This page intentionally left blank ORGANIC CHEMISTRY AS A SECOND LANGUAGE, 3e This page intentionally left blank ORGANIC CHEMISTRY AS A SECOND LANGUAGE, 3e Second Semester Topics DAVID KLEIN Johns Hopkins University JOHN WILEY & SONS, INC ASSOCIATE PUBLISHER EDITORIAL ASSISTANT MARKETING MANAGER SENIOR PRODUCTION EDITOR CREATIVE DIRECTOR SENIOR COVER DESIGNER COVER CREDITS Petra Recter Lauren Stauber Kristine Ruff Sujin Hong; Production Management Services provided by Prepare, Inc Harry Nolan Wendy Lai Background: © William Hopkins/iStockphoto Test tube: Untitled X-Ray/Nick Veasey/ Getty Images, Inc Bicycle: Igor Shikov/Shutterstock This book was set in 9/11 Times Roman by Prepare, Inc and printed and bound by Courier Westford The cover was printed by Courier Westford This book is printed on acid-free paper ϱ Founded in 1807, John Wiley & Sons, Inc has been a valued source of knowledge and understanding for more than 200 years, helping people around the world meet their needs and 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your local sales representative ISBN 978-1-118-14434-3 Printed in the United States of America 10 CONTENTS CHAPTER 1.1 1.2 1.3 1.4 1.5 1.6 IR SPECTROSCOPY Vibrational Excitation IR Spectra Wavenumber Signal Intensity Signal Shape 11 Analyzing an IR Spectrum CHAPTER 19 NMR SPECTROSCOPY 26 2.1 Chemical Equivalence 26 2.2 Chemical Shift (Benchmark Values) 30 2.3 Integration 35 2.4 Multiplicity 39 2.5 Pattern Recognition 41 2.6 Complex Splitting 43 2.7 No Splitting 44 2.8 Hydrogen Deficiency Index (Degrees of Unsaturation) 2.9 Analyzing a Proton NMR Spectrum 49 2.10 13C NMR Spectroscopy 53 CHAPTER 3.1 3.2 3.3 3.4 3.5 3.6 3.7 3.8 3.9 46 ELECTROPHILIC AROMATIC SUBSTITUTION 56 Halogenation and the Role of Lewis Acids 57 Nitration 61 Friedel-Crafts Alkylation and Acylation 64 Sulfonation 72 Activation and Deactivation 76 Directing Effects 78 Identifying Activators and Deactivators 88 Predicting and Exploiting Steric Effects 98 Synthesis Strategies 106 v vi CONTENTS CHAPTER 4.1 4.2 4.3 4.4 Criteria for Nucleophilic Aromatic Substitution SNAr Mechanism 115 Elimination-Addition 121 Mechanism Strategies 126 CHAPTER 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 5.9 KETONES AND ALDEHYDES 112 129 Preparation of Ketones and Aldehydes 129 Stability and Reactivity of CăO Bonds 133 H-Nucleophiles 135 O-Nucleophiles 140 S-Nucleophiles 153 N-Nucleophiles 155 C-Nucleophiles 165 Some Important Exceptions to the Rule 175 How to Approach Synthesis Problems 180 CHAPTER 6.1 6.2 6.3 6.4 6.5 6.6 6.7 NUCLEOPHILIC AROMATIC SUBSTITUTION CARBOXYLIC ACID DERIVATIVES Reactivity of Carboxylic Acid Derivatives General Rules 188 Acid Halides 192 Acid Anhydrides 201 Esters 203 Amides and Nitriles 213 Synthesis Problems 222 CHAPTER ENOLS AND ENOLATES 7.1 Alpha Protons 231 7.2 Keto-Enol Tautomerism 233 7.3 Reactions Involving Enols 238 7.4 Making Enolates 241 7.5 Haloform Reaction 244 7.6 Alkylation of Enolates 247 7.7 Aldol Reactions 252 7.8 Claisen Condensation 259 7.9 Decarboxylation 266 7.10 Michael Reactions 273 231 187 187 112 CONTENTS CHAPTER 8.1 8.2 8.3 8.4 8.5 8.6 AMINES 281 Nucleophilicity and Basicity of Amines 281 Preparation of Amines through SN2 Reactions 283 Preparation of Amines through Reductive Amination Acylation of Amines 291 Reactions of Amines with Nitrous Acid 295 Aromatic Diazonium Salts 298 Answer Key Index 345 301 287 vii This page intentionally left blank 342 ANSWERS 8.5) O 1) KOH N H 2) H 2N Br O 3) H2N NH2 8.7) No 8.8) Yes 8.12) 8.9) Yes 1) 8.10) No NH2 O [ H+ ] , Dean-Stark N H 2) LAH 3) H2O 8.13) H 1) CH3NH2 O N CH3 [ H+ ] , Dean-Stark 2) LAH 3) H2O 8.14) H2N 1) O [ H+ ] , Dean-Stark H N H 2) LAH 3) H2O 8.15) 1) [ H+ ] , Dean-Stark O NH2 H N 2) LAH 3) H2O 8.16) O 1) NH2 H [ H+ ] , Dean-Stark N H 2) LAH 3) H2O 8.18) OH 1) Na2Cr2O7, H2SO4, H2O + 2) CH3 NH2 [ H ] , Dean-Stark 3) LAH 4) H2O H N 343 ANSWERS 8.19) 1) BH3 • THF 2) H2O2, NaOH H N 3) PCC 4) [ H+ ] , Dean-Stark NH2 5) LAH 6) H2O 8.20) O H 1) H3O+ O N 2) [H+], CH3CH2CH2NH2 Dean-Stark 3) LAH 