Title Details

1 The Basics

BONDING AND MOLECULAR STRUCTURE 1

1.1 Life and the Chemistry of Carbon Compounds—We are Stardust 2

1.2 Atomic Structure 3

1.3 Chemical Bonds: The Octet Rule 5

1.4 HOW TO Write Lewis Structures 7

1.5 Formal Charges and HOW TO Calculate Them 12

1.6 Isomers: Different Compounds that Have the Same Molecular Formula 14

1.7 HOW TO Write and Interpret Structural Formulas 15

1.8 Resonance Theory 22

1.9 Quantum Mechanics and Atomic Structure 27

1.10 Atomic Orbitals and Electron Configuration 28

1.11 Molecular Orbitals 30

1.12 The Structure of Methane and Ethane: sp3 Hybridization 32

1.13 The Structure of Ethene (Ethylene): sp2 Hybridization 36

1.14 The Structure of Ethyne (Acetylene): sp Hybridization 40

1.15 A Summary of Important Concepts That Come from Quantum Mechanics 43

1.16 HOW TO Predict Molecular Geometry: The Valence Shell Electron Pair Repulsion Model 44

1.17 Applications of Basic Principles 47

2 Families of Carbon Compounds

FUNCTIONAL GROUPS, INTERMOLECULAR FORCES, AND INFRARED (IR) SPECTROSCOPY 55

2.1 Hydrocarbons: Representative Alkanes, Alkenes, Alkynes, and Aromatic Compounds 56

2.2 Polar Covalent Bonds 59

2.3 Polar and Nonpolar Molecules 61

2.4 Functional Groups 64

2.5 Alkyl Halides or Haloalkanes 65

2.6 Alcohols and Phenols 67

2.7 Ethers 69

2.8 Amines 70

2.9 Aldehydes and Ketones 71

2.10 Carboxylic Acids, Esters, and Amides 73

2.11 Nitriles 75

2.12 Summary of Important Families of Organic Compounds 76

2.13 Physical Properties and Molecular Structure 77

2.14 Summary of Attractive Electric Forces 85

2.15 Infrared Spectroscopy: An Instrumental Method for Detecting Functional Groups 86

2.16 Interpreting IR Spectra 90

2.17 Applications of Basic Principles 97

3 Acids and Bases

AN INTRODUCTION TO ORGANIC REACTIONS AND THEIR MECHANISMS 104

3.1 Acid–Base Reactions 105

3.2 HOW TO Use Curved Arrows in Illustrating Reactions 107

3.3 Lewis Acids and Bases 109

3.4 Heterolysis of Bonds to Carbon: Carbocations and Carbanions 111

3.5 The Strength of Brønsted–Lowry Acids and Bases: Ka and pKa 113

3.6 HOW TO Predict the Outcome of Acid–Base Reactions 118

3.7 Relationships Between Structure and Acidity 120

3.8 Energy Changes 123

3.9 The Relationship Between the Equilibrium Constant and the Standard Free-Energy Change, ΔG° 125

3.10 Acidity: Carboxylic Acids versus Alcohols 126

3.11 The Effect of the Solvent on Acidity 130

3.12 Organic Compounds as Bases 130

3.13 A Mechanism for an Organic Reaction 132

3.14 Acids and Bases in Nonaqueous Solutions 133

3.15 Acid–Base Reactions and the Synthesis of Deuterium- and Tritium-Labeled Compounds 134

3.16 Applications of Basic Principles 135

4 Nomenclature and Conformations of Alkanes and Cycloalkanes 142

4.1 Introduction to Alkanes and Cycloalkanes 143

4.2 Shapes of Alkanes 144

4.3 HOW TO Name Alkanes, Alkyl Halides, and Alcohols: The IUPAC System 146

4.4 HOW TO Name Cycloalkanes 153

4.5 HOW TO Name Alkenes and Cycloalkenes 156

4.6 HOW TO Name Alkynes 158

4.7 Physical Properties of Alkanes and Cycloalkanes 159

