Organic chemistry as a second language second semester topics 4e by david r klein

Trim Size: 6.125in x 9.25in ❦ ❦ Klein4e-Vol2 f01.tex V2 - December 9, 2015 9:58 P.M Page ii ❦ ❦ Trim Size: 6.125in x 9.25in ❦ Klein4e-Vol2 f01.tex V2 - December 9, 2015 9:58 P.M Page i ORGANIC CHEMISTRY AS A SECOND LANGUAGE, 4e ❦ ❦ ❦ Trim Size: 6.125in x 9.25in ❦ ❦ Klein4e-Vol2 f01.tex V2 - December 9, 2015 9:58 P.M Page ii ❦ ❦ Trim Size: 6.125in x 9.25in ❦ Klein4e-Vol2 f01.tex V2 - December 9, 2015 9:58 P.M Page iii ORGANIC CHEMISTRY AS A SECOND LANGUAGE, 4e Second Semester Topics DAVID KLEIN Johns Hopkins University ❦ ❦ ❦ Trim Size: 6.125in x 9.25in VICE PRESIDENT & DIRECTOR DEVELOPMENT EDITOR ASSISTANT DEVELOPMENT EDITOR SENIOR DIRECTOR PROJECT MANAGER PROJECT SPECIALIST PROJECT ASSISTANT SENIOR MARKETING MANAGER ASSISTANT MARKETING MANAGER ASSOCIATE DIRECTOR SENIOR CONTENT SPECIALIST PRODUCTION EDITOR COVER PHOTO CREDITS ❦ Klein4e-Vol2 f01.tex V2 - December 9, 2015 10:33 P.M Page iv Petra Recter Joan Kalkut Mallory Fryc Don Fowley Gladys Soto Nichole Urban Anna Melhorn Kristine Ruff Puja Katariwala Kevin Holm Nicole Repasky Bharathy Surya Prakash Abstract Pouring Coffee isolated: © Vasin Lee / Shutterstock Coffee beans pouring from scoop: © Fuse / Getty Images, Inc Espresso coffee in a glass cup on white background: © Rob Stark / Shutterstock Flask: © Norm Christiansen Large pink papaver (poppy): © Margaret Rowe/Garden Picture Library / Getty Images, Inc Poppies: © Kuttelvaserova Stuchelova / Shutterstock Studio Shot of Cherry Tomatoes in paper bag: © Jessica Peterson/Tetra Images / Corbis Images Cherry Tomatoes: © Natalie Erhova (summerky)/Shutterstock Evolution of red tomato isolated on white background: © Alena Brozova / Shutterstock Curl of smoke: © stavklem/Shutterstock This book was set in 9/11 Times LT Std Roman by SPi Global and printed and bound by Donnelley Harrisonburg This book is printed on acid-free paper ∞ Founded in 1807, John Wiley & Sons, Inc has been a valued source of knowledge and understanding for more than 200 years, helping people 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desk copy Outside of the United States, please contact your local sales representative ISBN: 978-1-119-11065-1 (PBK) Library of Congress Cataloging in Publication Data: Names: Klein, David R., author Title: Organic chemistry as a second language / David Klein Description: 4e [4th edition] | Hoboken, NJ : John Wiley & Sons, Inc., [2016] | Includes bibliographical references and index Identifiers: LCCN 2015039983 | ISBN 9781119110651 (pbk : alk paper) Subjects: LCSH: Chemistry, Organic—Study and teaching | Chemistry, Organic—Problems, exercises, etc Classification: LCC QD256 K54 2016 | DDC 547.0071/1—dc23 LC record available at http://lccn.loc.gov/2015039983 Printing identification and country of origin will either be included on this page and/or the end of the book In addition, if the ISBN on this page and the back cover not match, the ISBN on the back cover should be considered the correct ISBN Printed in the United States of America 10 ❦ ❦ Trim Size: 6.125in x 9.25in ❦ Klein4e-Vol2 ftoc.tex V1 - November 16, 2015 10:32 P.M Page v CONTENTS CHAPTER 1.1 1.2 1.3 1.4 ❦ Introduction to Aromatic Compounds Nomenclature of Aromatic Compounds Criteria for Aromaticity Lone Pairs 10 CHAPTER 2.1 2.2 2.3 2.4 2.5 2.6 AROMATICITY IR SPECTROSCOPY 13 Vibrational Excitation 14 IR Spectra 15 Wavenumber 16 Signal Intensity 21 Signal Shape 23 Analyzing an IR Spectrum 31 CHAPTER NMR SPECTROSCOPY ❦ 38 3.1 Chemical Equivalence 38 3.2 Chemical Shift (Benchmark Values) 42 3.3 Integration 47 3.4 Multiplicity 51 3.5 Pattern Recognition 54 3.6 Complex Splitting 55 3.7 No Splitting 57 3.8 Hydrogen Deficiency Index (Degrees of Unsaturation) 58 3.9 Analyzing a Proton NMR Spectrum 61 3.10 13 C NMR Spectroscopy 66 CHAPTER 4.1 4.2 4.3 4.4 4.5 4.6 ELECTROPHILIC AROMATIC SUBSTITUTION 69 Halogenation and the Role of Lewis Acids 70 Nitration 74 Friedel-Crafts Alkylation and Acylation 77 Sulfonation 84 Activation and Deactivation 89 Directing Effects 91 v ❦ Trim Size: 6.125in x 9.25in vi Klein4e-Vol2 ftoc.tex ❦ V1 - November 16, 2015 10:32 P.M Page vi CONTENTS 4.7 Identifying Activators and Deactivators 101 4.8 Predicting and Exploiting Steric Effects 111 4.9 Synthesis Strategies 119 CHAPTER 5.1 5.2 5.3 5.4 ❦ KETONES AND ALDEHYDES 142 Preparation of Ketones