Ch14 Deriv. of Carb. Acids

WILLIAM H.
BROWN
THOMAS POON
www.wiley.com/college/brown
CHAPTER FOURTEEN
Functional Derivatives
of Carboxylic Acids
Copyright2014JohnWiley&Sons,Inc.Allrightsreserved.
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 2014 John Wiley & Sons, Inc. All rights reserved.
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.
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.
14-4
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.
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.
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.
14-7
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.
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-.
14-9
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).
14-10
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.
14-11
Cephalosporins
The cephalosporins are also -lactam

antibiotics.
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.
14-13
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.
14-14
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.
14-15
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.
14-16
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.
14-17
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).
14-18
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.
14-19
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.
14-20
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.
14-21
Hydrolysis - Esters
Step 3: Proton transfer completes the reaction.
14-22
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.
14-23
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.
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.
14-25
Hydrolysis
14-26
Reaction with Alcohols
Acid chlorides react with alcohols and

phenols to give an ester and HCl.
14-27
Acid anhydrides react with alcohols to give

one mole of ester and one mole of carboxylic
acid.
Aspirin is prepared by the following reaction:
14-28
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)
14-29
Amides do not react with alcohols under any

conditions.
14-30
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.
14-31
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.
14-32
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.
14-33
Reaction with NH3 & Amines
14-34
Interconversion
FIGURE 14.1 Interconversion of functional groups.
14-35
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.
14-36

Step 1: Reaction of a nucleophile and an
electrophile to form a new covalent bond.
14-37

Step 2: Collapse of the carbonyl addition
intermediate to eject a leaving group and
regenerate the a carbonyl group.
14-38

Step 3: Reaction of a nucleophile with an
electrophile to form a new covalent bond.
14-39

Step 4: Add a proton. Proton transfer completes
the reaction.
14-40
Reduction
Esters are reduced by LiAlH4 to two alcohols.
The alcohol derived from the carbonyl group is
primary.
14-41
Reduction
NaBH4 does not normally reduce esters, but it
does reduce aldehydes and ketones.
14-42
Reduction
LiAlH4 reduction of an amide gives a 1, 2, or 3
amine, depending on the degree of substitution of
the amide.
14-43
Some Interconversions
from Example 14.8
14-44
Functional Derivatives of Carboxylic Acids
End Chapter 14
14-45

Ch14 Deriv. of Carb. Acids

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WILLIAM H.

In this chapter, we study four classes of

The functional group of an acid anhydride is

The functional group of an ester is an acyl

Lactone: a cyclic ester

Lactam: a cyclic amide.

6-hexanolactam is an intermediate in the

The cephalosporins are also -lactam

Nucleophilic acyl substitution: an additionelimination sequence resulting in substitution

Hydrolysis - Acid Chlorides

Hydrolysis - Acid Anhydrides

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

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

(A diester of ethylene glycol)

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 ammonia, 1, or 2

Reaction with NH3 & Amines

Esters with Grignard Reagents

Reaction of an ester other than a formate with a

Esters with Grignard Reagents

Esters with Grignard Reagents

Esters with Grignard Reagents

Esters with Grignard Reagents

Functional Derivatives of Carboxylic Acids

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