1. Chapter 19 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. 3

2. 19.1 Nomenclature of Carboxylic Acid Derivatives3

3. Naming Acyl Halides RC O X
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. 6

4. or but-3-enoyl chloride
Acyl Halides
CH3CCl O
Acetyl chloride O
H2C
CHCH2CCl
3-butenoyl chloride
or but-3-enoyl chloride O
CBr F
p-fluorobenzoyl bromide
or 4-fluorobenzoyl bromide 6

5. Naming Acid AnhydridesO O
RC-O-CR'
When two acyl groups are attached to the same O the structure is an anhydride.
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. 6

6. Benzoic heptanoic anhydride
Acid Anhydrides
CH3COCCH3 O
Acetic anhydride
C6H5COCC6H5 O
Benzoic anhydride
C6H5COC(CH2)5CH3 O
Benzoic heptanoic anhydride 6

7. Name as alkyl alkanoates.
Naming Esters
RC-OR' O
Name as alkyl alkanoates.
Cite the alkyl group attached to the oxygen first (R' above, derived from the alcohol in synthesis).
Name the acyl group second; substitute the suffix -ate for the -ic ending of the corresponding acid. 6

8. 2-chloroethyl benzoate
Esters
CH3COCH2CH3 O
Ethyl acetate O
CH3CH2COCH3
Methyl propanoate
COCH2CH2Cl O
2-chloroethyl benzoate 6

9. Naming Unsubstituted Amides
RC-NH2 O
Identify the carboxylic acid corresponding to the acyl group.
Replace the -ic acid or -oic acid ending with -amide. 6

10. Unsubstituted Amides O CH3CNH2 Acetamide O (CH3)2CHCH2CNH2
3-Methylbutanamide
CNH2 O
Benzamide 6

11. Naming N-substituted Amides
RCNHR' O
RCNR'2 O
and
Name the amide as before.
Precede the name of the amide with the name of the appropriate group or groups substituted on the N.
Precede the names of these groups with the letter N- standing for nitrogen and used as a locant. 6

12. N-Isopropyl-N-methylbutanamide
N-Substituted Amides
CH3CNHCH3 O
N-Methylacetamide
CN(CH2CH3)2 O
N,N-Diethylbenzamide O
CH3CH2CH2CNCH(CH3)2
CH3
N-Isopropyl-N-methylbutanamide 6

13. or: Name as an alkyl cyanide (functional class name).
Naming Nitriles RC N
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 with –onitrile.
or: Name as an alkyl cyanide (functional class name). 6

14. Ethanenitrile or: Acetonitrile or: Methyl cyanide CH3C N
Nitriles
Ethanenitrile or: Acetonitrile or: Methyl cyanide
CH3C N
C6H5C N
Benzonitrile N C
CH3CHCH3
2-Methylpropanenitrile or: Isopropyl cyanide 6

15. 19.2 Structure of Carboxylic Acid Derivatives3

16. Structure and Reactivity of the C=O
The key to managing the information in this chapter is the same as always: structure determines properties.
Stability of the carbonyl group in a structure is a key factor in determining the reactivity of the carbonyl in nucleophilic acyl substitution. 6

17. Reactivity and Stability of the Acid Derivatives
CH3C O Cl
Least stabilized
Most reactive
CH3C O
OCCH3
CH3C O
OCH2CH3
CH3C O
NH2
Most stabilized
Least reactive 6

18. Electron Delocalization and the Carbonyl Group
The main structural feature that distinguishes these acid derivatives from other compounds is the interaction of the substituent (X) with the carbonyl group. In resonance terms: – RC O X ••
• • + RC O X ••
• • RC O X
• • •• + –
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. 6

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

20. Orbital Overlap in Carboxylic Acid Derivatives
lone pair orbital of substituent 7

21. Combined Orbital Overlaps in these Derivatives
Electron pair of substituent delocalized into carbonyl orbital. 7

22. least stabilized C=O, most reactive C=O
RCCl O
RCOCR' O
RCOR' O
RCNR'2 O
RCO– O
most stabilized C=O, least reactive C=O 4

23. Acyl chlorides have the least stabilized carbonyl group. •• C O R Cl
• • •• – O
• •
• • R C + Cl
• • ••
Acyl chlorides have the least stabilized carbonyl group.
Delocalization of lone pair of Cl into C=O group is not efficient because C—Cl bond is too long. 11

24. Acid Anhydrides C R O O + – C R•• C R O
• • O ••
• • + – C R
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. The resonance structures indicate that neither C=O gets the full support of the electron pair. 11

