Alrasheed University College

Department of Pharmacy

Carboxylic Acids
and Their Derivatives
Lecture 4

Prepared by
Dr. Kutaiba Ibrahim Alzand
Introduction
Carboxylic Acid Derivatives

O O O O

R OH R Cl R O R'
carboxylic acid acid chloride acid anhydride

O O

R OR' R NR'2
ester amide

Ch. 17
 The carboxyl group, (-COOH), is one of the most widely occurring functional
groups in chemistry and biochemistry.
 Not only are carboxylic acids themselves important, but the carboxyl group is
the parent group of a large family of related compounds called acyl
compounds or carboxylic acid derivatives, shown in Table 17.1.

Ch. 17
Nomenclature
Rules
Carboxylic acid as parent (suffix): ending
with “–oic acid”
Carboxylate as parent (suffix): ending
with “–oate”

Ch. 17
Anhydrides are named by dropping the acid and
adding the word “anhydride”

Acid chloride suffix: “–oyl chloride”

Ester suffix: ending with “–oate”

Amide suffix: ending with “amide”

Nitrile suffix: ending with “nitrile”

Ch. 17
Examples
O O

OH OCH3
Ethanoic acid Methyl propanoate
(acetic acid)

O O O

O NH'2
Ethanoic anhydride Ethanamide
(acetic anhydride)

Ch. 17
Examples
O

O
Cl

O Na
Sodium benzoate Benzoyl chloride

H3C C N
Ethanenitrile

Ch. 17
Solved Problem
Give an IUPAC systematic name for the following compound.

Ch. 17
Practice Problem
Give an IUPAC systematic name for each of the following:

Answer:
(a) 2-Methylbutanoic acid
(b) (Z)-3-Pentenoic acid or (Z)-pent-3-enoic acid
(c) Sodium 4-bromobutanoate
(d) 5-Phenylpentanoic acid
(e) (E)-3-Ethyl-3-pentenoic acid or (E)-3-Ethylpent-3-enoic acid

Ch. 17
Practice Problem
Experiments show that the molecular weight of acetic acid in the vapor state (just
above its boiling point) is approximately 120. Explain the discrepancy between
this experimental value and the true value of approximately 60.

Answer:

Ch. 17 -
Acidity of Carboxylic Acids
O
H
R O

pKa ~ 4-5

Compare
pKa of H2O ~ 16
pKa of H2CO3 ~ 7
pK of HF ~ 3 Ch. 17
Acidity of Carboxylic Acids, Phenols & Alcohols

H H
O O O
H
O

pKa = 4.20 pKa = ~ 10 pKa = ~ 17

Ch. 17 -
 Acidity of Carboxylic Acids, Phenols
and Alcohols
O O
H
O O
+ H2 O
+ H3O+

Ch. 17 -
 Acidity of Carboxylic Acids, Phenols
and Alcohols
O
O
H
+ H3O+

+ H2O

O O O

Ch. 17 -
 Acidity of Carboxylic Acids, Phenols
and Alcohols

O O
H
+ H2O + H3O+

(NO resonance stabilization)

Ch. 17 -
Question
How could you distinguish these 3 by
simple chemical tests?
(acidity)
H H
O O O
H
O
> >

Ch. 17 -
 O O
H + Na OH + H2O
R O R O Na
(soluable )

O O Na
H
+ NaOH

(soluble in water)

O
H
+ NaOH No Reaction

(immiscible
with H2O)
Ch. 17 -
 O
O
H O Na + CO2(g) + H2O
O
+ NaHCO3
(gas evolved)

O
H
+ NaHCO3 No Reaction

O
H
+ NaHCO3 No Reaction

Ch. 17 -
 O O O O
Cl Cl
> > Cl > H
Cl OH Cl OH H OH H OH
Cl H H H

pKa 0.70 1.48 2.86 4.76

 Stability of conjugate bases

O O O O
Cl Cl Cl H
>

>

O > Cl O > H > O > H O

> >
Cl
>

Cl H H H

Ch. 17 -
 O Cl O

>
> > >
OH OH
>Cl
2-Chlorobutanoic acid 3-Chlorobutanoic acid
(pKa = 2.85) (pKa = 4.05)

O
Cl
>
> > >
OH

4-Chlorobutanoic acid
(pKa = 4.50)
Ch. 17 -
Solved Problem
Which carboxylic acid would you expect to be stronger, A or B?

