CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL SU BSTITUTION 541 (c) The reaction of phthalic anhydride with dimethylamine is analogous to that of part(b). The mide and the carboxylate salt of CN(CH3) 0+2(CH3)2NH H,N(CH Phthalic anhydride Dimethylamine amide fu In this case both the amide function and the ammonium carboxylate salt are incorporated into e same molecule (d) The disodium salt of phthalic acid is the product of hydrolysis of phthalic acid in excess sodium hydroxide CO +h,o cO Sodium Sodium phthalate Water 20.8(b) The tetrahedral intermediate is formed by nucleophilic addition of ammonia to one of the car- bonyl groups of acetic anhydride CH3COCCH CH COCCH Tetrahedral Dissociation of the tetrahedral intermediate occurs by loss of acetate as the leaving group HN: CHCTOCCH3 CH,, HN OCCH NE Ammonia tetrahedral Ammonium acetate (c) Dimethylamine is the nucleophile: it adds to one of the two equivalent carbonyl groups of phthalic anhydride HQ N(CH3)2 Phthalic Dimethylamine Tetrahedral anhydride Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
(c) The reaction of phthalic anhydride with dimethylamine is analogous to that of part (b). The organic products are an amide and the carboxylate salt of an amine. In this case both the amide function and the ammonium carboxylate salt are incorporated into the same molecule. (d) The disodium salt of phthalic acid is the product of hydrolysis of phthalic acid in excess sodium hydroxide. 20.8 (b) The tetrahedral intermediate is formed by nucleophilic addition of ammonia to one of the carbonyl groups of acetic anhydride. Dissociation of the tetrahedral intermediate occurs by loss of acetate as the leaving group. (c) Dimethylamine is the nucleophile; it adds to one of the two equivalent carbonyl groups of phthalic anhydride. Phthalic anhydride Dimethylamine Tetrahedral intermediate HN(CH3)2 O HO N(CH3)2 O O O O Ammonia tetrahedral Acetamide Ammonium acetate intermediate CH3CNH2 O H4N OCCH3 O O H CH3C OCCH3 O NH2 H3N Tetrahedral intermediate NH3 O CH3COCCH3 O CH3COCCH3 NH2 HO O 2NaOH Sodium hydroxide Phthalic anhydride O H2O Sodium phthalate Water CO Na CO Na O O O O 2(CH3)2NH Phthalic anhydride Dimethylamine O H2N(CH3)2 Product is an amine salt and contains an amide function. CO CN(CH3)2 O O O O CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL SUBSTITUTION 541 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
542 CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL SUBSTITUTION A second molecule of dimethylamine abstracts a proton from the tetrahedral intermediate L)NH N(CH3)2 CO H,N(CH3)2 Tetrahedral mediate sec Product of reaction imethy lamin (d) Hydroxide acts as a nucleophile to form the tetrahedral intermediate and as a base to facilitate Formation of tetrahedral intermediate: +m一 thalia anhydride OH HO O Dissociation of tetrahedral intermediate oH COH +h. In base, the remaining carboxylic acid group is deprotonated. Co-H OH CO 十 CO Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
