F I F T H E D I T I O N

FUNDAMENTALS O F

ORGANIC CHEMISTRY

T. W. G R A H A M S O L O M O N S

University of South Florida

® J O H N W l L E Y & S O N S , I N C .

New York Chichester Brisbane Toronto Singapore

N T E N T S

C H A P T E R 1 CARBON COMPOUNDS A N D CHEMICAL BONDS

1.1 Introduction 7 1.2 Development of Organic Chemistry as a Science 2 1.3 The Structural Theory of Organic Chemistry 3 1.4 Chemical Bonds: The Octet Rule 6 1.5 Writing Lewis Structures 8 1.6 Exceptions to the Octet Rule 10 1.7 Formal Charge 12 1.8 Resonance 75 1.9 Energy Changes 18 1.10 Quantum Mechanics 20 1.11 Atomic Orbitals 21 1.12 Molecular Orbitals 23 1.13 The Structure of Methane: sp3, Hybridization 26 1.14 The Structure of Borane: sp2 Hybridization 29 1.15 The Structure of Beryllium Hydride: sp Hybridization 31 1.16 A Summary of Important Concepts that Come from Quantum Mechanics 32 1.17 Molecular Geometry: The Valence Shell Electron-Pair Repulsion (VSEPR)

Model 34 1.18 Polar Covalent Bonds 38 1.19 Polar and Nonpolar Molecules 39 1.20 Representation of Structural Formulas 41

C H A P T E R 2

REPRESENTATIVE CARBON COMPOUNDS

2.1 Carbon-Carbon Covalent Bonds 52 2.2 Methane and Ethane: Representative Alkanes 52 2.3 Alkenes: Compounds Containing the Carbon-Carbon Double Bond; Ethene

and Propene 55 2.4 Orbital Hybridization and the Structure of Alkenes 56 2.5 Alkynes: Compounds Containing the Carbon-Carbon Triple Bond; Ethyne

(Acetylene) and Propyne 61 2.6 Orbital Hybridization and the Structure of Alkynes 62 2.7 Benzene: A Representative Aromatic Hydrocarbon 64 2.8 Functional Groups 65 2.9 Alkyl Halides or Haloalkanes 66 2.10 Alcohols 67

XIX

XX CONTENTS

2.11 Ethers 69 2.12 Amines 70 2.13 Aldehydes and Ketones 71 2.14 Carboxylic Acids, Amides, and Esters 72 2.15 Summary of Important Families of Organic Compounds 75 2.16 Physical Properties and Molecular Stracture 75 2.17 Summary of Attractive Electric Forces 83

C H A P T E R 3

A N INTRODUCTION TO ORGANIC REACTIONS: ACIDS A N D BASES

3.1 Reactions and Their Mechanisms 87 3.2 Acid-Base Reactions 90 3.3 Heterolysis of Bonds to Carbon: Carbocations and Carbanions 94 3.4 The Use of Curved Arrows in Illustrating Reactions 95 3.5 The Strength of Acids and Bases: Ka and pKa 96 3.6 Predicting the Outcome of Acid-Base Reactions 100 3.7 The Relationship between Structure and Acidity 102 3.8 The Relationship between the Equilibrium Constant and the Standard Free-

Energy Change, AG° 105 3.9 The Acidity of Carboxylic Acids 106 3.10 The Effect of the Solvent on Acidity 110 3.11 Organic Compounds as Bases 112 3.12 A Mechanism for an Organic Reaction 113 3.13 Acids and Bases in Nonaqueous Solutions 115 3.14 Acid-Base Reactions and the Synthesis of Deuterium- and Tritium-Labeled

