ORGANIC
`CHEMISTRY
`
`A
`Brief
`Course
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`MYLAN - EXHIBIT 1032
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`

`
`ABOUT THE COVER
`
`Roy Wiemann's cover painting depicts the spherical cluster of 60 carbon atoms
`known as "buckminsterfullerene." The existence of this substance was still contro­
`versial when it graced the cover of the first edition of F. A. Carey's Organic Chem­
`istry (McGraw-Hill, 1987), but its isolation has since been fully confirmed.
`
`Several figures are reproduced from other sources, and are acknowledged with the text. In addition, we wish
`to acknowledge the following:
`The 'H nuclear magnetic resonance spectra are reproduced with permission from "The Aldrich Library of
`NMR Spectra,"
`first edition, C.
`J. Pouchert and J. R. Campbell,
`the Aldrich Chemical Company, 1975, and
`from "The Aldrich Library of '3C and 'H FT NMR Spectra," Edition 1, C. J. Pouchert and J. Behnke, the
`Aldrich Chemical Company, 1993.
`Infrared spectra are reproduced with permission from the "The Aldrich Library of FT-IR Spectra," C. J.
`Pouchert,
`the Aldrich Chemical Company, 1985.
`Mass spectra are reproduced with permission from "EPA/NIH Mass Spectral Data Base," Supplement
`S. R. Heller and G. W. A. Milne, National Bureau of Standards, 1980.
`
`I,
`
`ORGANIC
`CHEMISTRY:
`A BRIEF COURSE
`
`SECOND EDITION
`
`ROBERT C. ATKINS
`James Madison University
`FRANCIS A. CAREY
`University of Virginia
`
`WCB
`McGraw-Hill
`Auckland
`St. Louis
`San Francisco
`New York
`Madrid
`Caracas
`Lisbon
`London
`Bogota
`Mexico City
`Milan
`Montreal
`New Delhi
`Singapore
`Sydney
`Tokyo
`Toronto
`
`San Juan
`
`

`
`WCB/McGraw-Hill
`
`A Division of The McGraw-Hill Companies
`ORGANIC CHEMISTRY: A BRIEF COURSE
`
`Copyright © 1997, 1990 by The McGraw-Hill Companies, Inc. All rights
`reserved. Printed in the United States of America. Except as permitted under the
`United States copyright Act of 1976, no part of this publication may be reproduced
`or distributed in any form or by any means, or stored in a data base or retrieval
`system, without the prior written permission of the publisher.
`
`Acknowledgments
`
`appear on page ii and on this page by reference.
`
`This book is printed on acid-free paper.
`
`2 3 4 5 6 7 8 9 0
`
`D O W D O W 9 0 9 8 7
`
`ISBN 0-07-011337-8
`
`This book was set in Times Roman by GTS Graphics.
`The editors were Karen J. Allanson, Sharon Geary, and David A. Damstra;
`the production supervisor was Denise L. Puryear.
`The cover was designed by Rafael Hernandez.
`The project was supervised by Deena Cloud.
`R. R. Donnelley & Sons Company was printer and binder.
`
`INTERNATIONAL EDITION
`
`Copyright © 1997, 1990. Exclusive rights by The McGraw-Hill Companies, Inc. For manufacture and
`export. This book cannot be re-exported from the country to which it is consigned by McGraw-Hill, The
`International Edition is not available in North America.
`
`When ordering this title, use ISBN 0-07-114005-0.
`
`Library of Congress Cataloging-in-Publication Data is available:
`LC Card #96-79060
`
`http://www.nihcollege.com
`
`{*
`
`ABOUT
`THE AUTHORS
`
`Robert C. Atkins was bom in Massachusetts and educated in New Jersey. He
`received an S.B. in chemistry from the Massachusetts Institute of Technology in
`1966 and a Ph.D. in organic chemistry from the University of Wisconsin at Madi­
`son in 1970. Following a year of postdoctoral study at Columbia University he was
`appointed to the faculty of James Madison University, where he holds the rank of
`professor of chemistry. He is the author of Study Guide to Accompany Chemistry:
`Principles and Applications (McGraw-Hill, 1979) and the coauthor (with Professor
`Carey) of Study Guide and Solutions Manual to Accompany Organic Chemistry
`(McGraw-Hill, 1996).
`Professor Atkins' research interests lie in the area of pyrolysis reaction mecha­
`nisms. He also has an active interest in laboratory safety, and has served for more
`than 20 years as his department's safety coordinator. For more than 10 years Pro­
`fessor Atkins also has volunteered as a technical advisor to both a local and a
`regional hazardous materials team.
`Bob and his wife Mary, a family nurse practitioner, have two grown children:
`CO
`^ Maureen, a college admissions counselor; and David, a Buddhist monk in Seoul.
`—
`South Korea.
`o
`
`ro
`jvj
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`S?
`c
`
`Francis A. Carey, a native of Pennsylvania, was educated in the public schools of
`Philadelphia, at Drexel University (B.S. in chemistry, 1959), and at Penn State (Ph.D.
