Carboxylic Acid Derivatives:

Nucleophilic Acyl Substitution

O
Carboxylic Acid Derivates
O RC-Y
Y: has electronegative
RCCl O O atom that can take a
O negative charge and
RCOCR' be a good leaving group
RCSR'
O

RCOR' O
RCNR'2 O
R-C≡N RCO–
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

•• • OH •• •
O• HNu -HX O•
R
C C Nu C
R X R Nu
X
•second stage is restoration of C=O by elimination
O
Most Least
CH3C Cl
reactive stabilized
O O
CH3C OCCH3
O
CH3C SCH2CH3

O
CH3C OCH2CH3

Least O Most
reactive CH3C NH2 stabilized
CO2H Derivative Reactivity
Order Depends On…..

1. Leaving Group Ability

(better leaving group; more reactive)
2. Resonance Stabilization of Derivative
(more stabilized; less reactive)
More Reactive Derivatives Have
Better Leaving Groups

O
Cl- weak base derived
CH3C Cl from strong conj acid;
Good Leaving Group

O O - ion is resonance
O stabilized
CH3C OCCH3 -OCCH
3
More Reactive Derivatives Have
Better Leaving Groups
O
OCH2CH3 is a
CH3C SCH2CH3
stronger base than
O SCH2CH3
CH3C OCH2CH3

O
-NH Very strong base;
2
CH3C NH2
poor leaving group
Resonance Stabilization makes the
CO2H Derivative Less Reactive

•• •
O• Acyl halides are not stabilized
R C by resonance due to mismatch
• Cl • in size between –X and C
• •
••

•• • •• • Both carbonyl groups

O• O•
complete to resonance
C •• C stabilize
R O R
••
Resonance Stabilization makes the
CO2H Derivative Less Reactive
•• •
O•
Thioesters are not stabilized
C ••
by resonance due to mismatch
R SR'
•• in size between –S and C

•• •
O• Resonance stabilization of
esters is more than thioesters
C •• (C and O are about same size)
R OR'
••
Resonance Stabalization makes the
CO2H Derivative Less Reactive
•• •
– • •• •
O• •O •

C +
C •• NR'2
R NR'2 R
•N is less electronegative than O; therefore,
amides are stabilized more than esters and
anhydrides; maximum stabalization in RCO2-
•• • – • •• •
O• •O •

C •• • – C
R O• R O ••
•• ••
most reactive
O Nucleophilic Acyl Substitution

RCCl O O
O
RCOCR'
RCSR'
a carboxylic acid O
derivative can be RCOR' O
converted by
nucleophilic acyl RCNR'2 O
substitution to any other
type that lies below it in RCO–
this table least reactive
Nomenclature of Acyl Halides

RC X
name the acyl group by dropping –e of parent alkane and adding suffix
–oyl ; then add the word chloride, fluoride, bromide, or iodide as
appropriate.
Acyl Halides

CH3CCl ethanoyl chloride

O

H2C CHCH2CCl 3-butenoyl chloride

F CBr p-fluorobenzoyl bromide

Reactions of Acyl Chlorides

Acyl chlorides react with carboxylic acids to give

acid anhydrides:

O O O O

RCCl + R'COH RCOCR' + HCl

H
O O

via: R C OCR'

Cl
Example

O O

CH3(CH2)5CCl + CH3(CH2)5COH

pyridine

O O

CH3(CH2)5COC(CH2)5CH3

(78-83%)
Reactions of Acyl Chlorides

Acyl chlorides react with alcohols to give esters:

O O

RCCl + R'OH RCOR' + HCl

Example

O O
pyridine
C6H5CCl + (CH3)3COH C6H5COC(CH3)3
Reactions of Acyl Chlorides

Acyl chlorides react with ammonia and amines

to give amides:
O O

RCCl + R'2NH + HO– RCNR'2 + H2O

+ Cl–

Example
O O
NaOH
C6H5CCl + HN C6H5CN
H2O
Reactions of Acyl Chlorides

Acyl chlorides react with water to give

carboxylic acids (carboxylate ion in base):

O O

RCCl + H2O RCOH + HCl

O O

RCCl + 2HO– RCO– + Cl–

+ H2O
Example

O O

C6H5CH2CCl + H2O C6H5CH2COH + HCl

Reactivity

Acyl chlorides undergo nucleophilic

substitution much faster than alkyl chlorides.

C6H5CCl C6H5CH2Cl
Relative rates of
1,000 1
hydrolysis (25°C)
Reactions of Acyl Chlorides with
Nucleophiles that Add Irreversibly

O O OH
2) R' MgBr 3) H+
R-C Cl + R' MgBr R-C R' R-C R'

R'

O O OH
3) H+
R-C Cl + LiAlH4 R-C H R-C H

H
Nomenclature & Preparation of
Carboxylic Acid Anhydrides

Anhydrides can be prepared from

acyl chlorides
Acid Anhydrides

O O

RCOCR'

when both acyl groups are the same, name by dropping –e

of parent alkane and add suffic –oic ; then add the word
anhydride

when the groups are different, list the names of both acyl
groups in alphabetical order and add the word anhydride
Acid Anhydrides

O O

CH3COCCH3 ethanoic anhydride

O O

C6H5COCC6H5 benzoic anhydride

O O

C6H5COC(CH2)5CH3 benzoic heptanoic anhydride

Reactions of Anhydrides to Form
COOH Derivatives

O O

RCOCR'
O

RCOR'
O
RCNR'2
O

RCO–
Reactions of Acid Anhydrides
Carboxylic acid anhydrides react with alcohols
to give esters:
O O O O

RCOCR + R'OH RCOR' + RCOH

O O

CH3COCCH3 + CH3CHCH2CH3 O

CH3COCHCH2CH3
OH
CH3
Reactions of Acid Anhydrides

Acid anhydrides react with ammonia and amines

to give amides:
O O O O

RCOCR + 2R'2NH RCNR'2 + RCO–

H +
O R'2NH2
R C NR'2
via:
OCR

O
Example

O O

CH3COCCH3 + H2N CH(CH3)2

O
CH3CNH CH(CH3)2

(98%)
Reactions of Acid Anhydrides

Acid anhydrides react with water to give

carboxylic acids (carboxylate ion in base):

O O O

RCOCR + H2O 2RCOH

O O O

RCOCR + 2HO– 2RCO– + H2O

Reactions of Acid Anhydrides with
Nucleophiles that Add Irreversibly

O OH
O O
2) R'' MgBr 3) H+
R-C R'' R-C R''
R-C O C R' + R'' MgBr

R''

O OH
O O
3) H+
+ LiAlH4 R-C H R-C H
R-C O C R'
H