25. Here the single C=O receives the full effect of the electron pair.
Esters O ••
• • C R
OR' ••
• • + – C R O
OR'
Lone pair donation from oxygen stabilizes the carbonyl group of an ester.
Stabilization greater than comparable stabilization of an anhydride or thioester.
Here the single C=O receives the full effect of the electron pair. 11

26. Amides O ••
• • C R
NR'2 ••
• • + – C R O
NR'2
~60% contribution ~40% contribution
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. 11

27. Activation energy for rotation about C—N bond is 75-85 kJ/mol.
Amides O ••
• • C R
NR'2 ••
• • + – C R O
NR'2
Amide resonance imparts significant double-bond character to C—N bond (so, N is not basic).
Activation energy for rotation about C—N bond is kJ/mol.
C—N bond distance is 135 pm in amides versus normal single-bond distance of 147 pm in amines. 11

28. This affords maximum stabilization of C=O.
Carboxylate Ions •• O
• • C R – ••
• • – C R O
The anion has very efficient electron delocalization and dispersal of negative charge.
This affords maximum stabilization of C=O. 11

29. 19.2 Reactivity of Carboxylic Acid Derivatives3

30. Reactivity is Related to Structure
Relative rate of hydrolysis
1011
107
< 10-2
1.0
Stabilization
RCCl O
very small
RCOCR' O
The more stabilized the carbonyl group, the less reactive it is.
small
RCOR' O
moderate
RCNR'2 O
large
1 3

31. Nucleophilic Acyl Substitution
The general reaction: O ••
• • C R X O ••
• • C R Y
+ HY
+ HX
This reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive). 11

32. least stabilized C=O, most reactive C=O
RCCl O
RCOCR' O
A carboxylic acid derivative can be converted by nucleophilic acyl substitution to any other derivative that lies below it in this table.
RCOR' O
RCNR'2 O
RCO– O
most stabilized C=O, least reactive C=O 4

33. 19.3 General Mechanism for Nucleophilic Acyl Substitution

34. Nucleophilic Acyl Substitution••
• • C R X O ••
• • C R Nu
+ HNu
+ HX
Reaction is feasible when a less stabilized carbonyl is converted to a more stabilized one (more reactive to less reactive).
The reaction mechanism can be viewed as two stages. 11

35. General Mechanism for Nucleophilic Acyl Substitution
The first stage of mechanism (formation of a tetrahedral intermediate) is analogous to nucleophilic addition to the C=O of aldehydes and ketones. O ••
• • C R X
HNu OH Nu
-HX
Stage1
Stage 2
The second stage is restoration of C=O by elimination.
1 4

36. General Mechanism for Nucleophilic Acyl Substitution
Complicating features of each stage involve acid-base chemistry.
Acid-base chemistry in first stage is familiar in that it has to do with acid/base catalysis of nucleophilic addition to C=O.
Acid-base chemistry in second stage concerns the form in which the tetrahedral intermediate exists under the reaction conditions and how it dissociates under those conditions.
1 4

37. The Tetrahedral Intermediate (TI)
Forms of the Tetrahedral Intermediate (TI) C R O X Nu
• • H •• C R O X Nu
• • H •• + O
• • C R X Nu •• –
• •
neutral TI
• •
Conjugate acid form of the tetrahedral intermediate (TI+)
Conjugate base form of the tetrahedral intermediate (TI–)
1 4

38. +B—H Dissociation of TI—H+ B H O R C X H + Nu C O R Nu + + X H •• • •
1 4

39. +B—H Dissociation of TI C R O X Nu H B C O R Nu X – + + •• • • • • ••
1 4

40. Dissociation of TI– •• C R O X Nu
• • – C O R Nu
• • •• X
• • – +
1 4

41. 19.4 Nucleophilic Acyl Substitution in Acyl Chlorides3

42. Preparation of Acyl Chlorides
Acid chlorides are formed from carboxylic acids and thionyl chloride (Section 12.7).
(CH3)2CHCOH O
(CH3)2CHCCl O
SOCl2 +
SO2 +
HCl
heat
(90%)
1 7

43. Reactions of Acyl Chlorides
RCCl O
RCOCR' O
RCOR' O
RCNR'2 O
RCO– O 4

44. Reactions of Acyl Chlorides
Acyl chlorides react with carboxylic acids to give acid anhydrides:
RCCl O
R'COH O
RCOCR' O + +
HCl C R O Cl
OCR' H
via: 4

45. Example CH3(CH2)5CCl O CH3(CH2)5COH O + CH3(CH2)5COC(CH2)5CH3 O
(combines with the HCl produced).
pyridine
CH3(CH2)5COC(CH2)5CH3 O
(78-83%) 4

