1. Dr. Wolf's CHM 201 & 202 19-1 Chapter 19 Carboxylic Acid Derivatives Nucleophilic Acyl Substitution

2. Dr. Wolf's CHM 201 & 202 19-2 Nomenclature of Carboxylic Acid Derivatives

3. Dr. Wolf's CHM 201 & 202 19-3 Acyl Halides RCOX name the acyl group and add the word chloride, fluoride, bromide, or iodide as appropriate acyl chlorides are, by far, the most frequently encountered of the acyl halides

4. Dr. Wolf's CHM 201 & 202 19-4 Acyl Halides CH 3 CCl O acetyl chloride 3-butenoyl chloride O H2CH2CH2CH2C CHCH 2 CCl OCBr F p-fluorobenzoyl bromide

5. Dr. Wolf's CHM 201 & 202 19-5 Acid Anhydrides when both acyl groups are the same, name the acid and add the word anhydride when the groups are different, list the names of the corresponding acids in alphabetical order and add the word anhydride RCOCR'OO

6. Dr. Wolf's CHM 201 & 202 19-6 Acid Anhydrides acetic anhydride benzoic anhydride benzoic heptanoic anhydride CH 3 COCCH 3 OO C 6 H 5 COCC 6 H 5 OO C 6 H 5 COC(CH 2 ) 5 CH 3 OO

7. Dr. Wolf's CHM 201 & 202 19-7 EstersEsters name as alkyl alkanoates cite the alkyl group attached to oxygen first (R') name the acyl group second; substitute the suffix -ate for the -ic ending of the corresponding acid RCOR'O

8. Dr. Wolf's CHM 201 & 202 19-8 EstersEsters CH 3 COCH 2 CH 3 O ethyl acetate methyl propanoate 2-chloroethyl benzoate O CH 3 CH 2 COCH 3 COCH 2 CH 2 Cl O

9. Dr. Wolf's CHM 201 & 202 19-9 Amides having an NH 2 group identify the corresponding carboxylic acid replace the -ic acid or -oic acid ending by -amide. RCNH 2 O

10. Dr. Wolf's CHM 201 & 202 19-10 Amides having an NH 2 group CH 3 CNH 2 Oacetamide 3-methylbutanamideO (CH 3 ) 2 CHCH 2 CNH 2 CNH2CNH2CNH2CNH2Obenzamide

11. Dr. Wolf's CHM 201 & 202 19-11 Amides having substituents on N name the amide as before precede the name of the amide with the name of the appropriate group or groups precede the names of the groups by the letter N- (standing for nitrogen and used as a locant) RCNHR' Oand RCNR' 2 O

12. Dr. Wolf's CHM 201 & 202 19-12 Amides having substituents on N CH 3 CNHCH 3 O N-methylacetamide N-isopropyl-N-methylbutanamide CN(CH 2 CH 3 ) 2 O N,N-diethylbenzamide O CH 3 CH 2 CH 2 CNCH(CH 3 ) 2 CH 3

13. Dr. Wolf's CHM 201 & 202 19-13 NitrilesNitriles add the suffix -nitrile to the name of the parent hydrocarbon chain (including the triply bonded carbon of CN) or: replace the -ic acid or -oic acid name of the corresponding carboxylic acid by -onitrile or: name as an alkyl cyanide (functional class name) RCN

14. Dr. Wolf's CHM 201 & 202 19-14 NitrilesNitriles CH 3 C N ethanenitrile or: acetonitrile or: methyl cyanide C6H5CC6H5CC6H5CC6H5CN benzonitrile N C CH 3 CHCH 3 2-methylpropanenitrile or: isopropyl cyanide

15. Dr. Wolf's CHM 201 & 202 19-15 Structure of Carboxylic Acid Derivatives

16. Dr. Wolf's CHM 201 & 202 19-16 The key to this chapter is the next slide. It lists the various carboxylic acids in order of decreasing reactivity toward their fundamental reaction type (nucleophilic acyl substitution). The other way to read the list is in order of increasing stabilization of the carbonyl group.

