Chapter 21

Carboxylic Acid Derivatives

Jo Blackburn
Richland College, Dallas, TX
Dallas County Community College District
2003, Prentice Hall
Organic Chemistry, 5
th
Edition
L. G. Wade, Jr.
Chapter 21 2
Acid Derivatives
All can be converted to the carboxylic
acid by acidic or basic hydrolysis.
Esters and amides common in nature.
=>
R C
O
X R C
O
O C
O
R' R C
O
O R R C
O
NH
2
R C N
RCOX (RCO)
2
O RCOOR RCONH
2
RCN
Chapter 21 3
Naming Esters
Esters are named as alkyl carboxylates.
Alkyl from the alcohol, carboxylate from
the carboxylic acid precursor.
isobutyl acetate
2-methylpropyl ethanoate
CH
3
CHCH
2
OCCH
3
CH
3
O
HCOCH
2
O
benzyl formate
benzyl methanoate
=>
Chapter 21 4
Cyclic Esters
Reaction of -OH and -COOH on same
molecule produces a cyclic ester, lactone.
To name, add word lactone to the IUPAC
acid name or replace the -ic acid of
common name with -olactone.
O
O
H
3
C
CH
3
4-hydroxy-2-methylpentanoic acid lactone
o-methyl--valerolactone
=>
Chapter 21 5
Amides
Product of the reaction of a carboxylic
acid and ammonia or an amine.
Not basic because the lone pair on
nitrogen is delocalized by resonance.
H
C
O
N
H
H
H
C
O
N
H
H
_
+
Bond angles around N
are close to 120. =>
Chapter 21 6
Classes of Amides
1 amide has one C-N bond (two N-H).
2 amide or N-substituted amide has
two C-N bonds (one N-H).
3 amide or N,N-disubstituted amide
has three C-N bonds (no N-H).


=>
Chapter 21 7
Naming Amides
For 1 amide, drop -ic or -oic acid from
the carboxylic acid name, add -amide.
For 2 and 3 amides, the alkyl groups
bonded to nitrogen are named with N-
to indicate their position.
CH
3
CHC N
O
CH
2
CH
3
CH
3
CH
3
N-ethyl-N,2-dimethylpropanamide
N-ethyl-N-methylisobutyramide
=>
Chapter 21 8
Cyclic Amides
Reaction of -NH
2
and -COOH on same
molecule produces a cyclic amide, lactam.
To name, add word lactam to the IUPAC
acid name or replace the -ic acid of
common name with -olactam.

N
O
CH
3
H
4-aminopentanoic acid lactam
-valerolactam
=>
Chapter 21 9
Nitriles
-CN can be hydrolyzed to carboxylic
acid, so nitriles are acid derivatives.
Nitrogen is sp hybridized, lone pair tightly
held, so not very basic. (pK
b
about 24).
=>
Chapter 21 10
Naming Nitriles
For IUPAC names, add -nitrile to the alkane
name.
Common names come from the carboxylic
acid. Replace -ic acid with -onitrile.
CH
3
CHCH
2
CH
2
CH
2
CN
Br
5-bromohexanenitrile
c-bromocapronitrile
C N
Cyclohexanecarbonitrile
=>
Chapter 21 11
Acid Halides
More reactive than acids; the halogen
withdraws e
-
density from carbonyl.
Named by replacing -ic acid with -yl halide.
C
O
Cl CH
3
CHCH
2
C
Br O
Br
benzoyl chloride
3-bromobutanoyl bromide
|-bromobutyryl bromide
=>
Chapter 21 12
Acid Anhydrides
Two molecules of acid combine with the
loss of water to form the anhydride.
Anhydrides are more reactive than acids,
but less reactive than acid chlorides.
A carboxylate ion is the leaving group in
nucleophilic acyl substitution reactions.
R C
O
O H R C
O
O H
R C
O
O C
O
R
=>
Chapter 21 13
Naming Anhydrides
The word acid is replaced with anhydride.
For a mixed anhydride, name both acids.
Diacids may form anhydrides if a 5- or 6-
membered ring is the product.
CH
3
C
O
O C
O
CH
3
ethanoic anhydride
acetic anhydride
O
O
O
1,2-benzenedicarboxylic anhydride
phthalic anhydride
=>
Chapter 21 14
Multifunctional Compounds
The functional group with the highest
priority determines the parent name.
Acid > ester > amide > nitrile >
aldehyde > ketone > alcohol > amine >
alkene > alkyne.
C
CN
O
OCH
2
CH
3
ethyl o-cyanobenzoate
=>
Chapter 21 15
Boiling Points
Even 3 amides have
strong attractions.
=>
Chapter 21 16
Melting Points
Amides have very high melting points.
Melting points increase with increasing
number of N-H bonds.
H C
O
N
CH
3
CH
3
CH
3
C
O
N
H
CH
3
CH
3
CH
2
C
O
N
H
H
m.p. -61C m.p. 28C m.p. 79C
=>
Chapter 21 17
Solubility
Acid chlorides and anhydrides are too
reactive to be used with water or alcohol.
Esters, 3 amides, and nitriles are good
polar aprotic solvents.
Solvents commonly used in organic
reactions:
Ethyl acetate
Dimethylformamide (DMF)
Acetonitrile
=>
Chapter 21 18
IR Spectroscopy
=>
=>
Chapter 21 19
1
H NMR Spectroscopy
=>
Chapter 21 20
13
C NMR Spectroscopy

