carboxylic acids - nucleofilic acyl substitution reaction dr akm shafiqul islam school of bioprocess...
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Carboxylic acids -Nucleofilic acyl substitution
reactionDr AKM Shafiqul Islam
School of Bioprocess Engineering
Mechanism of the Fischer Esterification
Step One – Protonation of the carbonyl oxygen:
O
CCH3 OH
O
CCH3 OH
HH
Mechanism of the Fischer Esterification
Step One – Protonation of the carbonyl oxygen:
O
CCH3 OH
O
CCH3 OH
HH
Mechanism of the Fischer Esterification
Step One – Protonation of the carbonyl oxygen:
O
CCH3 OH
O
CCH3 OH
HH
Mechanism of the Fischer Esterification
Step Two – Nucleophilic addition of the alcohol to form an oxonium ion intermediate:
O
CCH3 OH
H O
CCH3 OH
O
H
H CH2CH3
+ HOCH2CH3
Mechanism of the Fischer Esterification
Step Two – Nucleophilic addition of the alcohol to form an oxonium ion intermediate:
O
CCH3 OH
H O
CCH3 OH
O
H
H CH2CH3
+ HOCH2CH3
Mechanism of the Fischer Esterification
Step Two – Nucleophilic addition of the alcohol to form an oxonium ion intermediate:
O
CCH3 OH
H O
CCH3 OH
O
H
H CH2CH3
+ HOCH2CH3
Mechanism of the Fischer Esterification
Step Three – Proton reorganization to give a new oxonium ion intermediate:
HO
CCH3 OH
O
H
H CH2CH3
O
CCH3 OH
O
H
CH2CH3
H
Mechanism of the Fischer Esterification
Step Three – Proton reorganization to give a new oxonium ion intermediate:
HO
CCH3 OH
O
H
H CH2CH3
O
CCH3 OH
O
H
CH2CH3
H
Mechanism of the Fischer Esterification
Step Four – Elimination of water:
O
CCH3 OH
O
H
CH2CH3
H
C
O
CH3 OH
CH2CH3
+ H2O
Mechanism of the Fischer Esterification
Step Four – Elimination of water:
O
CCH3 OH
O
H
CH2CH3
H
C
O
CH3 OH
CH2CH3
+ H2O
Mechanism of the Fischer Esterification
Step Five – Deprotonation to give the ester:
C
O
CH3 OH
CH2CH3
C
O
CH3 O
CH2CH3
+ H
Mechanism of the Fischer Esterification
Step Five – Deprotonation to give the ester:
C
O
CH3 OH
CH2CH3
C
O
CH3 O
CH2CH3
+ H
Mechanism of the Fischer Esterification
Step Five – Deprotonation to give the ester:
C
O
CH3 OH
CH2CH3
C
O
CH3 O
CH2CH3
+ H
Note that only a catalytic amount of acid is needed
Preparation of EstersReaction 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
CCH3 Cl
+ HOCH2CH3
O
CCH3 O
CH2CH3 + HCl+ (CH3CH2)3NH Cl
(CH3CH2)3N(CH3CH2)2O
Preparation of EstersReaction 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
CCH3 Cl
+ HOCH2CH3
O
CCH3 O
CH2CH3 + HCl+ (CH3CH2)3NH Cl
(CH3CH2)3N(CH3CH2)2O
Preparation of EstersReaction 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
CCH3 Cl
+ HOCH2CH3
O
CCH3 O
CH2CH3+ HCl+ (CH3CH2)3NH Cl
(CH3CH2)3N(CH3CH2)2O
Esterification Mechanism
Step One – Nucleophilic addition of alcohol to acid chloride:
O
CCH3 Cl
+ HOCH2CH3
O
CCH3 ClO
H CH2CH3
Esterification Mechanism
Step One – Nucleophilic addition of alcohol to acid chloride:
O
CCH3 Cl
+ HOCH2CH3
O
CCH3 ClO
H CH2CH3
Esterification Mechanism
Step Two – Deprotonation of the tetrahedral intermediate:
O
CCH3 ClO
H CH2CH3
O
CCH3 ClO
CH2CH3Et3N
Esterification Mechanism
Step Two – Deprotonation of the tetrahedral intermediate:
O
CCH3 ClO
H CH2CH3
O
CCH3 ClO
CH2CH3Et3N
Esterification Mechanism
Step Three – Elimination of chloride anion:
O
CCH3 O
CH2CH3
O
CCH3 ClO
CH2CH3
Esterification Mechanism
Step Three – Elimination of chloride anion:
O
CCH3 O
CH2CH3
O
CCH3 ClO
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
CCH3 O
CH2CH3
O
CCH3 OH
+ H2O
+ HOCH2CH3
H
Base-Promoted Hydrolysis (Saponification)
This reaction is used to make soap
O
CCH3 O
CH2CH3
O
CCH3 O Na
+ NaOH
+ HOCH2CH3
H2O
Mechanism of Saponification
Step One – Nucleophilic addition of hydroxide anion:
O
CCH3 O
CH2CH3
OHO
CCH3 OCH2CH3OH
Mechanism of Saponification
Step One – Nucleophilic addition of hydroxide anion:
O
CCH3 O
CH2CH3
OHO
CCH3 OCH2CH3OH
Mechanism of Saponification
Step Two – Elimination of alkoxide anion:
O
CCH3 OCH2CH3OH
O
CCH3 O
H + OCH2CH3
Mechanism of Saponification
Step Two – Elimination of alkoxide anion:
O
CCH3 OCH2CH3OH
O
CCH3 O
H + OCH2CH3
Mechanism of Saponification
Step Three – Proton reorganization (acid–base reaction):
O
CCH3 O
+ HOCH2CH3
O
CCH3 O
H + OCH2CH3
Mechanism of Saponification
Step Three – Proton reorganization (acid–base reaction):
O
CCH3 O
+ HOCH2CH3
O
CCH3 O
H + OCH2CH3
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:
O
CCH3 OH
O
CCH3 O
C
O
CH3
OH
CO2H
OCCH3
CO2H
O
+
+
salicylic acid
acetyl salicylic acid
(aspirin)
acetic anhydride
Example of Esterification
Preparation of aspirin:
O
CCH3 OH
O
CCH3 O
C
O
CH3
OH
CO2H
OCCH3
CO2H
O
+
+
salicylic acid
acetyl salicylic acid
(aspirin)
acetic anhydride
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
O
CCH3 O NH4
O
CCH3 O
C
O
CH3
O
CCH3 NH2
+ 2 NH3
+
acetic anhydride
acetamide ammonium acetate
Example of Amide Formation
Preparation of acetamide
O
CCH3 O NH4
O
CCH3 O
C
O
CH3
O
CCH3 NH2
+ 2 NH3
+
acetic anhydride
acetamide ammonium acetate
Example of Amide Formation
Preparation of acetaminophen
O
CCH3 O
C
O
CH3acetic anhydride
NH2
HO
NHCCH3
HO
O
p-hydroxyaniline
acetaminophen (TYLENOL®)
+