Carboxylic acids Nucleofilic acyl substitution
reaction
Dr AKM Shafiqul Islam
School of Bioprocess Engineering
Mechanism of the Fischer
Esterification
Step One – Protonation of the carbonyl
oxygen:
O
CH3
C
O
H
OH
CH3
C
H
OH
Mechanism of the Fischer
Esterification
Step One – Protonation of the carbonyl
oxygen:
O
CH3
C
O
H
OH
CH3
C
H
OH
Mechanism of the Fischer
Esterification
Step One – Protonation of the carbonyl
oxygen:
O
CH3
C
O
H
OH
CH3
C
H
OH
Mechanism of the Fischer
Esterification
Step Two – Nucleophilic addition of the
alcohol to form an oxonium ion
intermediate:
O
CH3
C
O
H
+ HOCH2CH3
OH
CH3
H
H
C OH
O
CH2CH3
Mechanism of the Fischer
Esterification
Step Two – Nucleophilic addition of the
alcohol to form an oxonium ion
intermediate:
O
CH3
C
O
H
+ HOCH2CH3
OH
CH3
H
H
C OH
O
CH2CH3
Mechanism of the Fischer
Esterification
Step Two – Nucleophilic addition of the
alcohol to form an oxonium ion
intermediate:
O
CH3
C
O
H
+ HOCH2CH3
OH
CH3
H
H
C OH
O
CH2CH3
Mechanism of the Fischer
Esterification
Step Three – Proton reorganization to give
a new oxonium ion intermediate:
H
O
CH3
H
H
C OH
O
H
CH3
O
C OH
O
CH2CH3
H
CH2CH3
Mechanism of the Fischer
Esterification
Step Three – Proton reorganization to give
a new oxonium ion intermediate:
H
O
CH3
H
H
C OH
O
H
CH3
O
C OH
O
CH2CH3
H
CH2CH3
Mechanism of the Fischer
Esterification
Step Four – Elimination of water:
H
CH3
O
H
C OH
O
CH2CH3
CH3
C
O
H
O
CH2CH3
+ H2O
Mechanism of the Fischer
Esterification
Step Four – Elimination of water:
H
CH3
O
H
C OH
O
CH2CH3
CH3
C
O
H
O
CH2CH3
+ H2O
Mechanism of the Fischer
Esterification
Step Five – Deprotonation to give the
ester:
CH3
C
O
H
O
CH2CH3
CH3
C
O
O
+ H
CH2CH3
Mechanism of the Fischer
Esterification
Step Five – Deprotonation to give the
ester:
CH3
C
O
H
O
CH2CH3
CH3
C
O
O
+ H
CH2CH3
Mechanism of the Fischer
Esterification
Step Five – Deprotonation to give the
ester:
CH3
C
O
H
O
CH2CH3
CH3
C
O
O
+ H
CH2CH3
Note that only a catalytic amount of acid is needed
Preparation of Esters
Reaction of an acid chloride with an
alcohol
• An alcohol reacts with an acid chloride with
elimination of HCl.
Sometimes an amine base is added to
precipitate the HCl that is formed.
O
CH3
C
+ HOCH2CH3
Cl
(CH3CH2)3N
(CH3CH2)2O
O
CH3
C
CH2CH3 + HCl
O
+ (CH3CH2)3NH Cl
Preparation of Esters
Reaction of an acid chloride with an
alcohol
• An alcohol reacts with an acid chloride with
elimination of HCl.
• Sometimes an amine base is added to
precipitate the HCl that is formed.
O
CH3
C
+ HOCH2CH3
Cl
(CH3CH2)3N
(CH3CH2)2O
O
CH3
C
CH2CH3 + HCl
O
+ (CH3CH2)3NH Cl
Preparation of Esters
Reaction of an acid chloride with an
alcohol
• An alcohol reacts with an acid chloride with
elimination of HCl.
• Sometimes an amine base is added to
precipitate the HCl that is formed.
