Dehydration 184
5.12 The Mechanism of Acid-Catalyzed Dehydration of Alcohols 185
5.13 Rearrangements in Alcohol Dehydration 187
5.14 Dehydrohalogenation of Alkyl Halides 190
5.15 Mechanism of the Dehydrohalogenation of Alkyl Halides: The E2
Mechanism 192
5.16 Anti Elimination in E2 Reactions: Stereoelectronic Effects 194
5.17 A Different Mechanism for Alkyl Halide Elimination: The E1
Mechanism 196
5.18 SUMMARY 198
PROBLEMS 202
CHAPTER 6
REACTIONS OF ALKENES: ADDITION REACTIONS 208
6.1 Hydrogenation of Alkenes 208
6.2 Heats of Hydrogenation 209
6.3 Stereochemistry of Alkene Hydrogenation 212
6.4 Electrophilic Addition of Hydrogen Halides to Alkenes 213
6.5 Regioselectivity of Hydrogen Halide Addition: Markovnikov’s Rule 214
6.6 Mechanistic Basis for Markovnikov’s Rule 216
Rules, Laws, Theories, and the Scientific Method 217
6.7 Carbocation Rearrangements in Hydrogen Halide Addition to Alkenes 219
6.8 Free-Radical Addition of Hydrogen Bromide to Alkenes 220
xiv CONTENTS
6.9 Addition of Sulfuric Acid to Alkenes 223
6.10 Acid-Catalyzed Hydration of Alkenes 225
6.11 Hydroboration–Oxidation of Alkenes 227
6.12 Stereochemistry of Hydroboration–Oxidation 229
6.13 Mechanism of Hydroboration–Oxidation 230
6.14 Addition of Halogens to Alkenes 233
6.15 Stereochemistry of Halogen Addition 233
6.16 Mechanism of Halogen Addition to Alkenes: Halonium Ions 234
6.17 Conversion of Alkenes to Vicinal Halohydrins 236
6.18 Epoxidation of Alkenes 238
6.19 Ozonolysis of Alkenes 240
6.20 Introduction to Organic Chemical Synthesis 243
6.21 Reactions of Alkenes with Alkenes: Polymerization 244
Ethylene and Propene: The Most Important Industrial
Organic Chemicals 248
6.22 SUMMARY 249
PROBLEMS 252
CHAPTER 7
STEREOCHEMISTRY 259
7.1 Molecular Chirality: Enantiomers 259
7.2 The Stereogenic Center 260
7.3 Symmetry in Achiral Structures 264
7.4 Properties of Chiral Molecules: Optical Activity 265
7.5 Absolute and Relative Configuration 267
7.6 The Cahn–Ingold–Prelog R–S Notational System 268
7.7 Fischer Projections 271
7.8 Physical Properties of Enantiomers 272
Chiral Drugs 273
7.9 Reactions That Create a Stereogenic Center 274
7.10 Chiral Molecules with Two Stereogenic Centers 276
7.11 Achiral Molecules with Two Stereogenic Centers 279
Chirality of Disubstituted Cyclohexanes 281
7.12 Molecules with Multiple Stereogenic Centers 282
7.13 Reactions That Produce Diastereomers 284
7.14 Resolution of Enantiomers 286
7.15 Stereoregular Polymers 288
7.16 Stereogenic Centers Other Than Carbon 290
7.17 SUMMARY 290
PROBLEMS 293
CHAPTER 8
NUCLEOPHILIC SUBSTITUTION 302
8.1 Functional Group Transformation by Nucleophilic Substitution 302
8.2 Relative Reactivity of Halide Leaving Groups 305
8.3 The S
N
2 Mechanism of Nucleophilic Substitution 306
8.4 Stereochemistry of S
N
2 Reactions 307
8.5 How S
N
2 Reactions Occur 308
8.6 Steric Effects in S
N
2 Reactions 310
8.7 Nucleophiles and Nucleophilicity 312
An Enzyme-Catalyzed Nucleophilic Substitution of an
Alkyl Halide 314
CONTENTS xv
8.8 The S