and Aldehydes 142 Stability and Reactivity of C===O Bonds 146 H-Nucleophiles 148 O-Nucleophiles 153 S-Nucleophiles 166 N-Nucleophiles 168 C-Nucleophiles 178 Some Important Exceptions to the Rule 188 How to Approach Synthesis Problems 192 CHAPTER 7.1 7.2 7.3 7.4 7.5 7.6 7.7 125 Criteria for Nucleophilic Aromatic Substitution 125 SN Ar Mechanism 128 Elimination-Addition 134 Mechanism Strategies 139 CHAPTER 6.1 6.2 6.3 6.4 6.5 6.6 6.7 6.8 6.9 NUCLEOPHILIC AROMATIC SUBSTITUTION CARBOXYLIC ACID DERIVATIVES Reactivity of Carboxylic Acid Derivatives 200 General Rules 201 Acid Halides 205 Acid Anhydrides 214 Esters 216 Amides and Nitriles 226 Synthesis Problems 235 CHAPTER ENOLS AND ENOLATES 244 8.1 Alpha Protons 244 8.2 Keto-Enol Tautomerism 246 8.3 Reactions Involving Enols 251 8.4 Making Enolates 254 8.5 Haloform Reaction 257 8.6 Alkylation of Enolates 260 8.7 Aldol Reactions 265 8.8 Claisen Condensation 272 8.9 Decarboxylation 279 8.10 Michael Reactions 286 ❦ 200 ❦ Trim Size: 6.125in x 9.25in Klein4e-Vol2 ftoc.tex ❦ V1 - November 16, 2015 CONTENTS CHAPTER 9.1 9.2 9.3 9.4 9.5 9.6 AMINES 10:32 P.M Page vii vii 295 Nucleophilicity and Basicity of Amines 295 Preparation of Amines Through SN Reactions 297 Preparation of Amines Through Reductive Amination 301 Acylation of Amines 305 Reactions of Amines with Nitrous Acid 309 Aromatic Diazonium Salts 312 CHAPTER 10 10.1 10.2 10.3 10.4 DIELS-ALDER REACTIONS 315 Introduction and Mechanism 315 The Dienophile 318 The Diene 320 Other Pericyclic Reactions 326 Answers 329 Index 375 ❦ ❦ ❦ Trim Size: 6.125in x 9.25in ❦ ❦ Klein4e-Vol2 ftoc.tex V1 - November 16, 2015 10:32 P.M Page viii ❦ ❦ Trim Size: 6.125in x 9.25in 374 ❦ Klein4e-Vol2 bans.tex V3 - November 17, 2015 6:39 P.M Page 374 ANSWERS 10.15) 10.14) COCH3 (meso) H COOH COOH H COCH3 + COCH3 H COCH3 H Enantiomers 10.16) + O O O O Enantiomers ❦ ❦ ❦ Trim Size: 6.125in x 9.25in ❦ Klein4e-Vol2 bindex.tex V2 - November 17, 2015 6:06 P.M Page 375 INDEX A ❦ Acetals, 158–165 cyclic, 162–165 and imines/amines, 168–171 preparation of, 168–172 thioacetals vs., 166 Acetoacetic ester, 282 Acetoacetic ester synthesis, 282–283 Acetone, 281–283 Acid anhydrides, 200, 214–216, 226, 235–236 Acid chlorides, 80, 200, 210 Acid halides, 200, 205–214 and acylation of amines, 305–306 esters from, 216–217 ketones from, 238 and nucleophiles, 201–203 proton transfers in reactions, 204 reactions of, 207–212 reactivity of, 200, 216, 226, 235–236 synthesis of, 205–207 Acidic conditions: Gabriel synthesis in, 299 Grignard reagents in, 178–179 hydrolysis of amides in, 228–229 keto-enol tautomerism in, 247–249 ketones and aldehydes in, 75–76, 154–155, 157, 169–172, 247–249 N-nucleophiles in, 169–172 O-nucleophiles in, 154–155, 157 preparation of alkanes in, 167 preparation of esters in, 216–221 reverse of Fischer esterification in, 221–222, 225 SN Ar reactions in, 131–133 Acidity, 75–76 Acid sponge, 11 Activation, 89–111 and deactivation, 89–91 and directing effects, 91–101 identifying activators and deactivators, 101–111 Activators, 91–103, 105–107 and acylation of amines, 306–308 defined, 91 directing effects, 91–101 identifying, 101–103, 105–107 moderate, 102–103, 106 as ortho-para directors, 92–94, 96, 98, 107 overview, 105–107 predicting products of reaction, 108–111 strong, 98, 101–102, 105, 306–308 weak, 98–100, 103, 106 Acylation reactions: for amines, 305–309 Friedel-Crafts, 80–84 Acyl chloride, 80 Acyl group: in acylation of amines, 306–307 carbonyl vs., 45 in Friedel-Crafts acylation, 80, 82, 84 in synthesis strategies, 121–122 Acylium ion, 80 Addition: 1,2-addition, 287–288 1,4-addition, 288–289, 292–293 Addition-elimination mechanism (SN Ar mechanism), 128–134, 139–140 AlBr3 (aluminum tribromide), 70–74, 110, 113 AlCl3 (aluminum trichloride), 78–81 375 ❦ ❦ Trim Size: 6.125in x 9.25in 376 ❦ ❦ Klein4e-Vol2 bindex.tex V2 - November 17, 2015 6:06 P.M Page 376 INDEX Alcohols: and acid anhydrides, 215 and acid halides, 202, 207–208, 213 and amides, 227, 234 and carboxylic acids, 240–241 IR spectra of, 23–24 and ketones, 180 (See also O-nucleophiles) NMR spectra of, 57 primary, 142, 144 secondary, 142, 144–145 tertiary, 142 Aldehydes, see Ketones and aldehydes Aldehydic protons, 57 Aldol addition, 265–267 Aldol condensation, 266–273 Aldol reactions, 265–269 Alkanes, 18, 167, 173–174 Alkenes, 18, 184, 187 Alkoxide ions, 202, 204, 272–275 Alkoxy