17. Dr. Wolf's CHM 201 & 202 19-17 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

18. Dr. Wolf's CHM 201 & 202 19-18 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 +–

19. Dr. Wolf's CHM 201 & 202 19-19 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 +––

20. Dr. Wolf's CHM 201 & 202 19-20 Orbital overlaps in carboxylic acid derivatives  orbital of carbonyl group

21. Dr. Wolf's CHM 201 & 202 19-21 Orbital overlaps in carboxylic acid derivatives lone pair orbital of substituent

22. Dr. Wolf's CHM 201 & 202 19-22 Orbital overlaps in carboxylic acid derivatives electron pair of substituent delocalized into carbonyl  orbital

23. Dr. Wolf's CHM 201 & 202 19-23 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 + –

24. Dr. Wolf's CHM 201 & 202 19-24 RCCl O least stabilized C=O most stabilized C=O

25. Dr. Wolf's CHM 201 & 202 19-25 lone pair donation from oxygen stabilizes the carbonyl group of an acid anhydride the other carbonyl group is stabilized in an analogous manner by the lone pair Acid Anhydrides C R O O C O R O +–C R O O C R

26. Dr. Wolf's CHM 201 & 202 19-26 RCOCR' OO RCCl O least stabilized C=O most stabilized C=O

27. Dr. Wolf's CHM 201 & 202 19-27 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'

28. Dr. Wolf's CHM 201 & 202 19-28 RCOCR' OO RCCl O least stabilized C=O most stabilized C=O RCSR' O

29. Dr. Wolf's CHM 201 & 202 19-29 lone pair donation from oxygen stabilizes the carbonyl group of an ester stabilization greater than comparable stabilization of an anhydride or thioester Esters +–C R O OR' O C R OR'

30. Dr. Wolf's CHM 201 & 202 19-30 RCOCR' OO RCCl O RCOR' O least stabilized C=O most stabilized C=O RCSR' O

31. Dr. Wolf's CHM 201 & 202 19-31 lone pair donation from nitrogen stabilizes the carbonyl group of an amide N is less electronegative than O; therefore, amides are stabilized more than esters and anhydrides Amides +–C R O NR' 2 O C R NR' 2

32. Dr. Wolf's CHM 201 & 202 19-32 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

33. Dr. Wolf's CHM 201 & 202 19-33 RCOCR' OO RCCl O RCOR' O RCNR' 2 O least stabilized C=O most stabilized C=O RCSR' O

34. Dr. Wolf's CHM 201 & 202 19-34 very efficient electron delocalization and dispersal of negative charge maximum stabilization Carboxylate ions O C R – O –C R O O

35. Dr. Wolf's CHM 201 & 202 19-35 RCOCR' OO RCCl O RCOR' O RCNR' 2 O RCO – O least stabilized C=O most stabilized C=O RCSR' O

36. Dr. Wolf's CHM 201 & 202 19-36 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.

37. Dr. Wolf's CHM 201 & 202 19-37 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).

38. Dr. Wolf's CHM 201 & 202 19-38 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

39. Dr. Wolf's CHM 201 & 202 19-39 General Mechanism for Nucleophilic Acyl Substitution

40. Dr. Wolf's CHM 201 & 202 19-40 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).

41. Dr. Wolf's CHM 201 & 202 19-41 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.

42. Dr. Wolf's CHM 201 & 202 19-42 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

43. Dr. Wolf's CHM 201 & 202 19-43 General Mechanism for Nucleophilic Acyl Substitution second stage is restoration of C=O by elimination O C R X HNu C R OH X Nu O C R Nu -HX complicating features of each stage involve acid-base chemistry

44. Dr. Wolf's CHM 201 & 202 19-44 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.

45. Dr. Wolf's CHM 201 & 202 19-45 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.

46. Dr. Wolf's CHM 201 & 202 19-46 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 + ) O C R X Nu – Conjugate base of tetrahedral intermediate (TI – )

47. Dr. Wolf's CHM 201 & 202 19-47 Dissociation of TI—H + C R O X Nu H H + + B—H + C O RNu +X H B

48. Dr. Wolf's CHM 201 & 202 19-48 Dissociation of TI B C R O X Nu H + B—H + C O RNu +X –

49. Dr. Wolf's CHM 201 & 202 19-49 Dissociation of TI – C O RNu +X – C R O X Nu –

50. Dr. Wolf's CHM 201 & 202 19-50 Nucleophilic Substitution in Acyl Chlorides

51. Dr. Wolf's CHM 201 & 202 19-51 Preparation of Acyl Chlorides from carboxylic acids and thionyl chloride (Section 12.7) (CH 3 ) 2 CHCOH O SOCl 2 heat (CH 3 ) 2 CHCCl O+ SO 2 + HCl (90%)

