Organic Chemistry, 5th Edition

L. G. Wade, Jr.

Chapter 21
Carboxylic Acid Derivatives

Jo Blackburn
Richland College, Dallas, TX
Dallas County Community College District
2003, Prentice Hall
 Acid Derivatives
• All can be converted to the carboxylic
acid by acidic or basic hydrolysis.
• Esters and amides common in nature.

O O O O O
R C X R C O C R' R C O R R C NH2 R C N
RCOX (RCO)2O RCOOR RCONH2 RCN

=>
Chapter 21 2
 Naming Esters
• Esters are named as alkyl carboxylates.
• Alkyl from the alcohol, carboxylate from
the carboxylic acid precursor.
CH3 O O
CH3CHCH2OCCH3 HCOCH2

isobutyl acetate
2-methylpropyl ethanoate benzyl formate
benzyl methanoate

=>
Chapter 21 3
 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
H3C 4-hydroxy-2-methylpentanoic acid lactone
O -methyl--valerolactone
CH3
=>
Chapter 21 4
 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.
O O
C H C + H
H N H N
H H
Bond angles around N
are close to 120. =>
Chapter 21 5
 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 6
 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.
O CH3
N-ethyl-N,2-dimethylpropanamide
CH3CHC N CH2CH3 N-ethyl-N-methylisobutyramide
CH3 =>
Chapter 21 7
 Cyclic Amides
• Reaction of -NH2 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.
O

4-aminopentanoic acid lactam

N H -valerolactam
CH3 =>
Chapter 21 8
 Nitriles
• -CN can be hydrolyzed to carboxylic
acid, so nitriles are acid derivatives.
• Nitrogen is sp hybridized, lone pair tightly
held, so not very basic. (pKb about 24).

=>
Chapter 21 9
 Naming Nitriles
• For IUPAC names, add -nitrile to the alkane
name.
• Common names come from the carboxylic
acid. Replace -ic acid with -onitrile.
Br C N
CH3CHCH2CH2CH2CN

5-bromohexanenitrile
-bromocapronitrile Cyclohexanecarbonitrile
=>
Chapter 21 10
 Acid Halides
• More reactive than acids; the halogen
withdraws e- density from carbonyl.
• Named by replacing -ic acid with -yl halide.
O
Br O
C
Cl CH3CHCH2C Br

3-bromobutanoyl bromide
benzoyl chloride -bromobutyryl bromide
=>
Chapter 21 11
 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.
O O O O
R C O H H O C R R C O C R
=>
Chapter 21 12
 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. O
O O
CH3 C O C CH3 O

ethanoic anhydride O
acetic anhydride 1,2-benzenedicarboxylic anhydride
phthalic anhydride =>
Chapter 21 13
 Multifunctional Compounds
• The functional group with the highest
priority determines the parent name.
• Acid > ester > amide > nitrile >
aldehyde > ketone > alcohol > amine >
alkene > alkyne.
O
C
OCH2CH3 ethyl o-cyanobenzoate
CN =>
Chapter 21 14
 Boiling Points

Even 3 amides have

strong attractions.
Chapter 21 => 15
 Melting Points
• Amides have very high melting points.
• Melting points increase with increasing
number of N-H bonds.
O O O H
CH3 H
H C N CH3 C N CH3CH2 C N
CH3 CH3 H

m.p. -61C m.p. 28C m.p. 79C

=>
Chapter 21 16
 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
=>17
IR Spectroscopy

=> =>
Chapter 21 18
1H NMR Spectroscopy

=>
Chapter 21 19
13C NMR Spectroscopy

=>
Chapter 21 20
 Interconversion of
Acid Derivatives
• Nucleophile adds to the carbonyl to form a
tetrahedral intermediate.
• Leaving group leaves and C=O regenerates.

_
O O
_ O
C R C Y _
Nuc R Y C + Y
Nuc R Nuc

=>
Chapter 21 21
 Reactivity
Reactivity decreases as leaving group
becomes more basic.

=>
Chapter 21 22
Interconversion of Derivatives

More reactive
derivatives can be
converted to less
reactive
derivatives.

