Functional Derivatives of
Carboxylic Acids
• In this chapter, we focus on four classes of
organic compounds derived from carboxylic
acids.
• Under the general formula of each is a drawing to
show how it is related to the carboxyl group.
Parent Names of Carboxylic Derivatives
Acid Chlorides
• The functional group of an acid halide is an acyl
group bonded to a halogen.
• The most widely used are the acid chlorides.
• To name, change the suffix -ic acid to -yl chloride.
• Note this rule works for both IUPAC names and common names.
Acid Anhydrides
• The functional group of an acid anhydride is two
acyl groups bonded to an oxygen atom.
• Anhydrides may be symmetrical (two identical acyl
groups) or mixed (two different acyl groups).
• To name, replace acid of the parent acid by
anhydride.
Esters
• The functional group of an ester is an acyl group
bonded to -OR or -OAr.
• Name the alkyl or aryl group bonded to oxygen (instead
of a hydrogen) followed by the name of the acid.
• Change the suffix -ic acid to -ate.
Lactones
• Lactone: a cyclic ester
• IUPAC: name the parent carboxylic acid, drop the
suffix -oic acid, and add -olactone.
• The location of the oxygen atom on the carbon chain
is commonly indicated by a Greek letter.
Amides
• The functional group of an amide is an acyl
group bonded to a trivalent nitrogen.
• IUPAC: drop -oic acid from the name of the parent
acid and add -amide.
• If the amide nitrogen is bonded to an alkyl or aryl
group, name the group and show its location on
nitrogen by N-.
(IUPAC: ethanamide)
Lactams
• Lactam: a cyclic amide.
• Name the parent carboxylic acid, drop the suffix -oic acid
and add -olactam.
• The connection to the nitrogen atom in the ring is
commonly indicated by a Greek letter, a, b, etc.
• 6-hexanolactam is an intermediate in the synthesis of
nylon 6.
• The penicillins and cephalosporins are two families
of b-lactam antibiotics.
Nitriles
• The nitrile group is an sp carbon triply bonded to
a nitrogen.
• Applications
• Nitriles are very polar; therefore, they are excellent
polar aprotic solvents.
• Nitriles are also a component of many rubber
materials including hypoallergenic gloves.
• Even though nitriles contain nitrogen, they are very
poor bases.
• Nomenclature
• Nitriles are carboxylic acid derivatives;
therefore, their names are based on the name
of the corresponding carboxylic acid.
• Nitriles are named by replacing the suffix “oic
acid” with “enitrile”.
• The prefix for functional group is cyano-.
butanenitrile
Common name: acetonitrile
2-cyanopentane
Nucleophilic Acyl Substitution
• Nucleophilic acyl substitution: an additionelimination sequence resulting in substitution of
one nucleophile for another.
• The reaction depends on having a suitable leaving
group (Y) bonded to the acyl carbon to complete the
elimination.
• In the general reaction, the nucleophile does not
need to be an anion.
• Neutral molecules such as water, alcohols,
ammonia, and amines can also serve as
nucleophiles.
• Remember! The weaker the base, the better the
leaving group.
• Halide ion is the weakest base and the best
leaving group. Acid halides are, therefore, the
most reactive toward nucleophilic acyl
substitution.
• Amide ion is the strongest base and the
poorest leaving group; amides, therefore, are
the least reactive toward nucleophilic acyl
substitution.
Nucleophilic Acyl Substitution
The nucleophile tells you which product you'll produce!
O
C
H2O
acid or base
conditions
O
R
(acidic conditions)
carboxylic acid
R
G
R'OH
O
acid or base
conditions
C
R
OR'
G= -Cl, -OCR, -OH, -OR, -NH2
R'NH2
acid or base
conditions
acid chloride
(no catalyst
needed)
ester product
alcoholysis
O
amide
carboxylic
acid
anhydride
ester
O
C
R
NH
-
O
R
(basic conditions)
carboxylic acid salt
hydrolysis
O
C
C
OH
amide product
R'
aminolysis
Reactivity of Carbonyls to ANp
O
R
Most reactive
Cl
O
R
O
O
R
O
R
SR'
O
E
O
R
H
R
R'
O
O
R
OH
R
OR'
O
R
NR'2
O
least reactive
R
-
O
Reaction Summary
• Hydrolysis
• Acid chlorides, acid anhydrides, esters, amides,
nitriles
• Alcoholysis
• Acid chlorides, acid anhydrides, esters
• Aminolysis
• Acid chlorides, acid anhydrides, esters
• Esterification with Grignard reagent
• Metal hydride reduction
• Esters, amides
Hydrolysis - Acid Chlorides
• Low-molecular-weight acid chlorides react
rapidly with water to form a carboxylic acid
and HCl.
• Higher molecular-weight acid chlorides react
less readily.
Hydrolysis - Acid Anhydrides
• Low-molecular-weight acid anhydrides react
readily with water to give two molecules of
carboxylic acid.
• Higher-molecular-weight acid anhydrides also
react with water, but less readily.