46. Reactions of Acyl Chlorides
Acyl chlorides react with alcohols to give esters:
RCCl O
RCOR' O +
HCl
R'OH + H O C
via: R
OR' Cl 4

47. Example
C6H5CCl O
C6H5COC(CH3)3 O
pyridine +
(CH3)3COH
(80%) 4

48. Reactions of Acyl Chlorides
Acyl chlorides react with ammonia and amines to give amides:
RCCl O
RCNR'2 O +
R'2NH
+ HO– +
H2O H +
Cl– O C
via: R
NR'2 Cl 4

49. Example O O + C6H5CCl C6H5CN HN (87-91%)
NaOH +
H2O
(87-91%)
Can use two moles of amine instead of NaOH to neutralize the HCl produced. 4

50. Reactions of Acyl Chlorides
Acyl chlorides react with water to give carboxylic acids (or in base to give carboxylate ions):
RCCl O
RCOH O +
H2O +
HCl C R O Cl OH H
via:
RCCl O
RCO– O +
2 HO– +
Cl– +
H2O 4

51. Example
C6H5CH2CCl O
C6H5CH2COH O +
H2O +
HCl 4

52. Relative rates of hydrolysis (25o C) 1,000 1
Reactivity
Acyl chlorides undergo nucleophilic substitution much faster than alkyl chlorides.
C6H5CCl O
C6H5CH2Cl
Relative rates of hydrolysis (25o C)
1,000 1 4

53. 19.5 Nucleophilic Acyl Substitution in Acid Anhydrides
Anhydrides can be prepared from acyl chlorides as described in Table 19.1. 3

54. Some Anhydrides are Industrial Chemicals
CH3COCCH3 O
Acetic anhydride
Phthalic anhydride
Maleic anhydride 4

55. From Dicarboxylic Acids
Cyclic anhydrides with 5- and 6-membered rings can be prepared by dehydration of dicarboxylic acids with heat:
COH O O H H C
tetrachloroethane
130°C
+ H2O C H
COH O
(89%) 4

56. Reactions of Acid Anhydrides
Carboxylic acid anhydrides react with alcohols to give esters: O O O O
RCOCR +
RCOR' +
R'OH
RCOH C R O
OCR
OR' H
Reaction can be carried out in presence of pyridine (a base) or it can be catalyzed by acids.
Normally, symmetrical anhydrides are used (both R groups the same).
via: 4

57. Example O O CH3COCCH3 + CH3CHCH2CH3 OH CH3COCHCH2CH3 O CH3 (60%) H2SO4

58. Reactions of Acid Anhydrides
Acid anhydrides react with ammonia and amines to give amides: O O O O +
RCOCR
2 R'2NH
RCNR'2 +
RCO– C R O
OCR
NR'2 H +
R'2NH2
via: 4

59. Example O O
H2N
CH(CH3)2
CH3COCCH3 + O
CH3CNH
CH(CH3)2
(98%) 4

60. Reactions of Acid Anhydrides
Acid anhydrides react with water to give carboxylic acids (or carboxylate ion in base):
RCOCR O O +
H2O
2 RCOH
RCOCR O O +
2 HO–
2 RCO– +
H2O 4

61. Example
RCOCR O O H+ +
H2O
2 RCOH C R O
OCR OH H
via: 4

62. Example
COH O O +
H2O 4

63. 19.6 Sources of Esters 3

64. Esters are Very Common Natural Products
CH3COCH2CH2CH2CH3 O
Contributes to characteristic pear odor.
butyl acetate O
Contributes to characteristic apple odor.
CH3(CH2)3COCH2CH2CH2 (CH3)2
isoamyl pentanoate 2

65. R, R', and R" can be the same or different.
Esters of Glycerol
RCOCH
CH2OCR' O
CH2OCR"
R, R', and R" can be the same or different.
Called "triacylglycerols," "glyceryl triesters," or "triglycerides“.
Fats and oils are mixtures of glyceryl triesters. 2

66. Tristearin: found in many animal and vegetable fats.
Esters of Glycerol
CH3(CH2)16COCH
CH2OC(CH2)16CH3 O
Tristearin: found in many
animal and vegetable fats. 2

67. Cyclic Esters (Lactones)H
CH2(CH2)6CH3
(Z)-5-Tetradecen-4-olide (sex pheromone of female Japanese beetle) 2

68. 1. Fischer esterification (Sections 15.8 and 18.14)
Preparation of Esters
1. Fischer esterification (Sections 15.8 and 18.14)
2. From acyl chlorides (Sections 15.8 and 19.4)
3. From acid anhydrides (Sections 15.8 and 19.5)
4. From carboxylic acids using CH2N2 (class notes)
5. Baeyer-Villiger oxidation of ketones (Descriptive Passage 17 in text; see below.) O O O O + +
CH3CCH3
CF3COOH
CH3COCH3
CF3COH 5

