Organic Chemistry Fifth Edition

1
Chem 234 Organic Chemistry II Professor Duncan
J. Wardrop
Spring 2004
University of Illinois at Chicago
2
20.5Preparation ofCarboxylic Acid Anhydrides
3
Anhydrides are Important Building Blocks
Aceticanhydride
Phthalicanhydride
Maleicanhydride
4
Cyclic Anhydrides are Prepared for 1,n-Diacids

• Cyclic anhydrides with 5- and 6-membered rings
  can be prepared by dehydration of dicarboxylic
  acids

5
20.6Reactions ofCarboxylic Acid Anhydrides
6
Reactions of Anhydrides
7
Reactions of Anhydrides
Carboxylic acid anhydrides react with alcohols to
give esters

• 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

8
Reactions of Anhydrides
Carboxylic acid anhydrides react with alcoholsto
give esters


R'OH
via
9
Reactions of Anhydrides- Examples
10
Reactions of Anhydrides with Amines
Acid anhydrides react with ammonia and aminesto
give amides


2R'2NH
11
Reactions of Anhydrides with Amines- Example
12
Reactions of Anhydrides with Water
Acid anhydrides react with water to
givecarboxylic acids (carboxylate ion in base)

H2O
2RCOH


2HO
2RCO
H2O
13
Reactions of Anhydrides with Water
Acid anhydrides react with water to
givecarboxylic acids (carboxylate ion in base)

H2O
2RCOH
14
Reactions of Anhydrides with Water - Example

H2O
15
20.7Sources of Esters
16
Esters are Commonly Found in Natural Products
3-methylbutyl acetate

• also called "isopentyl acetate" and "isoamyl
  acetate"
• contributes to characteristic odor of bananas

17
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

18
Fat Oil are Mixtures of Glyceryl Triesters
Tristearin found in many animal and vegetable
fats
19
Lactones are Cyclic Esters
(Z)-5-Tetradecen-4-olide(sex pheromone of female
Japanese beetle)
20
Preparation of Lactones

• Fischer esterification (Sections 15.8 and 19.14)
• from acyl chlorides (Sections 15.8 and 20.4)
• from carboxylic acid anhydrides (Sections
  15.8and 20.6)
• Baeyer-Villiger oxidation of ketones (Section
  17.16)

21
20.8Physical Properties of Esters
22
Physical Properties of Ester - Boiling Point

• 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.

boilingpoint
28C
O
57C
CH3COCH3
99C
23
Physical Properties of Ester - Solubility

• Esters can form hydrogen bonds to water, so low
  molecular weight esters have significant
  solubility in water.
• Solubility decreases with increasing number of
  carbons.

Solubility(g/100 g)
0
O
33
CH3COCH3
12.5
24
20.9Reactions of EstersA Review and a Preview
25
Reactions of Esters

• with Grignard reagents (Section 14.10)
• reduction with LiAlH4 (Section 15.3)
• with ammonia and amines (Sections 20.12)
• hydrolysis (Sections 20.10 and 20.11)

26
20.10Acid-Catalyzed Ester Hydrolysis
27
Acid-Catalyzed Hydrolysis of Esters
Mechanism is just the reverse of Fischer
esterification

• maximize conversion to ester by removing water
• maximize ester hydrolysis by having large excess
  of water
• equilibrium is closely balanced because carbonyl
  group ofester and of carboxylic acid are
  comparably stabilized

28
Acid-Catalyzed Hydrolysis of Esters - Example
29
Acid-Catalyzed Hydrolysis of Esters - Mechanism

• 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)

30
First stage formation of tetrahedral
intermediate

• water adds to the carbonyl group of the ester
• this stage is analogous to the acid-catalyzed
  addition of water to a ketone

H
31
Second stage cleavage of tetrahedralintermediat
e

R'OH
H
32
Mechanism of formationoftetrahedral intermediate
33
Step 1

O

RC
O
R'


34
Step 1

• carbonyl oxygen is protonated because cation
  produced is stabilized by electron delocalization
  (resonance)

35
Step 2
36
Step 3
37
Cleavage of tetrahedralintermediate
38
Step 4
39
Step 5
40
Step 5
41
Step 6
42
Key Features of Acid-Catalyzed Hydrolysis

• Activation of carbonyl group by protonation of
  carbonyl oxygen
• Nucleophilic addition of water to carbonyl
  groupforms tetrahedral intermediate
• Elimination of alcohol from tetrahedral
  intermediate restores carbonyl group