4.8 Sigma Bonds and Bond Rotation 162

4.9 Conformational Analysis of Butane 164

4.10 The Relative Stabilities of Cycloalkanes: Ring Strain 167

4.11 Conformations of Cyclohexane: The Chair and the Boat 168

4.12 Substituted Cyclohexanes: Axial and Equatorial Hydrogen Groups 171

4.13 Disubstituted Cycloalkanes: Cis–Trans Isomerism 175

4.14 Bicyclic and Polycyclic Alkanes 179

4.15 Chemical Reactions of Alkanes 180

4.16 Synthesis of Alkanes and Cycloalkanes 180

4.17 HOW TO Gain Structural Information from Molecular Formulas and the Index of Hydrogen Deficiency 182

4.18 Applications of Basic Principles 184

5 Stereochemistry

CHIRAL MOLECULES 191

5.1 Chirality and Stereochemistry 192

5.2 Isomerism: Constitutional Isomers and Stereoisomers 193

5.3 Enantiomers and Chiral Molecules 195

5.4 Molecules Having One Chirality Center are Chiral 196

5.5 More about the Biological Importance of Chirality 199

5.6 HOW TO Test for Chirality: Planes of Symmetry 201

5.7 Naming Enantiomers: The R,S-System 202

5.8 Properties of Enantiomers: Optical Activity 206

5.9 The Origin of Optical Activity 211

5.10 The Synthesis of Chiral Molecules 213

5.11 Chiral Drugs 215

5.12 Molecules with More than One Chirality Center 217

5.13 Fischer Projection Formulas 223

5.14 Stereoisomerism of Cyclic Compounds 225

5.15 Relating Configurations through Reactions in which No Bonds to the Chirality Center Are Broken 227

5.16 Separation of Enantiomers: Resolution 231

5.17 Compounds with Chirality Centers Other than Carbon 232

5.18 Chiral Molecules That Do Not Possess a Chirality Center 232

6 Ionic Reactions

NUCLEOPHILIC SUBSTITUTION AND ELIMINATION REACTIONS OF ALKYL HALIDES 239

6.1 Alkyl Halides 240

6.2 Nucleophilic Substitution Reactions 241

6.3 Nucleophiles 243

6.4 Leaving Groups 245

6.5 Kinetics of a Nucleophilic Substitution Reaction: An SN2 Reaction 245

6.6 A Mechanism for the SN2 Reaction 246

6.7 Transition State Theory: Free-Energy Diagrams 248

6.8 The Stereochemistry of SN2 Reactions 251

6.9 The Reaction of Tert-Butyl Chloride with Water: An SN1 Reaction 253

6.10 A Mechanism for the SN1 Reaction 254

6.11 Carbocations 256

6.12 The Stereochemistry of SN1 Reactions 258

6.13 Factors Affecting the Rates of SN1 and SN2 Reactions 261

6.14 Organic Synthesis: Functional Group Transformations Using SN2 Reactions 271

6.15 Elimination Reactions of Alkyl Halides 275

6.16 The E2 Reaction 276

6.17 The E1 Reaction 278

6.18 HOW TO Determine Whether Substitution or Elimination Is Favored 280

6.19 Overall Summary 282

7 Alkenes and Alkynes I

PROPERTIES AND SYNTHESIS. ELIMINATION REACTIONS OF ALKYL HALIDES 291

7.1 Introduction 292

7.2 The (E)–(Z) System for Designating Alkene Diastereomers 292

7.3 Relative Stabilities of Alkenes 293

7.4 Cycloalkenes 296

7.5 Synthesis of Alkenes via Elimination Reactions 296

7.6 Dehydrohalogenation of Alkyl Halides 297

7.7 Acid-Catalyzed Dehydration of Alcohols 303

7.8 Carbocation Stability and the Occurrence of Molecular Rearrangements 309

7.9 The Acidity of Terminal Alkynes 313

7.10 Synthesis of Alkynes by Elimination Reactions 314