`1963). Following postdoctoral work at Harvard and military service, he was
`appointed to the chemistry faculty of the University of Virginia in 1966 where he
`now holds the rank of professor of chemistry.
`With his students. Professor Carey has published over forty research papers in
`synthetic and mechanistic organic chemistry. He is coauthor (with Richard J. Sund-
`berg) of Advanced Organic Chemistry,
`
`a two-volume treatment designed for gradu-
`^ ate students and advanced undergraduates, and Organic Chemistry, a best-selling
`introductory text for the two-semester organic course.
`Professor Carey's main interest shifted from research to undergraduate education
`in the early 1980s. He regularly teaches both semesters of general chemistry and
`organic chemistry to classes of over 400 students. He enthusiastically embraces
`applications of electronic media to chemistry teaching and sees multimedia presen­
`tations as the wave of the present.
`Frank and his wife Jill, who is a teacher/director of a preschool and a church
`organist, are the parents of three grown sons. Andy is an environmental chemist;
`Bob, an attorney; and Bill, a jazz guitarist.
`
`^3-
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`O ot
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`at
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`V
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`

`
`CONTENTS
`
`PREFACE
`
`CHAPTER 1
`INTRODUCTION TO ORGANIC CHEMISTRY;
`CHEMICAL BONDING
`
`1.1 Atoms and Electrons
`1.2
`Ionic Bonds
`1.3
`Covalent Bonds
`1.4
`Multiple Bonding in Lewis Structures
`1.5
`Polar Covalent Bonds
`1.6
`Formal Charge
`1.7
`Writing Structural Formulas of Organic Molecules
`1.8
`Isomers and Isomerism
`1.9
`Resonance
`1.10 The Shapes of Some Simple Molecules
`1.11 Molecular Polarity
`1.12 Orbital Hybridization and Bonding in Methane
`Linus Pauling
`1-13 sp3 Hybridization and Bonding in Ethane
`1.14 sp2 Hybridization and Bonding in Ethylene
`1-15 sp Hybridization and Bonding in Acetylene
`1-16 Summary
`Learning Objectives
`Additional Problems
`
`CHAPTER 2
`ALKANES AND CYCLOALKANES
`
`2.1
`2-2
`2-3
`
`Families of Organic Compounds. Hydrocarbons
`Functional Groups in Hydrocarbons
`Functionally Substituted Derivatives of Alkanes
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`1
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`X
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`J
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`xii CONTENTS
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`CONTENTS x i i j
`
`2.4
`2.5
`2.6
`2.7
`2.8
`2.9
`2.10
`2.11
`2.12
`2.13
`2.14
`2.15
`2.16
`2.17
`2.18
`2.19
`2.20
`
`2.21
`
`Introduction to Alkanes: Methane
`Ethane and Propane
`Conformations of Ethane and Propane
`Isomeric Alkanes. The Butanes
`Higher Alkanes
`Systematic IUPAC Nomenclature of Unbranched Alkanes
`Applying the IUPAC Rules. The Names of the CgH^ Isomers
`Alkyl Groups
`IUPAC Names of Highly Branched Alkanes
`Cycloalkane Nomenclature
`Conformations of Cyclopropane, Cyclobutane, and Cyclopentane
`Conformations of Cyclohexane
`Conformational Inversion (Ring Flipping) in Cyclohexane
`Disubstituted Cycloalkanes and Stereoisomerism
`Polycyclic Ring Systems
`Physical Properties of Alkanes
`Combustion of Alkanes
`Learning Objectives
`Summary
`Additional Problems
`
`CHAPTER 3
`INTRODUCTION TO ORGANIC CHEMICAL REACTIONS:
`ALCOHOLS AND ALKYL HALIDES
`
`3.1 Nomenclature of Alcohols and Alkyl Halides
`The Common Alcohols: Methanol, Ethanol,
`and Isopropyl Alcohol
`3.2 Classes of Alcohols and Alkyl Halides
`3.3 Bonding and Physical Properties of Alcohols and Alkyl Halides
`3.4 Acid-Base Properties of Organic Molecules
`3.5 Alcohols as Br0nsted Bases
`3.6
`Preparation of Alkyl Halides from Alcohols and Hydrogen Halides
`3.7 Mechanism of the Reaction of Alcohols with Hydrogen Halides
`3.8
`Structure, Bonding, and Stability of Carbocations
`3.9 Electrophiles and Nucleophiles
`Learning Objectives
`3.10 Summary
`Additional Problems
`
`CHAPTER 4
`ALKENES AND ALKYNES I. STRUCTURE AND PREPARATION
`
`4.1 Alkene Nomenclature
`Ethylene and Propene
`4.2
`Structure and Bonding in Alkenes
`4.3
`Stereoisomerism in Alkenes
`4.4 Classification of Alkenes
`
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`4.5
`Preparation of Alkenes. Elimination Reactions
`4.6 Dehydration of Alcohols
`4.7 The Mechanism of Acid-Catalyzed Dehydration of Alcohols
`4.8 Dehydrohalogenation of Alkyl Halides
`4.9 The E2 Mechanism of Dehydrohalogenation
`4.10 A Different Mechanism for Alkyl Halide Elimination:
`The El Mechanism
`4.11 Alkyne Nomenclature
`4.12 Structure and Bonding in Alkynes
`4.13 Preparation of Alkynes by Elimination Reactions
`Learning Objectives
`4.14 Summary
`Additional Problems
`
`CHAPTER 5
`ALKENES AND ALKYNES II. REACTIONS
`
`5.4
`5.5
`5.6
`5.7
`
`5.1 Hydrogenation of Alkenes
`Electrophilic Addition of Hydrogen Halides to Alkenes
`5.2
`Orientation of Hydrogen Halide Addition to Alkenes.