69. 19.7 Physical Properties of Esters3

70. 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.
Boiling point
CH3CHCH2CH3
CH3
28°C O
CH3COCH3
57°C
CH3CHCH2CH3 OH
99°C 12

71. Solubility decreases with increasing number of carbons. CH3CHCH2CH3
Solubility in Water
Solubility (g/100 g)
Esters can form hydrogen bonds to water, so low molecular weight esters have significant solubility in water.
Solubility decreases with increasing number of carbons.
CH3CHCH2CH3
CH3 ~0 O
CH3COCH3 33
CH3CHCH2CH3 OH
12.5 12

72. 19.8 Reactions of Esters: A Preview3

73. 1. Hydrolysis (Sections 19.9 and 19.10)
Reactions of Esters
1. Hydrolysis (Sections 19.9 and 19.10)
2. With ammonia and amines (Sections 19.11)
3. With Grignard reagents (Section 19.12)
4. Reduction with LiAlH4 (Section 19.13) 5

74. 19.9 Acid-Catalyzed Ester Hydrolysis3

75. Acid-Catalyzed Ester Hydrolysis
Is the reverse of Fischer esterification: O
RCOH O H+
RCOR' +
H2O +
R'OH
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. 5

76. Example O + H2O CHCOCH2CH3 Cl O + CH3CH2OH CHCOH Cl (80-82%) HCl, heat5

77. Mechanism of Acid-Catalyzed Ester Hydrolysis
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) 5

78. First Stage: Formation of Tetrahedral Intermediate
RCOR' +
H2O
Water adds to the carbonyl group of the ester.
This stage is analogous to the acid-catalyzed addition of water to a ketone. H+ RC OH
OR' 5

79. Second Stage: Cleavage of Tetrahedral IntermediateRC OH
OR'
The tetrahedral intermediate collapses and the carbonyl reforms losing R'OH.
This stage is favorable because of the excess water in the reaction. H+
RCOH O +
R'OH 5

80. Steps in the Mechanism of Formation of the Tetrahedral Intermediate
• • + H ••
Step 1 O
• • RC
protonation O R'
• • ••
• • O H •• + O H RC O R'
• • •• 8

81. •• RC O R'
• • + H
Step 1, cont.
Carbonyl oxygen is protonated because cation produced is stabilized by electron delocalization (resonance). •• + O H RC O R'
• • •• 8

82. Step 2 Step 3 RC OH OR' O + H + O H H O H O RC O R' RC OH OR' O + H RC
• • RC OH
OR' •• O + H •• + O H H
• • O H
• • O RC O R'
• • ••
deprotonation of HO+H
attack by water
• • RC OH
OR' •• O + H •• RC OH
OR'
• • O H O
• • H + 8

83. Steps in the Cleavage of the Tetrahedral Intermediate•• RC OH O
• • R'
Step 4 O
• • H +
protonation of R'OH + •• RC OH O
• • R' H H
• • O + 8

84. Step 5 OH OH RC + RC + O R' H + OH OH RC + RC O R' H +••
• • + + •• RC OH O
• • R' H
resonance stabilized cation
loss of R'OH RC OH •• + RC OH ••
• • + •• O R' H + 8

85. Step 6 H O + O H H O RC + OH O RC OH deprotonation •• •• •• •• •• ••8

86. Key Features of Mechanism
Protonation of carbonyl group activates carbonyl oxygen.
Nucleophilic addition of water to carbonyl group forms tetrahedral intermediate.
Elimination of alcohol from tetrahedral intermediate restores carbonyl group. 17

87. 18O Labeling Studies COCH2CH3 O + H2O COCH2CH3 O + H2O
Ethyl benzoate, labeled with 18O at the carbonyl oxygen, was subjected to acid-catalyzed hydrolysis.
Ethyl benzoate, recovered before the reaction had gone to completion, had lost its 18O label.
This observation is consistent with a tetrahedral intermediate. H+
COCH2CH3 O +
H2O 5

88. 18O Labeling Studies COCH2CH3 O + H2O C O H OH OCH2CH3 + H2O COCH2CH35

89. 19.10 Ester Hydrolysis in Base: Saponification3

90. Ester Hydrolysis in Aqueous Base
RCOR' O +
HO– O
RCO– +
R'OH
This reaction is called saponification.
It is not base catalyzed, base is a stoichiometric reactant.
This reaction is irreversible, because of strong stabilization of the carboxylate ion.
If the carboxylic acid is the desired product, saponification is followed by a separate acidification step (simply a pH adjustment). 5