7.11 Terminal Alkynes Can Be Converted to Nucleophiles for Carbon–Carbon Bond Formation 316

7.12 Hydrogenation of Alkenes 318

7.13 Hydrogenation: The Function of the Catalyst 320

7.14 Hydrogenation of Alkynes 321

7.15 An Introduction to Organic Synthesis 323

8 Alkenes and Alkynes II

ADDITION REACTIONS 337

8.1 Addition Reactions of Alkenes 338

8.2 Electrophilic Addition of Hydrogen Halides to Alkenes: Mechanism and Markovnikov’s Rule 340

8.3 Stereochemistry of the Ionic Addition to an Alkene 345

8.4 Addition of Water to Alkenes: Acid-Catalyzed Hydration 346

8.5 Alcohols from Alkenes through Oxymercuration–Demercuration: Markovnikov Addition 349

8.6 Alcohols from Alkenes through Hydroboration–Oxidation: Anti-Markovnikov Syn Hydration 352

8.7 Hydroboration: Synthesis of Alkylboranes 353

8.8 Oxidation and Hydrolysis of Alkylboranes 355

8.9 Summary of Alkene Hydration Methods 358

8.10 Protonolysis of Alkylboranes 359

8.11 Electrophilic Addition of Bromine and Chlorine to Alkenes 359

8.12 Stereospecific Reactions 363

8.13 Halohydrin Formation 364

8.14 Divalent Carbon Compounds: Carbenes 366

8.15 Oxidation of Alkenes: Syn 1,2-Dihydroxylation 368

8.16 Oxidative Cleavage of Alkenes 371

8.17 Electrophilic Addition of Bromine and Chlorine to Alkynes 374

8.18 Addition of Hydrogen Halides to Alkynes 374

8.19 Oxidative Cleavage of Alkynes 375

8.20 HOW TO Plan a Synthesis: Some Approaches and Examples 376

9 Nuclear Magnetic Resonance and Mass Spectrometry

TOOLS FOR STRUCTURE DETERMINATION 391

9.1 Introduction 392

9.2 Nuclear Magnetic Resonance (NMR) Spectroscopy 392

9.3 HOW TO Interpret Proton NMR Spectra 398

9.4 Nuclear Spin: The Origin of the Signal 401

9.5 Detecting the Signal: Fourier Transform NMR Spectrometers 403

9.6 The Chemical Shift 405

9.7 Shielding and Deshielding of Protons 406

9.8 Chemical Shift Equivalent and Nonequivalent Protons 408

9.9 Signal Splitting: Spin–Spin Coupling 411

9.10 Proton NMR Spectra and Rate Processes 420

9.11 Carbon-13 NMR Spectroscopy 422

9.12 Two-Dimensional (2D) NMR Techniques 428

9.13 An Introduction to Mass Spectrometry 431

9.14 Formation of Ions: Electron Impact Ionization 432

9.15 Depicting the Molecular Ion 432

9.16 Fragmentation 433

9.17 Isotopes in Mass Spectra 440

9.18 GC/MS Analysis 443

9.19 Mass Spectrometry of Biomolecules 444

10 Radical Reactions 457

10.1 Introduction: How Radicals Form and How They React 458

10.2 Homolytic Bond Dissociation Energies (DH􀀘) 460

10.3 Reactions of Alkanes with Halogens 463

10.4 Chlorination of Methane: Mechanism of Reaction 465

10.5 Halogenation of Higher Alkanes 468

10.6 The Geometry of Alkyl Radicals 471

10.7 Reactions That Generate Tetrahedral Chirality Centers 471

10.8 Allylic Substitution and Allylic Radicals 475

10.9 Benzylic Substitution and Benzylic Radicals 478

10.10 Radical Addition to Alkenes: The Anti-Markovnikov Addition of Hydrogen Bromide 481

10.11 Radical Polymerization of Alkenes: Chain-Growth Polymers 483

10.12 Other Important Radical Reactions 487

11 Alcohols and Ethers

SYNTHESIS AND REACTIONS 498

