Chapter 17

1. 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
2. Nomenclature and Physical
Properties
2A. Carboxylic Acids
❖ Nomenclature of Carboxylic Acids
● Rules
⧫ Carboxylic acid as parent
(suffix): ending with “–oic acid”
❖ Examples
 Naming Carboxylic Acids
❖ If derived from open-chain alkanes, replace the terminal -e of the alkane name
with -oic acid
❖ The carboxyl carbon atom is C1and it does count as a part of the chain

❖ Compounds with ⎯CO2H bonded to a ring are named using the suffix -
carboxylic acid
❖ The CO2H carbon atom is not numbered, but the ring carbon atom bearing the
carboxyl group is no. 1
 4
CO2H
3 2 1
CH3CHCH2CO2H
Common Names:
3-Methylbutanoic
acid
Carboxylic
HO
Acids
H and Nitriles
cis-4-Hydroxycyclohexane
carboxylic acid
CH3
H

Common Names CO2H

Maleic
CO2H acid
HCO2H Formic CO2H CO2H
CO2H CH2
CH3CO2H Acetic CH2
CH2 O
CO2H
CH3CH2CO2H Propionic CO2H
CO2H O Maleic
CH3CH2CH2CO2H Butyric anhydride
   Oxalic Malonic Succinic
O

CO2H CO2H C N
CN
CH3C N
CO2H

Benzoic Acid Phthalic Acid Acetonitrile Benzonitrile 3-Methylbutanenitrile

2B. Carboxylate Salts
❖ Nomenclature of Carboxylic Salts
● Rules
⧫ Carboxylate as parent (suffix):
ending with “–oate”
❖ Examples
2C. Acidity of Carboxylic Acids
O
H
R O

pKa ~ 4-5
❖ Compare
● pKa of H2O ~ 16
● pKa of H2CO3 ~ 7
● pKa of HF ~ 3
❖ When comparing acidity of organic
compounds, we compare the stability
of their conjugate bases. The more
stable the conjugate base, the stronger
the acid

CH3COOH CH3CH2OH

pKa 4.75 16
 O
+ H2O
CH3 O H
A1

CH3CH2 O H + H2O
A2
❖ The conjugate base B1 is more stable
(the anion is more delocalized) than B2
due to resonance stabilization

O O O

CH3 O CH3 O CH3 O

● Thus, A1 is a stronger acid than

A2
❖ Acidity of Carboxylic Acids, Phenols,
and Alcohols
❖ Acidity of Carboxylic Acids, Phenols,
and Alcohols
❖ Acidity of Carboxylic Acids, Phenols,
and Alcohols

O O
❖ Acidity of Carboxylic Acids, Phenols,
and Alcohols

O
H
+ H2O

(NO resonance
stabilization)
 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
Cl O > Cl O > H O > H O
>

Cl H H H
 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)
2D. 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(CH 2)4CO2H Adipic acid 153 4.4 5.6

CO2H
Phthalic acid 206-208 dec 2.9 5.4
CO2H
2E. Esters

❖ Nomenclature of Esters
● Rules
⧫ Ester as parent (suffix): ending
with “–oate”
❖ Examples
2F. Carboxylic Anhydrides
❖ Nomenclature of Carboxylic Anhydrides
● Rules
⧫ Most anhydrides are named by
dropping the word acid from
the name of the carboxylic acid
and then adding the word
“anhydride”
❖ Example
2G. Acyl Chlorides
❖ Nomenclature of Acid chlorides
● Rules
⧫ Acid chloride as parent (suffix):
ending with “–oyl chloride”

❖ Example
2H. Amides
❖ Nomenclature of Amides
● Rules
⧫ Amide as parent (suffix): ending
with “amide”
❖ Example
2I. Nitriles
❖ Nomenclature of Nitriles
● Rules
⧫ Nitrile as parent (suffix): ending
with “nitrile”

❖ Example
2J. Spectroscopic Properties of
Acyl Compounds
❖ IR Spectra
● The C=O stretching band occurs at
different frequencies for acids, esters,
and amides, and its precise location is
often helpful in structure determination

● Conjugation and electron-donating

groups bonded to the carbonyl shift
the location of the C=O absorption to
lower frequencies
❖ IR Spectra
● Electron-withdrawing groups bonded to
the carbonyl shift the C=O absorption
to higher frequencies

● The hydroxyl groups of carboxylic acids

also give rise to a broad peak in the
2500-3100 cm-1 region arising from
O–H stretching vibrations