N
1 Mechanism of Nucleophilic Substitution 315
8.9 Carbocation Stability and S
N
1 Reaction Rates 315
8.10 Stereochemistry of S
N
1 Reactions 318
8.11 Carbocation Rearrangements in S
N
1 Reactions 319
8.12 Effect of Solvent on the Rate of Nucleophilic Substitution 320
8.13 Substitution and Elimination as Competing Reactions 323
8.14 Sulfonate Esters as Substrates in Nucleophilic Substitution 326
8.15 Looking Back: Reactions of Alcohols with Hydrogen Halides 329
8.16 SUMMARY 330
PROBLEMS 332
CHAPTER 9
ALKYNES 339
9.1 Sources of Alkynes 339
9.2 Nomenclature 340
9.3 Physical Properties of Alkynes 341
9.4 Structure and Bonding in Alkynes: sp Hybridization 341
Natural and “Designed” Enediyne Antibiotics 344
9.5 Acidity of Acetylene and Terminal Alkynes 344
9.6 Preparation of Alkynes by Alkylation of Acetylene and Terminal Alkynes
346
9.7 Preparation of Alkynes by Elimination Reactions 348
9.8 Reactions of Alkynes 350
9.9 Hydrogenation of Alkynes 350
9.10 Metal–Ammonia Reduction of Alkynes 351
9.11 Addition of Hydrogen Halides to Alkynes 352
9.12 Hydration of Alkynes 355
9.13 Addition of Halogens to Alkynes 356
9.14 Ozonolysis of Alkynes 357
9.15 SUMMARY 357
PROBLEMS 358
CHAPTER 10
CONJUGATION IN ALKADIENES AND ALLYLIC SYSTEMS 365
10.1 The Allyl Group 365
10.2 Allylic Carbocations 366
10.3 Allylic Free Radicals 370
10.4 Allylic Halogenation 370
10.5 Classes of Dienes 372
10.6 Relative Stabilities of Dienes 374
10.7 Bonding in Conjugated Dienes 375
10.8 Bonding in Allenes 377
10.9 Preparation of Dienes 378
10.10 Addition of Hydrogen Halides to Conjugated Dienes 379
10.11 Halogen Addition to Dienes 382
10.12 The Diels–Alder Reaction 382
Diene Polymers 383
10.13 The π Molecular Orbitals of Ethylene and 1,3-Butadiene 386
10.14 A π Molecular Orbital Analysis of the Diels–Alder Reaction 388
10.15 SUMMARY 390
PROBLEMS 393
xvi CONTENTS
CHAPTER 11
ARENES AND AROMATICITY 398
11.1 Benzene 399
11.2 Kekulé and the Structure of Benzene 399
Benzene, Dreams, and Creative Thinking 401
11.3 A Resonance Picture of Bonding in Benzene 402
11.4 The Stability of Benzene 403
11.5 An Orbital Hybridization View of Bonding in Benzene 405
11.6 The π Molecular Orbitals of Benzene 405
11.7 Substituted Derivatives of Benzene and Their Nomenclature 406
11.8 Polycyclic Aromatic Hydrocarbons 408
Carbon Clusters, Fullerenes, and Nanotubes 410
11.9 Physical Properties of Arenes 411
11.10 Reactions of Arenes: A Preview 411
11.11 The Birch Reduction 412
11.12 Free-Radical Halogenation of Alkylbenzenes 414
11.13 Oxidation of Alkylbenzenes 416
11.14 Nucleophilic Substitution in Benzylic Halides 417
11.15 Preparation of Alkenylbenzenes 419
11.16 Addition Reactions of Alkenylbenzenes 419
11.17 Polymerization of Styrene 421
11.18 Cyclobutadiene and Cyclooctatetraene 422
11.19 Hückel’s Rule: Annulenes 423
11.20 Aromatic Ions 426
11.21 Heterocyclic Aromatic Compounds 430
11.22 Heterocyclic Aromatic Compounds and Hückel’s Rule 432
11.23 SUMMARY 433
PROBLEMS 437
CHAPTER 12
REACTIONS OF ARENES: ELECTROPHILIC AROMATIC
