546 CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL SUBSTITUTION 20.16 Methanol is the nucleophile that adds to the carbonyl group of the thioester. CHa CSCH, CHLOC6H5 CH3OH CH,CESCH,CH,OCH,- CH, COCH, HSCH,CHOCH OCH S-2-Phenoxyethyl Methanol Tetrahedral intermediate Methyl acetate 2-Phenoxyethanethiol 20. 17(b) Acetic anhydride is the anhydride that must be used; it transfers an acetyl group to suitable nucleophiles. The nucleophile in this case is methylamine. CH3COCCH3+ 2CH3NH CHaCNHCH3 CH,CO CH3NH Methylamine N-Methy lacetamid Methylammonium (c) The acyl group is HC-. Because the problem specifies that the acyl transfer agent is a methyl ester, methyl formate is one of the starting materials HCOCH2 HN(CHi) HCN(CH3)2+ CH,OH N, N-Dimethylformamide Methyl formate 20.18 Phthalic anhydride reacts with excess ammonia to give the ammonium salt of a compound known as phthalamic acid. o+ 2NH CO NH4 Phthalic Ammonium phthalamate anhydride Phthalimide is formed when ammonium phthalamate is heated NH H,O CO NHA 20. 19 Step 1: Protonation of the carbonyl oxygen CHC E CH-C Acetanilide Hydronium ion Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
20.16 Methanol is the nucleophile that adds to the carbonyl group of the thioester. 20.17 (b) Acetic anhydride is the anhydride that must be used; it transfers an acetyl group to suitable nucleophiles. The nucleophile in this case is methylamine. (c) The acyl group is . Because the problem specifies that the acyl transfer agent is a methyl ester, methyl formate is one of the starting materials. 20.18 Phthalic anhydride reacts with excess ammonia to give the ammonium salt of a compound known as phthalamic acid. Phthalimide is formed when ammonium phthalamate is heated. 20.19 Step 1: Protonation of the carbonyl oxygen CH3C O NHC6H5 Acetanilide H O H H Hydronium ion CH3C NC6H5 H OH Protonated form of amide O H H Water heat CNH2 O O CO NH4 Ammonium phthalamate O O Phthalimide NH3 Ammonia H2O Water NH O O Phthalic anhydride Ammonia Ammonium phthalamate (C8H10N2O3) 2NH3 O O CNH2 CO NH4 O O O Dimethylamine N,N-Dimethylformamide HN(CH3) 2 Methyl formate HCOCH3 O HCN(CH3)2 O Methyl alcohol CH3OH HC O Methylamine N-Methylacetamide 2CH3NH2 Acetic anhydride CH3COCCH3 O O CH3CNHCH3 O Methylammonium acetate CH3CO CH3NH3 O Methanol CH3OH S-2-Phenoxyethyl ethanethiolate CH3CSCH2CH2OC6H5 O Tetrahedral intermediate CH3C SCH2CH2OC6H5 OCH3 OH 2-Phenoxyethanethiol HSCH2CH2OC6H5 Methyl acetate CH3COCH3 O 546 CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL SU BSTITUTION 547 Step 2: Nucleophilic addition of water O:+ CH3C CH,C-NHCSH NHC H Water Protonated form Oxonium ion Step 3: Deprotonation of oxonium ion to give neutral form of tetrahedral intermediate CHiC-NHC6Hs O CHC-NHCH5 +H-o intermediate Step 4: Protonation of amino group of tetrahedral intermediate H :OH H CHC一NHCH3+HC CH2C一NC6H53+:O Tetrahedral tetrahedral intermediate water Step 5: Dissociation of N-protonated form of tetrahedral intermediate OH H 3C-NC6Hs CHC LNCAH oh H -Protonated form of onated form tetrahedral intermediate Step 6: Proton-transfer processes H o-H H,NCH O:+H,NCSH Hydronium ion Aniline Water Anilinium ion O→H H +:O: CH C +H-6 Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
Step 2: Nucleophilic addition of water Step 3: Deprotonation of oxonium ion to give neutral form of tetrahedral intermediate Step 4: Protonation of amino group of tetrahedral intermediate Step 5: Dissociation of N-protonated form of tetrahedral intermediate Step 6: Proton-transfer processes H O H H Hydronium ion O H H Protonated form Water of acetic acid O H CH3C OH O CH3C OH Acetic acid H2NC6H5 Aniline H3NC6H5 Hydronium ion Anilinium ion O H H H Water O H H N-Protonated form of tetrahedral intermediate CH3C OH NC6H5 OH H H OH CH3C OH Protonated form of acetic acid H2NC6H5 Aniline Tetrahedral intermediate CH3C OH NHC6H5 OH O H H N-Protonated form of Water tetrahedral intermediate CH3C OH NC6H5 OH H H H O H H Hydronium ion Tetrahedral intermediate CH3C OH NHC6H5 OH Oxonium ion CH3C OH NHC6H5 O H H O H H Water H O H H Hydronium ion O H H Water Protonated form of amide OH CH3C NHC6H5 Oxonium ion CH3C OH NHC6H5 O H H CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL SUBSTITUTION 547 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