=>
Chapter 21 21
Interconversion of
Acid Derivatives
Nucleophile adds to the carbonyl to form a
tetrahedral intermediate.
Leaving group leaves and C=O regenerates.
C
O
R Y
Nuc
_
C
O
R Y
Nuc
_
C
O
R Nuc
+ Y
_
=>
Chapter 21 22
Reactivity
Reactivity decreases as leaving group
becomes more basic.
=>
Chapter 21 23
Interconversion of Derivatives
More reactive
derivatives can be
converted to less
reactive
derivatives.
=>
Chapter 21 24
Acid Chloride to Anhydride
Acid or carboxylate ion attacks the C=O.
Tetrahedral intermediate forms.
Chloride ion leaves, C=O is restored, H
+
is
abstracted.
=>
+ HCl
C
O
R O
C
O
R'
_
C
O
R Cl
O
H C
O
R'
C
O
R Cl
R' C
O
O H
+
-
H
+
Chapter 21 25
Acid Chloride to Ester
Alcohol attacks the C=O.
Tetrahedral intermediate forms.
Chloride ion leaves, C=O is restored, H
+

is abstracted.
=>
+ HCl
C
O
R O
R'
_
C
O
R Cl
O
H R'
C
O
R Cl
+
-
H
+
R' O H
Chapter 21 26
Acid Chloride to Amide
Ammonia yields a 1 amide
A 1 amine yields a 2 amide
A 2 amine yields a 3 amide
C
O
R N
R'
2
_
C
O
R Cl
N
H R'
2
C
O
R Cl
+
R'
2
N H
R'
2
N H
R'
2
NH
2
+
Cl
-
+
=>
Chapter 21 27
Anhydride to Ester
Alcohol attacks one C=O of anhydride.
Tetrahedral intermediate forms.
Carboxylate ion leaves, C=O is
restored, H
+
is abstracted.
=>



_
C
O
R OR'
C
O
R O
C
O
R
R' O H
+
C
O
R O
O
H R'
C
O
R
_
O C
O
R +
Chapter 21 28
Anhydride to Amide
Ammonia yields a 1 amide
A 1 amine yields a 2 amide
A 2 amine yields a 3 amide
_
C
O
R NR'
2
C
O
R O
C
O
R
R'
2
N H
+
C
O
R O
N
H R'
2
C
O
R
_
O C
O
R +
=>
Chapter 21 29
Ester to Amide
Nucleophile must be NH
3
or 1 amine.
Prolonged heating required.
C
O
R NH
R'
_
C
O
R OCH
3
N
H R'
H
C
O
R OCH
3
+
R' NH
2
+
OCH
3
_
Surprise!
=>
Chapter 21 30
Leaving Groups
A strong base is not usually a leaving
group unless its in an exothermic step.