group, 274 Alkyl amines, 296 Alkylation: of ammonia, 297–298 decarboxylation vs., 281, 285 of enolates, 260–264 Friedel-Crafts, 77–81, 121 Alkyl diazonium salt, 311 Alkyl group: in amines, 295 electron donation by, 103 in Friedel-Crafts alkylation, 77, 80, 82, 84 in Grignard reaction, 181 migration of, 190–191 Alkyl halides: and alkylation of enolates, 260–264 in amine preparation, 297–300 and C-nucleophiles, 178, 183 nitrile preparation from, 230 NMR spectra of, 47 Alkynes, 18 Alkynyl protons, 47 Allylic protons, 47 α,β-unsaturated ketones, 271–272, 288–289, 291 Alpha (α) carbon, 244, 251 Alpha-halogenation, 252–253 Alpha (α) protons, 244–245, 269 Alpha (α) spin state, 38 Aluminum tetrabromide, 73 Aluminum tribromide, see AlBr3 Amide ions, 296 Amides: from amines, 296, 305–309 hydrolysis of, 228–229 reactions with, 208, 226–230, 234, 237 reactivity of, 200, 216, 235–236 Amination, reductive, 301–305 Amines, 138, 295–314 and acid anhydrides, 215 and acid halides, 208 acylation of, 305–309 and aromatic diazonium salts, 311–314 and esters, 232 IR spectra of, 27–28 as leaving group, 227 and nitrous acid, 309–312 as N-nucleophiles, 169–172 nucleophilicity and basicity of, 295–296 preparation of, 297–305 primary (see Primary amines) reductive amination of, 301–305 secondary, 27–28, 170–171, 295, 301–305 SN reactions with, 297–300 tertiary, 295 Aminobenzene, 134–135 Amino group, 101–102, 307–308, 313 Ammonia, 208, 297–298 Ammonium ion, 169, 297 Aniline, 134–135, 138–139, 308, 313 Antiaromaticity, 7–9 Aqueous acid, 205, 252 Arenes, Aromatic compounds, NMR spectra of, 60 Aromatic diazonium salts, 311–314 Aromaticity: criteria for, 6–10 ❦ ❦ Trim Size: 6.125in x 9.25in ❦ Klein4e-Vol2 bindex.tex V2 - November 17, 2015 6:06 P.M INDEX lone pairs, 10–12 nomenclature, 2–6 Aromatic methyl protons, 47 Aromatic protons, 46 Aromatic substitution, see Electrophilic aromatic substitution; Nucleophilic aromatic substitution Arrhenium ions, 72 Aryl amines, 296 Aryl diazonium salts, 310–314 Aryl halides, 300 Aryl protons, 47 Asymmetric stretching, 28 Atomic mass, wavenumber and, 16 Azeotropic distillation, 159 B ❦ Baeyer-Villiger oxidation, 188–192, 239 Basic conditions: hydration of nitriles in, 231 hydrolysis of amides in, 229 hydrolysis of esters in, 222–224 keto-enol tautomerism in, 248–249 Basicity, 73, 148, 295–296 Bending (of bonds), 14 Benzaldehyde, 269 Benzene: acylation of, 80 alkylation of, 78–79 halogenation of, 70–74 nitration of, 74–77 resonance-stabilized, substituted, 2, 89, 91–92 sulfonation of, 86–87 Benzyne, 135 β-hydroxy ketone, 265–266, 271 β-keto acids, 280 β-keto esters, 272, 275, 279–281 Beta (β) protons, 44–45 β spin state, 38 BF3 , 166 Bond strength wavenumber and, 16–20 Br+ , 71–72 Br− , 73 Page 377 377 Br2 (bromine), 69–74, 94, 110, 113, 252, 257–260 Broadband decoupling, 66 Broad signals (IR spectra), 23 Bromination reactions, 92, 97–98, 116, 313 Bromine, see Br2 2-Bromo-1-hydroxybenzene, 5-Bromo-2-chloroaniline, Bromoform, 259 2-Butanol, 24 Butyllithium (BuLi), 183 C C− : and acid halides, 208–209 exceptions to rule, 188 rule about expelling, 201–202 13 C, 66–68, 134–135 Cannizzaro reaction, 188 Carbanions, 8, 174 Carbocations: rearrangement of, 79–82 stability of, 77–78 stabilization, 128 Carbon nucleophiles, see C-nucleophiles Carbonyl group: acyl vs., 146 chemical shifts for, 66–67 in Claisen condensations, 273–274 electrophilicity, 154–155 and Grignard reagents, 179–180 IR spectra of, 19–20 in Michael reactions, 287 re-forming of, 149–151 rules of behavior, 147, 149–150, 180, 201–205 signal intensity for (in IR spectra), 21–22 violations of rules, 188–192 Carboxylate ion, 214, 223–224, 229, 259, 274 Carboxyl group, see Decarboxylation Carboxylic acid derivatives, 200–243 acid anhydrides, 214–216 acid halides, 202–214 amides and nitriles, 226–235 ❦ ❦ Trim Size: 6.125in x 9.25in 378 ❦ ❦ Klein4e-Vol2 bindex.tex V2 - November 17, 2015 6:06 P.M Page 378 INDEX Carboxylic acid derivatives (cont.) conversions of ketones/aldehydes and, 238–242 esters, 207–208, 216–226 general rules, 201–205 reactivity of, 200–201, 216, 226, 235–236 synthesis problems, 235–243 Carboxylic acids: and acid anhydrides, 214 alcohols from, 240–241 from aldehydes, 189 alpha-halogenation of, 253 from amides, 229 carboxylic acid derivatives vs., 200 and esters, 216–226 IR spectra of, 24–25 from methyl ketones, 259–260 NMR