1. Addition–Elimination
Chapter 17
Carboxylic Acids
and Their Derivatives
Nucleophilic
Addition–Elimination
at the Acyl Carbon

2. About The Authors
These PowerPoint Lecture Slides were created and prepared by Professor William Tam and his wife, Dr. Phillis Chang.
Professor William Tam received his B.Sc. at the University of Hong Kong in 1990 and his Ph.D. at the University of Toronto (Canada) in He was an NSERC postdoctoral fellow at the Imperial College (UK) and at Harvard University (USA). He joined the Department of Chemistry at the University of Guelph (Ontario, Canada) in 1998 and is currently a Full Professor and Associate Chair in the department. Professor Tam has received several awards in research and teaching, and according to Essential Science Indicators, he is currently ranked as the Top 1% most cited Chemists worldwide. He has published four books and over 80 scientific papers in top international journals such as J. Am. Chem. Soc., Angew. Chem., Org. Lett., and J. Org. Chem.
Dr. Phillis Chang received her B.Sc. at New York University (USA) in 1994, her M.Sc. and Ph.D. in 1997 and 2001 at the University of Guelph (Canada). She lives in Guelph with her husband, William, and their son, Matthew.

3. Introduction
Carboxylic Acid Derivatives

4. 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”

5. 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”

6. Examples

7. Examples

8. 2C. Acidity of Carboxylic Acids
pKa ~ 4-5
Compare
pKa of H2O ~ 16
pKa of H2CO3 ~ 7
pKa of HF ~ 3

9. When comparing acidity of organic compounds, we compare the stability of their conjugate bases. The more stable the conjugate base, the stronger the acid

11. The conjugate base B1 is more stable (the anion is more delocalized) than B2 due to resonance stabilization
Thus, A1 is a stronger acid than A2

12. Acidity of Carboxylic Acids, Phenols and Alcohols

13. Acidity of Carboxylic Acids, Phenols and Alcohols

14. Acidity of Carboxylic Acids, Phenols and Alcohols

15. (NO resonance stabilization)
Acidity of Carboxylic Acids, Phenols and Alcohols
(NO resonance stabilization)

16. 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

19. Stability of conjugate bases
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21. 2D. Dicarboxylic Acids

22. 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

23. 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 cm-1 region arising from O–H stretching vibrations
The N–H stretching vibrations of amides absorb between 3140 and 3500 cm-1

26. 1H NMR Spectra
The acidic protons of carboxylic acids are highly deshielded and absorb far downfield in the d region
The protons of the a carbon of carboxylic acids absorb in the d region

28. 13C NMR Spectra
The carbonyl carbon of carboxylic acids and their derivatives occurs downfield in the d region (see the following examples), but not as far downfield as for aldehydes and ketones (d )
The nitrile carbon is not shifted so far downfield and absorbs in the d region

29. 13C NMR chemical shifts for the carbonyl or nitrile carbon atom

30. Preparation of Carboxylic Acids
By oxidation cleavage of alkenes
Using KMnO4
Using ozonolysis

31. By oxidation of aldehydes & 1o alcohols
e.g.

32. By oxidation of alkyl benzene

33. By oxidation of benzene ring
e.g.

34. By hydrolysis of cyanohydrins and other nitriles
e.g.

35. By carbonation of Grignard reagents
e.g.

36. Acyl Substitution: Nucleophilic
Addition-Elimination at the Acyl Carbon
This nucleophilic acyl substitution occurs through a nucleophilic addition-elimination mechanism

37. This type of nucleophilic acyl substitution reaction is common for carboxylic acids and their derivatives

38. Not a good leaving group
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

39. 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

40. 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

41. Steric factor
Electronic factor
The strongly polarized acid derivatives react more readily than less polar ones

42. 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

43. Acyl Chlorides 5A. Synthesis of Acyl Chlorides
Conversion of carboxylic acids to acid chlorides
Common reagents
SOCl2
(COCl)2
PCl3 or PCl5

44. Mechanism

45. Nucleophilic acyl substitution reactions of acid chlorides
Conversion of acid chlorides to carboxylic acids

46. Mechanism

47. Conversion of acid chlorides to other carboxylic derivatives

48. Carboxylic Acid Anhydrides
6A. Synthesis of Carboxylic Acid Anhydrides

50. 6B. Reactions of Carboxylic Acid Anhydrides
Conversion of acid anhydrides to carboxylic acids

51. Mechanism

52. Conversion of acid anhydrides to other carboxylic derivatives

53. Esters
7A. Synthesis of Esters: Esterification

54. Mechanism

55. Esters from acyl chlorides

56. Esters from carboxylic acid anhydrides

57. 7B. Base-Promoted Hydrolysis of Esters: Saponification
Hydrolysis of esters under basic conditions: saponification

58. Mechanism

59. Hydrolysis of esters under acidic conditions

60. Mechanism

61. 7C. Lactones
Carboxylic acids whose molecules have a hydroxyl group on a g or d carbon undergo an intramolecular esterification to give cyclic esters known as g- or d-lactones

63. Lactones are hydrolyzed by aqueous base just as other esters are

64. Amides
8B. Amides from Acyl Chlorides

65. 8C. Amides from Carboxylic Anhydrides

68. 8D. Amides from Esters

69. 8E. Amides from Carboxylic Acids and Ammonium Carboxylates

70. DCC-Promoted amide synthesis

71. Mechanism

72. Mechanism (Cont’d)

73. 8F. Hydrolysis of Amides
Acid hydrolysis of amides

74. Mechanism

75. Basic hydrolysis of amides

76. Mechanism

77. 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

78. e.g.
dehydration

79. Example
Synthesis of
1o alkyl bromide
 SN2 reaction with ⊖CN works fine

80. But synthesis of
3o alkyl bromide
 No SN2 reaction

81. Solution
dehydration

82. 8H. Hydrolysis of Nitriles
Catalyzed by both acid and base

83. Examples

84. protonated nitrile
Mechanism
amide
tautomer
protonated
amide

85. Mechanism

86. 8I. Lactams

87. Derivatives of Carbonic Acid
9A. Alkyl Chloroformates and Carbamates (Urethanes)
Alkyl chloroformate

88. e.g.

89. Carbamates or urethanes

90. Protection
protected amine
Deprotection

91. Decarboxylation of Carboxylic Acids

92. There are two reasons for this ease of decarboxylation

93. Chemical Tests for Acyl Compounds
Recall: acidity of

96. Polyesters and Polyamides: Step-Growth Polymers

97. Polyamides

98. Example: Nylon 66
Applications: clothing, fibers, bearings

99. Example: Dacron (Mylar)
Applications: film, recording tape

100. Reactions of carboxylic acids
Summary of the Reactions of
Carboxylic Acids and Their Derivatives
Reactions of carboxylic acids

101. Reactions of acyl chlorides

102. Reactions of acyl chlorides (Cont’d)

103. Reactions of acid anhydrides

104. Reactions of esters

105. Reactions of nitriles

106. Reactions of amides

107.  END OF CHAPTER 17 