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This page intentionally left blank 16 VIA Lanthanum 138.91 89 Barium 137.33 88 Cesium 132.91 87 Francium (223) Actinium (227) # Actinide Se ries *Lanthanide Se ries Radium (226) Ra #Ac *La Ba Cs Fr 57 56 55 Zr Y Yttrium 88.906 Sr Strontium 87.62 Rb Rubidium 85.468 40 39 38 37 Ti 59 Pr Praseodymium 140.91 91 Pa Protactinium 231.04 58 Ce Cerium 140.12 90 Th Thorium 232.04 (261) Dubnium (262) Db 105 Tantalum 180.95 Ta 73 Niobium 92.906 Nb 41 Vanadium 50.942 V 23 Rutherfordium Rf 104 Hafnium 178.49 Hf 72 Zirconium 91.224 Titanium 47.867 Sc Scandium 44.956 Ca Calcium 40.078 K Potassium 39.098 22 21 20 19 Mn 25 Tc 43 Ru 44 Iron 55.845 Fe 26 62 Hassium (277) Hs 108 Osmium 190.23 Os 76 101.07 Pm Sm 61 Bohrium (264) Bh 107 Rhenium 186.21 Re 75 (98) Uranium 238.03 U 92 Neptunium (237) Np 93 Plutonium (244) Pu 94 Neodymium Promethium Sama rium (145) 150.36 144.24 Nd 60 Seaborgium (266) Sg 106 Tungsten 183.84 W 74 95.94 Molybdenum Technetium Ruthenium Mo 42 Chromium Manganese 51.996 54.938 Cr 24 Ds 110 Platinum 195.08 Pt 78 Palladium 106.42 Pd 46 Nickel 58.693 Ni 28 Rg 111 Gold 196.97 Au 79 Silver 107.87 Ag 47 Copper 63.546 Cu 29 11 IB Cn 112 Mercury 200.59 Hg 80 Cadmium 112.41 Cd 48 Zinc 65.409 Zn 30 12 IIB 96 Gadolinium 157.25 Gd 64 Americium (243) Curium (247) Am Cm 95 Europium 151.96 Eu 63 Berkelium (247) Bk 97 Terbium 158.93 Tb 65 Es 99 Holmium 164.93 Ho 67 (284) Uut 113 Thallium 204.38 Tl 81 Indium 114.82 In 49 Gallium 69.723 Ga 31 Aluminum 26.982 Californium Einsteinium (251) (252) Cf 98 Dysprosium 162.50 Dy 66 Meitnerium Darmstadtium Roentgenium Copernicium (268) (281) (272) (285) Mt 109 Iridium 192.22 Ir 77 Rhodium 102.91 Rh 45 Cobalt 58.933 Co 27 10 VIIIB S 9 VIIIB P 7 VIIB 8 VIIIB Si 5 VB Al 4 IVB 3 IIIB Mg Magnesium 24.305 Na Sodium 22,990 16 15 14 13 Fermium (257) Fm 100 Erb; ium 167.26 Er 68 Flerovium (289) Fl 114 Lead 207.2 Pb 82 Tin 118.71 Sn 50 Ge rmanium 72.64 Ge 32 Silicon 28.086 116 Polonium (209) Po 84 Tellurium 127.60 Te 52 Selenium 78.96 Se 34 Sulfur 32.065 Oxygen 15.999 O (258) Mendelevium Md 101 Thulium 168.93 Tm 69 (288) Nobelium (259) No 102 Ytterbium 173.04 Yb 70 Livermorium (293) Uup Lv 115 Bismuth 208.98 Bi 83 Antimony 121.76 Sb 51 Arsenic 74.922 As 33 Phosphorus 30.974 Nitrogen 14.007 N 8 12 Carbon 12.011 C 7 11 B 6 Boron 10.811 Carbon 12.011 5 Berylium 9.0122 6 VIB 15 VA Lithium 6.941 14 IVA Be 13 IIIA LI IUPAC recommendations: Chemical Abstracts Service group notation: 4 C 3 Symbol Name (IUPAC) Atomic mass 2 IIA H Hydrogen 1.0079 6 17 VIIA 118 Radon (222) Rn 86 Xenon 131.29 Xe 54 Krypton 83.798 Kr 36 Argon 39.948 Ar 18 Neon 20.180 Ne 10 Lawrencium (262) Lr 103 Lutetium 174.97 Lu 71 (294) (294) Uus Uuo 117 Astatine (210) At 85 Iodine 126.90 I 53 Bromine 79.904 Br 35 Chlorine 35.453 Cl 17 Fluorine 18.998 F 9 Helium 4.0026 He 2 Atomic number 1 EL E M E N T S 18 VIIIA OF THE 1 IA PE R I O D I C TA B L E Table 3.1 Relative Strength of Selected Acids and Their Conjugate Bases Acid Strongest acid Approximate pKa HSbF6 HI H2SO4 HBr HCl C6H5SO3H + (CH3)2OH + (CH3)2C=OH C6H5NH+ 3 CH3CO2H H2CO3 CH3COCH2COCH3 NH+ 4 C6H5OH HCO− 3 Weakest acid CH3NH+ 3 H2O CH3CH2OH (CH3)3COH CH3COCH3 HC≡CH C6H5NH2 H2 (i-Pr)2NH NH3 CH2=CH2 CH3CH3 −2.5 −1.74 −1.4 0.18 3.2 4.21 4.63 4.75 6.35 9.0 9.2 9.9 10.2 10.6 15.7 16 18 19.2 25 31 35 36 38 44 50 SbF− 6 I− HSO− 4 Br− Cl− C6H5SO− 3 (CH3)2O (CH3)2C=O Weakest base CH3OH H2O NO− 3 CF3CO− 2 F− C6H5CO− 2 C6H5NH2 CH3CO− 2 HCO− 3 − CH3COCHCOCH3 NH3 Increasing base strength Increasing acid strength + (CH3)OH2 H3O+ HNO3 CF3CO2H HF C6H5CO2H < −12 −10 −9 −9 −7 −6.5 −3.8 −2.9 Conjugate Base C6H5O− CO32− CH3NH2 HO− CH3CH2O− (CH3)3CO− − CH2COCH3 HC≡C− C6H5NH− H− (i-Pr)2N− − NH2 CH2=CH− CH3CH− 2 Strongest base Organic Chemistry T.W. Graham Solomons University of South Florida Craig B. Fryhle Pacific Lutheran University Scott A. Snyder University of Chicago 12e For Annabel and Ella. TWGS For my mother and in memory of my father. CBF For Cathy and Sebastian. SAS Vice President and Director: Petra Recter Development Editor: Joan Kalkut Associate Development Editor: Alyson Rentrop Senior Marketing Manager: Kristine Ruff Associate Director, Product Delivery: Kevin Holm Senior Production Editor: Elizabeth Swain Senior Designer: Maureen Eide Product Designer: Sean Hickey Senior Photo Editor: Mary Ann Price Design Director: Harry Nolan Text And Cover Designer: Maureen Eide Cover Images: Moai at Ahu Nau-Nau. Easter Island, Chile credit: Luis Castaneda Inc./Getty Images. Ahu Raraku Easter Island, Chile credit: Joshua Alan Davis/Getty Images. Medicine Bottle Credit: Frankhuang/Getty Images. Structure image from the RCSB PDB (www.rcsb.org) of 1FKB (Van Duyne, G. D., Standaert, R. F., Schreiber, S. L., Clardy, J. C. (1992) Atomic Structure of the Ramapmycin Human Immunophilin Fkbp-12 Complex, J. Amer. Chem. Soc. 1991, 113, 7433.) created with JSMol. This book is printed on acid-free paper. Copyright © 2016, 2014, 2011, 2008 John Wiley & Sons, Inc. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, scanning, or otherwise, except as permitted under Sections 107 or 108 of the 1976 United States Copyright Act, without either the prior written permission of the Publisher, or authorization through payment of the appropriate per-copy fee to the Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923, website www.copyright.com. Requests to the Publisher for permission should be addressed to the Permissions Department, John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030-5774, (201)748-6011, fax (201)748-6008, website http://www.wiley.com/go/permissions. Evaluation copies are provided to qualified academics and professionals for review purposes only, for use in their courses during the next academic year. These copies are licensed and may not be sold or transferred to a third party. Upon completion of the review period, please return the evaluation copy to Wiley. Return instructions and a free of charge return shipping label are available at www.wiley.com/go/returnlabel. Outside of the United States, please contact your local representative. Library of Congress Cataloging-in-Publication Data Names: Solomons, T. W. Graham, author. | Fryhle, Craig B. | Snyder, S. A. (Scott A.) Title: Organic chemistry. Description: 12th edition / T.W. Graham Solomons, Craig B. Fryhle, Scott A. Snyder. | Hoboken, NJ : John Wiley & Sons, Inc., 2016. | Includes index. Identifiers: LCCN 2015042208 | ISBN 9781118875766 (cloth) Subjects: LCSH: Chemistry, Organic—Textbooks. Classification: LCC QD253.2 .S65 2016 | DDC 547—dc23 LC record available at http://lccn.loc.gov/2015042208 ISBN 978-1-118-87576-6 Binder-ready version ISBN 978-1-119-07725-1 The inside back cover will contain printing identification and country of origin if omitted from this page. In addition, if the ISBN on the back cover differs from the ISBN on this page, the one on the back cover is correct. Printed in the United States of America 10 9 8 7 6 5 4 3 2 1 Brief Contents 1 The Basics Bonding and Molecular Structure 1 2 Families of Carbon Compounds Functional Groups, Intermolecular Forces, and Infrared (IR) Spectroscopy 55 3 Acids and Bases An Introduction to Organic R eactions and Their Mechanisms 104 4 Nomenclature and Conformations of Alkanes and Cycloalkanes 144 5 Stereochemistry Chiral Molecules 193 6 Nucleophilic Reactions Properties and Substitution Reactions of Alkyl Halides 240 7 Alkenes and Alkynes I Properties and Synthesis. Elimination Reactions of Alkyl Halides 282 8 Alkenes and Alkynes II Addition Reactions 337 9 Nuclear Magnetic Resonance and Mass Spectrometry Tools for Structure Determination 391 10 Radical Reactions 448 11 Alcohols and Ethers Synthesis and Reactions 489 12 Alcohols from Carbonyl Compounds Oxidation–Reduction and O rganometallic Compounds 534 13 Conjugated Unsaturated Systems 572 14 Aromatic Compounds 617 15 Reactions of Aromatic Compounds 660 16 Aldehydes and Ketones Nucleophilic Addition to the C arbonyl Group 711 17 Carboxylic Acids and Their Derivatives Nucleophilic Addition–Elimination at the Acyl Carbon 761 18 Reactions at the α Carbon of Carbonyl Compounds Enols and Enolates 811 19 Condensation and Conjugate Addition Reactions of Carbonyl Compounds More Chemistry of Enolates 849 20 21 22 23 24 25 Amines 890 Transition Metal Complexes Promoters of Key Bond-Forming Reactions 938 Carbohydrates 965 Lipids 1011 Amino Acids and Proteins 1045 Nucleic Acids and Protein Synthesis 1090 Glossary GL-1 Index I-1 Answers to Selected Problems can be found at www.wiley.com/college/solomons iii Contents 1 2 The Basics Families of Carbon Compounds Bonding and Molecular Structure 1 Functional Groups, Intermolecular Forces, and Infrared (IR) Spectroscopy 55 1.1 Life and the Chemistry of Carbon Compounds—We Are Stardust 2 The Chemistry of… Natural Products 2.1 Hydrocarbons: Representative Alkanes, Alkenes, Alkynes, and Aromatic Compounds 56 3 1.2 Atomic Structure 3 2.2 Polar Covalent Bonds 59 1.3 Chemical Bonds: The Octet Rule 5 2.3 Polar and Nonpolar Molecules 61 1.4 How To Write Lewis Structures 2.4 Functional Groups 64 1.5 Formal Charges and How To Calculate Them 12 2.5 Alkyl Halides or Haloalkanes 65 2.6 Alcohols and Phenols 67 2.7 Ethers 7 1.6 Isomers: Different Compounds that Have the Same Molecular Formula 14 69 1.7 How To Write and Interpret Structural Formulas 1.8 Resonance Theory 22 Anesthetics 69 1.9 Quantum Mechanics and Atomic Structure 27 2.8 Amines 1.10 Atomic Orbitals and Electron Configuration 28 2.9 Aldehydes and Ketones 71 1.11 Molecular Orbitals 30 2.10 Carboxylic Acids, Esters, and Amides 73 1.12 The Structure of Methane and Ethane: sp3 Hybridization 32 2.11 Nitriles 75 15 The Chemistry of… Calculated Molecular Models: Electron Density Surfaces 36 The Chemistry of… Ethers as General 70 2.12 Summary of Important Families of Organic Compounds 76 2.13 Physical Properties and Molecular Structure 77 1.13 The Structure of Ethene (Ethylene): sp 2 Hybridization 36 The Chemistry of… Fluorocarbons and Teflon 1.14 The Structure of Ethyne (Acetylene): sp Hybridization 40 1.15 A Summary of Important Concepts that Come from Quantum Mechanics 43 2.14 Summary of Attractive Electric Forces 85 The Chemistry of… Organic Templates Engineered to Mimic Bone Growth 86 2.15 Infrared Spectroscopy: An Instrumental Method for Detecting Functional Groups 86 1.16 H ow To Predict Molecular G eometry: The Valence epulsion Model 44 Shell Electron Pair R 2.16 Interpreting IR Spectra 90 1.17 Applications of Basic Principles 47 2.17 Applications of Basic Principles 97 [ WHY DO THESE TOPICS MATTER? ] [ WHY DO THESE TOPICS MATTER? ] iv 48 81 97 3 Acids and Bases An Introduction to Organic R eactions and Their Mechanisms 104 Acid–Base Reactions 3.2 How To Use Curved Arrows in Illustrating 105 107 Reaction of Water with Hydrogen Chloride: The Use of Curved Arrows 107 [ A MECHANISM FOR THE REACTION ] 3.3 How To Name Alkanes, Alkyl Halides, and Alcohols: The IUPAC System 148 4.4 How to Name Cycloalkanes 155 4.5 How To Name Alkenes and Cycloalkenes 4.6 How To Name Alkynes 158 160 4.7 Physical Properties of Alkanes and Cycloalkanes 161 3.1 Reactions 4.3 Lewis Acids and Bases 109 The Chemistry of… Pheromones: Communication by Means of Chemicals 163 4.8 Sigma Bonds and Bond Rotation 164 4.9 Conformational Analysis of Butane 166 The Chemistry of… Muscle Action 168 3.4 Heterolysis of Bonds to Carbon: Carbocations and Carbanions 111 4.10 The Relative Stabilities of Cycloalkanes: Ring Strain 168 3.5 The Strength of Brønsted–Lowry Acids and Bases: Ka and pKa 113 4.11 Conformations of Cyclohexane: The Chair and the Boat 170 How To Predict the Outcome of Acid–Base 3.6 Reactions 118 The Chemistry of… Nanoscale Motors and Molecular 3.7 Relationships between Structure and Acidity 120 3.8 Energy Changes 123 4.12 Substituted Cyclohexanes: Axial and Equatorial Hydrogen Groups 173 Switches 172 3.9 The Relationship between the Equilibrium Constant and the Standard Free-Energy Change, ∆G ° 125 4.13 Disubstituted Cycloalkanes: Cis–Trans Isomerism 177 3.10 Acidity: Carboxylic Acids versus Alcohols 126 4.14 Bicyclic and Polycyclic Alkanes 181 3.11 The Effect of the Solvent on Acidity 132 4.15 Chemical Reactions of Alkanes 182 3.12 Organic Compounds as Bases 132 4.16 Synthesis of Alkanes and Cycloalkanes 182 3.13 A Mechanism for an Organic Reaction 134 4.17 H ow To Gain Structural Information from Molecular Formulas and the Index of Hydrogen Deficiency 184 Reaction of tert-Butyl Alcohol with Concentrated Aqueous HCl 