`5.3
`Markovnikov's Rule
`Mechanistic Basis for Markovnikov's Rule
`Acid-Catalyzed Hydration of Alkenes
`Synthesis of Alcohols from Alkenes by Hydroboration-Oxidation
`Addition of Halogens to Alkenes
`Ethylene and Propene: The Most Important Industrial
`Organic Chemicals
`5.8
`Ozonolysis of Alkenes
`5.9
`Electrophilic Addition Reactions of Dienes
`5.10 The Diels-Alder Reaction
`5.11 Acidity of Acetylene and Terminal Alkynes
`5.12 Preparation of Alkynes by Alkylation
`5.13 Addition Reactions of Alkynes
`Hydrogenation
`Metal-Ammonia Reduction of Alkynes
`Addition of Hydrogen Halides to Alkynes
`Hydration of Alkynes
`5.14 Introduction to Organic Chemical Synthesis
`Learning Objectives
`5.15 Summary
`Additional Problems
`
`CHAPTER 6
`ARENES AND AROMATICITY
`
`6.1
`
`Structure and Bonding of Benzene
`Aromatic Compounds: History and Some Applications
`6.2 An Orbital Hybridization Model of Bonding in Benzene
`
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`x i y CONTENTS
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`CONTENTS XV
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`6.3 Nomenclature of Substituted Derivatives of Benzene
`6.4 Reactions of Arenes: Electrophilic Aromatic Substitution
`6.5 Mechanism of Electrophilic Aromatic Substitution
`6.6
`Intermediates in Electrophilic Aromatic Substitution
`Nitration
`Sulfonation
`Halogenation
`Friedel-Crafts Alkylation
`Friedel-Crafts Acylation
`6.7 Rate and Orientation in Electrophilic Aromatic Substitution
`Rate Effects of Substituents
`Orientation Effects of Substituents
`6.8 Mechanistic Explanation of Rate and Orientation Effects:
`Activating Groups
`6.9 Mechanistic Explanation of Rate and Orientation Effects:
`Deactivating Groups
`6.10 Mechanistic Explanation of Rate and Orientation Effects: Halogens
`6.11 Synthesis of Disubstituted Aromatic Compounds
`6.12 Aromatic Side-Chain Reactions
`6.13 Polycyclic Aromatic Hydrocarbons
`Chemical Carcinogens
`6.14 A General View of Aromaticity. Hiickei's Rule
`6.15 Heterocyclic Aromatic Compounds
`Learning Objectives
`6.16 Summary
`Additional Problems
`
`CHAPTER 7
`STEREOCHEMISTRY
`
`7.1 Mirror Images and Chirality
`7.2 Molecular Chirality. Enantiomers
`7.3 The Stereogenic Center
`7.4 Three-Dimensional Representations of Molecules. Perspective
`Views and Fischer Projections
`7.5
`Symmetry in Achiral Structures
`7.6 Optical Activity in Chiral Molecules
`7.7 Absolute Configurations
`7.8 The R-S Notational System of Absolute Configuration
`7.9 Naming Stereoisomeric Alkenes by the E-Z System
`7.10 Physical Properties of Enantiomers
`7.11 Stereochemistry of Chemical Reactions that Produce
`Stereogenic Centers
`Chiral Drugs
`7.12 Molecules with Two or More Stereogenic Centers
`7.13 Resolution of Enantiomers
`Learning Objectives
`7.14 Summary
`Additional Problems
`
`152
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`
`CHAPTER 8
`NUCLEOPHILIC SUBSTITUTION
`
`8.1
`8.2
`8.3
`
`Functional Group Transformation by Nucleophilic Substitution
`Relative Reactivity of Halide Leaving Groups
`Bimolecular Nucleophilic Substitution: The SN2 Mechanism
`Nucleophilic Substitution and Cancer
`Stereochemistry of SN2 Reactions
`Steric Effects in SN2 Reactions
`Unimolecular Nucleophilic Substitution: The SN1 Mechanism
`Carbocation Stability and the Rate of Substitution by
`the SN1 Mechanism
`Stereochemistry of SN1 Reactions
`Substitution and Elimination as Competing Reactions
`Learning Objectives
`8.10 Summary
`Additional Problems
`
`8.4
`8.5
`8.6
`8.7
`
`8.8
`8.9
`
`CHAPTER 9
`FREE RADICALS
`
`Structure and Stability of Free Radicals
`9.1
`9.2 Bond Dissociation Energies
`9.3 Chlorination of Methane
`9.4 Mechanism of Chlorination of Methane
`Halogenated Hydrocarbons and the Environment
`9.5 Halogenation of Alkanes
`9.6 Chlorofluorocarbons and the Environment
`9.7 Allylic Halogenation
`9.8
`Free-Radical Halogenation of Alkylbenzenes
`9.9
`Free-Radical Addition of Hydrogen Bromide to Alkenes
`9.10 Polymerization of Alkenes
`Free Radicals and Biology
`Learning Objectives