4) H2O 8.21) 1) O3 H N 2) DMS [ H+ ] , NH2 3) Dean-Stark 4) LAH 5) H2O 8.22) H 1) Et2 CuLi O 2) Cl + [H ], NH2 Dean-Stark 3) LAH 4) H2O 8.24) O H2 N 1) H2N Cl O Cl 2) O AlCl3 3) H3O+ 8.25) O H2N 1) Cl 2) Cl2 , AlCl3 3) H3 O+ H2N Cl N 344 ANSWERS 8.27) 8.28) Cl 8.29) N O N Cl N 8.30) N N N N 8.32) NH2 Br NO2 NO2 1) NaNO2 , HCl 2) CuBr 8.33) NH2 CN 1) NaNO2 , HCl NO2 8.34) 2) CuCN NO2 NH2 Cl 1) NaNO2 , HCl NO2 8.35) 2) CuCl NH2 NO2 Br 1) NaNO2 , HCl 2) CuBr 8.36) N NH2 CN 1) NaNO2 , HCl 2) CuCN Cl INDEX A Acetals, 145–152 cyclic, 149–152 and imines/amines, 155–158 preparation of, 145–149 thioacetals vs., 153 Acetic acid (CH3COOH), 239 Acetoacetic ester, 269 Acetoacetic ester synthesis, 269–270 Acetone, 268–270 Acid anhydrides, 187, 201–203, 213, 222–223 Acid chlorides, 67, 187, 197 Acid halides, 192–201 and acylation of amines, 291–292 and C-, H-, and O-nucleophiles, 188–190 and carboxylic acids, 201 esters from, 203–204 ketones from, 225 proton transfers in reactions, 191 reactions of, 194–199 reactivity of, 187, 203, 213, 222–223 synthesis of, 192–194 Acidic conditions: Gabriel synthesis in, 285 Grignard reagents in, 165–166 hydration of nitriles in, 217 hydrolysis of amides in, 215–216 keto-enol tautomerism in, 234–236 ketones and aldehydes in, 62–63, 141–142, 144, 156–159, 234–236 N-nucleophiles in, 156–159 O-nucleophiles in, 141–142, 144 preparation of alkanes in, 154 preparation of esters in, 203–208 reverse of Fischer esterification in, 208–209, 212 SNAr reactions in, 118–120 Acidity, 62–63 Activation, 76–98 and deactivation, 76–78 and directing effects, 78–88 identifying activators and deactivators, 88–98 Activators, 78–90, 92–94 and acylation of amines, 292–294 defined, 78 directing effects, 78–88 identifying, 88–90, 92–94 moderate, 89–90, 93, 293 as ortho-para directors, 79–81, 83, 85, 94 overview, 92–94 predicting products of reaction, 95–98 strong, 85, 88–89, 92, 292–294 weak, 85–87, 90, 93 Acylation reactions: for amines, 291–295 Friedel-Crafts, 67–71 Acyl chloride, 67 Acyl group: in acylation of amines, 292–293 carbonyl vs., 133 in Friedel-Crafts acylation, 67, 69, 71 in synthesis strategies, 108–109 Acid halides, 187 Acylium ion, 67 Addition: 1,2-addition, 274–275 1,4-addition, 275–276, 278–279 Addition-elimination mechanism (SNAr mechanism), 115–121, 126–127 AlBr3 (aluminum tribromide), 57–61, 97, 100 AlCl3 (aluminum trichloride), 65–68 Alcohols: and acid anhydrides, 202 and acid halides, 189, 194–195, 200 and amides, 214, 221 345 346 INDEX Alcohols (cont.) and carboxylic acids, 227–228 IR spectra of, 11–12 and ketones, 167 See also O-nucleophiles NMR spectra of, 32, 35, 45 primary, 129, 131 secondary, 129, 131–132 tertiary, 129 Aldehydes, see Ketones and aldehydes Aldehydic protons, 35, 45 Aldol addition, 252–254 Aldol condensation, 253–260 Aldol reactions, 252–256 Alkanes, 6, 154, 160–161 Alkenes, 6, 171, 174 Alkoxides, 259–261 Alkoxide ions, 189, 191, 204, 259, 262 Alkoxy group, 261 Alkyl amines, 282 Alkylation: of ammonia, 283–284 decarboxylation vs., 268, 272 of enolates, 247–251 Friedel-Crafts, 64–68, 108 Alkyl diazonium salt, 297 Alkyl group: in amines, 281 electron donation by, 90 in Friedel-Crafts alkylation, 64, 67, 69, 71 in Grignard reaction, 168 migration of, 177–178 Alkyl halides: and alkylation of enolates, 247–251 in amine preparation, 283–286 and C-nucleophiles, 165, 170 nitrile preparation from, 217 NMR spectra of, 35 Alkynes, Alkynyl protons, 35 Allylic protons, 35 ␣, -unsaturated ketones, 253, 258–259, 274–276, 278 Alpha (␣) carbon, 231, 238 Alpha-halogenation, 239–240 Alpha (␣) protons, 32–33, 231–232, 256 ␣ spin state, 26 Aluminum tetrabromide, 60 Aluminum tribromide, see AlBr3 Amides: from amines, 282, 291–295 hydrolysis of, 215–216, 292 reactions with, 195, 213–217, 221, 224 reactivity of, 187, 203, 222–223 Amide ions, 282 Amination, reductive, 287–291 Amines, 125, 281–300 and acid anhydrides, 202 and acid halides, 195 acylation of, 291–295 and aromatic diazonium salts, 297–300 and esters, 219 IR spectra of, 15–16 as leaving group, 214 and