=>
Chapter 21 23
 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.
O O
_ =>
O - H+ O O
C R C Cl
R' C O H R Cl C C + HCl
+O R O R'
H C R'
O

Chapter 21 24
 Acid Chloride to Ester
• Alcohol attacks the C=O.
• Tetrahedral intermediate forms.
• Chloride ion leaves, C=O is restored, H+
is abstracted.
=>
_
O O
- H+ O
C R C Cl
R' O H R Cl C R' + HCl
+O R O
H R'
Chapter 21 25
 Acid Chloride to Amide
• Ammonia yields a 1 amide
• A 1 amine yields a 2 amide
• A 2 amine yields a 3 amide
_
O O O
R'2 N H C R C Cl
R Cl C R'2
+N R N
+
H R'2 + -
R'2NH2 Cl
R'2 N H
=>
Chapter 21 26
 Anhydride to Ester
• Alcohol attacks one C=O of anhydride.
• Tetrahedral intermediate forms.
• Carboxylate ion leaves, C=O is
restored, H+ is abstracted.
=>
_
O O O O O O
_
C C R C O C R O C R + C
R' O H R O R
+O R OR'
H R'

Chapter 21 27
 Anhydride to Amide
• Ammonia yields a 1 amide
• A 1 amine yields a 2 amide
• A 2 amine yields a 3 amide
_
O O O O O O
_
C C R C O C R O C R + C
R'2 N H R O R
+N R NR'2
H R'2

=>
Chapter 21 28
 Ester to Amide
• Nucleophile must be NH3 or 1 amine.
• Prolonged heating required.
_
O O O
C _
R' NH2 R OCH3 R C OCH3 OCH3 + C R'
+N R NH
H R'
H

Surprise!

=>
Chapter 21 29
 Leaving Groups
A strong base is not usually a leaving
group unless it’s in an exothermic step.

=>
Chapter 21 30
 Transesterification
• 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

=>
Chapter 21 31
 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.

O O
CH3 C Cl + HOH CH3 C OH + HCl

=>
Chapter 21 32
 Acid Hydrolysis of Esters
• Reverse of Fischer esterification.
• Reaches equilibrium.
• Use a large excess of water.

O O
+
H + CH3OH
CH3 C OCH3 + HOH CH3 C OH

=>
Chapter 21 33
 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(CH2)16CH3.
=>
Chapter 21 34
 Hydrolysis of Amides
Prolonged heating in 6 M HCl or 40%
aqueous NaOH is required.

O O
-
H2O -
CH3 C NHCH3 + OH CH3 C O + CH3NH2

O O
H2O + -
CH3 C NHCH3 + HCl CH3 C OH + CH3NH3 Cl

=>
Chapter 21 35
 Hydrolysis of Nitriles
• Under mild conditions, nitriles hydrolyze
to an amide.
• Heating with aqueous acid or base will
hydrolyze a nitrile to an acid.
O O
C N C NH C O-
-
OH 2 - + NH3
OH
+ H2O
heat

=>
Chapter 21 36
 Reduction to Alcohols
Lithium aluminum hydride reduces acids,
acid chlorides, and esters to primary
alcohols.
O
C OCH CH CH2OH
2 3
1) LiAlH4
+ CH3CH2OH
2) H2O

=>
Chapter 21 37
 Reduction to Aldehydes
Acid chlorides will react with a weaker
reducing agent to yield an aldehyde.

CH3 O CH3 O
LiAl(t-BuO)3H
CH3CHCH2C Cl CH3CHCH2C H

=>
Chapter 21 38
 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.
O
1) LiAlH4
CH3 C NHCH3 CH3 CH2 NHCH3
2) H2O
=>
Chapter 21 39
 Organometallic Reagents
Grignard reagents and organolithium
reagents add twice to acid chlorides and
esters to give alcohols after protonation.

O OH

C OCH CH + C CH
2 3 2 CH3MgBr H3O 3
CH3
ether

=>
Chapter 21 40
 Grignard Reagents
and Nitriles
A Grignard reagent or organolithium reagent
attacks the cyano group to yield an imine
which is hydrolyzed to a ketone.
H3C MgBr H3C
C N C N + C O
CH3MgBr H3O
ether

=>
Chapter 21 41
 Acid Chloride Synthesis
• Use thionyl chloride, SOCl2, or oxalyl
chloride, (COCl)2.
• Other products are gases.
O O
C OH C Cl
SOCl2
+ SO2 + HCl

=>
Chapter 21 42
Acid Chloride Reactions (1)
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 =>
Chapter 21 43
Acid Chloride Reactions (2)
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
(2) H2O
R CH2OH 1° alcohol
O
Li(t-BuO)3AlH aldehyde
R C H
O
Z C R
AlCl3 Z
acylbenzene
=>
Chapter 21 44
 Industrial Synthesis
of Acetic Anhydride
• Four billion pounds/year produced.
• Use high heat (750°C) 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
=>
Chapter 21 45
 Lab Synthesis
of Anhydrides
• 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

O
anhydrides. C OH
O

O
C OH
O
O =>
Chapter 21 46
 Anhydride Reactions
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
AlCl3 Z
acylbenzene
=>
Chapter 21 47
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.
O O O O
CH3 C O C H + R NH2 H C NHR + CH3 C OH

• Use cyclic anhydrides to produce

a difunctional molecule. O
O
C OCH CH
2 3
O CH3CH2OH
=>
C OH
Chapter 21 48
O
O
 Synthesis of Esters
O O
+
H
R C OH + R'OH R C OR' + HOH
acid
O O
R C Cl + R'OH R C OR' + HCl
acid chloride
O O +
O
H
R C O C R + R'OH R C OR' + RCOOH
acid anhydride
O O
R C OH + CH2N2 R C OCH3 + N2
methyl ester =>
Chapter 21 49
 Reactions of Esters
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''
=>
Chapter 21 50
 Lactones
• Formation favored for five- and six-
membered rings.
OH H+ O
+ H2O
COOH O

• For larger rings, remove water to

shift equilibrium toward products
+ O
OH H
+ H2O
COOH
O

=>
Chapter 21 51
 Synthesis of Amides
O
O
heat
R C OH + R'NH2 R C NHR' + HOH
acid
O O
R C Cl + 2 R'2NH R C NR'2 + R'2NH2+Cl-
acid chloride
O O O
R C O C R + R'2NH R C NR'2 + RCOOH
acid anhydride
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 =>
Chapter 21 52
 Reactions of Amides
O
H2O
R C OH + R'NH2
H+ or -OH
acid and amine
(1) LiAlH4
R CH2NHR' amine
(2) H2O
O
Br-, OH-
R C NHR' R NH2 + CO2 1° amine

POCl3
R C N nitrile
(or P2O5)

=>
Chapter 21 53
 Lactam Formation
• Five- and six-membered rings can be
formed by heating - and -amino acids.
NH2 heat NH
COOH + H2O
O

• Smaller or larger rings do not form readily.

=>

Chapter 21 54
 -Lactams
• Highly reactive, 4-membered ring.
• Found in antibiotics isolated from fungi.

Amide  ester !!
=>
Chapter 21 55
 Synthesis of Nitriles
O
POCl3 R C N
R C NH2
1° amide
NaCN + -
R C N + Na X
R X
alkyl halide

+ CuCN
Ar N N Ar CN + N2
diazonium salt
O HO CN
HCN
R C R' R C R'
aldehyde KCN cyanohydrin
=>
or ketone
Chapter 21 56
 Reactions of Nitriles
O O
H2O H2O
R C NH2 R C OH
H+ or -OH H+ or -OH acid
amide
(1) LiAlH4 1° amine
R CH2NH2
(2) H2O
R C N N MgX O
+
R'MgX H3O
R C R' R C R'
ketone

=>
Chapter 21 57
 Thioesters
More reactive than esters because:
-S-R is a better leaving group than -O-R
Resonance overlap is not as effective.

=>
Chapter 21 58
 Carbonic Acid Esters
• CO2 in water contains some H2CO3.
• Diesters are stable.
• Synthesized from phosgene.
O O
Cl C Cl + 2 CH3CH2OH CH3CH2OCOCH2CH3
diethyl carbonate

=>
Chapter 21 59
 Urea and Urethanes
• 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 =>

Chapter 21 60
 Polymers
• Polycarbonates are long-chain esters of
carbonic acid.
• 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

=>
Chapter 21 61
End of Chapter 21

Chapter 21 62