A second molecule of dimethylamine abstracts a proton from the tetrahedral intermediate. (d) Hydroxide acts as a nucleophile to form the tetrahedral intermediate and as a base to facilitate its dissociation. Formation of tetrahedral intermediate: Dissociation of tetrahedral intermediate: In base, the remaining carboxylic acid group is deprotonated. CO CO O O H2O H CO CO O O OH O OH O O H COH CO O O HO H2O Tetrahedral intermediate O HO OH O O O OH O H2O OH Phthalic anhydride O O O O O OH OH O Tetrahedral intermediate second Product of reaction molecule of dimethylamine O N(CH3)2 O O H (CH3)2NH CN(CH3)2 CO O O H2N(CH3)2 542 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 543 20.9 The starting material contains three acetate ester functions. All three undergo hydrolysis in aqueous sulfuric acid H, O CH, COCH, CHCH,CH,CH,OCCH3 HOCH CHCH.CH CHOH 3CH-COI OCC OH The product is 1, 2, 5-pentanetriol. Also formed in the hydrolysis of the starting triacetate are three 20.10 Step 1: Protonation of the carbonyl oxygen O OH ChC OCHCH OCH2CH3 Ethyl benzoate Protonated form of ester Water Step 2: Nucleophilic addition of water H CHICA E C HSC--OCH,CH H, CH3 Water Protonated form of ester Step 3: Deprotonation of oxonium ion to give neutral form of tetrahedral intermediat C6HsC-QCH2CH,+jo: C6H5C-OCH2CH3 H- H edral Hydronium Step 4: Protonation of ethoxy oxygen H H CsH-C-OCH, CH2 + H C6HSC-OCH,CH3+: O Tetrahedra Oxonium ion Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
20.9 The starting material contains three acetate ester functions. All three undergo hydrolysis in aqueous sulfuric acid. The product is 1,2,5-pentanetriol. Also formed in the hydrolysis of the starting triacetate are three molecules of acetic acid. 20.10 Step 1: Protonation of the carbonyl oxygen Step 2: Nucleophilic addition of water Step 3: Deprotonation of oxonium ion to give neutral form of tetrahedral intermediate Step 4: Protonation of ethoxy oxygen Oxonium ion C6H5C OCH2CH3 OH HO H O H H Water C6H5C OCH2CH3 OH HO Tetrahedral intermediate O H H H Hydronium ion O H H C6H5C OCH2CH3 OH O H H C6H5C OCH2CH3 OH HO Tetrahedral intermediate O H H H Hydronium ion Water Protonated form of ester Oxonium ion O H H C6H5C OH O OCH2CH3 H H C6H5C OCH2CH3 OH Ethyl benzoate Hydronium ion C6H5C OCH2CH3 Protonated form of ester H H H O Water H H C6H5C O OCH2CH3 OH O 3CH3COH O H2O H O O CH3COCH2CHCH2CH2CH2OCCH3 OCCH3 O HOCH2CHCH2CH2CH2OH OH 1,2,5-Pentanetriol (C5H12O3) Acetic acid CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL SUBSTITUTION 543 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
544 CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL SUB Step 5: Dissociation of protonated form of tetrahedral intermediat This step yields ethyl alcohol and the protonated form of benzoic acid C6HSC-OCH,CH3 CHSC HOCH2 CH3 OH :OH H Protonated form Ethyl alcohol Step 6: Deprotonation of protonated form of benzoic acid H O H CaH CN CsSC H Benzoic acid Hydronium benzoic acid 20.11 To determine which oxygen of 4-butanolide becomes labeled withO, trace the path ofO-labeled water(0=O)as it undergoes nucleophilic addition to the carbonyl group to form the tetrahedral H,e sO-labeled The tetrahedral intermediate can revert to unlabeled 4-butanolide by loss of O-labeled water Alternatively it can lose ordinary water to give O-labeled lactone 8o-jJabeled Water The carbonyl oxygen is the one that is isotopically labeled in theO-enriched 4-butanolide. 20.12 On the basis of trimyristin's molecular formula CasHs,Os and of the fact that its hydrolysis gives only glycerol and tetradecanoic acid CH(CH)12 CO, H, it must have the structure shown CHa(CH2)n2CO OC(CH,)I2CH OC(CH)12CH3 (CasH86O6) Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
