1. Modified slides of William Tam & Phillis Chang Ch. 17 - 1 Chapter 17 Carboxylic Acids and Their Derivatives NucleophilicAddition–Elimination at the Acyl Carbon

2. Ch. 17 - 2 Carboxylic Acid Derivatives Introduction

3. Ch. 17 - 3 Nomenclature Rules Carboxylic acid as parent (suffix): ending with “–oic acid” Carboxylate as parent (suffix): ending with “–oate”

4. Ch. 17 - 4 Anhydrides are named by dropping the acid and adding the word “anhydride” Acid chloride suffix: “–oyl chloride” Ester suffix: ending with “–oate” Amide suffix: ending with “amide” Nitrile suffix: ending with “nitrile”

5. Ch. 17 - 5 Examples

6. Ch. 17 - 6 Examples

7. Ch. 17 - 7 Acidity of Carboxylic Acids pK a ~ 4-5 Compare pK a of H 2 O ~ 16 pK a of H 2 CO 3 ~ 7 pK a of HF ~ 3

8. Ch. 17 - 8  When comparing acidity of organic compounds, we compare the stability of their conjugate bases. The more stable the conjugate base, the stronger the acid

9. Ch. 17 - 9

10. Ch. 17 - 10  The conjugate base B 1 is more stable (the anion is more delocalized) than B 2 due to resonance stabilization ●Thus, A 1 is a stronger acid than A 2

11. Ch. 17 - 11 Acidity of Carboxylic Acids, Phenols & Alcohols

12. Ch. 17 - 12  Acidity of Carboxylic Acids, Phenols and Alcohols

13. Ch. 17 - 13  Acidity of Carboxylic Acids, Phenols and Alcohols

14. Ch. 17 - 14  Acidity of Carboxylic Acids, Phenols and Alcohols (NO resonance stabilization)

15. Ch. 17 - 15 Question How could you distinguish these 3 by simple chemical tests? (acidity)

16. Ch. 17 - 16

17. Ch. 17 - 17

18. Ch. 17 - 18  Stability of conjugate bases > > > > >>

19. Ch. 17 - 19 > > > > > > > > >

20. Ch. 17 - 20 Dicarboxylic Acids

21. Ch. 17 - 21 2J.Spectroscopic Properties of Acyl Compounds  IR Spectra ●The C=O stretching band occurs at different frequencies for acids, esters, and amides, and its precise location is often helpful in structure determination ●Conjugation and electron-donating groups bonded to the carbonyl shift the location of the C=O absorption to lower frequencies

22. Ch. 17 - 22  IR Spectra ●Electron-withdrawing groups bonded to the carbonyl shift the C=O absorption to higher frequencies ●The hydroxyl groups of carboxylic acids also give rise to a broad peak in the 2500-3100-cm -1 region arising from O– H stretching vibrations ●The N–H stretching vibrations of amides absorb between 3140 and 3500 cm -1

23. Ch. 17 - 23

24. Ch. 17 - 24

25. Ch. 17 - 25  1 H NMR Spectra ●The acidic protons of carboxylic acids are highly deshielded and absorb far downfield in the  10-12 region ●The protons of the a carbon of carboxylic acids absorb in the  2.0-2.5 region

26. Ch. 17 - 26

27. Ch. 17 - 27  13 C NMR Spectra ●The carbonyl carbon of carboxylic acids and their derivatives occurs downfield in the  160-180 region (see the following examples), but not as far downfield as for aldehydes and ketones (  180- 220) ●The nitrile carbon is not shifted so far downfield and absorbs in the  115-120 region

28. Ch. 17 - 28  13 C NMR chemical shifts for the carbonyl or nitrile carbon atom

29. Ch. 17 - 29 Preparation of Carboxylic Acids Oxidation cleavage of alkenes KMnO 4 ozonolysis

30. Ch. 17 - 30 Oxidation of aldehydes & 1 o alcohols

31. Ch. 17 - 31 Oxidation of alkyl benzene

32. Ch. 17 - 32 Oxidation of benzene ring

33. Ch. 17 - 33 Hydrolysis of cyanohydrins & nitriles

34. Ch. 17 - 34 Carbonation of Grignard reagents

35. Ch. 17 - 35 Nucleophilic Addition-Elimination at the Acyl Carbon Acyl substitution through nucleophilic addition- elimination

36. Ch. 17 - 36 Acyl derivatives

37. Ch. 17 - 37 aldehydes & ketones usually do not undergo this type of nucleophilic acyl substitution, lack an acyl leaving group A good leaving group Not a good leaving group

38. Ch. 17 - 38  Relative reactivity of carboxylic acid derivatives towards nucleophilic acyl substitution reactions ●There are 2 steps in a nucleophilic acyl substitution  The addition of the nucleophile to the carbonyl group  The elimination of the leaving group in the tetrahedral intermediate