Compounds 117 3.15 Some Important Terms and Concepts 118

C H A P T E R 4

ALKANES A N D CYCLOALKANES. CONFORMATIONS OF MOLECULES

4.1 Introduction to Alkanes and Cycloalkanes 123 4.2 Shapes of Alkanes 125 4.3 IUPAC Nomenclature of Alkanes, Alkyl Halides, and Alcohols 128 4.4 Nomenclature of Cycloalkanes 136 4.5 Physical Properties of Alkanes and Cycloalkanes 139 4.6 Sigma Bonds and Bond Rotation 142 4.7 Conformational Analysis of Butane 145 4.8 The Relative Stabilities of Cycloalkanes: Ring Strain 147 4.9 The Origin of Ring Strain in Cyclopropane and Cyclobutane: Angle Strain

and Torsional Strain 149 4.10 Conformations of Cyclohexane 151 4.11 Substituted Cyclohexanes: Axial and Equatorial Hydrogen Atoms 755 4.12 Disubstituted Cycloalkanes: cis-trans Isomerism 159 4.13 Bicyclic and Polycyclic Alkanes 163 4.14 Chemical Reactions of Alkanes 765 4.15 Synthesis of Alkanes and Cycloalkanes 765

CONTENTS XXI

4.16 Planning Organic Syntheses 169 4.17 Pheromones: Communication by Means of Chemicals 772 4.18 Some Important Terms and Concepts 173

C H A P T E R 5

STEREOCHEMISTRY. CHIRAL MOLECULES

5.1 Isomerism: Constitutional Isomers and Stereoisomers 178 5.2 Enantiomers and Chiral Molecules 180 5.3 The Biological Importance of Chirality 186 5.4 Historical Origin of Stereochemistry 187 5.5 Tests for Chirality: Planes of Symmetry 188 5.6 Nomenclature of Enantiomers: The (R-S) System 189 5.7 Properties of Enantiomers: Optical Activity 193 5.8 The Origin of Optical Activity 199 5.9 The Synthesis of Enantiomers 202 5.10 Chiral Drugs 204 5.11 Molecules with More Than One Stereocenter 205 5.12 Fischer Projection Formulas 210 5.13 Stereoisomerism of Cyclic Compounds 211 5.14 Relating Configurations through Reactions in Which No Bonds to the

Stereocenter Are Broken 214 5.15 Separation of Enantiomers: Resolution 218 5.16 Compounds with Stereocenters Other Than Carbon 279 5.17 Chiral Molecules That Do Not Possess a Tetrahedral Atom with Four

Different Groups 279 5.18 Some Important Terms and Concepts 220

C H A P T E R 6

IONIC REACTIONS — NUCLEOPHILIC SUBSTITUTION A N D ELIMINATION REACTIONS OF ALKYL HALIDES

6.1 Introduction 224 6.2 Physical Properties of Organic Halides 225 6.3 Nucleophilic Substitution Reactions 227 6.4 Nucleophiles 228 6.5 Leaving Groups 229 6.6 Thermodynamics and Kinetics of Chemical Reactions 229 6.7 Kinetics of a Nucleophilic Substitution Reaction: An SN2 Reaction 230 6.8 A Mechanism for the SN2 Reaction 232 6.9 Transition State Theory: Free-Energy Diagrams 233 6.10 The Stereochemistry of SN2 Reactions 237 6.11 The Reaction of ferf-Butyl Chloride with Hydroxide Ion: An SN1

Reaction 240 6.12 A Mechanism for the SN1 Reaction 241 6.13 Carbocations 243 6.14 The Stereochemistry of SN1 Reactions 246 6.15 Factors Affecting the Rates of SN1 and SN2 Reactions 248 6.16 Or ganic Synthesis: Functional Group Transformations Using SN2

Reactions 259

XXÜ CONTENTS

6.17 Elimination Reactions of Alkyl Halides 260 6.18 The E2 Reaction 263 6.19 The El Reaction 264 6.20 Substitution versus Elimination 265 6.21 Overall Summary 268 6.22 Some Important Terms and Concepts 269

C H A P T E R 7

ALKENES A N D ALKYNES I. PROPERTIES A N D SYNTHESIS

7.1 Introduction 277 7.2 Nomenclature of Alkenes and Cycloalkenes 278 7.3 Nomenclature of Alkynes 282 7.4 Physical Properties of Alkenes and Alkynes 283 7.5 Hydrogenation of Alkenes 283 7.6 Hydrogenation: The Function of the Catalyst 285 7.7 Hydrogenation of Alkynes 287 7.8 Molecular Formulas of Hydrocarbons: The Index of Hydrogen

