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