39. Ch. 17 - 39 Usually the addition is the rate- determining step (r.d.s.). Elimination usually occurs spontaneously to regenerate the carbonyl group Both steric and electronic factors that effect addition of a nucleophile

40. Ch. 17 - 40 Steric factor Electronic factor strongly polarized acid derivatives react more readily than less polar ones

41. Ch. 17 - 41 Thus, reactivity of It is usually possible to convert a more reactive acid derivative to a less reactive one, but not vice versa

42. Ch. 17 - 42 Acyl Chlorides Synthesis of Acyl Chlorides From carboxylic acids reagents SOCl 2 (COCl) 2 PCl 3 or PCl 5

43. Ch. 17 - 43 Mechanism

44. Ch. 17 - 44 Conversion of acid chlorides to carboxylic acids

45. Ch. 17 - 45 Mechanism

46. Ch. 17 - 46 Conversion to other carboxylic derivatives

47. Ch. 17 - 47 Carboxylic Acid Anhydrides Synthesis of Anhydrides

48. Ch. 17 - 48

49. Ch. 17 - 49 Reactions of Anhydrides Conversion to carboxylic acids

50. Ch. 17 - 50 Mechanism

51. Ch. 17 - 51 Conversion to other carboxylic derivatives

52. Ch. 17 - 52 Esters Esterification

53. Ch. 17 - 53 Mechanism

54. Ch. 17 - 54 Esters from acyl chlorides

55. Ch. 17 - 55 Esters from anhydrides

56. Ch. 17 - 56 Base-Promoted Hydrolysis of Esters Hydrolysis under basic conditions: saponification

57. Ch. 17 - 57 Mechanism

58. Ch. 17 - 58 Hydrolysis of esters under acidic conditions

59. Ch. 17 - 59 Mechanism

60. Ch. 17 - 60 Lactones Carboxylic acids whose molecules have a hydroxyl group on a  or  carbon undergo intramolecular esterification (cyclic esters) or  - or  -lactones

61. Ch. 17 - 61

62. Ch. 17 - 62 Lactones are hydrolyzed by aqueous base just as other esters are

63. Ch. 17 - 63 Amides Amides from Acyl Chlorides

64. Ch. 17 - 64 Amides from Carboxylic Anhydrides

65. Ch. 17 - 65

66. Ch. 17 - 66

67. Ch. 17 - 67 Amides from Esters

68. Ch. 17 - 68 Amides from Carboxylic Acids & Ammonium Carboxylates

69. Ch. 17 - 69 DCC-Promoted amide synthesis

70. Ch. 17 - 70 Mechanism

71. Ch. 17 - 71 Mechanism (Cont’d)

72. Ch. 17 - 72 Hydrolysis of Amides Acid hydrolysis of amides

73. Ch. 17 - 73 Mechanism

74. Ch. 17 - 74 Basic hydrolysis of amides

75. Ch. 17 - 75 Mechanism

76. Ch. 17 - 76 Nitriles from the Dehydration of Amides useful preparing nitriles not available by S N 2

77. Ch. 17 - 77 dehydration

78. Ch. 17 - 78 Synthesis 1 o alkyl bromide  S N 2

79. Ch. 17 - 79 But synthesis of 3 o alkyl bromide

80. Ch. 17 - 80 Solution dehydration

81. Ch. 17 - 81 Hydrolysis of Nitriles Catalyzed by both acid and base

82. Ch. 17 - 82 Examples

83. Ch. 17 - 83 Mechanism protonated nitrile protonated amide tautomer

84. Ch. 17 - 84 Mechanism

85. Ch. 17 - 85 Lactams

86. Ch. 17 - 86 Derivatives of Carbonic Acid Alkyl Chloroformates & Carbamates (Urethan es) Alkyl chloroformate

87. Ch. 17 - 87 e.g.

88. Ch. 17 - 88 Carbamates or urethanes

89. Ch. 17 - 89 Protection Deprotection protected amine

90. Ch. 17 - 90 Decarboxylation of Carboxylic Acids

91. Ch. 17 - 91 There are 2 reasons for decarboxylation

92. Ch. 17 - 92 Chemical Tests for Acyl Compounds Recall: acidity of

93. Ch. 17 - 93

94. Ch. 17 - 94

95. Ch. 17 - 95 Polyesters, Polyamides, Step-Growth Polymers Polyesters

96. Ch. 17 - 96 Polyamides

97. Ch. 17 - 97 Nylon 66

98. Ch. 17 - 98 Dacron (Mylar) Applications: film, recording tape

99. Ch. 17 - 99 Summary of the Reactions Reactions of carboxylic acids

100. Ch. 17 - 100 Reactions of acyl chlorides

101. Ch. 17 - 101 Reactions of acyl chlorides (Cont’d)

102. Ch. 17 - 102 Reactions of acid anhydrides

103. Ch. 17 - 103 Reactions of esters

104. Ch. 17 - 104 Reactions of nitriles

105. End- 105 Reactions of amides