Strategy and Answer: The electron-withdrawing effect of the nitro

group would help stabilize the conjugate base of B, whereas the
electron-donating effect of the methyl group in A would destabilize its
conjugate base. Therefore, B is expected to be the stronger acid.

Ch. 17 -
Practice Problem
Which acid of each pair shown here would you expect to be stronger?

Ch. 17 -
Ch. 17 -
Dicarboxylic Acids pKa
(at 25oC)
Common
Structure Name mp (oC) pK1 pK2
HO2C CO2H Oxalic acid 189 dec 1.2 4.2

HO2CCH2CO2H Malonic acid 136 2.9 5.7

HO2C(CH2)4CO2H Adipic acid 153 4.4 5.6

CO2H
Phthalic acid 206-208 dec 2.9 5.4
CO2H

Ch. 17 -
Preparation of Carboxylic Acids
Oxidation cleavage of alkenes
KMnO4
1. KMnO4, OH, heat
Ph 2. H3O+

OH
O
+
Ph O
OH
ozonolysis
HO OH
O O
1. O3
2. H2O2

Ch. 17 -
Oxidation of aldehydes & 1o alcohols
H 1. Ag2O OH

O 2. H3O+ O
OH
1. KMnO4, OH, heat
OH + O
2. H3O
O O
H2CrO4
H or OH OH

Ch. 17 -
Oxidation of alkyl benzene
O
R
1. KMnO4, OH, heat OH
2. H3O+

(R = 1o or 2o alkyl groups)

Ch. 17 -
Oxidation of benzene ring

1. O3, CH3COOH O

2. H2O2
OH

Ch. 17 -
Hydrolysis of cyanohydrins & nitriles
O
O NC HO C
HCN OH H+ OH

Ph CH3 Ph CH3 H2O Ph CH3

O
HCN +
H
Br CN C
H2O, heat OH

Ch. 17 -
Carbonation of Grignard reagents
Br MgBr
Mg
Et2O

Grignard reagents react with carbon 1. CO2

dioxide to yield magnesium carboxylates.
Acidification produces carboxylic acids: 2. H3O+
O

OH

Ch. 17 -
 This synthesis of carboxylic acids is applicable to primary, secondary,
tertiary, allyl, benzyl, and aryl halides, provided they have no groups
incompatible with a Grignard reaction:

Ch. 17 -
Practice Problem
Show how each of the following compounds could be converted to benzoic acid:

Answer:

Ch. 17 -
Ch. 17 -
Nucleophilic Addition-Elimination at the Acyl Carbon
 The reactions of carboxylic acids and their derivatives are characterized by
nucleophilic addition–elimination at their acyl (carbonyl) carbon atoms.
 The result is a substitution at the acyl carbon. Key to this mechanism is formatio
of a tetrahedral intermediate that returns to a carbonyl group after the elimination
of a leaving group.

O O
+ Nu
Nu
R Y R
Y
O
Y +
R Nu
(Y = leaving group, e.g. OR, NR2, Cl)
Acyl substitution through nucleophilic addition-elimination
Ch. 17 -
Acyl derivatives
O O O O

R OH R Cl R O R'
carboxylic acid acid chloride acid anhydride

O O

R OR' R NR'2
ester amide

Ch. 17 -
Usually the addition is the rate-
determining step (r.d.s.).
Elimination usually occurs
spontaneously to regenerate the
carbonyl group

Both steric and electronic factors that

effect addition of a nucleophile

Ch. 17 -
Steric factor
e.g.
O O
reactivity of >
Cl Cl

Electronic factor
strongly polarized acid derivatives react
more readily than less polar ones

Ch. 17 -
 Thus, reactivity of
O O O O O
> > >
R Cl R O R' R OR' R NR'2
most least
reactive reactive
It is usually possible to convert a more
reactive acid derivative to a less
reactive one, but not vice versa

Ch. 17 -
Acyl Chlorides
Synthesis of Acyl Chlorides
From carboxylic acids
O O

R OH R Cl

reagents
SOCl2 All of these reagents react with
carboxylic acids to give acyl chlorides
PCl3 in good yield:
PCl5