11.1 Structure and Nomenclature 499

11.2 Physical Properties of Alcohols and Ethers 501

11.3 Important Alcohols and Ethers 503

11.4 Synthesis of Alcohols from Alkenes 505

11.5 Reactions of Alcohols 507

11.6 Alcohols as Acids 509

11.7 Conversion of Alcohols into Alkyl Halides 510

11.8 Alkyl Halides from the Reaction of Alcohols with Hydrogen Halides 510

11.9 Alkyl Halides from the Reaction of Alcohols with PBr3 or SOCl2 513

11.10 Tosylates, Mesylates, and Triflates: Leaving Group Derivatives of Alcohols 514

11.11 Synthesis of Ethers 517

11.12 Reactions of Ethers 522

11.13 Epoxides 523

11.14 Reactions of Epoxides 525

11.15 Anti 1,2-Dihydroxylation of Alkenes via Epoxides 528

11.16 Crown Ethers 531

11.17 Summary of Reactions of Alkenes, Alcohols, and Ethers 532

12 Alcohols from Carbonyl Compounds

OXIDATION–REDUCTION AND ORGANOMETALLIC COMPOUNDS 542

12.1 Structure of the Carbonyl Group 543

12.2 Oxidation–Reduction Reactions in Organic Chemistry 544

12.3 Alcohols by Reduction of Carbonyl Compounds 546

12.4 Oxidation of Alcohols 551

12.5 Organometallic Compounds 556

12.6 Preparation of Organolithium and Organomagnesium Compounds 557

12.7 Reactions of Organolithium and Organomagnesium Compounds 558

12.8 Alcohols from Grignard Reagents 561

12.9 Protecting Groups 570

13 Conjugated Unsaturated Systems 581

13.1 Introduction 582

13.2 The Stability of the Allyl Radical 582

13.3 The Allyl Cation 586

13.4 Resonance Theory Revisited 587

13.5 Alkadienes and Polyunsaturated Hydrocarbons 591

13.6 1,3-Butadiene: Electron Delocalization 592

13.7 The Stability of Conjugated Dienes 595

13.8 Ultraviolet–Visible Spectroscopy 596

13.9 Electrophilic Attack on Conjugated Dienes: 1,4-Addition 604

13.10 The Diels–Alder Reaction: A 1,4-Cycloaddition Reaction of Dienes 608

14 Aromatic Compounds 626

14.1 The Discovery of Benzene 627

14.2 Nomenclature of Benzene Derivatives 628

14.3 Reactions of Benzene 630

14.4 The Kekulé Structure for Benzene 631

14.5 The Thermodynamic Stability of Benzene 632

14.6 Modern Theories of the Structure of Benzene 634

14.7 Hückel’s Rule: The 4n􀀌􀀁2 p Electron Rule 637

14.8 Other Aromatic Compounds 645

14.9 Heterocyclic Aromatic Compounds 648

14.10 Aromatic Compounds in Biochemistry 650

14.11 Spectroscopy of Aromatic Compounds 652

15 Reactions of Aromatic Compounds 669

15.1 Electrophilic Aromatic Substitution Reactions 670

15.2 A General Mechanism for Electrophilic Aromatic Substitution 671

15.3 Halogenation of Benzene 673

15.4 Nitration of Benzene 674

15.5 Sulfonation of Benzene 675

15.6 Friedel–Crafts Alkylation 676

15.7 Friedel–Crafts Acylation 678

15.8 Limitations of Friedel–Crafts Reactions 680

15.9 Synthetic Applications of Friedel–Crafts Acylations: The Clemmensen and Wolff–Kishner Reductions 683

15.10 Substituents Can Affect Both the Reactivity of the Ring and the Orientation of the Incoming Group 685

15.11 How Substituents Affect Electrophilic Aromatic Substitution: A Closer Look 690

15.12 Reactions of the Side Chain of Alkylbenzenes 699

15.13 Alkenylbenzenes 702

