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19.3 General Mechanism for Nucleophilic Acyl Substitution Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Nucleophilic Acyl Substitution •• •• O •• R C O •• + X HNu R C + Nu Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive). HX General Mechanism for Nucleophilic Acyl Substitution Involves formation and dissociation of a tetrahedral intermediate •• R C •• OH O •• HNu O •• -HX R C X Nu R C Nu X Both stages can involve several elementary steps. General Mechanism for Nucleophilic Acyl Substitution First stage of mechanism (formation of tetrahedral intermediate) is analogous to nucleophilic addition to C=O of aldehydes and ketones. •• OH O •• R C HNu R C X X Nu General Mechanism for Nucleophilic Acyl Substitution Second stage is restoration of C=O by elimination. Complicating features of each stage involve acid-base chemistry. •• R C •• OH O •• HNu O •• -HX R C X X Nu R C Nu General Mechanism for Nucleophilic Acyl Substitution Acid-base chemistry in first stage is familiar in that it has to do with acid/base catalysis of nucleophilic addition to C=O. •• R C •• OH O •• HNu O •• -HX R C X X Nu R C Nu General Mechanism for Nucleophilic Acyl Substitution Acid-base chemistry in second stage concerns form in which the tetrahedral intermediate exists under the reaction conditions and how it dissociates under those conditions. •• R C •• OH O •• HNu O •• -HX R C X X Nu R C Nu The Tetrahedral Intermediate Tetrahedral Intermediate (TI) •• H O •• R H R O •• •X • C H C •• Nu •• X+ Conjugate acid of tetrahedral intermediate (TI+) Nu •• R – •• • O •• • C Nu •• •• X Conjugate base of tetrahedral intermediate (TI–) Dissociation of TI—H+ B •• H R •• O •• C X + H •• Nu •• +B—H O •• + R C + Nu •• •X • H Dissociation of TI B •• H R •• O •• C X•• •• Nu •• +B—H O •• + R C + Nu •• • X •– • • Dissociation of TI– •• – •• O •• R X•• C •• Nu •• O •• R C + Nu •• • X •– • • 19.4 Nucleophilic Acyl Substitution in Acyl Chlorides Preparation of Acyl Chlorides From carboxylic acids and thionyl chloride (Section 12.7) O (CH3)2CHCOH O SOCl2 heat (CH3)2CHCCl + SO2 + HCl (90%) Reactions of Acyl Derivatives O RCCl O O RCOCR' O RCOR' O RCNR'2 O RCO– Reactions of Acyl Chlorides Acyl chlorides react with carboxylic acids to give acid anhydrides: O O O O RCCl + R'COH RCOCR' H via: R O O C OCR' Cl + HCl Example O O CH3(CH2)5CCl + CH3(CH2)5COH pyridine O O CH3(CH2)5COC(CH2)5CH3 (78-83%) Reactions of Acyl Chlorides Acyl chlorides react with alcohols to give esters: O O RCCl + R'OH RCOR' H O via: R C Cl OR' + HCl Example O O C6H5CCl + (CH3)3COH pyridine C6H5COC(CH3)3 (80%) Reactions of Acyl Chlorides Acyl chlorides react with ammonia and amines to give amides: O O RCCl + R'2NH + HO– RCNR'2 + H2O H + Cl– O via: R C Cl NR'2 Example O O C6H5CCl + HN NaOH H2O C6H5CN (87-91%) Reactions of Acyl Chlorides Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base): O RCCl + H2O O RCCl + 2HO– O RCOH + HCl + Cl– O RCO– + H2O Reactions of Acyl Chlorides Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base): O O RCCl + H2O RCOH H O via: R C Cl OH + HCl Example O C6H5CH2CCl + H2O O C6H5CH2COH + HCl Reactivity Acyl chlorides undergo nucleophilic substitution much faster than alkyl chlorides. O C6H5CCl Relative rates of hydrolysis (25°C) 1,000 C6H5CH2Cl 1 19.5 Nucleophilic Acyl Substitution in Acid Anhydrides Anhydrides can be prepared from acyl chlorides as described in Table 19.1. Some Anhydrides are Industrial Chemicals O O O O CH3COCCH3 O Acetic anhydride Phthalic anhydride O O O Maleic anhydride From Dicarboxylic Acids Cyclic anhydrides with 5- and 6-membered rings can be prepared by dehydration of dicarboxylic acids: O H COH C H C H tetrachloroethane O 130°C COH O O H O (89%) + H2 O Reactions of Anhydrides O O RCOCR' O RCOR' O RCNR'2 O RCO– Reactions of Acid Anhydrides Carboxylic acid anhydrides react with alcohols to give esters: O O RCOCR + R'OH O RCOR' O + RCOH Normally, symmetrical anhydrides are used (both R groups the same). Reaction can be carried out in presence of pyridine (a base) or it can be catalyzed by acids. Reactions of Acid Anhydrides Carboxylic acid anhydrides react with alcohols to give esters: O O O RCOCR + R'OH RCOR' H O via: R OR' C OCR O O + RCOH Example O O CH3COCCH3 + CH3CHCH2CH3 OH H2SO4 O CH3COCHCH2CH3 CH3 (60%) Reactions of Acid Anhydrides Acid anhydrides react with ammonia and amines to give amides: O O O RCNR'2 + RCO– RCOCR + 2R'2NH H + R'2NH2 O via: O R NR'2 C OCR O Example O O CH3COCCH3 + H2N CH(CH3)2 O CH3CNH CH(CH3)2 (98%) Reactions of Acid Anhydrides Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): O O RCOCR O + H2O O O RCOCR 2RCOH O + 2HO– 2RCO– + H2O Reactions of Acid Anhydrides Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): O O RCOCR O + H2O 2RCOH H O R OH C OCR O Example O O COH O + H2O COH O O