91. Example CH2OCCH3 CH3 O + NaOH O CH3CONa CH2OH CH3 + (95-97%)
water, methanol, heat O
CH3CONa
CH2OH
CH3 +
(95-97%) 5

92. Example O H2C CCOCH3 CH3 O H2C CCOH + CH3OH CH3 (87%)
1. NaOH, H2O, heat
2. H2SO4
CCOH
CH3 O
H2C +
CH3OH
(87%) 5

93. Soap-Making O CH3(CH2)yCOCH CH2OC(CH2)xCH3 O CH2OC(CH2)zCH3
Basic hydrolysis of the glyceryl triesters (from fats and oils) gives glcerol plus salts of long-chain carboxylic acids.
These salts are soaps.
K2CO3, H2O, heat O O O
CH3(CH2)xCOK
CH3(CH2)yCOK
CH3(CH2)zCOK 2

94. Which Bond is Broken when Esters are Hydrolyzed in Base ?
Two possibilities are proposed. ••
RCO O + R' – OH
• • •• O
• • – •• ••
RCO +
R'OH
• • •• ••
The first possibility is an SN2 attack by hydroxide on the alkyl group of the ester. Carboxylate would be the leaving group.
This does not occur. 5

95. Which Bond is Broken when Esters are Hydrolyzed in Base ?+ •• – OH
• • RC
OR' O
The second possibility is nucleophilic acyl substitution. This pathway shows the correct mechanism. 5

96. 18O Labeling Gives the Answer
CH3CH2COCH2CH3
NaOH + O O
CH3CH2CONa +
CH3CH2OH
18O is retained in alcohol, not in the carboxylate; therefore, nucleophilic acyl substitution must occur. 5

97. Stereochemistry Gives the Same Answer
CH3C
Alcohol has same configuration at chirality center as ester; therefore, nucleophilic acyl substitution is the mechanism.
This can not occur by SN2.
KOH, H2O HO H
C6H5
CH3
CH3COK O + C 5

98. Does it Proceed via a Tetrahedral Intermediate ?•• RC O
OR'
• • RC O
• • •• OH •• – OH
• • ••
OR' –
• • + +
Does nucleophilic acyl substitution proceed in a single step, or is a tetrahedral intermediate involved ? 5

99. 18O Labeling Studies COCH2CH3 O + H2O COCH2CH3 O + H2O
Ethyl benzoate, labeled with 18O at the carbonyl oxygen, was subjected to hydrolysis in base.
Ethyl benzoate, recovered before the reaction had gone to completion, had lost its 18O label.
This observation is consistent with a tetrahedral intermediate.
HO–
COCH2CH3 O +
H2O 5

100. 18O Labeling Studies COCH2CH3 O + H2O C OH OCH2CH3 COCH2CH3 O + H2O5

101. Mechanism of Ester Hydrolysis in Base
Involves two stages:
1) Formation of tetrahedral intermediate (2 steps).
2) Dissociation of tetrahedral intermediate (2 steps). 5

102. First Stage: Formation of aTetrahedral Intermediate+
H2O
RCOR' O
Base adds to the carbonyl group of the ester.
This stage is analogous to the base attack of a ketone or aldehyde carbonyl.
HO– RC OH
OR' 5

103. Second stage: cleavage of the tetrahedral intermediateRC OH
OR'
The tetrahedral intermediate collapses and the carbonyl reforms losing R'OH.
This stage is favorable because of the stable carboxylate ion.
HO–
RCO– O +
R'OH 5

104. Steps in the Mechanism of Formation of the Tetrahedral Intermediate•• RC O
OR'
• •
Step 1 O
• • H •• –
attack by base RC O
OR' ••
• • H – 8

105. Step 2 H O RC O OR' H – RC O OR' H – O H + protonation tetrahedral
• • •• H O RC O
OR' ••
• • H –
protonation RC O
OR' ••
• • H
• • – •• O H
tetrahedral
intermediate + 8

106. Steps in the Dissociation of the Tetrahedral IntermediateRC O
OR' ••
• • H
Step 3
• • – •• O H
deprotonation
and loss of RO – RC
• • O •• H
• • •• H O + ••
OR'
• • – + 8

107. Step 4 RC
• • O •• –
Protonation of the alkoxide and formation of carboxylate •• H
OR' RC
• • O •• H
HO–
H2O ••
OR'
• • – 8