15.14 Synthetic Applications 704

15.15 Allylic and Benzylic Halides in Nucleophilic Substitution Reactions 708

15.16 Reduction of Aromatic Compounds 710

16 Aldehydes and Ketones

NUCLEOPHILIC ADDITION TO THE CARBONYL GROUP 720

16.1 Introduction 721

16.2 Nomenclature of Aldehydes and Ketones 721

16.3 Physical Properties 723

16.4 Synthesis of Aldehydes 724

16.5 Synthesis of Ketones 729

16.6 Nucleophilic Addition to the Carbon–Oxygen Double Bond 732

16.7 The Addition of Alcohols: Hemiacetals and Acetals 735

16.8 The Addition of Primary and Secondary Amines 741

16.9 The Addition of Hydrogen Cyanide: Cyanohydrins 746

16.10 The Addition of Ylides: The Wittig Reaction 747

16.11 Oxidation of Aldehydes 751

16.12 The Baeyer–Villiger Oxidation 751

16.13 Chemical Analyses for Aldehydes and Ketones 753

16.14 Spectroscopic Properties of Aldehydes and Ketones 753

16.15 Summary of Aldehyde and Ketone Addition Reactions 756

17 Carboxylic Acids and Their Derivatives

NUCLEOPHILIC ADDITION–ELIMINATION AT THE ACYL CARBON 771

17.1 Introduction 772

17.2 Nomenclature and Physical Properties 772

17.3 Preparation of Carboxylic Acids 781

17.4 Acyl Substitution: Nucleophilic Addition–Elimination at the Acyl Carbon 784

17.5 Acyl Chlorides 786

17.6 Carboxylic Acid Anhydrides 788

17.7 Esters 789

17.8 Amides 796

17.9 Derivatives of Carbonic Acid 802

17.10 Decarboxylation of Carboxylic Acids 805

17.11 Chemical Tests for Acyl Compounds 807

17.12 Polyesters and Polyamides: Step-Growth Polymers 807

17.13 Summary of the Reactions of Carboxylic Acids and Their Derivatives 809

18 Reactions at the A Carbon of Carbonyl Compounds

ENOLS AND ENOLATES 821

18.1 The Acidity of the a Hydrogens of Carbonyl Compounds: Enolate Anions 822

18.2 Keto and Enol Tautomers 823

18.3 Reactions via Enols and Enolates 825

18.4 Lithium Enolates 831

18.5 Enolates of b-Dicarbonyl Compounds 834

18.6 Synthesis of Methyl Ketones: The Acetoacetic Ester Synthesis 835

18.7 Synthesis of Substituted Acetic Acids: The Malonic Ester Synthesis 840

18.8 Further Reactions of Active Hydrogen Compounds 844

18.9 Synthesis of Enamines: Stork Enamine Reactions 844

18.10 Summary of Enolate Chemistry 847

19 Condensation and Conjugate Addition Reactions of Carbonyl Compounds

MORE CHEMISTRY OF ENOLATES 858

19.1 Introduction 859

19.2 The Claisen Condensation: A Synthesis of b-Keto Esters 859

19.3 b-Dicarbonyl Compounds by Acylation of Ketone Enolates 864

19.4 Aldol Reactions: Addition of Enolates and Enols to Aldehydes and Ketones 865

19.5 Crossed Aldol Condensations 871

19.6 Cyclizations via Aldol Condensations 876

19.7 Additions to a,b-Unsaturated Aldehydes and Ketones 877

19.8 The Mannich Reaction 882

19.9 Summary of Important Reactions 884

20 Amines 897

20.1 Nomenclature 898

20.2 Physical Properties and Structure of Amines 899

20.3 Basicity of Amines: Amine Salts 901

20.4 Preparation of Amines 908

20.5 Reactions of Amines 917

20.6 Reactions of Amines with Nitrous Acid 918

20.7 Replacement Reactions of Arenediazonium Salts 920

20.8 Coupling Reactions of Arenediazonium Salts 924

