1. 19.3 General Mechanism for Nucleophilic Acyl Substitution Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

2. Nucleophilic Acyl Substitution O C R X + HNu O C R Nu + HX Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive).

3. General Mechanism for Nucleophilic Acyl Substitution Involves formation and dissociation of a tetrahedral intermediate Both stages can involve several elementary steps. O C R X HNu C R OH X Nu O C R Nu -HX

4. 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. O C R X HNu C R OH X Nu

5. General Mechanism for Nucleophilic Acyl Substitution Second stage is restoration of C=O by elimination. Complicating features of each stage involve acid-base chemistry. O C R X HNu C R OH X Nu O C R Nu -HX

6. 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. O C R X HNu C R OH X Nu O C R Nu -HX

7. General Mechanism for Nucleophilic Acyl Substitution O C R X HNu C R OH X Nu O C R Nu -HX 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.

8. The Tetrahedral Intermediate Tetrahedral Intermediate (TI) C R O X Nu H C R O X Nu H H + Conjugate acid of tetrahedral intermediate (TI + ) O C R X Nu – Conjugate base of tetrahedral intermediate (TI – )

9. Dissociation of TI—H + C R O X Nu H H + + B—H+ C O RNu +X H B

10. Dissociation of TI B C R O X Nu H + B—H+ C O RNu +X –

11. Dissociation of TI – C O RNu +X – C R O X Nu –

12. 19.4 Nucleophilic Acyl Substitution in Acyl Chlorides

13. Preparation of Acyl Chlorides From carboxylic acids and thionyl chloride (Section 12.7) (CH 3 ) 2 CHCOH O SOCl 2 heat (CH 3 ) 2 CHCCl O + SO 2 + HCl (90%)

14. RCO – O RCCl O RCOCR' OO RCOR' O RCNR' 2 O Reactions of Acyl Derivatives

15. Reactions of Acyl Chlorides + R'COH O RCOCR' OO + HCl Acyl chlorides react with carboxylic acids to give acid anhydrides: via: C R O Cl OCR' H O RCCl O

16. CH 3 (CH 2 ) 5 CCl O Example + CH 3 (CH 2 ) 5 COH O pyridine CH 3 (CH 2 ) 5 COC(CH 2 ) 5 CH 3 O O (78-83%)

17. Reactions of Acyl Chlorides + RCOR' O + HCl Acyl chlorides react with alcohols to give esters: R'OH via: C R O Cl OR' H RCCl O

18. Example + (CH 3 ) 3 COH pyridine (80%) C 6 H 5 COC(CH 3 ) 3 O C 6 H 5 CCl O

19. Reactions of Acyl Chlorides + RCNR' 2 O + H2OH2O Acyl chlorides react with ammonia and amines to give amides: R' 2 NH + HO – + Cl – via: C R O Cl NR' 2 H RCCl O

20. Example C 6 H 5 CCl O + NaOH (87-91%) H2OH2O HNHN C6H5CNC6H5CN O

21. Reactions of Acyl Chlorides + RCOH O + HCl Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base): H2OH2O + RCO – O + Cl – 2HO – + H2OH2O RCCl O O

22. O Reactions of Acyl Chlorides + RCOH O + HCl Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base): H2OH2O via: C R O Cl OH H

23. Example C 6 H 5 CH 2 CCl O + H2OH2O C 6 H 5 CH 2 COH O + HCl

24. Reactivity C 6 H 5 CCl O C 6 H 5 CH 2 Cl Acyl chlorides undergo nucleophilic substitution much faster than alkyl chlorides. Relative rates of hydrolysis (25°C) 1,0001

25. 19.5 Nucleophilic Acyl Substitution in Acid Anhydrides Anhydrides can be prepared from acyl chlorides as described in Table 19.1.

26. Some Anhydrides are Industrial Chemicals CH 3 COCCH 3 OO Acetic anhydride O O O O O O Phthalic anhydride Maleic anhydride

27. From Dicarboxylic Acids Cyclic anhydrides with 5- and 6-membered rings can be prepared by dehydration of dicarboxylic acids: C C H HCOH O O O O O H H tetrachloroethane 130°C (89%) + H 2 O

28. RCO – O RCOCR' OO RCOR' O RCNR' 2 O Reactions of Anhydrides

29. Reactions of Acid Anhydrides + RCOR' O + Carboxylic acid anhydrides react with alcohols to give esters: R'OH RCOH O 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. RCOCR OO

30. Reactions of Acid Anhydrides + RCOR' O + Carboxylic acid anhydrides react with alcohols to give esters: R'OH RCOH O via: C R O OCR OR' H O RCOCR OO

31. Example (60%) H 2 SO 4 + CH 3 COCCH 3 OO CH 3 CHCH 2 CH 3 OHOH CH 3 COCHCH 2 CH 3 O CH 3

32. Reactions of Acid Anhydrides + RCNR' 2 O + Acid anhydrides react with ammonia and amines to give amides: 2R' 2 NH RCO – O R' 2 NH 2 + via: C R O OCR NR' 2 H O RCOCR OO

33. Example (98%) + CH 3 COCCH 3 OO H2NH2NCH(CH 3 ) 2 O CH 3 CNH CH(CH 3 ) 2

34. Reactions of Acid Anhydrides + 2RCOH O Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): H2OH2O + 2RCO – O + 2HO – H2OH2O RCOCR OO OO

35. Reactions of Acid Anhydrides + 2RCOH O Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): H2OH2O RCOCR OO C R O OCR OHOH H O

36. Example + H2OH2O O O O COHCOH O COH O