108. Key Features of Mechanism
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. 17

109. 19.11 Reactions of Esters with Ammonia and Amines3

110. Esters react with ammonia and amines to give amides:
Reactions of Esters
Esters react with ammonia and amines to give amides:
RCOR' O
RCNR'2 O +
R'2NH +
R'OH
via: C R O
OR'
NR'2 H 4

111. Example
CCOCH3
CH3 O
H2C +
NH3
CCNH2
CH3 O
H2C +
CH3OH
(75%) 5

112. Example +
FCH2COCH2CH3 O
NH2
heat +
CH3CH2OH
FCH2CNH O
(61%) 4

113. 19.12 Reactions of Esters with Grignard Reagents: Synthesis of Tertiary Alcohols3

114. Grignard reagents react with esters
OCH3 •• R'
diethyl ether + R C
OCH3 •• – C R
MgX + O
• • O ••
MgX
• • •• –
The magnesium salt formed is unstable and dissociates under the reaction conditions to form a ketone and further reaction occurs. 23

115. Grignard reagents react with esters
OCH3 •• R'
diethyl ether + R C
OCH3 •• – R
MgX C + O
• • O ••
MgX
• • •• –
–CH3OMgX
This ketone further reacts with a second mole of the Grignard reagent to give a tertiary alcohol. C O R R'
• • •• 23

116. Example (CH3)2CHCOCH3 O 2 CH3MgBr + OH (CH3)2CHCCH3 CH3 (73%)
1. diethyl ether
2. H3O+
Two of the groups attached to the tertiary carbon come from the Grignard reagent. OH
(CH3)2CHCCH3
CH3
(73%) 26

117. 19.13 Reactions of Esters with Lithium Aluminum Hydride

118. Reduction of Esters Gives Primary Alcohols
Lithium aluminum hydride is preferred for laboratory reductions of acid derivatives.
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). 25

119. Example: Reduction of an Ester
1. LiAlH4 diethyl ether
2. H2O
(90%) O
COCH2CH3
CH3CH2OH
CH2OH + 10

120. 19.14 Amides 3

121. Physical Properties of Amides
Amides are less reactive toward nucleophilic acyl substitution than other acid derivatives due to the resonance interactions shown below. 5

122. Physical Properties of Amides
Amides are capable of hydrogen bonding. 5

123. Physical Properties of Amides
Amides are less acidic than carboxylic acids (but are more acidic than amines due to resonance).
Nitrogen is less electronegative than oxygen. 5

124. Amides are prepared from amines by acylation with:
Preparation of Amides
Amides are prepared from amines by acylation with:
1. Acyl chlorides (Table 19.1)
2. Anhydrides (Table 19.2)
3. Esters (Table 19.4) 5

125. Preparation of Amides
Amines do not typically react with carboxylic acids to give amides. The reaction that occurs is proton-transfer (acid-base reaction) that yields a salt.
RCOH O
RCO O + – +
R'NH2 +
R'NH3 5

126. Preparation of Amides
If no heat-sensitive groups are present, the resulting ammonium carboxylate salt can be converted to an amide by heating to force the elimination of water.
RCOH O
RCO O + – +
R'NH2 +
R'NH3
extreme heat
RCNHR' O +
H2O 5

127. The salt forms first then heat drives off water.
Example
COH O
H2N +
225°C = a lot of energy
The salt forms first then heat drives off water.
CNH O +
H2O
(80-84%) 4

128. 19.15 Hydrolysis of Amides 3

129. Hydrolysis of amides is irreversible.
After hydrolysis in acid solution, the amine product is protonated to give an ammonium salt (which is not nucleophilic).
RCNHR' O
RCOH O + + +
H2O + H +
R'NH3 5

130. Hydrolysis of Amides
After hydrolysis in basic solution the carboxylic acid product is deprotonated to give a carboxylate ion (which has no leaving group facility).
RCNHR' O
RCO O – – + HO +
R'NH2 5

131. Example: Acid Hydrolysis
CH3CH2CHCNH2 O
CH3CH2CHCOH O
H2O
NH4 +
HSO4 – +
H2SO4 heat
(88-90%) 4

132. Example: Basic Hydrolysis
CH3CNH O Br
NH2 Br
CH3COK O
KOH +
H2O heat
(95%) 4

133. Mechanism of Acid-Catalyzed Amide Hydrolysis
Acid-catalyzed amide hydrolysis proceeds via the customary two stages:
1. Formation of tetrahedral intermediate
2. Dissociation of tetrahedral intermediate 5

134. First Stage: Formation of Tetrahedral Intermediate+
H2O
RCNH2 O
Water adds to the carbonyl group of the amide.
This stage is analogous to the acid-catalyzed addition of water to a ketone. H+ RC OH
NH2 5