`9.11 Summary
`Additional Problems
`
`CHAPTER 10
`ALCOHOLS, ETHERS, AND PHENOLS
`
`10.1
`10.2
`10.3
`10.4
`10.5
`10.6
`10.7
`
`10.8
`
`Natural Sources of Alcohols
`Reactions that Yield Alcohols: A Review and a Preview
`Preparation of Alcohols by Reduction of Aldehydes and Ketones
`Reactions of Alcohols: A Review and a Preview
`Alcohols as Br0nsted Acids
`Conversion of Alcohols to Ethers
`Oxidation of Alcohols
`Biological Oxidation of Alcohols
`Introduction to Ethers
`
`213
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`X y i CONTENTS
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`CONTENTS XVH
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`10.9 Ether Nomenclature
`10.10 Ethers in Nature
`10.11 Preparation of Ethers
`10.12 Preparation of Epoxides
`10.13 Reactions of Epoxides
`Epoxides and Chemical Carcinogenesis
`10.14 Thiols
`10.15 Introduction to Phenols. Nomenclature
`10.16 Synthetic and Naturally Occurring Phenol Derivatives
`10.17 Acidity of Phenols
`10.18 Reactions of Phenols. Preparation of Aryl Ethers
`Accidental Formation of a Diaryl Ether: Dioxin
`10.19 Oxidation of Phenols. Quinones
`Learning Objectives
`10.20 Summary
`Additional Problems
`
`CHAPTER 11
`ALDEHYDES AND KETONES
`
`11.1 Nomenclature
`11.2
`Structure and Bonding of the Carbonyl Group
`11.3
`Physical Properties of Aldehydes and Ketones
`11.4
`Sources of Aldehydes and Ketones
`11.5 Reactions of Aldehydes and Ketones; A Review and a Preview
`Chemical Communication in the Insect World:
`How Bugs Bug Bugs
`11.6 Hydration of Aldehydes and Ketones
`11.7 Acetal Formation
`11.8 Cyanohydrin Formation
`11.9 Reaction with Primary Amines
`11.10 Reactions that Introduce New Carbon-Carbon Bonds.
`Organometallic Compounds
`Imines in Biological Chemistry
`11.11 Grignard Reagents
`11.12 Synthesis of Alcohols Using Grignard Reagents
`11.13 Grignard Reactions in Synthesis
`11.14 Oxidation of Aldehydes
`11.15 The a Carbon and Its Hydrogens
`11.16 Enols and Enolates. Enolization
`11.17 The Aldol Condensation
`Learning Objectives
`11.18 Summary
`Additional Problems
`
`CHAPTER 12
`CARBOXYLIC ACIDS
`
`12.1 Carboxylic Acid Nomenclature
`12.2
`Structure and Bonding of Carboxylic Acids
`12.3
`Physical Properties of Carboxylic Acids
`
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`12.8
`
`12.4 Acidity of Carboxylic Acids
`12.5
`Substituents and Acid Strength
`12.6
`Salts of Carboxylic Acids. Soap
`12.7
`Sources of Carboxylic Acids
`Prostaglandins
`Preparation of Carboxylic Acids by Carboxylation of
`Grignard Reagents
`12.9
`Preparation of Carboxylic Acids by the Hydrolysis of Nitriles
`12.10 Reactions of Carboxylic Acids
`Learning Objectives
`12.11 Summary
`Additional Problems
`
`CHAPTER 13
`CARBOXYLIC ACID DERIVATIVES
`
`13.1 Nomenclature of Carboxylic Acid Derivatives
`13.2
`Structure of Carboxylic Acid Derivatives
`13.3 Nucleophic Acyl Substitution. Hydrolysis
`Biological Acyl Transfer
`13.4 Natural Sources of Esters
`13.5
`Preparation of Esters. Fischer Esterification
`13.6 Mechanism of Fischer Esterification
`13.7
`Preparation of Esters. Additional Methods
`13.8 Reactions of Esters. Hydrolysis
`13.9 Reaction of Esters with Grignard Reagents
`13.10 Reduction of Esters
`13.11 Polyesters
`An Ester of an Inorganic Acid: Nitroglycerin
`13.12 Natural and Synthetic Amides
`13.13 Preparation of Amides
`13.14 Hydrolysis of Amides
`Learning Objectives
`13.15 Summary
`Additional Problems
`
`CHAPTER 14
`AMINES
`
`14.1
`14.2
`14.3
`
`14.4
`14.5
`14.6
`14.7
`14.8
`
`Amine Nomenclature
`Structure and Bonding of Amines
`Physical Properties of Amines
`Amines as Natural Products
`Basicity of Amines
`Preparation of Alkylamines by Alkylation of Ammonia
`Preparation of Alkylamines by Reduction
`Preparation of Arylamines
`Reactions of Amines: A Review and a Preview
`
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`xviii CONTENTS
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`CONTENTS xiX
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`14.9 Reaction of Amines with Alky! Halides
