1. Created by Professor William Tam & Dr. Phillis Chang Ch. 17 - 1 Chapter 17 Carboxylic Acids and Their Derivatives NucleophilicAddition–Elimination at the Acyl Carbon

2. Ch. 17 - 2 1.Introduction  Carboxylic Acid Derivatives

3. Ch. 17 - 3 2.Nomenclature and Physical Properties  Nomenclature of Carboxylic Acids and Derivatives. ●Rules:  Carboxylic acid as parent (suffix): ending with “–oic acid”  Carboxylate as parent (suffix): ending with “–oate”

4. Ch. 17 - 4  Most anhydrides are named by dropping the word acid from the name of the carboxylic acid and then adding the word “anhydride”  Acid chloride as parent (suffix): ending with “–oyl chloride”  Ester as parent (suffix): ending with “–oate”  Amide as parent (suffix): ending with “amide”  Nitrile as parent (suffix): ending with “nitrile”

5. Ch. 17 - 5  Examples:

6. Ch. 17 - 6  Examples:

7. Ch. 17 - 7 2C.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 (acetate) is more stable (a weaker base) than B 2 (ethoxide) due to resonance stabilization of the acetate anion. ●Thus, acetic acid (A 1 ) is a stronger acid than ethanol (A 2 ).

11. Ch. 17 - 11  Acidity of Carboxylic Acids, Phenols and 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  If you are given three unknown samples: one is benzoic acid; one is phenol; and one is cyclohexyl alcohol; how would you distinguish them by simple chemical tests ? ●Recall: acidity of

16. Ch. 17 - 16

17. Ch. 17 - 17

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

19. Ch. 17 - 19 > > > > > > > > >  More Examples:

20. Ch. 17 - 20 2D.Dicarboxylic Acids Note: pK 1 is always lower than pK 2.

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  IR Absorbances:

24. Ch. 17 - 24 IR Spectrum:

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  carbon of carboxylic acids absorb in the  2.0-2.5 region.

26. Ch. 17 - 26 H 1 NMR Spectrum:

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 3.Preparation of Carboxylic Acids  By oxidation cleavage of alkenes: ●Using KMnO 4 ●Using ozonolysis

30. Ch. 17 - 30  By oxidation of aldehydes & 1 o alcohols: ●e.g.

31. Ch. 17 - 31  By oxidation of alkyl benzene:

32. Ch. 17 - 32  By oxidation of benzene ring: ●e.g.

33. Ch. 17 - 33  By hydrolysis of cyanohydrins and other nitriles: ●e.g.

34. Ch. 17 - 34  By carbonation of Grignard reagents: ●e.g.

35. Ch. 17 - 35 4.Acyl Substitution: Nucleophilic Addition-Elimination at the Acyl Carbon  This nucleophilic acyl substitution occurs through a nucleophilic addition-elimination mechanism.

36. Ch. 17 - 36  This type of nucleophilic acyl substitution reaction is common for carboxylic acids and their derivatives.

37. Ch. 17 - 37  Unlike carboxylic acids and their derivatives, aldehydes & ketones usually do not undergo this type of nucleophilic acyl substitution, due to the lack of 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 step (the first step) is the rate-determining step (r.d.s.). As soon as the tetrahedral intermediate is formed, elimination usually occurs spontaneously to regenerate the carbonyl group. ●Thus, both steric and electronic factors that affect the rate of the addition of a nucleophile control the reactivity of the carboxylic acid derivative.

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

41. Ch. 17 - 41 ●Thus, reactivity of ●An important consequence of this reactivity:  It is usually possible to convert a more reactive acid derivative to a less reactive one, but not vice versa.

42. Ch. 17 - 42 5.Acyl Chlorides 5A. Synthesis of Acyl Chlorides  Conversion of carboxylic acids to acid chlorides: ●Common reagents  SOCl 2  (COCl) 2  PCl 3 or PCl 5

43. Ch. 17 - 43 ●Mechanism:

44. Ch. 17 - 44  Nucleophilic acyl substitution reactions of acid chlorides. ●Conversion of acid chlorides to carboxylic acids:

45. Ch. 17 - 45 ●Mechanism:

46. Ch. 17 - 46 ●Conversion of acid chlorides to other carboxylic derivatives:

47. Ch. 17 - 47 6.Carboxylic Acid Anhydrides 6A.Synthesis of Carboxylic Acid Anhydrides

48. Ch. 17 - 48

49. Ch. 17 - 49 6B.Reactions of Carboxylic Acid Anhydrides  Conversion of acid anhydrides to carboxylic acids:

50. Ch. 17 - 50 ●Mechanism:

51. Ch. 17 - 51  Conversion of acid anhydrides to other carboxylic derivatives:

52. Ch. 17 - 52 7.Esters 7A.Synthesis of Esters: Esterification This is called the Fischer Esterification.

53. Ch. 17 - 53  Mechanism:

54. Ch. 17 - 54  Esters from acyl chlorides:

55. Ch. 17 - 55  Esters from carboxylic acid anhydrides:

56. Ch. 17 - 56 7B.Base-Promoted Hydrolysis of Esters: Saponification  Hydrolysis of esters 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 7C.Lactones  Carboxylic acids whose molecules have a hydroxyl group on a  or  carbon undergo an intramolecular esterification to give cyclic esters known as  - 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 8.Amides 8B.Amides from Acyl Chlorides

64. Ch. 17 - 64 8C.Amides from Carboxylic Anhydrides

65. Ch. 17 - 65

66. Ch. 17 - 66

67. Ch. 17 - 67 8D.Amides from Esters

68. Ch. 17 - 68 8E.Amides from Carboxylic Acids and 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 8F.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 8G.Nitriles from the Dehydration of Amides  This is a useful synthetic method for preparing nitriles that are not available by nucleophilic substitution reactions between alkyl halides and cyanide ions

77. Ch. 17 - 77  e.g. dehydration

78. Ch. 17 - 78  Example ●Synthesis of 1 o alkyl bromide  S N 2 reaction with ⊖ CN works fine

79. Ch. 17 - 79 But synthesis of 3 o alkyl bromide  No S N 2 reaction

80. Ch. 17 - 80 Solution dehydration

81. Ch. 17 - 81 8H.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 8I.Lactams

86. Ch. 17 - 86 9.Derivatives of Carbonic Acid 9A.Alkyl Chloroformates and Carbamates (Urethanes)  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 10.Decarboxylation of Carboxylic Acids

91. Ch. 17 - 91  There are two reasons for this ease of decarboxylation

92. Ch. 17 - 92 11.Chemical Tests for Acyl Compounds  Recall: acidity of

93. Ch. 17 - 93

94. Ch. 17 - 94

95. Ch. 17 - 95 12.Polyesters and Polyamides: Step-Growth Polymers  Polyesters

96. Ch. 17 - 96  Polyamides

97. Ch. 17 - 97  Example: Nylon 66 ●Applications: clothing, fibers, bearings

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

99. Ch. 17 - 99 13.Summary of the Reactions of Carboxylic Acids and Their Derivatives  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. Ch. 17 - 105  Reactions of amides

106. Ch. 17 - 106  END OF CHAPTER 17 