Ch. 17 -
General Reactions

Ch. 17 -
Mechanism
O
Cl
O Cl O O
O Cl
R OH R O
Cl
O
O O
Cl
Cl R O
O
O O O
Cl + CO2 + CO + Cl
R O R Cl
Cl
O Ch. 17 -
Conversion of acid chlorides to
carboxylic acids

O base O
+ H2O
R Cl R OH

Ch. 17 -
 Mechanism
O O OH
H
R Cl H2O R O R OH
Cl H Cl

H
O B: O
B H +
R OH R OH

Ch. 17 -
Conversion to other carboxylic
derivatives
O
R'OH
(ester)
pyridine R OR'

O O
R'2NH
(amide)
R Cl R NR'2
O

O O
R' O Na
(acid anhydride)
R O R'

Ch. 17 -
Carboxylic Acid Anhydrides
Synthesis of Anhydrides
Carboxylic acids react with acyl chlorides in the presence of
pyridine to give carboxylic acid anhydrides.
O O
+ +
R OH R' Cl N

O O
+ Cl
R O R'
N
H
Ch. 17 -
 Sodium salts of carboxylic acids also react with acyl chlorides to give anhydrides:
O O O O
+ + Na Cl
R O Na R' Cl R O R'

O O
Cyclic anhydrides can be prepared
OH 300oC simply by heating the appropriate
O + H2O dicarboxylic acid. This method
OH
succeeds, however, only when
Succinic anhydride formation leads to a five-
O acid O Succinic
anhydride or six-membered ring:
O O

OH 230oC
O + H2O
OH
Phthalic Phthalic anhydride O
acid O (~100%)
Ch. 17 -
Reactions of Carboxylic Acid Anhydrides
 Because carboxylic acid anhydrides are highly reactive, they
can be used to prepare esters and amides.

Ch. 17 -
 Carboxylic acid anhydrides also undergo hydrolysis:

Ch. 17 -
Reactions of Anhydrides
Conversion to carboxylic acids

O O + O O
H
+ H2O +
R O R' R OH HO R'

Ch. 17 -
 Mechanism
H
O O H+ O O OH O

R O R' R O R' H2O R O R'

O
H H

H
O H2O O OH O
+ R'COOH
R OH R OH R O R'
OH
H

Ch. 17 -
Conversion to other carboxylic derivatives
O O
R'OH
+
R OR' R OH

O O

R O R'

O O
+
R2'NH R NR'2 R O NR' 2H2

Ch. 17 -
Esters
Synthesis of Esters: Esterification
Carboxylic acids react with alcohols to form esters through
a condensation reaction known as esterification:
O + O
H
+ R'OH + H2O
R OH R OR'

Ch. 17 -
Mechanism
H
O H+ O OH
H H H
R O R O R'OH R O
OH
"activated" R'

H
O H2O O OH2

R OR' R OR' R OR'

HO

Ch. 17 -
Esters from acyl chlorides

e.g. O

Cl
+ EtOH +
N
Benzoyl
chloride O

OEt
+ Cl
N
Ethyl benzoate
(80%) H
Ch. 17 -
Esters from anhydrides

e.g.
O O
OH
+
O
Acetic Benzoyl
anhydride alcohol
O

O
O
+
OH
Benzoyl acetate
Ch. 17 -
Base-Promoted Hydrolysis of Esters
Hydrolysis under basic conditions:
saponification

O OH O
+ R'OH
H2O
R OR' R O

Ch. 17 -
Mechanism
O O

R OR' R OR'
OH
HO

O
H + OR'
R O
+
O H O
R'OH +
R OH R O

Ch. 17 -
Hydrolysis of esters under acidic
conditions

O H + O
+ R'OH
H2O
R OR' R OH

Ch. 17 -
Mechanism
H
O H+ O OH

R OR' R OR' H2O R OR'

O
H H

H
O H2O O OH
+ R'OH R'
R OH R OH R O
OH
H

Ch. 17 -
Lactones
Carboxylic acids whose molecules have a
hydroxyl group on a  or  carbon
undergo intramolecular esterification

(cyclic esters) or - or -lactones

Ch. 17 -
 O H O H
H
 
R   OH O H O
O H O H
HO O H A
a -hydroxyacid R R

O O H

A + H O H + O O + O H
H H
R R
a -lactone
Ch. 17 -
Lactones are hydrolyzed by aqueous
base just as other esters are
O
O
H+/H2O
O C6H5
O
HA, slight excess
OH
C6H5
0oC
O HA, exactly
1 equiv.
C6H5
OH
OH Ch. 17 -
Amides
Amides from Acyl Chlorides Primary amines, secondary
amines, and ammonia all
react rapidly with acid
O O chlorides to
form amides.