`14.10 The Hofmann Elimination
`14.11 Nitrosation of Amines
`14.12 Reactions of Aryl Diazonium Salts
`14.13 Azo Coupling
`Sulfa Drugs
`Learning Objectives
`14.14 Summary
`Additional Problems
`
`CHAPTER 15
`CARBOHYDRATES
`
`15.9
`
`15.1 Classification of Carbohydrates
`15.2 Glyceraldehyde and the D-L System of Stereochemical Notation
`15.3 The Aldotetroses
`15.4 Aldopentoses and Aldohexoses
`15.5 Cyclic Forms of Carbohydrates: Furanose Forms
`15.6 Cyclic Forms of Carbohydrates: Pyranose Forms
`15.7 Hemiacetal Equilibrium
`15.8 Ketoses
`Sweeteners in Food
`Structural Variations in Carbohydrates
`Deoxy Sugars
`Amino Sugars
`Branched-Chain Carbohydrates
`15.10 Glycosides
`15.11 Disaccharides
`15.12 Polysaccharides
`15.13 Oxidation of Carbohydrates
`Learning Objectives
`15.14 Summary
`Additional Problems
`
`CHAPTER 16
`AMINO ACIDS, PEPTIDES, AND PROTEINS
`
`16.1
`Structure of Amino Acids
`16.2
`Stereochemistry of Amino Acids
`16.3 Acid-Base Behavior of Amino Acids
`Electrophoresis
`16.4
`Synthesis of Amino Acids
`16.5
`Peptides
`16.6
`Peptide Structure Determination: Amino Acid Analysis
`16.7
`Peptide Structure Determination: Principles of Sequence Analysis
`16.8
`End Group Analysis: The N Terminus
`16.9 End Group Analysis: The C Terminus
`16.10 Selective Hydrolysis of Peptides
`16.11 The Strategy of Peptide Synthesis
`16.12 Protecting Groups and Peptide Bond Formation
`
`386
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`
`Solid-Phase Peptide Synthesis: The Merrifield Method
`16.13 Secondary Structures of Peptides and Proteins
`16.14 Tertiary Structure of Peptides and Proteins
`16.15 Protein Quaternary Structure. Hemoglobin
`Learning Objectives
`16.16 Summary
`Additional Problems
`
`CHAPTER 17
`LIPIDS
`
`17.1 Classification of Lipids
`17.2
`Fats and Fatty Acids
`17.3
`Phospholipids
`17.4 Waxes
`17.5
`Steroids. Cholesterol
`HDL, LDL, and Cholesterol
`17.6 Vitamin D
`17.7 Bile Acids
`17.8 Corticosteroids
`17.9
`Sex Hormones
`Anabolic Steroids
`17.10 Biosynthesis. Acetyl Coenzyme A
`17.11 Terpene Biosynthesis
`17.12 Isopentenyl Pyrophosphate. The Biological Isoprene Unit
`Learning Objectives
`17.13 Summary
`Additional Problems
`
`CHAPTER 18
`NUCLEIC ACIDS
`
`18.1
`18.2
`18.3
`18.4
`18.5
`18.6
`
`18.7
`
`Pyrimidines and Purines
`Nucleosides
`Nucleotides
`Nucleic Acids
`Structure and Replication of DNA. The Double Helix
`DNA-Directed Protein Biosynthesis
`Cancer Chemotherapy
`AIDS
`Learning Objectives
`Summary
`Additional Problems
`
`CHAPTER 19
`SPECTROSCOPY
`
`19.1
`Electromagnetic Radiation
`19.2 General Principles of Spectroscopic Analysis
`
`440
`442
`443
`446
`447
`448
`449
`
`453
`
`453
`453
`456
`457
`458
`458
`459
`460
`460
`461
`462
`463
`464
`467
`469
`469
`470
`
`473
`
`473
`474
`476
`477
`479
`481
`482
`484
`485
`486
`486
`
`488
`
`488
`490
`
`

`
`XX CONTENTS
`
`19.3
`19.4
`19.5
`19.6
`19.7
`19.8
`19.9
`
`19.10
`19.11
`19.12
`
`19.13
`19.14
`
`19.15
`
`19.16
`
`Infrared Spectroscopy
`Ultraviolet-Visible (UV-VIS) Spectroscopy
`Nuclear Magnetic Resonance Spectroscopy
`Nuclear Shielding and Chemical Shift
`How Chemical Shift is Measured
`Chemical Shift and Molecular Structure
`Interpreting Proton ('H) NMR Spectra
`Number of Signals
`Chemical Shifts
`Signal Intensities
`Spin-Spin Splitting in NMR Spectroscopy
`Patterns of Spin-Spin Splitting
`Connecting Spectroscopy and Structural Type
`Alcohols and Ethers
`Aldehydes and Ketones
`Carboxylic Acids
`Carboxylic Acid Derivatives
`Amines
`Magnetic Resonance Imaging
`Carbon-13 Nuclear Magnetic Resonance
`Mass Spectrometry
`Gas Chromatography, GC/MS, and MS/MS
`Molecular Formula as a Clue to Structure
`Learning Objectives
`Summary
`Additional Problems
`
`IN-TEXT PROBLEMS
`
`ANSWERS TO
`GLOSSARY
`INDEX
`
`491
`494
`496
`497
`497
`499
`500
`500
`501
`501
`502
`504
`506
`506
`507
`507
`509
`510
`511
`512
`514
`516
`518
`519
`519
`520
`
`A-l
`
`G-0
`
`1-1
`
`PREFACE
`
`"A combination of brevity and comprehensibility is by no means an easy thing to
`(Anonymous in the British weekly The Spectator, 1887).