548 CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL SUBSTITUTION 20.20 Step 1: Nucleophilic addition of hydroxide ion to the carbonyl group HCN(CH,), HC-N(%) Hydroxide N N-Dimethylformamide Step 2: Proton transfer to give neutral form of tetrahedral intermediate HC-N(CH) +H CoH HC一N(CH3)2+:OH oH OH Anionic form Water Tetrahedral Hydroxide of tetrahedral intermediate Step 3: Proton transfer from water to nitrogen of tetrahedral intermediate H OH HC-N(CH3)2+ HOH HCNH(CH3)2 : OH Tetrahedral N-Protonated form Step 4: Dissociation of N-protonated form of tetrahedral intermediate H HCNH(CH3) H,O:+ HC\ HN(CH3)2 Hydroxide Water Formic acid Dimethylamine f tetrahedral intermediate Step 5: Irreversible formation of formate ion Hydroxide Formate 20.21 A synthetic scheme becomes apparent when we recognize that a primary amine may be obtained by Hofmann rearrangement of the primary amide having one more carbon in its acyl group. This amid may, in turn, be prepared from the corresponding carboxylic acid. CHaCH,, CHa CH,CHLCNH2 CHaCH,CH,CO,H Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
20.20 Step 1: Nucleophilic addition of hydroxide ion to the carbonyl group Step 2: Proton transfer to give neutral form of tetrahedral intermediate Step 3: Proton transfer from water to nitrogen of tetrahedral intermediate Step 4: Dissociation of N-protonated form of tetrahedral intermediate Step 5: Irreversible formation of formate ion 20.21 A synthetic scheme becomes apparent when we recognize that a primary amine may be obtained by Hofmann rearrangement of the primary amide having one more carbon in its acyl group. This amide may, in turn, be prepared from the corresponding carboxylic acid. CH3CH2CH2NH2 CH3CH2CH2CNH2 CH3CH2CH2CO2H O Water OH HOH Hydroxide ion Formic acid O HC O H Formate ion O HC O HC NH(CH3)2 O H OH N-Protonated form of tetrahedral intermediate Dimethylamine HN(CH3) HO 2 Hydroxide ion H2O Water O HC OH Formic acid HC N(CH3)2 OH OH Tetrahedral intermediate OH Hydroxide ion Water H OH N-Protonated form of tetrahedral intermediate HC NH(CH3)2 OH OH HC N(CH3)2 OH OH Tetrahedral intermediate HC N(CH3)2 O OH Anionic form of tetrahedral intermediate OH Hydroxide ion Water H OH HC N(CH3)2 O OH Anionic form of tetrahedral intermediate HO Hydroxide ion HCN(CH3)2 O N,N-Dimethylformamide 548 CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL SUBSTITUTION 549 The desired reaction scheme is therefore CHaCH,CH,CO, H 2. NH; CHa CH CNH2 h.o. NaOH CH3,NH2 Butanoic acid 20.22 (a) Ethanenitrile has the same number of carbon atoms as ethyl alcohol. This suggests a reaction g Via an al P,O CH3CH,OH CH CNH CH2C≡N Ethyl alcohol Ethanenitrile The necessary amide is prepared from ethanol CHCH.OH Nay Cr or Hg0. L. SOC CH COH CHICNH Ethyl alcohol Acetic acid Acetamide b) Propanenitrile may be prepared from ethyl alcohol by way of a nucleophilic substitution reac tion of the corresponding bromide CH, CH,OH-1→ CH, CH, Br-→ CHCH,CN 20.23 Step 1: Protonation of the nitrile RC≡NH+H,O Nitrile Protonate Step 2: Nucleophilic addition of water OH Protonated Protonated form Step 3: Deprotonation of imino acid NH hOt Protonated form Water Imino acid Hydronium Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
The desired reaction scheme is therefore 20.22 (a) Ethanenitrile has the same number of carbon atoms as ethyl alcohol. This suggests a reaction scheme proceeding via an amide. The necessary amide is prepared from ethanol. (b) Propanenitrile may be prepared from ethyl alcohol by way of a nucleophilic substitution reaction of the corresponding bromide. 20.23 Step 1: Protonation of the nitrile Step 2: Nucleophilic addition of water Step 3: Deprotonation of imino acid Water OH2 Hydronium ion H3O NH RC HO H Protonated form of imino acid NH RC OH Imino acid RC NH Protonated form of nitrile H2O Water NH RC OH2 Protonated form of imino acid H2O Hydronium Water ion H O H H RC NH Protonated form of nitrile Nitrile RC N CH3CH2OH Ethyl alcohol CH3CH2Br Ethyl bromide CH3CH2CN Propanenitrile PBr3 NaCN or HBr CH3CH2OH Ethyl alcohol CH3COH O Acetic acid CH3CNH2 O Acetamide Na2Cr2O7, H2O H2SO4, heat 1. SOCl2 2. NH3 CH3CH2OH Ethyl alcohol CH3CNH2 O Acetamide Ethanenitrile CH3C N P4O10 CH3CH2CH2CO2H Butanoic acid CH3CH2CH2CNH2 O Butanamide CH3CH2CH2NH2 1-Propanamine 1. SOCl2 2. NH3 Br2 H2O, NaOH CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL SUBSTITUTION 549 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website