134 [ A MECHANISM FOR THE REACTION ] 3.14 Acids and Bases in Nonaqueous Solutions 135 3.15 Acid–Base Reactions and the Synthesis of Deuterium- and Tritium-Labeled Compounds 136 3.16 Applications of Basic Principles 137 [ WHY DO THESE TOPICS MATTER? ] 187 See Special Topic A, 13C NMR Spectroscopy—A Practical Introduction, in WileyPLUS 5 Stereochemistry Chiral Molecules 193 Nomenclature and Conformations of Alkanes and Cycloalkanes 5.1 Shapes of Alkanes 146 Chirality and Stereochemistry 194 5.2 Isomerism: Constitutional Isomers and Stereoisomers 195 5.3 Introduction to Alkanes and Cycloalkanes 145 The Chemistry of… Petroleum Refining 4.2 [ WHY DO THESE TOPICS MATTER? ] 138 4 4.1 4.18 Applications of Basic Principles 186 145 Enantiomers and Chiral Molecules 197 5.4 Molecules Having One Chirality Center are Chiral 198 5.5 More about the Biological Importance of Chirality 201 v 5.6 How To Test for Chirality: Planes of Symmetry 203 5.7 Naming Enantiomers: The R,S-System 204 5.8 Properties of Enantiomers: Optical Activity 208 5.9 Racemic Forms 213 Mechanism for [ A MECHANISM FOR THE REACTION ] the SN1 Reaction 256 6.11 Carbocations 257 6.12 The Stereochemistry of SN1 Reactions 259 The [ A MECHANISM FOR THE REACTION ] 5.10 The Synthesis of Chiral Molecules 214 Stereochemistry of an SN1 Reaction 260 5.11 Chiral Drugs 216 The Chemistry of… Selective Binding of Drug Enantiomers to Left- and Right-Handed Coiled DNA 218 6.13 Factors Affecting the Rates of SN1 and SN2 Reactions 262 5.12 Molecules with More than One Chirality Center 218 6.14 Organic Synthesis: Functional Group Transformations Using SN2 Reactions 272 5.13 Fischer Projection Formulas 224 The Chemistry of… Biological Methylation: A Biological 5.14 Stereoisomerism of Cyclic Compounds 226 5.15 Relating Configurations through Reactions in Which No Bonds to the Chirality Center Are Broken 228 5.16 Separation of Enantiomers: Resolution 232 5.17 Compounds with Chirality Centers Other than Carbon 233 234 Alkenes and Alkynes I Introduction 283 7.2 The (E )–(Z ) System for Designating Alkene Diastereomers 283 Nucleophilic Reactions Properties and Substitution Reactions of Alkyl Halides 240 6.1 Alkyl Halides 241 6.2 Nucleophilic Substitution Reactions 242 6.3 Nucleophiles 244 6.4 Leaving Groups Relative Stabilities of Alkenes 284 7.4 Cycloalkenes 7.5 Synthesis of Alkenes: Elimination Reactions 287 7.6 Dehydrohalogenation 288 7.7 The E2 Reaction 289 287 [ A MECHANISM FOR THE REACTION ] Mechanism for the E2 Reaction 290 E2 Elimination Where There Are Two Axial β Hydrogens 295 A Mechanism for the SN2 Reaction [ A MECHANISM FOR THE REACTION ] 247 Mechanism for E2 Elimination Where the Only Axial β Hydrogen Is from a Less Stable Conformer 296 [ A MECHANISM FOR THE REACTION ] 7.8 The E1 Reaction 297 [ A MECHANISM FOR THE REACTION ] the SN2 Reaction 248 6.7 Transition State Theory: Free-Energy Diagrams 249 6.8 The Stereochemistry of SN2 Reactions [ A MECHANISM FOR THE REACTION ] Stereochemistry of an SN2 Reaction 7.3 [ A MECHANISM FOR THE REACTION ] 246 6.5 Kinetics of a Nucleophilic S ubstitution Reaction: An SN2 Reaction 246 252 The 254 6.9 The Reaction of tert-Butyl Chloride with Water: An SN1 Reaction 254 6.10 A Mechanism for the SN1 Reaction vi 275 7 7.1 6 6.6 [ WHY DO THESE TOPICS MATTER? ] Properties and Synthesis. Elimination Reactions of Alkyl Halides 282 5.18 Chiral Molecules that Do Not Possess a Chirality Center 233 [ WHY DO THESE TOPICS MATTER? ] Nucleophilic Substitution Reaction 273 255 Mechanism for the E1 Reaction 298 7.9 Elimination and Substitution Reactions Compete With Each Other 299 7.10 Elimination of Alcohols: Acid-Catalyzed Dehydration 303 Acid-Catalyzed Dehydration of Secondary or Tertiary Alcohols: An E1 Reaction 306 [ A MECHANISM FOR THE REACTION ] Dehydration of a [ A MECHANISM FOR THE REACTION ] Primary Alcohol: An E2 Reaction 308 7.11 Carbocation Stability and the Occurrence of Molecular Rearrangements 308 8.5 Alcohols from Alkenes through Oxymercuration–Demercuration: Markovnikov Addition 349 [ A MECHANISM FOR THE REACTION ] [ A MECHANISM FOR THE REACTION ] Oxymercuration 351 7.12 The Acidity of Terminal Alkynes 312 8.6 Alcohols from Alkenes through Hydroboration–Oxidation: Anti-Markovnikov Syn Hydration 352 7.13 Synthesis of Alkynes by Elimination Reactions 313 8.7 [ A MECHANISM FOR THE REACTION ] [ A MECHANISM FOR THE REACTION ] Dehydrohalogenation of vic-Dibromides to Form Alkynes 314 Hydroboration Formation of a Rearranged Alkene During Dehydration of a Primary Alcohol 311 8.8 7.14 Terminal Alkynes Can Be Converted to Nucleophiles for Carbon–Carbon Bond Formation 315 7.15 Hydrogenation of Alkenes 317 Industry Oxidation and Hydrolysis of Alkylboranes 355 Oxidation of Trialkylboranes 356 Summary of Alkene Hydration Methods 358 8.10 Protonolysis of Alkylboranes 359 318 7.16 Hydrogenation: The Function of the Catalyst 319 7.17 Hydrogenation of Alkynes 320 The Dissolving [ A MECHANISM FOR THE REACTION ] 354 [ A MECHANISM FOR THE REACTION ] 8.9 The Chemistry of… Hydrogenation in the Food Hydroboration: Synthesis of Alkylboranes 353 Metal Reduction of an Alkyne 321 8.11 Electrophilic Addition of Bromine and Chlorine to Alkenes 359 Addition of [ A MECHANISM FOR THE REACTION ] Bromine to an Alkene 361 The Chemistry of… The Sea: A Treasury of Biologically 7.18 An Introduction to Organic Synthesis 322 Active Natural P roducts 362 The Chemistry of… From the Inorganic to the 8.12 Stereospecific Reactions 363 Organic 324 [ The stereochemistry of the Reaction ] [ WHY DO THESE TOPICS MATTER? ] 326 Addition of Bromine to cis- and trans-2-Butene 364 8.13 Halohydrin Formation 364 8 Halohydrin [ A MECHANISM FOR THE REACTION ] Formation from an Alkene 365 Alkenes and Alkynes II The Chemistry of… Citrus-Flavored Soft Drinks 366 8.14 Divalent Carbon Compounds: Carbenes 366 Addition Reactions 337 8.15 Oxidation of Alkenes: Syn 1,2-Dihydroxylation 368 8.1 Addition Reactions of Alkenes 338 The Chemistry of… Catalytic Asymmetric 8.2 Electrophilic Addition of Hydrogen Halides to Alkenes: Mechanism and Markovnikov’s Rule 340 [ A MECHANISM FOR THE REACTION ] Addition of a Hydrogen Halide to an Alkene 341 [ A MECHANISM FOR THE REACTION ] Dihydroxylation 370 8.16 Oxidative Cleavage of Alkenes 371 Ozonolysis of [ A MECHANISM FOR THE REACTION ] an Alkene 373 Addition of HBr to 2-Methylpropene 343 8.3 Stereochemistry of the Ionic Addition to an Alkene 345 [ The stereochemistry of the Reaction ] Ionic 8.17 Electrophilic Addition of Bromine and Chlorine to Alkynes 374 8.18 Addition of Hydrogen Halides to Alkynes 374 Addition to an Alkene 345 8.19 Oxidative Cleavage of Alkynes 375 8.4 Addition of Water to Alkenes: Acid-Catalyzed Hydration 346 8.20 H ow to Plan a Synthesis: Some Approaches and Examples 376 [ A MECHANISM FOR THE REACTION ] Hydration of an Alkene 346 Acid-Catalyzed [ WHY DO THESE TOPICS MATTER? ] 381 vii 9 Nuclear Magnetic Resonance and Mass Spectrometry Introduction 10.3 Reactions of Alkanes with Halogens 454 Radical [ A MECHANISM FOR THE REACTION ] Chlorination of Methane 456 10.5 392 Halogenation of Higher Alkanes 459 Radical [ A MECHANISM FOR THE REACTION ] 9.2 Nuclear Magnetic Resonance (NMR) Spectroscopy 392 9.3 Homolytic Bond Dissociation Energies (DH °) 451 10.4 Chlorination of Methane: Mechanism of Reaction 456 Tools for Structure Determination 391 9.1 10.2 Halogenation of Ethane 459 10.6 How To Interpret Proton NMR Spectra 398 9.4 Shielding and Deshielding of Protons: More about Chemical Shift 401 9.5 Chemical Shift Equivalent and Nonequivalent Protons 403 The Geometry of Alkyl Radicals 462 10.7 Reactions that Generate Tetrahedral Chirality Centers 462 The Stereochemistry of Chlorination at C2 of Pentane 463 [ A MECHANISM FOR THE REACTION ] The [ A MECHANISM FOR THE REACTION ] 9.6 Spin–Spin Coupling: More about Signal Splitting and Nonequivalent or Equivalent Protons 407 Stereochemistry of Chlorination at C3 of (S)-2-Chloropentane 464 9.7 Proton NMR Spectra and Rate Processes 412 10.8 Allylic Substitution and Allylic Radicals 466 9.8 Carbon-13 NMR Spectroscopy 414 10.9 Benzylic Substitution and Benzylic Radicals 469 9.9 Two-Dimensional (2D) NMR Techniques 420 10.10 Radical Addition to Alkenes: The Anti-Markovnikov Addition of Hydrogen Bromide 472 The Chemistry of… Magnetic Resonance Imaging in Medicine 423 Anti- [ A MECHANISM FOR THE REACTION ] 9.10 An Introduction to Mass Spectrometry 423 Markovnikov Addition of HBr 472 9.11 Formation of Ions: Electron Impact Ionization 424 10.11 Radical Polymerization of Alkenes: Chain-Growth Polymers 474 9.12 Depicting the Molecular Ion 424 Radical [ A MECHANISM FOR THE REACTION ] 9.13 Fragmentation 425 Polymerization of Ethene (Ethylene) 475 9.14 Isotopes in Mass Spectra 432 10.12 Other Important Radical Reactions 478 9.15 GC/MS Analysis The Chemistry of… Antioxidants 435 480 9.16 Mass Spectrometry of Biomolecules 436 The Chemistry of… Ozone Depletion and [ WHY DO THESE TOPICS MATTER? ] Chlorofluorocarbons (CFCs) 481 436 See Special Topic B, NMR Theory and Instrumentation, in WileyPLUS [ WHY DO THESE TOPICS MATTER? ] 10 11 10.1 Introduction: How Radicals Form and How They React 449 Synthesis and Reactions 489 [ A MECHANISM FOR THE REACTION ] Hydrogen Atom Abstraction 450 Radical Addition to a π Bond 450 The Chemistry of… Acne Medications viii See Special Topic C, Chain-Growth Polymers, in WileyPLUS Alcohols and Ethers Radical Reactions [ A MECHANISM FOR THE REACTION ] 482 450 11.1 Structure and Nomenclature 490 11.2 Physical Properties of Alcohols and Ethers 492 11.3 Important Alcohols and Ethers 494 The Chemistry of… Ethanol as a Biofuel 495 The Chemistry of… Cholesterol and Heart Disease 496 11.4 Synthesis of Alcohols from Alkenes 496 11.5 Reactions of Alcohols 498 11.6 Alcohols as Acids 500 11.7 Conversion of Alcohols into Alkyl Halides 501 11.8 Alkyl Halides from the Reaction of Alcohols with Hydrogen Halides 501 11.9 Alkyl Halides from the Reaction of Alcohols with PBr3 or SOCl2 504 11.10 Tosylates, Mesylates, and Triflates: Leaving Group Derivatives of Alcohols 505 [ A MECHANISM FOR THE REACTION ] Conversion of an Alcohol into a Mesylate (an Alkyl Methanesulfonate) 507 11.11 Synthesis of Ethers 507 Intermolecular Dehydration of A lcohols to Form an Ether 508 [ A MECHANISM FOR THE REACTION ] [ A MECHANISM FOR THE REACTION ] Ether Synthesis The Williamson 509 Ether Cleavage by Strong Acids 513 11.13 Epoxides 514 [ A MECHANISM FOR THE REACTION ] Alkene Epoxidation 515 515 11.14 Reactions of Epoxides 516 [ A MECHANISM FOR THE REACTION ] Acid-Catalyzed Ring Opening of an Epoxide 516 [ A MECHANISM FOR THE REACTION ] Base-Catalyzed Ring Opening of an Epoxide 517 11.15 Anti 1,2-Dihydroxylation of Alkenes via Epoxides 519 The Chemistry of… Environmentally Friendly Alkene Oxidation Methods 11.16 Crown Ethers 521 522 The Chemistry of… Transport Antibiotics and Crown Ethers Oxidation–Reduction and O rganometallic Compounds 534 12.1 Structure of the Carbonyl Group 535 523 PHOTO CREDIT: FSTOP/Image Source Limited 12.2 Oxidation–Reduction Reactions in Organic Chemistry 536 12.3 Alcohols by Reduction of Carbonyl Compounds 537 Reduction of Aldehydes and Ketones by Hydride Transfer 539 [ A MECHANISM FOR THE REACTION ] The Chemistry of… Alcohol Dehydrogenase— A Biochemical Hydride Reagent 539 The Chemistry of… Stereoselective Reductions of Carbonyl Groups 541 12.4 Oxidation of Alcohols 542 The Swern [ A MECHANISM FOR THE REACTION ] Oxidation 543 Chromic Acid [ A MECHANISM FOR THE REACTION ] 12.5 545 Organometallic Compounds 547 12.6 Preparation of Organolithium and Organomagnesium Compounds 548 12.7 Reactions of Organolithium and Organomagnesium Compounds 549 The Grignard [ A MECHANISM FOR THE REACTION ] The Chemistry of… The Sharpless Asymmetric Epoxidation Alcohols from Carbonyl Compounds Oxidation 11.12 Reactions of Ethers 513 [ A MECHANISM FOR THE REACTION ] 12 Reaction 552 12.8 Alcohols from Grignard Reagents 552 12.9 Protecting Groups 561 [ WHY DO THESE TOPICS MATTER? ] 562 See First Review Problem SET in WileyPLUS 13 Conjugated Unsaturated Systems 13.1 Introduction 573 PHOTO CREDIT: (house plant) Media Bakery; (carrot) Image Source; (blue jeans) Media Bakery 13.2 The Stability of the Allyl Radical 573 11.17 Summary of Reactions of Alkenes, Alcohols, and Ethers 523 13.3 The Allyl Cation 577 13.4 Resonance Theory Revisited 578 [ WHY DO THESE TOPICS MATTER? ] 13.5 Alkadienes and Polyunsaturated Hydrocarbons 582 525 ix 13.6 1,3-Butadiene: Electron Delocalization 583 15.3 13.7 The Stability of Conjugated Dienes 586 [ A MECHANISM FOR THE REACTION ] 13.8 Ultraviolet–Visible Spectroscopy 587 13.9 Electrophilic Attack on Conjugated Dienes: 1,4-Addition 595 Halogenation of Benzene 664 Aromatic Bromination 15.4 Nitration of Benzene 665 [ A MECHANISM FOR THE REACTION ] 15.5 The Chemistry of… Molecules with the Nobel Prize in [ A MECHANISM FOR THE REACTION ] Their Synthetic Lineage 608 Benzene 667 608 [ A MECHANISM FOR THE REACTION ] Acylation The Discovery of Benzene 618 14.2 Nomenclature of Benzene Derivatives 619 14.3 Reactions of Benzene 621 14.4 The Kekulé Structure for Benzene 622 14.5 The Thermodynamic Stability of Benzene 623 14.6 Modern Theories of the Structure of Benzene 625 14.7 Hückel’s Rule: The 4n + 2 π Electron Rule 628 14.8 Other Aromatic Compounds 636 The Chemistry of… Nanotubes Heterocyclic Aromatic Compounds 639 The Chemistry of… Aryl Halides: Their Uses and 643 14.11 Spectroscopy of Aromatic Compounds 644 The Chemistry of… Sunscreens (Catching the Sun’s Rays and What Happens to Them) 648 [ WHY DO THESE TOPICS MATTER? ] 649 See Special Topic D, Electrocyclic and Cycloaddition Reactions, in WileyPLUS 15 Reactions of Aromatic Compounds Electrophilic Aromatic Substitution Reactions 661 15.2 A General Mechanism for Electrophilic Aromatic Substitution 662 x 669 Friedel–Crafts 671 15.7 Synthetic Applications of Friedel–Crafts A cylations: The Clemmensen and Wolff–Kishner Reductions 673 The Chemistry of… DDT 676 15.8 Existing Substituents Direct the Position of Electrophilic Aromatic Substitution 677 15.9 Activating and Deactivating Effects: How Electron-Donating and Electron-Withdrawing Groups Affect the Rate of an EAS Reaction 684 15.10 Directing Effects in Disubstituted Benzenes 685 639 14.10 Aromatic Compounds in Biochemistry 641 15.1 Friedel–Crafts 668 The Chemistry of… Industrial Styrene Synthesis 14.1 Environmental Concerns Sulfonation of Friedel–Crafts Reactions 668 Alkylation Aromatic Compounds 14.9 15.6 Sulfonation of Benzene 666 [ A MECHANISM FOR THE REACTION ] 14 Nitration of Benzene 666 13.10 The Diels–Alder Reaction: A 1,4-Cycloaddition Reaction of Dienes 599 [ WHY DO THESE TOPICS MATTER? ] Electrophilic 664 15.11 Reactions of Benzene Ring Carbon Side Chains 686 15.12 Synthetic Strategies 689 15.13 The SNAr Mechanism: Nucleophilic Aromatic Substitution by Addition-Elimination 691 [ A MECHANISM FOR THE REACTION ] The SNAr Mechanism 692 The Chemistry of… Bacterial Dehalogenation of a PCB Derivative 693 15.14 Benzyne: Nucleophilic Aromatic Substitution by Elimination–Addition 694 [ A MECHANISM FOR THE REACTION ] The Benzyne Elimination–Addition Mechanism 694 The Chemistry of… Host–Guest Trapping of Benzyne 697 15.15 Reduction of Aromatic Compounds 697 [ A MECHANISM FOR THE REACTION ] Birch Reduction 698 [ WHY DO THESE TOPICS MATTER? ] 699 16 16.10 The Addition of Ylides: The Wittig Reaction 737 Reaction 739 16.11 Oxidation of Aldehydes 741 Nucleophilic Addition to the C arbonyl Group 711 16.1 Introduction 16.2 Nomenclature of Aldehydes and Ketones 712 16.3 Physical Properties 712 714 The Chemistry of… Aldehydes and Ketones in Perfumes 16.4 715 16.12 The Baeyer–Villiger Oxidation 741 [ A MECHANISM FOR THE REACTION ] Villiger Oxidation The Baeyer– 742 16.13 Chemical Analyses for Aldehydes and Ketones 743 16.14 Spectroscopic Properties of Aldehydes and Ketones 743 16.15 S ummary of Aldehyde and Ketone Addition Reactions 746 Synthesis of Aldehydes 715 [ A MECHANISM FOR THE REACTION ] The Wittig [ A MECHANISM FOR THE REACTION ] Aldehydes and Ketones Reduction of [ WHY DO THESE TOPICS MATTER? ] Reduction of an 17 747 an Acyl Chloride to an Aldehyde 718 [ A MECHANISM FOR THE REACTION ] Ester to an Aldehyde 719 [ A MECHANISM FOR THE REACTION ] Reduction of a Nitrile to an Aldehyde 719 16.5 Synthesis of Ketones 720 16.6 Nucleophilic Addition to the Carbon–Oxygen Double Bond: Mechanistic Themes 723 Addition of a Strong Nucleophile to an Aldehyde or Ketone 724 [ A MECHANISM FOR THE REACTION ] Acid-Catalyzed Nucleophilic Addition to an Aldehyde or Ketone 724 [ A MECHANISM FOR THE REACTION ] 16.7 The Addition of Alcohols: Hemiacetals and Acetals 726 [ A MECHANISM FOR THE REACTION ] Acid-Catalyzed Hemiacetal Formation 726 [ A MECHANISM FOR THE REACTION ] Acetal Formation Acid-Catalyzed 728 16.8 The Addition of Primary and Secondary Amines 731 [ A MECHANISM FOR THE REACTION ] Imine Formation 732 Nucleophilic Addition– Elimination at the Acyl Carbon 761 17.1 Introduction 762 17.2 Nomenclature and Physical Properties 762 17.3 Preparation of Carboxylic Acids 770 17.4 Acyl Substitution: Nucleophilic Addition–Elimination at the Acyl Carbon 773 Acyl Substitution by Nucleophilic Addition–Elimination 773 [ A MECHANISM FOR THE REACTION ] 17.5 Acyl Chlorides 775 Synthesis of Acyl Chlorides Using Thionyl Chloride 776 [ A MECHANISM FOR THE REACTION ] 17.6 Carboxylic Acid Anhydrides 777 17.7 Esters 778 [ A MECHANISM FOR THE REACTION ] Acid-Catalyzed Esterification 779 [ A MECHANISM FOR THE REACTION ] [ A MECHANISM FOR THE REACTION ] The Wolff–Kishner Reduction 733 [ A MECHANISM FOR THE REACTION ] Carboxylic Acids and Their Derivatives Enamine Base-Promoted Hydrolysis of an Ester 782 Formation 734 17.8 Amides 784 The Chemistry of… A Very Versatile Vitamin, Pyridoxine [ A MECHANISM FOR THE REACTION ] DCC-Promoted (Vitamin B6) 735 Amide Synthesis 787 16.9 The Addition of Hydrogen Cyanide: Cyanohydrins 736 The Chemistry of… Some Hot Topics Related to [ A MECHANISM FOR THE REACTION ] Formation 736 Structure and Activity 787 Cyanohydrin [ A MECHANISM FOR THE REACTION ] Acidic Hydrolysis of an Amide 789 xi [ A MECHANISM FOR THE REACTION ] Basic Hydrolysis 18.7 Synthesis of Substituted Acetic Acids: The Malonic Ester Synthesis 830 Acidic [ A MECHANISM FOR THE REACTION ] Basic Hydrolysis 18.8 Further Reactions of Active Hydrogen Compounds 833 of an Amide 789 [ A MECHANISM FOR THE REACTION ] The Malonic Ester Synthesis of Substituted Acetic Acids 830 Hydrolysis of a Nitrile 791 [ A MECHANISM FOR THE REACTION ] of a Nitrile 791 The Chemistry of… Penicillins 17.9 18.9 Synthesis of Enamines: Stork Enamine Reactions 834 792 Derivatives of Carbonic Acid 792 18.10 Summary of Enolate Chemistry 837 17.10 Decarboxylation of Carboxylic Acids 795 [ WHY DO THESE TOPICS MATTER? ] 17.11 P olyesters and Polyamides: Step-Growth Polymers 797 17.12 Summary of the Reactions of Carboxylic Acids and Their Derivatives 798 [ WHY DO THESE TOPICS MATTER? ] 19 802 See Special Topic E, Step-Growth Polymers, in WileyPLUS 18 Reactions at the α Carbon of Carbonyl Compounds 19.1 Introduction 850 19.2 The Claisen Condensation: A Synthesis of β-Keto Esters 850 [ A MECHANISM FOR THE REACTION ] 18.1 The Acidity of the α Hydrogens of Carbonyl Compounds: Enolate Anions 812 Condensation Keto and Enol Tautomers 813 18.3 Reactions via Enols and Enolates 815 Condensation 19.3 β-Dicarbonyl Compounds by Acylation of Ketone Enolates 855 Acid-Catalyzed 19.4 Aldol Reactions: Addition of Enolates and Enols to Aldehydes and Ketones 856 Enolization 816 [ A MECHANISM FOR THE REACTION ] [ A MECHANISM FOR THE REACTION ] Base-Promoted Halogenation of Aldehydes and Ketones 817 Addition Acid-Catalyzed Halogenation of Aldehydes and Ketones 818 the Aldol Addition Product 858 [ A MECHANISM FOR THE REACTION ] The Haloform Reaction 819 The Chemistry of… Chloroform in Drinking Water [ A MECHANISM FOR THE REACTION ] [ A MECHANISM FOR THE REACTION ] Dehydration of An Acid- Catalyzed Aldol Condensation 858 The Chemistry of… A Retro-Aldol Reaction in 819 Glycolysis—Dividing Assets to Double the ATP Yield 860 Lithium Enolates 821 19.5 18.5 Enolates of β-Dicarbonyl Compounds 824 [ A MECHANISM FOR THE REACTION ] 18.6 Synthesis of Methyl Ketones: The Acetoacetic Ester Synthesis 825 The Aldol 857 18.4 xii The Dieckmann 853 Base-Catalyzed Enolization 815 [ A MECHANISM FOR THE REACTION ] The Claisen 851 [ A MECHANISM FOR THE REACTION ] 18.2 [ A MECHANISM FOR THE REACTION ] Condensation and Conjugate Addition Reactions of Carbonyl Compounds More Chemistry of Enolates 849 Enols and Enolates 811 [ A MECHANISM FOR THE REACTION ] 838 Crossed Aldol Condensations 861 A Directed Aldol Synthesis Using a Lithium Enolate 865 19.6 Cyclizations via Aldol Condensations 867 [ A MECHANISM FOR THE REACTION ] Cyclization 20.8 The Aldol 867 20.9 Reactions of Amines with Sulfonyl C hlorides The Chemistry of… Polyketide Anticancer Antibiotic Biosynthesis Antimetabolites 920 [ A MECHANISM FOR THE REACTION ] 20.10 Synthesis of Sulfa Drugs 921 The Conjugate Addition of HCN 870 [ A MECHANISM FOR THE REACTION ] The Conjugate Addition of an Amine 871 [ A MECHANISM FOR THE REACTION ] The Michael 19.8 The Mannich 875 Summary of Important Reactions 876 [ WHY DO THESE TOPICS MATTER? ] 877 See Special TopicS F, Thiols, Sulfur Ylides, and Disulfides, and G, Thiol Esters and Lipid Biosynthesis, in WileyPLUS 20 Amines Nomenclature The Chemistry of… Biologically Important Amines 899 Preparation of Amines 901 [ A MECHANISM FOR THE REACTION ] Reductive 904 Promoters of Key Bond-Forming Reactions 938 21.1 Organometallic Compounds in Previous Chapters 939 21.2 Transition Metal Elements and Complexes 939 21.3 How to Count Electrons in a Metal Complex The Chemistry of… Homogeneous Asymmetric Catalytic Hydrogenation: E xamples Involving l-DOPA, (S)-Naproxen, and Aspartame 946 The Hofmann 908 Cross-Coupling Reactions 947 [ A MECHANISM FOR THE REACTION ] The Heck– Mizoroki Reaction Using an Aryl Halide Substrate 948 20.5 Reactions of Amines 909 The Chemistry of… The Wacker Oxidation 20.6 Reactions of Amines with Nitrous Acid 911 The Chemistry of… Complex Cross Couplings 21.7 [ A MECHANISM FOR THE REACTION ] Diazotization 912 The Chemistry of… N -Nitrosoamines 940 [ A MECHANISM FOR THE REACTION ] Homogeneous Hydrogenation Using Wilkinson’s Catalyst 945 21.6 [ A MECHANISM FOR THE REACTION ] Rearrangement Transition Metal Complexes 21.5 Homogeneous Hydrogenation: Wilkinson’s Catalyst 944 PHOTO CREDIT: © Eric Isselée/iStockphoto Basicity of Amines: Amine Salts 894 Amination 21 21.4 Mechanistic Steps in the Reactions of Some Transition Metal Complexes 942 891 20.2 Physical Properties and Structure of Amines 892 20.4 927 See Special Topic H, Alkaloids, in WileyPLUS 874 The Chemistry of… A Suicide Enzyme Substrate 20.3 20.13 Summary of Preparations and R eactions of Amines 924 The Mannich Reaction 874 [ A MECHANISM FOR THE REACTION ] 20.1 20.12 Eliminations Involving Ammonium Compounds 923 873 Reaction 19.9 20.11 Analysis of Amines 921 [ WHY DO THESE TOPICS MATTER? ] 871 The Chemistry of… Conjugate Additions to Activate Drugs 919 The Chemistry of… Essential Nutrients and 868 19.7 Additions to α,β-Unsaturated Aldehydes and Ketones 869 Addition Coupling Reactions of Arenediazonium Salts 917 20.7 Replacement Reactions of Arenediazonium Salts 913 952 Olefin Metathesis 955 [ A MECHANISM FOR THE REACTION ] 912 950 The Olefin Metathesis Reaction 955 The Chemistry of… Organic Chemistry Alchemy: Turning Simple A lkenes into “Gold” 957 xiii 21.8 Transition Metals in Nature: Vitamin B12 and Vanadium Haloperoxidases 958 [ WHY DO THESE TOPICS MATTER? ] 959 See Second Review Problem SET in WileyPLUS 23.1 Introduction 1012 The Chemistry of… Olestra and Other Fat Carbohydrates 22.1 Introduction 22.2 Monosaccharides 22.3 Mutarotation 22.4 Glycoside Formation Substitutes 966 968 1019 The Chemistry of… Self-Assembled Monolayers—Lipids in Materials Science and Bioengineering 1020 973 23.3 974 Formation of a Terpenes and Terpenoids 1021 The Chemistry of… The Bombardier Beetle’s Noxious Spray 1025 974 Hydrolysis of a [ A MECHANISM FOR THE REACTION ] 975 23.4 Steroids 1026 The Chemistry of… The Enzyme Aromatase 22.5 Other Reactions of Monosaccharides 976 22.6 Oxidation Reactions of Monosaccharides 979 22.7 Reduction of Monosaccharides: Alditols 984 22.8 Reactions of Monosaccharides with Phenylhydrazine: Osazones 984 Phenylosazone [ A MECHANISM FOR THE REACTION ] Formation 1016 The Chemistry of… Poison Ivy [ A MECHANISM FOR THE REACTION ] Glycoside Lipids 23.2 Fatty Acids and Triacylglycerols 1012 22 Glycoside 23 985 1031 23.5 Prostaglandins 1035 23.6 Phospholipids and Cell Membranes 1036 The Chemistry of… STEALTH® Liposomes for Drug Delivery 1039 23.7 Waxes 1040 [ WHY DO THESE TOPICS MATTER? ] 1040 22.9 Synthesis and Degradation of Monosaccharides 986 22.10 The d Family of Aldoses 988 22.11 F ischer’s Proof of the Configuration of d -(+)-Glucose 988 24 22.12 Disaccharides 990 Amino Acids and Proteins The Chemistry of… Artificial Sweeteners 24.1 Introduction 1046 (How Sweet It