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Dr. Wolf's CHM 201 & 202 20-1
20.1020.10Ester Hydrolysis in Base:Ester Hydrolysis in Base:
SaponificationSaponification
Dr. Wolf's CHM 201 & 202 20-2
is called is called saponificationsaponification
is irreversible, because of strong stabilization of carboxylateis irreversible, because of strong stabilization of carboxylate
ionion
if carboxylic acid is desired product, saponification is followedif carboxylic acid is desired product, saponification is followed
by a separate acidification step (simply a pH adjustment)by a separate acidification step (simply a pH adjustment)
Ester Hydrolysis in Aqueous BaseEster Hydrolysis in Aqueous Base
RCORCO––
OO
++ R'R'OOHHRCRCOOR'R'
OO
++ HOHO––
Dr. Wolf's CHM 201 & 202 20-3
ExampleExample
water-methanol, heatwater-methanol, heat
(95-97%)(95-97%)
CHCH22OOCCHCCH33
CHCH33
OO
++ NaOHNaOH CHCH22OOHH
CHCH33
OO
CHCH33CONaCONa++
Dr. Wolf's CHM 201 & 202 20-4
ExampleExample
(87%)(87%)
++CCOHCCOH
CHCH33
OO
HH22CC
1. NaOH, H1. NaOH, H22O, heatO, heat
2. H2. H22SOSO44
CHCH33OOHH
CCCCOOCHCH33
CHCH33
OO
HH22CC
Dr. Wolf's CHM 201 & 202 20-5
Soap-MakingSoap-Making
CHCH33(CH(CH22))yyCCOOCHCH
CHCH22OOC(CHC(CH22))xxCHCH33OO
CHCH22OOC(CHC(CH22))zzCHCH33
OO
OO
Basic hydrolysis of Basic hydrolysis of
the glyceryl the glyceryl
triesters (from fats triesters (from fats
and oils) gives and oils) gives
salts of long-chain salts of long-chain
carboxylic acids.carboxylic acids.
These salts are These salts are
soaps.soaps.
KK22COCO33, H, H22O, heatO, heat
CHCH33(CH(CH22))xxCOKCOK
OO
CHCH33(CH(CH22))yyCOKCOK
OO
CHCH33(CH(CH22))zzCOKCOK
OO
Dr. Wolf's CHM 201 & 202 20-6
Which bond is broken when esters areWhich bond is broken when esters arehydrolyzed in base?hydrolyzed in base?
RCRCOO
OO
++R'R'••••
––OOHH••••••••
••••
••••
••••••••
RCRCOO
OO
++ R'R'OOHH••••
••••
••••••••
––••••
••••
••••
One possibility is an SOne possibility is an SNN2 attack by hydroxide on the alkyl 2 attack by hydroxide on the alkyl
group of the ester. Carboxylate is the leaving group.group of the ester. Carboxylate is the leaving group.
Dr. Wolf's CHM 201 & 202 20-7
Which bond is broken when esters areWhich bond is broken when esters arehydrolyzed in base?hydrolyzed in base?
++••••
––OHOH••••••••
RCRC
OO
OORR''••••
••••
••••••••
++ OOR'R'––
••••••••
••••
A second possibility is nucleophilic acyl A second possibility is nucleophilic acyl
substitution. substitution.
RCRC
OO••••••••
••••
••••OHOH
Dr. Wolf's CHM 201 & 202 20-8
1818O Labeling gives the answerO Labeling gives the answer
1818O retained in alcohol, not carboxylate; therefore O retained in alcohol, not carboxylate; therefore
nucleophilic acyl substitution. nucleophilic acyl substitution.
CHCH33CHCH22CCOOCHCH22CHCH33
OO
NaOHNaOH++
CHCH33CHCH22CONaCONa
OO
CHCH33CHCH22OOHH++
Dr. Wolf's CHM 201 & 202 20-9
Stereochemistry gives the same answerStereochemistry gives the same answer
alcohol has same alcohol has same
configuration at configuration at
chirality center as chirality center as
ester; therefore, ester; therefore,
nucleophilic acyl nucleophilic acyl
substitutionsubstitution
not Snot SNN2 2 CHCH33COKCOK
OO
++
CHCH33CC
OO
CCOO
HHCC66HH55
CHCH33
CC
HHOO
HHCC66HH55
CHCH33
KOH, HKOH, H22OO
Dr. Wolf's CHM 201 & 202 20-10
Does it proceed via a tetrahedral intermediate?Does it proceed via a tetrahedral intermediate?
