1. Chapter 20 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution

2. 20.2 Structure and Reactivity of Carboxylic Acid Derivatives

3. Stability and Reactivity of Carboxylic Acid Derivatives The key to managing the information in this chapter is the same as always: structure determines properties. The key structural feature is how well the carbonyl group is stabilized. The key property is reactivity in nucleophilic acyl substitution.

4. CH 3 C OCl O OCCH 3 O CH 3 C O SCH 2 CH 3 CH 3 C O OCH 2 CH 3 CH 3 C O NH 2 Most reactive Least reactive Least stabilized Most stabilized

5. Electron Delocalization and the Carbonyl Group The main structural feature that distinguishes acyl chlorides, anhydrides, thioesters, esters and amides is the interaction of the substituent with the carbonyl group. It can be represented in resonance terms as: RC O X –RC O X + RC O X +–

6. Electron Delocalization and the Carbonyl Group The extent to which the lone pair on X can be delocalized into C=O depends on: 1) The electronegativity of X. 2) How well the lone pair orbital of X interacts with the  orbital of C=O. RC O X RC O X + RC O X +––

7. Orbital Overlaps in Carboxylic Acid Derivatives  orbital of carbonyl group

8. Orbital Overlaps in Carboxylic Acid Derivatives Lone pair orbital of substituent

9. Orbital Overlaps in Carboxylic Acid Derivatives Electron pair of substituent is delocalized into carbonyl  orbital.

10. Acyl chlorides have the least stabilized carbonyl group. Delocalization of lone pair of Cl into C=O group is not effective because C—Cl bond is too long. Acyl Chlorides C O R Cl C O R Cl + –

11. RCCl O Least stabilized C=O Most stabilized C=O

12. Lone pair donation from oxygen stabilizes carbonyl group of an acid anhydride. The other carbonyl group is stabilized in an analogous manner by the lone pair. However, since both carbonyl groups compete for the same lone pair, stabilization of each is reduced. Acid Anhydrides C R O O C O R O +–C R O O C R

13. RCOCR' OO RCCl O Least stabilized C=O Most stabilized C=O

14. Sulfur (like chlorine) is a third-row element. Electron donation to C=O from third-row elements is not very effective. Resonance stabilization of C=O in thioesters is not significant. Thioesters +–C R O SR' O C R SR'

15. RCOCR' OO RCCl O Least stabilized C=O Most stabilized C=O RCSR' O

16. Lone pair donation from oxygen stabilizes carbonyl group of an ester. Stabilization greater than comparable stabilization of an anhydride or thioester. Esters +–C R O OR' O C R OR'

17. RCOCR' OO RCCl O RCOR' O Least stabilized C=O Most stabilized C=O RCSR' O

18. Lone pair donation from nitrogen stabilizes carbonyl group of an amide. N is less electronegative than O; therefore, amides stabilized more than esters and anhydrides. Amides +–C R O NR' 2 O C R NR' 2

19. Amide resonance imparts significant double-bond character to C—N bond. Activation energy for rotation about C—N bond is 75-85 kJ/mol. C—N bond distance is 135 pm in amides versus normal single-bond distance of 147 pm in amines. Amides +–C R O NR' 2 O C R NR' 2

20. RCOCR' OO RCCl O RCOR' O RCNR' 2 O Least stabilized C=O Most stabilized C=O RCSR' O

21. Very efficient electron delocalization and dispersal of negative charge. Maximum stabilization. Carboxylate Ions O C R – O –C R O O

22. RCOCR' OO RCCl O RCOR' O RCNR' 2 O RCO – O Least stabilized C=O Most stabilized C=O RCSR' O

23. Reactivity Is Related to Structure RCOCR' OO RCCl O RCOR' O RCNR' 2 OStabilization very small small large moderate Relative rate of hydrolysis 10 11 10 7 < 10 -2 1.0 The more stabilized the carbonyl group, the less reactive it is.

24. Nucleophilic Acyl Substitution In general: O C R X + HY O C R Y + HX Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive).

25. RCOCR' OO RCCl O RCOR' O RCNR' 2 O RCO – O RCSR' O Most reactive Least reactive A carboxylic acid derivative can be converted by nucleophilic acyl substitution to any other type that lies below it in this table.

26. 20.3 General Mechanism for Nucleophilic Acyl Substitution

27. Nucleophilic Acyl Substitution O C R X + HNu O C R Nu + HX Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive).

28. General Mechanism for Nucleophilic Acyl Substitution Involves formation and dissociation of a tetrahedral intermediate. O C R X HNu C ROHX Nu O C R Nu -HX Both stages can involve several elementary steps.

29. General Mechanism for Nucleophilic Acyl Substitution First stage of mechanism (formation of tetrahedral intermediate) is analogous to nucleophilic addition to C=O of aldehydes and ketones. O C R X HNu C ROHX Nu

30. General Mechanism for Nucleophilic Acyl Substitution Second stage is restoration of C=O by elimination. Complicating features of each stage involve acid- base chemistry. O C R X HNu C R OH X Nu O C R Nu -HX

31. General Mechanism for Nucleophilic Acyl Substitution O C R X HNu C R OH X Nu O C R Nu -HX Acid-base chemistry in first stage is familiar in that it has to do with acid-base catalysis of nucleophilic addition to C=O.

32. General Mechanism for Nucleophilic Acyl Substitution O C R X HNu C R OH X Nu O C R Nu -HX Acid-base chemistry in second stage concerns form in which the tetrahedral intermediate exists under the reaction conditions and how it dissociates under those conditions.

33. The Tetrahedral Intermediate Tetrahedral intermediate (TI) C R O X Nu H C R O X Nu H H + Conjugate acid of tetrahedral intermediate (TI-H + ) O C R X Nu – Conjugate base of tetrahedral intermediate (TI – )

34. Dissociation of TI—H + C R O X Nu H H + + B—H + C O RNu +X H B

35. Dissociation of TI B C R O X Nu H + B—H + C O RNu +X –

36. Dissociation of TI – C O RNu +X – C R O X Nu –

37. 20.4 Nucleophilic Substitution in Acyl Chlorides

38. Preparation of Acyl Chlorides From carboxylic acids and thionyl chloride (12.7) (CH 3 ) 2 CHCOH O SOCl 2 heat (CH 3 ) 2 CHCCl O+ SO 2 + HCl (90%)

39. RCOCR'OO RCCl O RCOR'O RCNR' 2 O RCO – O Reactions of Acyl Chlorides

40. RCCl O Reactions of Acyl Chlorides + R'COH O RCOCR' OO+ HCl Acyl chlorides react with carboxylic acids to give acid anhydrides: via: C R O Cl OCR' HO

41. CH 3 (CH 2 ) 5 CCl OExample + CH 3 (CH 2 ) 5 COH Opyridine CH 3 (CH 2 ) 5 COC(CH 2 ) 5 CH 3 OO(78-83%)

42. RCCl O Reactions of Acyl Chlorides + RCOR' O+ HCl Acyl chlorides react with alcohols to give esters: R'OH via: C R O Cl OR' H

43. Example C 6 H 5 CCl O+ (CH 3 ) 3 COH pyridine (80%) C 6 H 5 COC(CH 3 ) 3 O

44. RCCl O Reactions of Acyl Chlorides + RCNR' 2 O+ H2OH2OH2OH2O Acyl chlorides react with ammonia and amines to give amides: R' 2 NH + HO – + Cl – via: C R O Cl NR' 2 H

45. Example C 6 H 5 CCl O+ NaOH (87-91%) H2OH2OH2OH2O HNHNHNHN C6H5CNC6H5CNC6H5CNC6H5CNO

46. RCCl O Reactions of Acyl Chlorides + RCOH O+ HCl Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base): H2OH2OH2OH2O RCCl O+ RCO – O+ Cl – 2HO – + H2OH2OH2OH2O

47. RCCl O Reactions of Acyl Chlorides + RCOH O+ HCl H2OH2OH2OH2O via: C R O Cl OHOHOHOHH Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base):

48. Example C 6 H 5 CH 2 CCl O+ H2OH2OH2OH2O C 6 H 5 CH 2 COH O+ HCl

49. Reactivity C 6 H 5 CCl O C 6 H 5 CH 2 Cl Acyl chlorides undergo nucleophilic substitution much faster than alkyl chlorides. Relative rates of hydrolysis (25°C) 1,0001

50. 20.5 Nucleophilic Acyl Substitution in Carboxylic Acid Anhydrides Anhydrides can be prepared from acyl chlorides

51. Some Anhydrides Are Industrial Chemicals CH 3 COCCH 3 OO Acetic anhydride OO OOO O Phthalic anhydride Maleic anhydride

52. From Dicarboxylic Acids Cyclic anhydrides with 5- and 6-membered rings can be prepared by dehydration of dicarboxylic acids. C C H HCOH COHOO OO O H H tetrachloroethane130°C (89%) + H 2 O

53. RCOCR'OO RCOR'O RCNR' 2 O RCO – O Reactions of Anhydrides

54. Reactions of Acid Anhydrides + RCOR' O+ Carboxylic acid anhydrides react with alcohols to give esters: R'OH RCOCR OORCOHO Normally, symmetrical anhydrides are used (both R groups the same). Reaction can be carried out in presence of pyridine (a base) or it can be catalyzed by acids.

55. Reactions of Acid Anhydrides + RCOR' O+ Carboxylic acid anhydrides react with alcohols to give esters: R'OH RCOCR OORCOHOvia: C R O OCR OR' HO

56. Example (60%) H 2 SO 4 + CH 3 COCCH 3 OO CH 3 CHCH 2 CH 3 OHOHOHOH CH 3 COCHCH 2 CH 3 O CH 3

57. Reactions of Acid Anhydrides + RCNR' 2 O+ Acid anhydrides react with ammonia and amines to give amides: 2R' 2 NH RCOCR OO RCO – O R' 2 NH 2 + via: C R O OCR NR' 2 HO

58. Example (98%) + CH 3 COCCH 3 OO H2NH2NH2NH2N CH(CH 3 ) 2 O CH 3 CNH CH(CH 3 ) 2

59. Reactions of Acid Anhydrides + 2RCOH O Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): H2OH2OH2OH2O + 2RCO – O+ 2HO – H2OH2OH2OH2O RCOCR OO OO

60. Reactions of Acid Anhydrides + 2RCOH O Acid anhydrides react with water to give carboxylic acids (carboxylate ion in base): H2OH2OH2OH2O RCOCR OO C R O OCR OHHO

61. Example + H2OH2OH2OH2OOO O COHOCOH O

62. 20.8 Reactions of Esters: A Review and a Preview

63. With Grignard reagents (14.10) Reduction with LiAlH 4 (15.3) With ammonia and amines (20.11) Hydrolysis (20.9 and 20.10) Reactions of Esters

65. 20.9 Acid-Catalyzed Ester Hydrolysis

66. Maximize conversion to ester by removing water. Maximize ester hydrolysis by having large excess of water. Equilibrium is closely balanced because carbonyl group of ester and of carboxylic acid are comparably stabilized. Acid-Catalyzed Ester Hydrolysis RCOH O+ R'OH RCOR' O+ H2OH2OH2OH2O H+H+H+H+ The reverse of Fischer esterification.

67. Example HCl, heat + H2OH2OH2OH2OO CHCOCH 2 CH 3 Cl + CH 3 CH 2 OH OCHCOH Cl (80-82%)

68. Is the reverse of the mechanism for acid- catalyzed esterification. Like the mechanism of esterification, it involves two stages: 1) Formation of tetrahedral intermediate (3 steps) 2) Dissociation of tetrahedral intermediate (3 steps) Mechanism of Acid-Catalyzed Ester Hydrolysis

69. First Stage: Formation of Tetrahedral Intermediate RCOHOH OR' + H2OH2OH2OH2O RCOR' O H+H+H+H+ Water adds to the carbonyl group of the ester. This stage is analogous to the acid- catalyzed addition of water to a ketone.

70. Second Stage: Cleavage of Tetrahedral Intermediate RCOHOH OR' + R'OH H+H+H+H+ RCOHO

71. Mechanism of Formation of Tetrahedral Intermediate

72. Step 1 RC O OR' O + HHH RC O OR' + H O H H

73. Step 1 RC O OR' + H Carbonyl oxygen is protonated because cation produced is stabilized by electron delocalization (resonance). RC O OR' + H

74. Step 2 O H H RC O OR' + H RC OH OR' O + H H

75. Step 3 O HH RC OH OR' O H H + O H H H + RC OH OR' O H

76. Cleavage of Tetrahedral Intermediate

77. Step 4 O HH H + RC OH O OH R' RC OH O OHOHOHOH R' H + O H H

78. Step 5 RC OH O OH R' H + O R' H + RC OH OH +

79. Step 5 RC OHOH + RC OH OH +

80. Step 6 RC OOH + H O H H + O H HH RC O OH

81. Activation of carbonyl group by protonation of carbonyl oxygen. Nucleophilic addition of water to carbonyl group forms tetrahedral intermediate. Elimination of alcohol from tetrahedral intermediate restores carbonyl group. Key Features of Mechanism

82. 18 O Labeling Studies + H2OH2OH2OH2O COCH 2 CH 3 O O+ H2OH2OH2OH2O Ethyl benzoate, labeled with 18 O at the carbonyl oxygen, was subjected to acid-catalyzed hydrolysis. Ethyl benzoate, recovered before the reaction had gone to completion, had lost a portion of its 18 O label. This observation is consistent with a tetrahedral intermediate. H+H+H+H+

83. 18 O Labeling Studies C OHOHOHOHOH OCH 2 CH 3 COCH 2 CH 3 O H+H+H+H+ + H2OH2OH2OH2O + H2OH2OH2OH2O O H+H+H+H+

84. 20.10 Ester Hydrolysis in Base: Saponification

85. This reaction is also called saponification. It is irreversible, because of stability of carboxylate ion. If carboxylic acid is desired product, saponification is followed by a separate acidification step (simply a pH adjustment). Ester Hydrolysis in Aqueous Base RCO – O+ R'OH RCOR' O+ HO –

86. Example water-methanol, heat (95-97%) CH 2 OCCH 3 CH 3 O+ NaOH CH 2 OH CH 3 O CH 3 CONa +

87. Example (87%) + CCOH CH 3 O H2CH2CH2CH2C 1. NaOH, H 2 O, heat 2. H 2 SO 4 CH 3 OH CCOCH 3 CH 3 O H2CH2CH2CH2C

88. Soap-Making CH 3 (CH 2 ) y COCH CH 2 OC(CH 2 ) x CH 3 O CH 2 OC(CH 2 ) z CH 3 O O Basic hydrolysis of the glyceryl triesters (from fats and oils) gives salts of long- chain carboxylic acids. These salts are soaps. K 2 CO 3, H 2 O, heat CH 3 (CH 2 ) x COK O CH 3 (CH 2 ) y COK O CH 3 (CH 2 ) z COK O

89. Which Bond Is Broken when Esters Are Hydrolyzed in Base? RCO O + R' – OH RCO O + R'OH – One possibility is an S N 2 attack by hydroxide on the alkyl group of the ester. Carboxylate is the leaving group.

90. + –OH RC O OR' + OR' – A second possibility is nucleophilic acyl substitution. RC O OH Which Bond Is Broken when Esters Are Hydrolyzed in Base?

91. 18 O Labeling Gives the Answer 18 O retained in alcohol, not carboxylate; therefore, nucleophilic acyl substitution. CH 3 CH 2 COCH 2 CH 3 ONaOH + CH 3 CH 2 CONa O CH 3 CH 2 OH +

92. Stereochemistry Gives the Same Answer Alcohol has same configuration at chirality center as ester; therefore, nucleophilic acyl substitution, not S N 2. CH 3 COK O+ CH 3 C O C OH C6H5C6H5C6H5C6H5 CH 3 C HOHOHOHOH C6H5C6H5C6H5C6H5 KOH, H 2 O

93. Does It Proceed via a Tetrahedral Intermediate? + –OH RC O OR' + OR' – Does nucleophilic acyl substitution proceed in a single step or is a tetrahedral intermediate involved? RC O OH

94. 18 O Labeling Studies + H2OH2OH2OH2O COCH 2 CH 3 O O+ H2OH2OH2OH2O Ethyl benzoate, labeled with 18 O at the carbonyl oxygen, was subjected to hydrolysis in base. Ethyl benzoate, recovered before the reaction had gone to completion, had lost a portion of its 18 O label. This observation is consistent with a tetrahedral intermediate. HO –

95. 18 O Labeling Studies C OHOHOHOHOH OCH 2 CH 3 + H2OH2OH2OH2O COCH 2 CH 3 O HO – COCH 2 CH 3 O+ H2OH2OH2OH2O HO –

96. Involves two stages: 1)Formation of tetrahedral intermediate 2)Dissociation of tetrahedral intermediate Mechanism of Ester Hydrolysis in Base

97. First Stage: Formation of Tetrahedral Intermediate RCOHOH OR' + H2OH2OH2OH2O RCOR' O Water adds to the carbonyl group of the ester. This stage is analogous to the base-catalyzed addition of water to a ketone. HO –

98. Second Stage: Cleavage of Tetrahedral Intermediate RCOHOH OR' + R'OH RCO – O HO –

99. Mechanism of Formation of Tetrahedral Intermediate

100. Step 1 RC O OR' RC O OR' O H – O H –

101. Step 2 RC O OR' O H – HO H RC O OR' O H H – O H

102. Dissociation of Tetrahedral Intermediate

103. Step 3 RC O OR' O H H – O H HO H OR' – RC O O H

104. Step 4 OR' – RC O O H HO – RC O O – H OR' H2OH2OH2OH2O

105. Nucleophilic addition of hydroxide ion to carbonyl group in first step. Tetrahedral intermediate formed in first stage. Hydroxide-induced dissociation of tetrahedral intermediate in second stage. Key Features of Mechanism

106. 20.11 Reactions of Esters with Ammonia and Amines

107. RCOR'O RCNR' 2 O RCO – O Reactions of Esters

108. + RCNR' 2 O+ Esters react with ammonia and amines to give amides: R' 2 NH RCOR' O R'OH via: C R O OR' NR' 2 H

109. Example (75%) + CCNH 2 CH 3 O H2CH2CH2CH2C CH 3 OH CCOCH 3 CH 3 O H2CH2CH2CH2C + NH3NH3NH3NH3 H2OH2OH2OH2O

110. Example (61%) + FCH 2 COCH 2 CH 3 O NH2NH2NH2NH2 + CH 3 CH 2 OH FCH 2 CNH Oheat

111. Thioesters

112. Thioesters Thioesters are compounds of the type: RCSR' O Thioesters are intermediate in reactivity between anhydrides and esters. Thioester carbonyl group is less stabilized than oxygen analog because C—S bond is longer than C—O bond which reduces overlap of lone pair orbital and C=O  orbital.

113. Thioesters RCSR' O+NuH RCNu O+ R'SH via: C R O SR' NuH

114. Thioesters Many biological nucleophilic acyl substitutions involve thioesters.

115. 20.12 Amides

116. Physical Properties of Amides Amides are less reactive toward nucleophilic acyl substitution than other acid derivatives. C C O O H H N N H H H H C C O O H H N N H H H H C C O O H H N N H H H H Formamide

117. Physical Properties of Amides Amides are capable of hydrogen bonding.

118. Physical Properties of Amides Amides are capable of hydrogen bonding.

119. Amides are less acidic than carboxylic acids. Nitrogen is less electronegative than oxygen. C C H H 3 3 C C H H 2 2 N N H H 2 2 C C H H 3 3 C C N N H H 2 2 O O C C H H 3 3 C C N N C C C C H H 3 3 O O H H C C H H 3 3 C C O O H H O O 36 15 10 5 5 Physical Properties of Amides O O pKa:

120. Acyl chlorides AnhydridesEsters Preparation of Amides Amides are prepared from amines by acylation with:

121. Preparation of Amides Amides are also sometimes prepared directly from amines and carboxylic acids. The first step is a proton-transfer (acid-base) reaction between the carboxylic acid and the amine to form an ammonium carboxylate salt. RCOHO+ R'NH 2 RCOO R'NH 3 + –

122. Preparation of Amides Then, if no heat-sensitive groups are present, the resulting ammonium carboxylate salt can be converted to an amide by heating. RCOHO+ R'NH 2 RCOO R'NH 3 + – heat RCNHR' O+ H2OH2OH2OH2O

123. Example COHO+ H2NH2NH2NH2N 225°C + H2OH2OH2OH2O (80-84%) CNHCNHCNHCNHO

124. 20.13 Hydrolysis of Amides

125. Hydrolysis of Amides Hydrolysis of amides is irreversible. In acid solution, the amine product is protonated to give an ammonium salt. + R'NH 3 + RCOHO RCNHR' O+ H2OH2OH2OH2O H + +

126. Hydrolysis of Amides In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. RCNHR' O+ R'NH 2 – RCOOHO + –

127. Example: Acid Hydrolysis (88-90%) CH 3 CH 2 CHCNH 2 O CH 3 CH 2 CHCOH O H2OH2OH2OH2O H 2 SO 4, heat + NH4NH4NH4NH4+ HSO 4 HSO 4 –

128. Example: Basic Hydrolysis (95%) CH 3 COK OKOH H 2 O heat + CH 3 CNH OBr NH2NH2NH2NH2Br

129. Acid-catalyzed amide hydrolysis proceeds via the customary two stages: 1)Formation of tetrahedral intermediate 2)Dissociation of tetrahedral intermediate Mechanism of Acid-Catalyzed Amide Hydrolysis

130. First Stage: Formation of Tetrahedral Intermediate RCOHOH NH2NH2NH2NH2 + H2OH2OH2OH2O RCNH 2 O H+H+H+H+ Water adds to the carbonyl group of the amide. This stage is analogous to the acid- catalyzed addition of water to a ketone.

131. Second Stage: Cleavage of Tetrahedral Intermediate + H+H+H+H+ RCOHO RCOHOH NH2NH2NH2NH2 NH4NH4NH4NH4+

132. Mechanism of Formation of Tetrahedral Intermediate

133. Step 1 O + HHH RC O NH2NH2NH2NH2 + H O H H RC O NH2NH2NH2NH2

134. Step 1 Carbonyl oxygen is protonated because cation produced is stabilized by electron delocalization (resonance). RC O NH2NH2NH2NH2 + H RC O NH2NH2NH2NH2 + H

135. Step 2 RC OH NH2NH2NH2NH2 O + H H O HH RC O NH2NH2NH2NH2 + H

136. Step 3 O HH O H H H + NH2NH2NH2NH2 RC OH O H RC OH NH2NH2NH2NH2 O + H H

137. Cleavage of Tetrahedral Intermediate

138. Step 4 O HH H + H2NH2NH2NH2N RC OH O H O H H RC OH H2NH2NH2NH2N OHOHOHOH H +

139. Step 5 RC OH H2NH2NH2NH2N OHOHOHOH H + RC OH OH + + NH3NH3NH3NH3 H3OH3OH3OH3O + NH4NH4NH4NH4+

140. Step 6 O H H RC O OH +H + O H HH RC O OH

141. Involves two stages: 1)Formation of tetrahedral intermediate 2)Dissociation of tetrahedral intermediate Mechanism of Amide Hydrolysis in Base

142. First Stage: Formation of Tetrahedral Intermediate RCOHOH NH2NH2NH2NH2 + H2OH2OH2OH2O RCNH 2 O Water adds to the carbonyl group of the amide. This stage is analogous to the base-catalyzed addition of water to a ketone. HO –

143. Second Stage: Cleavage of Tetrahedral Intermediate + RCOO RCOHOH NH2NH2NH2NH2 NH3NH3NH3NH3 – HO –

144. Mechanism of Formation of Tetrahedral Intermediate

145. Step 1 RC O NH2NH2NH2NH2 O H – O H – RC O NH2NH2NH2NH2

146. Step 2 HO H RC O NH2NH2NH2NH2 O H – RC O NH2NH2NH2NH2 O H H – O H

147. Dissociation of Tetrahedral Intermediate

148. Step 3 H2NH2NH2NH2N RC OH O H O HH RC OH H2NH2NH2NH2N OHOHOHOH H + O H –

149. Step 4 RC O H3NH3NH3NH3N OHOHOHOH + H – O H HO H NH3NH3NH3NH3 RC O O H

150. Step 5 RC O O H HO – RC O O – NH3NH3NH3NH3

151. 20.14 Lactams

152. Lactams Lactams are cyclic amides. Some are industrial chemicals, others occur naturally. N H O  -Caprolactam*: used to prepare a type of nylon.    *Caproic acid is the common name for hexanoic acid.

153. Lactams Lactams are cyclic amides. Some are industrial chemicals, others occur naturally. Penicillin G: a  -lactam antibiotic   CH 3 S CO 2 H O N C 6 H 5 CH 2 CNH O

154. Fate of  -Lactam Antibiotics Fate of  -Lactam Antibiotics

155. Section 20.18 Spectroscopic Analysis of Carboxylic Acid Derivatives

156. C=O stretching frequency depends on whether the compound is an acyl chloride, anhydride, ester or amide. Infrared Spectroscopy CH 3 CCl O CH 3 COCH 3 O CH 3 COCCH 3 OO CH 3 CNH 2 O 1822 cm -1 1748and 1815 cm -1 1736 cm -1 1694 cm -1 C=O stretching frequency:

157. Anhydrides have two peaks due to C=O stretching. One results from symmetrical stretching of the C=O unit, the other from an antisymmetrical stretch. Infrared Spectroscopy 1748and 1815 cm -1 CH 3 COCCH 3 OO C=O stretching frequency:

158. Nitriles, whose hydrolysis yields carboxylic acids (19.12) and are thus often considered carboxylic acid derivatives, are readily identified by absorption due to carbon-nitrogen triple bond stretching in the 2210-2260 cm -1 region. Infrared Spectroscopy CH 3 C N Acetonitrile

159. 1 H NMR readily distinguishes between isomeric esters of the type: 1 H NMR RCOR' Oand R'COR O OC H is less shielded than OC C H

160. 1 H NMR CH 3 COCH 2 CH 3 Oand For example: CH 3 CH 2 COCH 3 O Both have a triplet-quartet pattern for an ethyl group and a methyl singlet. They can be identified, however, on the basis of chemical shifts.

161. Chemical shift ( , ppm) Ethyl Acetate and Methyl Propanoate 01.02.03.04.05.0 CH 3 COCH 2 CH 3 O 01.02.03.04.05.0 CH 3 CH 2 COCH 3 O

162. 13 C NMR Carbonyl carbon is at low field (  160-180 ppm) but not as deshielded as the carbonyl carbon of an aldehyde or ketone (  190-215 ppm). The carbon of a CN group appears near  120 ppm.