spectra of, 47 preparation of, 143 substituted, 285 in synthesis problems, 236–237 Catalysts, 73, 157 C-attack (of enolates), 255 CBr3 group, 258–259 C=C double bond, 21–22, 84 CH2 group (methylene group), 39–40 CH3 group, see Methyl group Charge negative, 126, 129–130, 289 partial, 90–91 C–H bonds, 14–15, 17–18, 22–23 Chemical equivalence, 51 Chemical shift (δ), 66–67 CH group (methine group), 40 Chloride ion (Cl− ), 205–206 Chlorine, 93, 105 Chlorobenzene, 92–93, 134–135 Chloroethane, 59 Chloro group, 200, 313 Chlorohexane, 79 Chromium oxidations, 142–143 cis-disubstituted dienophile, 318 Claisen condensations, 272–279 Clemmensen reduction, 68–82, 167, 174 C=N double bond, 170 C-nucleophiles, 178–188 and carboxylic acid derivatives, 202–203 Grignard reagent, 178–182 H- vs., 180–181 phosphorus ylide, 182–187 sulfur ylide, 185–187 C–O bond, 14–15 C=O double bond, 142–144, 146–147 Common names, Complex splitting (NMR spectra), 55–56 Concentrated fuming sulfuric acid, 86–87, 113 Condensation reactions: aldol, 266–273 Claisen, 272–279 defined, 266 Dieckmann, 279 Conjugate addition, 288 Conjugated diene, 320 Conjugated ketones, 19–20 COOH group, see Carboxylic acids Copper salts, 313 Coupling constant (J value), 53, 55–57 Coupling, long-range, 52 Crossed aldol condensations, 269 Crossed Claisen condensations, 277 Cross-over problems, 239–242, 259 Cyanide, 230 Cyano group, 104, 229, 231, 313 Cyclic acetals, 162–165 Cycloaddition reactions, 326–327 Cyclobutadiene, Cyclooctatetraene, Cyclopentadiene, 8, 321 D δ, see Chemical shift; Partial charge Deactivation, 89–111 and activation, 89–91 and directing effects, 91–101 identifying activators and deactivators, 101–111 Deactivators, 91–111 defined, 91 ❦ ❦ Trim Size: 6.125in x 9.25in ❦ Klein4e-Vol2 bindex.tex V2 - November 17, 2015 6:06 P.M INDEX ❦ directing effects, 91–101 identifying, 103–107 as meta-directors, 92, 93, 96, 98, 107 moderate, 103–104, 106 overview, 105–107 predicting products of reaction, 108–111 strong, 98–100, 104–106 weak, 103, 106 Dean-Stark trap, 159, 162, 175 Decarboxylation, 279–286 alkylation vs., 281, 285 with β-keto esters, 279–281 malonic ester synthesis, 284–286 and substituted derivatives of acetone, 281–283 Decoupling, broadband, 66 Degree of unsaturation, 59–61 Deprotonation See also Proton transfer of amines, 295–296 of carbonyl group electrophilic, 155–157 Claisen condensation, 278 in keto-enol tautomerism, 247–250 in SN Ar mechanism, 131–132 Deshielded protons, 38 Desulfonation, 87, 89, 114 Desulfurization (with Raney nickel), 167, 174 Diagnostic region (IR spectra), 17, 30–31 Diastereomeric hydrazones, 173 Diastereomeric oximes, 172, 176 Diazonium ion, 311 Diazonium salts, 311–314 Dieckmann condensation, 279 Diels-Alder reaction, 136 diene, 320–326 dienophile, 318–320 mechanism, 315–318 monosubstituted ethylene, 317 pericyclic reactions, 326–327 Diene, 320–326 Dienophile, 318–320 Diethyl malonate, 284–285 Dilute sulfuric acid, 87 Dimethyl sulfide (DMS), 186 Dipole moment, 21–22 379 Directing effects, 91–101 and activation/deactivation, 91–101 and induction/resonance, 92–93 of multiple groups on a ring, 97–100 and positions on monosubstituted benzene, 91–92 predicting products from, 93–100 Distillation, azeotropic, 159 Distribution of bond strength, 24 DMS (dimethyl sulfide), 186 Double bonds, 16, 19, 69 C=C, 21–22, 85 C=N, 170, 302 C=O, 142–144, 146–147 HDI for, 60 IR signals for, 30–31 P=O, 183–184 S=O, 85, 206 Double enolates, 256, 275 Doublet (NMR spectra), 51 Downfield (NMR spectra), 43 Dow process, 134 E Electrocyclic reactions, 326–327 Electromagnetic radiation, 13–14 Electromagnetic spectrum, 13 Electron density, 69–70, 90 Electron-donating groups, 77, 93, 103 Electronegativity, 43–44, 90 Electron-withdrawing groups, 90, 93, 125–126, 316 Electrophiles: bromine as, 69–70 carbonyl group as, 146–147 and nucleophiles, 69–70 Electrophilic aromatic substitution, 69–124 activation and deactivation, 89–91 defined, 72 directing effects, 91–101 electrophiles and nucleophiles in reactions, 69–70 Friedel-Crafts alkylation and acylation, 77–84 halogenation and Lewis acids, 70–74 ❦ Page 379 ❦ Trim Size: 6.125in x 9.25in 380 ❦ ❦ Klein4e-Vol2 bindex.tex V2 - November 17, 2015 6:06 P.M Page 380 INDEX Electrophilic aromatic substitution (cont.) identifying activators and deactivators, 101–111 nitration, 74–77 nucleophilic vs., 139 steric