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20.13 Preparation of Amides

20.13 Preparation of Amides. Preparation of Amides. Amides are prepared from amines by acylation with:. acyl chlorides (Table 20.2) anhydrides (Table 20.3) esters (Table 20.6). O. O. RCO. RCOH. Preparation of Amides.

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20.13 Preparation of Amides

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  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–

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