O
CH3
C
+ HOCH2CH3
Cl
(CH3CH2)3N
(CH3CH2)2O
O
CH3
C
CH2CH3 + (CH3CH2)3NH Cl
O
+ HCl
Esterification Mechanism
Step One – Nucleophilic addition of
alcohol to acid chloride:
O
O
CH3
C
+ HOCH2CH3
Cl
C Cl
O
H
CH2CH3
CH3
Esterification Mechanism
Step One – Nucleophilic addition of
alcohol to acid chloride:
O
O
CH3
C
+ HOCH2CH3
Cl
C Cl
O
H
CH2CH3
CH3
Esterification Mechanism
Step Two – Deprotonation of the
tetrahedral intermediate:
O
C Cl
O
H
CH2CH3
CH3
Et3N
O
CH3
C Cl
O
CH2CH3
Esterification Mechanism
Step Two – Deprotonation of the
tetrahedral intermediate:
O
C Cl
O
H
CH2CH3
CH3
Et3N
O
CH3
C Cl
O
CH2CH3
Esterification Mechanism
Step Three – Elimination of chloride anion:
CH3
O
O
C Cl
O
CH2CH3
C
CH3
O
CH2CH3
Esterification Mechanism
Step Three – Elimination of chloride anion:
CH3
O
O
C Cl
O
CH2CH3
C
CH3
O
CH2CH3
Reactions of Esters
Hydrolysis
• Esters are normally unreactive with water.
• However, in the presence of either aqueous
acid (aq. HCl or H2SO4) or aqueous base
(NaOH or KOH), they can be hydrolyzed.
Acid-Catalyzed Hydrolysis
The reverse of the Fischer esterification
O
CH3
C
O
CH2CH3 + H2O
H
O
CH3
C
+ HOCH2CH3
OH
Base-Promoted Hydrolysis
(Saponification)
This reaction is used to make soap
O
CH3
C
O
CH2CH3 + NaOH
H2O
O
CH3
C
O Na
+ HOCH2CH3
Mechanism of Saponification
Step One – Nucleophilic addition of
hydroxide anion:
O
O
CH3
C
OH
O
CH2CH3
CH3
C OCH CH
2
3
OH
Mechanism of Saponification
Step One – Nucleophilic addition of
hydroxide anion:
O
O
CH3
C
OH
O
CH2CH3
CH3
C OCH CH
2
3
OH
Mechanism of Saponification
Step Two – Elimination of alkoxide anion:
CH3
O
O
C OCH CH
2
3
OH
C
CH3
O
H +
OCH2CH3
Mechanism of Saponification
Step Two – Elimination of alkoxide anion:
CH3
O
O
C OCH CH
2
3
OH
C
CH3
O
H +
OCH2CH3
Mechanism of Saponification
Step Three – Proton reorganization (acid–
base reaction):
O
CH3
C
O
H +
OCH2CH3
O
CH3
C
O
+ HOCH2CH3
Mechanism of Saponification
Step Three – Proton reorganization (acid–
base reaction):
O
CH3
C
O
H +
OCH2CH3
O
CH3
C
O
+ HOCH2CH3
Reactions of Anhydrides
Esterification (Alcoholysis)
• Anhydrides react with alcohols to give one
molecule of ester and one molecule of
carboxylic acid—a useful method for the
preparation of esters.
Example of Esterification
Preparation of aspirin:
OH
+
CO2H
CH3
salicylic acid
O
O
C
C
O
CH3
acetic anhydride
O
OCCH3
O
+
CO2H
acetyl salicylic acid
(aspirin)
CH3
C
OH
Example of Esterification
Preparation of aspirin:
OH
+
CO2H
CH3
salicylic acid
O
O
C
C
O
CH3
acetic anhydride
O
OCCH3
O
+
CO2H
acetyl salicylic acid
(aspirin)
CH3
C
OH
Reactions of Anhydrides
Reaction with Ammonia and Amines –
Formation of Amides
• Anhydrides react with ammonia, as well as 1o
or 2o amines, to form amides.
• Note that two moles of amine are required
(one forms the amide, the other acts as a
base).
Example of Amide Formation
Preparation of acetamide
CH3
O
O
C
C
O
+ 2 NH3
CH3
acetic anhydride
O
CH3
C
O
+
NH2
acetamide
CH3
C
O NH4
ammonium acetate
Example of Amide Formation
Preparation of acetamide
CH3
O
O
C
C
O
+ 2 NH3
CH3
acetic anhydride
O
CH3
C
O
+
NH2
acetamide
CH3
C
O NH4
ammonium acetate
Example of Amide Formation
Preparation of acetaminophen
NH2
+
HO
CH3
p-hydroxyaniline
O
O
C
C
O
CH3
acetic anhydride
O
NHCCH3
HO
acetaminophen
(TYLENOL®)