52. Dr. Wolf's CHM 201 & 202 19-52 RCOCR'OO RCCl O RCOR'O RCNR' 2 O RCO – O Reactions of Acyl Chlorides

53. Dr. Wolf's CHM 201 & 202 19-53 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

54. Dr. Wolf's CHM 201 & 202 19-54 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%)

55. Dr. Wolf's CHM 201 & 202 19-55 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

56. Dr. Wolf's CHM 201 & 202 19-56 Example C 6 H 5 CCl O+ (CH 3 ) 3 COH pyridine (80%) C 6 H 5 COC(CH 3 ) 3 O

57. Dr. Wolf's CHM 201 & 202 19-57 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

58. Dr. Wolf's CHM 201 & 202 19-58 Example C 6 H 5 CCl O+ NaOH (87-91%) H2OH2OH2OH2O HNHNHNHN C6H5CNC6H5CNC6H5CNC6H5CNO

59. Dr. Wolf's CHM 201 & 202 19-59 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

60. Dr. Wolf's CHM 201 & 202 19-60 RCCl O Reactions of Acyl Chlorides + RCOH O+ HCl Acyl chlorides react with water to give carboxylic acids (carboxylate ion in base): H2OH2OH2OH2O via: C R O Cl OHOHOHOHH

61. Dr. Wolf's CHM 201 & 202 19-61 Example C 6 H 5 CH 2 CCl O+ H2OH2OH2OH2O C 6 H 5 CH 2 COH O+ HCl

62. Dr. Wolf's CHM 201 & 202 19-62 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

63. Dr. Wolf's CHM 201 & 202 19-63 Nucleophilic Acyl Substitution in Carboxylic Acid Anhydrides Anhydrides can be prepared from acyl chlorides as described in Table 20.1

64. Dr. Wolf's CHM 201 & 202 19-64 Some anhydrides are industrial chemicals CH 3 COCCH 3 OO Acetic anhydride OO OOO O Phthalic anhydride Maleic anhydride

65. Dr. Wolf's CHM 201 & 202 19-65 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

66. Dr. Wolf's CHM 201 & 202 19-66 RCOCR'OO RCOR'O RCNR' 2 O RCO – O Reactions of Anhydrides

67. Dr. Wolf's CHM 201 & 202 19-67 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

68. Dr. Wolf's CHM 201 & 202 19-68 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

69. Dr. Wolf's CHM 201 & 202 19-69 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

70. Dr. Wolf's CHM 201 & 202 19-70 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

71. Dr. Wolf's CHM 201 & 202 19-71 Example (98%) + CH 3 COCCH 3 OO H2NH2NH2NH2N CH(CH 3 ) 2 O CH 3 CNH CH(CH 3 ) 2

72. Dr. Wolf's CHM 201 & 202 19-72 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

73. Dr. Wolf's CHM 201 & 202 19-73 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

74. Dr. Wolf's CHM 201 & 202 19-74 Example + H2OH2OH2OH2OOO O COHOCOH O

75. Dr. Wolf's CHM 201 & 202 19-75 Sources of Esters

76. Dr. Wolf's CHM 201 & 202 19-76 CH 3 COCH 2 CH 2 CH(CH 3 ) 2 O Esters are very common natural products 3-methylbutyl acetate also called "isopentyl acetate" and "isoamyl acetate” contributes to characteristic odor of bananas

77. Dr. Wolf's CHM 201 & 202 19-77 Esters of Glycerol R, R', and R" can be the same or different called "triacylglycerols," "glyceryl triesters," or "triglycerides" fats and oils are mixtures of glyceryl triesters RCOCH CH 2 OCR' O CH 2 OCR" OO

78. Dr. Wolf's CHM 201 & 202 19-78 Esters of Glycerol CH 3 (CH 2 ) 16 COCH CH 2 OC(CH 2 ) 16 CH 3 O OO Tristearin: found in many animal and vegetable fats

79. Dr. Wolf's CHM 201 & 202 19-79 Cyclic Esters (Lactones) (Z)-5-Tetradecen-4-olide (sex pheromone of female Japanese beetle) OO H H CH 2 (CH 2 ) 6 CH 3

80. Dr. Wolf's CHM 201 & 202 19-80 Fischer esterification (Chapter 15) from acyl chlorides (Chapters 15 and 19) from carboxylic acid anhydrides (Chapters 15 and 19) Preparation of Esters