=>
Chapter 21 31
Transesterification
One alkoxy group can be replaced by
another with acid or base catalyst.
Use large excess of preferred alcohol.
C
O
OCH
2
CH
3
+ CH
3
OH
H
+
or
-
OCH
3
C
O
OCH
3
CH
3
CH
2
OH +
=>
Chapter 21 32
Hydrolysis of Acid
Chlorides and Anhydrides
Hydrolysis occurs quickly, even in moist air
with no acid or base catalyst.
Reagents must be protected from moisture.
+
CH
3
C
O
Cl HOH
CH
3
C
O
OH + HCl
=>
Chapter 21 33
Acid Hydrolysis of Esters
Reverse of Fischer esterification.
Reaches equilibrium.
Use a large excess of water.
+
CH
3
C
O
OCH
3
HOH
CH
3
C
O
OH + CH
3
OH
H
+
=>
Chapter 21 34
Saponification
Base-catalyzed hydrolysis of ester.
Saponification means soap-making.
Soaps are made by heating NaOH with
a fat (triester of glycerol) to produce the
sodium salt of a fatty acid - a soap.
One example of a soap is sodium
stearate, Na
+ -
OOC(CH
2
)
16
CH
3
.
=>
Chapter 21 35
Hydrolysis of Amides
Prolonged heating in 6 M HCl or 40%
aqueous NaOH is required.
+
CH
3
C
O
NHCH
3
-
OH
CH
3
C
O
O
-
+ CH
3
NH
2
H
2
O
+
CH
3
C
O
NHCH
3
HCl
CH
3
C
O
OH + CH
3
NH
3
+
Cl
-
H
2
O
=>
Chapter 21 36
Hydrolysis of Nitriles
Under mild conditions, nitriles hydrolyze
to an amide.
Heating with aqueous acid or base will
hydrolyze a nitrile to an acid.
+
H
2
O
C N
-
OH
C
O
NH
2
-
OH
heat
C
O
O
-
+
NH
3
=>
Chapter 21 37
Reduction to Alcohols
Lithium aluminum hydride reduces acids,
acid chlorides, and esters to primary
alcohols.
=>
CH
3
CH
2
OH
+
CH
2
OH
H
2
O 2)
1)
LiAlH
4
C
O
OCH
2
CH
3
Chapter 21 38
Reduction to Aldehydes
Acid chlorides will react with a weaker
reducing agent to yield an aldehyde.
=>
CH
3
CHCH
2
C
CH
3
O
H
LiAl(t-BuO)
3
H
CH
3
CHCH
2
C
CH
3
O
Cl
Chapter 21 39
Reduction to Amines
Lithium aluminum hydride reduces amides
and nitriles to amines.
Nitriles and 1 amides reduce to 1 amines.
A 2 amide reduces to a 2 amine.
A 3 amide reduces to a 3 amine.
CH
3
C
O
NHCH
3
CH
3
CH
2
NHCH
3
LiAlH
4
1)
2) H
2
O
=>
Chapter 21 40
Organometallic Reagents
Grignard reagents and organolithium
reagents add twice to acid chlorides and
esters to give alcohols after protonation.
C
O
OCH
2
CH
3
CH
3
MgBr
ether
C
OH
CH
3
CH
3
2
H
3
O
+
=>
Chapter 21 41
Grignard Reagents
and Nitriles
A Grignard reagent or organolithium reagent
attacks the cyano group to yield an imine
which is hydrolyzed to a ketone.
C N
CH
3
MgBr
ether
H
3
O
+
C N
H
3
C
MgBr
C O
H
3
C
=>
Chapter 21 42
Acid Chloride Synthesis
Use thionyl chloride, SOCl
2
, or oxalyl
chloride, (COCl)
2
.
Other products are gases.
C
O
OH
SOCl
2
C
O
Cl
+ +
SO
2
HCl
=>
Chapter 21 43
Acid Chloride Reactions (1)
H
2
O
R'OH
R'NH
2
R'COOH
R C
O
Cl
R C
O
OH + HCl
R C
O
OR'
R C
O
NHR'
R C
O
O C
O
R' + HCl
+ HCl
+ HCl
acid
ester
amide
acid anhydride
=>
Chapter 21 44
Acid Chloride Reactions (2)
R C
O
H
R CH
2
OH
R C
O
R'
R C
OH
R'
R'
R C
O
Cl
H
2
O (2)
(1)
2 R'MgX
R'
2
CuLi
(1)
(2) H
2
O
LiAlH
4
Li( BuO)
3
AlH t-
Z
AlCl
3
C
O
R
Z
3 alcohol
ketone
1 alcohol
aldehyde
acylbenzene
=>
Chapter 21 45
Industrial Synthesis
of Acetic Anhydride
Four billion pounds/year produced.
Use high heat (750C) and triethyl
phosphate catalyst to produce ketene.
CH
3
C
O
OH
(EtO)
3
P O
heat
C
H
H
C O
C
H
H
C O
+
CH
3
C
O
OH CH
3
C
O
O C
O
CH
3
=>
Chapter 21 46
Lab Synthesis
of Anhydrides
React acid chloride with carboxylic acid
or carboxylate ion.
C
O