Is) 993 24.2 Amino Acids 1047 24.3 Synthesis of α-Amino Acids 1053 22.13 Polysaccharides 994 22.14 Other Biologically Important Sugars 998 22.15 Sugars that Contain Nitrogen 999 22.16 Glycolipids and Glycoproteins of the Cell S urface: Cell Recognition and the Immune System 1001 The Chemistry of… Patroling Leukocytes and Sialyl Lewisx Acids 1002 22.17 Carbohydrate Antibiotics [ A MECHANISM FOR THE REACTION ] Formation of an α-Aminonitrile during the Strecker Synthesis 1054 24.4 Polypeptides and Proteins 1055 24.5 Primary Structure of Polypeptides and Proteins 1058 24.6 Examples of Polypeptide and Protein Primary Structure 1062 1003 22.18 Summary of Reactions of Carbohydrates 1004 The Chemistry of… Sickle-Cell Anemia [ WHY DO THESE TOPICS MATTER? ] 24.7 xiv 1004 1064 Polypeptide and Protein Synthesis 1065 24.8 Secondary, Tertiary, and Quaternary Structures of Proteins 1071 24.9 Introduction to Enzymes 1075 25.4 Deoxyribonucleic Acid: DNA 1098 25.5 RNA and Protein Synthesis 1105 25.6 Determining the Base Sequence of DNA: The Chain-Terminating (Dideoxynucleotide) Method 1113 25.7 Laboratory Synthesis of Oligonucleotides 1116 25.8 Polymerase Chain Reaction 1118 25.9 Sequencing of the Human Genome: An Instruction Book for the Molecules of Life 1120 24.10 Lysozyme: Mode of Action of an Enzyme 1077 The ChemiSTry oF… Carbonic Anhydrase: Shuttling the Protons 1079 24.11 Serine Proteases 1079 24.12 Hemoglobin: A Conjugated Protein 1081 The ChemiSTry oF… Some Catalytic Antibodies 1081 [ WHY DO THESE TOPICS MATTER? ] 24.13 Purification and Analysis of Polypeptides and Proteins 1083 GloSSary 24.14 Proteomics index 1085 [ WHY DO THESE TOPICS MATTER? ] 1087 1121 Gl-1 i-1 anSWerS To SeleCTed ProBlemS can be found at www.wiley.com/college/solomons eula 25 Nucleic Acids and Protein Synthesis 25.1 Introduction 1091 25.2 Nucleotides and Nucleosides 1092 25.3 Laboratory Synthesis of Nucleosides and Nucleotides 1095 xv Preface “It’s Organic Chemistry!” That’s what we want students to exclaim after they become acquainted with our subject. Our lives revolve around organic chemistry, whether we all realize it or not. When we understand organic chemistry, we see how life itself would be impossible without it, how the quality of our lives depends upon it, and how examples of organic chemistry leap out at us from every direction. That’s why we can envision students enthusiastically exclaiming “It’s organic chemistry!” when, perhaps, they explain to a friend or family member how one central theme—organic chemistry— pervades our existence. We want to help students experience the excitement of seeing the world through an organic lens, and how the unifying and simplifying nature of organic chemistry helps make many things in nature comprehensible. Our book makes it possible for students to learn organic chemistry well and to see the marvelous ways that organic chemistry touches our lives on a daily basis. Our book helps students develop their skills in critical thinking, problem solving, and analysis—skills that are so important in today’s world, no matter what career paths they choose. The richness of organic chemistry lends itself to solutions for our time, from the fields of health care, to energy, sustainability, and the environment. After all, it’s organic chemistry! Energized by the power of organic chemistry and the goals of making our book an even more efficient and relevant tool for learning, we have made a number of important changes in this edition. New To This Edition.... We share the same goals and motivations as our colleagues in wanting to give students the best experience that they can have in organic chemistry. We also share the challenges of deciding what students need to know and how the material should be organized. In that spirit, our reviewers and adopters have helped guide a number of the changes that we have made in this edition. Simultaneously achieving efficiency and adding breadth We have redistributed and streamlined material from our old Chapter 21 about phenols, aryl halides, aryl ethers, benzyne, and nucleophilic aromatic substitution in a way that eliminates redundancy and places it in the context of other relevant material earlier in the book. At the same time, we wanted to update and add breadth to our book by creating a new Chapter 21, Transition Metal Complexes about transition metal organometallic compounds and their uses in organic synthesis. Previously, transformations like the Heck-Mizoroki, Suzuki-Miyaura, Stille, Sonogashira, and olefin metathesis reactions had only been part of a special topic in our book, but as the exposure of undergraduates to these processes has become more widespread, we felt it essential to offer instructors a chapter that they could incorporate into their course if they wished. Streamlining and redistributing the content in our old Chapter 21 allowed us to do this, and we thank our reviewers for helping to prompt this change. Transition metal organometallic complexes: Promoters of key bond-forming reactions Our new Chapter 21 brings students a well-rounded and manageable introduction to transition metal organometallic complexes and their use in organic synthesis. We begin the chapter with an introduction to the structure and common mechanistic steps of reactions involving transition metal organometallic compounds. We then introduce the essentials of important cross-coupling reactions such as the Heck-Mizoroki, Suzuki-Miyaura, Stille, Sonogashira, dialkylcuprate (Gilman), and olefin metathesis reactions at a level that is practical and useful for undergraduates. We intentionally organized the chapter so that instructors could move directly to the practical applications of these important reactions if they desire, skipping general background information on transition metal complexes if they wished. Aromatic efficiency Our coverage of aromatic substitution reactions (Chapter 15) has been refocused by making our presentation of electrophilic aromatic substation more efficient at the same time as we included topics of nucleophilic aromatic substation and benzyne that had xvi reviously been in Chapter 21. Now all types of aromatic substitution reactions are combined in p one chapter, with an enhanced flow that is exactly the same length as the old chapter solely on electrophilic aromatic reactions. A focus on the practicalities of spectroscopy Students in an introductory organic chemistry course need to know how to use spectroscopic data to explore structure more than they need to understand the theoretical underpinnings of spectroscopy. To that end, we have shortened Chapter 9, Nuclear Magnetic Resonance by placing aspects of NMR instrumentation and theory in a new special topic that is a standalone option for instructors and students. At the same time, we maintain our emphasis on using spectroscopy to probe structure by continuing to introduce IR in Chapter 2, Families of Carbon Compounds: Functional Groups, Intermolecular Forces, and Infrared (IR) Spectroscopy, where students can learn to easily correlate functional groups with their respective infrared signatures and use IR data for problems in subsequent chapters. Organizing nucleophilic substitution and elimination topics Some instructors find it pedagogically advantageous to present and assess their students’ knowledge of nucleophilic substitution reactions before they discuss elimination reactions. Following the advice of some reviewers, we have adjusted the transition between Chapters 6, Nucleophilic Reactions: Properties and Substitution Reactions of Alkyl Halides and 7, Alkenes and Alkynes I: Properties and Synthesis ; Elimiantion Reactions of Alkyl Halides so that an instructor can pause cleanly after Chapter 6 to give an assessment on substitution, or flow directly into Chapter 7 on elimination reactions if they wish. Synthesizing the Material The double entendre in the name of our new Synthesizing the Material problems is not lost in the ether. In this new group of problems, found at the end 8.2 ElEctrophilic Addition of hydrogEn hAlidEs to AlkEnEs 343 of Chapters 6-21, students are presented with either multistep synthetic transformations and Figure 8.2 Free-energy diagrams unknown products, or target must deduce by retrosynthetic Br δ molecules whose precursors they for the addition of HBr to propene. ∆G (2°) is less than ∆G (1°). Hδ analysis. Problems in our Synthesizing the Material groups often call upon reagents and transforCH CH CH This transition mations covered in prior chapters. Thus,+ while students work on synthesizing a chemical material, state resembles δ CH CH CH a 1° carbocation. they are also synthesizing knowledge. δ + Br − ‡ ‡ + δ+ 3 2 Free energy Br − δ+ This transition state resembles a 2° carbocation. CH3CH H + 3 2 − 2 CH2 + CH3CHCH3 + Br− Ongoing Pedagogical Strengths CH3CH CH2 + HBr Mechanisms: Showing How Reactions Work Student success in organic chemistry 𝚫G (2°) 𝚫 G (1°) CH CH CH Br hinges on understanding mechanisms. We do all that we can to insure that our mechanism boxes CH CHBrCH contain every detail needed Reaction to help students learn and understand how reactions work. Over the coordinate years reviewers that book excels(andinultimately depicting clear and accurate mechanisms. This reactionsaid leading to theour secondary carbocation to 2-bromo• Thehave propane) has the lower freethenergy of activation. This is reasonable because its continues to be truestate inresembles our 12the more edition, and it is now augmented by animated mechanism videos transition stable carbocation. the primary carbocation (and ultimately to 1-bromopropane) approach when introducing new • The reaction leading found in WileyPLUS withtoORION. We also use a mechanistic has a higher free energy of activation because its transition state resembles a less stable primary carbocation. This second reaction is much slower and does not compete reaction types so that students can understand the generalities and appreciate common themes. For appreciably with the first reaction. example, ourThechapters onwithcarbonyl chemistry organized according to the mechanistic themes 2-methylpropene produces onlyare 2-bromo-2-methylpropane, reaction of HBr for the same reason regarding carbocations stability. Here, in the first step (i.e., the attachof nucleophilic and reactivity the α-carbon, Mechanistic themes are ment of addition, the proton) the acyl choice substitution, is even more pronounced—between a tertiaryat carbocation and a primary carbocation. Thus, 1-bromo-2-methylpropane is not obtained as a also emphasized regarding alkene addition reactions, oxidation and reduction, and electrophilic product of the reaction because its formation would require the formation of a primary carbocation. Such a reaction would have a much higher free energy of activation than that aromatic substitution. leading to a tertiary carbocation. ‡ ‡ 3 3 2 2 3 • Rearrangements invariably occur when the carbocation initially formed by addition [ of HX to an alkene can rearrange to a more stable one (see Section 7.11 and Practice Problem 8.3). A MechAnisM for the reAction Addition of HBr to 2-Methylpropene [ This reaction takes place: H3C CH3 H3C C C—CH2—H CH2 H3C H + Br H3C Br CH3 − 3° Carbocation (more stable carbocation) C Major CH3 product Br 2-Bromo-2-methylpropane A Mechanism for the Reaction Stepped out reactions with just the right amount of detail provide the tools for students to understand rather than memorize reaction mechanisms. This reaction does not occur to any appreciable extent: CH3 H3C C H3C Br CH2 CH3 C H H CH3 + CH3 CH2 Br − 1° Carbocation (less stable carbocation) C CH2 Br Little formed H 1-Bromo-2-methylpropane xvii solom_c08_337-390v3.0.2.indd 343 29/10/15 11:10 am • Carbon atoms that are electron poor because of bond polarity, but are not carbocations, can also be electrophiles. They can react with the electron-rich centers of Lewis bases in reactions such as the following: B − δ+ + C O δ− B C − O Lewis acid (electrophile) Lewis base Cementing knowledge by working problems: As athletes Carbanions are Lewis bases. Carbanions seek a proton orand some musicians other positiveknow, center pracwhich is they can donate their electron pair and thereby neutralize theirtonegative tice makes perfect. Thetosame true with organic chemistry. Students need workcharge. all kinds of When a Lewis base seeks a positive center other than a proton, especially that of a carbon problems to learn chemistry. Our book has over 1400 in-text