Step 5: Dissociation of protonated form of tetrahedral intermediate This step yields ethyl alcohol and the protonated form of benzoic acid. Step 6: Deprotonation of protonated form of benzoic acid 20.11 To determine which oxygen of 4-butanolide becomes labeled with 18O, trace the path of 18O-labeled water as it undergoes nucleophilic addition to the carbonyl group to form the tetrahedral intermediate. The tetrahedral intermediate can revert to unlabeled 4-butanolide by loss of 18O-labeled water. Alternatively it can lose ordinary water to give 18O-labeled lactone. The carbonyl oxygen is the one that is isotopically labeled in the 18O-enriched 4-butanolide. 20.12 On the basis of trimyristin’s molecular formula C45H86O6 and of the fact that its hydrolysis gives only glycerol and tetradecanoic acid CH3(CH2)12CO2H, it must have the structure shown. CH3(CH2)12CO OC(CH2)12CH3 OC(CH2)12CH3 O O O Trimyristin (C45H86O6) H OH O OH Tetrahedral intermediate O O 18O-labeled 4-butanolide H2O Water 4-Butanolide O O 18O-labeled water H2O H Tetrahedral intermediate O OH OH (O 18O) Benzoic acid C6H5C OH O Water O H H Hydronium ion H O H H Protonated form of benzoic acid C6H5C OH O H Oxonium ion C6H5C OCH2CH3 OH OH H Protonated form of benzoic acid C6H5C OH OH Ethyl alcohol HOCH2CH3 544 CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL SUBSTITUTION Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website
CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL SUBSTITUTION 545 20.13 Because ester hydrolysis in base proceeds by acyl-oxygen cleavage, the O label becomes ncorporated into acetate ion(e=O) CH3CHLCH CH2CH,OCCH3 .H CHa CH,CH,CH,CH,OH CCH3 Pentyl acetate Hydroxide l-Pentanol Acetate 20.14 Step 1: Nucleophilic addition of hydroxide ion to the carbonyl group C6HSC--OC OCH.C Step 2: Proton transfer from water to give neutral form of tetrahedral intermediate OH chCOCHCH +Hcoh CHSC-OCH, CH,+ Anionic form of Water Tetrahedral Hydroxide Step 3: Dissociation of tetrahedral intermediate H-0: HO:+ CH.C-OCH CH,- HOH OCHCH Hydroxide Tetrahedral intermediate Benzoic acid Ethoxide i Step 4: Proton transfer from benzoic acid :OH—C6 HO Benzoic acid Hydroxide Benzoate ion Water 20.15 The starting material is a lactone, a cyclic ester. The ester function is converted to an amide by nucleophilic acyl substitution CHNH+ CH3NHCCH CH,CHCH3 OH Methylamine 4-Pentanolide 4-Hydroxy-N-methylpentanamide Back Forward Main Menu TOC Study Guide Toc Student OLC MHHE Website
20.13 Because ester hydrolysis in base proceeds by acyl–oxygen cleavage, the 18O label becomes incorporated into acetate ion . 20.14 Step 1: Nucleophilic addition of hydroxide ion to the carbonyl group Step 2: Proton transfer from water to give neutral form of tetrahedral intermediate Step 3: Dissociation of tetrahedral intermediate Step 4: Proton transfer from benzoic acid 20.15 The starting material is a lactone, a cyclic ester. The ester function is converted to an amide by nucleophilic acyl substitution. Methylamine 4-Pentanolide 4-Hydroxy-N-methylpentanamide CH3NH2 O CH3 O CH3NHCCH2CH2CHCH3 OH O Benzoic acid Hydroxide ion O C6H5C O H Benzoate ion Water O C6H5C O HO HOH Tetrahedral intermediate C6H5C OCH2CH3 H O OH C6H5C O OH Benzoic acid OCH2CH3 Ethoxide ion HO Hydroxide ion HOH Water C6H5C OCH2CH3 OH OH Tetrahedral intermediate C6H5C OCH2CH3 O OH Anionic form of tetrahedral intermediate OH Hydroxide ion Water H OH C6H5C OCH2CH3 O OH Anionic form of tetrahedral intermediate C6H5C O OCH2CH3 Ethyl benzoate HO Hydroxide ion Pentyl acetate Hydroxide ion CH3CH2CH2CH2CH2OH 1-Pentanol CCH3 O O Acetate ion CH3CH2CH2CH2CH2O CCH3 OH O (O 18O) CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC ACYL SUBSTITUTION 545 Back Forward Main Menu TOC Study Guide TOC Student OLC MHHE Website