SUBSTITUTION 443
12.1 Representative Electrophilic Aromatic Substitution Reactions of
Benzene 444
12.2 Mechanistic Principles of Electrophilic Aromatic Substitution 444
12.3 Nitration of Benzene 447
12.4 Sulfonation of Benzene 448
12.5 Halogenation of Benzene 448
12.6 Friedel–Crafts Alkylation of Benzene 450
12.7 Friedel–Crafts Acylation of Benzene 453
12.8 Synthesis of Alkylbenzenes by Acylation–Reduction 455
12.9 Rate and Regioselectivity in Electrophilic Aromatic Substitution 457
12.10 Rate and Regioselectivity in the Nitration of Toluene 458
12.11 Rate and Regioselectivity in the Nitration of (Trifluoromethyl)benzene 461
12.12 Substituent Effects in Electrophilic Aromatic Substitution: Activating
Substituents 463
12.13 Substituent Effects in Electrophilic Aromatic Substitution: Strongly
Deactivating Substituents 466
12.14 Substituent Effects in Electrophilic Aromatic Substitution: Halogens 469
12.15 Multiple Substituent Effects 470
12.16 Regioselective Synthesis of Disubstituted Aromatic Compounds 472
CONTENTS xvii
12.17 Substitution in Naphthalene 474
12.18 Substitution in Heterocyclic Aromatic Compounds 475
12.19 SUMMARY 477
PROBLEMS 480
CHAPTER 13
SPECTROSCOPY 487
13.1 Principles of Molecular Spectroscopy: Electromagnetic Radiation 488
13.2 Principles of Molecular Spectroscopy: Quantized Energy States 489
13.3 Introduction to
1
H NMR Spectroscopy 490
13.4 Nuclear Shielding and
1
H Chemical Shifts 493
13.5 Effects of Molecular Structure on
1
H Chemical Shifts 494
13.6 Interpreting Proton NMR Spectra 497
13.7 Spin–Spin Splitting in NMR Spectroscopy 500
13.8 Splitting Patterns: The Ethyl Group 503
13.9 Splitting Patterns: The Isopropyl Group 505
13.10 Splitting Patterns: Pairs of Doublets 505
13.11 Complex Splitting Patterns 507
13.12
1
H NMR Spectra of Alcohols 509
13.13 NMR and Conformations 510
13.14
13
C NMR Spectroscopy 510
13.15
13
C Chemical Shifts 512
13.16
13
C NMR and Peak Intensities 513
13.17
13
C—
1
H Coupling 515
13.18 Using DEPT to Count the Hydrogens Attached to
13
C 515
Magnetic Resonance Imaging 517
13.19 Infrared Spectroscopy 518
13.20 Ultraviolet-Visible (UV-VIS) Spectroscopy 522
13.21 Mass Spectrometry 526
Gas Chromatography, GC/MS, and MS/MS 530
13.22 Molecular Formula as a Clue to Structure 532
13.23 SUMMARY 533
PROBLEMS 536
CHAPTER 14
ORGANOMETALLIC COMPOUNDS 546
14.1 Organometallic Nomenclature 547
14.2 Carbon–Metal Bonds in Organometallic Compounds 547
14.3 Preparation of Organolithium Compounds 549
14.4 Preparation of Organomagnesium Compounds: Grignard Reagents 550
14.5 Organolithium and Organomagnesium Compounds as Br?nsted Bases 551
14.6 Synthesis of Alcohols Using Grignard Reagents 553
14.7 Synthesis of Alcohols Using Organolithium Reagents 554
14.8 Synthesis of Acetylenic Alcohols 556
14.9 Retrosynthetic Analysis 557
14.10 Preparation of Tertiary Alcohols from Esters and Grignard Reagents 560
14.11 Alkane Synthesis Using Organocopper Reagents 561
14.12 An Organozinc Reagent for Cyclopropane Synthesis 563