problems that students can use to atom, chemists call it a nucleophile (meaning nucleus loving; the nucleo- part of the name comes from Problems nucleus, the positive center of anlearn atom).where to begin. Practice Problems cement their knowledge. Solved help students nucleophile a Lewis base that seeks a positive center such as a positively • Aand help them hone their skills commitis knowledge to memory. Many more problems at the end charged carbon atom. each chapter help students reinforce their learning, focus on specific areas of content, and assess Since electrophiles are also Lewis acids (electron pair acceptors) and nucleophiles are their overall skill level with material. Learning Group in Lewis that bases chapter’s (electron pair donors), why do chemists haveProblems two terms engage for them?students The answer that Lewis acid and throughout Lewis base are terms that are used when synthesizing information andis concepts from a chapter andgenerally, can bebut used toone facilitate or the other reacts to form a bond to a carbon atom, we usually call it an electrophile or collaborative learning in small groups, or serve as a culminating activity that demonstrates stua nucleophile. dent mastery over an integrated set of principles. Supplementary material provided to instructors δ− δ+ − − Nu + C of O learningNu C OHundreds more online includes suggestions about how to orchestrate the use groups. problems are available through WileyPLUS with Electrophile ORION, to help students target their learning Nucleophile and achieve mastery. Instructors can flip their classroom by doing in-class problem solving using + − Learning Group Problems, clicker questions, and other problems, while allowing our textbook + Nu C Nu C and tutorial resources in WileyPlus to provide out of class learning. Electrophile SOLVED PROBLEMS model problem solving strategies. PRACTICE PROBLEMS provides opportunities to check progress. Nucleophile Solved Problem 3.3 Identify the electrophile and the nucleophile in the following reaction, and add curved arrows to indicate the flow of electrons for the bond-forming and bond-breaking steps. O O H − + C − H N N 3.5 the stRength of BRønsted–lowRy Acids And BAses: K a And pK a 113 STRATEgy AND ANSWER: The aldehyde carbon is electrophilic due to the electronegativity of the carbonyl oxygen. The cyanide anion acts as a Lewis base and is the nucleophile, donating an electron pair to the carbonyl carbon, and causing an electron pair to shift to the oxygen so that no atom has more than an octet of electrons. c03AcidsandBases_PressOptimized.indd 112 O δ− O 25/08/15 6:32 pm − δ+ H − + C N H N Use the curved-arrow notation to write the reaction that would take place between (ch3)2nh and boron trifluoride. Identify the Lewis acid, Lewis base, nucleophile, and electrophile and assign appropriate formal charges. Practice Problem 3.4 Laying the foundation earlier, getting to the heart of the matter quickly: Certain 3.5 the stRength of BRønsted–lowRy Acids tools are absolutely key to success in organic chemistry. Among And BAses: Ka And pKa them is the ability to draw structural formulas quickly and correctly. In this edition, we help students learn these skills even sooner Many reactionsby involve the transfer of a of proton by an acid–base reaction. An use curved arrows earlier in the thanorganic ever before moving coverage structural formulas and the important consideration, therefore, is the relative strengths of compounds that could text (Section 3.2). We have woven together instruction about Lewis structures, covalent bonds, potentially act as Brønsted–Lowry acids or bases in a reaction. hclthat and h so , acetic acid is a much weaker In contrast the strong acids, such asso and dash to structural formulas, students build their skills in these areas as a coherent unit, 2 4 acid. When acetic acid dissolves in water, the following reaction does not proceed to using organic examples that include alkanes, alkenes, alkynes, and alkyl halides. Similarly, Lewis completion: and Brønsted-Lowry acid-base chemistry is fundamental to student success. We present a streamO O lined and highly efficient route to student mastery of these concepts in Chapter 3. + CH C OH + H 2O CH C O− + H 3O 3 3 Increased emphasis on multistep synthesis: Critical thinking and analysis skills are key to problem Multistep organic synthesis Experiments showsolving that in a and 0.1 Mlife. solution of acetic acid at 25 °C only aboutproblems 1% of the are perfectly suited to honing acetic acidskills. molecules transferring protons to water. Therefore, acetic this by edition we their introduce new Synthesizing theacid Material problems at the end of these In ionize is a weak acid. As we shall see next, acid strength is characterized in terms of acidity Chapters 6-21. These problems sharpen students’ analytical skills in synthesis and retrosynthesis, constant (Ka ) or pKa values. and help them synthesize their knowledge by integrating chemical reactions that they have learned throughout the course. 3.5A the Acidity constant, Ka Because the reaction that occurs in an aqueous solution of acetic acid is an equilibrium, we can describe it with an expression for the equilibrium constant (Keq): xviii Keq = [h3o+][ch3co2− ] [ch3co2h][h2o] For dilute aqueous solutions, the concentration of water is essentially constant (∼55.5 M), so we can rewrite the expression for the equilibrium constant in terms of a new constant (Ka) called the acidity constant: A strong balance of synthetic methods Students need to learn methods of organic syn- thesis that are useful, as environmentally friendly as possible, and that are placed in the best overall contextual framework. As mentioned earlier, our new Chapter 21 gives mainstream coverage to reactions that are now essential to practicing organic chemists – transitional metal organometallic reactions. Other modern methods that we cover include the Jacobsen and Sharpless epoxidations (in The Chemistry of… boxes). In the 11th edition we incorporated the Swern oxidation (Section 12.4), long held as a useful oxidation method and one that provides a less toxic alternative to chromate oxidations in some cases. We also restored coverage of the Wolff-Kishner reduction (Section 16.8C) and the Baeyer-Villiger oxidation (Section 16.12), two methods whose importance has been proven by the test of time. The chemistry of radical reactions was also refocused and streamlined by reducing thermochemistry content and by centralizing the coverage of allylic and benzylic radical substitutions (including NBS reactions) in Chapter 10. “Why do these topics matter?” is a feature that bookends each chapter with a teaser in the opener and a captivating example of organic chemistry in the closer. The chapter opener seeks to whet the student’s appetite both for the core chemistry in that chapter as well as hint at a prize that comes at the end of the chapter in the form of a “Why do these topics matter?” vignette. These closers consist of fascinating nuggets of organic chemistry that stem from research relating to medical, environmental, and other aspects of organic chemistry in the world around us, as well as the history of the science. They show the rich relevance of what students have learned to applications that have direct bearing on our lives and wellbeing. For example, in Chapter 6, the opener talks about some of the benefits and drawbacks of making substitutions in a recipe, and then compares such changes to the nucleophilic displacement reactions that similarly allow chemists to change molecules and their properties. The closer then shows how exactly such reactivity has enabled scientists to convert simple table sugar into the artificial sweetener Splenda which is 600 times as sweet, but has no calories! Key Ideas as Bullet Points The amount of content covered in organic chemistry can be over- whelming to students. To help students focus on the most essential topics, key ideas are emphasized as bullet points in every section. In preparing bullet points, we have distilled appropriate concepts into simple declarative statements that convey core ideas accurately and clearly. No topic is ever presented as a bullet point if its integrity would be diminished by oversimplification, however. “How to” Sections Students need to master important skills to support their conceptual learn- ing. “How to” Sections throughout the text give step-by-step instructions to guide students in performing important tasks, such as using curved arrows, drawing chair conformations, planning a Grignard synthesis, determining formal charges, writing Lewis structures, and using 13C and 1H NMR spectra to determine structure. The Chemistry of . . . Virtually every instructor has the goal of showing students how organic chemistry relates to their field of study and to their everyday life experience. The authors assist their colleagues in this goal by providing boxes titled “The Chemistry of . . .” that provide interesting and targeted examples that engage the student with chapter content. Summary and Review Tools: At the end of each chapter, Summary and Review Tools provide visually oriented roadmaps and frameworks that students can use to help organize and assimilate concepts as they study and review chapter content. Intended to accommodate diverse learning styles, these include Synthetic Connections, Concept Maps, thematic Mechanism Review Summaries, and the detailed Mechanism for the Reaction boxes already mentioned. We also provide Helpful Hints and richly annotated illustrations throughout the text. Special Topics: Instructors and students can use our Special Topics to augment their coverage in a number of areas. 13C NMR can be introduced early in the course using the special topic that comes after Chapter 4 on the structure of alkanes and cycloalkanes. Polymer chemistry, now a required topic by the American Chemistry Society for certified bachelor degrees, can be covered in more depth than already presented in Chapters 10 and 17 by using the special topics that follow these chapters. Our special topic on electrocyclic and cycloaddition reactions can be used to augment students’ understanding of these reactions after their introduction to conjugated alkenes, xix the Diels-Alder reaction, and aromatic compounds in Chapters 13-15. In-depth coverage of some topics in biosynthesis and natural products chemistry can be invoked using our special topics on biosynthesis and alkaloids. Organization—An Emphasis on the Fundamentals So much of organic chemistry makes sense and can be generalized if students master and apply a few fundamental concepts. Therein lays the beauty of organic chemistry. If students learn the essential principles, they will see that memorization is not needed to succeed. Most important is for students to have a solid understanding of structure—of hybridization and geometry, steric hindrance, electronegativity, polarity, formal charges, and resonance —so that they can make intuitive sense of mechanisms. It is with these topics that we begin in Chapter 1. In Chapter 2 we introduce the families of functional groups—so that students have a platform on which to apply these concepts. We also introduce intermolecular forces, and infrared (IR) spectroscopy—a key tool for identifying functional groups. Throughout the book we include calculated models of molecular orbitals, electron density surfaces, and maps of electrostatic potential. These models enhance students’ appreciation for the role of structure in properties and reactivity. We begin our study of mechanisms in the context of acid-base chemistry in Chapter 3. Acid-base reactions are fundamental to organic reactions, and they lend themselves to introducing several important topics that students need early in the course: (1) curved arrow notation for illustrating mechanisms, (2) the relationship between free-energy changes and equilibrium constants, and (3) the importance of inductive and resonance effects and of solvent effects. In Chapter 3 we present the first of many “A Mechanism for the Reaction” boxes, using an example that embodies both Brønsted-Lowry and Lewis acid-base principles. All throughout the book, we use boxes like these to show the details of key reaction mechanisms. All of the Mechanism for the Reaction boxes are listed in the Table of Contents so that students can easily refer to them when desired. A central theme of our approach is to emphasize the relationship between