Deficiency 288 7.9 Relative Stabilities of Alkenes 291 7.10 Cycloalkenes 295 7.11 Synthesis of Alkenes via Elimination Reactions 296 7.12 Dehydrohalogenation of Alkyl Halides 296 7.13 Dehydration of Alcohols 302 7.14 Carbocation Stability and the Transition State 305 7.15 Carbocation Stability and the Occurrence of Molecular Rearrangements 307 7 Ab Alkenes by Debromination of Vicinal Dibromides 309 7.17 Summary of Methods for the Preparation of Alkenes 311 7.18 Synthesis of Alkynes by Elimination Reactions 312 7.19 The Acidity of Terminal Alkynes 314 7.20 Replacement of the Acetylenic Hydrogen Atom of Terminal Alkynes 315

C H A P T E R 8

ALKENES A N D ALKYNES II. ADDIT ION REACTIONS

8.1 Introduction: Addition to Alkenes 32\ 8.2 Addition of Hydrogen Halides to Alkenes: Markovnikov's Rule 323 8.3 Stereochemistry of the Ionic Addition to an Alkene 329 8.4 Addition of Sulfuric Acid to Alkenes 329 8.5 Addition of Water to Alkenes: Acid-Catalyzed Hydration 330 8.6 Addition of Bromine and Chlorine to Alkenes 333 8.7 Stereochemistry of the Addition of Halogens to Alkenes 335 8.8 Halohydrin Formation 339 8.9 Oxidations of Alkenes: Syn Hydroxylation 340 8.10 Oxidative Cleavage of Alkenes 342 8.11 Summary of Addition Reactions of Alkenes 345 8.12 Addition of Bromine and Chlorine to Alkynes 345 8.13 Addition of Hydrogen Halides to Alkynes 347 8.14 Oxidati ve Cleavage of Alkynes 348 8.15 Summary of Addition Reactions of Alkynes 348

CONTENTS XXÜi

8.16 Synthetic Strategies Revisited 348 8.17 Simple Chemical Tests for Alkanes, Alkenes, Alkynes, Alkyl Halides, and

Alcohols 353

C H A P T E R 9

RADICAL REACTIONS

9.1 Introduction 360 9.2 Homolytic Bond Dissociation Energies 362 9.3 The Reactions of Alkanes with Halogens 367 9.4 Chlorination of Methane: Mechanism of Reaction 369 9.5 Chlorination of Methane: Energy Changes 372 9.6 Halogenation of Higher Alkanes 380 9.7 The Geometry of Alkyl Radicals 384 9.8 Reactions That Generate Tetrahedral Stereocenters 384 9.9 Radical Addition to Alkenes: The Anti-Markovnikov Addition of Hydrogen

Bromide 387 9.10 Radical Polymerization of Alkenes: Chain-Growth Polymers 389 9.11 Other Important Radical Chain Reactions 391 9.12 Some Important Terms and Concepts 395

C H A P T E R 1 0

ALCOHOLS A N D ETHERS

10.1 Structure and Nomenclature 399 10.2 Physical Properties of Alcohols and Ethers 402 10.3 Important Alcohols and Ethers 404 10.4 Synthesis of Alcohols from Alkenes 406 10.5 Alcohols from Alkenes through Oxymercuration-Demercuration 407 10.6 Hydroboration: Synthesis of Organoboranes 410 10.7 Alcohols from Alkenes Through Hydroboration-Oxidation 413 10.8 Reactions of Alcohols 416 10.9 Alcohols as Acids 477 10.10 Conversion of Alcohols into Mesylates and Tosylates 419 10.11 Mesylates and Tosylates in SN2 Reactions 420 10.12 Alkyl Phosphates 421 10.13 Conversion of Alcohols into Alkyl Halides 422 10.14 Alkyl Halides from the Reactions of Alcohols with Hydrogen Halides 423 10.15 Alkyl Halides from the Reactions of Alcohols with PBr3 or SOCl2 425 10.16 Synthesis of Ethers 427 10.17 Reactions of Ethers 431 10.18 Epoxides 432 10.19 Reactions of Epoxides 434 10.20 Anti Hydroxylation of Alkenes via Epoxides 437 10.21 Summary of Reactions of Alcohols and Ethers 438 10.22 Crown Ethers: Nucleophilic Substitution Reactions in Relatively Nonpolar

