CH 14

9/18/2018
WILLIAM H. BROWN
THOMAS POON
www.wiley.com/college/brown
CHAPTER FOURTEEN
Functional
Derivatives of
Carboxylic Acids
Copyright © 2017 John Wiley & Sons, Inc. All rights reserved.
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.
Copyright © 2017 John Wiley & Sons, Inc. All rights reserved. 14-2
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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.
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.
Esters
• The functional group of an ester is an acyl

group bonded to -OR or –OAr group.
– 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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Lactones
• Lactone: a cyclic ester

– IUPAC: name the parent carboxylic acid, drop the
suffix -ic acid, and add -lactone.
– The location of the oxygen atom on the carbon
chain is commonly indicated by a Greek letter.
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.
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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-.
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.
Cephalosporins
• The cephalosporins are also -lactam

antibiotics.
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Characteristic Reactions
• Nucleophilic acyl substitution: an addition-

elimination sequence resulting in substitution
of one nucleophile for another.
– The reaction depends on having a suitable
leaving group (Y) bonded to the acyl carbon.
– In the general reaction on the previous screen, the
nucleophile as show 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: the weaker the
base, the better the leaving group.
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– 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.
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.
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 ester hydrolysis is
formation of a tetrahedral carbonyl addition intermediate
(TCAI) 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.
– (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 and ejection of
the leaving group.
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.
Hydrolysis - Esters
– Step 3: Proton transfer completes the reaction. This acid-
base reaction drives the reaction to completion.
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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.
Hydrolysis - Amides
• Hydrolysis of an amide requires much more

vigorous conditions than does hydrolysis of an
ester.
– Hydrolysis in aqueous acid requires one mole of acid for
each mole of amide.
– The products are a carboxylic acid and an ammonium
salt.
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Hydrolysis - Amides
– Hydrolysis of an amide in aqueous base requires

one mole of base per mole of amide.
– The products are a carboxylate salt and an
amine.
Hydrolysis
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Reaction with Alcohols
• 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 by the following reaction:
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• Esters undergo an exchange reaction called

transesterification.
– The exchange is acid catalyzed.
– The original -OR group is exchanged for a new
-OR group.
• 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 mole to form the amide and
one mole 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 mole to form the amide and one mole to
neutralize the carboxylic acid byproduct.
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• Esters react with ammonia, 1° and 2° amines

to form amides.
– Esters are less reactive toward NH3 and amines
than either acid halides or acid anhydrides.
• Amides do not react with NH3, 1°, or 2°

amines.
Reaction with NH3 & Amines
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Interconversion
• Figure 14.1 Interconversion of functional groups.
Esters with Grignard Reagents
• Reaction of a formate ester with two moles of

Grignard reagent followed by hydrolysis in aqueous
acid gives a 2° alcohol.
• Reaction of an ester other than a formate with a

Grignard reagent and then H3O+ gives a 3° alcohol.
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– 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 a carbonyl group.
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– 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.
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Reduction
– Esters are reduced by LiAlH4 to two alcohols.

– The alcohol derived from the carbonyl group is
primary.
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.
Some Interconversions
– from Example 14.8
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Functional Derivatives of Carboxylic Acids
End Chapter 14
23

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9/18/2018

• In this chapter, we study four classes of

• The functional group of an acid halide is an acyl

• The functional group of an acid anhydride is

• A phosphoric acid anhydride contains two

• The functional group of an ester is an acyl

• Lactone: a cyclic ester

• Phosphoric acid forms mono-, di-, and triesters.

• Lactam: a cyclic amide.

– 6-hexanolactam is an intermediate in the

• The penicillins are a family of -lactam antibiotics.

• The cephalosporins are also -lactam

• Nucleophilic acyl substitution: an addition-

– Halide ion is the weakest base and the best

Hydrolysis - Acid Chlorides

– Low-molecular-weight acid chlorides react rapidly

Hydrolysis - Acid Anhydrides

– Low-molecular-weight acid anhydrides react

• Hydrolysis of an ester in aqueous base is

– Base-promoted ester hydrolysis involves

– Step 2: Collapse of the carbonyl addition intermediate to

• There are two major differences between

• Hydrolysis of an amide requires much more

– Hydrolysis of an amide in aqueous base requires

Reaction with Alcohols

• Acid chlorides react with alcohols and

Reaction with Alcohols

• Acid anhydrides react with alcohols to give

– Aspirin is prepared by the following reaction:

Reaction with Alcohols

• Esters undergo an exchange reaction called

Reaction with Alcohols

• Amides do not react with alcohols under any

Reaction with NH3 and Amines

• Acid halides react with ammonia,1° and 2°

Reaction with NH3 and Amines

• Acid anhydrides react with ammonia,1° and

Reaction with NH3 and Amines

• Esters react with ammonia, 1° and 2° amines

• Amides do not react with NH3, 1°, or 2°

Reaction with NH3 & Amines

• Figure 14.1 Interconversion of functional groups.

Esters with Grignard Reagents

• Reaction of a formate ester with two moles of

• Reaction of an ester other than a formate with a

Esters with Grignard Reagents

– Step 1: Reaction of a nucleophile and an

Esters with Grignard Reagents

– Step 2: Collapse of the carbonyl addition

Esters with Grignard Reagents

– Step 3: Reaction of a nucleophile with an

Esters with Grignard Reagents

– Step 4: Add a proton. Proton transfer completes

– Esters are reduced by LiAlH4 to two alcohols.

– NaBH4 does not normally reduce esters, but it

– LiAlH4 reduction of an amide gives a 1°, 2°, or 3°

– from Example 14.8

Functional Derivatives of Carboxylic Acids

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