structure and reactivity. This is why we choose an organization that combines the most useful features of a functional group approach with one based on reaction mechanisms. Our philosophy is to emphasize mechanisms and fundamental principles, while giving students the anchor points of functional groups to apply their mechanistic knowledge and intuition. The structural aspects of our approach show students what organic chemistry is. Mechanistic aspects of our approach show students how it works. And wherever an opportunity arises, we show them what it does in living systems and the physical world around us. In summary, our writing reflects the commitment we have as teachers to do the best we can to help students learn organic chemistry and to see how they can apply their knowledge to improve our world. The enduring features of our book have proven over the years to help students learn organic chemistry. The changes in our 12th edition make organic chemistry even more accessible and relevant. Students who use the in-text learning aids, work the problems, and take advantage of the resources and practice available in WileyPLUS with ORION (our online teaching and learning solution) will be assured of success in organic chemistry. FOR ORGANIC CHEMISTRY A Powerful Teaching and Learning Solution WileyPLUS with ORION provides students with a personal, adaptive learning experience so they can build their proficiency on topics and use their study time most effectively. WileyPLUS with ORION helps students learn by working with them as their knowledge grows, by learning about them. xx New To WileyPLUS with ORION for Organic Chemistry, 12e Hallmark review tools in the print version of Organic Chemistry such as Concept Maps and Summaries of Reactions are also now interactive exercises that help students develop core skills and competencies • N ew interactive Concept Map exercises • N ew interactive Summary of Reactions exercises • N ew interactive Mechanism Review exercises • N ew video walkthroughs of key mechanisms NEW INTERACTIVES: Interactive versions of Concept Maps, Synthetic Connections, and other review tools help students test their knowledge and develop core competencies. begin practice Unique to ORION, students begin by taking a quick diagnostic for any chapter. This will determine each student’s baseline proficiency on each topic in the chapter. Students see their individual diagnostic report to help them decide what to do next with the help of ORION’s recommendations. For each topic, students can either Study, or Practice. Study directs the students to the specific topic they choose in WileyPLUS, where they can read from the e-textbook, or use the variety of relevant resources available there. Students can also practice, using questions and feedback powered by ORION’s adaptive learning engine. Based on the results of their diagnostic and ongoing practice, ORION will present students with questions appropriate for their current level of understanding, and will continuously adapt to each student, helping them build their proficiency. ORION includes a number of reports and ongoing recommendations for students to help them maintain their proficiency over time for each topic. Students can easily access ORION from multiple places within WileyPLUS. It does not require any additional registration, and there will not be any additional charge for students maintain using this adaptive learning system. xxi Breadth and Depth in Available Assessments: Four unique vehicles for assessment are available to instructors for creating online homework and quizzes and are designed to enable and support problem-solving skill development and conceptual understanding w i l e y P l u s a ss e ssm e n t for organic chemistry R eact i o n E x pl o rer Meaningful practice with mechanisms and synthesis (a database of over 100,000 algorithm-generated problems) I n C hapter / E O C assess m e n t 90-100% of Review Problems and end of chapter questions are coded for online assessment C o n cept Mastery Pre-built concept mastery assignments (from A database of over 25,000 questions) T est B a n k Rich Testbank consisting of over 3,000 questions Reaction Explorer A student’s ability to understand mechanisms and predict synthesis reactions greatly impacts her/his level of success in the course. Reaction Explorer is an interactive system for learning and practicing reactions, syntheses and mechanisms in organic chemistry with advanced echanism diagrams. support for the automatic generation of random problems and curved arrow m Mechanism Explorer: valuable practice with reactions and mechanisms Synthesis Explorer: meaningful practice doing single and multi-step synthesis End of Chapter Problems. Approximately 90% of the end of chapter problems are included in WileyPLUS with ORION. Many of the problems are algorithmic and feature structure drawing/assessment functionality using MarvinSketch, with immediate answer feedback and video question assistance. A subset of these end of chapter problems is linked to Guided Online tutorials which are stepped-out problem-solving tutorials that walk the student through the problem, offering individualized feedback at each step. Prebuilt concept mastery assignments Students must continously practice and work organic chemistry in order to master the concepts and skills presented in the course. Prebuilt concept mastery assignments offer students ample opportunities for practice, covering all the major topics and concepts within an organic chemistry course. Each assignment is organized by topic and features feedback for incorrect answers. These assignments are drawn from a unique database of over 25,000 questions, over half of which require students to draw a structure using MarvinSketch. xxii What do students receive with WileyPLUS with ORION? • • • • he complete digital textbook, saving students up to 60% off the cost of a printed text. T Question assistance, including links to relevant sections in the online digital textbook. Immediate feedback and proof of progress, 24/7. Integrated, multi-media resources that address your students’ unique learning styles, levels of proficiency, and levels of preparation by providing multiple study paths and encourage more active learning. WileyPLUS with ORION Student resources Chapter 0 General Chemistry Refresher. To ensure students have mastered the necessary prerequisite content from general chemistry, and to eliminate the burden on instructors to review this material in lecture, WileyPLUS with ORION now includes a complete chapter of core general chemistry topics with corresponding assignments. Chapter 0 is available to students and can be assigned in WileyPLUS to ensure and gauge understanding of the core topics required to succeed in organic chemistry. Prelecture Assignments. Preloaded and ready to use, these assignments have been carefully designed to assess students prior to their coming to class. Instructors can assign these pre-created quizzes to gauge student preparedness prior to lecture and tailor class time based on the scores and participation of their students. Video Mini-Lectures, Office Hour Videos, and Solved Problem Videos In each chapter, several types of video assistance are included to help students with conceptual understanding and problem solving strategies. The video mini-lectures focus on challenging concepts; the office hours videos take these concepts and apply them to example problems, emulating the experience that a student would get if she or he were to attend office hours and ask for assistance in working a problem. The Solved Problem videos demonstrate good problems solving strategies for the student by walking through in text solved problems using audio and a whiteboard. The goal is to illustrate good problem solving strategies. Skill Building Exercises are animated exercises with instant feedback to reinforce the key skills required to succeed in organic chemistry. 3D Molecular Visualizations use the latest visualization technologies to help students visualize concepts with audio. Instructors can assign quizzes based on these visualizations in WileyPLUS. What do instructors receive with WileyPLUS with ORION? • Reliable resources that reinforce course goals inside and outside of the classroom. • T he ability to easily identify students who are falling behind by tracking their progress and offering assistance easily, even before they come to office hours. Using WileyPLUS with ORION simplifies and automates such tasks as student performance assessment, creating assignments, scoring student work, keeping grades, and more. Media-rich course materials and assessment content that allow you to customize your classroom presentation with a wealth of resources and functionality from PowerPoint slides to a database of rich visuals. You can even add your own materials to your WileyPLUS with ORION course. • Additional Instructor Resources All Instructor Resources are available within WileyPLUS with ORION or they can be accessed by contacting your local Wiley Sales Representative. Many of the assets are located on the book companion site, www.wiley.com/college/solomons xxiii Test Bank Authored by Robert Rossi, of Gloucester County College, Jeffrey Allison, of Austin Community College, and Gloria Silva, of Carnegie Melon University. PowerPoint Lecture slides PowerPoint Lecture Slides have been prepared by Professor William Tam, of the University of Guelph and his wife, Dr. Phillis Chang, and Gary Porter, of Bergen Community College. Personal Response System (“Clicker”) Questions Digital Image Library Images from the text are available online in JPEG format. Instructors may use these images to customize their presentations and to provide additional visual support for quizzes and exams. Additional Student Resources Study Guide and Solutions Manual (Paperback: 978-1-119-07732-9; Binder-Ready: 978-1-119-07733-6) The Study Guide and Solutions Manual for Organic Chemistry, Twelfth Edition, authored by Graham Solomons, Craig Fryhle, and Scott Snyder with prior contributions from Robert Johnson (Xavier University) and Jon Antilla (University of South Florida), contains explained solutions to all of the problems in the text. The Study Guide also contains: • An introductory essay “Solving the Puzzle—or—Structure is Everything” that serves as a bridge from general to organic chemistry • Summary tables of reactions by mechanistic type and functional group • A review quiz for each chapter • A set of hands-on molecular model exercises • Solutions to problems in the Special Topics that are found with the text in WileyPLUS. Molecular Visions™ Model Kits We believe that the tactile and visual experience of manipulating physical models is key to students’ understanding that organic molecules have shape and occupy space. To support our pedagogy, we have arranged with the Darling Company to bundle a special ensemble of Molecular Visions™ model kits with our book (for those who choose that option). We use Helpful Hint icons and margin notes to frequently encourage students to use hand-held models to investigate the three-dimensional shape of molecules we are discussing in the book. Customization and Flexible Options to Meet Your Needs Wiley Custom Select allows you to create a textbook with precisely the content you want, in a simple, three-step online process that brings your students a cost-efficient alternative to a traditional textbook. Select from an extensive collection of content at http://customselect.wiley.com, upload your own materials as well, and select from multiple delivery formats—full color or black and white print with a variety of binding options, or eBook. Preview the full text online, get an instant price quote, and submit your order; we’ll take it from there. WileyFlex offers content in flexible and cost-saving options to students. Our goal is to deliver our learning materials to our customers in the formats that work best for them, whether it’s a traditional text, eTextbook, WileyPLUS, loose-leaf binder editions, or customized content through Wiley Custom Select. xxiv Acknowledgments We are especially grateful to the following people who provided detailed reviews and participated in focus groups that helped us prepare this new edition of Organic Chemistry. Arizona Cindy Browder, Northern Arizona University Tony Hascall, Northern Arizona University Arkansas Kenneth Carter, University of Central Arkansas Sean Curtis, University of Arkansas-Fort Smith