Aprotic Solvents by Phase-Transfer Catalysis 442

C H A P T E R 1 1 s

ALCOHOLS FROM CARBONYL COMPOUNDS, OXIDATION -REDUCTION A N D ORGANOMETALLIC COMPOUNDS

11.1 Introduction 450 11.2 Oxidation-Reduction Reactions in Organic Chemistry 452

XXIV CONTENTS

11.3 Alcohols by Reduction of Carbonyl Compounds 454 11.4 Oxidation of Alcohols 457 11.5 Organometallic Compounds 462 11.6 Preparation of Organolithium and Organomagnesium Compounds 463 11.7 Reactions of Organolithium and Organomagnesium Compounds 465 11.8 Alcohols from Grignard Reagents 468

C H A P T E R 1 2

CONJUGATED UNSATURATED SYSTEMS

12.1 Introduction 480 12.2 Allylic Substitution and the Allyl Radical 481 12.3 The Stability of the Allyl Radical 485 12.4 The Allyl Cation 489 12.5 Summary of Rules for Resonance 490 12.6 Alkadienes and Polyunsaturated Hydrocarbons 495 12.7 1,3-Butadiene: Electron Delocalization 496 12.8 The Stability of Conjugated Dienes 498 12.9 Electrophilic Attack on Conjugated Dienes: 1,4 Addition 500 12.10 The Diels-Alder Reaction: A 1,4-Cycloaddition Reaction of Dienes 504

FIRST R E V I E W PROBLEM SET 514

C H A P T E R 1 3

SPECTROSCOPIC METHODS OF STRUCTURE DETERMINATION

13.1 Introduction. The Electromagnetic Spectrum 518 13.2 Visible and Ultraviolet Spectroscopy 520 13.3 Infrared Spectroscopy 525 13.4 Nuclear Magnetic Resonance Spectroscopy 532 13.5 Nuclear Spin: The Origin of the Signal 536 13.6 Shielding and Deshielding of Protons 538 13.7 The Chemical Shift 540 13.8 Chemical Shift Equivalent and Nonequivalent Protons 542 13.9 Signal Splitting: Spin-Spin Coupling 544 13.10 Proton NMR Spectra and Rate Processes 554 13.11 Carbon-13 NMR Spectroscopy 557 13.12 Magnetic Resonance Imaging in Medicine 561

C H A P T E R 1 4

AROMATIC COMPOUNDS

14.1 Introduction 570 14.2 Nomenclature of Benzene Derivatives 577 14.3 Reactions of Benzene 573 14.4 The Kekule Structure for Benzene 575 14.5 The Stability of Benzene 576 14.6 Modern Theories of the Structure of Benzene 577 14.7 Hückel's Rule: The (An + 2) TT Electron Rule 580 14.8 Other Aromatic Compounds 589

CONTENTS XXV

14.9 Heterocyclic Aromatic Compounds 593 14.10 Aromatic Compounds in Biochemistry 595 14.11 Spectroscopy of Aromatic Compounds 597 14.12 A Summary of Important Terms and Concepts 602

C H A P T E R 1 5

REACTIONS OF AROMATIC COMPOUNDS

15.1 Electrophilic Aromatic Substitution Reactions 611 15.2 A General Mechanism for Electrophilic Aromatic Substitution:

Arenium Ions 612 15.3 Halogenation of Benzene 614 15.4 Nitration of Benzene 616 15.5 Sulfonation of Benzene 677 15.6 Friedel-Crafts Alkylation 679 15.7 Friedel-Crafts Acylation 620 15.8 Limitations of Friedel-Crafts Reactions 623 15.9 Synthetic Applications of Friedel-Crafts Acylations. The Clemmensen