`achieve."
`
`Our goal in writing the first edition was to prepare a text that was both modem
`in outlook and selective in coverage.
`This
`
`revision was undertaken in the same spirit.
`To that end, the second edition is strengthened by:
`
`• a new order of topics
`• clearer presentation of reaction mechanisms
`• a glossary
`• new graphics
`
`Who are the students in this course? They are a diverse and ambitious group,
`majoring in a variety of programs
`including biology, nutrition, engineering,
`agricul­
`tural sciences,
`environmental sciences,
`and the allied health sciences. They share
`in
`common a need to learn something about organic compounds, their structure, prop­
`erties, nomenclature, and applications, although not at the level of detail typical of
`the year-long organic chemistry course. Although the scope of the material to which
`they are exposed is less, these students still need to master the same reasoning
`processes as those who are enrolled in the more traditional two-semester
`sequence,
`and they need just as much guidance. We have designed this text to provide that
`guidance.
`This second edition, like the first edition, is characterized by:
`
`• a traditional functional-group organization
`• an emphasis on reaction mechanisms, including curved-arrow notation
`• an abundance of annotated summary tables
`• learning objectives
`• frequent presentation of solved sample problems to illustrate the reasoning
`processes used in organic chemistry
`• numerous boxed
`
`essays illustrating
`chemistry
`
`the
`
`
`
`development and applications of organic
`
`I
`
`i
`
`ORGANIZATION
`
`As the Table of Contents indicates, this text is organized according to families of
`organic compounds and their functional groups, but not blindly so. Certainly alkanes
`
`xxi
`
`

`
`B9KBZBHHB
`
`CHAPTER 13
`
`CARBOXYLIC ACID
`DERIVATIVES
`
`t
`c
`5"1
`
`w
`1
`II
`
`I
`
`he previous two chapters described three classes of organic compounds
`terized by the presence of a carbonyl |/C=oj
`boxylic acids. We will now expand our discussion to include the principal classes
`of these, esters and amides, are
`acid
`derivatives.
`Two
`especially
`of carboxylic
`tant in both organic and biochemistry and will receive particular
`emphasis.
`
`group: aldehydes,
`
`ketones, and car­
`
`charac­
`
`13.1 NOMENCLATURE OF CARBOXYLIC ACID
`DERIVATIVES
`
`Each of the carboxylic acid derivatives we will encounter possesses an acyl group>
`
`O
`
`O
`
`or ArC— attached to a halogen, oxygen, or nitrogen atom. The four classes
`R C —
`of carboxylic acid derivatives
`are:
`
`O
`
`1. Acyl chlorides: RCC1
`O O
`
`2. Anhydrides: RCOCR
`o
`3. Esters: RCOR'
`O
`
`O
`
`O
`
`344
`
`4. Amides: RCNH2,
`
`RCNHR',
`
`and
`
`RCNR'2
`
`13.1 NOMENCLATURE OF
`
`CARBOXYLIC
`
`ACID
`
`345
`DERIVATIVES
`
`The systematic names ot each class are based on the name of the corresponding
`carboxylic acid. Acyl chlorides are named by replacing the -ic acid ending of the
`carboxylic acid name with -yl chloride.
`
`O
`
`CHjCCl
`
`O
`
`C C I
`
`Acetyl chloride
`(from acetic acid)
`
`Benzoyl chloride
`(from benzoic acid)
`
`Anhydrides
`word anhydride.