California Thomas Bertolini, University of Southern California Rebecca Broyer, University of Southern California Paul Buonora, California State UniveristyLong Beach Steven Farmer, Sonoma State University Andreas Franz, University of the Pacific John Spence, California State Univesity Sacramento Daniel Wellman, Chapman University Pavan Kadandale, University of California Irvine Jianhua Ren, University of the Pacific Harold (Hal) Rogers, California State University Fullerton Liang Xue, University of the Pacific Connecticut Andrew Karatjas, Southern Connecticut State University Florida Evonne Rezler, Florida Atlantic University Solomon Weldegirma, University of South Florida Georgia Indiana Ned Bowden, University of Iowa Olga Rinco, Luther College Brian Love, East Carolina University Jim Parise, Duke University Cornelia Tirla, University of North CarolinaPembroke Wei You, University of Norch CarolinaChapel Hill Kentucky NORTH DAKOTA Mark Blankenbuehler, Morehead State University Karla Wohlers, North Dakota State University Louisiana Ohio Marilyn Cox, Louisiana Tech Univeristy August Gallo, University of LouisianaLafayette Sean Hickey, University of New Orleans Kevin Smith, Louisiana State University Neil Ayres, University of Cincinnati Benjamin Gung, Miami University Allan Pinhas, University of Cincinnati Joel Shulman, University of Cincinnati Massachusetts Donna Nelson, University of OklahomaNorman Campus Paul Morgan, Butler University Iowa Philip Le Quesne, Northeastern University Samuel Thomas, Tufts University Michigan Scott Ratz, Alpena Community College Ronald Stamper, University of Michigan Minnesota Eric Fort, University of St. Thomas Mississippi Douglas Masterson, University of Southern Mississippi Gerald Rowland, Mississippi State University New Jersey Bruce Hietbrink, Richard Stockton College David Hunt, The College of New Jersey Subash Jonnalagadda, Rowan University Robert D Rossi, Gloucester County College New Mexico Donald Bellew, University of New Mexico New York Owen McDougal, Boise State University Todd Davis, Idaho State University Joshua Pak, Idaho State University Brahmadeo Dewprashad, Borough of Manhattan Community College Barnabas Gikonyo, State University of New York-Geneseo Joe LeFevre, State University of New York-Oswego Galina Melman, Clarkson University Gloria Proni, City College of New YorkHunter College Illinois North Carolina Valerie Keller, University of Chicago Richard Nagorski, Illinois State University Erik Alexanian, University of North Carolina -Chapel Hill Christine Whitlock, Georgia Southern University Idaho Oklahoma Pennsylvania Joel Ressner,West Chester University of Pennsylvania South Carolina Carl Heltzel, Clemson University South Dakota Grigoriy Sereda, University of South Dakota Tennessee Ramez Elgammal, University of Tennessee Knoxville Scott Handy, Middle Tennessee State University Aleksey Vasiliev, East Tennessee State University Texas Jeff Allison, Austin Community College Hays Campus Shawn Amorde, Austin Community College Jennifer Irvin,Texas State University-San Marcos Wisconsin Elizabeth Glogowski, University of Wisconsin Eau Claire Tehshik Yoon, University of WisconsinMadison Canada Jeremy Wulff, University of Victoria France-Isabelle Auzanneau, University of Guelph xxv Many people have helped with this edition, and we owe a great deal of thanks to each one of them. We thank Sean Hickey (University of New Orleans) for his reviews and assistance with aspects of WileyPlus. We are grateful to Alan Shusterman (Reed College) and Warren Hehre (Wavefunction, Inc.) for assistance in prior editions regarding explanations of electrostatic potential maps and other calculated molecular models. We would also like to thank those scientists who allowed us to use or adapt figures from their research as illustrations for a number of the topics in our book. A book of this scope could not be produced without the excellent support we have had from many people at John Wiley and Sons, Inc. Joan Kalkut, Sponsoring Editor, led the project from the outset and provided careful oversight and encouragement through all stages of work on the 12th edition. We thank Nick Ferrari, Editor, for his guidance and support as well. Elizabeth Swain brought the book to print through her incredible skill in orchestrating the production process and converting manuscript to final pages. Photo Editor MaryAnn Price obtained photographs that so aptly illustrate examples in our book. Maureen Eide led development of the striking new design of the 12th edition. Alyson Rentrop coordinated work on the Study Guide and Solutions Manual as well as WileyPlus components. Mallory Fryc ensured coordination and cohesion among many aspects of this project, especially regarding reviews and supplements. Kristine Ruff enthusiastically and effectively helped tell the ‘story’ of our book to the many people we hope will consider using it. Without the support of Petra Recter, Vice President and Publisher, this book would not have been possible. We are thankful to all of these people and others behind the scenes at Wiley for the skills and dedication that they provided to bring this book to fruition. TWGS with gratitude to my wife Judith for her continuing support. She joins me in dedicating this edition to our granddaughter, Ella, and her mother, Annabel. CBF would like to thank Deanna, who has been a steadfast life partner since first studying chemistry together decades ago. He also thanks his daughter Heather for help with some chemical formulas. His mother, whose model of scholarly endeavors continues, and father, who shared many science-related tidbits, have always been inspirational. SAS would like to thank his parents, his mentors, his colleagues, and his students for all that they have done to inspire him. Most of all, he would like to thank his wife Cathy for all that she does and her unwavering support. T. W. Graham Solomons Craig B. Fryhle Scott A. Snyder xxvi About the Authors T. W. Graham Solomons did his undergraduate work at The Citadel and received his doctorate in organic chemistry in 1959 from Duke University where he worked with C. K. Bradsher. Following this he was a Sloan Foundation Postdoctoral Fellow at the University of Rochester where he worked with V. Boekelheide. In 1960 he became a charter member of the faculty of the University of South Florida and became Professor of Chemistry in 1973. In 1992 he was made Professor Emeritus. In 1994 he was a visiting professor with the Faculté des Sciences Pharmaceutiques et Biologiques, Université René Descartes (Paris V). He is a member of Sigma Xi, Phi Lambda Upsilon, and Sigma Pi Sigma. He has received research grants from the Research Corporation and the American Chemical Society Petroleum Research Fund. For several years he was director of an NSF-sponsored Undergraduate Research Participation Program at USF. His research interests have been in the areas of heterocyclic chemistry and unusual aromatic compounds. He has published papers in the Journal of the American Chemical Society, the Journal of Organic Chemistry, and the Journal of Heterocyclic Chemistry. He has received several awards for distinguished teaching. His organic chemistry textbooks have been widely used for 30 years and have been translated into French, Japanese, Chinese, Korean, Malaysian, Arabic, Portuguese, Spanish, Turkish, and Italian. He and his wife Judith have a daughter who is a building conservator and a son who is a research biochemist. Craig Barton Fryhle is a Professor of Chemistry at Pacific Lutheran University where he served as Department Chair for roughly 15 years. He earned his B.A. degree from Gettysburg College and Ph.D. from Brown University. His experiences at these institutions shaped his dedication to mentoring undergraduate students in chemistry and the liberal arts, which is a passion that burns strongly for him. His research interests have been in areas relating to the shikimic acid pathway, including molecular modeling and NMR spectrometry of substrates and analogues, as well as structure and reactivity studies of shikimate pathway enzymes using isotopic labeling and mass spectrometry. He has mentored many students in undergraduate research, a number of who have later earned their Ph.D. degrees and gone on to academic or industrial positions. He has participated in workshops on fostering undergraduate participation in research, and has been an invited participant in efforts by the National Science Foundation to enhance undergraduate research in chemistry. He has received research and instrumentation grants from the National Science Foundation, the M J. Murdock Charitable Trust, and other private foundations. His work in chemical education, in addition to textbook coauthorship, involves incorporation of student-led teaching in the classroom and technology-based strategies in organic chemistry. He has also developed experiments for undergraduate students in organic laboratory and instrumental analysis courses. He has been a volunteer with the hands-on science program in Seattle public schools, and Chair of the Puget Sound Section of the American Chemical Society. His passion for climbing has led to ascents of high peaks in several parts of the world. He resides in Seattle with his wife, where both enjoy following the lives of their two daughters as they unfold in new ways and places. Scott A. Snyder grew up in the suburbs of Buffalo NY and was an undergraduate at Williams College, where he graduated summa cum laude in 1999. He pursued his doctoral studies at The Scripps Research Institute in La Jolla CA under the tutelege of K. C. Nicolaou as an NSF, Pfizer, and Bristol-Myers Squibb predoctoral fellow. While there, he co-authored the graduate textbook Classics in Total Synthesis II with his doctoral mentor. Scott was then an NIH postdoctoral fellow with E. J. Corey at Harvard University. In 2006, Scott began his independent career at Columbia University, moved to The Scripps Research Institute on their Jupiter FL campus in 2013, and in 2015 assumed his current position as Professor of Chemistry at the University of Chicago. His research interests lie in the arena of natural products total synthesis, particularly in the realm of unique polyphenols, alkaloids, and halogenated materials. To date, he has trained more than 60 students at the high school, undergraduate, graduate, and postdoctoral levels and co-authored more than 50 research and review articles. Scott has received a number of awards and honors, including a Camille and Henry Dreyfus New Faculty Award, an Amgen Young Investigator Award, an Eli Lilly Grantee Award, a Bristol-Myers Squibb Unrestricted Grant Award, an Alfred P. Sloan Foundation Fellowship, a DuPont Young Professor Award, and an Arthur C. Cope Scholar Award from the American Chemical Society. He has also received awards recognizing his teaching, including a Cottrell Scholar Award from the Research Corporation for Science Advancement. He lives in Chicago with his wife Cathy and son Sebastian where he enjoys gardening, cooking, cycling, and watching movies. xxvii To the Student Contrary to what you may have heard, organic chemistry does not have to be a difficult course. It will be a rigorous course, and it will offer a challenge. But you will learn more in it than in almost any course you will take—and what you learn will have a special relevance to life and the world around you. However, because organic chemistry can be approached in a logical and systematic way, you will find that with the right study habits, mastering organic chemistry can be a deeply satisfying experience. Here, then, are some suggestions about how to study: 1. Keep up with your work from day to day—never let yourself get behind. Organic chemistry is a course in which one idea almost always builds on another that has gone before. It is essential, therefore, that you keep up with, or better yet, be a little ahead of your instructor. Ideally, you should try to stay one day ahead of your instructor’s lectures in your own class preparations. Your class time, then, will be much more helpful because you will already have some understanding of the assigned material. Use WileyPlus study tools (Including ORION) to help with your pre-class learning. 2. Study material in small units, and be sure that you understand each new section before you go on to the next. Again, because of the cumulative nature of organic chemistry, your studying will be much more effective if you take each new idea as it comes and try to understand it completely before you move on to the next concept. 