Reduction 625 15.10 Effect of Substituents on Reactivity and Orientation 626 15.11 Theory of Substituent Effects on Electrophilic Aromatic Substitution 630 15.12 Reactions of the Side Chain of Alkylbenzenes 640 15.13 Alkenylbenzenes 645 15.14 Synthetic Applications 647 15.15 Allylic and Benzylic Halides in Nucleophilic Substitution Reactions 651 15.16 Reduction of Aromatic Compounds: The Birch Reduction 653

C H A P T E R 1 6

ALDEHYDES A N D KETONES I. NUCLEOPHILIC ADDITIONS TO THE CARBONYL GROUP

16.1 Introduction 660 16.2 Nomenclature of Aldehydes and Ketones 667 16.3 Physical Properties 662 16.4 Synthesis of Aldehydes 664 16.5 Synthesis of Ketones 668 16.6 Nucleophilic Addition to the Carbon-Oxygen Double Bond 672 16.7 The Addition of Water and Alcohols: Hydrates and Acetals 676 16.8 The Addition of Derivatives of Ammonia 684 16.9 The Addition of Hydrogen Cyanide 688 16.10 The Addition of Ylides: The Wittig Reaction 690 16.11 The Addition of Organometallic Reagents: The Reformatsky Reaction 694 16.12 Oxidation of Aldehydes and Ketones 696 16.13 Chemical Analysis of Aldehydes and Ketones 698 16.14 Spectroscopic Properties of Aldehydes and Ketones 698 16.15 Summary of the Addition Reactions of Aldehydes and Ketones 701

C H A P T E R 1 7

ALDEHYDES A N D KETONES I I . ALDOL REACTIONS

17.1 The Acidity of the a Hydrogens of Carbonyl Compounds: Enolate Ions 709 17.2 Keto and Enol Tau tomers 777

XXvi CONTENTS

17.3 Reactions via Enols and Enolate Ions 772 17.4 The Haloform Reaction 775 17.5 The Aldol Reaction: The Addition of Enolate Ions to Aldehydes and

Ketones 718 17.6 Crossed Aldol Reactions 727 17.7 Cyclizations via Aldol Condensations 728 17.8 Acid-Catalyzed Aldol Condensations 729 17.9 Additions to a,/3-Unsaturated Aldehydes and Ketones 730

C H A P T E R 1 8

CARBOXYLIC ACIDS A N D THEIR DERIVATIVES. NUCLEOPHILIC SUBSTITUTION AT THE ACYL CARBON

18.1 Introduction 740 18.2 Nomenclature and Physical Properties 740 18.3 Preparation of Carboxylic Acids 757 18.4 Nucleophilic Substitutions at the Acyl Carbon 753 18.5 Acyl Chlorides 756 18.6 Carboxylic Acid Anhydrides 758 18.7 Esters 760 18.8 Amides 768 18.9 a-Halo Acids: The Hell-Volhard-Zelinski Reaction 776 18.10 Derivatives of Carbonic Acid 778 18.11 Decarboxylation of Carboxylic Acids 787 18.12 Chemical Tests for Acyl Compounds 783 18.13 Step-Growth Polymers 783 18.14 Summary of the Reactions of Carboxylic Acids and Their Derivatives 789

C H A P T E R 1 9

SYNTHESIS A N D REACTIONS OF ß-DlCARBONYL COMPOUNDS: MORE CHEMISTRY OF ENOLATE IONS

19.1 Introduction 803 19.2 The Claisen Condensation: The Synthesis of /3-Keto Esters 804 19.3 The Acetoacetic Ester Synthesis: Synthesis of Substituted Acetones 877 19.4 The Malonic Ester Synthesis: Synthesis of Substituted Acetic Acids 818 19.5 Further Reactions of Active Hydrogen Compounds 821 19.6 Direct Alkylation of Esters and Nitriles 823 19.7 Alkylation of 1,3-Dithianes 824 19.8 The Knoevenagel Condensation 826 19.9 Michael Additions 826 19.10 The Mannich Reaction 828 19.11 Synthesis of Enamines: Stork Enamine Reactions 829 19.12 Barbiturates 833 19.13 Summary of Important Reactions 834