R Cl R Cl
H N R"
:NHR'R" R'

O O
R"
Cl + R'R"NH2 + R" :Cl:
R N R N R'
R' H
R"R'HN: Ch. 17 -
Amides from Carboxylic Anhydrides
Acid anhydrides react with ammonia and with primary and secondary amines
to form amides through reactions that are analogous to those of acyl chlorides:

O O H R'
+ 2 N
R O R R"

O O H

R' + H N R'
R N R O R"
R"
R', R" can be H, alkyl, or aryl.
Ch. 17 -
 Cyclic anhydrides react with ammonia or an amine in the same
general way as acyclic anhydrides; however, the reaction yields a
product that is both an amide and an ammonium salt. Acidifying the
ammonium salt gives a compound that is both an amide and an acid:

O O

H2O NH2
O + 2 NH3
warm O NH4

O O Ammonium
Phthalamic O
anhydride phthalamate
(94%)
NH2 H3O+
OH (- NH4+)

Phthalamic acid
O
(81%)
Ch. 17 -
 Heating the amide acid causes dehydration to occur and gives an
imide. Imides contain the linkage

O O

NH2 150-160oC
N H
OH

+ H2O O
O
Phthalamic acid Phthalimide
(~ 100%)

Ch. 17 -
Amides from Esters
 Esters undergo nucleophilic addition–elimination at their acyl carbon atoms
when they are treated with ammonia (called ammonolysis) or with primary
and secondary amines.
 These reactions take place much more slowly than those of acyl chlorides
and anhydrides, but they can still be synthetically useful:
O
O H R' R'
+ N R N + R'"OH
R OR'" R" R"

R' and/or R" may be H.

e.g. O O
Me
OMe MeNH2 N
heat H
+ MeOH
Ch. 17 -
Amides from Carboxylic Acids &
Ammonium Carboxylates Carboxylic acids react with aqueous
ammonia to form ammonium salts:
O O
+ NH3
R OH R O NH4
Because of the low reactivity of the carboxylate ion
toward nucleophilic addition–elimination, further heat
reaction does not usually take place in aqueous
solution. However, if we evaporate the water and
subsequently heat the dry salt, dehydration produces O
an amide:
H2O +
R NH2

Ch. 17 -
DCC-Promoted amide synthesis
O O
1. DCC
R' + DCU
R OH 2. R'NH2 R N
H

 Dicyclohexylcarbodiimide (DCC)
 Dicyclohexylurea (DCU)

Ch. 17 -
Mechanism
C6H11
N
:
:
O:

:
R N C6H11
R C + C
C O C
:O H

:
:N

:
H O: N:
:

:
C6H11 C6H11

:
R N C6H11

: :
C O C

:
H O
: N:
C6H11

Ch. 17 -
Mechanism (Cont’d)
: :
O

:
:
R N C6H11 N C6H11
proton C

: :
C O C R O C
transfer
:

:
H O: N: NHC6H11
:

:
C6H11 reactive intermediate
:

: :
:

O N C6H11

:
R' NH2
: :

R C O C
NH2 NHC6H11
:

:
:
R' O: NHC6H11

: :
R C + O C
NHR' NHC6H11

:
an amide N,N'-Dicyclohexylurea
(DCU) Ch. 17 -
Hydrolysis of Amides
Acid hydrolysis of amides
 Amides undergo hydrolysis when they are heated with aqueous acid
or aqueous base.

