2

Introduction
The carboxyl group (-CO2H) is the parent group of a
family of compounds called acyl compounds or
carboxylic acid derivatives
Esters and amides common in nature.
 Recall that aldehydes and ketones undergo nucleophilic
addition to the carbon-oxygen double bond
 The carbonyl group of carboxylic acids and their derivatives
undergo nucleophilic addition-elimination

The nucleophile reacts at the carbonyl group to form a tetrahedral

intermediate
The tetrahedral intermediate eliminates a leaving group (L)
The carbonyl group is regenerated; the net effect is an acyl
substitution
Reactivity decreases as leaving group becomes
more basic.
More
reactive
derivatives
can be
converted to
less reactive
derivatives.
 More reactive than acids; the halogen
withdraws e- density from carbonyl.
Named by replacing -ic acid with -yl halide.
 O
H2O
R C OH + HCl acid
O
R'OH
O R C OR' + HCl ester
R C Cl O
R'NH2
R C NHR' + HCl amide
O O
R'COOH
R C O C R' + HCl
acid anhydride
 OH
(1) 2 R'MgX
R C R' 3 alcohol
(2) H2O
R'
O
R'2CuLi
O R C R' ketone
R C Cl
(1) LiAlH4
R CH2OH 1 alcohol
(2) H2O
O
Li(t-BuO)3AlH aldehyde
R C H
O
Z C R acylbenzene
AlCl3 Z
 Alcohol attacks the C=O.
Tetrahedral intermediate forms.
Chloride ion leaves, C=O is restored, H+ is
abstracted.

_
O
O O
- H+
C
R' O H R Cl R C Cl C R' + HCl
+O R O
H R'
 _
O
O O
R'2 N H C
R Cl R C Cl C R'2
+N R N
+
H R'2 + -
R'2NH2 Cl
R'2 N H

_
O
O O O O
- H+
C
R' C O H R Cl R C Cl C C + HCl
+O R O R'
H C R'
O
 Most anhydrides are named by dropping the word acid
from the carboxylic acid name and adding the word
anhydride
 React acid chloride with carboxylic acid or
carboxylate ion.
O O O
C Cl O C O C CH
_ 3
+ CH3 C O

Heat dicarboxylic acids to form cyclic anhydrides.

O
O
C OH
O
C OH
O
O
 Acid chlorides react with carboxylic acids to form
mixed or symmetrical anhydrides
It is necessary to use a base such as pyridine

Sodium carboxylates react readily with acid

chlorides to form anhydrides
 Cyclic anhydrides with 5- and 6-membered rings can
be synthesized by heating the appropriate diacid
 Four billion pounds/year produced.
Use high heat (750C) and triethyl phosphate
catalyst to produce ketene.

O heat
(EtO)3P O H
CH3 C OH C C O
H

O O O
H
C C O + CH3 C OH CH3 C O C CH3
H
 O
H2O
R C OH + RCOOH acid
+
O
R'OH, H
O O R C OR' + RCOOH ester
R C O C R O
R'NH2
R C NHR' + RCOOH amide
O
Z
C R acylbenzene
AlCl3 Z
 The names of esters are derived from the names of the
corresponding carboxylic acid and alcohol from which the ester
would be made
The alcohol portion is named first and has the ending yl The
carboxylic acid portion follows and its name ends with -ate or
-oate
Synthesis of Esters
From Carboxylic Acids
with ROH via mineral acid catalysis
via the use of diazomethane
From Acid Chlorides
From Acid Anhydrides
Esterification

Acid catalyzed reaction of alcohols and carboxylic acids to form

esters is called Fischer esterification
Fischer esterification is an equilibrium process
Ester formation is favored by use of a large excess of either the
alcohol or carboxylic acid
Ester formation is also favored by removal of water
Esterification with labeled methanol gives a product labeled only at
the oxygen atom bonded to the methyl group
The reverse reaction is acid-catalyzed ester hydrolysis
Esters from Acid Chlorides

Esters from Carboxylic Acid Anhydrides

Base-Promoted Hydrolysis of Esters: Saponification
Reaction of an ester with sodium hydroxide results in the formation of a
sodium carboxylate and an alcohol

The mechanism is reversible until the alcohol product is formed

Protonation of the alkoxide by the initially formed carboxylic acid is irreversible
 One alkoxy group can be replaced by
another with acid or base catalyst.
Use large excess of preferred alcohol.

O O
C OCH CH C OCH
2 3 + - 3
H or OCH3
+ CH3OH + CH3CH2OH
 O
H2O
R C OH + R'OH acid
O
R''OH,
+ - R C OR'' + R'OH ester
H or OR''
O O
R''NH2
R C OR' R C NHR'' + R'OH amide

(1) LiAlH4
R CH2OH 1 alcohol
(2) H2O
OH
(1) 2 R''MgX
R C R''
(2) H2O 3 alcohol
R''
 Formation favored for five- and six-membered rings.

+ O
OH H
+ H2O
COOH O

For larger rings, remove water to shift equilibrium toward products

+ O
OH H
+ H2O
COOH
O
 g- or d-Hydroxyacids undergo acid catalyzed reaction to give
cyclic esters known as g- or d-lactones, respectively
 Lactones can be hydrolyzed with aqueous base
Acidification of the carboxylate product can lead back to
the original lactone if too much acid is added
 Amides with no substituents on nitrogen are named by replacing -
ic acid in the name with amide
Amides with one or two hydrogens on nitrogen form very strong
hydrogen bonds and have high melting and boiling points
Hydrogen bonding between amides in proteins and peptides is an
important factor in determining their 3-dimensional shape
Amides From Acyl Chlorides

Amides from Carboxylic Anhydrides

Amides from Carboxylic Acids and Ammonium Carboxylates

Direct reaction of carboxylic acids and ammonia yields ammonium salts

Some ammonium salts of carboxylic acids can be dehydrated to the amide
at high temperatures
This is generally a poor method of amide synthesis

A good way to synthesize an amide is to convert a carboxylic acid to an acid

chloride and to then to react the acid chloride with ammonia or an amine
 Dicylohexylcarbodiimide (DCC) is a reagent used to form amides from carboxylic
acids and amines
DCC activates the carbonyl group of a carboxylic acid toward nucleophilic addition-
elimination
 O O
R C OR'' + R'NH2 R C NHR' + R''OH
ester O
+ -
R C N + H2O H or OH
R C NH2
nitrile

O
H2O
R C OH + R'NH2
H+ or -OH
acid and amine
(1) LiAlH4
(2) H2O
R CH2NHR' amine
O
Br-, OH-
R C NHR' R NH2 + CO2 1 amine

POCl3
R C N nitrile
(or P2O5)
Hydrolysis of Amides : heating an amide in concentrated
aqueous acid or base causes hydrolysis
 Five- and six-membered rings can be formed by heating
g- and d-amino acids.

NH2 heat NH
COOH + H2O
O
Smaller or larger rings do not form readily.
-Lactams : found in antibiotics isolated from fungi.
 Urea is the diamide of carbonic acid.
Urethanes are esters of a monoamide of carbonic acid.
O O
Cl C Cl + 2 NH3 H2N C NH2
urea
O O
N C O NH C OH NH C OR
H2O ROH

a carbamic acid a urethane

Polyurethanes are formed when a diol reacts with a diisocyanate.

O O
O CH2CH2 O C HN NH C
O C N N C O
HOCH2CH2OH
CH3
CH3
n