81. Dr. Wolf's CHM 201 & 202 19-81 Physical Properties of Esters

82. Dr. Wolf's CHM 201 & 202 19-82 Boiling Points Esters have higher boiling points than alkanes because they are more polar. Esters cannot form hydrogen bonds to other ester molecules, so have lower boiling points than alcohols. CH 3 CHCH 2 CH 3 CH 3 CH 3 COCH 3 O CH 3 CHCH 2 CH 3 OH28°C 57°C 99°C boiling point

83. Dr. Wolf's CHM 201 & 202 19-83 Solubility in Water Esters can form hydrogen bonds to water, so low molecular weight esters have significant solubility in water. Solubility decreases with increasing number of carbons. CH 3 CHCH 2 CH 3 CH 3 CH 3 COCH 3 O CH 3 CHCH 2 CH 3 OH~0 33 12.5 Solubility (g/100 g)

84. Dr. Wolf's CHM 201 & 202 19-84 Reactions of Esters: A Review and a Preview

85. Dr. Wolf's CHM 201 & 202 19-85 with Grignard reagents (Chapters 14 & 19) reduction with LiAlH 4 (Chapters 15 & 19) with ammonia and amines (Chapter 19) hydrolysis (Chapter 19) Reactions of Esters

86. Dr. Wolf's CHM 201 & 202 19-86 Acid-Catalyzed Ester Hydrolysis

87. Dr. Wolf's CHM 201 & 202 19-87 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+ is the reverse of Fischer esterification

88. Dr. Wolf's CHM 201 & 202 19-88 Example HCl, heat + H2OH2OH2OH2OO CHCOCH 2 CH 3 Cl + CH 3 CH 2 OH OCHCOH Cl (80-82%)

89. Dr. Wolf's CHM 201 & 202 19-89 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

90. Dr. Wolf's CHM 201 & 202 19-90 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

91. Dr. Wolf's CHM 201 & 202 19-91 Second stage: cleavage of tetrahedral intermediate RCOHOH OR' + R'OH H+H+H+H+ RCOHO

92. Dr. Wolf's CHM 201 & 202 19-92 Mechanism of formation of tetrahedral intermediate

93. Dr. Wolf's CHM 201 & 202 19-93 Step 1 RC O OR' O + HHH RC O OR' + H O H H

94. Dr. Wolf's CHM 201 & 202 19-94 Step 1 RC O OR' + H carbonyl oxygen is protonated because cation produced is stabilized by electron delocalization (resonance) RC O OR' + H

95. Dr. Wolf's CHM 201 & 202 19-95 Step 2 O H H RC O OR' + H RC OH OR' O + H H

96. Dr. Wolf's CHM 201 & 202 19-96 Step 3 O HH RC OH OR' O H H + O H H H + RC OH OR' O H

97. Dr. Wolf's CHM 201 & 202 19-97 Cleavage of tetrahedral intermediate

98. Dr. Wolf's CHM 201 & 202 19-98 Step 4 O HH H + RC OH O OH R' RC OH O OH R' H + O H H

99. Dr. Wolf's CHM 201 & 202 19-99 Step 5 RC OH O OH R' H + O R' H + RC OH OH +

100. Dr. Wolf's CHM 201 & 202 19-100 Step 5 RC OHOH + RC OH OH +

101. Dr. Wolf's CHM 201 & 202 19-101 Step 6 RC OOH + H O H H + O H HH RC O OH

102. Dr. Wolf's CHM 201 & 202 19-102 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

103. Dr. Wolf's CHM 201 & 202 19-103 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 its 18 O label. This observation is consistent with a tetrahedral intermediate. H+H+H+H+

104. Dr. Wolf's CHM 201 & 202 19-104 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+

105. Dr. Wolf's CHM 201 & 202 19-105 Ester Hydrolysis in Base: Saponification

106. Dr. Wolf's CHM 201 & 202 19-106 is called saponification is irreversible, because of strong stabilization 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 –

107. Dr. Wolf's CHM 201 & 202 19-107 Example water-methanol, heat (95-97%) CH 2 OCCH 3 CH 3 O+ NaOH CH 2 OH CH 3 O CH 3 CONa +

108. Dr. Wolf's CHM 201 & 202 19-108 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

109. Dr. Wolf's CHM 201 & 202 19-109 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

110. Dr. Wolf's CHM 201 & 202 19-110 Which bond is broken when esters are hydrolyzed in base? RCO O + R' – OHOHOHOH 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.

111. Dr. Wolf's CHM 201 & 202 19-111 Which bond is broken when esters are hydrolyzed in base? + –OH RC O OR'OR'OR'OR' + OR' – A second possibility is nucleophilic acyl substitution. RC O OH

112. Dr. Wolf's CHM 201 & 202 19-112 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 +

113. Dr. Wolf's CHM 201 & 202 19-113 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

114. Dr. Wolf's CHM 201 & 202 19-114 Does it proceed via a tetrahedral intermediate? + –OH RC O OR'OR'OR'OR' + OR' – Does nucleophilic acyl substitution proceed in a single step, or is a tetrahedral intermediate involved? RC O OH

115. Dr. Wolf's CHM 201 & 202 19-115 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 its 18 O label. This observation is consistent with a tetrahedral intermediate. HO –

116. Dr. Wolf's CHM 201 & 202 19-116 18 O Labeling Studies C OHOHOHOHOH OCH 2 CH 3 + H2OH2OH2OH2O COCH 2 CH 3 O HO – COCH 2 CH 3 O+ H2OH2OH2OH2O HO –

117. Dr. Wolf's CHM 201 & 202 19-117 Involves two stages: 1)formation of tetrahedral intermediate 2)dissociation of tetrahedral intermediate Mechanism of Ester Hydrolysis in Base

118. Dr. Wolf's CHM 201 & 202 19-118 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 –

119. Dr. Wolf's CHM 201 & 202 19-119 Second stage: cleavage of tetrahedral intermediate RCOHOH OR' + R'OH RCOHO HO –

120. Dr. Wolf's CHM 201 & 202 19-120 Mechanism of formation of tetrahedral intermediate

121. Dr. Wolf's CHM 201 & 202 19-121 Step 1 RC O OR' RC O OR' O H – O H –

122. Dr. Wolf's CHM 201 & 202 19-122 Step 2 RC O OR' O H – HO H RC O OR' O H H – O H

123. Dr. Wolf's CHM 201 & 202 19-123 Dissociation of tetrahedral intermediate

124. Dr. Wolf's CHM 201 & 202 19-124 Step 3 RC O OR' O H H – O H HO H OR' – RC O O H

125. Dr. Wolf's CHM 201 & 202 19-125 Step 4 OR' – RC O O H HO – RC O O – H OR' H2OH2OH2OH2O

126. Dr. Wolf's CHM 201 & 202 19-126 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

127. Dr. Wolf's CHM 201 & 202 19-127 Reactions of Esters with Ammonia and Amines

128. Dr. Wolf's CHM 201 & 202 19-128 RCOR'O RCNR' 2 O RCO – O Reactions of Esters

129. Dr. Wolf's CHM 201 & 202 19-129 Reactions of Esters + 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

130. Dr. Wolf's CHM 201 & 202 19-130 Example (75%) + CCNH 2 CH 3 O H2CH2CH2CH2C CH 3 OH CCOCH 3 CH 3 O H2CH2CH2CH2C + NH3NH3NH3NH3 H2OH2OH2OH2O

131. Dr. Wolf's CHM 201 & 202 19-131 Example (61%) + FCH 2 COCH 2 CH 3 O NH2NH2NH2NH2 + CH 3 CH 2 OH FCH 2 CNH Oheat

132. Dr. Wolf's CHM 201 & 202 19-132 Preparation of Tertiary Alcohols From Esters and Grignard Reagents

133. Dr. Wolf's CHM 201 & 202 Grignard reagents react with esters RMgX C O – MgX + –––– ++++ R C O diethyl ether OCH 3 R' R' but species formed is unstable and dissociates under the reaction conditions to form a ketone Dr. Wolf's CHM 201 & 202 19-133

134. Dr. Wolf's CHM 201 & 202 Grignard reagents react with esters RMgX C O – MgX + –––– ++++ R C O diethyl ether OCH 3 R' R' –CH 3 OMgX C ORR' this ketone then goes on to react with a second mole of the Grignard reagent to give a tertiary alcohol Dr. Wolf's CHM 201 & 202 19-134

135. Dr. Wolf's CHM 201 & 202 ExampleExample 2 CH 3 MgBr + (CH 3 ) 2 CHCOCH 3 O 1. diethyl ether 2. H 3 O + (CH 3 ) 2 CHCCH 3 OH CH 3 (73%) Two of the groups attached to the tertiary carbon come from the Grignard reagent Dr. Wolf's CHM 201 & 202 19-135

136. Dr. Wolf's CHM 201 & 202 19-136 Reactions of Esters with Lithium Aluminum Hydride

137. Dr. Wolf's CHM 201 & 202 Lithium aluminum hydride preferred for laboratory reductions Sodium borohydride reduction is too slow to be useful Catalytic hydrogenolysis used in industry but conditions difficult or dangerous to duplicate in the laboratory (special catalyst, high temperature, high pressure Reduction of Esters Gives Primary Alcohols Dr. Wolf's CHM 201 & 202 19-137

138. Dr. Wolf's CHM 201 & 202 Example: Reduction of an Ester 1. LiAlH 4 diethyl ether 2. H 2 O (90%)O COCH 2 CH 3 CH 3 CH 2 OH CH 2 OH + Dr. Wolf's CHM 201 & 202 19-138

139. Dr. Wolf's CHM 201 & 202 19-139 Amides

140. Dr. Wolf's CHM 201 & 202 19-140 Physical Properties of Amides Amides are less reactive toward nucleophilic acyl substitution than other acid derivatives.

141. Dr. Wolf's CHM 201 & 202 19-141 Physical Properties of Amides Amides are capable of hydrogen bonding.

142. Dr. Wolf's CHM 201 & 202 19-142 Physical Properties of Amides Amides are less acidic than carboxylic acids. Nitrogen is less electronegative than oxygen.

143. Dr. Wolf's CHM 201 & 202 19-143 acyl chlorides anhydridesesters Preparation of Amides Amides are prepared from amines by acylation with:

144. Dr. Wolf's CHM 201 & 202 19-144 Preparation of Amides Amines do not react with carboxylic acids to give amides. The reaction that occurs is proton-transfer (acid-base). RCOHO+ R'NH 2 RCOO+ R'NH 3 + – If no heat-sensitive groups are present, the resulting ammonium carboxylate salts can be converted to amides by heating.

145. Dr. Wolf's CHM 201 & 202 19-145 Preparation of Amides Amines do not react with carboxylic acids to give amides. The reaction that occurs is proton-transfer (acid-base). RCOHO+ R'NH 2 RCOO+ R'NH 3 + – heat RCNHR' O+ H2OH2OH2OH2O

146. Dr. Wolf's CHM 201 & 202 19-146 Example COHO+ H2NH2NH2NH2N 225°C + H2OH2OH2OH2O (80-84%) CNHCNHCNHCNHO

147. Dr. Wolf's CHM 201 & 202 19-147 Hydrolysis of Amides

148. Dr. Wolf's CHM 201 & 202 19-148 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 + +

149. Dr. Wolf's CHM 201 & 202 19-149 Hydrolysis of Amides In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. RCNHR' O+ R'NH 2 – RCOOHO + –

150. Dr. Wolf's CHM 201 & 202 19-150 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 –

151. Dr. Wolf's CHM 201 & 202 19-151 Example: Basic Hydrolysis (95%) CH 3 COK OKOH H 2 O heat + CH 3 CNH OBr NH2NH2NH2NH2Br

152. Dr. Wolf's CHM 201 & 202 19-152 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

153. Dr. Wolf's CHM 201 & 202 19-153 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

154. Dr. Wolf's CHM 201 & 202 19-154 Second stage: cleavage of tetrahedral intermediate + H+H+H+H+ RCOHO RCOHOH NH2NH2NH2NH2 NH4NH4NH4NH4+

155. Dr. Wolf's CHM 201 & 202 19-155 Mechanism of formation of tetrahedral intermediate

156. Dr. Wolf's CHM 201 & 202 19-156 Step 1 O + HHH RC O NH2NH2NH2NH2 + H O H H RC O NH2NH2NH2NH2

157. Dr. Wolf's CHM 201 & 202 19-157 Step 1 carbonyl oxygen is protonated because cation produced is stabilized by electron delocalization (resonance) RC O NH2NH2NH2NH2 + H RC O NH2NH2NH2NH2 + H

158. Dr. Wolf's CHM 201 & 202 19-158 Step 2 RC OH NH2NH2NH2NH2 O + H H O HH RC O NH2NH2NH2NH2 + H

159. Dr. Wolf's CHM 201 & 202 19-159 Step 3 O HH O H H H + NH2NH2NH2NH2 RC OH O H RC OH NH2NH2NH2NH2 O + H H

160. Dr. Wolf's CHM 201 & 202 19-160 Cleavage of tetrahedral intermediate

161. Dr. Wolf's CHM 201 & 202 19-161 Step 4 O HH H + H2NH2NH2NH2N RC OH O H O H H RC OH H2NH2NH2NH2N OH H +

162. Dr. Wolf's CHM 201 & 202 19-162 Step 5 RC OH H2NH2NH2NH2N OH H + + RC OH OH + NH3NH3NH3NH3

163. Dr. Wolf's CHM 201 & 202 19-163 Step 6 + RC OH OH + RC OH H2NH2NH2NH2N OH H + NH3NH3NH3NH3 H3OH3OH3OH3O+ NH4NH4NH4NH4 +