14.13 Carbenes and Carbenoids 565
14.14 Transition-Metal Organometallic Compounds 566
14.15 Ziegler–Natta Catalysis of Alkene Polymerization 567
xviii CONTENTS
An Organometallic Compound That Occurs Naturally:
Coenzyme B
12
568
14.16 SUMMARY 570
PROBLEMS 573
CHAPTER 15
ALCOHOLS, DIOLS, AND THIOLS 579
15.1 Sources of Alcohols 579
15.2 Preparation of Alcohols by Reduction of Aldehydes and Ketones 583
15.3 Preparation of Alcohols by Reduction of Carboxylic Acids and Esters 587
15.4 Preparation of Alcohols from Epoxides 587
15.5 Preparation of Diols 589
15.6 Reactions of Alcohols: A Review and a Preview 590
15.7 Conversion of Alcohols to Ethers 590
15.8 Esterification 593
15.9 Esters of Inorganic Acids 595
15.10 Oxidation of Alcohols 596
Economic and Environmental Factors in Organic Synthesis 598
15.11 Biological Oxidation of Alcohols 600
15.12 Oxidative Cleavage of Vicinal Diols 602
15.13 Preparation of Thiols 603
15.14 Properties of Thiols 604
15.15 Spectroscopic Analysis of Alcohols 605
15.16 SUMMARY 607
PROBLEMS 611
CHAPTER 16
ETHERS, EPOXIDES, AND SULFIDES 619
16.1 Nomenclature of Ethers, Epoxides, and Sulfides 619
16.2 Structure and Bonding in Ethers and Epoxides 621
16.3 Physical Properties of Ethers 622
16.4 Crown Ethers 622
Polyether Antibiotics 624
16.5 Preparation of Ethers 625
16.6 The Williamson Ether Synthesis 626
16.7 Reactions of Ethers: A Review and a Preview 627
16.8 Acid-Catalyzed Cleavage of Ethers 628
16.9 Preparation of Epoxides: A Review and a Preview 630
16.10 Conversion of Vicinal Halohydrins to Epoxides 630
16.11 Reactions of Epoxides: A Review and a Preview 632
16.12 Nucleophilic Ring-Opening Reactions of Epoxides 633
16.13 Acid-Catalyzed Ring-Opening Reactions of Epoxides 635
16.14 Epoxides in Biological Processes 637
16.15 Preparation of Sulfides 638
16.16 Oxidation of Sulfides: Sulfoxides and Sulfones 639
16.17 Alkylation of Sulfides: Sulfonium Salts 640
16.18 Spectroscopic Analysis of Ethers 641
16.19 SUMMARY 643
PROBLEMS 647
CONTENTS xix
CHAPTER 17
ALDEHYDES AND KETONES: NUCLEOPHILIC ADDITION TO THE CARBONYL
GROUP 654
17.1 Nomenclature 654
17.2 Structure and Bonding: The Carbonyl Group 657
17.3 Physical Properties 658
17.4 Sources of Aldehydes and Ketones 659
17.5 Reactions of Aldehydes and Ketones: A Review and a Preview 661
17.6 Principles of Nucleophilic Addition: Hydration of Aldehydes and
Ketones 663
17.7 Cyanohydrin Formation 667
17.8 Acetal Formation 668
17.9 Acetals as Protecting Groups 671
17.10 Reaction with Primary Amines: Imines 672
17.11 Reaction with Secondary Amines: Enamines 674
Imines in Biological Chemistry 675
17.12 The Wittig Reaction 677
17.13 Planning an Alkene Synthesis via the Wittig Reaction 678
17.14 Stereoselective Addition to Carbonyl Groups 681
17.15 Oxidation of Aldehydes 682
17.16 Baeyer–Villiger Oxidation of Ketones 683
17.17 Spectroscopic Analysis of Aldehydes and Ketones 684
17.18 SUMMARY 688
PROBLEMS 691
CHAPTER 18
ENOLS AND ENOLATES 701
18.1 The H9251-Carbon Atom and Its Hydrogens 702