43
Investigation of Mechanism via 18O Labeling
Studies

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

H2O
44
Investigation of Mechanism via 18O Labeling
Studies

H2O
H
45
20.11Ester Hydrolysis in BaseSaponification
46
Ester Hydrolysis in Aqueous Base

• is called saponification
• is irreversible, because of strong stabilization
  of carboxylate ion
• if carboxylic acid is desired product,
  saponification is followedby a separate
  acidification step (simply a pH adjustment)

47
Ester Hydrolysis in Aqueous Base - Example 1

NaOH
water-methanol, heat

(95-97)
48
Ester Hydrolysis in Aqueous Base - Example 2
49
Manufacture of Soap

• Basic hydrolysis of the glyceryl triesters (from
  fats and oils) gives salts of long-chain
  carboxylic acids.
• These salts are soaps.

K2CO3, H2O, heat
CH3(CH2)xCOK
CH3(CH2)yCOK
CH3(CH2)zCOK
50
Is the Mechanism BAL2 or BAC2?

• One possibility is an SN2 attack by hydroxide on
  the alkyl group of the ester. Carboxylate is the
  leaving group.
• This mechaism would be designated BAL2
• B (Basic conditions)
• AL (Carbonyl-OAlkyl bond breaking in
  rate-determining step)
• 2 (Reaction is second order - rate
  kesterhydroxide

51
Is the Mechanism BAL2 or BAC2?

• A second possibility is nucleophilic acyl
  substitution.

52
18O Labeling gives the answer

• 18O retained in alcohol, not carboxylate
  therefore nucleophilic acyl substitution.

53
Stereochemistry gives the same answer

• alcohol has same configuration at chirality
  center as ester therefore, nucleophilic acyl
  substitution
• not SN2

KOH, H2O

54
Does it proceed via a tetrahedral intermediate?

• Does nucleophilic acyl substitution proceed in a
  single step, or is a tetrahedral intermediate
  involved?

55
18O Labeling Studies

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

H2O
56
18O Labeling Studies

H2O
HO
HO

H2O
57
Mechanism of Ester Hydrolysisin Base

• Involves two stages
• 1) formation of tetrahedral intermediate 2) diss
  ociation of tetrahedral intermediate

58
First stage formation of tetrahedral
intermediate

• water adds to the carbonyl group of the ester
• this stage is analogous to the base-catalyzed
  addition of water to a ketone

HO
59
Second stage cleavage of tetrahedralintermediat
e

R'OH
HO
60
Mechanism of formationoftetrahedral intermediate
61
Step 1
62
Step 2
63
Dissociation oftetrahedral intermediate
64
Step 3
65
Step 4
H2O
66
Key Features of Mechanism

• Nucleophilic addition of hydroxide ion to
  carbonylgroup in first step
• Tetrahedral intermediate formed in first stage
• Hydroxide-induced dissociation of
  tetrahedralintermediate in second stage

67
20.11Reactions of Esterswith Ammonia and Amines
68
Reactions of Esters
69
Reactions of Esters
Esters react with ammonia and aminesto give
amides


R'2NH
RCOR'
R'OH
70
Example
H2O

CH3OH
(75)
71
Example
heat
(61)
72
20.14Preparation of Amides
73
Preparation of Amides
Amides are prepared from amines by acylationwith

• acyl chlorides (Table 20.1)
• anhydrides (Table 20.2)
• esters (Table 20.5)

74
Preparation of Amides
Amines do not react with carboxylic acids to
giveamides. The reaction that occurs is
proton-transfer(acid-base).




R'NH3
R'NH2

• If no heat-sensitive groups are present, the
  resulting ammonium carboxylate salts can be
  converted to amides by heating.

75
Preparation of Amides
Amines do not react with carboxylic acids to
giveamides. The reaction that occurs is
proton-transfer(acid-base).




R'NH3
R'NH2
heat

H2O
76
Example


225C

H2O
(80-84)
77
20.15Lactams
78
Lactams
Lactams are cyclic amides. Some are
industrialchemicals, others occur naturally.
79
Lactams
Lactams are cyclic amides. Some are
industrialchemicals, others occur naturally.
Highly reactive
80
20.16Imides
81
Imides
Imides have 2 acyl groups attached to
thenitrogen.
82
Imides
The most common examples are cyclic imides.
O
NH
O
Phthalimide
Succinimide
83
Preparation of Imides
Cyclic imides are prepared by heating the
ammonium salts of dicarboxylic acids.
NH3
84
20.17Hydrolysis of Amides
85
Hydrolysis of Amides
Hydrolysis of amides is irreversible. In acid
solution the amine product is protonated to
give an ammonium salt.