nitrous acid, 295–298 as N-nucleophiles, 156–159 nucleophilicity and basicity of, 281–282 preparation of, 283–291 primary, see Primary amines reductive amination of, 287–291 secondary, 15–16, 157–158, 281, 287–291 SN2 reactions with, 283–286 tertiary, 281 Aminobenzene, 121–122 Amino group, 88–89, 293–294, 299 Ammonia, 195, 283–284 Ammonium ion, 156, 283 Aniline, 121–122, 125–126, 294, 299 Aqueous acid, 192, 239 Aromatic compounds, NMR spectra of, 28, 48 Aromatic diazonium salts, 298–300 Aromatic methyl protons, 35 Aromatic protons, 34 Aromatic substitution, see Electrophilic aromatic substitution; Nucleophilic aromatic substitution Arrhenium ions, 59 Aryl amines, 282 Aryl diazonium salts, 297–300 Aryl halides, 286 Aryl protons, 35 Asymmetric stretching, 16 Atomic mass, wavenumber and, Azeotropic distillation, 146 B Baeyer-Villiger reaction, 175–179, 226 Basic conditions: hydration of nitriles in, 218 hydrolysis of amides in, 216 hydrolysis of esters in, 209–211 INDEX keto-enol tautomerism in, 235–236 Basicity, 60, 135, 281–282 Bending (of bonds), Benzaldehyde, 256 Benzene: alkylation of, 65–66 acylation of, 67 halogenation of, 57–61 nitration of, 61–64 substituted, 76, 78–79 sulfonation of, 73–74 Benzyne, 122 -hydroxy ketone, 252–253, 258 -keto acids, 267 -keto esters, 259, 262, 266–268 Beta () protons, 32–33  spin state, 26 BF3, 153 Bond strength, wavenumber and, 4–8 Brϩ, 58–59 BrϪ, 60 Br2 (bromine), 56–61, 81, 97, 100, 239, 244–247 Broadband decoupling, 54 Broad signals (IR spectra), 11 Bromination reactions, 79, 84–85, 103, 299 Bromine, see Br2 Bromoform, 246 Butane, 36–37 2-Butanol, 12 tert-Butyl group: multiplicity of, 40–41 NMR splitting pattern, 41–42 steric effects for, 100, 104–105 Butyllithium (BuLi), 170 C CϪ: and acid halides, 195–196 exceptions to rule, 175, 245 rule about expelling, 137, 188–189 13C, 53–55, 121–122 Cannizzaro reaction, 175 Carbanions, 161 Carbocations: rearrangement of, 66–69 stability of, 64–65 stabilization, 115 Carbon nucleophiles, see C-nucleophiles Carbonyl group: acyl vs., 133 chemical shifts for, 32, 54 in Claisen condensations, 260–261 electrophilicity, 141–142 and Grignard reagents, 166–167 IR spectra of, 7–8 in Michael reactions, 274 re-forming of, 136–138 rules of behavior, 134, 136–137, 167, 188–192 signal intensity for (in IR spectra), 9–10 violations of rules, 175–179 Carboxylate ion, 201, 210–211, 216, 246, 261 Carboxyl group, see Decarboxylation Carboxylic acids: and acid anhydrides, 201 alcohols from, 227–228 from aldehydes, 176, 178 alpha-halogenation of, 240 347 from amides, 216 carboxylic acid derivatives vs., 187 and esters, 203–213 IR spectra of, 12–13 from methyl ketones, 246–247 NMR spectra of, 35 preparation of, 130 substituted, 272 in synthesis problems, 223–224 Carboxylic acid derivatives, 187–230 acid anhydrides, 201–203 acid halides, 189–201 amides and nitriles, 213–222 conversions of ketones/aldehydes and, 225–229 esters, 194–195, 203–213 general rules, 188–192 reactivity of, 187–188, 203, 213, 222–223 synthesis problems, 222–230 Catalysts, 60, 144 C-attack (of enolates), 242 CBr3 group, 245–246 C:C double bond, 9–10, 72 CH2 group (methylene group), 27–28 CH3COOH (acetic acid), 239 CH3 group, see Methyl group Charge: negative, 113, 116–117, 135, 276 partial, 77–78 CßH bonds, 2–3, 5–6, 10–11 Chemical equivalence, 26–30, 39 348 INDEX Chemical shift ( ␦ ), 30–35, 49, 53–54 CH group (methine group), 28 Chloride ion (ClϪ), 192–193 Chlorine, 80, 92 Chlorobenzene, 79–80, 121–122 Chloroethane, 47 Chloro group, 187, 299 Chlorohexane, 66 Chromium oxidations, 129–130 Claisen condensations, 259–266 Clemmensen reduction, 68–69, 154, 161 C:N double bond, 157, 288 13C NMR spectroscopy, 53–55 C-nucleophiles, 165–175 and carboxylic acid derivatives, 189–190 Grignard reagent, 165–169 H- vs., 167–168 phosphorus ylide, 169–174 sulfur ylide, 172–174 CßO bond, 2–3 C:O double bond, 129–131, 133–134 Complex splitting (NMR spectra), 43–44 Concentrated fuming sulfuric acid, 73–74, 100 Condensation reactions: aldol, 253–260 Claisen, 259–266 