● The N–H stretching vibrations of

amides absorb between 3140 and 3500
cm-1
❖ 1H NMR Spectra
● The acidic protons of carboxylic
acids are highly deshielded and
absorb far downfield in the d 10-12
region

● The protons of the  carbon of

carboxylic acids absorb in the d
2.0-2.5 region
❖ 13C
NMR Spectra
● The carbonyl carbon of carboxylic
acids and their derivatives occur
downfield in the d 160-180 region
(see the following examples), but
not as far downfield as for
aldehydes and ketones (d 180-
220)
● The nitrile carbon is not shifted so
far downfield and absorbs in the d
115-120 region
❖ 13C NMR chemical shifts for the
carbonyl or nitrile carbon atom
O O O
C C C
H3C OH H3C OEt H3C Cl
d 177.2 d 170.7 d 170.3

O
C H3C C N
H3C NH2
d 172.6 d 117.4
3. Preparation of Carboxylic Acids
❖ By oxidative cleavage of alkenes
● Using KMnO4

● Using ozonolysis
❖ By oxidation of aldehydes & 1o alcohols
● e.g.
H 1. Ag2O OH

2. H3O+ O
O

O O
H2CrO4
H or OH OH
❖ By oxidation of alkyl benzene
❖ By oxidation of benzene ring
● e.g.

1. O3, CH3COOH O

2. H2O2
OH
❖ By hydrolysis of cyanohydrins and
other nitriles
● e.g.
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
❖ By carbonation of Grignard reagents
● e.g.
Br MgBr
Mg
Et2O

1. CO2
2. H3O+
O

OH
4. Acyl Substitution: Nucleophilic
Addition-Elimination at the Acyl
Carbon
O O
+ Nu
Nu
R Y R
Y
O
Y +
R Nu
(Y = leaving group, e.g. OR, NR2, Cl)
❖ This nucleophilic acyl substitution
occurs through a nucleophilic
addition-elimination mechanism
❖ This type of nucleophilic acyl
substitution reaction is common for
carboxylic acids and their 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
 A good
O leaving O O
group
R Y R H R R'
a carboxylic acid
derivative Not a good
leaving group
4A. Relative Reactivity of Acyl Compounds

❖ Relative reactivity of carboxylic acid

derivatives towards nucleophilic acyl
substitution reactions
● There are 2 steps in a nucleophilic
acyl substitution
⧫ The addition of the nucleophile
to the carbonyl group
⧫ The elimination of the leaving
group in the tetrahedral
intermediate
● Usually the addition step (the first
step) is the rate-determining step
(r.d.s.). As soon as the tetrahedral
intermediate is formed, elimination
usually occurs spontaneously to
regenerate the carbonyl group

● Thus, both steric and electronic

factors that affect the rate of the
addition of a nucleophile control
the reactivity of the carboxylic acid
derivative
● Steric factor
e.g.
O O
reactivity of >
Cl Cl

● Electronic factor
⧫ The strongly polarized acid
derivatives react more readily
than less polar ones
 ● Thus, reactivity of
O O O O O
> > >
R Cl R O R' R OR' R NR'2
most least
reactive reactive
● An important consequence of this
reactivity
⧫ It is usually possible to convert a
more reactive acid derivative into a
less reactive one, but not vice versa
4B. Synthesis of Acid Derivatives
❖ In general, less reactive acyl
compounds can be synthesized from
more reactive ones, but the reverse is
usually difficult and, when possible,
requires special reagents.

❖ Synthesis of acid derivatives by acyl

substitution requires that the reactant
have a better leaving group at the
acyl carbon than the product.
5. Acyl Chlorides
5A. Synthesis of Acyl Chlorides
❖ Conversion of carboxylic acids to acid
chlorides O O

R OH R Cl

● Common reagents
⧫ SOCl2
⧫ (COCl)2
⧫ PCl3 or PCl5
 ● Mechanism

O O
Cl
R O
Cl
O
O O
Cl
Cl R O
O
O O O
Cl + CO 2 + CO + Cl
R O R Cl
Cl
O
5B. Reactions of Acyl Chlorides

❖ Nucleophilic acyl substitution reactions

of acid chlorides
● Conversion of acid chlorides to
carboxylic acids
O base O
+ H2O
R Cl R OH
● Mechanism
O
H
R O
Cl H

H
O B: O
B H +
R OH R OH
 ● Conversion of acid chlorides 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'
6. Carboxylic Acid Anhydrides
6A. Synthesis of Carboxylic Acid
Anhydrides
O O
+ +
R OH R' Cl N

O O
+ Cl
R O R'
N
H
 O O O O
+ + Na Cl
R O Na R' Cl R O R'
O O

OH 300oC
O + H2O
OH
Succinic O Succinic
O acid anhydride
O O

OH 230oC
O + H2O
OH
Phthalic Phthalic anhydride O
acid O (~100%)
What is the product of the following
reaction?

a) I
b) II
c) III
d) IV

© 2014 by John Wiley & Sons, Inc. All rights reserved.