135. Second Stage: Cleavage of Tetrahedral IntermediateRC OH
NH2
RCOH O H+
NH4 + +
The –NH2 is protonated, the carbonyl reforms and NH3 and a proton are released. 5

136. Steps in the Mechanism of Formation of the Tetrahedral Intermediate
• • + H RC O
NH2 ••
• •
Step 1
protonation RC O
NH2 ••
• • + H
• • O H + 8

137. RC O
NH2 ••
• • + H
Step 1, cont.
Carbonyl oxygen is protonated and the cation produced is resonance stabilized by electron delocalization. RC O
NH2 ••
• • + H 8

138. Step 2 Step 3 RC OH NH2 O + H RC O NH2 + H O H O H NH2 RC OH O H RC OH••
• • O + H RC O
NH2 ••
• • + H
• • O H
• • O H
attack by water
deprotonation
NH2 RC OH ••
• • O H RC OH
NH2 ••
• • O + H H + + H O
• • H 8

139. Steps in the Cleavage of the Tetrahedral IntermediateRC OH
H2N ••
• • H +
NH2 RC OH ••
• • O H O
• • H +
protonation
loss of NH3 RC OH
H2N ••
• • H + RC OH ••
• • +
• • O H + +
NH3
• • 8

140. RC OH + Step 6 RC OH + O H + O H RC O OH RC O OH + H +•• +
Step 6 RC OH ••
• • +
resonance stabilized O •• H + O H •• •• RC O •• OH
• • RC O OH •• + H +
deprotonation 8

141. Mechanism of Amide Hydrolysis in Base
Base hydrolysis Involves two stages:
1. Formation of tetrahedral intermediate.
2. Dissociation of tetrahedral intermediate. 5

142. First Stage: Formation of Tetrahedral Intermediate+
H2O
RCNH2 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– RC OH
NH2 5

143. Second Stage: Cleavage of Tetrahedral IntermediateRC OH
NH2
RCO O
HO– – +
NH3
Water protonates the –NH2, base removes a proton from the geminal diol and as the carbonyl reforms, NH3 leaves. Then base deprotonates the –COOH. 5

144. Steps in the Mechanism of Formation of the Tetrahedral IntermediateRC O
NH2 ••
• • RC O
NH2 ••
• • H –
• • •• H O O
• • H •• –
protonation
base attack
Step 1
Step 2 RC O
NH2 ••
• • H – •• H O
• • H
• • – •• O H RC O
• • ••
NH2
• • 8

145. Steps in the Dissociation of the Tetrahedral Intermediate
H2N RC OH ••
• • O H •• H O
• •
• • – •• O H
protonation •• RC OH O
• • H •• •• +
H3N
Step 3
deprotonation
Step 4 RC OH
H2N ••
• • H + RC
• • O •• H
• • •• H O
• • O H •• – +
NH3
• • + + 8

146. Steps in the Dissociation of the Tetrahedral IntermediateRC
• • O •• H
NH3
• •
deprotonation RC
• • O •• –
HO– 8

147. 19.16 Lactams 3

148. Lactams are cyclic amides.
Some are industrial chemicals, others occur naturally. N H O
-Caprolactam*: used
commercially to prepare
a type of nylon.
(N is on the -carbon.)     
*Caproic acid is the common name for hexanoic acid. 5

149. Penicillin G: a -lactam antibiotic
Lactams
A naturally occurring lactams:
Penicillin G: a -lactam antibiotic  
CH3 S
CO2H O N
C6H5CH2CNH 5

150. 19.17 Preparation of Nitriles3

151. Preparation of Nitriles
Nitriles are prepared by:
1. Nucleophilic substitution by cyanide on alkyl halides (Sections 8.1 and 8.11).
2. Cyanohydrin formation (Section 17.7).
3. Dehydration of amides. 5

152. These two reactions add a carbon. (75%)
By substitution:
Example
KCN
CH3(CH2)8CH2Cl
CH3(CH2)8CH2C N
ethanol- water
(95%)
SN2
Example
By cyanohydrin:
CH3CH2CCH2CH3 O
CH3CH2CCH2CH3 OH C N
KCN H+
These two reactions add a carbon.
(75%) 4

153. By dehydration of amides:
Example
By dehydration of amides:
This method uses the reagent P4O10 (often written as P2O5) as a dehydrating agent.
(CH3)2CHCNH2 O
P4O10
200°C
(CH3)2CHC N
(69-86%) 5