++••••
––OHOH••••••••
RCRC
OO
OORR''••••
••••
••••••••
++ OOR'R'––
••••••••
••••
Does nucleophilic acyl substitution proceed in a Does nucleophilic acyl substitution proceed in a
single step, or is a tetrahedral intermediate single step, or is a tetrahedral intermediate
involved?involved?
RCRC
OO••••••••
••••
••••OHOH
Dr. Wolf's CHM 201 & 202 20-11
1818O Labeling StudiesO Labeling Studies
++ HH22OO
COCHCOCH22CHCH33
OO
COCHCOCH22CHCH33
OO
++ HH22OO
Ethyl benzoate, labeled with Ethyl benzoate, labeled with 1818O at the carbonyl O at the carbonyl
oxygen, was subjected to hydrolysis in base.oxygen, was subjected to hydrolysis in base.
Ethyl benzoate, recovered before the reaction Ethyl benzoate, recovered before the reaction
had gone to completion, had lost its had gone to completion, had lost its 1818O label.O label.
This observation is consistent with a tetrahedral This observation is consistent with a tetrahedral
intermediate.intermediate.
HOHO––
Dr. Wolf's CHM 201 & 202 20-12
1818O Labeling StudiesO Labeling Studies CC
OOHH
OHOH
OCHOCH22CHCH33
++ HH22OO
COCHCOCH22CHCH33
OO
HOHO–– COCHCOCH22CHCH33
OO
++ HH22OO
HOHO––
Dr. Wolf's CHM 201 & 202 20-13
Involves two stages: Involves two stages:
1)1) formation of tetrahedral intermediateformation of tetrahedral intermediate
2)2) dissociation of tetrahedral intermediatedissociation of tetrahedral intermediate
Mechanism of Ester HydrolysisMechanism of Ester Hydrolysisin Basein Base
Dr. Wolf's CHM 201 & 202 20-14
First stage: First stage: formation of tetrahedral intermediateformation of tetrahedral intermediateFirst stage: First stage: formation of tetrahedral intermediateformation of tetrahedral intermediate
RCRC
OHOH
OHOH
OOR'R'
++ HH22OORCRCOOR'R'
OO
water adds to the water adds to the
carbonyl group of the carbonyl group of the
esterester
this stage is analogous this stage is analogous
to the base-catalyzed to the base-catalyzed
addition of water to a addition of water to a
ketoneketone
HOHO––
Dr. Wolf's CHM 201 & 202 20-15
Second stage: Second stage: cleavage of tetrahedralcleavage of tetrahedralintermediateintermediate
Second stage: Second stage: cleavage of tetrahedralcleavage of tetrahedralintermediateintermediate
RCRC
OHOH
OHOH
OOR'R'
++ R'R'OOHHRCOHRCOH
OO
HOHO––
Dr. Wolf's CHM 201 & 202 20-16
Mechanism of formationMechanism of formationofof
tetrahedral intermediatetetrahedral intermediate
Dr. Wolf's CHM 201 & 202 20-17
Step 1Step 1Step 1Step 1
RCRC
OO
OOR'R'
•••• ••••
••••••••
RCRC
OO
OOR'R'
••••••••
••••••••
OO ••••
HH••••
––
••••
OO ••••
HH••••
•••• ––
Dr. Wolf's CHM 201 & 202 20-18
Step 2Step 2Step 2Step 2
RCRC
OO
OOR'R'
••••••••
••••••••
OO ••••
HH••••
––
••••
••••••••
HHOO
HH
RCRC
OO
OOR'R'
••••
••••••••
OO ••••
HH••••
••••
HH
••••––••••
••••OO
HH
Dr. Wolf's CHM 201 & 202 20-19
Dissociation ofDissociation oftetrahedral intermediatetetrahedral intermediate
Dr. Wolf's CHM 201 & 202 20-20
Step 3Step 3Step 3Step 3
RCRC
OO
OOR'R'
••••
••••••••
OO ••••
HH••••
••••
HH
••••––••••
••••OO
HH
••••••••
HHOO
HH
OOR'R'••••••••
–– ••••
RCRC
••••
OO•••• ••••
••••OO HH
Dr. Wolf's CHM 201 & 202 20-21
Step 4Step 4Step 4Step 4
OOR'R'••••••••
–– ••••
RCRC
••••
OO•••• ••••
••••OO HH
HOHO––
RCRC
••••
OO•••• ••••
••••OO ••••
––
HH OOR'R'••••
••••
HH22OO
Dr. Wolf's CHM 201 & 202 20-22
Nucleophilic addition of hydroxide ion to carbonylNucleophilic addition of hydroxide ion to carbonylgroup in first stepgroup in first step
