Carboxylic acid derivatives: Reactivity

considerations
oxygen - more -ve. Will pull e-s toward it.
O- O
O
R C Y +
C C Y-
R Y Z R Z

tetrahedral
Z-
intermediate

Weaker the base, the better the leaving group

weak base does not share its e- as strongly as a strong base
therefore weaker bond and easier to break
called: nucleophilic acyl substitution reaction
for a reaction to occur, nucleophile must be stronger base than leaving
group. 1
Relative basicity of leaving group
O
Cl- < -OC R < -OR ~ -OH < -NH2
least most
basic basic
good leaving group not a good leaving
group

O O

C C
R Cl R NH2
most reactive least reactive

-NH is more basic than -OH

2

-NH2 will not leave when -OH attacks C

amides cannot be converted to carboxylic acids by nucleophilic
acyl substitution.
2
With neutral nucleophiles, there is an additional step in the mechanism.

O
-
O O- +
O C
-H
C H2O R C Y R C Y R OH
R Y OH + Y-
O
H H additional step

3
Reactions of acyl halides
O O O O
C Cl CH3C O- C O C CH3 + Cl-
+
form anhydrides

O O
+
C Cl CH3OH C OCH3 H+ + Cl-
+
form esters

O O
+
C Cl + H2O C OH H+ + Cl-
form acids

O O
C Cl + 2 CH3NH2 C N CH3 + CH3NH3+ Cl-
must be double because H
H+ released reacts with amine
and cannot act as nucleophile form amides

4
Reactions of acid anhydrides

O O
CH3 C O C CH3 + Cl- no reaction

O O O O
CH3 C O C CH3 + CH3OH CH3 C OCH3 + CH3 C OH

O O O
CH3 C O C CH3 + H2 O 2 CH3 C OH

O
O O
CH3 C NHCH3 +
CH3 C O C CH3 + 2 CH3NH2 + CH3NH3
O
+ CH3CO-

5
Reactions of Esters
O O
CH3CH2C OCH2CH3 + CH3NH2 CH3CH2C NHCH3 + CH3CH2OH

proton picked up by CH3CH2O- (more basic than the amine) therefore only one equivalent
of CH3NH2 used.

O O
+
H
CH3 C OCH3 + H 2O CH3C OH + CH3OH

O O
C OCH3 + CH3CH2OH H+ C OCH2CH3 + CH3OH

transesterification reaction - one ester converted to another

very slow therefore catalysed by H+

Because -OH and -OCH3 have almost the same basicities, excess water
or alcohol must be used to drive the reaction to completion.
6
O O- + O-
-H
CH3 C OCH3 CH3 C OCH3 CH3 C OCH3
OH2 OH
O H OH and OCH3 have almost the same
H basicity and therefore equally likely to be
expelled.

O- O-

CH3 C OCH3 CH3 C OCH3

OH OH

O O
acid base
- -
CH3 C OCH3 + OH CH3 C OH + OCH3
more basic than
The irreversible carboxylate anion
acid-base reaction therefore protonated.
drives the reaction to Drives the reaction to
completion. completion.
O
CH3 C O- + CH3OH 7
Mechanism for acid catalysed ester hydrolysis
O OH OH
H+
CH3 C OCH3 CH3 C OCH3 + H2O CH3 C OCH3
+
-H OH2

tetrahedral intermediate I

H+ -H+
H+protonates the C=O oxygen - makes it
more susceptible to Nu attack
OH
H+ protonates OCH3 therby decreasing its CH3 C OCH3
basicity and making it a better leaving group. OH

H+ -H+

O OH OH
H+
CH3 C OH CH3 C OH + CH3OH CH3 C OCH3
-H+ OH H

tetrahedral intermediate II 8
OH- ion promoted ester hydrolysis
O O O
- CH3 C OCH3 -
CH3 C OCH3 + OH CH3 C OH + CH3O
OH

-
OH H2O

O
OH
CH3 C O- + CH3OH
CH3 C OCH3
OH

OH- is a better nucleophile than H2O and more readily attacks the
carbonyl carbon.
A smaller fraction of the tetrahedral intermediate becomes protonated in
basic solution.
9
Reactions of carboxylic acids
O O
+
H
CH3 C OH + CH3OH CH3C OCH3 + H2O

must use excess alcohol to make the reaction go,

since OH- and OCH3- have same basicity.

O O
when heated loses
CH3C OH + CH3CH2NH2 CH3C O- H3NCH2CH3 H O to form amide
2
ammonium carboxylate salt formed

225 oC
O
CH3C NHCH2CH3 + H 2O

Carboxylate anions more unreactive toward nucleophilic substitution than

amides. 10
Reactions of amides
acid and base catalysed hydrolysis of amides - similar mechanism to
ester hydrolysis.
O +
O
H
CH3C NHCH2CH3 + H2O CH3C OH + CH3CH2NH3

O O
OH-
C NHCH3 + H2O C O- + CH3NH2

1o amide can be converted to a nitrile.

O
P2O5, POCl3 or SOCl2
CH3CH2C NH2 CH3CH2C N
o
85 C

11