`
`are named in a similar manner. The word acid is replaced with the
`
`o o
`
`C H 3 C O C C H 3
`
`o o
`coc
`
`/ \
`
`Acetic anhydride
`
`Benzoic anhydride
`
`The alkyl or aryl group and the acyl portion of an ester are specified indepen-
`dently.
`
`O
`
`RC—OR'
`t
`
`Acyl portion
`
`Alkyl or
`aryl group
`
`The alkyl or aryl group (R') attached
`first, followed by the acyl
`to oxygen is named
`portion as a separate word. The -ic ending of the corresponding
`
`acid is replaced by
`impor­
`•ate.
`
`o
`
`o
`
`C H 3 C O C H 2 C H 3
`
`C H 3 C H 2 C O C H 3
`
`o
`// \
`
`C O C H 2 C H 2 C I
`
`Ethyl acetate
`
`Methyl
`propanoate
`
`2-Chloroethyl
`benzoate
`
`O
`The names of amides of the type R C N H 2
`are derived from carboxylic acids by
`
`^ ac'ng the -oic (or -ic) acid ending with -amide.
`
`O
`
`C H 3 C N H 2
`
`/ \
`
`O
`
`O
`
`CNH2
`
`(CH3)2CHCH2CNH2
`
`Acetamide
`
`Benzamide
`
`3-Methylbutanamide
`
`Co
`
`o
`o
`type RCNHR' and RCNR'2 are named as /V-alkyl and /V./V-dialkyl
`0f the
`e derivatives of a parent amide.
`
`1
`
`...
`
`

`
`f
`
`346 CARBOXYLIC ACID
`
`DERIVATIVES
`
`13.2 STRUCTURE OF
`
`CARBOXYLIC
`
`ACID
`
`347
`DERIVATIVES
`
`its
`the carbonyl group and decreases
`Electron release from the substituent stabilizes
`electrophilic character.
`
`The of this electron extent
`
`delocalization depends on
`
`the elec­
`tron-donating properties of the substituent X. Generally, the less electronegative X
`is, the better it donates electrons to the carbonyl group and the greater its stabiliz­
`ing effect.
`Resonance stabilization in acyl chlorides is not nearly as pronounced as in other
`derivatives of carboxylic acids:
`
`CO;
`R—C ^
`Vfl
`:C1:
`
`R—C
`
`:0:
`
`:C1:
`
`Weak resonance
`stabilization
`
`O
`
`C H 3 C N H C H 3
`
`O
`
`/ \ CN(CH2 C H 3 ) 2
`
`O
`
`C H 3 C H2CH2CNCH( C H 3 ) 2
`
`/V-Methyl-
`acetamide
`
`N,W-Diethylbenzamide
`
`C H 3
`W-Isopropyl-W-
`methylbutanamide
`
`PROBLEM 13.1 Write a structural formula for each of the following compounds:
`
`(a) 2-Phenylbutanoyl chloride
`( b ) 2-Phenylbutanoic
`anhydride
`(c) Butyl 2-phenylbutanoate
`
`( d ) 2-Phenylbutyl butanoate
`(e) 2-Phenylbutanamide
`( f ) A/-Ethyl-2-phenylbutanamlde
`
`(a) When the name of an acyl group is followed by "chlo-
`SAMPLE SOLUTION
`ride," It designates
`an acyl chloride. A 2-phenylbutanoyl group is a four-carbon acyl unit
`that bears a phenyl substituent at C-2.
`
`O
`
`CH3CH2CHCCI
`1
`CeHs
`
`2-Phenylbutanoyl
`
`chloride
`
`13.2 STRUCTURE OF CARBOXYLIC ACID DERIVATIVES
`
`Like other carbonyl-containing compounds we have studied—aldehydes, ketones,
`and carboxylic
`acids—derivatives of carboxylic
`acids have a planar arrangement of
`bonds
`to the carbonyl
`group. An important
`
`structural feature of acyl chlorides,
`anhy­
`drides, esters, and amides is that the atom, X, attached to the acyl group bears an
`unshared pair of electrons
`that can interact with the carbonyl TT system, as shown in
`Figure 13.1.
`Electron delocalization in carboxylic acids and its derivatives is represented in
`from the following structures:
`resonance terms by contributions
`
`CO;
`R—C
`
`X
`
`:0:
`R—C ^
`NO.
`X
`
`= 0:
`/
`R—C
`\ +
`X
`
`I
`
`O
`
`X = OH; carboxylic
`acid
`X = CI: acyl
`chloride
`X = OCR; anhydride
`
`X
`
`o
`X = OR; ester
`X = NR2; amide
`
`FIGURE 13.1 The three a bonds originating at the carbonyl carbon are coplanar. T P
`of the carbonyl carbon, the carbonyl oxygen, and the atom by which group X is a,tacrie|0ca|ized-
`acyl group overlap to form an extended n system
`through which the TT electrons are
`
`rbits'5
`
`i
`
`l
`
`HUB
`
`The carbon-chlorine bond is long, and overlap between the 3p orbitals of chlorine
`and the TT orbital of the carbonyl group is poor. Consequently, there is little delo­
`calization of the electron pairs of chlorine
`into the TT system. The carbonyl group of
`an acyl chloride
`feels
`
`the normal electron-withdrawing inductive
`effect
`of a chlorine
`
`substituent without a significant
`compensating electron-releasing
`effect due to lone-
`pair donation by chlorine. This makes the carbonyl carbon of an acyl chloride more
`susceptible to attack by nucleophiles than that of other carboxylic acid derivatives.