Hydrolysis - Esters
• Esters are hydrolyzed only slowly, even in boiling water.
• Hydrolysis becomes more rapid if they are heated with
either aqueous acid or aqueous base.
• Hydrolysis in aqueous acid is the reverse of Fischer
esterification.
• The key step in the mechanism of hydrolysis is formation
of a tetrahedral carbonyl addition intermediate followed
by its collapse (see the next screen for details).
Mechanism for the Acid-Catalyzed
Hydrolysis of Esters
1) Addition of a proton
increases the
electrophilic
character of the
carbonyl carbon.
2) Reaction of a
nucleophile with an
electrophile to form
a new covalent
bond
3) proton transfer
4) collapse of the TCAI
to eliminate a
leaving group.
• Hydrolysis of an ester in aqueous base is often
called saponification.
• Each mole of ester hydrolyzed requires 1 mole of
base; for this reason, ester hydrolysis in aqueous
base is said to be base promoted.
• Base-promoted ester hydrolysis involves formation of
a tetrahedral carbonyl addition intermediate followed
by its collapse.
Mechanism for the Base-Catalyzed
Hydrolysis of Esters
• Step 1: Reaction of a nucleophile and an electrophile
to form a new covalent bond.
• Step 2: Collapse of the tetrahedral carbonyl addition
intermediate to eliminate a leaving group.
• Step 3: Proton transfer completes the reaction.
• There are two major differences between acidcatalyzed and base-promoted ester hydrolysis.
1. For acid-catalyzed hydrolysis, acid is required in
only catalytic amounts; for base-promoted
hydrolysis, equimolar amounts of ester and base are
required.
2. Hydrolysis of an ester in aqueous acid is reversible;
base-promoted hydrolysis is irreversible because a
carboxylate anion is not susceptible to nucleophilic
attack.
Hydrolysis - Amides
• Hydrolysis of an amide requires much more
vigorous conditions than hydrolysis of an ester.
• Hydrolysis in aqueous acid requires 1 mole of acid for
each mole of amide.
• The products are a carboxylic acid and an ammonium
salt.
• Hydrolysis of an amide in aqueous base
requires 1 mole of base per mole of amide.
• The products are a carboxylate salt and an
amine.
Summary of Hydrolysis Reactions
Preparation and Hydrolysis of Nitriles
• When a 1° or 2° alkyl halide is treated with a
cyanide ion, the CN- acts as a nucleophile in an
SN2 reaction.
• Hydrolysis occurs with a strong acid or strong base.
Reaction with Alcohols (Alcoholysis)
• Acid chlorides react with alcohols and phenols to
give an ester and HCl.
• Acid anhydrides react with alcohols to give one
mole of ester and one mole of carboxylic acid.
• Aspirin is prepared via alcoholysis by the following
reaction:
• Esters undergo an exchange reaction called
transesterification.
• The exchange is acid catalyzed.
• The original -OR group is exchanged for a new -OR
group.
O
2
O
OCH3
+
HO
H2SO4
OH
O
O
+ 2CH3OH
O
Methyl
benzoate
1,2-Ethandiol
(Ethylene glycol)
(A diester of ethylene glycol)
• Amides do not react with alcohols under any
conditions.
Reaction with Amines (Aminolysis)
• Acid halides react with ammonia, 1° and 2°
amines to form amides.
• Two moles of the amine are required per mole of acid
chloride; one to form the amide and one to neutralize
the HCl byproduct.
• Acid anhydrides react with ammonia, 1° and 2°
amines to form amides.
• Two moles of ammonia or amine are required; one to
form the amide and one to neutralize the carboxylic
acid byproduct.
• Esters react with ammonia, 1° and 2° amines to
form amides.
• Esters are less reactive than either acid halides or
acid anhydrides.
• Amides do not react with ammonia, 1°, or 2°
amines.
Summary of Reactions with NH3 & Amines
Reactivity of Carbonyls to ANp
• Interconversion of functional groups.
Esters with Grignard Reagents
• Reaction of a formic ester with two moles of
Grignard reagent followed by hydrolysis gives a
2° alcohol.
• Reaction of an ester other than a formic ester
with a Grignard reagent gives a 3° alcohol.
Mechanism of Reaction of Esters with
Grignard Reagents
• Step 1: Reaction of a nucleophile and an
electrophile to form a new covalent bond.
• Step 2: Collapse of the carbonyl addition
intermediate to eject a leaving group and
regenerate the carbonyl group.
• Step 3: Reaction of a nucleophile with an
electrophile to form a new covalent bond.
• Step 4: Add a proton. Proton transfer
completes the reaction.
Metal Hydride Reduction
• Esters are reduced by LiAlH4 to two alcohols.
• The alcohol derived from the carbonyl group
is primary.
• NaBH4 does not normally reduce esters, but it
does reduce aldehydes and ketones.
• LiAlH4 reduction of an amide gives a 1°, 2°, or
3° amine, depending on the degree of
substitution of the amide.
Some Interconversions