18.2 H9251 Halogenation of Aldehydes and Ketones 703
18.3 Mechanism of H9251 Halogenation of Aldehydes and Ketones 703
18.4 Enolization and Enol Content 705
18.5 Stabilized Enols 707
18.6 Base-Catalyzed Enolization: Enolate Anions 708
18.7 The Haloform Reaction 711
The Haloform Reaction and the Biosynthesis of Trihalomethanes 713
18.8 Some Chemical and Stereochemical Consequences of Enolization 713
18.9 The Aldol Condensation 715
18.10 Mixed Aldol Condensations 719
18.11 Effects of Conjugation in H9251,H9252-Unsaturated Aldehydes and Ketones 720
18.12 Conjugate Addition to H9251,H9252-Unsaturated Carbonyl Compounds 722
18.13 Additions of Carbanions to H9251,H9252-Unsaturated Ketones: The Michael
Reaction 724
18.14 Conjugate Addition of Organocopper Reagents to H9251,H9252-Unsaturated Carbonyl
Compounds 724
18.15 Alkylation of Enolate Anions 725
18.16 SUMMARY 726
PROBLEMS 726
xx CONTENTS
CHAPTER 19
CARBOXYLIC ACIDS 736
19.1 Carboxylic Acid Nomenclature 737
19.2 Structure and Bonding 738
19.3 Physical Properties 739
19.4 Acidity of Carboxylic Acids 740
19.5 Salts of Carboxylic Acids 742
Quantitative Relationships Involving Carboxylic Acids 743
19.6 Substituents and Acid Strength 745
19.7 Ionization of Substituted Benzoic Acids 747
19.8 Dicarboxylic Acids 748
19.9 Carbonic Acid 749
19.10 Sources of Carboxylic Acids 750
19.11 Synthesis of Carboxylic Acids by the Carboxylation of Grignard
Reagents 750
19.12 Synthesis of Carboxylic Acids by the Preparation and Hydrolysis of
Nitriles 752
19.13 Reactions of Carboxylic Acids: A Review and a Preview 753
19.14 Mechanism of Acid-Catalyzed Esterification 754
19.15 Intramolecular Ester Formation: Lactones 758
19.16 H9251 Halogenation of Carboxylic Acids: The Hell–Volhard–Zelinsky
Reaction 759
19.17 Decarboxylation of Malonic Acid and Related Compounds 760
19.18 Spectroscopic Analysis of Carboxylic Acids 763
19.19 SUMMARY 765
PROBLEMS 768
CHAPTER 20
CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL
SUBSTITUTION 774
20.1 Nomenclature of Carboxylic Acid Derivatives 775
20.2 Structure of Carboxylic Acid Derivatives 777
20.3 Nucleophilic Substitution in Acyl Chlorides 780
20.4 Preparation of Carboxylic Acid Anhydrides 783
20.5 Reactions of Carboxylic Acid Anhydrides 784
20.6 Sources of Esters 787
20.7 Physical Properties of Esters 788
20.8 Reactions of Esters: A Review and a Preview 790
20.9 Acid-Catalyzed Ester Hydrolysis 791
20.10 Ester Hydrolysis in Base: Saponification 794
20.11 Reaction of Esters with Ammonia and Amines 799
20.12 Thioesters 800
20.13 Preparation of Amides 800
20.14 Lactams 803
20.15 Imides 804
20.16 Hydrolysis of Amides 804
20.17 The Hofmann Rearrangement 807
Condensation Polymers: Polyamides and Polyesters 809
20.18 Preparation of Nitriles 813
20.19 Hydrolysis of Nitriles 815
20.20 Addition of Grignard Reagents to Nitriles 816
CONTENTS xxi
20.21 Spectroscopic Analysis of Carboxylic Acid Derivatives 817
20.22 SUMMARY 819
PROBLEMS 822
CHAPTER 21
ESTER ENOLATES 831