Tetrahedral intermediate formed in first stageTetrahedral intermediate formed in first stage
Hydroxide-induced dissociation of tetrahedralHydroxide-induced dissociation of tetrahedralintermediate in second stageintermediate in second stage
Key Features of MechanismKey Features of Mechanism
Dr. Wolf's CHM 201 & 202 20-23
20.1120.11Reactions of EstersReactions of Esters
with Ammonia and Amineswith Ammonia and Amines
Dr. Wolf's CHM 201 & 202 20-24
RCOR'RCOR'
OO
RCNR'RCNR'22
OO
RCORCO––
OO
Reactions of EstersReactions of Esters
Dr. Wolf's CHM 201 & 202 20-25
Reactions of EstersReactions of Esters
++ RCRCNNR'R'22
OO
++
Esters react with ammonia and aminesEsters react with ammonia and aminesto give amides:to give amides:
R'R'22NNHHRCRCOOR'R'
OO
R'R'OOHH
via:via: CCRR
OO
OOR'R'
NNR'R'22
HH
Dr. Wolf's CHM 201 & 202 20-26
ExampleExample
(75%)(75%)
++CCCCNNHH22
CHCH33
OO
HH22CC CHCH33OOHH
CCCCOOCHCH33
CHCH33
OO
HH22CC ++ NNHH33
HH22OO
Dr. Wolf's CHM 201 & 202 20-27
ExampleExample
(61%)(61%)
++FCHFCH22CCOOCHCH22CHCH33
OO NNHH22
++ CHCH33CHCH22OOHHFCHFCH22CCNNHH
OO heatheat
Dr. Wolf's CHM 201 & 202 20-28
20.1220.12
AmidesAmides
Dr. Wolf's CHM 201 & 202 20-29
Physical Properties of AmidesPhysical Properties of Amides
Amides are less reactive toward nucleophilic Amides are less reactive toward nucleophilic
acyl substitution than other acid derivatives.acyl substitution than other acid derivatives.
C
O
H NH
H
C
O
H NH
H
C
O
H NH
HFormamide
Dr. Wolf's CHM 201 & 202 20-30
Physical Properties of AmidesPhysical Properties of Amides
Amides are capable of hydrogen bonding.Amides are capable of hydrogen bonding.
C
O
H NH
HC
O
H NH
H
C
O
H NH
H
Dr. Wolf's CHM 201 & 202 20-31
Physical Properties of AmidesPhysical Properties of Amides
Amides are less acidic than carboxylic acids. Amides are less acidic than carboxylic acids.
Nitrogen is less electronegative than oxygen.Nitrogen is less electronegative than oxygen.
CH3CH2NH2 CH3CNH2
O
CH3CNCCH3
O O
H
CH3COH
O
pKa (approximate) 36 15 10 5
Dr. Wolf's CHM 201 & 202 20-32
acyl chlorides (Table 20.1)acyl chlorides (Table 20.1)
anhydrides (Table 20.2)anhydrides (Table 20.2)
esters (Table 20.5)esters (Table 20.5)
Preparation of AmidesPreparation of Amides
Amides are prepared from amines by acylationAmides are prepared from amines by acylation
with:with:
Dr. Wolf's CHM 201 & 202 20-33
Preparation of AmidesPreparation of Amides
Amines do Amines do notnot react with carboxylic acids to give react with carboxylic acids to give
amides. The reaction that occurs is proton-transferamides. The reaction that occurs is proton-transfer
(acid-base).(acid-base).
RCOHRCOH
OO
++ R'R'NNHH22 RCORCO
OO
++ R'R'NNHH33
++––
If no heat-sensitive groups are present, the If no heat-sensitive groups are present, the
resulting ammonium carboxylate salts can be resulting ammonium carboxylate salts can be
converted to amides by heating.converted to amides by heating.
Dr. Wolf's CHM 201 & 202 20-34
Preparation of AmidesPreparation of Amides
Amines do Amines do notnot react with carboxylic acids to give react with carboxylic acids to give
amides. The reaction that occurs is proton-transferamides. The reaction that occurs is proton-transfer
(acid-base).(acid-base).
RCOHRCOH
OO
++ R'R'NNHH22 RCORCO
OO
++ R'R'NNHH33
++––
heatheat
RCRCNNHR'HR'
OO
++ HH22OO
Dr. Wolf's CHM 201 & 202 20-35
ExampleExample COHCOH
OO
++
HH22NN
225°C225°C
++ HH22OO
(80-84%)(80-84%)
CCNNHH
OO
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