Carboxylic Acid Derivatives

Carboxylic Acid Derivatives

Acyl group bound to
electronegative element

O O

R OH R X

Carboxylic acid Carboxylic acid

derivative

O O O

R Cl R O R

Acyl chloride Acid anhydride

O O
R' R'
R O R N
R''
Ester Amide
Carboxylic Acid Derivatives
 Examples

Acyl chlorides

O
Acetyl chloride
Cl

Acid anhydrides

O O
Acetic anhydride
O

Esters

O
Ethyl acetate
O

Amides

O
N-ethyl acetamide
N
H

Nitriles

Ethane nitrile
H3C Acetonitrile
Interconversion of Carboxylic Acid Derivatives
Carboxylic Acid Derivatives
Carboxylic Acid Derivatives
 Methods of Preparation of
Acyl Chlorides

Acid chlorides are prepared by the reaction

between a carboxylic acid and phosphorus
trichloride PCl3, phosphorus pentachloride PCl5, or
thionyl chloride SOCl2. The choice of reagent is
governed by the boiling points of the products. The
boiling point of the acid chloride formed should not
be near that of the by-products.
 Physical Properties
The lower acyl chlorides are colourless
liquids with boiling points in the same
range as those of alkanes of
comparable relative molecular mass, a
fact which implies that there is very little
association between molecules, Acyl
chlorides have strong, unpleasant
odours due partly to the hydrogen
chloride formed when they react with
water. Benzoyl chloride is also
lacharymatory, that is, it induces tears.
 Chemical Properties
The aliphatic members of the series are
highly reactive compounds. The aromatic
acyl chloride are considerably less reactive,
because the partial positive on the carbon
atom of the functional group is less. Acid
chlorides undergo nucleophilic
substitution.
They are the most reactive of the
carboxylic acid derivatives. The
nucleophiles are water, alcohol, ammonia
and amines.
 Reactions of Acid Halides

11
 Naming Esters, RCO2R’

• Name R’ and then, after a

space, the carboxylic acid
(RCOOH), with the “-ic acid”
ending replaced
by “-ate”

Ethyl Ethanoate

12
 Direct Reaction between Carboxylic
Acid and an Alcohol
A general method of preparation of esters is the
reaction of an alcohol with a carboxylic acid in the
presence of a strong mineral acid such as
concentrated sulphuric acid or dry hydrogen
chloride gas as catalyst.
However the reaction is reversible, the forward
process being known as esterification while the
backward process is known as the hydrolysis of an
ester.

13
Conversion of Carboxylic Acids into Esters
Esters are usually prepared from carboxylic
acids

14
 ESTERS PREPARATION

From Silver Salts of Carboxylic Acids

The silver salts of carboxylic acids react on
heating with alkyl halides to give
esters.
 Physical Properties

The ester containing up to ten carbon atoms per

molecule are liquids and the lower numbers of the
series are very volatile. Because association by
hydrogen bonding is not possible, the esters boil at
considerably lower boiling points than their parent
acids. The ester of low relative molecular mass are
fairly soluble in water but the solubility decreases as
the relative molecular mass increases. Some boiling
points are given below.

Boiling points of esters

Formula Name Boiling Point (0C)
HCOOCH3 Methyl methonate 32
CH3 COOCH3 Methyl ethanoate 56
CH3COOC2H5 Ethyl ethanoate 77
CH3COOC3H7 Propyl ethanoate 101
Commercial Value of Esters

Esters are used extensively in industry. In an

attempt to reproduce the flavours and aromas
of natural fruits, manufacturers use esters as
artificial essences and in synthetic perfumes.

Artificial Flavours
Name of Ester Flavour
3 - Methyl butyl ethanoate Banana
Methyl butanoate Pineapple
Ethyl n - butanoate Apple
Noctyl ethanoate Orange
Benzyl ethanoate Peach

By far the most important use of esters is as

solvents. In industry they are used as solvents
for cellulose nitrate, oils, gums, raising
varnishes and paints.
Carboxylic Acids and Esters in Nature
Reactivity is related to structure

Stabilization of carbonyl by e-–donation

:
: :
O: O: O:
:

:
R X R X R X

Reactivity order:

acyl chloride > anhydride > ester > amide

O O O O O
> > R' > R'
R Cl R O R R O R N
R''
Derivatives differ in degree stabilization

Acyl chlorides:

:
:
: O: :O: :O:
: :

: :
R R Cl: R
Cl : Cl :

:
not a significant
poor orbital contributor
overlap

Anhydrides:
:

:
:O : :O : :O : :O :
:O:
: :

R R O R R O R

:
:

: O: R
Esters:
:

O : O: : O:
R' R'
: :

R O R O
:

Amides:
:

: O: : O: : O:
:

R NR'2 R NR'2 R NR'2

significant
very effective
contributor
 Reactions of Esters
Hydrolysis of Ester
 Reactions of Acid
Anhydrides
• Similar to acid chlorides in
reactivity

22
Figure 20.1
 Reactivity is related to structure
Relative rate
Stabilization of hydrolysis

O
very small
1011
R Cl
Acyl chloride

O O
small 107
R O R
Acid anhydride

O
R' moderate 1.0
R O
Ester

O
R' large
R N < 10-2
R''
Amide

The more stabilized the carbonyl group,

the less reactive it is
 Acyl halide nomenclature

Acyl halides: replace -ic acid with -yl chloride

O
Acetyl chloride
Cl

O
O
Br
Cl
F

p-fluorobenzoyl
3-butenoyl chloride
bromide
 Synthesis of acyl chlorides

Overall Reaction:
O O
SOCl2
OH Cl

Mechanism:
O O
+
S
OH Cl Cl
 Acyl chloride hydrolysis

Acyl chlorides react with water to give:

carboxylic acids or carboxylate ion
*pay attention to pH!!!

R Cl

+ H 2O + 2 NaOH

O O

R OH R O-

+ HCl + 2 Na+
+ Cl-

carboxylic acid carboxylate ion

(in water) (in base)
 Acyl chloride hydrolysis mechanism

First Stage:

H R H R
slow +O R fast
+ O O- H O C O H
: O:
Cl H Cl
H C
Tetrahedral
Cl intermediate

Second Stage:

R H R
fast
H O C O H + O + H3O+
:O :
Cl H O
H
+ Cl-
Tetrahedral
intermediate
 Acyl chloride reactions
Make: anhydrides, esters, amides, carboxylic acids
(Table 20.1)
Example 1:
O O
+
Cl OH
heptanoyl chloride heptanoic acid

pyridine

O O

O
+ HCl
heptanoic anhydride
(78 - 83%)

Example 2:
O

Cl + OH

benzoyl chloride
pyridine

O
+ HCl
tert-butyl benzoate
(80%)
 Acyl chloride reactions
Make: anhydrides, esters, amides, carboxylic acids
(Table 20.1)

Cl + HN

benzoyl
piperidine
chloride

NaOH
H2O

O + H2O + Cl-
N

N-benzoylpiperidine
(87 - 91%)
Figure 20.1
 Acid anhydride nomenclature

Acid anhydrides: when both acyl groups are same,

replace acid with anhydride

when both acyl groups are

different, cite acids alphabetically
and
add anhydride

O O
Acetic anhydride
O

O O O O

O O (CH2)5

Benzoic heptanoic
Benzoic anhydride
anhydride
 Acid anhydride reactivity

O O O O
+ HY: +
R O R R Y: HO R

bond cleavage

Anhydrides readily converted to

more stable carboxylic acids,
esters, amides, not acid
chlorides

Nucleophilic acyl substitutions

can be
catalyzed by acids
Acid anhydride hydrolysis mechanism

Step 1

H fast O OH
O :
+ H + H2O
O: O O O

H
Step 2

O OH
O OH H slow
+ :O : O
O O
H H H
Nucleophile

Step 3

O OH O OH
H fast
O + + H3O+
:O: O
O OH
H H H
Tetrahedral
intermediate
Step 4, 5, 6
H
O H O O
+
H + H
O O : O O
OH
O
H : + H3O+
H O H
H
 Acid anhydride reactions
Make: esters, amides, carboxylic acids
(Table 20.2)
O O HO
Example 1
+
O
sec-butyl alcohol

H2SO4

O
O
+ HO
O
sec-butyl acetate
(60%)

Example 2 O O H2N
+
O

p-isopropylaniline

O O
N +
HO
H
p-isopropylacetanilide
(98%)
 Ester nomenclature
Esters: name alkyl attached to oxygen, then
acyl (replace -ic acid with -ate)

O
Ethyl acetate
O

O
Methyl salicylate
O
(wintergreen oil)
OH

O
Cl 2-chloroethyl
O
benzoate
 Ester synthesis

Fischer esterification

O O
H2SO4
OH MeOH O

via

OH
OH
OCH3

Tetrahedral
intermediate

Esters also from acyl chlorides

and acid anhydrides
 Methyl ester NMR
NH2 NH2
H2SO4
OH O
MeOH
Br O Br O

-OCH3
-CH3

CDCl3 EtOAc
(solvent) EtOAc

H2O

EtOAc
 Ester hydrolysis
Acid-catalyzed - see anhydride
hydrolysis mechanism, or text
Mechanism 20.3
Base-catalyzed IRREVERSIBLE!!!
O O-
Step 1:
R' R OR'
R O OH
HO-