21.1 The Claisen Condensation 832
21.2 Intramolecular Claisen Condensation: The Dieckmann Reaction 835
21.3 Mixed Claisen Condensations 836
21.4 Acylation of Ketones with Esters 837
21.5 Ketone Synthesis via H9252-Keto Esters 838
21.6 The Acetoacetic Ester Synthesis 839
21.7 The Malonic Ester Synthesis 842
21.8 Barbiturates 845
21.9 Michael Additions of Stabilized Anions 846
21.10 H9251 Deprotonation of Carbonyl Compounds by Lithium Dialkylamides 847
21.11 SUMMARY 850
PROBLEMS 853
CHAPTER 22
AMINES 858
22.1 Amine Nomenclature 859
22.2 Structure and Bonding 861
22.3 Physical Properties 863
22.4 Measures of Amine Basicity 864
22.5 Basicity of Amines 865
Amines as Natural Products 869
22.6 Tetraalkylammonium Salts as Phase-Transfer Catalysts 871
22.7 Reactions That Lead to Amines: A Review and a Preview 872
22.8 Preparation of Amines by Alkylation of Ammonia 872
22.9 The Gabriel Synthesis of Primary Alkylamines 875
22.10 Preparation of Amines by Reduction 877
22.11 Reductive Amination 879
22.12 Reactions of Amines: A Review and a Preview 881
22.13 Reaction of Amines with Alkyl Halides 883
22.14 The Hofmann Elimination 883
22.15 Electrophilic Aromatic Substitution in Arylamines 886
22.16 Nitrosation of Alkylamines 888
22.17 Nitrosation of Arylamines 891
22.18 Synthetic Transformations of Aryl Diazonium Salts 892
22.19 Azo Coupling 895
From Dyes to Sulfa Drugs 896
22.20 Spectroscopic Analysis of Amines 897
22.21 SUMMARY 900
PROBLEMS 907
CHAPTER 23
ARYL HALIDES 917
23.1 Bonding in Aryl Halides 917
23.2 Sources of Aryl Halides 918
xxii CONTENTS
23.3 Physical Properties of Aryl Halides 918
23.4 Reactions of Aryl Halides: A Review and a Preview 919
23.5 Nucleophilic Substitution in Nitro-Substituted Aryl Halides 922
23.6 The Addition–Elimination Mechanism of Nucleophilic Aromatic
Substitution 923
23.7 Related Nucleophilic Aromatic Substitution Reactions 926
23.8 The Elimination–Addition Mechanism of Nucleophilic Aromatic Substitution:
Benzyne 927
23.9 Diels–Alder Reactions of Benzyne 931
23.10 SUMMARY 932
PROBLEMS 934
CHAPTER 24
PHENOLS 939
24.1 Nomenclature 939
24.2 Structure and Bonding 940
24.3 Physical Properties 941
24.4 Acidity of Phenols 942
24.5 Substituent Effects on the Acidity of Phenols 944
24.6 Sources of Phenols 946
24.7 Naturally Occurring Phenols 946
24.8 Reactions of Phenols: Electrophilic Aromatic Substitution 948
24.9 Acylation of Phenols 949
24.10 Carboxylation of Phenols: Aspirin and the Kolbe–Schmitt Reaction 952
24.11 Preparation of Aryl Ethers 954
Agent Orange and Dioxin 955
24.12 Cleavage of Aryl Ethers by Hydrogen Halides 956
24.13 Claisen Rearrangement of Allyl Aryl Ethers 957
24.14 Oxidation of Phenols: Quinones 958
24.15 Spectroscopic Analysis of Phenols 960
24.16 SUMMARY 962
PROBLEMS 965
CHAPTER 25
CARBOHYDRATES 972
25.1 Classification of Carbohydrates 972
25.2 Fischer Projections and the D–L Notation 973
25.3 The Aldotetroses 974
25.4 Aldopentoses and Aldohexoses 976
25.5 A Mnemonic for Carbohydrate Configurations 978