20.9 Reactions of Amines with Sulfonyl Chlorides 926

20.10 Synthesis of Sulfa Drugs 928

20.11 Analysis of Amines 929

20.12 Eliminations Involving Ammonium Compounds 931

20.13 Summary of Preparations and Reactions of Amines 932

21 Phenols and Aryl Halides

NUCLEOPHILIC AROMATIC SUBSTITUTION 944

21.1 Structure and Nomenclature of Phenols 945

21.2 Naturally Occurring Phenols 946

21.3 Physical Properties of Phenols 947

21.4 Synthesis of Phenols 947

21.5 Reactions of Phenols as Acids 949

21.6 Other Reactions of the O􀁊H Group of Phenols 952

21.7 Cleavage of Alkyl Aryl Ethers 952

21.8 Reactions of the Benzene Ring of Phenols 953

21.9 The Claisen Rearrangement 956

21.10 Quinones 957

21.11 Aryl Halides and Nucleophilic Aromatic Substitution 959

21.12 Spectroscopic Analysis of Phenols and Aryl Halides 966

22 Carbohydrates 979

22.1 Introduction 980

22.2 Monosaccharides 982

22.3 Mutarotation 987

22.4 Glycoside Formation 988

22.5 Other Reactions of Monosaccharides 990

22.6 Oxidation Reactions of Monosaccharides 994

22.7 Reduction of Monosaccharides: Alditols 999

22.8 Reactions of Monosaccharides with Phenylhydrazine: Osazones 999

22.9 Synthesis and Degradation of Monosaccharides 1000

22.10 The D Family of Aldoses 1002

22.11 Fischer’s Proof of the Configuration of D-(+)-Glucose 1003

22.12 Disaccharides 1005

22.13 Polysaccharides 1009

22.14 Other Biologically Important Sugars 1013

22.15 Sugars That Contain Nitrogen 1014

22.16 Glycolipids and Glycoproteins of the Cell Surface: Cell Recognition and the Immune System 1016

22.17 Carbohydrate Antibiotics 1018

22.18 Summary of Reactions of Carbohydrates 1019

23 Lipids 1027

23.1 Introduction 1028

23.2 Fatty Acids and Triacylglycerols 1028

23.3 Terpenes and Terpenoids 1037

23.4 Steroids 1040

23.5 Prostaglandins 1049

23.6 Phospholipids and Cell Membranes 1050

23.7 Waxes 1054

24 Amino Acids and Proteins 1060

24.1 Introduction 1061

24.2 Amino Acids 1062

24.3 Synthesis of a-Amino Acids 1068

24.4 Polypeptides and Proteins 1070

24.5 Primary Structure of Polypeptides and Proteins 1073

24.6 Examples of Polypeptide and Protein Primary Structure 1077

24.7 Polypeptide and Protein Synthesis 1080

24.8 Secondary, Tertiary, and Quaternary Structures of Proteins 1086

24.9 Introduction to Enzymes 1090

24.10 Lysozyme: Mode of Action of an Enzyme 1092

24.11 Serine Proteases 1094

24.12 Hemoglobin: A Conjugated Protein 1096

24.13 Purification and Analysis of Polypeptides and Proteins 1098

25 Nucleic Acids and Protein Synthesis 1105

25.1 Introduction 1106

25.2 Nucleotides and Nucleosides 1107

25.3 Laboratory Synthesis of Nucleosides and Nucleotides 1110

25.4 Deoxyribonucleic Acid: DNA 1113

25.5 RNA and Protein Synthesis 1120

25.6 Determining the Base Sequence of DNA: The Chain-Terminating (Dideoxynucleotide) Method 1128

25.7 Laboratory Synthesis of Oligonucleotides 1131

25.8 The Polymerase Chain Reaction 1133

25.9 Sequencing of the Human Genome: An Instruction Book for the Molecules of Life 1135

ANSWERS TO SELECTED PROBLEMS A-1

GLOSSARY GL-1

INDEX I-1