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WILLIAM H.

BROWN
THOMAS POON
www.wiley.com/college/brown

CHAPTER FOURTEEN

Functional Derivatives
of Carboxylic Acids
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14-1

Carboxyl Derivatives

In this chapter, we study 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.

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14-2

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.

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14-3

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.

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Acid Anhydrides
A phosphoric acid anhydride contains two
phosphoryl groups bonded to an oxygen atom.
Shown here are two phosphoric anhydrides. Each shown
as it would be ionized at pH 7.4, the pH of blood.

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14-5

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
followed by the name of the acid.
Change the suffix -ic acid to -ate.

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14-6

Lactones

Lactone: a cyclic ester


IUPAC: name the parent carboxylic acid, drop the
suffix -ic acid, and add -olactone.
The location of the oxygen atom on the carbon
chain is commonly indicated by a Greek letter.

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Phosphoric esters
Phosphoric acid forms mono-, di-, and triesters.
Name by giving the name of the alkyl or aryl group(s)
bonded to oxygen(s) followed by the word phosphate.
In more complex phosphate esters, it is common to name
the organic molecule followed by phosphate.

Copyright 2014 John Wiley & Sons, Inc. All rights reserved.

14-8

Amides
The functional group of an amide is an acyl group
bonded to a trivalent nitrogen.
IUPAC: drop -ic 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-.

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Lactam

Lactam: a cyclic amide.


Name the parent carboxylic acid, drop the suffix
ic acid and add -lactam.
The location of the nitrogen atom in the ring is
commonly indicated by a Greek letter, , , etc.

6-hexanolactam is an intermediate in the


synthesis of nylon 6 (Section 17.5A).
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The Penicillins
The penicillins are a family of -lactam antibiotics.
The structural feature common to all penicillins is a
lactam ring fused to a five-membered ring containing
one S atom and one N atom.

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Cephalosporins

The cephalosporins are also -lactam


antibiotics.

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14-12

Characteristic Reactions

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.

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Characteristic Reactions
In the general reaction on the previous screen, the
nucleophile as an anion; this need not be the case.
Neutral molecules such as water, alcohols, ammonia, and
amines can also serve as nucleophiles.
In the general reaction, we showed the leaving group as
an anion to illustrate an important point about them: the
weaker the base, the better the leaving group.

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14-14

Characteristic Reactions
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.

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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.

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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.

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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).

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Hydrolysis - Esters
(1) Addition of a
proton increases the
electrophilic
character of the
carbonyl carbon.
Then follows
(2) Reaction of a
nucleophile with an
electrophile to form a
new covalent bond
followed by (3) proton
transfer and (4)
collapse of the TCAI
to eject a leaving
group.
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Hydrolysis - Esters

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.
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Hydrolysis - Esters
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.

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Hydrolysis - Esters
Step 3: Proton transfer completes the reaction.

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Hydrolysis - Esters

There are two major differences between


acid-catalyzed 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.
Copyright 2014 John Wiley & Sons, Inc. All rights reserved.

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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.

Copyright 2014 John Wiley & Sons, Inc. All rights reserved.

14-24

Hydrolysis - Amides
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.

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Hydrolysis

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Reaction with Alcohols

Acid chlorides react with alcohols and


phenols to give an ester and HCl.

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Reaction with Alcohols

Acid anhydrides react with alcohols to give


one mole of ester and one mole of carboxylic
acid.

Aspirin is prepared by the following reaction:

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Reaction with Alcohols

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

OCH3

HO

H2SO4
OH

O
O

+ 2CH3OH
O

Methyl
benzoate

1,2-Ethandiol
(Ethylene glycol)

(A diester of ethylene glycol)

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Reaction with Alcohols

Amides do not react with alcohols under any


conditions.

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Reaction with NH3 and Amines

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.

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14-31

Reaction with NH3 and Amines

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.

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14-32

Reaction with NH3 and Amines

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.
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Reaction with NH3 & Amines

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Interconversion
FIGURE 14.1 Interconversion of functional groups.

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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 formate with a


Grignard reagent gives a 3 alcohol.
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Esters with Grignard Reagents


Step 1: Reaction of a nucleophile and an
electrophile to form a new covalent bond.

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Esters with Grignard Reagents


Step 2: Collapse of the carbonyl addition
intermediate to eject a leaving group and
regenerate the a carbonyl group.

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Esters with Grignard Reagents


Step 3: Reaction of a nucleophile with an
electrophile to form a new covalent bond.

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Esters with Grignard Reagents


Step 4: Add a proton. Proton transfer completes
the reaction.

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Reduction
Esters are reduced by LiAlH4 to two alcohols.
The alcohol derived from the carbonyl group is
primary.

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Reduction
NaBH4 does not normally reduce esters, but it
does reduce aldehydes and ketones.

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Reduction
LiAlH4 reduction of an amide gives a 1, 2, or 3
amine, depending on the degree of substitution of
the amide.

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Some Interconversions
from Example 14.8

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Functional Derivatives of Carboxylic Acids

End Chapter 14
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