defined, 253 Dieckmann, 266 Conjugate addition, 275 Conjugated ketones, 7–8 COOH group, see Carboxylic acids Copper salts, 299 Coupling, long-range, 40 Coupling constant (J value), 41, 43–45 Crossed aldol condensations, 256 Crossed Claisen condensations, 264 Cross-over problems, 226–229, 246 Cyanide, 217 Cyano group, 91, 216, 218, 299 Cyclic acetals, 149–152 Cyclohexane, 46–47 Cyclohexanone, 247–249 D Deactivation, 76–98 and activation, 76–78 and directing effects, 78–88 identifying activators and deactivators, 88–98 Deactivators, 78–98 defined, 78 directing effects, 78–88 identifying, 90–94 as meta-directors, 79, 80, 83, 85, 94 moderate, 90–91, 93 overview, 92–94 predicting products of reaction, 95–98 strong, 85–87, 91–93 weak, 90, 93 Dean-Stark trap, 146, 149, 162 Decarboxylation, 266–273 alkylation vs., 268, 272 with -keto esters, 266–268 malonic ester synthesis, 271–273 and substituted derivatives of acetone, 268–270 Decoupling, broadband, 54 Degree of unsaturation, 47–49 ␦, see Chemical shift; Partial charge Deprotonation See also Proton transfer of amines, 281–282 of carbonyl group electrophilic, 142–144 Claisen condensation, 265 in keto-enol tautomerism, 234–237 in SNAr mechanism, 118–119 Deshielded protons, 26 Desulfonation, 74, 76, 101 Desulfurization (with Raney nickel), 154, 161 Diagnostic region (IR spectra), 5, 18–19 Diastereomeric hydrazones, 160 Diastereomeric imines, 157 Diastereomeric oximes, 159, 163 Diazonium ion, 297 Diazonium salts, 297–300 Dieckmann condensation, 266 Diels-Alder reaction, 123 Diethyl malonate, 271–272 Dilute sulfuric acid, 74, 101 2,3-Dimethyl-2-butene, 10 Dimethyl ketone, 268 Dimethyl sulfide (DMS), 173 Dipole moment, 9–10 Directing effects, 78–88 and activation/ deactivation, 78–88 and induction/ resonance, 79–80 of multiple groups on a ring, 84–87 INDEX and positions on monosubstituted benzene, 78–79 predicting products from, 80–87 Distillation, azeotropic, 146 Distribution of bond strength, 12 DMS (dimethyl sulfide), 173 Double bonds, 4, 7, 56 C:C, 9–10, 72 C:N, 157, 288 C:O, 129–131, 133–134 HDI for, 48 IR signals for, 18–19 P:O, 170–171 S:O, 72, 193 Double enolates, 243, 262 Doublet (NMR spectra), 39 Downfield (NMR spectra), 31 Dow process, 121 E Electromagnetic radiation, 1–2 Electromagnetic spectrum, Electron density, 56–57, 77 Electron-donating groups, 77, 80, 90 Electronegativity, 31–32, 77 Electron-withdrawing groups, 77, 80, 112–113 Electrophiles: bromine as, 56–57 carbonyl group as, 133–134 and nucleophiles, 56–57 Electrophilic aromatic substitution, 56–111 activation and deactivation, 76–78 defined, 59 directing effects, 78–88 electrophiles and nucleophiles in reactions, 56–57 Friedel-Crafts alkylation and acylation, 64–71 halogenation and Lewis acids, 57–61 identifying activators and deactivators, 88–98 nitration, 61–64 nucleophilic vs., 126 steric effects, 98–105 sulfonation, 72–76 synthesis strategies, 106–111 Electrophilic centers (of ␣, -unsaturated ketones), 274 Electrophilicity, 57, 141–142 Elimination-addition reactions, 121–127 Enamines, 155, 157–158, 277–280 Energy levels, vibrational, 2–3 Enols: defined, 233 keto-enol tautomerism, 233–238 from Michael reactions, 274–275 reactions with, 238–241 Enolates, 231–280 aldol reactions, 252–258 alkylation of, 247–251 and alpha protons, 231–232 Claisen condensation, 259–266 349 and decarboxylation reactions, 266–273 defined, 235 double, 243, 262 ester, 259–266 haloform reactions, 244–247 and keto-enol tautomerism, 233–238 Micheal reactions, 273–280 preparation of, 241–244 and reactions with enols, 238–241 highly stabilized, 243 Epoxides, 173–174 Esters, 203–213 acetoacetic ester synthesis, 269–270 and acids, 192 and amides, 214, 224 and amines, 219 -keto, 259, 262, 266–268 bond strength of, built-in leaving groups of, 260 in Claisen condensation, 260–261 hydrolysis reactions of, 208–213 from ketones, 176 malonic ester synthesis, 271–273 methyl, 261 NMR spectra of, 32 and O-nucleophiles, 150–151 preparation of, 190, 194–195, 203–208 reactivity of, 187, 203, 213, 222–223 Ester