C H A P T E R 2 0

AMINES

20.1 Nomenclature 843 20.2 Physical Properties and Stracture of Amines 845

CONTENTS XXVÜ

20.3 Basicity of Amines: Amine Salts 847 20.4 Some Biologically Important Amines 854 20.5 Preparation of Amines 857 20.6 Reactions of Amines 865 20.7 Reactions of Amines with Nitrous Acid 867 20.8 Replacement Reactions of Arenediazonium Salts 870 20.9 Coupling Reactions of Arenediazonium Salts 874 20.10 Reactions of Amines with Sulfonyl Chlorides 876 20.11 The Sulfa Drags: Sulfanilamide 878 20.12 Analysis of Amines 882 20.13 Eliminations Involving Ammonium Compounds 884 20.14 Summary of Preparations and Reactions of Amines 886

C H A P T E R 2 1

PHENOLS A N D ARYL HALIDES: NUCLEOPHILIC AROMATIC SUBSTITUTION

21.1 Structure and Nomenclature of Phenols 897 21.2 Naturally Occurring Phenols 899 21.3 Physical Properties of Phenols 899 21.4 Synthesis of Phenols 900 21.5 Reactions of Phenols as Acids 904 21.6 Other Reactions of the O—H Group of Phenols 907 21.7 Cleavage of Alkyl Aryl Ethers 907 21.8 Reactions of the Benzene Ring of Phenols 908 21.9 The Claisen Rearrangement 970 21.10 Quinones 972 21.11 Aryl Halides and Nucleophilic Aromatic Substitution 914 21.12 Spectroscopic Analysis of Phenols and Aryl Halides 920 21.13 Summary of Important Reactions 920

S E C O N D R E V I E W P R O B L E M SET 927

C H A P T E R 2 2

CARBOHYDRATES

22.1 Introduction 934 22.2 Monosaccharides 937 22.3 Mutarotation 943 22.4 Glycoside Formation 944 22.5 Other Reactions of Monosaccharides 947 22.6 Oxidation Reactions of Monosaccharides 949 22.7 Reduction of Monosaccharides: Alditols 955 22.8 Reactions of Monosaccharides with Phenylhydrazine: Osazones 955 22.9 Synthesis and Degradation of Monosaccharides 957 22.10 The D Family of Aldoses 959 22.11 Fischer's Proof of the Configuration of D-(+)-Glucose 967 22.12 Disaccharides 963 22.13 Polysaccharides 967 22.14 Other Biologically Important Sugars 972

xxviii CONTENTS

C H A R T E R 2 3

ÜPIDS

23.1 Introduction 979 23.2 Fatty Acids and Triacylglycerols 980 23.3 Terpenes and Terpenoids 988 23.4 Steroids 992 23.5 Prostaglandins 1003

C H A P T E R 2 4

AMINO ACIDS, PROTEINS,AND NUCLEIC ACIDS

24.1 Introduction 7070 24.2 Amino Acids 7077 24.3 Laboratory Synthesis of a-Amino Acids 7076 24.4 Analysis of Polypeptides and Proteins 7027 24.5 Amino Acid Sequence of Polypeptides and Proteins 1024 24.6 Primary Structures of Polypeptides and Proteins 7028 24.7 Polypeptide and Protein Synthesis 70J2 24.8 Secondary and Tertiary Structures of Proteins 70J7 24.9 Nucleic Acids 1044 24.10 Nucleotides and Nucleosides 1044 24.11 Laboratory Synthesis of Nucleosides and Nucleotides 1048 24.12 Deoxyribonucleic Acid: DNA 7052 24.13 RNA and Protein Synthesis 7059

A N S W E R S T O SELECTED PROBLEMS A-1

GLOSSARY G-l

I N D E X 7-7