effects, 111–118 sulfonation, 85–89 synthesis strategies, 119–124 Electrophilic centers (of α, β-unsaturated ketones), 287 Electrophilicity, 70, 154–155 Elimination-addition reactions, 134–140 Enamines, 168, 170–171, 291–294 endo position, 323–324 Energy levels, vibrational, 14–15 Enolates, 244–294 aldol reactions, 265–271 alkylation of, 260–264 and alpha protons, 244–245 Claisen condensation, 272–279 and decarboxylation reactions, 279–286 defined, 248 double, 256, 275 ester, 272–279 haloform reactions, 257–260 highly stabilized, 256 and keto-enol tautomerism, 246–251 Micheal reactions, 286–294 preparation of, 254–257 and reactions with enols, 251–254 Enols: defined, 246 keto-enol tautomerism, 246–251 from Michael reactions, 287–288 reactions with, 251–254 Epoxides, 186–187 Ester enolates, 272–279 Esterification reactions: Fischer, 219–221 reverse of Fischer, 221–222, 225 trans-, 275 Esters, 216–226 acetoacetic ester synthesis, 282–283 and acids, 205 and amides, 227, 237 and amines, 232 β-keto, 272, 275, 279–281 bond strength of, 20 built-in leaving groups of, 273 in Claisen condensation, 273–274 hydrolysis reactions of, 221–226 from ketones, 189 malonic ester synthesis, 284–286 methyl, 274 and O-nucleophiles, 163–164 preparation of, 203, 207–208, 216–221 reactivity of, 200, 216, 226, 235–236 Ethane, 59–60 Ethanol (EtOH), 56–57, 151, 276 Ethoxide, 274–275 Ethyl acetoacetate, 282, 284 Ethyl amine, 60 Ethyl carbocation, 79 Ethyl chloride, 263 Ethylene glycol, 162, 163, 165 Ethyl group, 53–54, 78–79 EtOH, see Ethanol Excitation, vibrational, 14–15 exo position, 323–324 F FeBr3 , 71 Fingerprint region (IR spectra), 17 Fischer esterification, 219–222, 225 Five-membered rings, Friedel-Crafts acylation, 80–84, 121 Friedel-Crafts alkylation, 77–81, 121 Fuming sulfuric acid, 86–87, 113 Functional groups See also specific groups identifying, with IR spectroscopy, 15 temporary modification of, 308 Furan, 11 G Gabriel synthesis, 298–300 Gamma protons, 44 Grignard reagent, 178–182, 209, 213, 215 ❦ ❦ Trim Size: 6.125in x 9.25in ❦ Klein4e-Vol2 bindex.tex V2 - November 17, 2015 6:06 P.M INDEX ❦ 381 H I H− : and acid halides, 208 exceptions to rule, 188 rule about expelling, 201–202 Haloform reactions, 257–260 Halogenation reactions, 70–74 Halogens, 94 and enols, 257–260 hydrogen deficiency index for, 59 resonance vs induction for, 92–93, 105 as weak activators, 103 HDI (hydrogen deficiency index), 58–61 Hell-Volhard-Zelinksky reaction, 253 Hemiacetals, 158 H NMR spectrum, see Proton NMR spectrum H-nucleophiles, 148–153, 167–181, 202–203 Hückel number of electrons, 7, 8, 11 Hybridized atomic orbitals, 17–19 Hydration reactions, 230–231 Hydrazine (NH2 NH2 ), 172–174, 299 Hydrazone, 173–174 Hydride ions, 148 Hydride shift, 79 Hydrogen bonding, 24–25 Hydrogen deficiency index (HDI), 58–61 Hydrogen nucleophiles, see H-nucleophiles Hydrolysis reactions: of amides, 227–229 of esters, 221–226 in Gabriel synthesis, 298 Hydroxide: in aldol condensations, 267 in alkylation of enolates, 261 in Claisen condensation, 272–273 in electrophilic aromatic substitutions, 132, 134, 138, 140 in haloform reaction, 257–258 Hydroxide ion, 135 Hydroxybenzene, Hydroxylamine (NH2 OH), 171–172, 176 Hydroxyl protons, 57 Hyperconjugation, 103 Imines, 168–171, 173, 301–305 Iminium group, 291 Induction: carbonyl group, 146 nitrobenzene, 91 and resonance, 90–93 of strong deactivators, 104–105 In situ preparation, 310 Integration (NMR spectra), 47–50, 61, 66 Intramolecular Claisen condensation, 279 Intramolecular Fischer esterification, 219 Intramolecular proton transfer, 189–190 Intramolecular reactions, 219 Iodination, 74 Iodoform, 259 Ionic reactions, 315 IR absorption spectra, 15–37 analyzing, 30–37 signal intensity, 21–23 signal shape, 23–30 vibrational excitation, 14–15 wavenumber, 16–20 IR spectroscopy, 13–37 analyzing IR spectra, 30–37 and electromagnetic radiation, 13–14 Isopropyl benzene, 79 Isopropyl chloride, 79 Isopropyl group, 53–54 Isotopic labeling, 134–135 J Jones reagent, 142–144 J value (coupling constant), 53, 55–57 K Keto-enol tautomerism, 246–251 Ketones and aldehydes, 132–199 from acid halides, 202, 209, 238 in aldol reactions, 265–271 amines from, 303 β-hydroxy ketone, 265–266, 271 bond strength of, 19–20 α,β-unsaturated ketones, 266, 271–272, 287–289, 291 ❦ Page 381 ❦ Trim Size: 6.125in x 9.25in 382 ❦ ❦ Klein4e-Vol2 bindex.tex V2 - November 17, 2015 6:06 P.M Page 382 INDEX Ketones and aldehydes (cont.) and Cannizzaro/Baeyer-Villiger reactions, 188–192 Clemmensen reduction of, 75–76, 167, 174 and C-nucleophiles, 178–188 C=O bonds of, 146–147 conjugated ketones, 19–20 conversions of, 238–242 from decarboxylation reactions, 281 dimethyl ketone, 281 and enols, 251–253 and H-nucleophiles, 148–153 keto-enol tautomerism, 246–251 methyl ketones, 259–260 and N-nucleophiles, 168–177 and O-nucleophiles, 153–165 preparation of, 142–145 “protecting" a ketone, 163–165 rules of behavior, 201–202 and S-nucleophiles, 166–168 in synthesis problems, 193–199 unsaturated ketones, 19–20 Kinetics, thermodynamics vs., 262 L Labile protons, 57 LAH (lithium aluminum hydride): and acid halides, 210 in formation of cyclic acetals, 163–164 H-nucleophiles from, 149–153 reduction of imine with, 301 LDA (lithium diisopropylamide), 261–264, 296 Leaving groups: and acid anhydride formation, 214–215 of amides, 227 of carboxylic acid derivatives, 200 for nucleophilic aromatic substitution, 125–126 Lewis acids, 71, 73, 80, 82 LiAlH4 , see LAH (lithium aluminum hydride) Lithium dialkyl cuprates (R2 CuLi), 209, 212, 215, 239, 290 Lithium diisopropylamide (LDA), 261–264, 296 Location (of proton NMR signal), 39 Lone pair of electrons, 10–12, 101–103, 295 Long-range coupling, 52 M Magnesium, 178 Major products, 111–113 Malonic ester, 284 Malonic ester synthesis, 284–286 MCPBA (meta-chloro peroxybenzoic acid), 189, 191–192 Meisenheimer complex, 128–130 MeOH, 151–152, 277 meta-directors, 92–93, 96, 98, 107 meta-disubstitution, meta position, 92 Methine group (CH group), 40 Methine protons, 44, 47 Methoxide, 274, 278 Methyl ester, 274 Methyl group (CH3 group): in bromination reactions, 92 directing effects for, 97–99 installing, on aromatic ring, 77–79 IR spectra of, 28 as leaving group, 127 steric effects for, 117–118 Methyl ketones, 259–260 Michael acceptors, 289–291 Michael addition, 288 Michael donors, 289–294 Michael reactions, 286–294 1,2-additions, 287–288 1,4-additions, 288–289, 292–293 with enamines, 291–294 and Michael donors/acceptors, 289–294 Migration, alkyl group, 190–191 Migratory aptitude, 191 Minor product, 111–113 Moderate activators, 102–103, 106, 307 Moderate deactivators, 103–104, 106 Molecular formula (with NMR spectra), 61 ❦ ❦ Trim Size: 6.125in x 9.25in ❦ Klein4e-Vol2 bindex.tex V2 - November 17, 2015 6:06 P.M INDEX Monosubstituted benzene, 91–92 MO (molecular orbital) theory, Multiplicity, 51–53, 61 N ❦ n+1 rule, 51 NaBH4 (sodium borohydride), 148–149, 151–152 NaH (sodium hydride), 148 Narrow signals (IR spectra), 23 Negative charge, 126, 129–130, 148, 289 NH2 NH2 (hydrazine), 172–174, 299 NH2 OH (hydroxylamine), 171–172, 176 Nitration, 74–77 Nitric acid, 75–77, 95, 108–109, 309 Nitriles, 229–231 Nitrobenzene, 75–77, 91–92 Nitrogen gas, 174 Nitro group: as deactivator, 91, 97–99, 104–105 directing effects of, 92 as electron-withdrawing group, 125 in nitration reactions, 76–77 in synthesis strategies, 120–122 Nitrosamine, 310–311 Nitrosonium ion, 310–311 Nitrous acid, 309–312 NMR spectroscopy, see Nuclear magnetic resonance spectroscopy N-nitroso amine, 310–311 N-nucleophiles, 168–177 mechanisms for reactions, 174–176 NH2 NH2 , 172–174 NH2 OH, 171–172 primary amines, 169–172 products of reactions, 176–177 secondary amines, 170–171 NO+2 , 75–76, 108 Nomenclature, of aromaticity, 2–6 Nonaromaticity, 8–9 Nuclear magnetic resonance (NMR) spectroscopy, 13, 38–68 13 C NMR, 66–68 analyzing H NMR spectra, 61–65 383 complex splitting, 55–56 hydrogen deficiency index, 58–61 integration, 47–50 multiplicity, 51–53 pattern recognition, 53–55 without splitting, 56–57 Nucleophiles: carbon (see C-nucleophiles) electron density of, 70 hydrogen, 148–153 nitrogen (see N-nucleophiles) oxygen (see O-nucleophiles) reactions with electrophiles, 69–70 and reactivity of aromatic ring, 89–91 stabilized, 291 strength of, 148 sulfur, 166–168 Nucleophilic aromatic substitution, 125–141 criteria for, 125–127 elimination-addition, 134–139 mechanism strategies for, 139–141 SN Ar mechanism, 128–134 Nucleophilicity and activation, 90–91 of alpha (α) carbon, 251 of amines, 295–296 basicity vs., 73, 148 and electron density, 70 O O-attack, 255 O–H bond, 15 OH group, 90–93, 98, 101 O-nucleophiles, 153–165 acetal formation, 158–162 and carboxylic acid derivatives, 202–203 cyclic acetals, 