6B. Reactions of Carboxylic Acid
Anhydrides
❖ Conversion of acid anhydrides to
carboxylic acids

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

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

O
H H

H
O H 2O O OH O
+ R'COOH
R OH R OH R O R'
OH
H
❖ Conversion of acid anhydrides to other
carboxylic derivatives

Not two
Esters or
Amides
7. Esters
7A. Synthesis of Esters: Esterification

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

Who brings the oxygen into ester?

❖ Mechanism
H
O H+ O OH
H H H
R O R O R'OH R O
OH
"activated" R'

H
O H 2O O OH2

R OR' R OR' R OR'

HO
❖ Esters from acyl chlorides
e.g. O

Cl
+ EtOH +
N
Benzoyl
chloride O

OEt
+ Cl
N
Ethyl benzoate
(80%) H
❖ Esters from carboxylic acid anhydrides
e.g.
O O
OH
+
O
Acetic Benzoyl
anhydride alcohol
O

O
O
+
OH
Benzoyl acetate
7B. Base-Promoted Hydrolysis of
Esters: Saponification
❖ Hydrolysis of esters under basic
conditions: saponification

Acidic Condition?
Basic Condition?
❖ Mechanism
O O

R OR' R OR'
OH
HO

O
H + OR'
R O
O H+ O
R'OH +
R OH R O
❖ Hydrolysis of esters under acidic
conditions

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

R OR' R OR' H2O R OR'

O
H H

H
O H 2O O OH
+ R'OH R'
R OH R OH R O
OH
H
7C. Lactones
❖ Carboxylic acids whose molecules
have a hydroxyl group on a  or d
carbon undergo an intramolecular
esterification to give cyclic esters
known as - or d-lactones
 O H O H
H
 
R d  OH O H O
O H O H
HO O H A
a d-hydroxyacid R R

O O H

A + H O H + O O + O H
H H
R R
a d-lactone
❖ 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
8. Amides
8A. Synthesis of Amides
❖ Amides can be prepared in a variety
of ways, starting with acyl chlorides,
acid anhydrides, esters, carboxylic
acids, and carboxylate salts.

❖ All of these methods involve

nucleophilic addition–elimination
reactions by ammonia or an amine at
an acyl carbon.
8B. Amides from Acyl Chlorides
O O

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

O
R"
:Cl:
R N R'
H
R"R'HN:
8C. Amides from Carboxylic
Anhydrides
 O O

H2O NH2
O + 2 NH3
warm O NH4

O O Ammonium
Phthalamic O
anhydride phthalamate
(94%)
NH2 H3O+
OH (- NH 4+)

Phthalamic acid
O
(81%)
 O O

NH2 150-160oC
N H
OH

+ H2O O
O
Phthalamic acid Phthalimide
(~ 100%)
 8D. Amides from Esters
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 MeNH 2 N
heat H
+ MeOH
8E. Amides from Carboxylic Acids and
Ammonium Carboxylates

O O
+ NH3
R OH R O NH4

heat

O
H2O +
R NH2
❖ DCC-Promoted amide synthesis

O O
1. DCC
R' + DCU
R OH 2. R'NH2 R N
H
❖ Mechanism (reading)
C6H11
N
:
O:

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

:
:O O:

:
H :N H N:
:

:
C6H11 C6H11
Dicyclohexyl-
carbodiimide

:
(DCC) R N C6H11

: :
C O C

:
H O N:
: C6H11
❖ Mechanism (Cont’d)
8F. Hydrolysis of Amides

❖ Acid hydrolysis of amides

❖ Mechanism
H
:O : H+ O OH

:
H 2O

R NH2 R NH 2 R NH2

:
H O
H

H
:O : O : OH
:
+ NH3
R OH R OH R NH3
HO
❖ Basic hydrolysis of amides
❖ Mechanism

O OH O O

R NH 2
H + NH2
R NH2 R O
HO
 8G. Nitriles from the Dehydration of
Amides
: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 ions
❖ e.g.