O + O
H
+ NH4
R NH2 H2O, heat R OH

Ch. 17 -
Mechanism
H
:O : O OH

:
H+ H2O

R NH2 R NH2 R NH2

:
H O
H

H
:O : O : OH
:
+ NH3
R OH R OH R NH3
HO

Ch. 17 -
Basic hydrolysis of amides
O  O
OH
+ NH3
R NH2 H2O, heat R O

Ch. 17 -
Mechanism

O OH O O
H + NH2
R NH2 R NH2 R O
HO

O
NH3 +
R O

Ch. 17 -
Nitriles from the Dehydration of Amides
 Amides react with P4O10 or with boiling acetic anhydride to
form nitriles:

:O : P4O10 or (CH3CO)2O
R C N: + H3PO4
heat
:

R NH2 (a nitrile) (or CH3CO2H)

(H2O)

 This is a useful synthetic method for preparing nitriles that

are not available by nucleophilic substitution reactions
between alkyl halides and cyanide ion.

Ch. 17 -
 O
C N
NH2 P4O10

dehydration

Ch. 17 -
Synthesis C N

NaCN
Br CN
DMSO

1o alkyl bromide SN2

Ch. 17 -
 CN
But synthesis of

Br NaCN
No SN2
DMSO (only E2)

3o alkyl bromide

Ch. 17 -
Solution
O

Br 1. Mg, Et2O
OH
2. CO2
3. H3O+

O 1. SOCl2
2. NH3
CN
NH2
P4O10

dehydration
Ch. 17 -
Hydrolysis of Nitriles
 Nitriles are related to carboxylic acids because complete
hydrolysis of a nitrile produces a carboxylic acid or a
carboxylate anion:

O
base or acid
R C N
H2O, heat R OH

Catalyzed by both acid and base

Ch. 17 -
Examples
H2SO4 OH
CN
H2O, 
O
(82%)

OH
CN
1. NaOH, H2O,  O
2. H3O+ (68%)

Ch. 17 -
Mechanism protonated nitrile
H
R C N: R C NH R C NH + : O H
H

:
H O H slow
: amide
tautomer H

:
H H H H2O

:
:

O: O: :O H
H O H +
C C C
:

R NH2 R NH R NH

:
:
protonated
amide
H
O: several steps O
+ NH4
C (amide hydrolysis)
R NH2 R OH Ch. 17 -
:
Mechanism

:
:
:
N H OH NH

: :
R C N: +
:
O H
R OH R OH
: :
:
O H

H
O HO O HO H OH
:

: :
R NH2 R NH2 R NH
O H OH OH OH OH
H
HO
HO H

O O
H OH
:

R NH2 + NH3 + OH
R O
O Ch. 17 -
Lactams O
O
O 
 NH
 NH
 
 NH   
a -lactam a -lactam a -lactam
R = C6H5CH2 Penicillin G
H
R N S CH3 R = C6H5CH Ampicillin

O N CH3 NH2
O
CO2H Penicillin V
R = C6H5OCH2

Ch. 17 -
Derivatives of Carbonic Acid
Alkyl Chloroformates & Carbamates (Urethanes)
 Treating carbonyl dichloride with one molar equivalent of an
alcohol leads to the formation of an alkyl chloroformate:

Alkyl chloroformate
O O
ROH + + HCl
Cl Cl RO Cl
alkyl
chloroformate

Ch. 17 -
e.g.

O
OH
+
RO Cl

O Cl
HCl +

Benzyl
chloroformate
Ch. 17 -
  Alkyl chloroformates react with ammonia or amines to yield
compounds called carbamates or urethanes:

Carbamates or urethanes

O O
+ R'NH2
RO Cl OH RO NHR'
a carbamate
(or urethane)

Ch. 17 -
Protection protected amine
O O


R
O Cl OH N O
R NH2 +
H

Deprotection
R NH2 + CO2 +
O H2, Pd

R
N O
H
Br
R NH3 + CO2 +
HBr, CH2CO2H

Ch. 17 -
Decarboxylation of Carboxylic Acids
 The reaction whereby a carboxylic acid loses CO2 is called a
decarboxylation:
O
decarboxylation
R H + CO2
R OH
 Carboxylic acids that have a carbonyl group one carbon
removed from the carboxylic acid group, called β-keto acids,
decarboxylate readily when they are heated to 100–150 8C.
O O o O
100-150 C
+ CO2
R OH R
A -keto acid

Ch. 17 -
There are 2 reasons for decarboxylation
O O O
: : : :
O
CO2 HA

: :
R O: R : R
acylacetate ion

:
O
: :
resonance-stabilized
anion
R
H H
O O O O
CO2

R O R R
-keto acid enol ketone

Ch. 17 -
There are two reasons for this ease of decarboxylation:
1. When the acid itself decarboxylates, it can do so through a six-
membered cyclic transition state:

This reaction produces an enol (alkene-alcohol) directly and

avoids an anionic intermediate. The enol then tautomerizes
to a methyl ketone.