enolates, 259–266 Esterification reactions: Fischer, 206–208 reverse of Fischer, 208–209, 212 trans-, 262 Ethane, 47–48 350 INDEX Ethanol (EtOH), 44–45, 47, 138, 263 Ethers, 32 Ethoxide, 261–262 Ethyl acetoacetate, 269, 271 Ethyl amine, 48 Ethylbenzene, 34 Ethyl carbocation, 66 Ethyl chloride, 250 Ethylene glycol, 149, 150, 152 Ethyl group, 41–42, 65–66 EtOH, see Ethanol Excitation, vibrational, 2–3 F FeBr3, 58 Fingerprint region (IR spectra), Fischer esterification, 206–209, 212 Fluorine, 31 Friedel-Crafts acylation, 67–71, 108 Friedel-Crafts alkylation, 64–68, 108 Fuming sulfuric acid, 73–74, 100 Functional groups See also specific groups chemical shift for, 32–33 identifying, with IR spectroscopy, temporary modification of, 294 G Gabriel synthesis, 284–286 Gamma protons, 32 Grignard reagent, 165–169, 189, 196, 200, 202 H HϪ: and acid halides, 195 exceptions to rule, 175, 245 rule about expelling, 137, 188–189 Haloform reactions, 244–247 Halogens, 81 and enols, 244–247 hydrogen deficiency index for, 47 resonance vs induction for, 79–80, 92 as weak activators, 90 Halogenation reactions, 57–61 HDI (hydrogen deficiency index), 46–49 Hell-Volhard-Zelinksky reaction, 240 Hemiacetals, 145 1-Hexene, 46–47 1H NMR spectrum, see Proton NMR spectrum H-nucleophiles, 135–140, 167–168, 189–190 Hybridized atomic orbitals, 5–7 Hydration reactions, 217–218 Hydrazine (NH2NH2), 159–161, 285 Hydrazone, 160–161 Hydride ions, 135 Hydride shift, 66 Hydrogenation reactions, 288 Hydrogen bonding, 12–13 Hydrogen deficiency index (HDI), 46–49 Hydrogen nucleophiles, see H-nucleophiles Hydrolysis reactions: of amides, 214–216, 292 of esters, 208–213 in Gabriel synthesis, 285 Hydroxide: in aldol condensations, 254 in alkylation of enolates, 248 in Claisen condensation, 259–260 in electrophilic aromatic substitutions, 119, 121, 125, 127 in haloform reaction, 244–245 Hydroxide ion, 122 Hydroxylamine (NH2OH), 158–159, 163 Hydroxyl protons, 45 Hyperconjugation, 90 I Imines, 155–158, 160, 287–291 Iminium group, 278 Induction: carbonyl group, 133 nitrobenzene, 78 and resonance, 77–80 of strong deactivators, 91–92 Inductive effects (in NMR spectroscopy), 31–32 In situ preparation, 296 Integration (NMR spectra), 35–38, 49, 53 Intramolecular Claisen condensation, 266 Intramolecular Fischer esterification, 206 Intramolecular proton transfer, 176–177 Intramolecular reactions, 162, 206 Iodination, 61 Iodoform, 246 IR absorption spectra, 3–25 analyzing, 18–25 signal intensity, 9–11 signal shape, 11–18 wavenumber, 4–8 IR spectroscopy, 1–25 INDEX analyzing IR spectra, 18–25 and electromagnetic radiation, 1–2 IR spectra, 3–25 signal intensity, 9–11 signal shape, 11–18 vibrational excitation, 2–3 wavenumber, 4–8 Isopropyl benzene, 66 Isopropyl chloride, 66 Isopropyl group, 41–42 Isotopic labeling, 121–122 J Jones reagent, 129–131 J value (coupling constant), 41, 43–45 K Keto-enol tautomerism, 233–238 Ketones and aldehydes, 129–186 from acid halides, 189, 196, 225 in aldol reactions, 252–258 ␣, -unsaturated ketones, 253, 258–259, 274–276, 278 amines from, 289 -hydroxy ketone, 252–253, 258 bond strength of, 7–8 and Cannizzaro/BaeyerVilliger reactions, 175–179 Clemmensen reduction of, 62–63, 154, 161 and C-nucleophiles, 165–175 C:O bonds of, 133–134 conjugated ketones, 7–8 conversions of, 225–229 from decarboxylation reactions, 268 dimethyl ketone, 268 and enols, 238–240 and H-nucleophiles, 135–140 keto-enol tautomerism, 233–238 methyl ketones, 246–247 NMR chemical shift for, 35 and N-nucleophiles, 155–164 and O-nucleophiles, 140–152 preparation of, 129–132 “protecting” a ketone, 150–152 rules of behavior, 188–189 and S-nucleophiles, 153–155 in synthesis problems, 180–186 unsaturated ketones, 7–8 Kinetics, thermodynamics vs., 249 L Labile protons, 45 LAH (lithium aluminum hydride): and acid anhydrides, 202 and acid halides, 197 in formation of cyclic acetals, 150–151 Grignard reagent vs., 168 H-nucleophiles from, 136–140 reduction of imine with, 287 LDA (lithium diisopropylamide), 248–251, 282 Leaving groups: 351 and acid