20.13 Hydrolysis of Amides

1. 20.13Hydrolysis of Amides

2. O O RCNHR' RCOH Hydrolysis of Amides Hydrolysis of amides is irreversible. In acid solution the amine product is protonated to give an ammonium salt. + + + R'NH3 + + H2O H

3. O O RCNHR' RCO Hydrolysis of Amides In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. – – + R'NH2 + HO

4. O O CH3CH2CHCNH2 CH3CH2CHCOH + – NH4 HSO4 Example: Acid Hydrolysis H2O + H2SO4heat (88-90%)

5. O NH2 CH3CNH O CH3COK Br Br Example: Basic Hydrolysis KOH + H2Oheat (95%)

6. Mechanism of Acid-CatalyzedAmide Hydrolysis • Acid-catalyzed amide hydrolysis proceeds viathe customary two stages: • 1) formation of tetrahedral intermediate2) dissociation of tetrahedral intermediate

7. O + RCNH2 H2O OH NH2 RC OH First stage: formation of tetrahedral intermediate • water adds to the carbonyl group of the amide • this stage is analogous to the acid-catalyzed addition of water to a ketone H+

8. O + RCOH NH4 OH NH2 RC OH Second stage: cleavage of tetrahedralintermediate + H+

9. Mechanism of formationoftetrahedral intermediate

10. H •• O H O •• •• + H RC NH2 •• H •• + H O O •• •• H RC NH2 •• Step 1

11. •• H O •• RC + NH2 •• + H O RC NH2 •• Step 1 • carbonyl oxygen is protonated because cation produced is stabilized by electron delocalization (resonance)

12. •• OH H •• + RC O •• H NH2 •• •• + H O H RC O •• •• H NH2 •• Step 2

13. •• OH H •• + H RC O •• O H •• •• NH2 •• H •• OH H •• H RC O •• + •• O H •• NH2 •• H Step 3

14. Cleavage of tetrahedralintermediate

15. •• OH •• •• H RC OH •• + O •• •• H2N H H •• OH H •• RC O •• •• H H2N O H •• •• + H Step 4

16. •• OH •• •• RC OH •• + H2N H •• OH •• NH3 + RC •• + •• OH •• Step 5

17. •• OH •• •• RC OH •• + H2N H •• + OH H3O •• NH3 RC •• + •• OH •• Step 6 + NH4 +

18. •• •• + OH OH •• RC RC + •• •• OH OH •• •• Step 6

19. •• H H O + H •• O •• •• H H O RC •• •• OH •• + O H RC •• OH •• Step 6 ••

20. Mechanism of Amide Hydrolysisin Base • Involves two stages: • 1) formation of tetrahedral intermediate 2) dissociation of tetrahedral intermediate

21. O + RCNH2 H2O OH NH2 RC OH First stage: formation of tetrahedral intermediate • water adds to the carbonyl group of the amide • this stage is analogous to the base-catalyzed addition of water to a ketone HO–

22. O RCO OH NH2 RC OH Second stage: cleavage of tetrahedralintermediate – + NH3 HO–

23. Mechanism of formationoftetrahedral intermediate

24. •• O •• H RC O •• •• – •• NH2 •• – •• O H •• •• RC O •• •• NH2 •• Step 1

25. •• O H H •• – •• O RC O •• •• •• •• H NH2 •• – •• •• O H O •• H •• •• H RC O •• •• NH2 •• Step 2

26. Dissociation oftetrahedral intermediate

27. •• OH •• •• H RC OH •• + O – •• •• H2N •• H •• OH H •• RC O •• •• H H2N O H •• •• •• Step 3

28. – •• O •• •• H •• •• O H O •• •• H RC NH3 O H •• •• •• Step 4 •• H O •• •• RC OH •• + H3N

29. •• O •• RC – O •• •• •• •• O •• RC NH3 O H •• •• •• Step 5 HO–

30. 20.14Lactams

31.     -Caprolactam*: used toprepare a type of nylon  N O H *Caproic acid is the common name for hexanoic acid. Lactams Lactams are cyclic amides. Some are industrialchemicals, others occur naturally.

32. O C6H5CH2CNH  S CH3  CH3 N O CO2H Penicillin G: a -lactam antibiotic Lactams Lactams are cyclic amides. Some are industrialchemicals, others occur naturally.

33. 20.15Preparation of Nitriles

34. Preparation of Nitriles Nitriles are prepared by: • nucleophilic substitution by cyanide onalkyl halides (Sections 8.1 and 8.13) • cyanohydrin formation (Section 17.7) • dehydration of amides

35. CH3(CH2)8CH2C N Example KCN • SN2 CH3(CH2)8CH2Cl ethanol-water (95%)

36. O OH CH3CH2CCH2CH3 CH3CH2CCH2CH3 C N Example KCN H+ (75%)

37. O P4O10 N (CH3)2CHCNH2 (CH3)2CHC 200°C Preparation of Nitriles By dehydration of amides • uses the reagent P4O10 (often written as P2O5) (69-86%)

38. 20.16Hydrolysis of Nitriles

39. O + + + NH4 + + 2H2O H RCN RCOH Hydrolysis of Nitriles Hydrolysis of nitriles resembles the hydrolysisof amides. The reaction is irreversible. Ammonia is produced and is protonated to ammonium ion in acid solution.

40. O – – + + + H2O HO RCO RCN NH3 Hydrolysis of Nitriles In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion.

41. O CH2CN CH2COH H2O H2SO4heat NO2 NO2 Example: Acid Hydrolysis (92-95%)

42. O 1. KOH, H2O, heat CH3(CH2)9COH 2. H+ Example: Basic Hydrolysis CH3(CH2)9CN (80%)

43. O O N RC RCNH2 RCOH Mechanism of Hydrolysis of Nitriles • Hydrolysis of nitriles proceeds via thecorresponding amide. • We already know the mechanism of amidehydrolysis. • Therefore, all we need to do is to see how amides are formed from nitriles under the conditions of hydrolysis. H2O H2O

44. O N RC RCNH2 Mechanism of Hydrolysis of Nitriles OH • The mechanism of amide formation is analogousto that of conversion of alkynes to ketones. • It begins with the addition of water across thecarbon-nitrogen triple bond. • The product of this addition is the nitrogen analog of an enol. It is transformed to an amideunder the reaction conditions. H2O NH RC

45. H H – O O •• •• •• •• •• RC N RC •• N •• •• – Step 1

46. H O •• •• RC H N H O H •• •• •• – •• O •• •• RC H N H O •• •• •• – •• Step 2

47. H O •• •• H H O •• •• •• O – •• •• H RC – O N •• H •• •• •• RC N H •• Step 3

48. •• •• O O •• •• RC RC – N N H H •• •• – •• •• •• O O H •• •• H •• H H Step 4

49. 20.17Addition of Grignard Reagentsto Nitriles

50. NMgX NH N RC RCR' RCR' Addition of Grignard Reagents to Nitriles • Grignard reagents add to carbon-nitrogen triplebonds in the same way that they add to carbon-oxygen double bonds. • The product of the reaction is an imine. R'MgX H2O diethylether