162–165 overview of formation process, 153–158 Order of events (in synthesis problems), 119–122 OR (alkoxy) group, 103 ortho-disubstitution, ❦ Page 383 ❦ Trim Size: 6.125in x 9.25in 384 Klein4e-Vol2 bindex.tex V2 - November 17, 2015 6:06 P.M Page 384 INDEX ortho-para directors, 92–94, 96, 98, 107 ortho position, 92 leaving and electron-withdrawing groups in, 126, 129–130 and steric effects, 112–114 Overtone of C=O signal in IR spectra, 34 Oxidation reactions, 142–143, 242 Oxidation state (of nitriles), 229 Oximes, 172, 176 Oxophilicity, 183 Oxygen nucleophiles, see O-nucleophiles Ozonolysis, 143–144, 184 P ❦ ❦ para-disubstitution, para position, 92 leaving and electron-withdrawing groups in, 126, 129–130 and steric effects, 112–113, 117 Partial charge (α), 90–91 Pattern recognition, NMR spectroscopy, 53–55 π bonds, 10, 19, 104, 315 PCC (pyridinium chlorochromate), 143–144 Pericyclic reactions, 280, 315, 326–327 Peroxy acids, 188–189, 192 Phenol, 89–90, 135–136, 138 Phenolic proton, 130–132 Phenyl group, 191 Phosphorus ylides, 182–187 Phthalimide, 298 P–O bond, 183 P=O double bond, 183–184 Polarizability, 148 Polybromination, 308 p orbitals, Preparation See also Synthesis of acetals, 158–162 of alkanes, 167 of amines, 297–305 of enolates, 254–257 of esters, 203, 207–208, 216–221 of ketones and aldehydes, 142–145 of nitriles, 230 in situ, 310 Primary alcohols, 142, 144 Primary alkyl amines, 311 Primary alkyl halides, 260 Primary amines, 169–172, 295 IR signal shape, 27–28 and nitrosonium ion, 310–311 preparation of, 297–300 Primary aryl amines, 311 Propyl group, 79, 81–82, 112, 120–121 “Protecting" a ketone, 163–165 Protonation See also Proton transfer of carbonyl group, 155–157 in keto-enol tautomerism, 247–250 of nitrogen atom, 11 in SN Ar mechanism, 131–132 Proton NMR spectrum (1 H NMR spectrum), 38–65 analyzing, 61–65 complex splitting, 55–56 and hydrogen deficiency index, 58–61 integration, 35–50 multiplicity, 51–53 pattern recognition, 53–55 without splitting, 56–57 Protons, 57 alpha, 244–245 beta, 44–45 gamma, 44 labile, 57 relative number of (in NMR spectra), 48 shielded vs deshielded, 38 Proton splitting, 51–53, 55–57 Proton transfer and carboxylic acid derivatives, 204–205 drawing, 73 in hydration of nitriles, 230–231 in imine formation, 169–170 intramolecular, 189–190 in one-step synthesis of esters, 217–218 in O-nucleophile and ketone/aldehyde reactions, 157–158 in reverse Fischer esterification, 222 Pyridine, 11, 207, 214–215 ❦ ❦ Trim Size: 6.125in x 9.25in ❦ Klein4e-Vol2 bindex.tex V2 - November 17, 2015 6:06 P.M INDEX Pyridinium chloride, 207 Pyridinium chlorochromate (PCC), 143–144 Pyrrole, 11 Q Quartets (in NMR spectra), 51 Quaternary ammonium salt, 297 Quaternary products, 297 Quintets (in NMR spectra), 51 R ❦ R2 CuLi, see Lithium dialkyl cuprates Radical reactions, 315 Raney nickel, 166–167, 174 Reactivity of aromatic ring, 89–91 of carbonyl group, 146–147 of carboxylic acid derivatives, 200–201, 216, 226, 235–236 Reagents for acid halide reactions, 212–214 for electrophilic vs nucleophilic substitution reactions, 139–140 Grignard, 178–182, 209, 213, 215 for preparation of ketones and aldehydes, 142–145 for synthesis problems, 120 Wittig, 183, 184 Reduction-oxidation reactions, 242 Reduction reactions: amine preparation, 301–305 Clemmensen, 81–82, 167, 174 with Grignard reagent, 181 with H-nucleophiles, 151–152 with N-nucleophiles, 174 with O-nucleophiles, 164–165 with Raney nickel, 166–167, 174 of thioacetals, 166–167 Wolff-Kishner, 174 Reductive amination, 301–305 Resonance: and bond strength, 19–20 carbonyl group, 146 of carboxylate ion, 223 Page 385 385 and induction, 90–93 keto-enol tautomerism vs., 246 Resonance-stabilized benzene, Resonance-stabilized tropylium cation, Resonance structures, 72, 74 of activators and deactivators, 101–102 of aryl amines, 296 of α,β-unsaturated ketones, 287 Diels-Alder reaction, 316 of enamines, 291–292 of enolates, 255 of Meisenheimer complex, 129 Retrosynthetic analysis, 196–197 Reverse of Fischer esterification, 221–222, 225 S Salts: copper, 313 diazonium, 311–314 quaternary ammonium, 296 Sandmeyer reactions, 313 Saponification, 223–224 Saturated compounds, 58 s-cis conformation, 320–321 Secondary alcohols, 142, 144–145 Secondary amines, 27–28, 170–171, 295, 301–305 Seven-membered rings, Sigma bonds, 51–52 Sigma complex, 72, 76, 78, 86, 129 