20.3 General Mechanism for Nucleophilic Acyl Substitution

1. 20.3General MechanismforNucleophilic Acyl Substitution

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

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

4. •• OH O HNu •• R C C Nu R X X General Mechanism for Nucleophilic Acyl Substitution first stage of mechanism (formation of tetrahedralintermediate) is analogous to nucleophilic additionto C=O of aldehydes and ketones

5. •• OH •• O O HNu -HX •• •• R C C C Nu R X R Nu X General Mechanism for Nucleophilic Acyl Substitution second stage is restoration of C=O by elimination complicating features of each stage involveacid-base chemistry

6. •• OH •• O O HNu -HX •• •• R C C C Nu R X R Nu X General Mechanism for Nucleophilic Acyl Substitution Acid-base chemistry in first stage is familiar in thatit has to do with acid/base catalysis of nucleophilic addition to C=O.

7. •• OH •• O O HNu -HX •• •• R C C C Nu R X R Nu X General Mechanism for Nucleophilic Acyl Substitution Acid-base chemistry in second stage concernsform in which the tetrahedral intermediate existsunder the reaction conditions and how it dissociatesunder those conditions.

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

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

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

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

12. 20.4Nucleophilic Substitutionin Acyl Chlorides

13. O O (CH3)2CHCOH (CH3)2CHCCl Preparation of Acyl Chlorides from carboxylic acids and thionyl chloride(Section 12.7) SOCl2 + + SO2 HCl heat (90%)

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

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

16. O O CH3(CH2)5CCl CH3(CH2)5COH O O CH3(CH2)5COC(CH2)5CH3 Example + pyridine (78-83%)

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

18. O O C6H5COC(CH3)3 C6H5CCl Example pyridine + (CH3)3COH (80%)

19. O O RCNR'2 RCCl H O via: R NR'2 C Cl Reactions of Acyl Chlorides Acyl chlorides react with ammonia and aminesto give amides: + + R'2NH + HO– H2O + Cl–

20. O O C6H5CN C6H5CCl HN Example NaOH + H2O (87-91%)

21. O O RCOH RCCl O O RCO– RCCl Reactions of Acyl Chlorides Acyl chlorides react with water to givecarboxylic acids (carboxylate ion in base): + + H2O HCl + + 2HO– Cl– + H2O

22. O O RCOH RCCl H O R OH C Cl Reactions of Acyl Chlorides Acyl chlorides react with water to givecarboxylic acids (carboxylate ion in base): + + H2O HCl via:

23. O O C6H5CH2COH C6H5CH2CCl Example + + H2O HCl

24. O C6H5CCl Reactivity • Acyl chlorides undergo nucleophilic substitution much faster than alkyl chlorides. C6H5CH2Cl Relative rates ofhydrolysis (25°C) 1,000 1

25. 20.5Nucleophilic Acyl Substitution in Carboxylic Acid Anhydrides • Anhydrides can be prepared from acyl chlorides as described in Table 20.1

26. O O O O CH3COCCH3 O O O O Some anhydrides are industrial chemicals Aceticanhydride Phthalicanhydride Maleicanhydride

27. O O H COH H C tetrachloroethane O 130°C C H H COH O O From dicarboxylic acids • Cyclic anhydrides with 5- and 6-membered rings can be prepared by dehydration of dicarboxylic acids + H2O (89%)

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

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

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

31. O O + CH3CHCH2CH3 CH3COCCH3 OH O CH3COCHCH2CH3 CH3 Example H2SO4 (60%)

32. O O O O RCNR'2 RCO– RCOCR H + O R'2NH2 R NR'2 C via: OCR O Reactions of Acid Anhydrides Acid anhydrides react with ammonia and aminesto give amides: + + 2R'2NH

33. O O H2N CH(CH3)2 CH3COCCH3 O CH3CNH CH(CH3)2 Example + (98%)

34. O O O RCOCR O O O RCOCR Reactions of Acid Anhydrides Acid anhydrides react with water to givecarboxylic acids (carboxylate ion in base): + H2O 2RCOH + + 2HO– 2RCO– H2O

35. O O O RCOCR H O R OH C OCR O Reactions of Acid Anhydrides Acid anhydrides react with water to givecarboxylic acids (carboxylate ion in base): + H2O 2RCOH

36. O O COH O COH O O Example + H2O