anhydride formation, 201–202 of amides, 214 for carbonyl formation, 137 of carboxylic acid derivatives, 187 for nucleophilic aromatic substitution, 112–113 Lewis acids, 58, 60, 67, 69 LiAlH4, see LAH (lithium aluminum hydride) Lithium aluminum hydride, see LAH Lithium dialkyl cuprates (R2CuLi), 196, 199, 202, 226, 277 Lithium diisopropylamide (LDA), 248–251, 282 Location (of proton NMR signal), 27 Lone pair of electrons, 88–90, 281 Long-range coupling, 40 M Magnesium, 165 Magnetic moment, 26 Major products, 98–100 Malonic ester, 271 Malonic ester synthesis, 271–273 MCPBA (meta-chloro peroxybenzoic acid), 176, 178–179 Meisenheimer complex, 115–117 MeOH, 138–139, 264 meta-Chloro peroxybenzoic acid, see MCPBA meta-directors, 79–80, 83, 85, 94 meta position, 79 meta-Xylene, 102–103 Methine group (CH group), 28 352 INDEX Methine protons, 32, 35 Methoxide, 261, 265 Methylene group (CH2 group), 27–28 Methylene protons, 32, 35 Methyl ester, 261 Methyl group (CH3 group): in bromination reactions, 79 directing effects for, 84–86 in haloform reaction, 245 installing, on aromatic ring, 64–66 IR spectra of, 16 as leaving group, 114 NMR spectra of, 28, 34 steric effects for, 104–105 Methyl ketones, 246–247 Methyl protons, 32, 35 Michael acceptors, 276–278 Michael addition, 275 Michael donors, 276–280 Michael reactions, 273–280 with enamines, 277–280 and Michael donors/acceptors, 276–280 1,4-additions, 275–276, 278–279 1,2-additions, 274–275 Migration, alkyl group, 177–178 Migratory aptitude, 178 Minor product, 98–100 Moderate activators, 89–90, 93, 293 Moderate deactivators, 90–91, 93 Molecular formula (with NMR spectra), 49 Monosubstituted benzene, 78–79 Multiplets (NMR signals), 44 Multiplicity, 39–41, 49 N NaBH4 (sodium borohydride), 135–136, 138–139, 150 NaH (sodium hydride), 135 Narrow signals (IR spectra), 11 Negative charge, 113, 116–117, 135, 276 NH2 group, see Amines NH2NH2 (hydrazine), 159–161, 285 NH2OH (hydroxylamine), 158–159, 163 Nitration, 61–64 Nitric acid, 62–64, 82, 95–96, 295 Nitriles, 216–218 Nitrobenzene, 62–64, 78–79 Nitrogen gas, 161 Nitrogen nucleophiles, see N-nucleophiles Nitro group: as deactivator, 78, 84–86, 91–92 directing effects of, 79 as electron-withdrawing group, 112 in nitration reactions, 63–64 in synthesis strategies, 107–109 1-Nitropropane, 44 Nitrosamine, 296–297 Nitrosonium ion, 296–297 Nitrous acid, 295–298 NMR spectroscopy, see Nuclear magnetic resonance spectroscopy N-nitroso amine, 296–297 N-nucleophiles, 155–164 mechanisms for reactions, 161–163 NH2NH2, 159–161 NH2OH, 158–159 primary amines, 156–159 products of reactions, 163–164 secondary amines, 157–158 NO2ϩ, 62–63, 95 nϩ1 rule, 39 Nuclear magnetic resonance, 26 Nuclear magnetic resonance (NMR) spectroscopy, 1, 26–55 13C NMR, 53–55 analyzing 1H NMR spectra, 49–53 and chemical equivalence, 26–30 chemical shift, 30–35 complex splitting, 43–44 hydrogen deficiency index, 46–49 integration, 35–38 multiplicity, 39–41 pattern recognition, 41–43 without splitting, 44–45 Nuclear spin, 26 Nucleophiles: carbon, see C-nucleophiles electron density of, 57 hydrogen, 135–140 nitrogen, see Nnucleophiles oxygen, see Onucleophiles reactions with electrophiles, 56–57 and reactivity of aromatic ring, 76–78 stabilized, 278 strength of, 135 sulfur, 153–155 Nucleophilic aromatic substitution, 112–128 INDEX criteria for, 112–114 elimination-addition, 121–126 mechanism strategies for, 126–128 SNAr mechanism, 115–121 Nucleophilicity: and activation, 77–78 of alpha (␣) carbon, 238 of amines, 281–282 basicity vs., 60, 135 and electron density, 57 O O-attack, 242 OßH bond, OH group, 77–80, 85, 88, 206 O-nucleophiles, 140–152 Acetal formation, 145–149 and carboxylic acid derivatives, 189–190 cyclic acetals, 149–152 ketones and N- vs., 155–158 overview of formation process, 140–145 Order of events (in synthesis problems), 106–109 OR (alkoxy) group, 90 ortho-para directors, 79–81, 83, 85, 94 ortho position, 79 leaving and electronwithdrawing groups in, 113, 116–117 and steric effects, 99–101 Overtone of C:O signal in IR