Ch. 17 -
2. When the carboxylate anion decarboxylates, it forms a
resonance-stabilized anion:

This type of anion, is much more

stable than simply RCH2:-, the
anion that would have been
produced by decarboxylation in
the absence of a β-carbonyl group.
It is known as an enolate.

Ch. 17 -
Chemical Tests for Acyl Compounds

Recall: acidity of

H H
O O O
H
O
> >

Ch. 17 -
 O O
H + Na OH + H 2O
R O R O Na
(soluable in water)

O O Na
H
+ NaOH

(soluble in water)

O
H
+ NaOH No Reaction

(immiscible
with H2O)
Ch. 17 - 1
O O
H
O O Na
+ NaHCO3

+ CO2(g) + H2O
(gas evolved)

O
H
+ NaHCO3 No Reaction

O
H
+ NaHCO3 No Reaction

Ch. 17 - 1
Polyesters, Polyamides,
Step-Growth Polymers

Polyesters
O O

HO OH + HO n OH
m
-H2O

O O
O O
n
m
(a polyester) Ch. 17 - 1
Polyamides
O O

+ n
H2N N H Cl Cl
m
H
-HCl

H H O O
N N
n
m
(a polyamide)
Ch. 17 - 1
Nylon 66
O
OH NH2
n HO + n H2N
O

heat

O H

N
N + 2n H2O

O H
(Nylon 66) n

Ch. 17 - 1
Dacron (Mylar)
O O
OH
n + n HO
CH3O OCH3

200oC

O
O
O + 2n CH3OH
O
n
(Dacron)

Applications: film, recording tape

Ch. 17 - 1
 Summary of the Reactions
Reactions of carboxylic acids
O
O C
1. P, X2 R O
R C
OH 2. H2O
NaOH or NaHCO3
X or other bases
O
O
RCH2OH
1. LiAlH4 R OH R'OH, H+,  C
R OR'
2. H2O, H+

O SOCl2 O
O O or PCl3
C C or PCl5 C
R O R' R' Cl R Cl
base Ch. 17 - 1
Reactions of acyl chlorides
O O

R NR' R OH
H2O
R'2NH

R Cl
R'OH, base
R'COOH
base
O O O

R O R' R OR'
Ch. 17 - 1
Reactions of acyl chlorides (Cont’d)
O

R R OH

1. LiAlH4
benzene
AlCl3 2. H3O+
O

R Cl 1. LiAlH(OtBu)3, -78oC
2. H3O+

OH 1. R'MgX O

R' 2. H3O+
R R H
R'
Ch. 17 - 1
Reactions of acid anhydrides
O O
+
R OH HO R'

H2O

O O
R"2NH R"OH

R O R'
O O O O
+ +
R NR" R' O NR"2H2 R OR" HO R'

Ch. 17 - 1
Reactions of esters
O
O
R H
R OH
1. DIBAL, -78oC R OH

1. LiAlH4 2. H3O+
H2O, H+, 
2. H3O+ O
OH O

1. R"MgX 1. OH- R OH
R R" R OR'
R" 2. H3O+ 2. H2O, H+

NH3 R"OH, H+, 

O O

R NH2 R OR"
Ch. 17 - 1
Reactions of nitriles
O
R NH2
R OH

1. LiAlH4 H+, H2O, 

2. H3O+
R C N

OH, H2O, 
1. LiAlH(OtBu)3
or DIBAL, -78oC O
O
2. H3O+
R O
R H

Ch. 17 - 1
Reactions of amides
O
+ HNR'2
R OH

H2O, H+ or OH-

P4O10 (P2O5)
or Ac2O, D O 1. LiAlH4
(R' = H only) R' 2. H3O+
R N
R'

R C N
R NR'2

End- 11