R'NH3


H2O
H
86
Hydrolysis of Amides
In basic solution the carboxylic acid product is
deprotonated to give a carboxylate ion.



R'NH2

HO
87
Example Acid Hydrolysis
H2O

H2SO4heat
(88-90)
88
Example Basic Hydrolysis
KOH

H2Oheat
(95)
89
Mechanism of Acid-CatalyzedAmide Hydrolysis

• Acid-catalyzed amide hydrolysis proceeds viathe
  customary two stages
• 1) formation of tetrahedral intermediate 2) diss
  ociation of tetrahedral intermediate

90
First stage formation of tetrahedral
intermediate

• water adds to the carbonyl group of the amide
• this stage is analogous to the acid-catalyzed
  addition of water to a ketone

H
91
Second stage cleavage of tetrahedralintermediat
e

H
92
Mechanism of formationoftetrahedral intermediate
93
Step 1
94
Step 1

• carbonyl oxygen is protonated because cation
  produced is stabilized by electron delocalization
  (resonance)

95
Step 2
96
Step 3
97
Cleavage of tetrahedralintermediate
98
Step 4
99
Step 5
100
Step 6

NH4

101
Step 6
102
Step 6

103
Mechanism of Amide Hydrolysisin Base

• Involves two stages
• 1) formation of tetrahedral intermediate 2) diss
  ociation of tetrahedral intermediate

104
First stage formation of tetrahedral
intermediate

• water adds to the carbonyl group of the amide
• this stage is analogous to the base-catalyzed
  addition of water to a ketone

HO
105
Second stage cleavage of tetrahedralintermediat
e


NH3
HO
106
Mechanism of formationoftetrahedral intermediate
107
Step 1
108
Step 2
109
Dissociation oftetrahedral intermediate
110
Step 3
111
Step 4

H
O


RC
OH


H3N
112
Step 5
HO
113
20.18Preparation of Nitriles
114
Preparation of Nitriles
Nitriles are prepared by

• nucleophilic substitution by cyanide onalkyl
  halides (Sections 8.1 and 8.13)
• cyanohydrin formation (Section 17.7)
• dehydration of amides

115
Example
KCN
CH3(CH2)8CH2Cl
ethanol-water
(95)

• SN2

116
Example
KCN
H
(75)
117
Preparation of Nitriles
By dehydration of amides

• uses the reagent P4O10 (often written as P2O5)

(69-86)
118
20.19Hydrolysis of Nitriles
119
Hydrolysis of Nitriles
Hydrolysis of nitriles resembles the
hydrolysisof amides. The reaction is
irreversible. Ammonia is produced and is
protonated to ammonium ion in acid solution.
120
Hydrolysis of Nitriles
In basic solution the carboxylic acid product is
deprotonated to give a carboxylate ion.
121
Example Acid Hydrolysis
(92-95)
122
Example Basic Hydrolysis
CH3(CH2)9CN
(80)
123
Mechanism of Hydrolysis of Nitriles
H2O
H2O

• Hydrolysis of nitriles proceeds via
  thecorresponding amide.
• We already know the mechanism of
  amidehydrolysis.
• Therefore, all we need to do is to see how
  amides are formed from nitriles under the
  conditions of hydrolysis.

124
Mechanism of Hydrolysis of Nitriles
OH
H2O
RC
NH

• The mechanism of amide formation is analogousto
  that of conversion of alkynes to ketones.
• It begins with the addition of water across
  thecarbon-nitrogen triple bond.
• The product of this addition is the nitrogen
  analog of an enol. It is transformed to an
  amideunder the reaction conditions.

125
Step 1
126
Step 2
127
Step 3
128
Step 4
129
20.20Addition of Grignard Reagentsto Nitriles
130
Addition of Grignard Reagents to Nitriles
R'MgX
H2O
diethylether

• Grignard reagents add to carbon-nitrogen
  triplebonds in the same way that they add to
  carbon-oxygen double bonds.
• The product of the reaction is an imine.

131
Addition of Grignard Reagents to Nitriles
R'MgX
H2O
diethylether
H3O
Imines are readily hydrolyzed to
ketones.Therefore, the reaction of Grignard
reagents with nitriles can be used as a synthesis
of ketones.
132
Example
CH3MgI
1. diethyl ether
2. H3O, heat
(79)
133
Information Suggested Problems
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Suggested Problems 20.29-20.38 -----------------
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