164. Dr. Wolf's CHM 201 & 202 19-164 Step 6 RC OHOH + RC OH OH +

165. Dr. Wolf's CHM 201 & 202 19-165 Step 6 O H H RC O OH +H + O H HH RC O OH

166. Dr. Wolf's CHM 201 & 202 19-166 Involves two stages: 1)formation of tetrahedral intermediate 2)dissociation of tetrahedral intermediate Mechanism of Amide Hydrolysis in Base

167. Dr. Wolf's CHM 201 & 202 19-167 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 –

168. Dr. Wolf's CHM 201 & 202 19-168 Second stage: cleavage of tetrahedral intermediate + RCOO RCOHOH NH2NH2NH2NH2 NH3NH3NH3NH3 – HO –

169. Dr. Wolf's CHM 201 & 202 19-169 Mechanism of formation of tetrahedral intermediate

170. Dr. Wolf's CHM 201 & 202 19-170 Step 1 RC O NH2NH2NH2NH2 O H – O H – RC O NH2NH2NH2NH2

171. Dr. Wolf's CHM 201 & 202 19-171 Step 2 HO H RC O NH2NH2NH2NH2 O H – RC O NH2NH2NH2NH2 O H H – O H

172. Dr. Wolf's CHM 201 & 202 19-172 Dissociation of tetrahedral intermediate

173. Dr. Wolf's CHM 201 & 202 19-173 Step 3 H2NH2NH2NH2N RC OH O H O HH RC OH H2NH2NH2NH2N OH H + O H –

174. Dr. Wolf's CHM 201 & 202 19-174 Step 4 RC O H3NH3NH3NH3N OH + H – O H HO H NH3NH3NH3NH3 RC O O H

175. Dr. Wolf's CHM 201 & 202 19-175 Step 5 RC O O H HO – RC O O – NH3NH3NH3NH3

176. Dr. Wolf's CHM 201 & 202 19-176 Lactams

177. Dr. Wolf's CHM 201 & 202 19-177 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.

178. Dr. Wolf's CHM 201 & 202 19-178 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

179. Dr. Wolf's CHM 201 & 202 19-179 Preparation of Nitriles

180. Dr. Wolf's CHM 201 & 202 19-180 nucleophilic substitution by cyanide on alkyl halides cyanohydrin formation dehydration of amides Preparation of Nitriles Nitriles are prepared by:

181. Dr. Wolf's CHM 201 & 202 19-181 Example (95%) CH 3 (CH 2 ) 8 CH 2 Cl KCN ethanol- water CH 3 (CH 2 ) 8 CH 2 C N SN2SN2SN2SN2

182. Dr. Wolf's CHM 201 & 202 19-182 Example (75%) KCN H+H+H+H+ CH 3 CH 2 CCH 2 CH 3 O OHOHOHOHC N

183. Dr. Wolf's CHM 201 & 202 19-183 uses the reagent P 4 O 10 (often written as P 2 O 5 ) Preparation of Nitriles By dehydration of amides (CH 3 ) 2 CHCNH 2 O P 4 O 10 200°C (CH 3 ) 2 CHC N(69-86%)

184. Dr. Wolf's CHM 201 & 202 19-184 Hydrolysis of Nitriles

185. Dr. Wolf's CHM 201 & 202 19-185 Hydrolysis of Nitriles Hydrolysis of nitriles resembles the hydrolysis of amides. The reaction is irreversible. Ammonia is produced and is protonated to ammonium ion in acid solution. + NH4NH4NH4NH4 + RCOHO RCN + 2H 2 O H + +

186. Dr. Wolf's CHM 201 & 202 19-186 Hydrolysis of Nitriles In basic solution the carboxylic acid product is deprotonated to give a carboxylate ion. + – RCOOHO + – NH3NH3NH3NH3 RCN + H2OH2OH2OH2O

187. Dr. Wolf's CHM 201 & 202 19-187 Example: Acid Hydrolysis (92-95%)O H2OH2OH2OH2O H 2 SO 4 heat CH 2 CN NO 2 CH 2 COH NO 2

