1. 20.13 Preparation of Amides 1

2. Amides are prepared from amines by acylation with:
Preparation of Amides
Amides are prepared from amines by acylation with:
acyl chlorides (Table 20.2)
anhydrides (Table 20.3)
esters (Table 20.6) 5

3. Preparation of Amides
Amines do not react with carboxylic acids to give amides. The reaction that occurs is proton-transfer (acid-base).
RCOH O
RCO O + – +
R'NH2 +
R'NH3
If no heat-sensitive groups are present, the resulting ammonium carboxylate salts can be converted to amides by heating. 5

4. Preparation of Amides
Amines do not react with carboxylic acids to give amides. The reaction that occurs is proton-transfer (acid-base).
RCOH O
RCO O + – +
R'NH2 +
R'NH3
heat
RCNHR' O +
H2O 5

5. Example
COH O
H2N +
225°C
CNH O +
H2O
(80-84%) 4

6. 20.14 Lactams 1

7. e-Caprolactam*: used to prepare a type of nylon e
Lactams
Lactams are cyclic amides. Some are industrial chemicals, others occur naturally. g b N H O d a
e-Caprolactam*: used to prepare a type of nylon e
*Caproic acid is the common name for hexanoic acid. 5

8. Penicillin G: a b-lactam antibiotic
Lactams
Lactams are cyclic amides. Some are industrial chemicals, others occur naturally. a b
CH3 S
CO2H O N
C6H5CH2CNH
Penicillin G: a b-lactam antibiotic 5

9. 20.15 Imides 1

10. Imides have 2 acyl groups attached to the nitrogen.
RCNCR O R' 5

11. The most common examples are cyclic imides.NH O O NH O
Succinimide
Phthalimide 5

12. Preparation of Imides
Cyclic imides are prepared by heating the ammonium salts of dicarboxylic acids.
HOCCH2CH2COH O
OCCH2CH2CO O –
NH3
NH4 +
NH4 + NH O
heat 5

13. 20.16 Hydrolysis of Amides 10

14. Hydrolysis of Amides
Hydrolysis of amides is irreversible. In acid solution the amine product is protonated to give an ammonium salt.
RCNHR' O
RCOH O + + +
H2O + H +
R'NH3 5

15. In basic solution the carboxylic acid product
Hydrolysis of Amides
In basic solution the carboxylic acid product
is deprotonated to give a carboxylate ion.
RCNHR' O
RCO O – – + HO +
R'NH2 5

16. Example: Acid Hydrolysis
CH3CH2CHCNH2 O
CH3CH2CHCOH O
H2O
NH4 +
HSO4 – +
H2SO4 heat
(88-90%) 4

17. Example: Basic Hydrolysis
CH3CNH O Br
NH2 Br
CH3COK O
KOH +
H2O heat
(95%) 4

18. Mechanism of Acid-Catalyzed Amide Hydrolysis
Acid-catalyzed amide hydrolysis proceeds via the customary two stages:
1) formation of tetrahedral intermediate 2) dissociation of tetrahedral intermediate 5

19. First stage: formation of tetrahedral intermediate+
H2O
RCNH2 O
water adds to the carbonyl group of the amide
this stage is analogous to the acid-catalyzed addition of water to a ketone H+ RC OH
NH2 5

20. Second stage: cleavage of tetrahedral intermediate
RCOH O
NH4 + + H+ RC OH
NH2 5

21. Mechanism of formation of tetrahedral intermediate8

22. Step 1 O
• • + H RC O
NH2 ••
• • 8

23. Step 1 O
• • + H RC O
NH2 ••
• •
• • O H RC O
NH2 ••
• • + H 8

24. Step 1 RC O
NH2 ••
• • + H
carbonyl oxygen is protonated because cation produced is stabilized by electron delocalization (resonance) RC O
NH2 ••
• • + H 8

25. Step 2 RC O
NH2 ••
• • + H
• • O H 8

26. Step 2 RC OH
NH2 ••
• • O + H RC O
NH2 ••
• • + H
• • O H 8

27. Step 3 RC OH
NH2 ••
• • O + H
• • O H 8

28. Step 3 RC OH
NH2 ••
• • O + H
• • O H
NH2 RC OH ••
• • O H O
• • H + 8

29. Cleavage of tetrahedral intermediate8

30. Step 4
H2N RC OH ••
• • O H O
• • H + 8

31. Step 4 RC OH
H2N ••
• • H +
• • O H
H2N RC OH ••
• • O H O
• • H + 8

32. Step 5 RC OH
H2N ••
• • H + 8

33. Step 5 RC OH
H2N ••
• • H + RC OH ••
• • + +
NH3
• • 8

34. Step 6 RC OH
H2N ••
• • H + +
NH4 RC OH ••
• • +
H3O + +
NH3
• • 8

35. Step 6 RC OH •• + RC OH ••
• • + 8

36. Step 6 + O H •• RC O •• OH
• • O •• H RC O •• OH + H 8

37. Mechanism of Amide Hydrolysis in Base
Involves two stages:
1) formation of tetrahedral intermediate 2) dissociation of tetrahedral intermediate 5

38. First stage: formation of tetrahedral intermediate+
H2O
RCNH2 O
water adds to the carbonyl group of the amide
this stage is analogous to the base-catalyzed addition of water to a ketone
HO– RC OH
NH2 5

39. Second stage: cleavage of tetrahedral intermediate
RCO O – +
NH3
HO– RC OH
NH2 5

40. Mechanism of formation of tetrahedral intermediate8

41. Step 1 RC O
NH2 ••
• • O
• • H •• – 8

42. Step 1 RC O
NH2 ••
• • O
• • H •• – RC O
NH2 ••
• • H – 8

43. Step 2 RC O
NH2 ••
• • H –
• • •• H O 8

44. Step 2 H O H – O H RC O NH2 RC O NH2 H – H O •• • • •• • • • • •• • •8

45. Dissociation of tetrahedral intermediate8

46. Step 3
H2N RC OH ••
• • O H O
• • H •• 8

47. Step 3 RC OH H2N H + O H – H2N RC OH O H O H •• • • • • •• •• • • • •8

48. Step 4 •• H O
• •
• • – •• O H •• RC OH •• +
H3N 8

49. Step 4 H O – O H RC OH + H3N H O RC O H NH3 •• • • •• •• • • •• •• ••8

50. Step 5 RC
• • O •• – RC
• • O •• H
HO–
NH3
• • 8