spectra, 22 Oxidation reactions, 129–130, 229 Oxidation state (of nitriles), 216 Oximes, 159, 163 Oxophilicity, 170 Oxygen nucleophiles, see O-nucleophiles Ozonolysis, 130–131, 171 P para position, 79 leaving and electronwithdrawing groups in, 113, 116–117 and steric effects, 99–100, 104 Partial charge (␦), 77–78 Pattern recognition, NMR spectroscopy, 41–43 PCC (pyridinium chlorochromate), 130–131 Pericyclic reactions, 267 Peroxy acids, 175–176, 179 Phenol, 76–77, 122–123, 125 Phenolic proton, 117–119 Phenyl group, 178 Phosphorus ylides, 169–174 Phthalimide, 284 bonds, 7, 91 electrons, 34–35 PßO bond, 170 P:O double bond, 170–171 Polarizability, 135 Polybromination, 294 Preparation See also Synthesis of acetals, 145–149 of alkanes, 154 of amines, 283–291 of carboxylic acids, 130 of enolates, 241–244 of esters, 190, 194–195, 203–208 of ketones and aldehydes, 129–132 of nitriles, 217 in situ, 296 Primary alcohols, 129, 131 Primary alkyl amines, 297 353 Primary alkyl halides, 247 Primary amines, 156–159, 281 IR signal shape, 15–16 and nitrosonium ion, 296–297 preparation of, 283–286 Primary aryl amines, 297 Propylbenzene, 66–67, 98–99 Propyl carbocation, 66 Propyl chloride, 66 Propyl group, 66, 68–69, 99, 107–108 “Protecting” a ketone, 150–152 Protons, 35, 45 alpha, 32–33, 231–232, 256 beta, 32–33 gamma, 32 labile, 45 relative number of (in NMR spectra), 36 shielded vs deshielded, 26 Protonation See also Proton transfer of carbonyl group, 142–144 Claisen condensation, 265 in keto-enol tautomerism, 234–237 in SNAr mechanism, 118–119 Proton NMR spectrum (1H NMR spectrum), 26–53 analyzing, 49–53 chemical equivalence, 26–30 chemical shift, 30–35 complex splitting, 43–44 and hydrogen deficiency index, 46–49 integration, 35–38 multiplicity, 39–41 354 INDEX Proton NMR (cont.) pattern recognition, 41–43 without splitting, 44–45 Proton splitting, 39–41, 43–45 Proton transfer: and carboxylic acid derivatives, 191–192 drawing, 60 and Grignard reagents, 166 in hydration of nitriles, 217–218 in imine formation, 156–157 intramolecular, 176–177 in one-step synthesis of esters, 204–205 in O-nucleophile and ketone/aldehyde reactions, 144–145 in reverse Fischer esterification, 209 Pyridine, 194, 201–202 Pyridinium chloride, 194 Pyridinium chlorochromate (PCC), 130–131 Q Quartets (in NMR spectra), 39 Quaternary ammonium salt, 283 Quaternary products, 283 Quintets (in NMR spectra), 39 R R2CuLi, see Lithium dialkyl cuprates Raney nickel, 153–154, 161 Reactivity: of aromatic ring, 76–78 of carbonyl group, 133–134 of carboxylic acid derivatives, 187–188, 203, 213, 222–223 and Friedel-Crafts alkylation/acylation, 71 Reagents: for acid halide reactions, 199–201 for electrophilic vs nucleophilic substitution reactions, 126–127 Grignard, 165–169, 189, 196, 200, 202 for preparation of ketones and aldehydes, 129–132 for synthesis problems, 107 Wittig, 170, 171 Reduction-oxidation reactions, 229 Reduction reactions: amine preparation, 287–291 Clemmensen, 68–69, 154, 161 with Grignard reagent, 168 with H-nucleophiles, 138–139 with N-nucleophiles, 161 with O-nucleophiles, 151–152 with Raney nickel, 153–154, 161 of thioacetals, 153–154 Wolff-Kishner, 161 Reductive amination, 287–291 Relative number of protons (in NMR spectra), 36 Resonance: and bond strength, 7–8 carbonyl group, 133 of carboxylate ion, 210 and induction, 77–80 keto-enol tautomerism vs., 233 nuclear magnetic, 26 Resonance structures, 59, 61 of activators and deactivators, 88–89, 91 of ␣, -unsaturated ketones, 274 of aryl amines, 282 of enamines, 277–278 of enolates, 242 of Meisenheimer complex, 116 Retrosynthetic analysis, 183–184 Reverse of Fischer esterification, 208–209, 212 S Salts: copper, 299 diazonium, 297–300 quaternary ammonium, 283 Sandmeyer reactions, 299 Saponification, 210–211 Saturated compounds, 46 Secondary alcohols, 129, 131–132 Secondary alkyl group, 178 Secondary amines, 15–16, 157–158, 281, 287–291 Shielded protons, 26 Sigma bonds, 39–40 Sigma complex, 59, 63, 65, 73, 116 Signal intensity (IR spectra), 9–11 Signal shape (in IR