`Anhydrides are better stabilized by electron delocalization
`than are acyl chlorides.
`The lone-pair electrons
`of oxygen are delocalized more effectively into the carbonyl
`group. Resonance involves both carbonyl groups of an anhydride.
`p
`:0:
`:0:
`c. .(>C^
`o
`R
`The carbonyl group of an ester is stabilized more than is that of an anhydride.
`Since both acyl groups of an anhydride compete
`for the oxygen lone pair, each car­
`bonyl is stabilized less than the single carbonyl group of an ester.
`
`:0:
`Cj
`
`:0:
`
`R
`
`R
`
`R
`
`:0:
`c
`
`O
`
`R
`
`--O:
`c
`
`R
`
`CO:
`R—C ^
`OR'
`Ester
`
`O:
`
`O
`
`is more effective
`
`than
`R
`
`C^7.
`O
`
`R
`
`Anhydride
`
`Esters are stabilized by resonance to about the same extent as carboxylic acids
`hill
`not as much as amides. Nitrogen is less electronegative than oxygen and is a
`tter electron-pair donor.
`
`CO:
`R—C _
`NfT1.
`NR'2
`
`:0:
`/
`R—C
`
`NR'2
`
`Very effective
`resonance
`stabilization
`
`Electr
`on release from nitrogen stabilizes the carbonyl group of amides and
`deer
`eases the rate at which nucleophiles attack the carbonyl carbon. Nucleophilic
`fconhT8 attack electrophilic
`
`sites in a molecule; if electrons
`are donated to an elec-
`t lc s'te in a molecule by a substituent, then the tendency of that molecule to
`with nucleophiles decreases.
`
`r
`L
`
`y
`">
`
`—1
`
`, **
`
`

`
`348 CARBOXYLIC ACID
`
`DERIVATIVES
`
`13.3 NUCLEOPHILIC ACYL
`
`SUBSTITUTION.
`
`349
`HYDROLYSIS
`
`O
`
`philic substitution in alkyl chlorides. Benzoyl chloride (C6H5CCI),
`for example,
`reacts with water almost 1000 times faster
`than benzyl chloride (C6H5CH2C1) does.
`Nucleophilic acyl substitution does not involve unstable intermediates such as the
`carbocations
`formed in SN1 reactions of alkyl halides, nor does it proceed by way
`of the crowded transition
`states that characterize the SN2 mechanism of nucleophilic
`alkyl substitution. The transition state for nucleophilic acyl substitution leads to an
`intermediate that has a tetrahedral arrangement of bonds.
`
`PROBLEM 13.2
`of the strong Irrl-
`Acyl chlorides are called lachrymators because
`tating effect they have on the eyes. This effect comes about from the reaction with
`moisture naturally present in our eyes. Write a balanced equation showing the reaction
`of benzoyl chloride with water, and outline a mechanism for this reaction.
`
`The relative ease of hydrolysis of the various acid derivatives can be used as a
`measure of the chemical reactivity of these compounds. Acyl chlorides undergo
`hydrolysis 100 billion times faster than esters. In fact, the reaction of an acyl chlo­
`ride with water can occur with explosive
`force, producing large quantities of heat.
`
`BIOLOGICAL ACYL TRANSFER
`
`1
`
`c
`
`Gil;
`
`»
`
`mi
`HI
`
`-
`
`13.3 NUCLEOPHILIC ACYL SUBSTITUTION. HYDROLYSIS
`
`reaction of carboxylic acid derivatives is nucleophilic acyl sub­
`The most important
`stitution as represented by the general equation;
`
`O
`
`O
`
`RCY + HZ: (orZO
`
`> RCZ + HY: (orY:")
`
`the various carboxylic
`substitution is the main process by which
`
`acyl
`Nucleophilic
`are inferconverted,
`
`both in the laboratory and in biological
`systems.
`acid derivatives
`To illustrate the mechanism of the reaction, let us examine the hydrolysis of an acyl
`derivative. Hydrolysis is the reaction with water, and it converts the various car­
`boxylic acid derivatives to the corresponding carboxylic acid.
`
`O
`
`O
`
`+ H20
`RCY
`Carboxylic acid
`Water
`derivative
`
`> RCOH +
`Carboxylic
`acid
`
`HY
`Conjugate acid
`of leaving group
`
`Acyl chlorides (Y = CI) react rapidly with water. The accepted mechanism for
`hydrolysis
`of an acyl chloride is outlined in Figure 13.2.
`addition to the
`In the first stage of the mechanism, water undergoes nucleophilic