Understanding Carboxylic Acid Derivatives: Reactions and Applications

1. CARBOXYLIC ACID DERIVATIVES

2. CARBOXYLIC ACID An acyl group

3. CARBOXYLIC ACID DERIVATIVES (Acyl derivatives) Carboxylic acid Carboxylic acid amide Carboxylic acid chloride Carboxylic acid ester Carboxylic acid anhydride Nitrile

4. Nucleophilic acyl substitution in carboxylic acid derivatives Net effect – replacing group Y with Nu Y is a leaving group: -Cl, -OR’, -NH2, -NHR’, NR’2, -OCOR

5. Some nucleophilic acyl substitution reactions of carboxylic acids Carboxylic acid Acid chloride Amide Anhydride Ester

6. Reactivity of carboxylic acid derivatives in nucleophilic acyl substitution < < < Steric factors (substitution at α carbon) determine reactivity within a series of the same kind of acid derivatives Less reactive (sterically hindered) More reactive (sterically unhindered) < R E A C T I V I T Y

7. Reactivity of carboxylic acid derivatives Electronic factors (polarization of carbonyl group) determine reactivity of diferent acid derivatives < < < Amide Ester Acid anhydride Acid chloride Less reactive More reactive < R E A C T I V I T Y

8. Interconversions of carboxylic acid derivatives More reactive Acid chloride Acid anhydride Ester Less reactive Amide

9. General reactions of carboxylic acid derivatives (overview) H2O R’MgX Grignard reaction hydrolysis Acyl derivative R’OH alcoholysis [H] reduction NH3 aminolysis

10. ACID HALIDES X = Cl or Br

11. Preparation 1. Reaction with thionyl chloride Oxalyl chloride (COCl)2 or phosphorus trichloride (PCl3) can be used 2. Reaction with phosphorus tribromide

12. Examples: 90% yield 97% yield

13. Reactions of acid chlorides H2O R’MgX Ketone Acid chloride Acid R’MgX R’OH NH3 [H] 3 Alcohol Ester [H] Amide Aldehyde 1 Alcohol

14. Hydrolysis: conversion of acid chlorides into acids Using of acid chlorides as acylating agents requires anhydrous conditions

15. Alcoholysis: conversion of acid chlorides into esters Excellent method for esters preparation Amine (pyridine) added for HCl scavenging

16. Examples: 97% yield 80% yield Pyridine is added for hydrogen chloride scavenging

17. Aminolysis: conversion of acid chlorides into amides Primary amide Secondary amide Tertiary amide Excellent method for amides preparation

18. Example: Schotten-Baumann reaction Sedative agent (an amide)

19. Reduction: conversion of acid chlorides into alcohols 96% yield Cannot be isolated

20. Reduction: conversion of acid chlorides into aldehydes 96% yield LiAlH(O-t-Bu)3 : lithium tri-tert-butoxyaluminum hydride, less powerful than LiAlH4 reducing agent

21. Reaction of acid chlorides with Grignard reagents – tertiary alcohol formation Cannot be isolated 92% yield

22. Reaction of acid chlorides with Gilman reagents – ketone formation Lithium diorganocopper 92% yield Male ant hormone

23. ACID ANHYDRIDES

24. Preparation 1. Reaction between acid chloride and acid salt Both symmetrical and unsymmetrical anhydrides can be prepared 64% yield

25. Preparation 2. Dehydration of dicarboxylic acids – formation of cyclic anhydrides

26. 2. Dehydration of dicarboxylic acids – formation of cyclic anhydrides

27. Reactions of acid anhydrides [H] H2O Acid anhydride Aldehyde R’OH NH3 Acid [H] Ester Amide 1 Alcohol

28. Acetic anhydride is most frequently used for preparation of acetates of complex alcohols or substituted acetamides from amines. Examples: Component of anti headache drugs

29. ESTERS

30. Preparation 1. Reaction of carboxylic acid with alcohol (Fischer esterification) Limited to simple primary and secondary alcohols 2. Reaction of carboxylic acid salt with alkyl halide Limited to primary halides

31. Preparation 3. Reaction of carboxylic acid with diazomethane Limited to methyl esters 4. Reaction of acid chloride with alcohol Extremely general

32. Examples of esters synthesis: Pineapple aroma 97% yield Banana aroma

33. Examples of esters synthesis: 100% yield TOXIC AND EXPLOSIVE!

34. Esters in nature Plant oils and animal fats are esters of glycerol and carboxylic acids C12-C22

35. Reactions of esters [H] Ester H2O Aldehyde 2R’’MgX NH3 [H] Acid + Alcohol Amide 3 Alcohol 1 Alcohol

36. Acid catalysed hydrolysis of esters (reversible)

37. Base catalysed hydrolysis of esters (irreversible)

38. Evidence supporting proposed mechanism

39. Aminolysis: conversion of esters into amides Method is not often used since higher yields are normally obtained by aminolysis of acid chlorides

40. Reduction: conversion of esters into alcohols 91% yield 86% yield

41. Reduction: conversion of esters into aldehydes 91% yield DIBAH= DIISOBUTYLALUMINUM HYDRIDE (i-Bu)2AlH

42. Reaction of esters with Grignard reagents – tertiary alcohol formation 96% yield

43. AMIDES Primary Secondary Tertiary

44. Preparation Primary amide Secondary amide Tertiary amide

45. Amides in nature Amide bonds

46. Reactions of amides Acidic hydrolysis [H] Amide H2O, HCl Basic hydrolysis H2O, NaOH Amine

47. NITRILES

48. Preparation: 1. Substitution of bromine by cyanide Limited to primary halides

49. Preparation 2. Dehydration of primary amides Method of general utility. SOCl2 (thionyl chloride) P2O5 (phosphorus pentoxide) POCl3 (phosphorus oxychloride) Ac2O (acetic anhydride) DEHYDRATING AGENTS

50. Similarity of nitriles to carbonyl compounds