Cl
+ CH
3
C
O
O
_
C
O
O
C
O
CH
3
Heat dicarboxylic acids to form cyclic
anhydrides.
C
O
OH
C
O
OH
O
O
O
=>
Chapter 21 47
Anhydride Reactions
R C
O
O C
O
R
R C
O
OH + RCOOH
R C
O
OR'
R C
O
NHR' + RCOOH
+ RCOOH
AlCl
3
H
2
O
R'OH, H
+
R'NH
2
Z
C
O
R
Z
acid
ester
amide
=>
acylbenzene
Chapter 21 48
Anhydride vs. Acid Chloride
Acetic anhydride is cheaper, gives a
better yield than acetyl chloride.
Use acetic formic anhydride to produce
formate esters and formamides.
+
CH
3
C
O
OH
CH
3
C
O
O C
O
H R NH
2 H C
O
NHR +
Use cyclic anhydrides to produce
a difunctional molecule.
C
O
OCH
2
CH
3
C
O
OH
O
O
O
CH
3
CH
2
OH
=>
Chapter 21 49
Synthesis of Esters
R C
O
OR'
R C
O
OH
+ R'OH
H
+
+ HOH
acid
R C
O
OR' R C
O
Cl + R'OH + HCl
acid chloride
R C
O
OR'
R C
O
O C
O
R + R'OH
H
+
+ RCOOH
acid anhydride
R C
O
OH CH
2
N
2
+ R C
O
OCH
3
N
2
+
methyl ester
=>
Chapter 21 50
Reactions of Esters
R C
O
OR'
R C
O
OH + R'OH
R C
O
OR''
R C
O
NHR'' + R'OH
+ R'OH
R CH
2
OH
R C
OH
R''
R''
H
2
O (2)
(1)
2 R''MgX
(1)
(2) H
2
O
LiAlH
4
H
2
O
R''OH,
R''NH
2
H
+
or
-
OR''
acid
ester
amide
1 alcohol
3 alcohol
=>
Chapter 21 51
Lactones
Formation favored for five- and six-
membered rings.
O
O
COOH
OH
H
+
H
2
O +
For larger rings, remove water to
shift equilibrium toward products
H
+
H
2
O +
O
O
OH
COOH
=>
Chapter 21 52
Synthesis of Amides
R C
O
OH + HOH + R'NH
2
heat
R C
O
NHR'
acid
R C
O
O C
O
R + RCOOH R'
2
NH R C
O
NR'
2
+
acid anhydride
R C
O
OR'' + R''OH R'NH
2
R C
O
NHR' +
ester
R C
O
NH
2
R C N + H
2
O
H
+
or OH
-
nitrile
=>
acid chloride
R'
2
NH
2
+
Cl
-
+ R C
O
NR'
2
R'
2
NH + 2
R C
O
Cl
Chapter 21 53
Reactions of Amides
R C
O
OH + R'NH
2
R C
O
NHR'
R CH
2
NHR'
(1)
(2) H
2
O
LiAlH
4
H
2
O
H
+
or
-
OH
Br
-
, OH
-
R NH
2
+
CO
2
POCl
3
(or P
2
O
5
)
R C N
acid and amine
amine
1 amine
=>
nitrile
Chapter 21 54
Lactam Formation
Five- and six-membered rings can be
formed by heating - and o-amino acids.
NH
O
COOH
NH
2
heat
+
H
2
O
Smaller or larger rings do not form readily.
=>
Chapter 21 55
|-Lactams
Highly reactive, 4-membered ring.
Found in antibiotics isolated from fungi.
Amide ester !!
=>
Chapter 21 56
Synthesis of Nitriles
R C
O
NH
2
R C N
POCl
3
1 amide
R C N +
R X
NaCN
Na
+
X
-
alkyl halide
+ Ar N N
+
CuCN
Ar CN
N
2
diazonium salt
R C
O
R'
HCN
KCN
R C R'
HO CN
aldehyde
or ketone
cyanohydrin
=>
Chapter 21 57
Reactions of Nitriles
R C
O
NH
2
R CH
2
NH
2
(1)
(2)
LiAlH
4
H
2
O
H
+
or
-
OH
R C N
H
+
or
-
OH
H
2
O
R C
O
OH
H
2
O
R'MgX
R C
N
R'
MgX
H
3
O
+
R C
O
R'
ketone
=>
amide
acid
1 amine
Chapter 21 58
Thioesters
More reactive than esters because:

-
S-R is a better leaving group than
-
O-R
Resonance overlap is not as effective.
=>
Chapter 21 59
Carbonic Acid Esters
CO
2
in water contains some H
2
CO
3
.
Diesters are stable.
Synthesized from phosgene.
+ C
O
Cl Cl
CH
3
CH
2
OCOCH
2
CH
3
O
2 CH
3
CH
2
OH
diethyl carbonate
=>
Chapter 21 60
Urea and Urethanes
Urea is the diamide of carbonic acid.
Urethanes are esters of a monoamide
of carbonic acid.
+ C
O
Cl Cl
C
O
NH
2
H
2
N
2 NH
3
urea
N C O
H
2
O
NH C OH
O
a carbamic acid
ROH
NH C OR
O
a urethane
=>
Chapter 21 61
Polymers
Polycarbonates are long-chain esters of
carbonic acid.
Polyurethanes are formed when a diol
reacts with a diisocyanate.
N C O N C O
CH
3
HOCH
2
CH
2
OH
NH C HN
CH
3
C
O
O CH
2
CH
2
O
O
n
=>
Chapter 21 62
End of Chapter 21