O
C N
NH2 P4O10

dehydration
❖ Example
● Synthesis of

NaCN
Br CN
DMSO

1o alkyl bromide
 SN2 reaction with
⊖CN works fine
 CN
But synthesis of

Br NaCN
No Reaction!
DMSO

3o alkyl bromide
 No SN2 reaction
Solution
O

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

O 1. SOCl2
2. NH3
CN
NH2
P4O10

dehydration
8H. Hydrolysis of Nitriles

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

❖ Catalyzed by both acid and base

❖ Examples

H2SO4 OH
CN
H2O, 
O
(82%)
 protonated nitrile
❖ Mechanism(R) H
R C N: R C NH R C NH + : O H
H

:
H O H slow
: amide
tautomer H

:
H H H H 2O

:
:O
:

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

R NH2 R NH R NH

:
:
protonated
amide
H several steps O
O: + NH4
(amide hydrolysis)
C R OH
R NH 2
:
 ❖ Mechanism

:
:
:
N H OH NH

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

H
O HO O HO H
:

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

O O
H OH
+ NH3 + OH
:

R NH2
R O
O
8I. Lactams
O
O
O 
 NH
 NH
 d
 NH   
a -lactam a -lactam a d-lactam

R = C6H5CH2 Penicillin G
H
R N S CH3 R = C6H5CH Ampicillin

O N CH3 NH2
O
CO2H Penicillin V
R = C6H5OCH2
9. Derivatives of Carbonic Acid
9A. Alkyl Chloroformates and
Carbamates (Urethanes)
❖ Alkyl chloroformate
❖ e.g.
❖ Carbamates or urethanes
❖ Protection protected amine

❖ Deprotection
10. Decarboxylation of Carboxylic
Acids
O
decarboxylation
R H + CO2
R OH

O O o O
100-150 C
+ CO2
R OH R
A -keto acid
 H H
O O O O
−CO2

R O R R
-keto acid enol ketone
O O O O
: : : :
−CO2 HA
: :

R O: R : R
acylacetate ion
:

O
: :
resonance-stabilized
anion
R
10A. Decarboxylation of Carboxyl
Radicals
❖ Although the carboxylate ions (RCO2‾) of
simple aliphatic acids do not decarboxylate
readily, carboxyl radicals (RCO2•) do. They
decarboxylate by losing CO2 and producing
alkyl radicals:
11. Chemical Tests for Acyl
Compounds
❖ Recall: acidity of

Copyright © 2016 by John Wiley & Sons, Inc. All rights reserved.
 O O
H + Na OH + H2O
R O R O Na
(soluble in water)

O O Na
H
+ NaOH

(soluble in water)

O
H
+ NaOH No Reaction

(immiscible
with H2O)
Copyright © 2016 by John Wiley & Sons, Inc. All rights reserved.
O
H
+ NaHCO 3 No Reaction

O
H
+ NaHCO 3 No Reaction

Copyright © 2016 by John Wiley & Sons, Inc. All rights reserved.
12. Polyesters and Polyamides:
Step-Growth Polymers
❖ Polyesters O O

HO OH + HO n OH
m
-H2O

O O
O O
n
m
(a polyester)
❖ Polyamides
O O

+ n
H2N N H Cl Cl
m
H
-HCl

H H O O
N N
n
m
(a polyamide)
❖ Example: Nylon 66 (each piece has 6C)
O
OH NH2
n HO + n H2N
O

heat

O H

N
N + 2n H2O

O H
(Nylon 66) n

● Applications: clothing, fibers, bearings

❖ Example: Dacron (Mylar)
O O
OH
n + n HO
CH3O OCH3

200oC

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

● Applications: film, recording tape

13. Summary of the Reactions of
Carboxylic Acids and Their
Derivatives
 ❖ Reactions of carboxylic acids
O
C
R O

NaOH or NaHCO 3
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 PCl 3
C C or PCl 5 C
R O R' R' Cl R Cl
base
❖ Reactions of acyl chlorides
O

R OH
H2O

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

R O R' R OR'
❖ Reactions of acyl chlorides (Cont’d)

R OH

1. LiAlH4
2. H3O+
O

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

OH 1. R'MgX O

R' 2. H3O+
R R H
R'
❖ Reactions of acid anhydrides
O O
+
R OH HO R'

H2O

O O

R O R'
 ❖ Reactions of esters

R OH
R OH

1. LiAlH4
H2O, H+, 
2. H3O+
OH O

R" 1. R"MgX R OR'

R +
R" 2. H3O

NH3 R"OH, H+, 

O O

R NH2 R OR"
❖ Reactions of nitriles
O
R NH2
R OH

1. LiAlH 4 H+, H2O, 

2. H3O+
R C N
❖ Reactions of amides

O 1. LiAlH4
R' 2. H3O+
R N
R'

R NR'2