Sigmatropic rearrangements, 326–327 Signal intensity (IR spectra), 21–23 Signal shape (in IR spectra), 23–30 C–H bonds, 28 N–H bonds, 27–28 and O–H bonds, 23–27 Single bonds, 16 C–H, 14–15, 17–18, 22–23 C–O, 14–15 IR signals for, 30–31 O–H, 15 P–O, 183 X–H, 16, 31 SN reactions, 128 ❦ ❦ Trim Size: 6.125in x 9.25in 386 ❦ ❦ Klein4e-Vol2 bindex.tex V2 - November 17, 2015 6:06 P.M Page 386 INDEX SN reactions, 128, 183, 186, 297–300 SN Ar mechanism, 128–134, 139–140 S-nucleophiles, 166–168 SO2 gas, 207 SO3 , 85–86 SO3 H group, 86–87 Sodium amide, 296 Sodium dichromate, 144 Sodium nitrate, 309 S=O double bonds, 206 s orbitals, 18 sp2 -hybridized carbon atoms, 67 sp2 hybridized nitrogen, 10–11 sp3 -hybridized carbon atoms, 67 sp3 hybridized nitrogen, 11 Spectroscopy, see IR spectroscopy; Nuclear magnetic resonance (NMR) spectroscopy sp-hybridized carbon atoms, 67 Splitting, proton, see Proton splitting sp orbitals, 18 Stability of β-keto ester, 275 of carbonyl group, 147 of enolates, 256, 288–289 of negative charge, 148 Stabilized nucleophiles, 291 Step-curves (in NMR spectra), 48 Steric effects, 111–118 for carbonyl group, 147 of multiple groups on rings, 115–118 and substitution with propyl benzene, 111–112 in synthesis strategies, 112–115, 120–121 Stork enamine synthesis, 292–293 s-trans conformation, 321 Stretching (of bonds), 14, 28 Strong acids, 75–76 Strong activators, 98, 101–102, 105, 306–308 Strong bases, 148 Strong deactivators, 98–100, 104–106 Strong nucleophile, 148 Substituted benzenes, Substituted carboxylic acids, 285 Sulfonation, 85–89, 113 Sulfur, 85, 166 Sulfuric acid: concentrated fuming, 86–87, 113 dilute, 87, 114 and nitric acid, 75–77, 95, 108–109 in preparation of ketones, 142 Sulfur nucleophiles, 166–168 Sulfur ylide, 185–187 Symmetric stretching, 28 Symmetry and integration values, 49 of ketones, 170–172 Synthesis See also Preparation acetoacetic ester, 282–283 of acid halides, 205–207 of aniline, 138–139 of carboxylic acid derivatives, 235–243 with electrophilic aromatic substitution, 119–124 Gabriel, 298–300 of ketones and aldehydes, 193–199 malonic ester, 284–286 and steric effects, 112–115, 120–121 Stork enamine, 292–293 Synthesis problems cross-over problems, 239–242 multiple answers to, 197 order of events in, 119–122 retrosynthetic analysis for, 196–197 working backwards, 196–197 Systematic names, T Tautomers, 246 Temporary modification of functional groups, 308 tert-Butyl group multiplicity of, 52–53 NMR splitting pattern, 53–54 steric effects for, 113, 117–118 ❦ ❦ Trim Size: 6.125in x 9.25in ❦ Klein4e-Vol2 bindex.tex V2 - November 17, 2015 6:06 P.M INDEX Tertiary alcohols, 142 Tertiary amines, 295 Tetrahedral intermediate, 155–157, 203 Tetrahydrofuran (THF), 261 Thermodynamics, kinetics vs., 262 THF (tetrahydrofuran), 261 Thioacetals, 166–167 Thionyl chloride, 206 3D drawing, 322 Toluene, 92 trans-disubstituted dienophile, 318 trans-esterification, 275 Trichloromethyl group, 105 Triphenylphosphine, 182–183 Triple bonds, 16, 19, 31, 60 Tropylium cation, U ❦ Unsaturated compounds, 58 Unsaturated ketones, 19–20 Unsaturation, degree of, 59–61 UV–Vis spectroscopy, 13–14 V Vibrational excitation, 14–15 Vinylic protons, 47 Page 387 387 W Water and acetal formation, 158–159 and acid anhydrides, 215 and acid halides, 204 in keto-enol tautomerism, 250 as proton source, 151, 153 removing Lewis acids with, 82 removing protons with, 76–77 Wavelength, 15 Wavenumber (in IR spectra), 15–20 Weak activators, 98–100, 103, 106 Weak bases, 148 Weak deactivators, 103, 106 Wittig reaction, 183–185 Wittig reagent, 183–184 Wolff-Kishner reduction, 174 X X–H bonds, 16, 31 Y Ylides, 182–187 Z Zinc amalgam, 81–82 ❦ ❦ WILEY END USER LICENSE AGREEMENT Go to www.wiley.com/go/eula to access Wiley’s ebook EULA ... DEVELOPMENT EDITOR ASSISTANT DEVELOPMENT EDITOR SENIOR DIRECTOR PROJECT MANAGER PROJECT SPECIALIST PROJECT ASSISTANT SENIOR MARKETING MANAGER ASSISTANT MARKETING MANAGER ASSOCIATE DIRECTOR SENIOR CONTENT... aromatic, nonaromatic, or antiaromatic WORKED PROBLEM 1.7 antiaromatic: ❦ Characterize the following ion as aromatic, nonaromatic, or Answer In order to be nonaromatic, it must fail the first criterion... structure In other words, does the carbonyl group have more double-bond character or more single-bond character? The second resonance structure exhibits charge separation, as well as a carbon atom