spectra), 11–18 CßH bonds, 16 NßH bonds, 15–16 and OßH bonds, 11–15 INDEX Single bonds, CßH, 2–3, 5–6, 10–11 CßO, 2–3 IR signals for, 18–19 OßH, PßO, 170 XßH, 4, 19 Singlets (in NMR spectra), 39 SN1 reactions, 115 SN2 reactions, 115, 170, 173, 283–286 SNAr mechanism, 115–121, 126–127 S-nucleophiles, 153–155 SO2 gas, 194 SO3, 72–73 SO3H group, 73–74 Sodium amide, 282 Sodium borohydride, see NaBH4 Sodium dichromate, 129, 131 Sodium hydride (NaH), 135 Sodium nitrate, 295 S:O double bonds, 72, 193 s orbitals, Spectroscopy, see IR spectroscopy; Nuclear magnetic resonance (NMR) spectroscopy sp-hybridized carbon atoms, 54 sp2-hybridized carbon atoms, 54 sp3-hybridized carbon atoms, 54 Splitting, proton, see Proton splitting sp orbitals, Stability: of -keto ester, 262 of carbonyl group, 134 of enolates, 243, 275–276 of negative charge, 135 Stabilized nucleophiles, 278 Step-curves (in NMR spectra), 36 Steric effects, 98–105 for carbonyl group, 134 of multiple groups on rings, 102–105 and substitution with propyl benzene, 98–99 in synthesis strategies, 99–102, 107–108 Stork enamine synthesis, 279–280 Stretching (of bonds), 2, 16 Strong acids, 62–63 Strong activators, 85, 88–89, 92, 292–294 Strong bases, 135 Strong deactivators, 85–87, 91–93 Strong nucleophile, 135 Substituted carboxylic acids, 272 Substitution reactions, 59 See also Electrophilic aromatic substitution; Nucleophilic aromatic substitution Sulfonation, 72–76, 100 Sulfur, 72, 153 Sulfuric acid: concentrated fuming, 73–74, 100 dilute, 74, 101 and nitric acid, 62–64, 82, 95–96 in preparation of ketones, 129 Sulfur nucleophiles, 153–155 Sulfur ylide, 172–174 Symmetric stretching, 16 Symmetry: and integration values, 37 of ketones, 157–159 Synthesis See also Preparation 355 acetoacetic ester, 269–270 of acid halides, 192–194 of aniline, 125–126 of carboxylic acid derivatives, 222–230 with electrophilic aromatic substitution, 106–111 Gabriel, 284–286 of ketones and aldehydes, 180–186 malonic ester, 271–273 and steric effects, 99–102, 107–108 Stork enamine, 279–280 Synthesis problems: cross-over problems, 226–229 multiple answers to, 184 order of events in, 106–109 retrosynthetic analysis for, 183–184 working backwards, 183–184 T Tautomers, 233 Temporary modification of functional groups, 294 tert-Butyl group: multiplicity of, 40–41 NMR splitting pattern, 41–42 steric effects for, 100, 104–105 Tertiary alcohols, 129 Tertiary amines, 281 Tetrahedral intermediate, 142–144, 190 Tetrahydrofuran (THF), 248 Tetramethylsilane (TMS), 30 Thermodynamics, kinetics vs., 249 356 INDEX THF (tetrahydrofuran), 248 Thioacetals, 153–154 Thionyl chloride, 193 TMS (tetramethylsilane), 30 Toluene, 79 trans-esterification, 262 Trichloromethyl group, 92 Triphenylphosphine, 169–170 Triple bonds, 4, 7, 19, 48 Triplets (in NMR spectra), 39 U Unsaturated compounds, 46 Unsaturated ketones, 7–8 Unsaturation, degree of, 47–49 Upfield (in NMR spectra), 31 UV-Vis spectroscopy, 1–2 V Vibrational excitation, 2–3 Vinylic protons, 35 W Water: and acetal formation, 145–146 and acid anhydrides, 202 and acid halides, 191 in keto-enol tautomerism, 237 as proton source, 138, 140 removing Lewis acids with, 69 removing protons with, 63–64 Wavelength, Wavenumber (in IR spectra), 3–8 Weak activators, 85–87, 90, 93 Weak bases, 135 Weak deactivators, 90, 93 Wittig reaction, 170–172 Wittig reagent, 170–171 Wolff-Kishner reduction, 161 X X–H bonds, 4, 19 Y Ylides, 169–174 Z Zinc amalgam, 68–69 ...This page intentionally left blank ORGANIC CHEMISTRY AS A SECOND LANGUAGE, 3e This page intentionally left blank ORGANIC CHEMISTRY AS A SECOND LANGUAGE, 3e Second Semester Topics DAVID KLEIN. .. atomic orbitals: hybridized atomic orbitals p sp sp sp s 0% s character 25% s character 33% s character 50% s character 100% s character As illustrated, sp orbitals have more s character than the... eat every morning John always has a brownie, Peter always has a French roll, Mary always has a blueberry muffin, etc Now imagine that you walk into the bakery just after it opens, and you are told