Step 2:

OH
O-
R OR' + H OH R OR' + HO-
OH OH
Tetrahedral
intermediate
Step 3:
H
O O H
OH- + R OR' + R'O-
O +
R OH H
OH

Step 4:

R'O- + H OH R'O H + HO-

O O H
H + HO- + O
R O R O- H

Carboxylate ion stable under basic conditions

 Ester reactions

O NH2
F +
O

Ethyl fluoroacetate Cyclohexylamine

O
F + OH
N
H
N- Ethanol
fluoroacetamide
Cyclohe
(61%)
xyl-

Amine must be 1º or 2º (need an H

that can be replaced by an acyl
group)
 Amide nomenclature

Amides: replace -ic acid with -amide

O
acetamide
NH2

O
3-methyl butanamide
NH2

NH2 benzamide

O
N-ethyl acetamide
N
H

N N,N-dimethyl benzamide
 Amide properties

Delocalization of electrons decreases

positive character of carbonyl carbon

Amides less reactive than other

carboxylic acid derivatives toward
nucleophilic acyl substitution
:

:
: O: : O: : O:
:

H NH2 H NH2 H NH2

significant
Formamide
contributor

N less electronegative than O

increasing acidity

O O O O
NH2 N OH
NH2
H
amine amide imide carbox. acid

pKa: 36 15 10 5
 Amide properties

O
O-
: CH3 CH3
H 3C N H3C N
CH3 CH3

N,N-dimethyl acetamide

H2O

DMSO
(solvent)
 Amide physical properties

Large dipole effective H-bonding

: O:
H
H :
N
δ+
H
H
δ−
:N H
:
O: δ+ δ−

: :
H O
:
H N
H
δ+
H

: O: δ−
H
:

H N
H

Trends due to intermolecular H-bonding

O O
O
N N NH2
H

N,N- N-methyl
acetamide
dimethyl acetamide
acetamide
- 20 31 80
mp (oC)

bp (oC) 165 206 221

H-bonds 0 1 2
 Amide synthesis

Preparation from amines by

acylation with:

• acyl chlorides

• acid anhydrides

• esters

Only substitution reaction amide

undergoes is hydrolysis
 Amide hydrolysis
Step 1:
O H OH H
+ H + O
R NH2 O R NH2 H

Step 2: H
OH
H OH
O + R NH2
H R NH2 O
H H

Step 3: OH
H OH H
R NH2 + O R NH2 + H O
O H OH H
H H
Tetrahedral
intermediate
Step 4:
OH H OH H
R R O
NH2 + H O NH3 +
OH H OH H

Step 5:
OH OH
R NH3 + NH3
OH R OH

Step 6:
H H
H O + :NH3 O + NH4+
H H

OH H O
+ O + H3O+
R OH H R OH

IRREVERSIBLE!!!
 Amide hydrolysis

Acid-catalyzed IRREVERSIBLE

+ +
NH3 H3O+ NH4 + H2O

Base-catalyzed IRREVERSIBLE

O O
+ HO- + H 2O
R OH R O-
 Lactams

Lactams are cyclic amides

(like lactones are cyclic
esters)
Ring can be O
NH
many sizes
 Nitrile nomenclature

Nitriles: add nitrile to name of

hydrocarbon chain which R C N
includes the nitrile C
atom
-or-

replace -ic acid with -onitrile

-or-

name as alkyl cyanide

Ethane nitrile
H3C C Acetonitrile
N Methyl
cyanide

C Benzonitrile
N

2-methylpropane nitrile
C isopropyl cyanide
N
 Nitrile synthesis

- + R X R C +
N X-
C: N
nitrile

O OH
+ HCN R C N
R R' R'
cyanohydrin
 Addition to nitriles

Nitrile C less reactive to

nucleophilic addition than a
carbonyl

Strongly basic
nucleophiles, ie. Grignards,
do react
The resulting imine can be hydrolyzed
to a ketone
NMgX
R C + R'MgX
N Et2O R R'
Nitrile Grignard

H3O+

O NH
H3O+
R R' heat R R'

Ketone Imine
 Nitrile hydrolysis

Hydrolysis yields a carboxylic acid

IRREVERSIBLE in the presence of
acids or bases

R C + H2O + H3O+
N
Nitrile

O
+ +
NH4
R OH

R C + H2O + HO-
N
Nitrile

O
+ NH3
R O-
 Summary

Reactivity order:

acyl chloride > anhydride > ester > amide

O O O O O
> > R' > R'
R Cl R O R R O R N
R'
'

Reactivity toward more stable derivative

All undergo hydrolysis to carboxylic acid

Pay attention to pH!!! It will tell you if

the reaction is IRREVERSIBLE