25.6 Cyclic Forms of Carbohydrates: Furanose Forms 978
25.7 Cyclic Forms of Carbohydrates: Pyranose Forms 981
25.8 Mutarotation 985
25.9 Ketoses 986
25.10 Deoxy Sugars 987
25.11 Amino Sugars 988
25.12 Branched-Chain Carbohydrates 988
25.13 Glycosides 988
25.14 Disaccharides 991
25.15 Polysaccharides 993
25.16 Cell-Surface Glycoproteins 995
25.17 Carbohydrate Structure Determination 996
25.18 Reduction of Carbohydrates 996
CONTENTS xxiii
How Sweet It Is! 997
25.19 Oxidation of Carbohydrates 998
25.20 Cyanohydrin Formation and Carbohydrate Chain Extension 1001
25.21 Epimerization, Isomerization, and Retro-Aldol Cleavage Reactions of
Carbohydrates 1003
25.22 Acylation and Alkylation of Hydroxyl Groups in Carbohydrates 1004
25.23 Periodic Acid Oxidation of Carbohydrates 1005
25.24 SUMMARY 1006
PROBLEMS 1008
CHAPTER 26
LIPIDS 1015
26.1 Acetyl Coenzyme A 1016
26.2 Fats, Oils, and Fatty Acids 1017
26.3 Fatty Acid Biosynthesis 1019
26.4 Phospholipids 1022
26.5 Waxes 1024
26.6 Prostaglandins 1024
26.7 Terpenes: The Isoprene Rule 1025
26.8 Isopentenyl Pyrophosphate: The Biological Isoprene Unit 1028
26.9 Carbon–Carbon Bond Formation in Terpene Biosynthesis 1029
26.10 The Pathway from Acetate to Isopentenyl Pyrophosphate 1032
26.11 Steroids: Cholesterol 1034
Good Cholesterol? Bad Cholesterol? What’s the
Difference? 1038
26.12 Vitamin D 1038
26.13 Bile Acids 1039
26.14 Corticosteroids 1040
26.15 Sex Hormones 1040
Anabolic Steroids 1041
26.16 Carotenoids 1042
26.17 SUMMARY 1042
PROBLEMS 1045
CHAPTER 27
AMINO ACIDS, PEPTIDES, AND PROTEINS. NUCLEIC ACIDS 1051
27.1 Classification of Amino Acids 1052
27.2 Stereochemistry of Amino Acids 1052
27.3 Acid–Base Behavior of Amino Acids 1057
Electrophoresis 1060
27.4 Synthesis of Amino Acids 1061
27.5 Reactions of Amino Acids 1063
27.6 Some Biochemical Reactions of Amino Acids 1063
27.7 Peptides 1067
27.8 Introduction to Peptide Structure Determination 1070
27.9 Amino Acid Analysis 1070
27.10 Partial Hydrolysis of Peptides 1071
27.11 End Group Analysis 1071
27.12 Insulin 1073
27.13 The Edman Degradation and Automated Sequencing of Peptides 1074
27.14 The Strategy of Peptide Synthesis 1076
xxiv CONTENTS
27.15 Amino Group Protection 1077
27.16 Carboxyl Group Protection 1079
27.17 Peptide Bond Formation 1079
27.18 Solid-Phase Peptide Synthesis: The Merrifield Method 1082
27.19 Secondary Structures of Peptides and Proteins 1084
27.20 Tertiary Structure of Peptides and Proteins 1086
27.21 Coenzymes 1088
27.22 Protein Quaternary Structure: Hemoglobin 1089
27.23 Pyrimidines and Purines 1090
27.24 Nucleosides 1091
27.25 Nucleotides 1092
27.26 Nucleic Acids 1093
27.27 Structure and Replication of DNA: The Double Helix 1094
27.28 DNA-Directed Protein Biosynthesis 1096
AIDS 1098
27.29 DNA Sequencing 1100
27.30 SUMMARY 1103
PROBLEMS 1106
APPENDIX 1 PHYSICAL PROPERTIES A-1
APPENDIX 2 ANSWERS TO IN-TEXT PROBLEMS A-9
APPENDIX 3 LEARNING CHEMISTRY WITH MOLECULAR MODELS:
Using SpartanBuild and SpartanView A-64
GLOSSARY G-1
CREDITS C-1
INDEX I-1