3. Work all of the in-chapter and assigned problems. One way to check your progress is to work each of the inchapter problems when you come to it. These problems have been written just for this purpose and are designed to help you decide whether or not you understand the material that has just been explained. You should also carefully study the Solved Problems. If you understand a Solved Problem and can work the related in-chapter problem, then you should go on; if you cannot, then you should go back and study the preceding material again. Work all of the problems assigned by your instructor from the text and WileyPlus. A notebook for homework is helpful. When you go to your instructor for help, show her/ him your attempted homework, either in written form or in WileyPlus online format. 4. Write when you study. Write the reactions, mechanisms, structures, and so on, over and over again. Organic chemistry is best assimilated through the fingertips by writing, and not through the eyes by simply looking, or by highlighting mate- xxviii rial in the text, or by referring to flash cards. There is a good reason for this. Organic structures, mechanisms, and reactions are complex. If you simply examine them, you may think you understand them thoroughly, but that will be a misperception. The reaction mechanism may make sense to you in a certain way, but you need a deeper understanding than this. You need to know the material so thoroughly that you can explain it to someone else. This level of understanding comes to most of us (those of us without photographic memories) through writing. Only by writing the reaction mechanisms do we pay sufficient attention to their details, such as which atoms are connected to which atoms, which bonds break in a reaction and which bonds form, and the three-dimensional aspects of the structures. When we write reactions and mechanisms, connections are made in our brains that provide the long-term memory needed for success in organic chemistry. We virtually guarantee that your grade in the course will be directly proportional to the number of pages of paper that your fill with your own writing in studying during the term. 5. Learn by teaching and explaining. Study with your student peers and practice explaining concepts and mechanisms to each other. Use the Learning Group Problems and other exercises your instructor may assign as vehicles for teaching and learning interactively with your peers. 6. Use the answers to the problems in the Study Guide in the proper way. Refer to the answers only in two circumstances: (1) When you have finished a problem, use the Study Guide to check your answer. (2) When, after making a real effort to solve the problem, you find that you are completely stuck, then look at the answer for a clue and go back to work out the problem on your own. The value of a problem is in solving it. If you simply read the problem and look up the answer, you will deprive yourself of an important way to learn. 7. Use molecular models when you study. Because of the three-dimensional nature of most organic molecules, molecular models can be an invaluable aid to your understanding of them. When you need to see the three-dimensional aspect of a particular topic, use the Molecular Visions™ model set that may have been packaged with your textbook, or buy a set of models separately. An appendix to the Study Guide that accompanies this text provides a set of highly useful molecular model exercises. 8. Make use of the rich online teaching resources in WileyPLUS including ORION’s adaptive learning system. c h a p t e r 1 The Basics Bonding and Molecular Structure O rganic chemistry plays a role in all aspects of our lives, from the clothing we wear, to the pixels of our television and computer screens, to preservatives in food, to the inks that color the pages of this book. If you take the time to under- stand organic chemistry, to learn its overall logic, then you will truly have the power to change society. Indeed, organic chemistry provides the power to synthesize new drugs, to engineer molecules that can make computer processors run more quickly, to understand why grilled meat can cause cancer and how its effects can be combated, and to design ways to knock the calories out of sugar while still making food taste deliciously sweet. It can explain biochemical processes like aging, neural functioning, and cardiac arrest, and show how we can prolong and improve life. It can do almost anything. In this chapter we will consider: • what kinds of atoms make up organic molecules • the principles that determine how the atoms in organic molecules are bound together • how best to depict organic molecules [ WHY DO THESE TOPICS MATTER? ] At the end of the chapter, we will see how some of the unique organic structures that nature has woven together possess amazing properties that we can harness to aid human health. See for additional examples, videos, and practice. photo credits: computer screen: Be Good/Shutterstock; capsules: Ajt/Shutterstock 1 2 Chapter 1 The Basics: Bonding and Molecular Structure NASA/Photo Researchers, Inc. 1.1 Life and the Chemistry of Carbon Compounds—We are Stardust Supernovae were the crucibles in which the heavy elements were formed. Organic chemistry is the chemistry of compounds that contain the element carbon. If a compound does not contain the element carbon, it is said to be inorganic. Look for a moment at the periodic table inside the front cover of this book. More than a hundred elements are listed there. The question that comes to mind is this: why should an entire field of chemistry be based on the chemistry of compounds that contain this one element, carbon? There are several reasons, the primary one being this: carbon compounds are central to the structure of living organisms and therefore to the existence of life on Earth. We exist because of carbon compounds. What is it about carbon that makes it the element that nature has chosen for living organisms? There are two important reasons: carbon atoms can form strong bonds to other carbon atoms to form rings and chains of carbon atoms, and carbon atoms can also form strong bonds to elements such as hydrogen, nitrogen, oxygen, and sulfur. Because of these bond-forming properties, carbon can be the basis for the huge diversity of compounds necessary for the emergence of living organisms. From time to time, writers of science fiction have speculated about the possibility of life on other planets being based on the compounds of another element—for example, silicon, the element most like carbon. However, the bonds that silicon atoms form to each other are not nearly as strong as those formed by carbon, and therefore it is very unlikely that silicon could be the basis for anything equivalent to life as we know it. 1.1A What Is the Origin of the Element Carbon? Through the efforts of physicists and cosmologists, we now understand much of how the elements came into being. The light elements hydrogen and helium were formed at the beginning, in the Big Bang. Lithium, beryllium, and boron, the next three elements, were formed shortly thereafter when the universe had cooled somewhat. All of the heavier elements were formed millions of years later in the interiors of stars through reactions in which the nuclei of lighter elements fuse to form heavier elements. The energy of stars comes primarily from the fusion of hydrogen nuclei to produce helium nuclei. This nuclear reaction explains why stars shine. Eventually some stars begin to run out of hydrogen, collapse, and explode—they become supernovae. Supernovae explosions scatter heavy elements throughout space. Eventually, some of these heavy elements drawn by the force of gravity became part of the mass of planets like the Earth. 1.1B How Did Living Organisms Arise? This question is one for which an adequate answer cannot be given now because there are many things about the emergence of life that we do not understand. However, we do know this. Organic compounds, some of considerable complexity, are detected in outer space, and meteorites containing organic compounds have rained down on Earth since it was formed. A meteorite that fell near Murchison, Victoria, Australia, in 1969 was found to contain over 90 different amino acids, 19 of which are found in living organisms on Earth. While this does not mean that life arose in outer space, it does suggest that events in outer space may have contributed to the emergence of life on Earth. In 1924 Alexander Oparin, a biochemist at the Moscow State University, postulated that life on Earth may have developed through the gradual evolution of carbon-based molecules in a “primordial soup” of the compounds that were thought to exist on a prebiotic Earth: methane, hydrogen, water, and ammonia. This idea was tested by experiments carried out at the University of Chicago in 1952 by Stanley Miller and Harold Urey. They showed that amino acids and other complex organic compounds are synthesized when an electric spark (think of lightning) passes through a flask containing a mixture of these four compounds (think of the early atmosphere). Miller and Urey reported in their 1953 publication that five amino acids (essential constituents of proteins) were formed. In 2008, examination of archived solutions from Miller and Urey’s original experiments revealed that 22 amino acids, rather than the 5 amino acids originally reported, were actually formed. 3 1.2 Atomic Structure Similar experiments have shown that other precursors of biomolecules can also arise in this way—compounds such as ribose and adenine, two components of RNA. Some RNA molecules can not only store genetic information as DNA does, they can also act as catalysts, as enzymes do. There is much to be discovered to explain exactly how the compounds in this soup became living organisms, but one thing seems certain. The carbon atoms that make up our bodies were formed in stars, so, in a sense, we are stardust. 1.1C Development of the Science of Organic Chemistry The science of organic chemistry began to flower with the demise of a nineteenth century theory called vitalism. According to vitalism, organic compounds were only those that came from living organisms, and only living things could synthesize organic compounds through intervention of a vital force. Inorganic compounds were considered those compounds that came from nonliving sources. Friedrich Wöhler, however, discovered in 1828 that an organic compound called urea (a constituent of urine) could be made by evaporating an aqueous solution of the inorganic compound ammonium cyanate. With this discovery, the synthesis of an organic compound, began the evolution of organic chemistry as a scientific discipline. An RNA molecule O NH4+NCO− Ammonium cyanate heat H 2N C NH2 Urea Despite the demise of vitalism in science, the word “organic” is still used today by some people to mean “coming from living organisms” as in the terms “organic vitamins” and “organic fertilizers.” The commonly used term “organic food” means that the food was grown without the use of synthetic fertilizers and pesticides. An “organic vitamin” means to these people that the vitamin was isolated from a natural source and not synthesized by a chemist. While there are sound arguments to be made against using food contaminated with certain pesticides, while there may be environmental benefits to be obtained from organic farming, and while “natural” vitamins may contain beneficial substances not present in synthetic vitamins, it is impossible to argue that pure OH “natural” vitamin C, for example, is healthier than pure O CH—CH2OH “synthetic” vitamin C, since the two substances are iden- O C CH tical in all respects. In science today, the study of compounds from living organisms is called natural products C C chemistry. In the closer to this chapter we will consider HO OH more about why natural products chemistry is important. FOODCOLLECTION/Image Source The Chemistry of... Natural Products Vitamin C is found in various citrus fruits. Vitamin C 1.2 Atomic Structure Before we begin our study of the compounds of carbon we need to review some basic but familiar ideas about the chemical elements and their structure. • The compounds we encounter in chemistry are made up of elements combined in different proportions. • Elements are made up of atoms. An atom (Fig. 1.1) consists