188. Dr. Wolf's CHM 201 & 202 19-188 Example: Basic Hydrolysis (80%) CH 3 (CH 2 ) 9 COH O CH 3 (CH 2 ) 9 CN 1. KOH, H 2 O, heat 2. H +

189. Dr. Wolf's CHM 201 & 202 19-189 Hydrolysis of nitriles proceeds via the corresponding amide. We already know the mechanism of amide hydrolysis. Therefore, all we need to do is to see how amides are formed from nitriles under the conditions of hydrolysis. Mechanism of Hydrolysis of Nitriles RCN H2OH2OH2OH2O RCNH 2 O H2OH2OH2OH2O RCOHO

190. Dr. Wolf's CHM 201 & 202 19-190 The mechanism of amide formation is analogous to that of conversion of alkynes to ketones. It begins with the addition of water across the carbon-nitrogen triple bond. The product of this addition is the nitrogen analog of an enol. It is transformed to an amide under the reaction conditions. Mechanism of Hydrolysis of Nitriles RCN H2OH2OH2OH2O RCNH 2 ORC NHNHNHNH OH

191. Dr. Wolf's CHM 201 & 202 19-191 Step 1 O H – RCN RC O N – H

192. Dr. Wolf's CHM 201 & 202 19-192 Step 2 RC O N – H O HH – O H RC O N HH

193. Dr. Wolf's CHM 201 & 202 19-193 Step 3 – O H RC O N HH – RC O N H O HH

194. Dr. Wolf's CHM 201 & 202 19-194 Step 4 – RC O N H O H H NRC O H H – O H

195. Dr. Wolf's CHM 201 & 202 19-195 Addition of Grignard Reagents to Nitriles

196. Dr. Wolf's CHM 201 & 202 19-196 Grignard reagents add to carbon-nitrogen triple bonds in the same way that they add to carbon- oxygen double bonds. The product of the reaction is an imine. Addition of Grignard Reagents to Nitriles RCNR'MgX RCR' NMgX H2OH2OH2OH2O RCR' NHNHNHNH diethyl ether

197. Dr. Wolf's CHM 201 & 202 19-197 Addition of Grignard Reagents to Nitriles RCNR'MgX RCR' NMgX H2OH2OH2OH2O RCR' NHNHNHNH diethyl ether RCR'O H3O+H3O+H3O+H3O+ Imines are readily hydrolyzed to ketones. Therefore, the reaction of Grignard reagents with nitriles can be used as a synthesis of ketones.

198. Dr. Wolf's CHM 201 & 202 19-198 Example (79%) F3CF3CF3CF3C C N + CH 3 MgI 1. diethyl ether 2. H 3 O +, heat F3CF3CF3CF3C CCH 3 O

199. Dr. Wolf's CHM 201 & 202 19-199 Spectroscopic Analysis of Carboxylic Acid Derivatives

200. Dr. Wolf's CHM 201 & 202 19-200 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 C=O stretching frequency

201. Dr. Wolf's CHM 201 & 202 19-201 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 C=O stretching frequency

202. Dr. Wolf's CHM 201 & 202 19-202 Nitriles are readily identified by absorption due to carbon-nitrogen triple bond stretching in the 2210- 2260 cm -1 region. Infrared Spectroscopy

203. Dr. Wolf's CHM 201 & 202 19-203 1 H NMR readily distinguishes between isomeric esters of the type: 1 H NMR RCOR' Oand R'COR O O C H is less shielded than OC C H

204. Dr. Wolf's CHM 201 & 202 19-204 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.

205. Dr. Wolf's CHM 201 & 202 19-205 Chemical shift ( , ppm) Figure 20.9 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

206. Dr. Wolf's CHM 201 & 202 19-206 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.

207. Dr. Wolf's CHM 201 & 202 19-207 UV-VIS CH 3 CCl O 235 nm CH 3 COCH 3 O 225 nm CH 3 COCCH 3 OO 207 nm CH 3 CNH 2 O 214 nm n  * absorption: max

208. Dr. Wolf's CHM 201 & 202 19-208 Most carboxylic acid derivatives give a prominent peak for an acylium ion derived by the fragmentation shown. Mass Spectrometry + RCX O RCX +O RC O+ X

209. Dr. Wolf's CHM 201 & 202 19-209 Amides, however, cleave in the direction that gives a nitrogen-stabilized cation. Mass Spectrometry +R RCNR' 2 O + RCNR' 2 O +O C NR' 2

210. Dr. Wolf's CHM 201 & 202 19-210 End of Chapter 19