20.13 Preparation of Amides

1. 20.13Preparation of Amides

2. Preparation of Amides Amides are prepared from amines by acylationwith: • acyl chlorides (Table 20.2) • anhydrides (Table 20.3) • esters (Table 20.6)

3. O O RCO RCOH Preparation of Amides Amines do not react with carboxylic acids to giveamides. The reaction that occurs is proton-transfer(acid-base). • If no heat-sensitive groups are present, the resulting ammonium carboxylate salts can be converted to amides by heating. + – + R'NH3 + R'NH2

4. O O RCO RCOH O RCNHR' Preparation of Amides Amines do not react with carboxylic acids to giveamides. The reaction that occurs is proton-transfer(acid-base). + – + R'NH3 + R'NH2 heat + H2O

5. O H2N COH O CNH Example + 225°C + H2O (80-84%)

6. 20.14Lactams

7. N O H Lactams Lactams are cyclic amides. Some are industrialchemicals, others occur naturally. g b a d e-Caprolactam*: used toprepare a type of nylon e *Caproic acid is the common name for hexanoic acid.

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

9. 20.15Imides

10. O O RCNCR R' Imides Imides have 2 acyl groups attached to thenitrogen.

11. O NH O Imides The most common examples are cyclic imides. O NH O Succinimide Phthalimide

12. O O O O – – HOCCH2CH2COH OCCH2CH2CO + + O NH4 NH4 NH O Preparation of Imides Cyclic imides are prepared by heating the ammonium salts of dicarboxylic acids. NH3 heat

13. 20.16Hydrolysis of Amides

14. 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

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

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

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

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

19. 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+

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

21. Mechanism of formationoftetrahedral intermediate

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

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

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

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

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

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

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

29. Cleavage of tetrahedralintermediate

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

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

32. •• OH •• •• RC OH •• + H2N H Step 5

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

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

35. •• •• + OH OH •• RC RC + •• •• OH OH •• •• Step 6

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

37. Mechanism of Amide Hydrolysisin Base • Involves two stages: • 1) formation of tetrahedral intermediate2) dissociation of tetrahedral intermediate

38. 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–

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

40. Mechanism of formationoftetrahedral intermediate

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

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

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

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

45. Dissociation oftetrahedral intermediate

46. •• OH H •• RC O •• •• H H2N O H •• •• •• Step 3

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

48. – •• O •• •• H Step 4 •• H O •• •• RC OH •• + H3N

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

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