154. 19.18 Hydrolysis of Nitriles3

155. Hydrolysis of Nitriles in Acid+
NH4
RCOH O
RCN
2H2O H
Hydrolysis of nitriles in acidic solution resembles the hydrolysis of amides.
The reaction is irreversible.
Ammonia is produced and is protonated to ammonium ion in the acid solution. 5

156. Example: Acid Hydrolysis
H2O
H2SO4 heat
CH2CN
NO2
CH2COH
(92-95%) 4

157. Hydrolysis of Nitriles in Base+ –
RCO O HO
NH3
RCN
H2O
And as with amides in basic solution, the carboxylic acid product is deprotonated to give a carboxylate ion.
If the carboxylic acid form is desired it must be protonated in a subsequent step. 5

158. Example: Basic Hydrolysis
CH3(CH2)9COH O
1. KOH, H2O, heat
2. H+
CH3(CH2)9CN
(80%) 4

159. Mechanism of Hydrolysis of Nitriles
RCNH2 O
RCOH O
H2O
H2O RC N
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. 5

160. Mechanism of Hydrolysis of NitrilesOH
RCNH2 O
H2O RC N RC NH
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 imine-like product of this addition is the nitrogen analog of an enol. It tautomerizes to an amide under the reaction conditions. 5

161. Steps in the Mechanism of basic Hydrolysis of Nitriles
• • H •• – RC O N
• • – H
Step 1
base attack RC N
• • RC O N
• • – H RC O N
• • H ••
Step 2
protonation + O
• • •• H
• • – O •• H 8

162. H Step 3 O H O + O – H RC – O N H RC N deprotonation • • •• • • •• • •8

163. Step 4 O RC RC – N H N – O + O H H H protonation •• • • • • •• •• • •8

164. 19.19 Addition of Grignard Reagents to Nitriles3

165. Addition of Grignard Reagents to Nitriles
RCR'
NMgX
RCR' NH
R'MgX
H2O RC N
ether imine salt
H3O+
Grignard and R-Li reagents add to nitrile triple bonds in the same way that they add to carbon-oxygen double bonds.
The product of the reaction is an imine salt.
Hydrolysis converts the salt to a ketone and destroys unreacted RMgX or RLi reagent. Thus, reaction of RMgX or RLi with nitriles can be used as a synthesis of ketones.
RCR' O 5

166. Example F3C C N + CH3MgI F3C CCH3 O (79%) 1. diethyl ether
2. H3O+, heat
F3C
CCH3 O
(79%) 4

167. Addition of Gilman’s Reagent (R2CuLi) to Acid Chlorides3

168. Acid Chlorides and Dialkylcopper lithium
(R)2CuLi is a milder reagent than RMgX so it adds only one time to an acid chloride.
C6H5CCl O
+ (CH3)2CuLi
1. diethyl ether
2. H2O
C6H5CCH3 O 4

169. 19.20 Spectroscopic Analysis of Carboxylic Acid Derivatives3

170. Infrared Spectroscopy
C=O stretching frequency depends on whether the compound is an acyl chloride, anhydride, ester, or amide.
1822 cm-1
1748
and
1815 cm-1
1736 cm-1
1694 cm-1
C=O stretching frequency : O
CH3COCCH3 O O O
CH3CCl
CH3COCH3
CH3CNH2 6

171. Infrared Spectroscopy
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.
Anhydride C=O stretching frequency :
1748
and
1815 cm-1
CH3COCCH3 O
Nitriles are readily identified by absorption due to carbon-nitrogen triple bond stretching in the cm-1 region. 6

172. 1H NMR RCOR' O R'COR O and O O C H is less shielded than C H
1H NMR readily distinguishes between isomeric esters of the type:
RCOR' O
R'COR O
and O O C H
is less shielded than C H 6

173. 1H NMR For example: CH3COCH2CH3 O CH3CH2COCH3 O and
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. 6

174. 1H NMR
Ethyl ester
Methyl ester 1

175. 13C NMR
Carbonyl carbon is at low field ( ppm), but not as deshielded as the carbonyl carbon of an aldehyde or ketone ( ppm).
The carbon of a CN group appears near  120 ppm.

176. UV-VIS n* absorption: max O CH3COCCH3 O O O CH3CCl CH3COCH3 CH3CNH26

177. Mass Spectrometry
Most carboxylic acid derivatives give a prominent peak for an acylium ion derived by the fragmentation shown.
RCX •• O
• •
RCX •+ O
• • RC O +
• • + •
• • X

178. Mass Spectrometry
Amides, however, cleave in the direction that gives a nitrogen-stabilized cation.
RCNR'2 •• O
• • •+
RCNR'2 O
• • •• + O C
• •
NR'2 •• • R +

179. End of Chapter 19 Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution3