CHAPTER 20
CARBOXYLIC ACID DERIVATIVES: NUCLEOPHILIC
ACYL SUBSTITUTION
T
his chapter differs from preceding ones in that it deals with several related classes
of compounds rather than just one. Included are
1. Acyl chlorides,
2. Carboxylic acid anhydrides,
3. Esters of carboxylic acids,
4. Carboxamides,
,,
and
These classes of compounds are classified as carboxylic acid derivatives. All may be
converted to carboxylic acids by hydrolysis.
H11001H11001RCX
O
X
Carboxylic acid
derivative
H
2
O
Water
HX
Conjugate acid
of leaving group
Carboxylic
acid
RCOH
O
X
RCNRH11032
2
O
X
RCNHRH11032
O
X
RCNH
2
O
X
RCORH11032
O
X
RCOCR
O
X
O
X
RCCl
O
X
774
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The hydrolysis of a carboxylic acid derivative is but one example of a nucleophilic
acyl substitution. Nucleophilic acyl substitutions connect the various classes of car-
boxylic acid derivatives, with a reaction of one class often serving as preparation of
another. These reactions provide the basis for a large number of functional group trans-
formations both in synthetic organic chemistry and in biological chemistry.
Also included in this chapter is a discussion of the chemistry of nitriles, compounds
of the type RCPN. Nitriles may be hydrolyzed to carboxylic acids or to amides and,
so, are indirectly related to the other functional groups presented here.
20.1 NOMENCLATURE OF CARBOXYLIC ACID DERIVATIVES
With the exception of nitriles (RCPN), all carboxylic acid derivatives consist of an acyl
group attached to an electronegative atom. Acyl groups are named by replacing
the -ic acid ending of the corresponding carboxylic acid by -yl. Acyl halides are named
by placing the name of the appropriate halide after that of the acyl group.
Although acyl fluorides, bromides, and iodides are all known classes of organic com-
pounds, they are encountered far less frequently than are acyl chlorides. Acyl chlorides
will be the only acyl halides discussed in this chapter.
In naming carboxylic acid anhydrides in which both acyl groups are the same, we
simply specify the acyl group and add the word “anhydride.” When the acyl groups are
different, they are cited in alphabetical order.
The alkyl group and the acyl group of an ester are specified independently. Esters
are named as alkyl alkanoates. The alkyl group RH11032 of is cited first, followed by
the acyl portion . The acyl portion is named by substituting the suffix -ate for the
-ic ending of the corresponding acid.
CH
3
COCH
2
CH
3
O
Ethyl acetate
CH
3
CH
2
COCH
3
O
Methyl propanoate
COCH
2
CH
2
Cl
O
2-Chloroethyl benzoate
RC±
O
X
RCORH11032
O
X
CH
3
COCCH
3
O
X
O
X
Acetic anhydride
C
6
H
5
COCC
6
H
5
O
X
O
X
Benzoic anhydride
C
6
H
5
COC(CH
2
)
5
CH
3
O
X
O
X
Benzoic heptanoic anhydride
F CBr
O
p-Fluorobenzoyl bromide
CHCH
2
CCl
O
CH
2
3-Butenoyl
chloride
CH
3
CCl
O
Acetyl chloride
(RC±)
O
X
20.1 Nomenclature of Carboxylic Acid Derivatives 775
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Aryl esters, that is, compounds of the type , are named in an analogous way.
The names of amides of the type are derived from carboxylic acids by
replacing the suffix -oic acid or -ic acid by -amide.
We name compounds of the type and as N-alkyl- and N,N-dialkyl-
substituted derivatives of a parent amide.
Substitutive IUPAC names for nitriles add the suffix -nitrile to the name of the
parent hydrocarbon chain that includes the carbon of the cyano group. Nitriles may also
be named by replacing the -ic acid or -oic acid ending of the corresponding carboxylic
acid with -onitrile. Alternatively, they are sometimes given functional class IUPAC
names as alkyl cyanides.
PROBLEM 20.1 Write a structural formula for each of the following compounds:
(a) 2-Phenylbutanoyl bromide (e) 2-Phenylbutanamide
(b) 2-Phenylbutanoic anhydride (f) N-Ethyl-2-phenylbutanamide
(c) Butyl 2-phenylbutanoate (g) 2-Phenylbutanenitrile
(d) 2-Phenylbutyl butanoate
SAMPLE SOLUTION (a) A 2-phenylbutanoyl group is a four-carbon acyl unit that
bears a phenyl substituent at C-2. When the name of an acyl group is followed
by the name of a halide, it designates an acyl halide.
CH
3
CH
2
CHCBr
C
6
H
5
O
2-Phenylbutanoyl bromide
Ethanenitrile
(acetonitrile)
CH
3
CN
Benzonitrile
C
6
H
5
CN
2-Methylpropanenitrile
(isopropyl cyanide)
CH
3
CHCH
3
CN
N-Methylacetamide
CH
3
CNHCH
3
O
N,N-Diethylbenzamide
C
6
H
5
CN(CH
2
CH
3
)
2
O
N-Isopropyl-N-methyl-
butanamide
CH
3
CH
2
CH
2
CNCH(CH
3
)
2
O
CH
3
RCNRH11032
2
O
X
RCNHRH11032
O
X
CH
3
CNH
2
O
X
Acetamide
C
6
H
5
CNH
2
O
X
Benzamide
(CH
3
)
2
CHCH
2
CNH
2
O
X
3-Methylbutanamide
RCNH
2
O
X
RCOAr
O
X
776 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
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20.2 STRUCTURE OF CARBOXYLIC ACID DERIVATIVES
Figure 20.1 shows the structures and electrostatic potentials of the various derivatives of
acetic acid–acetyl chloride, acetic anhydride, ethyl acetate, acetamide, and acetonitrile.
Like the other carbonyl-containing compounds that we’ve studied, acyl chlorides, anhy-
drides, esters, and amides all have a planar arrangement of bonds to the carbonyl group.
An important structural feature of acyl chlorides, anhydrides, esters, and amides is
that the atom attached to the acyl group bears an unshared pair of electrons that can
interact with the carbonyl H9266 system, as shown in Figure 20.2.
This electron delocalization can be represented in resonance terms by contributions
from the following resonance structures:
Electron release from the substituent stabilizes the carbonyl group and decreases its elec-
trophilic character. The extent of this electron delocalization depends on the electron-
R
X
C
H11001
H11002
O
R
X
C
H11001
H11002
O
R
X
C
O
20.2 Structure of Carboxylic Acid Derivatives 777
CH
3
CCl CH
3
COCCH
3
CH
3
CSCH
2
CH
3
CH
3
COCH
2
CH
3
CH
3
CNH
2
O
O
O
O
O
O
O
O
O
O
O
O
CH
3
CPN
Acetyl chloride Acetic anhydride Ethyl thioacetate
AcetonitrileAcetamideEthyl acetate
FIGURE 20.1 The
structures and electrostatic
potential maps of various de-
rivatives of acetic acid. These
models may be viewed on
Learning By Modeling.
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donating properties of the substituent X. Generally, the less electronegative X is, the bet-
ter it donates electrons to the carbonyl group and the greater its stabilizing effect.
Resonance stabilization in acyl chlorides is not nearly as pronounced as in other
derivatives of carboxylic acids:
Because the carbon–chlorine bond is so long—typically on the order of 180 pm for acyl
chlorides—overlap between the 3p orbitals of chlorine and the H9266 orbital of the carbonyl
group is poor. Consequently, there is little delocalization of the electron pairs of chlo-
rine into the H9266 system. The carbonyl group of an acyl chloride feels the normal electron-
withdrawing inductive effect of a chlorine substituent without a significant compensat-
ing electron-releasing effect due to lone-pair donation by chlorine. This makes the
carbonyl carbon of an acyl chloride more susceptible to attack by nucleophiles than that
of other carboxylic acid derivatives.
Acid anhydrides are better stabilized by electron delocalization than are acyl chlo-
rides. The lone-pair electrons of oxygen are delocalized more effectively into the car-
bonyl group. Resonance involves both carbonyl groups of an acid anhydride.
The carbonyl group of an ester is stabilized more than is that of an anhydride.
Since both acyl groups of an anhydride compete for the oxygen lone pair, each carbonyl
is stabilized less than the single carbonyl group of an ester.
Esters are stabilized by resonance to about the same extent as carboxylic acids but
not as much as amides. Nitrogen is less electronegative than oxygen and is a better
electron-pair donor.
is more effective than
Ester
R
ORH11032
C
O
R
C C
R
O O
O
Acid anhydride
C C
RR
O O
H11002
O
H11001
R
C C
R
O O
O R
C
O
C
R
H11001
O O
H11002
R C
H11001
H11002
O
Cl
R
Cl
C
O
Weak resonance
stabilization
778 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
O
C
X
X H11005 OH; carboxylic acid
X H11005 Cl; acyl chloride
X H11005 OCR; acid anhydride
X
O
X H11005 OR; ester
X H11005 NR
2
; amide
FIGURE 20.2 The
three H9268 bonds originating at
the carbonyl carbon are
coplanar. The p orbital of the
carbonyl carbon, its oxygen,
and the atom by which
group X is attached to the
acyl group overlap to form
an extended H9266 system
through which the H9266 elec-
trons are delocalized.
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Amide resonance is a powerful stabilizing force and gives rise to a number of structural
effects. Unlike the pyramidal arrangement of bonds in ammonia and amines, the bonds
to nitrogen in amides lie in the same plane. The carbon–nitrogen bond has considerable
double-bond character and, at 135 pm, is substantially shorter than the normal 147-pm
carbon–nitrogen single-bond distance observed in amines.
The barrier to rotation about the carbon–nitrogen bond in amides is 75 to 85 kJ/mol
(18–20 kcal/mol).
This is an unusually high rotational energy barrier for a single bond and indicates that
the carbon–nitrogen bond has significant double-bond character, as the resonance picture
suggests.
PROBLEM 20.2 The
1
H NMR spectrum of N,N-dimethylformamide shows a sep-
arate signal for each of the two methyl groups. Can you explain why?
Electron release from nitrogen stabilizes the carbonyl group of amides and
decreases the rate at which nucleophiles attack the carbonyl carbon. Nucleophilic
reagents attack electrophilic sites in a molecule; if electrons are donated to an elec-
trophilic site in a molecule by a substituent, then the tendency of that molecule to react
with external nucleophiles is moderated.
An extreme example of carbonyl group stabilization is seen in carboxylate anions:
The negatively charged oxygen substituent is a powerful electron donor to the carbonyl
group. Resonance in carboxylate anions is more effective than resonance in carboxylic
acids, acyl chlorides, anhydrides, esters, and amides.
Table 20.1 summarizes the stabilizing effects of substituents on carbonyl groups to
which they are attached. In addition to a qualitative ranking, quantitative estimates of the
relative rates of hydrolysis of the various classes of acyl derivatives are given. A weakly
stabilized carboxylic acid derivative reacts with water faster than does a more stabilized one.
Most methods for their preparation convert one class of carboxylic acid derivative
to another, and the order of carbonyl group stabilization given in Table 20.1 bears directly
on the means by which these transformations may be achieved. A reaction that converts
one carboxylic acid derivative to another that lies below it in the table is practical; a
reaction that converts it to one that lies above it in the table is not. This is another way
of saying that one carboxylic acid derivative can be converted to another if the reaction
R C
H11002
O
O
R C
O
O
H11002
E
act
H11005 75–85 kJ/mol
(18–20 kcal/mol)
C
RH11032
RH11033
R
O
NC N
R
O RH11032
RH11033
R C
H11001
H11002
O
NRH11032
2
R
NRH11032
2
C
O
Very effective
resonance stabilization
20.2 Structure of Carboxylic Acid Derivatives 779
Recall that the rotational
barrier in ethane is only 12
kJ/mol (3 kcal/mol).
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leads to a more stabilized carbonyl group. Numerous examples of reactions of this type
will be presented in the sections that follow. We begin with reactions of acyl chlorides.
20.3 NUCLEOPHILIC SUBSTITUTION IN ACYL CHLORIDES
Acyl chlorides are readily prepared from carboxylic acids by reaction with thionyl chlo-
ride (Section 12.7).
On treatment with the appropriate nucleophile, an acyl chloride may be converted
to an acid anhydride, an ester, an amide, or a carboxylic acid. Examples are presented
in Table 20.2.
PROBLEM 20.3 Apply the knowledge gained by studying Table 20.2 to help you
predict the major organic product obtained by reaction of benzoyl chloride with
each of the following:
(a) Acetic acid (d) Methylamine, CH
3
NH
2
(b) Benzoic acid (e) Dimethylamine, (CH
3
)
2
NH
(c) Ethanol (f) Water
SAMPLE SOLUTION (a) As noted in Table 20.2, the reaction of an acyl chloride
with a carboxylic acid yields an acid anhydride.
Carboxylic
acid
RCOH
O
Acyl
chloride
RCCl
O
H11001
Thionyl
chloride
SOCl
2
H11001
Sulfur
dioxide
SO
2
H11001
Hydrogen
chloride
HCl
2-Methylpropanoic acid
(CH
3
)
2
CHCOH
O
2-Methylpropanoyl chloride (90%)
(CH
3
)
2
CHCCl
O
SOCl
2
heat
780 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
TABLE 20.1
Relative Stability and Reactivity of Carboxylic Acid
Derivatives
Relative rate
of hydrolysis*
10
11
10
7
1.0
H11021 10
H110022
Acyl chloride
Anhydride
Ester
Amide
Carboxylic acid
derivative
Carboxylate anion
Stabilization
Very small
Small
Moderate
Large
Very large
RCCl
O
X
RCOCR
O
X
O
X
RCORH11032
O
X
RCNRH11032
2
O
X
RCO
H11002
O
X
*Rates are approximate and are relative to ester as standard substrate at pH 7.
One of the most useful reac-
tions of acyl chlorides was
presented in Section 12.7.
Friedel–Crafts acylation of
aromatic rings takes place
when arenes are treated
with acyl chlorides in the
presence of aluminum
chloride.
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The product is a mixed anhydride. Acetic acid acts as a nucleophile and substi-
tutes for chloride on the benzoyl group.
C
6
H
5
CCl
O
Benzoyl chloride
C
6
H
5
COCCH
3
O O
Acetic benzoic anhydride
H11001 CH
3
COH
O
Acetic acid
20.3 Nucleophilic Substitution in Acyl Chlorides 781
TABLE 20.2 Conversion of Acyl Chlorides to Other Carboxylic Acid Derivatives
Reaction (section) and comments
Reaction with carboxylic acids (Section
20.4) Acyl chlorides react with carboxylic
acids to yield acid anhydrides. When this
reaction is used for preparative purposes,
a weak organic base such as pyridine is
normally added. Pyridine is a catalyst for
the reaction and also acts as a base to
neutralize the hydrogen chloride that is
formed.
Reaction with alcohols (Section 15.8) Acyl
chlorides react with alcohols to form
esters. The reaction is typically carried out
in the presence of pyridine.
Reaction with ammonia and amines (Sec-
tion 20.13) Acyl chlorides react with
ammonia and amines to form amides. A
base such as sodium hydroxide is normally
added to react with the hydrogen chlor-
ide produced.
Hydrolysis (Section 20.3) Acyl chlorides
react with water to yield carboxylic acids.
In base, the acid is converted to its carbox-
ylate salt. The reaction has little prepara-
tive value because the acyl chloride is
nearly always prepared from the carboxyl-
ic acid rather than vice versa.
General equation and specific example
Acyl
chloride
RCCl
O
X
Carboxylic
acid
RH11032COH
O
X
Acid
anhydride
RCOCRH11032
O
X
O
X
H11001 HCl
Hydrogen
chloride
H11001
H11001
pyridine
Heptanoyl
chloride
CH
3
(CH
2
)
5
CCl
O
X
Heptanoic
acid
CH
3
(CH
2
)
5
COH
O
X
Heptanoic anhydride
(78–83%)
CH
3
(CH
2
)
5
COC(CH
2
)
5
CH
3
O
X
O
X
H11001
pyridine
Benzoyl
chloride
C
6
H
5
CCl
O
X
tert-Butyl
alcohol
(CH
3
)
3
COH
tert-Butyl
benzoate (80%)
C
6
H
5
COC(CH
3
)
3
O
X
Ester
RCORH11032
O
X
HCl
Hydrogen
chloride
H11001RH11032OH
Alcohol
H11001
Acyl
chloride
RCCl
O
X
Amide
RCNRH11032
2
O
X
Cl
H11002
Chloride
ion
H
2
O
Water
H11001H11001RH11032
2
NH
Ammonia
or amine
HO
H11002
Hydroxide
H11001H11001
Acyl
chloride
RCCl
O
X
Carboxylic
acid
RCOH
O
X
HCl
Hydrogen
chloride
H
2
O
Water
H11001H11001
Acyl
chloride
RCCl
O
X
H11001
NaOH
H
2
O
Benzoyl
chloride
C
6
H
5
CCl
O
X
Piperidine
HN
N-Benzoylpiperidine
(87–91%)
C
6
H
5
C±N
O
X
H11001
Phenylacetyl
chloride
C
6
H
5
CH
2
CCl
O
X
Water
H
2
O H11001
Phenylacetic
acid
C
6
H
5
CH
2
COH
O
X
Hydrogen
chloride
HCl
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The mechanisms of all the reactions cited in Table 20.2 are similar to the mecha-
nism of hydrolysis of an acyl chloride outlined in Figure 20.3. They differ with respect
to the nucleophile that attacks the carbonyl group.
In the first stage of the mechanism, water undergoes nucleophilic addition to the
carbonyl group to form a tetrahedral intermediate. This stage of the process is analogous
to the hydration of aldehydes and ketones discussed in Section 17.6.
The tetrahedral intermediate has three potential leaving groups on carbon: two
hydroxyl groups and a chlorine. In the second stage of the reaction, the tetrahedral inter-
mediate dissociates. Loss of chloride from the tetrahedral intermediate is faster than loss
of hydroxide; chloride is less basic than hydroxide and is a better leaving group. The
tetrahedral intermediate dissociates because this dissociation restores the resonance-
stabilized carbonyl group.
PROBLEM 20.4 Write the structure of the tetrahedral intermediate formed in
each of the reactions given in Problem 20.3. Using curved arrows, show how each
tetrahedral intermediate dissociates to the appropriate products.
SAMPLE SOLUTION (a) The tetrahedral intermediate arises by nucleophilic addi-
tion of acetic acid to benzoyl chloride.
Loss of a proton and of chloride ion from the tetrahedral intermediate yields the
mixed anhydride.
C
6
H
5
CCl
O
Benzoyl
chloride
C
6
H
5
COCCH
3
HO
Cl
O
Tetrahedral intermediate
H11001 CH
3
COH
O
Acetic acid
782 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
O
H
H
Water
C
R
H11001 C
R
O
slow
O
H11002
O
H11001
H
H
fast
HOC
R
O H
Acyl chloride Tetrahedral
intermediate
First stage: Formation of the tetrahedral intermediate by nucleophilic addition of
water to the carbonyl group
Second stage: Dissociation of the tetrahedral intermediate by dehydrohalogenation
HOC
R
O
Cl
Tetrahedral
intermediate
H
O
H
H
H11001
Water
fast
C
R
O
HO
H11001
H
H
Carboxylic
acid
Hydronium
ion
O
H11001
H H11001 Cl
Chloride
ion
H11002
Cl Cl
Cl
FIGURE 20.3 Hydrolysis of acyl chloride proceeds by way of a tetrahedral intermediate. For-
mation of the tetrahedral intermediate is rate-determining.
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Nucleophilic substitution in acyl chlorides is much faster than in alkyl chlorides.
The sp
2
-hybridized carbon of an acyl chloride is less sterically hindered than the sp
3
-
hybridized carbon of an alkyl chloride, making an acyl chloride more open toward nucle-
ophilic attack. Also, unlike the S
N
2 transition state or a carbocation intermediate in an
S
N
1 reaction, the tetrahedral intermediate in nucleophilic acyl substitution has a stable
arrangement of bonds and can be formed via a lower energy transition state.
20.4 PREPARATION OF CARBOXYLIC ACID ANHYDRIDES
After acyl halides, acid anhydrides are the most reactive carboxylic acid derivatives.
Three of them, acetic anhydride, phthalic anhydride, and maleic anhydride, are indus-
trial chemicals and are encountered far more often than others. Phthalic anhydride and
maleic anhydride have their anhydride function incorporated into a ring and are referred
to as cyclic anhydrides.
The customary method for the laboratory synthesis of acid anhydrides is the reac-
tion of acyl chlorides with carboxylic acids (Table 20.2).
This procedure is applicable to the preparation of both symmetrical anhydrides (R and
RH11032 the same) and mixed anhydrides (R and RH11032 different).
H11001 Cl
H11002
RCCl
O
Acyl
chloride
H11001
O
RH11032COH
Carboxylic
acid
H11001
N
Pyridine
O O
RCOCRH11032
Carboxylic
acid anhydride
N
H
H11001
Pyridinium
chloride
Acetic
anhydride
CH
3
COCCH
3
O O
O
O
O
Phthalic
anhydride
O
O
O
Maleic
anhydride
CCl
O
Benzoyl chloride
1,000Relative rate of hydrolysis
(80% ethanol–20% water; 25°C)
CH
2
Cl
Benzyl chloride
1
H11001 HCl
Hydrogen
chloride
C
6
H
5
COCCH
3
O O
Acetic benzoic
anhydride
C
6
H
5
COCCH
3
H
O
Cl
O
Tetrahedral
intermediate
20.4 Preparation of Carboxylic Acid Anhydrides 783
Acid anhydrides rarely occur
naturally. One example is the
putative aphrodisiac can-
tharidin, obtained from a
species of beetle.
O
CH
3
O
CH
3
O
O
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PROBLEM 20.5 Benzoic anhydride has been prepared in excellent yield by
adding one molar equivalent of water to two molar equivalents of benzoyl chlo-
ride. How do you suppose this reaction takes place?
Cyclic anhydrides in which the ring is five- or six-membered are sometimes pre-
pared by heating the corresponding dicarboxylic acids in an inert solvent:
20.5 REACTIONS OF CARBOXYLIC ACID ANHYDRIDES
Nucleophilic acyl substitution in acid anhydrides involves cleavage of a bond between
oxygen and one of the carbonyl groups. One acyl group is transferred to an attacking
nucleophile; the other retains its single bond to oxygen and becomes the acyl group of
a carboxylic acid.
One reaction of this type, Friedel–Crafts acylation (Section 12.7), is already familiar to us.
An acyl cation is an intermediate in Friedel–Crafts acylation reactions.
PROBLEM 20.6 Write a structural formula for the acyl cation intermediate in
the preceding reaction.
Conversions of acid anhydrides to other carboxylic acid derivatives are illustrated
in Table 20.3. Since a more highly stabilized carbonyl group must result in order for
nucleophilic acyl substitution to be effective, acid anhydrides are readily converted to
carboxylic acids, esters, and amides but not to acyl chlorides.
RCOCR
O O
Acid
anhydride
H11001 ArH
Arene
RCAr
O
Ketone
H11001 RCOH
O
Carboxylic
acid
AlCl
3
AlCl
3
CH
3
COCCH
3
OO
Acetic
anhydride
H11001 OCH
3
F
o-Fluoroanisole
CH
3
C OCH
3
F
O
3-Fluoro-4-methoxyacetophenone
(70–80%)
H11001 CH
3
CO
2
H
Acetic
acid
Bond cleavage
occurs here in
an acid anhydride.
RC
O
OCR
O
H11001 HY
Nucleophile
RC
O
Y
Product of
nucleophilic
acyl substitution
H11001 HOCR
O
Carboxylic
acid
tetrachloroethane
130°C
H
C
HO
2
CCO
2
H
H
C
Maleic acid
O O
O
Maleic anhydride
(89%)
H11001 H
2
O
Water
784 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
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PROBLEM 20.7 Apply the knowledge gained by studying Table 20.3 to help you
predict the major organic product of each of the following reactions:
(a)
(b) Acetic anhydride H11001 ammonia (2 mol) ±￡
(c) Phthalic anhydride H11001 (CH
3
)
2
NH (2 mol) ±￡
(d) Phthalic anhydride H11001 sodium hydroxide (2 mol) ±￡
H
H11001
Benzoic anhydride H11001 methanol
20.5 Reactions of Carboxylic Acid Anhydrides 785
TABLE 20.3 Conversion of Acid Anhydrides to Other Carboxylic Acid Derivatives
Reaction (section) and
comments
Reaction with alcohols (Section
15.8) Acid anhydrides react with
alcohols to form esters. The
reaction may be carried out in
the presence of pyridine or it
may be catalyzed by acids. In
the example shown, only one
acetyl group of acetic anhydride
becomes incorporated into the
ester; the other becomes the
acetyl group of an acetic acid
molecule.
Reaction with ammonia and
amines (Section 20.13) Acid
anhydrides react with ammonia
and amines to form amides.
Two molar equivalents of amine
are required. In the example
shown, only one acetyl group of
acetic anhydride becomes incor-
porated into the amide; the
other becomes the acetyl group
of the amine salt of acetic acid.
Hydrolysis (Section 20.5) Acid
anhydrides react with water to
yield two carboxylic acid func-
tions. Cyclic anhydrides yield
dicarboxylic acids.
General equation and specific example
H11001
H
2
SO
4
Acetic
anhydride
CH
3
COCCH
3
O
X
O
X
sec-Butyl
alcohol
HOCHCH
2
CH
3
CH
3
W
sec-Butyl
acetate (60%)
CH
3
COCHCH
2
CH
3
CH
3
O
X
W
Carboxylic
acid
RCOH
O
X
Acid
anhydride
RCOCR
O
X
O
X
H11001H11001
Ester
RCORH11032
O
X
RH11032OH
Alcohol
Ammonium
carboxylate
salt
RCO
H11002
O
X
H
2
NRH11032
2
H11001
Acid
anhydride
RCOCR
O
X
O
X
H11001H11001
Amide
RCNRH11032
2
O
X
2RH11032
2
NH
Amine
Acid
anhydride
RCOCRH11032
O
X
O
X
H11001
Carboxylic
acid
2RCOH
O
X
H
2
O
Water
H11001
Acetic
anhydride
CH
3
COCCH
3
O
X
O
X
H
2
N CH(CH
3
)
2
p-Isopropylaniline p-Isopropylacetanilide
(98%)
CH
3
CNH
O
X
CH(CH
3
)
2
Phthalic
anhydride
O
O
O
H11001
Water
H
2
O
Phthalic
acid
COH
O
X
COH
X
O
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SAMPLE SOLUTION (a) Nucleophilic acyl substitution by an alcohol on an acid
anhydride yields an ester.
The first example in Table 20.3 introduces a new aspect of nucleophilic acyl sub-
stitution that applies not only to acid anhydrides but also to acyl chlorides, esters, and
amides. Nucleophilic acyl substitutions can be catalyzed by acids.
We can see how an acid catalyst increases the rate of nucleophilic acyl substitu-
tion by considering the hydrolysis of an acid anhydride. Formation of the tetrahedral
intermediate is rate-determining and is the step that is accelerated by the catalyst. The
acid anhydride is activated toward nucleophilic addition by protonation of one of its car-
bonyl groups:
The protonated form of the acid anhydride is present to only a very small extent, but it
is quite electrophilic. Water (and other nucleophiles) add to a protonated carbonyl group
much faster than they do to a neutral one. Thus, the rate-determining nucleophilic addi-
tion of water to form a tetrahedral intermediate takes place more rapidly in the presence
of an acid than in its absence.
Acids also catalyze the dissociation of the tetrahedral intermediate. Protonation of its car-
bonyl oxygen permits the leaving group to depart as a neutral carboxylic acid molecule,
which is a less basic leaving group than a carboxylate anion.
fast fast
HO
R
C OH
O
C
R
O
Tetrahedral
intermediate
HO
H
R
C O
O
C
R
OH
H11001
H
H11001
H11001 H
H11001
Proton
H110012RC
O
OH
Two carboxylic
acid molecules
rate-
determining
step fast, H11002H
H11001
H
2
O
Water
C
R
C
R
H11001
OH
O
O
Protonated form of
an acid anhydride
H
2
O
R
H11001
C OH
O
C
R
O
HO
R
C OH
O
C
R
O
Tetrahedral
intermediate
RCOCR
O O
Acid
anhydride
RCOCR
HO
H11001
O
Protonated form of
acid anhydride
H11001 H
H11001
Proton
fast
C
6
H
5
COCC
6
H
5
O O
Benzoic
anhydride
C
6
H
5
COCH
3
O
Methyl benzoate
C
6
H
5
COH
O
Benzoic acid
H11001 CH
3
OH
Methanol
H11001
H
H11001
786 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
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This pattern of increased reactivity resulting from carbonyl group protonation has
been seen before in nucleophilic additions to aldehydes and ketones (Section 17.6) and
in the mechanism of the acid-catalyzed esterification of carboxylic acids (Section 19.14).
Many biological reactions involve nucleophilic acyl substitution and are catalyzed by
enzymes that act by donating a proton to the carbonyl oxygen, the leaving group, or
both.
PROBLEM 20.8 Write the structure of the tetrahedral intermediate formed in
each of the reactions given in Problem 20.7. Using curved arrows, show how each
tetrahedral intermediate dissociates to the appropriate products.
SAMPLE SOLUTION (a) The reaction given is the acid-catalyzed esterification of
methanol by benzoic anhydride. The first step is the activation of the anhydride
toward nucleophilic addition by protonation.
The tetrahedral intermediate is formed by nucleophilic addition of methanol to
the protonated carbonyl group.
Acid anhydrides are more stable and less reactive than acyl chlorides. Acetyl chlo-
ride, for example, undergoes hydrolysis about 100,000 times more rapidly than acetic
anhydride at 25°C.
20.6 SOURCES OF ESTERS
Many esters occur naturally. Those of low molecular weight are fairly volatile, and many
have pleasing odors. Esters often form a significant fraction of the fragrant oil of fruits
and flowers. The aroma of oranges, for example, contains 30 different esters along with
10 carboxylic acids, 34 alcohols, 34 aldehydes and ketones, and 36 hydrocarbons.
Protonated form of
benzoic anhydride
H11001 H
H11001
ProtonBenzoic anhydride
C
6
H
5
COCC
6
H
5
O O
C
6
H
5
COCC
6
H
5
HO
H11001
O
20.6 Sources of Esters 787
CH
3
O
H
Methanol
H11001
C
6
H
5
O
C
C
C
6
H
5
OH
O
Protonated form
of benzoic
anhydride
CCH
3
O
H
H11001
C
6
H
5
OH
O
C
C
6
H
5
O
Tetrahedral intermediate
CCH
3
O
C
6
H
5
OH
O
C
C
6
H
5
O
H11001 H
H11001
H11001H11001
Tetrahedral
intermediate
CCH
3
O
C
6
H
5
OH
O
C
C
6
H
5
O
H11001
Proton
H
H11001
Proton
H
H11001
CCH
3
O
H
C
6
H
5
O
O
C
C
6
H
5
OH
H11001
Methyl
benzoate
C
6
H
5
COCH
3
O
Benzoic
acid
C
6
H
5
COH
O
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Among the chemicals used by insects to communicate with one another, esters
occur frequently.
Esters of glycerol, called glycerol triesters, triacylglycerols, or triglycerides, are
abundant natural products. The most important group of glycerol triesters includes those
in which each acyl group is unbranched and has 14 or more carbon atoms.
Fats and oils are naturally occurring mixtures of glycerol triesters. Fats are mixtures that
are solids at room temperature; oils are liquids. The long-chain carboxylic acids obtained
from fats and oils by hydrolysis are known as fatty acids.
The chief methods used to prepare esters in the laboratory have all been described
earlier, and are summarized in Table 20.4.
20.7 PHYSICAL PROPERTIES OF ESTERS
Esters are moderately polar, with dipole moments in the 1.5 to 2.0-D range.
Dipole–dipole attractive forces give esters higher boiling points than hydrocarbons of
similar shape and molecular weight. Because they lack hydroxyl groups, however, ester
molecules cannot form hydrogen bonds to each other; consequently, esters have lower
boiling points than alcohols of comparable molecular weight.
CH
3
(CH
2
)
16
CO
OC(CH
2
)
16
CH
3
OC(CH
2
)
16
CH
3
O O
O
Tristearin, a trioctadecanoyl ester
of glycerol found in many animal and
vegetable fats
COCH
2
CH
3
H
H
O
Ethyl cinnamate
(one of the constituents of
the sex pheromone of the
male oriental fruit moth)
H
CH
2
(CH
2
)
6
CH
3
H
O
O
(Z)-5-Tetradecen-4-olide
(sex pheromone of female
Japanese beetle)
CH
3
COCH
2
CH
2
CH(CH
3
)
2
O
3-Methylbutyl acetate
(contributes to characteristic
odor of bananas)
COCH
3
OH
O
Methyl salicylate
(principal component of oil
of wintergreen)
788 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
3-Methylbutyl acetate is
more commonly known as
isoamyl acetate.
Notice that (Z)-5-tetradecen-
4-olide is a cyclic ester. Recall
from Section 19.15 that cyclic
esters are called lactones and
that the suffix -olide is char-
acteristic of IUPAC names for
lactones.
A molecular model of
tristearin is shown in
Figure 26.2.
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20.7 Physical Properties of Esters 789
TABLE 20.4 Preparation of Esters
Reaction (section) and
comments
From carboxylic acids (Sections
15.8 and 19.14) In the presence
of an acid catalyst, alcohols and
carboxylic acids react to form
an ester and water. This is the
Fischer esterification.
From acyl chlorides (Sections
15.8 and 20.3) Alcohols react
with acyl chlorides by nucleo-
philic acyl substitution to yield
esters. These reactions are typi-
cally performed in the presence
of a weak base such as pyri-
dine.
From carboxylic acid anhy-
drides (Sections 15.8 and 20.5)
Acyl transfer from an acid
anhydride to an alcohol is a
standard method for the prep-
aration of esters. The reaction
is subject to catalysis by either
acids (H
2
SO
4
) or bases (pyri-
dine).
Baeyer-Villiger oxidation of
ketones (Section 17.16)
Ketones are converted to esters
on treatment with peroxy
acids. The reaction proceeds by
migration of the group RH11032 from
carbon to oxygen. It is the
more highly substituted group
that migrates. Methyl ketones
give acetate esters.
General equation and specific example
H11001
H
2
SO
4
Propanoic
acid
CH
3
CH
2
COH
O
X
1-Butanol
CH
3
CH
2
CH
2
CH
2
OH H11001
Water
H
2
O
Butyl propanoate
(85%)
CH
3
CH
2
COCH
2
CH
2
CH
2
CH
3
O
X
Carboxylic
acid
RCOH
O
X
H11001H11001
Ester
RCORH11032
O
X
RH11032OH
Alcohol
H
2
O
Water
H
H11001
Acyl
chloride
RCCl
O
X
H11001H11001 H11001
Ester
RCORH11032
O
X
RH11032OH
Alcohol
N
Pyridine Pyridinium
chloride
N
H
H11001
Cl
H11002
H11001
pyridine
CCl
O
2
N
O
2
N
O
X
3,5-Dinitrobenzoyl
chloride
COCH
2
CH(CH
3
)
2
O
2
N
O
2
N
O
X
Isobutyl
3,5-dinitrobenzoate
(85%)
(CH
3
)
2
CHCH
2
OH
Isobutyl
alcohol
Acid
anhydride
RCOCR
O
X
O
X
H11001H11001RH11032OH
Alcohol Ester
RCORH11032
O
X
Carboxylic
acid
RCOH
O
X
H11001
pyridine
CH
2
OH
CH
3
O
m-Methoxybenzyl
alcohol
CH
2
OCCH
3
CH
3
O
O
X
m-Methoxybenzyl
acetate (99%)
Acetic
anhydride
CH
3
COCCH
3
O
X
O
X
Ketone
RCRH11032
O
X
Peroxy
acid
RH11033COOH
O
X
Carboxylic
acid
RH11033COH
O
X
H11001H11001
Ester
RCORH11032
O
X
CF
3
CO
2
OH
Cyclopropyl
methyl ketone
CH
3
C
O
X
Cyclopropyl
acetate (53%)
CH
3
CO
O
X
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Esters can participate in hydrogen bonds with substances that contain hydroxyl
groups (water, alcohols, carboxylic acids). This confers some measure of water solubil-
ity on low-molecular-weight esters; methyl acetate, for example, dissolves in water to
the extent of 33 g/100 mL. Water solubility decreases as the carbon content of the ester
increases. Fats and oils, the glycerol esters of long-chain carboxylic acids, are practically
insoluble in water.
20.8 REACTIONS OF ESTERS: A REVIEW AND A PREVIEW
The reaction of esters with Grignard reagents and with lithium aluminum hydride, both
useful in the synthesis of alcohols, were described earlier. They are reviewed in Table 20.5.
Nucleophilic acyl substitutions at the ester carbonyl group are summarized in Table
20.6. Esters are less reactive than acyl chlorides and acid anhydrides. Nucleophilic acyl
substitution in esters, especially ester hydrolysis, has been extensively investigated from
a mechanistic perspective. Indeed, much of what we know concerning the general topic
2-Methylbutane:
mol wt 72, bp 28°C
CH
3
CHCH
2
CH
3
CH
3
2-Butanol:
mol wt 74, bp 99°C
CH
3
CHCH
2
CH
3
OH
Methyl acetate:
mol wt 74, bp 57°C
CH
3
COCH
3
O
790 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
TABLE 20.5 Summary of Reactions of Esters Discussed in Earlier Chapters
Reaction (section) and
comments
Reaction with Grignard
reagents (Section 14.10)
Esters react with two
equivalents of a Grignard
reagent to produce terti-
ary alcohols. Two of the
groups bonded to the car-
bon that bears the
hydroxyl group in the ter-
tiary alcohol are derived
from the Grignard
reagent.
Reduction with lithium
aluminum hydride (Sec-
tion 15.3) Lithium alumi-
num hydride cleaves
esters to yield two alco-
hols.
General equation and specific example
Ester
RCORH11032
O
X
Tertiary
alcohol
RCRH11033
W
W
OH
RH11033
2RH11033MgX
Grignard
reagent
H11001 RH11032OH
Alcohol
H11001
1. diethyl ether
2. H
3
O
H11001
2CH
3
MgI
Methylmagnesium
iodide
H11001 CH
3
CH
2
OH
Ethanol
H11001
1. diethyl
ether
2. H
3
O
H11001
Ethyl
cyclopropanecarboxylate
COCH
2
CH
3
O
X
2-Cyclopropyl-2-
propanol (93%)
CCH
3
CH
3
W
W
OH
Ester
RCORH11032
O
X
RH11032OH
Alcohol
RCH
2
OH
Primary
alcohol
H11001
1. LiAlH
4
2. H
2
O
H11001COCH
2
CH
3
O
X
Ethyl benzoate
CH
2
OH
Benzyl
alcohol (90%)
CH
3
CH
2
OH
Ethyl
alcohol
1. LiAlH
4
2. H
2
O
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20.9 Acid-Catalyzed Ester Hydrolysis 791
TABLE 20.6 Conversion of Esters to Other Carboxylic Acid Derivatives
Reaction (section) and comments
Reaction with ammonia and amines (Sec-
tion 20.13) Esters react with ammonia and
amines to form amides. Methyl and ethyl
esters are the most reactive.
Hydrolysis (Sections 20.9 and 20.10) Ester
hydrolysis may be catalyzed either by acids
or by bases. Acid-catalyzed hydrolysis is an
equilibrium-controlled process, the reverse
of the Fischer esterification. Hydrolysis in
base is irreversible and is the method usual-
ly chosen for preparative purposes.
General equation and specific example
Ester
RCORH11032
O
X
Amide
RCNRH11033
2
O
X
RH11033
2
NH
Amine
H11001 RH11032OH
Alcohol
H11001
Ester
RCORH11032
O
X
Carboxylic
acid
RCOH
O
X
H
2
O
Water
H11001 RH11032OH
Alcohol
H11001
Fluoroacetamide
(90%)
FCH
2
CNH
2
O
X
Ethyl
fluoroacetate
FCH
2
COCH
2
CH
3
O
X
H
2
O
NH
3
Ammonia
H11001 CH
3
CH
2
OH
Ethanol
H11001
H11001
1. H
2
O, NaOH
2. H
H11001
COCH
3
O
2
N
O
X
Methyl
m-nitrobenzoate
COH
O
2
N
O
X
m-Nitrobenzoic
acid (90–96%)
CH
3
OH
Methanol
of nucleophilic acyl substitution comes from studies carried out on esters. The follow-
ing sections describe those mechanistic studies.
20.9 ACID-CATALYZED ESTER HYDROLYSIS
Ester hydrolysis is the most studied and best understood of all nucleophilic acyl substi-
tutions. Esters are fairly stable in neutral aqueous media but are cleaved when heated
with water in the presence of strong acids or bases. The hydrolysis of esters in dilute
aqueous acid is the reverse of the Fischer esterification (Sections 15.8 and 19.14):
When esterification is the objective, water is removed from the reaction mixture to
encourage ester formation. When ester hydrolysis is the objective, the reaction is carried
out in the presence of a generous excess of water.
CHCOCH
2
CH
3
O
Cl
Ethyl
2-chloro-2-phenylacetate
H11001 H
2
O
Water
HCl
heat
CHCOH
O
Cl
2-Chloro-2-phenylacetic
acid (80–82%)
H11001 CH
3
CH
2
OH
Ethyl
alcohol
H11001H11001RCORH11032
O
X
Ester
H
2
O
Water
RH11032OH
AlcoholCarboxylic
acid
RCOH
O
X
H
H11001
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PROBLEM 20.9 The compound having the structure shown was heated with
dilute sulfuric acid to give a product having the molecular formula C
5
H
12
O
3
in
63–71% yield. Propose a reasonable structure for this product. What other organic
compound is formed in this reaction?
The mechanism of acid-catalyzed ester hydrolysis is presented in Figure 20.4. It
is precisely the reverse of the mechanism given for acid-catalyzed ester formation in Sec-
tion 19.14. Like other nucleophilic acyl substitutions, it proceeds in two stages. A tetra-
hedral intermediate is formed in the first stage, and this tetrahedral intermediate disso-
ciates to products in the second stage.
A key feature of the first stage is the site at which the starting ester is protonated.
Protonation of the carbonyl oxygen, as shown in step 1 of Figure 20.4, gives a cation
that is stabilized by electron delocalization. The alternative site of protonation, the alkoxy
oxygen, gives rise to a much less stable cation.
CH
3
COCH
2
CHCH
2
CH
2
CH
2
OCCH
3
OCCH
3
OO
O
?
H
2
O, H
2
SO
4
heat
792 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
Step 1: Protonation of the carbonyl oxygen of the ester
H
H
O
H11001
H
ORH11032
O
H11001
Ester
RC
Hydronium
ion
ORH11032
O
H11001
RC
H
Protonated
form of ester
H11001
H
H
O
Water
Step 2: Nucleophilic addition of water to protonated form of ester
O
H
H
Water
H11001
ORH11032
O
H11001
RC
H
Protonated
form of ester
RC ORH11032
O
H11001
HH
OH
Oxonium ion
Step 3: Deprotonation of the oxonium ion to give the neutral form of the
tetrahedral intermediate
RC ORH11032
O
H11001
HH
OH
Oxonium
ion
H11001
H
H
O
Water
RC ORH11032
OH
OH
Tetrahedral
intermediate
H11001
H
H
O
H11001
H
Hydronium
ion
X X
X
—Cont.
FIGURE 20.4 The mecha-
nism of acid-catalyzed ester
hydrolysis. Steps 1 through 3
show the formation of the
tetrahedral intermediate.
Dissociation of the tetrahe-
dral intermediate is shown
in steps 4 through 6.
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20.9 Acid-Catalyzed Ester Hydrolysis 793
Protonated form
of carboxylic acid
Step 6: Deprotonation of the protonated carboxylic acid
O
O
RC
H11001
H
H11001
H
H
O
Water
H
H
O
H11001
H
Hydronium
ion
OH
O
Carboxylic
acid
RC
H
H11001
X X
Protonated form
of carboxylic acid
Step 4: Protonation of the tetrahedral intermediate at its alkoxy oxygen
RC ORH11032
OH
OH
Tetrahedral
intermediate
H11001
H
H
O
H11001
H
Hydronium
ion
RC O
RH11032
OH
OH
H11001
H
H
O
Water
H
H11001
Oxonium ion
Step 5: Dissociation of the protonated form of the tetrahedral intermediate to an
alcohol and the protonated form of the carboxylic acid
RC O
RH11032
OH
OH
H
H11001
Oxonium ion
OH
OH
H11001RC O
RH11032
H
H11001
Alcohol
X
FIGURE 20.4 (Continued)
Protonation of the carbonyl oxygen, as emphasized earlier in the reactions of alde-
hydes and ketones, makes the carbonyl group more susceptible to nucleophilic attack. A
water molecule adds to the carbonyl group of the protonated ester in step 2. Loss of a
proton from the resulting oxonium ion gives the neutral form of the tetrahedral inter-
mediate in step 3 and completes the first stage of the mechanism.
Once formed, the tetrahedral intermediate can revert to starting materials by merely
reversing the reactions that formed it, or it can continue onward to products. In the sec-
ond stage of ester hydrolysis, the tetrahedral intermediate dissociates to an alcohol and
a carboxylic acid. In step 4 of Figure 20.4, protonation of the tetrahedral intermediate at
Positive charge is delocalized.
ORH11032
RC
OH
H11001
ORH11032
RC
OH
H11001
Protonation of carbonyl oxygen
Positive charge is localized
on a single oxygen.
H11001
ORH11032
RC
O
H
Protonation of alkoxy oxygen
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its alkoxy oxygen gives a new oxonium ion, which loses a molecule of alcohol in step
5. Along with the alcohol, the protonated form of the carboxylic acid arises by dissoci-
ation of the tetrahedral intermediate. Its deprotonation in step 6 completes the process.
PROBLEM 20.10 On the basis of the general mechanism for acid-catalyzed ester
hydrolysis shown in Figure 20.4, write an analogous sequence of steps for the spe-
cific case of ethyl benzoate hydrolysis.
The most important species in the mechanism for ester hydrolysis is the tetrahe-
dral intermediate. Evidence in support of the existence of the tetrahedral intermediate
was developed by Professor Myron Bender on the basis of isotopic labeling experiments
he carried out at the University of Chicago. Bender prepared ethyl benzoate, labeled with
the mass-18 isotope of oxygen at the carbonyl oxygen, then subjected it to acid-catalyzed
hydrolysis in ordinary (unlabeled) water. He found that ethyl benzoate, recovered from
the reaction before hydrolysis was complete, had lost a portion of its isotopic label. This
observation is consistent only with the reversible formation of a tetrahedral intermediate
under the reaction conditions:
The two OH groups in the tetrahedral intermediate are equivalent, and so either the
labeled or the unlabeled one can be lost when the tetrahedral intermediate reverts to ethyl
benzoate. Both are retained when the tetrahedral intermediate goes on to form benzoic
acid.
PROBLEM 20.11 In a similar experiment, unlabeled 4-butanolide was allowed
to stand in an acidic solution in which the water had been labeled with
18
O. When
the lactone was extracted from the solution after 4 days, it was found to contain
18
O. Which oxygen of the lactone do you think became isotopically labeled?
20.10 ESTER HYDROLYSIS IN BASE: SAPONIFICATION
Unlike its acid-catalyzed counterpart, ester hydrolysis in aqueous base is irreversible.
This is because carboxylic acids are converted to their corresponding carboxylate anions
under these conditions, and these anions are incapable of acyl transfer to alcohols.
H11001H11001RCORH11032
O
X
Ester
HO
H11002
Hydroxide ion
RH11032OH
AlcoholCarboxylate
ion
RCO
H11002
O
X
O
O
4-Butanolide
794 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
C
C
6
H
5
OCH
2
CH
3
O
Ethyl benzoate
(labeled with
18
O)
C
C
6
H
5
OCH
2
CH
3
O
Ethyl benzoate
H11001 H
2
O
Water
H
H11001
H
H11001
HO OH
C
C
6
H
5
OCH
2
CH
3
Tetrahedral
intermediate
H11001 H
2
O
Water
(labeled with
18
O)
Since it is consumed, hydrox-
ide ion is a reactant, not a
catalyst.
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To isolate the carboxylic acid, a separate acidification step following hydrolysis is nec-
essary. Acidification converts the carboxylate salt to the free acid.
Ester hydrolysis in base is called saponification, which means “soap making.”
Over 2000 years ago, the Phoenicians made soap by heating animal fat with wood ashes.
Animal fat is rich in glycerol triesters, and wood ashes are a source of potassium car-
bonate. Basic cleavage of the fats produced a mixture of long-chain carboxylic acids as
their potassium salts.
Potassium and sodium salts of long-chain carboxylic acids form micelles that dissolve
grease (Section 19.5) and have cleansing properties. The carboxylic acids obtained by
saponification of fats are called fatty acids.
PROBLEM 20.12 Trimyristin is obtained from coconut oil and has the molecular
formula C
45
H
86
O
6
. On being heated with aqueous sodium hydroxide followed by
acidification, trimyristin was converted to glycerol and tetradecanoic acid as the
only products. What is the structure of trimyristin?
In one of the earliest kinetic studies of an organic reaction, carried out in the 19th
century, the rate of hydrolysis of ethyl acetate in aqueous sodium hydroxide was found
to be first order in ester and first order in base.
1. NaOH, H
2
O, heat
2. H
2
SO
4
H11001 CH
3
OH
Methyl alcoholMethyl 2-methylpropenoate
(methyl methacrylate)
CCOCH
3
CH
2
O
CH
3
2-Methylpropenoic
acid (87%)
(methacrylic acid)
CCOHCH
2
O
CH
3
CH
2
OCCH
3
CH
3
O
o-Methylbenzyl
acetate
H11001 NaOH
Sodium
hydroxide
water–
methanol
heat
NaOCCH
3
O
Sodium
acetate
H11001 CH
2
OH
CH
3
o-Methylbenzyl alcohol
(95–97%)
20.10 Ester Hydrolysis In Base: Saponification 795
Procedures for making a va-
riety of soaps are given in
the May 1998 issue of the
Journal of Chemical Educa-
tion, pp. 612–614.
CH
3
(CH
2
)
x
CO
O
OC(CH
2
)
z
CH
3
OC(CH
2
)
y
CH
3
O
O
K
2
CO
3
, H
2
O
heat
HOCH
2
CHCH
2
OH
OH
Glycerol
H11001 KOC(CH
2
)
x
CH
3
O
KOC(CH
2
)
y
CH
3
O
KOC(CH
2
)
z
CH
3
O
H11001H11001
Potassium carboxylate salts
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Overall, the reaction exhibits second-order kinetics. Both the ester and the base are
involved in the rate-determining step or in a rapid step that precedes it.
Two processes that are consistent with second-order kinetics both involve hydrox-
ide ion as a nucleophile but differ in the site of nucleophilic attack. One of these
processes is an S
N
2 reaction in which hydroxide displaces carboxylate from the alkyl
group of the ester. We say that this pathway involves alkyl–oxygen cleavage, because it
is the bond between oxygen and the alkyl group of the ester that breaks. The other
process involves acyl–oxygen cleavage, with hydroxide attacking the carbonyl group.
Alkyl–oxygen cleavage
Acyl–oxygen cleavage
Convincing evidence that ester hydrolysis in base proceeds by the second of these
two paths, namely, acyl–oxygen cleavage, has been obtained from several sources. In
one experiment, ethyl propanoate labeled with
18
O in the ethoxy group was hydrolyzed.
On isolating the products, all the
18
O was found in the ethyl alcohol; there was no
18
O
enrichment in the sodium propanoate.
The carbon–oxygen bond broken in the process is therefore the one between oxygen and
the acyl group. The bond between oxygen and the ethyl group remains intact.
H11001H11001CH
3
CH
2
OH
18
O-labeled
ethyl alcohol
NaOH
Sodium
hydroxide
18
O-labeled ethyl
propanoate
CH
3
CH
2
COCH
2
CH
3
O
Sodium
propanoate
CH
3
CH
2
CONa
O
HO
H11002
Hydroxide
ion
H11001 RC ORH11032
O
Ester
slow
fast
RCOH
O
H11001 RH11032O
H11002
H11001RCO
O
H11002
Carboxylate
ion
RH11032OH
Alcohol
RC O RH11032
O
Ester
OH
H11002
Hydroxide
ion
RCO
O
H11002
Carboxylate
ion
H11001 RH11032 OH
Alcohol
Rate H11005 k[CH
3
COCH
2
CH
3
][NaOH]
O
H11001H11001CH
3
CH
2
OH
Ethanol
NaOH
Sodium
hydroxide
Ethyl acetate
CH
3
COCH
2
CH
3
O
Sodium acetate
CH
3
CONa
O
796 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
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PROBLEM 20.13 In a similar experiment, pentyl acetate was subjected to saponi-
fication with
18
O-labeled hydroxide in
18
O-labeled water. What product do you
think became isotopically labeled here, acetate ion or 1-pentanol?
Identical conclusions in support of acyl–oxygen cleavage have been obtained from
stereochemical studies. Saponification of esters of optically active alcohols proceeds with
retention of configuration.
None of the bonds to the stereogenic center are broken when acyl–oxygen cleavage
occurs. Had alkyl–oxygen cleavage occurred instead, it would have been accompanied
by inversion of configuration at the stereogenic center to give (S)-(H11002)-1-phenylethyl
alcohol.
Once it was established that hydroxide ion attacks the carbonyl group in basic ester
hydrolysis, the next question to be addressed concerned whether the reaction is concerted
or involves an intermediate. In a concerted reaction acyl–oxygen cleavage occurs at the
same time that hydroxide ion attacks the carbonyl group.
In an extension of the work described in the preceding section, Bender showed
that basic ester hydrolysis was not concerted and, like acid hydrolysis, took place by
way of a tetrahedral intermediate. The nature of the experiment was the same, and the
results were similar to those observed in the acid-catalyzed reaction. Ethyl benzoate
enriched in
18
O at the carbonyl oxygen was subjected to hydrolysis in base, and sam-
ples were isolated before saponification was complete. The recovered ethyl benzoate was
found to have lost a portion of its isotopic label, consistent with the formation of a tetra-
hedral intermediate:
All these facts—the observation of second-order kinetics, acyl–oxygen cleavage,
and the involvement of a tetrahedral intermediate—are accommodated by the reaction
mechanism shown in Figure 20.5. Like the acid-catalyzed mechanism, it has two distinct
HO
H11002
Hydroxide
ion
H11001
Ester
RCORH11032
O
HO C
R
O
ORH11032
H9254H11002 H9254H11002
Representation of
transition state for
concerted displacement
RCOH
O
Carboxylic
acid
H11001 RH11032O
H11002
Alkoxide
ion
KOH
ethanol–water
CH
3
C
O
OC
CH
3
C
6
H
5
H
(R)-(H11001)-1-Phenylethyl
acetate
CH
3
COK
O
Potassium
acetate
H11001 HO C
CH
3
C
6
H
5
H
(R)-(H11001)-1-Phenylethyl
alcohol
(80% yield; same
optical purity as ester)
20.10 Ester Hydrolysis in Base: Saponification 797
C
C
6
H
5
OCH
2
CH
3
O
Ethyl benzoate
(labeled with
18
O)
H11001 H
2
O
Water
HO
H11002
HO
H11002
HO OH
C
C
6
H
5
OCH
2
CH
3
Tetrahedral
intermediate
C
C
6
H
5
OCH
2
CH
3
O
Ethyl benzoate
H11001 H
2
O
Water
(labeled with
18
O)
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stages, namely, formation of the tetrahedral intermediate and its subsequent dissociation.
All the steps are reversible except the last one. The equilibrium constant for proton
abstraction from the carboxylic acid by hydroxide is so large that step 4 is, for all intents
and purposes, irreversible, and this makes the overall reaction irreversible.
798 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
OH
Step 1: Nucleophilic addition of hydroxide ion to the carbonyl group
ORH11032
H11001
Ester
RC
Step 2: Proton transfer to anionic form of tetrahedral intermediate
O
HO
H11002
Hydroxide
ion
Anionic form of
tetrahedral intermediate
RC ORH11032
OH
O
H11002
Anionic form of
tetrahedral intermediate
RC ORH11032
OH
H11001 OHH
Water
RC ORH11032
OH
Tetrahedral
intermediate
H11001
H11002
OH
Hydroxide
ion
Step 3: Dissociation of tetrahedral intermediate
H11001HO
H11002
Hydroxide
ion
Tetrahedral
intermediate
RC ORH11032
OH
OH
OH
H11001 RC
O
H
H
O H11001
Water Carboxylic
acid
H11002
ORH11032
Alkoxide
ion
Step 4: Proton transfer steps yield an alcohol and a carboxylate anion
H11001RO
H11002
Alkoxide ion
OHH
Water
RO H H11001
H11002
OH
Alcohol Hydroxide ion
O
RC
H
O
H11001
Carboxylic acid
(stronger acid)
H11002
OH
Hydroxide ion
(stronger base)
O
H11002
RC
O
H11001
Carboxylate ion
(weaker base)
O
H
H
Water
(weaker acid)
O
H11002
X
X
X X
FIGURE 20.5 The mechanism of ester hydrolysis in basic solution.
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Steps 2 and 4 are proton-transfer reactions and are very fast. Nucleophilic addi-
tion to the carbonyl group has a higher activation energy than dissociation of the tetra-
hedral intermediate; step 1 is rate-determining.
PROBLEM 20.14 On the basis of the general mechanism for basic ester hydrol-
ysis shown in Figure 20.5, write an analogous sequence of steps for the saponifi-
cation of ethyl benzoate.
20.11 REACTION OF ESTERS WITH AMMONIA AND AMINES
Esters react with ammonia to form amides.
Ammonia is more nucleophilic than water, making it possible to carry out this reaction
using aqueous ammonia.
Amines, which are substituted derivatives of ammonia, react similarly:
The amine must be primary (RNH
2
) or secondary (R
2
NH). Tertiary amines (R
3
N) can-
not form amides, because they have no proton on nitrogen that can be replaced by an
acyl group.
PROBLEM 20.15 Give the structure of the expected product of the following
reaction:
The reaction of ammonia and amines with esters follows the same general mech-
anistic course as other nucleophilic acyl substitution reactions. A tetrahedral intermedi-
ate is formed in the first stage of the process and dissociates in the second stage.
CH
3
NH
2
CH
3
O
O H11001
heat
O
FCH
2
COCH
2
CH
3
Ethyl fluoroacetate
H11001 NH
2
Cyclohexylamine
O
FCH
2
CNH
N-Cyclohexyl-
fluoroacetamide (61%)
H11001 CH
3
CH
2
OH
Ethyl alcohol
H
2
O
H11001H11001 CH
3
OH
Methyl alcoholMethyl 2-methylpropenoate
CCOCH
3
CH
2
O
CH
3
Ammonia
NH
3
2-Methylpropenamide
(75%)
CCNH
2
CH
2
O
CH
3
H11001RCORH11032
O
X
Ester
NH
3
Ammonia
H11001 RH11032OH
AlcoholAmide
RCNH
2
O
X
20.11 Reaction of Esters with Ammonia and Amines 799
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Formation of tetrahedral intermediate
Dissociation of tetrahedral intermediate
Although both stages are written as equilibria, the overall reaction lies far to the right
because the amide carbonyl is stabilized to a much greater extent than the ester carbonyl.
20.12 THIOESTERS
Thioesters, compounds of the type , undergo the same kinds of reactions as esters
and by similar mechanisms. Nucleophilic acyl substitution of a thioester gives a thiol
along with the product of acyl transfer. For example:
PROBLEM 20.16 Write the structure of the tetrahedral intermediate formed in
the reaction just described.
The carbon–sulfur bond of a thioester is rather long—typically on the order of 180
pm—and delocalization of the sulfur lone-pair electrons into the H9266 orbital of the car-
bonyl group is not as effective as in esters. Nucleophilic acyl substitution reactions of
thioesters occur faster than those of simple esters. A number of important biological
processes involve thioesters; several of these are described in Chapter 26.
20.13 PREPARATION OF AMIDES
Amides are readily prepared by acylation of ammonia and amines with acyl chlorides,
anhydrides, or esters.
Acylation of ammonia (NH
3
) yields an amide .
Primary amines (RNH
2
) yield N-substituted amides .(RH11032CNHR)
O
X
(RH11032CNH
2
)
O
X
H11001H11001HSCH
2
CH
2
OC
6
H
5
2-Phenoxyethanethiol
(90%)
CH
3
OH
MethanolS-2-Phenoxyethyl
ethanethioate
CH
3
CSCH
2
CH
2
OC
6
H
5
O
Methyl
acetate
CH
3
COCH
3
O
HCl
RCSRH11032
O
X
RC ORH11032
HO
NH
2
Tetrahedral
intermediate
RC
O
NH
2
Amide
H11001 RH11032OH
Alcohol
H11001RCORH11032
O
Ester
NH
3
Ammonia
RCORH11032
H11001
NH
3
O
H11002
RCORH11032
NH
2
OH
Tetrahedral
intermediate
800 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
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Secondary amines (R
2
NH) yield N,N-disubstituted amides .
Examples illustrating these reactions may be found in Tables 20.2, 20.3, and 20.6.
Two molar equivalents of amine are required in the reaction with acyl chlorides
and acid anhydrides; one molecule of amine acts as a nucleophile, the second as a Br?n-
sted base.
It is possible to use only one molar equivalent of amine in these reactions if some other
base, such as sodium hydroxide, is present in the reaction mixture to react with the hydro-
gen chloride or carboxylic acid that is formed. This is a useful procedure in those cases
in which the amine is a valuable one or is available only in small quantities.
Esters and amines react in a 1:1 molar ratio to give amides. No acidic product is
formed from the ester, and so no additional base is required.
PROBLEM 20.17 Write an equation showing the preparation of the following
amides from the indicated carboxylic acid derivative:
(a) from an acyl chloride
(b) from an acid anhydride
(c) from a methyl ester
SAMPLE SOLUTION (a) Amides of the type are derived by acylation of
ammonia.
(CH
3
)
2
CHCCl
O
2-Methylpropanoyl
chloride
(CH
3
)
2
CHCNH
2
O
2-Methylpropanamide
NH
4
Cl
Ammonium chloride
H11001 2NH
3
Ammonia
H11001
RCNH
2
O
HCN(CH
3
)
2
O
CH
3
CNHCH
3
O
(CH
3
)
2
CHCNH
2
O
H11001H11001CH
3
OH
Methanol
R
2
NH
Amine Methyl ester
RH11032COCH
3
O
Amide
RH11032CNR
2
O
H11001H11001R
2
NH
2
H11001
Cl
H11002
Hydrochloride salt
of amine
2R
2
NH
Amine Acyl chloride
RH11032CCl
O
Amide
RH11032CNR
2
O
H11001H11001R
2
NH
2
H11001
H11002
OCRH11032
O
Carboxylate salt
of amine
2R
2
NH
Amine Acid anhydride
RH11032COCRH11032
O O
Amide
RH11032CNR
2
O
(RH11032CNR
2
)
O
X
20.13 Preparation of Amides 801
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Two molecules of ammonia are needed because its acylation produces, in addi-
tion to the desired amide, a molecule of hydrogen chloride. Hydrogen chloride
(an acid) reacts with ammonia (a base) to give ammonium chloride.
All these reactions proceed by nucleophilic addition of the amine to the carbonyl
group. Dissociation of the tetrahedral intermediate proceeds in the direction that leads to
an amide.
The carbonyl group of an amide is stabilized to a greater extent than that of an acyl chlo-
ride, anhydride, or ester; amides are formed rapidly and in high yield from each of these
carboxylic acid derivatives.
Amides are sometimes prepared directly from carboxylic acids and amines by a
two-step process. The first step is an acid–base reaction in which the acid and the amine
combine to form an ammonium carboxylate salt. On heating, the ammonium carboxy-
late salt loses water to form an amide.
In practice, both steps may be combined in a single operation by simply heating a car-
boxylic acid and an amine together:
A similar reaction in which ammonia and carbon dioxide are heated under pres-
sure is the basis of the industrial synthesis of urea. Here, the reactants first combine,
yielding a salt called ammonium carbamate:
On being heated, ammonium carbamate undergoes dehydration to form urea:
H
3
N
Ammonia
H11001 O C O
Carbon dioxide
NH
3
H11002
H
3
N C
H11001
O
O
H11001
NH
4
H11002
H
2
N C
O
O
Ammonium carbamate
H11001H11001H
2
O
Water
C
6
H
5
NH
2
AnilineBenzoic acid
C
6
H
5
COH
O
N-Phenylbenzamide
(80–84%)
C
6
H
5
CNHC
6
H
5
O
225°C
RCOH
O
Carboxylic
acid
H11001 RH11032
2
NH
Amine Ammonium
carboxylate salt
RCO
H11002
O
RH11032
2
NH
2
H11001
RCNRH11032
2
O
Amide
H11001 H
2
O
Water
heat
RCX
O
Acylating
agent
H11001 RH11032
2
NH
Amine
RC X
HO
NRH11032
2
Tetrahedral
intermediate
RCNRH11032
2
O
Amide
H11001 HX
Conjugate acid
of leaving group
802 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
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Over 10
10
lb of urea—most of it used as fertilizer—is produced annually in the United
States by this method.
These thermal methods for preparing amides are limited in their generality. Most
often amides are prepared in the laboratory from acyl chlorides, acid anhydrides, or
esters, and these are the methods that you should apply to solving synthetic problems.
20.14 LACTAMS
Lactams are cyclic amides and are analogous to lactones, which are cyclic esters. Most
lactams are known by their common names, as the examples shown illustrate.
Just as amides are more stable than esters, lactams are more stable than lactones.
Thus, although H9252-lactones are difficultly accessible (Section 19.15), H9252-lactams are among
the best known products of the pharmaceutical industry. The penicillins and
cephalosporins, which are so useful in treating bacterial infections, are H9252-lactams and are
customarily referred to as H9252-lactam antibiotics.
These antibiotics inhibit a bacterial enzyme that is essential for cell wall formation. A
nucleophilic site on the enzyme reacts with the carbonyl group in the four-membered
ring, and the ring opens to acylate the enzyme. Once its nucleophilic site is acylated, the
enzyme is no longer active and the bacteria die. The H9252-lactam rings of the penicillins
and cephalosporins combine just the right level of stability in aqueous media with reac-
tivity toward nucleophilic substitution to be effective acylating agents toward this criti-
cal bacterial enzyme.
C
6
H
5
CH
2
CNH
O
S
N
CH
3
CO
2
H
CH
3
O
Penicillin G
CH
3
NH
2
O
N
S
CO
2
H
C
6
H
5
CHCNH
O
Cephalexin
O
N
CH
3
N-Methylpyrrolidone
(a polar aprotic
solvent)
N
H
O
H9280-Caprolactam
(industrial chemical
used to prepare a type of nylon)
H11001
NH
4
H11002
H
2
N C
O
O
Ammonium carbamate
heat
H
2
NCNH
2
O
Urea
H11001 H
2
O
Water
20.14 Lactams 803
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20.15 IMIDES
Compounds that have two acyl groups bonded to a single nitrogen are known as imides.
The most common imides are cyclic ones:
Cyclic imides can be prepared by heating the ammonium salts of dicarboxylic
acids:
PROBLEM 20.18 Phthalimide has been prepared in 95% yield by heating the
compound formed on reaction of phthalic anhydride (Section 20.4) with excess
ammonia. This compound has the molecular formula C
8
H
10
N
2
O
3
. What is its struc-
ture?
20.16 HYDROLYSIS OF AMIDES
The only nucleophilic acyl substitution reaction that amides undergo is hydrolysis.
Amides are fairly stable in water, but the amide bond is cleaved on heating in the pres-
ence of strong acids or bases. Nominally, this cleavage produces an amine and a car-
boxylic acid.
In acid, however, the amine is protonated, giving an ammonium ion, RH11032
2
N
H11001
H
2
:
RCNRH11032
2
O
Amide
H11001 H
3
O
H11001
Hydronium ion
RCOH
O
Carboxylic
acid
H11001 RH11032 RH11032N
H11001
H
H
Ammonium ion
RCN
RH11032
O
RH11032
Amide
H11001 H
2
O
Water
RCOH
O
Carboxylic
acid
H11001 HN
RH11032
RH11032
Amine
HOCCH
2
CH
2
COH
O O
Succinic acid
H11001 2NH
3
Ammonia
heat
O O
NH
4
H11001
NH
4
H11001
H11002
OCCH
2
CH
2
CO
H11002
Ammonium succinate
NH
O
O
Succinimide
(82–83%)
RN
CRH11032
O
CRH11032
O
Imide
H
O
N
O
Succinimide
NH
O
O
Phthalimide
804 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
Replacement of the proton
on nitrogen in succinimide
by bromine gives N-bromo-
succinimide, a reagent used
for allylic and benzylic
brominations (Sections 10.4
and 11.12).
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In base the carboxylic acid is deprotonated, giving a carboxylate ion:
The acid–base reactions that occur after the amide bond is broken make the overall
hydrolysis irreversible in both cases. The amine product is protonated in acid; the car-
boxylic acid is deprotonated in base.
Mechanistically, amide hydrolysis is similar to the hydrolysis of other carboxylic
acid derivatives. The mechanism of the hydrolysis in acid is presented in Figure 20.6. It
proceeds in two stages; a tetrahedral intermediate is formed in the first stage and disso-
ciates in the second.
The amide is activated toward nucleophilic attack by protonation of its carbonyl
oxygen. The cation produced in this step is stabilized by resonance involving the nitro-
gen lone pair and is more stable than the intermediate in which the amide nitrogen is
protonated.
Once formed, the O-protonated intermediate is attacked by a water molecule in step
2. The intermediate formed in this step loses a proton in step 3 to give the neutral form
of the tetrahedral intermediate. The tetrahedral intermediate has its amino group (±NH
2
)
attached to sp
3
-hybridized carbon, and this amino group is the site at which protonation
Most stable resonance forms of
an O-protonated amide
NH
2
OH
H11001
R C R C
NH
2
OH
H11001
Protonation of carbonyl oxygen
An acylammonium ion; the positive
charge is localized on nitrogen
Protonation of amide nitrogen
R C
HN
H11001
O
HH
CH
3
CH
2
CHCNH
2
O
2-Phenylbutanamide
H
2
O, H
2
SO
4
heat
CH
3
CH
2
CHCOH
O
2-Phenylbutanoic
acid
(88–90%)
H11001
H11001
NH
4
HSO
4
H11002
Ammonium hydrogen
sulfate
KOH
ethanol–
water, heat
CH
3
CO
H11002
O
K
H11001
Potassium
acetate
H11001CH
3
CNH Br
O
N-(4-Bromophenyl)acetamide
(p-bromoacetanilide)
H
2
N Br
p-Bromoaniline (95%)
RCNRH11032
2
O
Amide
H11001 HO
H11002
Hydroxide ion
RCO
H11002
O
Carboxylate ion
H11001
Amine
RH11032 N
RH11032
H
20.16 Hydrolysis of Amides 805
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806 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
Protonated form
of carboxylic acid
Tetrahedral
intermediate
NH
2
NH
3
NH
3
NH
3
NH
2
NH
2
NH
2
NH
2
Step 1: Protonation of the carbonyl oxygen of the amide
NH
2
RC
O
H11001
Amide
O
H11001
Hydronium ion
H
H11001 O
H
H
Water
H
H
NH
2
RC
OH
H11001
Protonated form of amide
H11001
O
Water
H
H
Step 2: Nucleophilic addition of water to the protonated form of the amide
O
Water
H
H
H11001 RC
OH
Protonated form of amide
H11001
RC
O
Oxonium ion
H11001
OH
HH
Step 3: Deprotonation of the oxonium ion to give the neutral form of the tetrahedral
intermediate
RC
H11001
O
Oxonium ion
OH
HH
RC
OH
OH
H11001
H11001
O
Hydronium ion
H
H
H
Tetrahedral
intermediate
Step 4: Protonation of the tetrahedral intermediate at its amino nitrogen
RC
OH
OH
H11001 O
H11001
Hydronium ion
H
H
H
RC
OH
OH
Ammonium ion
Step 5: Dissociation of the N-protonated form of the tetrahedral intermediate to give
ammonia and the protonated form of the carboxylic acid
RC
OH
OH
Ammonium ion
H11001
RC
H11001
OH
OH
H11001
Ammonia
H11001 O
H
H
Water
H11001
X X
X
X
—Cont.
FIGURE 20.6 The mecha-
nism of amide hydrolysis in
acid solution. Steps 1 through
3 show the formation of the
tetrahedral intermediate.
Dissociation of the tetrahe-
dral intermediate is shown
in steps 4 through 6.
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occurs in step 4. Cleavage of the carbon–nitrogen bond in step 5 yields the protonated form
of the carboxylic acid, along with a molecule of ammonia. In acid solution ammonia is
immediately protonated to give ammonium ion, as shown in step 6. This protonation step
has such a large equilibrium constant that it makes the overall reaction irreversible.
PROBLEM 20.19 On the basis of the general mechanism for amide hydrolysis in
acidic solution shown in Figure 20.6, write an analogous sequence of steps for the
hydrolysis of acetanilide, .
In base the tetrahedral intermediate is formed in a manner analogous to that pro-
posed for ester saponification. Steps 1 and 2 in Figure 20.7 show the formation of the
tetrahedral intermediate in the basic hydrolysis of amides. In step 3 the basic amino group
of the tetrahedral intermediate abstracts a proton from water, and in step 4 the derived
ammonium ion undergoes basic dissociation. Conversion of the carboxylic acid to its
corresponding carboxylate anion in step 5 completes the process and renders the over-
all reaction irreversible.
PROBLEM 20.20 On the basis of the general mechanism for basic hydrol-
ysis shown in Figure 20.7, write an analogous sequence for the hydrolysis of
N,N-dimethylformamide, .
20.17 THE HOFMANN REARRANGEMENT
On treatment with bromine in basic solution, amides of the type undergo an inter-
esting reaction that leads to amines. This reaction was discovered by the nineteenth cen-
tury German chemist August W. Hofmann and is called the Hofmann rearrangement.
The group R attached to the carboxamide function may be alkyl or aryl.
H11001H11001 H11001H11001H11001RCNH
2
O
X
Amide
4HO
H11002
Hydroxide
ion
2Br
H11002
Bromide
ion
CO
3
2H11002
Carbonate
ion
Br
2
Bromine
2H
2
O
Water
RNH
2
Amine
RCNH
2
O
X
HCN(CH
3
)
2
O
CH
3
CNHC
6
H
5
O
20.17 The Hofmann Rearrangement 807
Protonated form
of carboxylic acid
Step 6: Proton transfer processes yielding ammonium ion and the carboxylic acid
O
H11001
Hydronium ion
H
H
H
NH
3
H11001
Ammonia
O
Water
H
H
H11001 NH
4
Ammonium ion
RC
OH
H11001
OH
H11001 O
H
H
Water
RC
O
H11001
OH
H11001 O
H
H
Carboxylic
acid
Hydronium
ion
H
H11001
X X
FIGURE 20.6 (Continued)
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808 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
NH
3 NH
3
O
NH
3
NH
2
NH
2
NH
2
NH
2
Step 1: Nucleophilic addition of hydroxide ion to the carbonyl group
NH
2
H11001
Amide
RC
Step 2: Proton transfer to anionic form of tetrahedral intermediate
O
HO
H11002
Hydroxide
ion
Anionic form of
tetrahedral intermediate
RC
OH
O
H11002
Anionic form of
tetrahedral intermediate
RC
OH
H11001 OHH
Water
RC
OH
OH
Tetrahedral
intermediate
H11001
H11002
OH
Hydroxide
ion
Step 3: Protonation of amino nitrogen of tetrahedral intermediate
Step 4: Dissociation of N-protonated form of tetrahedral intermediate
O
RC
H
O
H11001
Carboxylic acid
(stronger acid)
H11002
OH
Hydroxide ion
(stronger base)
O
H11002
RC
O
H11001
Carboxylate ion
(weaker base)
O
H
H
Water
(weaker acid)
O
H11002
Tetrahedral
intermediate
RC H11001 OHH
Water
OH
RC
OH
OH
Ammonium
ion
H11001
H11002
OH
Hydroxide
ion
OH
H11001
H11001HO
H11002
Hydroxide
ion
Ammonium
ion
RC
OH
H
OH
H11001 RC
O
H
H
O H11001
Water Carboxylic
acid
Ammonia
Step 5: Irreversible formation of carboxylate anion
H11001
X
X X
X
FIGURE 20.7 The mechanism of amide hydrolysis in basic solution.
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20.17 The Hofmann Rearrangement 809
CONDENSATION POLYMERS. POLYAMIDES AND POLYESTERS
A
ll fibers are polymers of one kind or another.
Cotton, for example, is cellulose, and cellulose
is a naturally occurring polymer of glucose.
Silk and wool are naturally occurring polymers of
amino acids. An early goal of inventors and entrepre-
neurs was to produce fibers from other naturally oc-
curring polymers. Their earliest efforts consisted of
chemically modifying the short cellulose fibers ob-
tained from wood so that they could be processed
into longer fibers more like cotton and silk. These ef-
forts were successful, and the resulting fibers of mod-
ified cellulose, known generically as rayon, have
been produced by a variety of techniques since the
late nineteenth century.
A second approach involved direct chemical
synthesis of polymers by connecting appropriately
chosen small molecules together into a long chain. In
1938, E. I. Du Pont de Nemours and Company an-
nounced the development of nylon, the first syn-
thetic polymer fiber.
The leader of Du Pont’s effort was Wallace H.
Carothers,
*
who reasoned that he could reproduce the
properties of silk by constructing a polymer chain held
together, as is silk, by amide bonds. The necessary
amide bonds were formed by heating a dicarboxylic
acid with a diamine. Hexanedioic acid (adipic acid) and
1,6-hexanediamine (hexamethylenediamine) react to
give a salt that, when heated, gives a polyamide called
nylon 66. The amide bonds form by a condensation re-
action, and nylon 66 is an example of a condensation
polymer.
HOC(CH
2
)
4
COH
O O
Adipic acid
H11001 H
2
N(CH
2
)
6
NH
2
Hexamethylenediamine
H11002
OC(CH
2
)
4
C
OO
NH(CH
2
)
6
NHC(CH
2
)
4
C
O O
NH(CH
2
)
6
NH
3
H11001
n
Nylon 66
H11002
OC(CH
2
)
4
CO
H11002
O O
H
3
N(CH
2
)
6
NH
3
H11001H11001
heat, H11002H
2
O
H11002
OC
O
H11001
C
O
NH NHC
O
C
O
NH NH
3
n
Kevlar (a polyamide of the aramid class)
Kevlar fibers are very strong, which makes Kevlar a
popular choice in applications where the ratio of
strength to weight is important. For example, a cable
made from Kevlar weighs only one fifth as much as a
steel one but is just as strong. Kevlar is also used to
make lightweight bulletproof vests.
Nomex is another aramid fiber. Kevlar and
Nomex differ only in that the substitution pattern in
the aromatic rings is para in Kevlar but meta in
Nomex. Nomex is best known for its fire-resistant
properties and is used in protective clothing for fire-
fighters, astronauts, and race-car drivers.
The first “6” in nylon 66 stands for the number of
carbons in the diamine, the second for the number of
carbons in the dicarboxylic acid. Nylon 66 was an im-
mediate success and fostered the development of a
large number of related polyamides, many of which
have also found their niche in the marketplace.
A slightly different class of polyamides is the
aramids (aromatic polyamides). Like the nylons, the
aramids are prepared from a dicarboxylic acid and a
diamine, but the functional groups are anchored to
benzene rings. An example of an aramid is Kevlar,
which is a polyamide derived from 1,4-benzenedicar-
boxylic acid (terephthalic acid) and 1,4-benzenedi-
amine (p-phenylenediamine):
*For an account of Carothers’ role in the creation of nylon, see the September 1988 issue of the Journal of Chemical Education (pp. 803–808).
—Cont.
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810 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
HOC
O
C
O
OCH
2
CH
2
OC
O
C
O
OCH
2
CH
2
OH
n
Dacron (a polyester)
HO C
CH
3
CH
3
C
O
O C
CH
3
CH
3
HOO
n
Lexan (a polycarbonate)
In terms of the number of scientists and engi-
neers involved, research and development in polymer
chemistry is the principal activity of the chemical in-
dustry. The initial goal of making synthetic materials
that are the equal of natural fibers has been more
than met; it has been far exceeded. What is also im-
portant is that all of this did not begin with a chance
discovery. It began with a management decision to
do basic research in a specific area, and to support it
in the absence of any guarantee that success would
be quickly achieved.
?
The production of polyester fibers leads that of all
other types. Annual United States production of poly-
ester fibers is 1.6 million tons versus 1.4 million tons
for cotton and 1.0 million tons for nylon. Wool and
silk trail far behind at 0.04 and 0.01 million tons, re-
spectively.
Not all synthetic polymers are used as fibers.
Mylar, for example, is chemically the same as Dacron,
but is prepared in the form of a thin film instead of a
fiber. Lexan is a polyester which, because of its impact
resistance, is used as a shatterproof substitute for
glass. It is a polycarbonate having the structure
shown:
?
The April 1988 issue of the Journal of Chemical Education contains a number of articles on polymers, including a historical review
entitled “Polymers Are Everywhere” (pp. 327–334) and a glossary of terms (pp. 314–319).
Polyesters are a second class of condensation
polymers, and the principles behind their synthesis
parallel those of polyamides. Ester formation between
the functional groups of a dicarboxylic acid and a diol
serve to connect small molecules together into a long
polyester. The most familiar example of a polyester is
Dacron, which is prepared from 1,4-benzenedicar-
boxylic acid and 1,2-ethanediol (ethylene glycol):
The relationship of the amine product to the amide reactant is rather remarkable.
The overall reaction appears as if the carbonyl group had been plucked out of the amide,
leaving behind a primary amine having one less carbon atom than the amide.
(CH
3
)
3
CCH
2
CNH
2
O
3,3-Dimethylbutanamide
Br
2
, NaOH
H
2
O
(CH
3
)
3
CCH
2
NH
2
2,2-Dimethylpropanamine (94%)
Br
2
, KOH
H
2
O
CNH
2
Br
O
m-Bromobenzamide
NH
2
Br
m-Bromoaniline (87%)
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20.17 The Hofmann Rearrangement 811
PROBLEM 20.21 Outline an efficient synthesis of 1-propanamine
(CH
3
CH
2
CH
2
NH
2
) from butanoic acid.
The mechanism of the Hofmann rearrangement (Figure 20.8) involves three stages:
1. Formation of an N-bromo amide intermediate (steps 1 and 2)
2. Rearrangement of the N-bromo amide to an isocyanate (steps 3 and 4)
3. Hydrolysis of the isocyanate (steps 5 and 6)
RNH
2
Step 1: Deprotonation of the amide. Amides of the type RCNH
2
are about as acidic as water, so appreciable
quantities of the conjugate base are present at equilibrium in aqueous base. The conjugate base of an amide
is stabilized by electron delocalization in much the same way that an enolate anion is.
N
R H11001
Amide
H11002
O
Hydroxide ion
H
R
O
H11002
H11001
Conjugate base of amide
O
Water
H
H
Step 2: Reaction of the conjugate base of the amide with bromine. The product of this step is an N-bromo amide.
Overall Reaction
RCNH
2
O
H11001
Amide Bromine
Br
2
H11001 4HO
H11002
Hydroxide ion Amine Bromide ion
2Br
H11002
H11001 CO
3
2H11002
Carbonate ion
2H
2
O
Water
H11001
O
C
H
H
O
N
H
K H11015 1
N
R H11001
Conjugate base of
amide
Br
Bromine
C
H
O
H11002
Br
N
R
N-Bromo amide
C
O
Br
H
H11001 Br
H11002
Bromide ion
Step 3: Deprotonation of the N-bromo amide. The electron-withdrawing effect of the bromine substituent reinforces
that of the carbonyl group and makes the N-bromo amide even more acidic than the starting amide.
N
R H11001
H11002
O
Hydroxide ion
H O
H11002
H11001
Conjugate base of
N-bromo amide
O
Water
H
H
C
Br
H
O
N Br
RC
N-bromo amide
C
X
X
X
X
X
X
X
X
—Cont.
FIGURE 20.8 The mecha-
nism of the Hofmann re-
arrangement.
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Formation of the N-bromo amide intermediate is relatively straightforward. The
base converts the amide to its corresponding anion (step 1), which acts as a nucleophile
toward bromine (step 2).
Conversion of the N-bromo amide to its conjugate base in step 3 is also easy to
understand. It is an acid–base reaction exactly analogous to that of step 1. The anion
produced in step 3 is a key intermediate; it rearranges in step 4 by migration of the alkyl
(or aryl) group from carbon to nitrogen, with loss of bromide from nitrogen. The prod-
uct of this rearrangement is an isocyanate. The isocyanate formed in the rearrangement
step then undergoes basic hydrolysis in steps 5 and 6 to give the observed amine.
Among the experimental observations that contributed to elaboration of the mech-
anism shown in Figure 20.8 are the following:
1. Only amides of the type undergo the Hofmann rearrangement. The amide
nitrogen must have two protons attached to it, of which one is replaced by bromine
to give the N-bromo amide, whereas abstraction of the second by base is neces-
sary to trigger the rearrangement. Amides of the type form N-bromo
amides under the reaction conditions, but these N-bromo amides do not rearrange.
RCNHRH11032
O
X
RCNH
2
O
X
812 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
Step 5: Hydrolysis of the isocyanate begins by base-catalyzed addition of water to form an N-alkylcarbamic acid.
R NCOH11001 H
2
O
O
OH
CN
R
H
N-Alkylcarbamic acid
Step 6: The N-alkylcarbamic acid is unstable and dissociates to an amine and carbon dioxide. Carbon dioxide is
converted to carbonate ion in base. (Several steps are actually involved; in the interests of brevity, they are
summarized as shown.)
O
OH
CN
R
H
N-Alkylcarbamic acid
2HO
H11002
H11001
Hydroxide ion
RNH
2
Amine
CO
3
2H11002
Carbonate ion
H
2
O
Water
H11001H11001
N-Alkyl isocyanate
X
X
XX
N-Alkyl isocyanate
Step 4: Rearrangement of the conjugate base of the N-bromo amide. The group R migrates from carbon to nitrogen,
and bromide is lost as a leaving group from nitrogen. The product of this rearrangement is an N-alkyl
isocyanate.
R C
O
H11002
Conjugate base of N-bromo amide
Br
R NCOH11001 Br
H11002
Bromide ion
N
FIGURE 20.8 (Continued )
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2. Rearrangement proceeds with retention of configuration at the migrating group.
The new carbon–nitrogen bond is formed at the same face of the migrating car-
bon as the bond that is broken. The rearrangement step depicted in Figure 20.8
satisfies this requirement. Presumably, carbon–nitrogen bond formation is con-
certed with carbon–carbon bond cleavage.
3. Isocyanates are intermediates. When the reaction of an amide with bromine is car-
ried out in methanol containing sodium methoxide instead of in aqueous base, the
product that is isolated is a carbamate.
Carbamates are esters of carbamic acid . Carbamates are also known
as urethans. They are relatively stable and are formed by addition of alcohols to
isocyanates.
Carbamic acid itself and N-substituted derivatives of carbamic acid are
unstable; they decompose spontaneously to carbon dioxide and ammonia or an
amine. Thus in aqueous solution, an isocyanate intermediate yields an amine via
the corresponding carbamic acid; in methanol, an isocyanate is converted to an
isolable methyl carbamate. If desired, the carbamate can be isolated, purified, and
converted to an amine in a separate hydrolysis operation.
Although the Hofmann rearrangement is complicated with respect to mechanism,
it is easy to carry out and gives amines that are sometimes difficult to prepare by other
methods.
20.18 PREPARATION OF NITRILES
Nitriles are organic compounds that contain the ±CPN functional group. We have
already discussed the two main procedures by which they are prepared, namely, the
nucleophilic substitution of alkyl halides by cyanide and the conversion of alde-
hydes and ketones to cyanohydrins. Table 20.7 reviews aspects of these reactions. Nei-
ther of the reactions in Table 20.7 is suitable for aryl nitriles (ArCPN); these com-
pounds are readily prepared by a reaction to be discussed in Chapter 22.
(H
2
NCOH)
O
X
RN C O
Isocyanate
H11001 CH
3
OH
Methanol
RNHCOCH
3
O
Methyl N-alkylcarbamate
(H
2
NCOH)
O
X
CH
3
(CH
2
)
14
CNH
2
O
Hexadecanamide
CH
3
(CH
2
)
14
NHCOCH
3
O
Methyl N-pentadecylcarbamate (84–94%)
Br
2
, NaOCH
3
CH
3
OH
Br
2
, NaOH
H
2
O
C
6
H
5
CH
2
C CNH
2
OH
H
3
C
(S)-(H11001)-2-Methyl-3-phenylpropanamide
C
6
H
5
CH
2
C NH
2
H
H
3
C
(S)-(H11001)-1-Phenyl-2-propanamine
20.18 Preparation of Nitriles 813
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Both alkyl and aryl nitriles are accessible by dehydration of amides.
Among the reagents used to effect the dehydration of amides is the compound P
4
O
10
,
known by the common name phosphorus pentoxide because it was once thought to have
the molecular formula P
2
O
5
. Phosphorus pentoxide is the anhydride of phosphoric acid
and is used in a number of reactions requiring dehydrating agents.
PROBLEM 20.22 Show how ethyl alcohol could be used to prepare (a) CH
3
CN
and (b) CH
3
CH
2
CN. Along with ethyl alcohol you may use any necessary inorganic
reagents.
(CH
3
)
2
CHC N
2-Methylpropanenitrile
(69–86%)
(CH
3
)
2
CHCNH
2
O
2-Methylpropanamide
P
4
O
10
200°C
RC N
Nitrile
(R may be alkyl
or aryl)
H11001 H
2
O
Water
RCNH
2
O
Amide
(R may be alkyl
or aryl)
814 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
TABLE 20.7 Preparation of Nitriles
Reaction (section) and comments
Nucleophilic substitution by cya-
nide ion (Sections 8.1, 8.13) Cya-
nide ion is a good nucleophile
and reacts with alkyl halides to
give alkyl nitriles. The reaction is
of the S
N
2 type and is limited to
primary and secondary alkyl
halides. Tertiary alkyl halides
undergo elimination; aryl and
vinyl halides do not react.
Cyanohydrin formation (Section
17.7) Hydrogen cyanide adds to
the carbonyl group of aldehydes
and ketones.
General equation and specific example
KCN
ethanol–
water
CH
3
(CH
2
)
8
CH
2
Cl
1-Chlorodecane Undecanenitrile (95%)
CH
3
(CH
2
)
8
CH
2
CN
H11001H11001
Halide
ion
X
H11002
Alkyl
halide
R X
Cyanide
ion
NPC
H11002
Nitrile
RCPN
Cyanohydrin
RCRH11032
W
W
OH
CPN
Aldehyde or
ketone
RCRH11032
O
X
HCN
Hydrogen
cyanide
H11001
3-Pentanone
cyanohydrin (75%)
CH
3
CH
2
CCH
2
CH
3
W
W
OH
CN
3-Pentanone
CH
3
CH
2
CCH
2
CH
3
O
X
KCN
H
H11001
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An important nitrile is acrylonitrile, CH
2
?CHCN. It is prepared industrially from
propene, ammonia, and oxygen in the presence of a special catalyst. Polymers of acry-
lonitrile have many applications, the most prominent being their use in the preparation
of acrylic fibers.
20.19 HYDROLYSIS OF NITRILES
Nitriles are classified as carboxylic acid derivatives because they are converted to car-
boxylic acids on hydrolysis. The conditions required are similar to those for the hydrol-
ysis of amides, namely, heating in aqueous acid or base for several hours. Like the
hydrolysis of amides, nitrile hydrolysis is irreversible in the presence of acids or bases.
Acid hydrolysis yields ammonium ion and a carboxylic acid.
In aqueous base, hydroxide ion abstracts a proton from the carboxylic acid. In order to
isolate the acid a subsequent acidification step is required.
Nitriles are susceptible to nucleophilic addition. In their hydrolysis, water adds
across the carbon–nitrogen triple bond. In a series of proton-transfer steps, an amide is
produced:
We already discussed both the acidic and basic hydrolysis of amides (see Section 20.16).
All that remains to complete the mechanistic picture of nitrile hydrolysis is to examine
the conversion of the nitrile to the corresponding amide.
Nucleophilic addition to the nitrile may be either acid- or base-catalyzed. In aque-
ous base, hydroxide adds to the carbon–nitrogen triple bond:
RC N
Nitrile
H11001 H
2
O
Water
RC
OH
NH
Imino acid
RC
NH
2
O
Amide
RC N
Nitrile
H11001 H
2
O
Water
H11001 HO
H11002
Hydroxide
ion
RCO
H11002
O
Carboxylate
ion
H11001 NH
3
Ammonia
1. KOH, H
2
O, heat
2. H
H11001CH
3
(CH
2
)
9
CN
Undecanenitrile
O
CH
3
(CH
2
)
9
COH
Undecanoic acid (80%)
RC N
Nitrile
H11001 H
2
O
Water
H11001 H
3
O
H11001
Hydronium
ion
RCOH
O
Carboxylic
acid
H11001 NH
4
H11001
Ammonium
ion
H
2
O, H
2
SO
4
heat
O
2
N CH
2
CN
p-Nitrobenzyl cyanide
O
O
2
N CH
2
COH
p-Nitrophenylacetic acid (92–95%)
20.19 Hydrolysis of Nitriles 815
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The imino acid is transformed to the amide by the sequence
PROBLEM 20.23 Suggest a reasonable mechanism for the conversion of a nitrile
(RCN) to the corresponding amide in aqueous acid.
Nucleophiles other than water can also add to the carbon–nitrogen triple bond of
nitriles. In the following section we will see a synthetic application of such a nucle-
ophilic addition.
20.20 ADDITION OF GRIGNARD REAGENTS TO NITRILES
The carbon–nitrogen triple bond of nitriles is much less reactive toward nucleophilic
addition than is the carbon–oxygen double bond of aldehydes and ketones. Strongly basic
nucleophiles such as Grignard reagents, however, do react with nitriles in a reaction that
is of synthetic value:
The imine formed by nucleophilic addition of the Grignard reagent to the nitrile is nor-
mally not isolated but is hydrolyzed directly to a ketone. The overall sequence is used
as a means of preparing ketones.
PROBLEM 20.24 Write an equation showing how you could prepare ethyl
phenyl ketone from propanenitrile and a Grignard reagent. What is the structure
of the imine intermediate?
RC N
Nitrile
H11001 RH11032MgX
Grignard
reagent
RCRH11032
NH
Imine
RCRH11032
O
Ketone
1. diethyl ether
2. H
2
O
H
2
O, H
H11001
heat
OH
H11002
Hydroxide
ion
OH
H11002
Hydroxide
ion
H11001 H11001RC
O
NH
Amide
anion
RC
O
NH
2
Amide
RC
OH
NH
Imino
acid
HOH
Water
H11002
HO
H11002
Hydroxide
ion
H11001 RC N
Nitrile
H11002
RC
OH
N
H
2
O
OH
H11002
RC
OH
NH
Imino acid
816 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
CN
F
3
C
m-(Trifluoromethyl)benzonitrile
H11001 CH
3
MgI
Methylmagnesium
iodide
1. diethyl ether
2. H
2
O, H
H11001
,
heat
C
O
CCH
3
F
3
C
m-(Trifluoromethyl)acetophenone
(79%)
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Organolithium reagents react in the same way and are often used instead of
Grignard reagents.
20.21 SPECTROSCOPIC ANALYSIS OF CARBOXYLIC ACID
DERIVATIVES
Infrared: Infrared spectroscopy is quite useful in identifying carboxylic acid deriva-
tives. The carbonyl stretching vibration is very strong, and its position is sensitive to the
nature of the carbonyl group. In general, electron donation from the substituent decreases
the double-bond character of the bond between carbon and oxygen and decreases the
stretching frequency. Two distinct absorptions are observed for the symmetric and anti-
symmetrical stretching vibrations of the anhydride function.
Nitriles are readily identified by absorption due to ±CPN stretching in the
2210–2260 cm
H110021
region.
1
H NMR: Chemical-shift differences in their
1
H NMR spectra aid the structure deter-
mination of esters. Consider the two isomeric esters: ethyl acetate and methyl propanoate.
As Figure 20.9 shows, the number of signals and their multiplicities are the same for
both esters. Both have a methyl singlet and a triplet–quartet pattern for their ethyl group.
CH
3
CCl
O
X
Acetyl
chloride
H9263
C?O
H11005 1822 cm
H110021
CH
3
COCCH
3
O
X
O
X
Acetic
anhydride
H9263
C?O
H11005 1748 cm
H110021
and 1815 cm
H110021
CH
3
COCH
3
O
X
Methyl
acetate
H9263
C?O
H11005 1736 cm
H110021
CH
3
CNH
2
O
X
Acetamide
H9263
C?O
H11005 1694 cm
H110021
20.21 Spectroscopic Analysis of Carboxylic Acid Derivatives 817
CH
3
CH
2
COCH
3
2.03.04.05.0 1.0 0.0
Chemical shift (δ, ppm)
CH
3
COCH
2
CH
3
2.0 1.0 0.03.04.05.0
Chemical shift (δ, ppm)
(a)(b)
O
X
O
X
FIGURE 20.9 The 200-MHz
1
H NMR spectra of (a) ethyl
acetate and (b) methyl pro-
panoate.
The C
?
O stretching vi-
brations of these com-
pounds may be viewed on
Learning By Modeling.
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Notice, however, that there is a significant difference in the chemical shifts of the cor-
responding signals in the two spectra. The methyl singlet is more shielded ( H9254 2.0 ppm)
when it is bonded to the carbonyl group of ethyl acetate than when it is bonded to the
oxygen of methyl propanoate (H9254 3.6 ppm). The methylene quartet is more shielded
(H9254 2.3 ppm) when it is bonded to the carbonyl group of methyl propanoate than when it
is bonded to the oxygen of ethyl acetate (H9254 4.1 ppm). Analysis of the number of peaks
and their splitting patterns will not provide an unambiguous answer to structure assign-
ment in esters; chemical-shift data must also be considered.
The chemical shift of the N±H proton of amides appears in the range H9254 5–8 ppm.
It is often a very broad peak; sometimes it is so broad that it does not rise much over
the baseline and can be lost in the background noise.
13
C NMR: The
13
C NMR spectra of carboxylic acid derivatives, like the spectra of car-
boxylic acids themselves, are characterized by a low-field resonance for the carbonyl car-
bon in the range H9254 160–180 ppm. The carbonyl carbons of carboxylic acid derivatives
are more shielded than those of aldehydes and ketones, but less shielded than the sp
2
-
hybridized carbons of alkenes and arenes.
The carbon of a CPN group appears near H9254 120 ppm.
UV-VIS: The following values are typical for the n→H9266,* absorption associated with
the C?O group of carboxylic acid derivatives.
Mass Spectrometry: A prominent peak in the mass spectra of most carboxylic acid
derivatives corresponds to an acylium ion derived by cleavage of the bond to the car-
bonyl group:
Amides, however, tend to cleave in the opposite direction to produce a nitrogen-stabilized
acylium ion:
R
NRH11032
2
O
H11001
C R H11001 O
H11001
[ NRH11032
2
C
H11001
O C NRH11032
2
]
RO
H11001
C H11001 XR
X
O
H11001
C
CH
3
CCl
O
X
Acetyl
chloride
235nmH9261
max
CH
3
COCCH
3
O
X
O
X
Acetic
anhydride
225nm
CH
3
COCH
3
O
X
Methyl
acetate
207nm
CH
3
CNH
2
O
X
Acetamide
214nm
818 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
Singlet
H9254 2.0 ppm
Quartet
H9254 4.1 ppm
Triplet
H9254 1.3 ppm
O
CH
3
COCH
2
CH
3
Ethyl acetate
Singlet
H9254 3.6 ppm
Quartet
H9254 2.3 ppm
Triplet
H9254 1.2 ppm
O
CH
3
OCCH
2
CH
3
Methyl propanoate
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20.22 SUMMARY
Section 20.1 This chapter concerns the preparation and reactions of acyl chlorides,
acid anhydrides, esters, amides, and nitriles. These compounds are gen-
erally classified as carboxylic acid derivatives, and their nomenclature is
based on that of carboxylic acids (Section 20.1).
Section 20.2 The structure and reactivity of carboxylic acid derivatives depend on how
well the atom bonded to the carbonyl group donates electrons to it.
Electron-pair donation stabilizes the carbonyl group and makes it less
reactive toward nucleophilic acyl substitution.
Nitrogen is a better electron-pair donor than oxygen, and amides have a
more stabilized carbonyl than esters and anhydrides. Chlorine is the poor-
est electron-pair donor, and acyl chlorides have the least stabilized car-
bonyl group and are the most reactive.
Section 20.3 The characteristic reaction of acyl chlorides, acid anhydrides, esters, and
amides is nucleophilic acyl substitution. Addition of a nucleophilic
reagent HY
:
to the carbonyl group leads to a tetrahedral intermediate that
dissociates to give the product of substitution:
Acyl chlorides are converted to anhydrides, esters, and amides by nucle-
ophilic acyl substitution.
RC
O
X
Carboxylic
acid derivative
RC
OH
X
Y
Tetrahedral
intermediate
H11001 HY
Nucleophile
HX
Conjugate acid
of leaving
group
RC
O
Y
Product of
nucleophilic
acyl substitution
H11001
RCCl
O
X
Least stabilized
carbonyl group
Most reactive
RCOCR
O
X
O
X
RCORH11032
O
X
RCNRH11032
2
O
X
Most stabilized
carbonyl group
Least reactive
H11022H11022H11022
C
X
O
R
C
R
O
H11002
X
H11001
RCCl
O
X
Acyl
chloride
RCOCR
O
X
O
X
Carboxylic
acid anhydride
RCORH11032
O
X
Ester
RCNRH11032
2
O
X
Amide
RCPN
Nitrile
20.22 Summary 819
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Examples of each of these reactions may be found in Table 20.2.
Section 20.4 Acid anhydrides may be prepared from acyl chlorides in the laboratory,
but the most commonly encountered ones (acetic anhydride, phthalic
anhydride, and maleic anhydride) are industrial chemicals prepared by
specialized methods.
Section 20.5 Acid anhydrides are less reactive toward nucleophilic acyl substitution than
acyl chlorides, but are useful reagents for preparing esters and amides.
Table 20.3 presents examples of these reactions.
Section 20.6 Esters occur naturally or are prepared from alcohols by Fischer esterifi-
cation or by acylation with acyl chlorides or acid anhydrides (see Table
20.4).
Section 20.7 Esters are polar and have higher boiling points than alkanes of compa-
rable size and shape. Esters don’t form hydrogen bonds to other ester
molecules so have lower boiling points than analogous alcohols. They
can form hydrogen bonds to water and so are comparable to alcohols with
respect to their solubility in water.
Section 20.8 Esters react with Grignard reagents and are reduced by lithium aluminum
hydride (Table 20.5).
Section 20.9 Ester hydrolysis can be catalyzed by acids and its mechanism (Figure
20.4) is the reverse of the mechanism for Fischer esterification. The reac-
tion proceeds via a tetrahedral intermediate.
RCOCR
O O
Acid
anhydride
H11001H11001RH11032OH
Alcohol
RCORH11032
O
Ester
RCOH
O
Carboxylic
acid
RCOCR
O O
Acid
anhydride
2RH11032
2
NH
Amine
RCNRH11032
2
O
Amide
H11001
H11002
OCR
O
RH11032
2
NH
2
H11001
Ammonium
carboxylate salt
H11001
RCCl
O
Acyl
chloride
RH11032COH
O
Carboxylic
acid
RCOCRH11032
O O
Acid
anhydride
H11001 HCl
Hydrogen
chloride
H11001
RCCl
O
Acyl chloride
RH11032OH
Alcohol
RCORH11032
O
Ester
H11001 HCl
Hydrogen
chloride
H11001
RCCl
O
Acyl
chloride
2RH11032
2
NH
Amine
RCNRH11032
2
O
Amide
H11001 RH11032
2
NH
2
H11001
Cl
H11002
Ammonium
chloride salt
H11001
820 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
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Section 20.10 Ester hydrolysis in basic solution is called saponification and proceeds
through the same tetrahedral intermediate (Figure 20.5) as in acid-catalyzed
hydrolysis. Unlike acid-catalyzed hydrolysis, saponification is irreversible
because the carboxylic acid is deprotonated under the reaction conditions.
Section 20.11 Esters react with amines to give amides.
Section 20.12 Thioesters undergo reactions analogous to those of esters, but at faster
rates. A sulfur atom stabilizes a carbonyl group less effectively than an
oxygen.
Section 20.13 Amides are normally prepared by the reaction of amines with acyl chlo-
rides, anhydrides, or esters.
Section 20.14 Lactams are cyclic amides.
Section 20.15 Imides are compounds that have two acyl groups attached to nitrogen.
Section 20.16 Like ester hydrolysis, amide hydrolysis can be achieved in either aque-
ous acid or aqueous base. The process is irreversible in both media. In
base, the carboxylic acid is converted to the carboxylate anion; in acid,
the amine is protonated to an ammonium ion:
O
RCNRH11032
2
Amide
H11001 H
2
O
Water
H
3
O
H11001
HO
H11002
O
RCOH
Carboxylic
acid
Ammonium
ion
RH11032
2
NH
2
H11001
H11001
O
RCO
H11002
Carboxylate
ion
Amine
RH11032
2
NHH11001
C
ORH11032
O
R
Ester
C
SRH11032
O
R
Thioester
RH11032OH
Alcohol
RCORH11032
O
Ester
RH11033
2
NH
Amine
RCNRH11033
2
O
Amide
H11001H11001
H11001H11001HO
H11002
Hydroxide
ion
RH11032OH
Alcohol
RCORH11032
O
Ester
RCO
H11002
O
Carboxylate
ion
RC
OH
OH
ORH11032
Tetrahedral intermediate
in ester hydrolysis
20.22 Summary 821
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Section 20.17 The Hofmann rearrangement converts amides of the type to
primary amines (RNH
2
). The carbon chain is shortened by one carbon
with loss of the carbonyl group:
Section 20.18 Nitriles are prepared by nucleophilic substitution (S
N
2) of alkyl halides
with cyanide ion, by converting aldehydes or ketones to cyanohydrins
(Table 20.7) or by dehydration of amides.
Section 20.19 The hydrolysis of nitriles to carboxylic acids is irreversible in both acidic
and basic solution.
Section 20.20 Nitriles are useful starting materials for the preparation of ketones by
reaction with Grignard reagents.
Section 20.21 Acyl chlorides, anhydrides, esters, and amides all show a strong band for
C?O stretching in the infrared. The range extends from about 1820
cm
H110021
(acyl chlorides) to 1690 cm
H110021
(amides). Their
13
C NMR spectra
are characterized by a peak near H9254180 ppm for the carbonyl carbon.
1
H NMR spectroscopy is useful for distinguishing between the groups R
and RH11032 in esters (RCO
2
RH11032). The protons on the carbon bonded to O in
RH11032 appear at lower field (less shielded) than those on the carbon bonded
to C?O.
PROBLEMS
20.25 Write a structural formula for each of the following compounds:
(a) m-Chlorobenzoyl bromide
(b) Trifluoroacetic anhydride
(c) cis-1,2-Cyclopropanedicarboxylic anhydride
(d) Ethyl cycloheptanecarboxylate
(e) 1-Phenylethyl acetate
(f) 2-Phenylethyl acetate
(g) p-Ethylbenzamide
(h) N-Ethylbenzamide
(i) 2-Methylhexanenitrile
RC N
Nitrile
H11001 RH11032MgX
Grignard reagent
RCRH11032
O
Ketone
1. diethyl ether
2. H
2
O, H
H11001
RC N
Nitrile
RCOH
O
Carboxylic acid
H
2
O, H
H11001
or
1. H
2
O, HO
H11002
2. H
H11001
O
RCNH
2
Amide
RNH
2
Amine
Br
2
NaOH
RCNH
2
O
X
822 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
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20.26 Give an acceptable IUPAC name for each of the following compounds:
(a) (f) (CH
3
)
2
CHCH
2
CH
2
CPN
(b) (g)
(c) (h)
(d) (i)
(e)
20.27 Write a structural formula for the principal organic product or products of each of the fol-
lowing reactions:
(a) Acetyl chloride and bromobenzene, AlCl
3
(b) Acetyl chloride and 1-butanethiol
(c) Propanoyl chloride and sodium propanoate
(d) Butanoyl chloride and benzyl alcohol
(e) p-Chlorobenzoyl chloride and ammonia
(f)
(g)
(h)
(i)
(j)
(k) Acetic anhydride and 3-pentanol
(l)
O
O
and aqueous sodium hydroxide
O
OO
and 1,3-pentadiene
O
OO
and benzene, AlCl
3
O
OO
and aqueous ammonia
O
OO
and aqueous sodium hydroxide
O
OO
and water
H
3
C
H
3
C
O
O
O
(CH
3
)
2
CHCH
2
CH
2
CN(CH
3
)
2
O
ClCH
2
CH
2
COCCH
2
CH
2
Cl
OO
(CH
3
)
2
CHCH
2
CH
2
CNHCH
3
O
CH
3
OCCH
2
O
(CH
3
)
2
CHCH
2
CH
2
CNH
2
O
CH
3
COCH
2
O
CH
3
CHCH
2
CBr
Cl
O
Problems 823
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(m)
(n)
(o)
(p) Ethyl phenylacetate and methylamine (CH
3
NH
2
)
(q)
(r)
(s)
(t)
(u)
(v)
(w)
(x) (CH
3
)
2
CHCH
2
CPN and aqueous hydrochloric acid, heat
(y) p-Methoxybenzonitrile and aqueous sodium hydroxide, heat
(z) Propanenitrile and methylmagnesium bromide, then H
3
O
H11001
(aa)
(bb) Product of (aa)
KOH, H
2
O
H
3
C CH
3
C
NH
2
O
H11001 Br
2
NaOCH
3
CH
3
OH
CNH
2
O
and P
4
O
10
C
6
H
5
CNHCH
3
O
and aqueous sulfuric acid, heat
C
6
H
5
NHCCH
3
O
and aqueous hydrochloric acid, heat
and aqueous hydrochloric acid, heat
OO
N
CH
3
and aqueous sodium hydroxide
OO
N
CH
3
and aqueous hydrochloric acid, heat
O
N
CH
3
and aqueous sodium hydroxide
O
N
CH
3
O
O
and excess methylmagnesium bromide, then H
3
O
H11001
O
O
and lithium aluminum hydride, then H
2
O
O
O
and aqueous ammonia
824 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
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20.28 Using ethanol as the ultimate source of all the carbon atoms, along with any necessary inor-
ganic reagents, show how you could prepare each of the following:
(a) Acetyl chloride (f) Ethyl cyanoacetate
(b) Acetic anhydride (g) Acetamide
(c) Ethyl acetate (h) Methylamine (CH
3
NH
2
)
(d) Ethyl bromoacetate (i) 2-Hydroxypropanoic acid
(e) 2-Bromoethyl acetate
20.29 Using toluene as the ultimate source of all the carbon atoms, along with any necessary inor-
ganic reagents, show how you could prepare each of the following:
(a) Benzoyl chloride (f) Benzyl cyanide
(b) Benzoic anhydride (g) Phenylacetic acid
(c) Benzyl benzoate (h) p-Nitrobenzoyl chloride
(d) Benzamide (i) m-Nitrobenzoyl chloride
(e) Benzonitrile (j) Aniline
20.30 The saponification of
18
O-labeled ethyl propanoate was described in Section 20.10 as one
of the significant experiments that demonstrated acyl–oxygen cleavage in ester hydrolysis. The
18
O-labeled ethyl propanoate used in this experiment was prepared from
18
O-labeled ethyl alcohol,
which in turn was obtained from acetaldehyde and
18
O-enriched water. Write a series of equations
showing the preparation of (where O H11005
18
O) from these starting materials.
20.31 Suggest a reasonable explanation for each of the following observations:
(a) The second-order rate constant k for saponification of ethyl trifluoroacetate is over
1 million times greater than that for ethyl acetate (25°C).
(b) The second-order rate constant for saponification of ethyl 2,2-dimethylpropanoate,
(CH
3
)
3
CCO
2
CH
2
CH
3
, is almost 100 times smaller than that for ethyl acetate (30°C).
(c) The second-order rate constant k for saponification of methyl acetate is 100 times greater
than that for tert-butyl acetate (25°C).
(d) The second-order rate constant k for saponification of methyl m-nitrobenzoate is 40
times greater than that for methyl benzoate (25°C).
(e) The second-order rate constant k for saponification of 5-pentanolide is over 20 times
greater than that for 4-butanolide (25°C).
(f) The second-order rate constant k for saponification of ethyl trans-4-tert-butylcyclo-
hexanecarboxylate is 20 times greater than that for its cis diastereomer (25°C).
CO
2
CH
2
CH
3
Ethyl trans-4-tert-
butylcyclohexanecarboxylate
CO
2
CH
2
CH
3
Ethyl cis-4-tert-
butylcyclohexanecarboxylate
O O
5-Pentanolide
O
O
4-Butanolide
CH
3
CH
2
COCH
2
CH
3
O
X
Problems 825
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20.32 The preparation of cis-4-tert-butylcyclohexanol from its trans stereoisomer was carried out
by the following sequence of steps. Write structural formulas, including stereochemistry, for com-
pounds A and B.
Step 1:
Step 2:
Step 3:
20.33 The ketone shown was prepared in a three-step sequence from ethyl trifluoroacetate. The
first step in the sequence involved treating ethyl trifluoroacetate with ammonia to give a compound
A. Compound A was in turn converted to the desired ketone by way of a compound B. Fill in the
missing reagents in the sequence shown, and give the structures of compounds A and B.
20.34 Ambrettolide is obtained from hibiscus and has a musk-like odor. Its preparation from a
compound A is outlined in the table that follows. Write structural formulas, ignoring stereochem-
istry, for compounds B through G in this synthesis. (Hint: Zinc, as used in step 4, converts vici-
nal dibromides to alkenes.)
O O
Ambrettolide
HOC(CH
2
)
5
CH
OO
CH
3
CH
3
O
CH(CH
2
)
7
CH
2
OH
Compound A
NH
3
CF
3
COCH
2
CH
3
O
CF
3
CC(CH
3
)
3
O
Compound A Compound B
NaOH
H
2
O
Compound B
OH
H11001
N,N-dimethylformamide
heat
Compound B
(C
17
H
24
O
2
)
Compound A CONa
O
OH
H11001 SO
2
ClCH
3
pyridine
Compound A
(C
17
H
26
O
3
S)
826 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
Step
1.
2.
3.
4.
5.
6.
7.
Reactant
Compound A
Compound B
Compound C
Compound D
Compound E
Compound F
Compound G
Reagents
H
2
O, H
H11001
, heat
HBr
Ethanol, H
2
SO
4
Zinc, ethanol
Sodium acetate, acetic acid
KOH, ethanol, then H
H11001
Heat
Product
Compound B
(C
16
H
32
O
5
)
Compound C
(C
16
H
29
Br
3
O
2
)
Compound D
(C
18
H
33
Br
3
O
2
)
Compound E
(C
18
H
33
BrO
2
)
Compound F
(C
20
H
36
O
4
)
Compound G
(C
16
H
30
O
3
)
Ambrettolide
(C
16
H
28
O
2
)
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20.35 The preparation of the sex pheromone of the bollworm moth, (E )-9,11-dodecadien-1-yl
acetate, from compound A has been described. Suggest suitable reagents for each step in this
sequence.
(a)
(b)
(c)
(d)
20.36 Outline reasonable mechanisms for each of the following reactions:
(a)
(b)
20.37 Identify compounds A through D in the following equations:
(a)
(b)
(c)
(d) CH
3
CH
2
CH
2
CH
2
NH
2
H11001
140°C
CCl
O
ClC
O
S
BrBr
Compound D
(C
10
H
9
Br
2
NO
2
S)
heat
COH
COHHOC
O
OO
Compound C
(C
9
H
4
O
5
)
H11001 H
2
O
Compound B
(a lactone, C
6
H
10
O
2
)
CH
3
CCH
2
CH
2
COCH
2
CH
3
O O
1. CH
3
MgI (1 equiv), diethyl ether
2. H
3
O
H11001
Compound A
(C
22
H
18
O
4
)
CClCH
3
O
O
H11001 CCH
O
OH
pyridine
spontaneous
OSH
2
NCH
2
CH
2
N
HS
H
O
O
O
H11001 BrMgCH
2
CH
2
CH
2
CH
2
MgBr
1. THF
2. H
3
O
H11001
HO CH
2
CH
2
CH
2
OH
Compound D
(E)-9,11-Dodecadien-1-yl acetate
CHCH CH(CH
2
)
7
CH
2
OCCH
3
O
CH
2
Compound C
Compound D
CHCH CH(CH
2
)
7
CH
2
OHCH
2
Compound B
Compound C
CHCH CH(CH
2
)
7
CO
2
CH
3
CH
2
Compound A (E isomer)
HOCH
2
CH CH(CH
2
)
7
CO
2
CH
3
Compound B
HCCH CH(CH
2
)
7
CO
2
CH
3
O
Problems 827
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20.38 When compounds of the type represented by A are allowed to stand in pentane, they are
converted to a constitutional isomer.
Hydrolysis of either A or B yields RNHCH
2
CH
2
OH and p-nitrobenzoic acid. Suggest a reason-
able structure for compound B, and demonstrate your understanding of the mechanism of this reac-
tion by writing the structure of the key intermediate in the conversion of compound A to com-
pound B.
20.39 (a) In the presence of dilute hydrochloric acid, compound A is converted to a constitutional
isomer, compound B.
Suggest a reasonable structure for compound B.
(b) The trans stereoisomer of compound A is stable under the reaction conditions. Why does
it not rearrange?
20.40 Poly(vinyl alcohol) is a useful water-soluble polymer. It cannot be prepared directly from
vinyl alcohol, because of the rapidity with which vinyl alcohol (CH
2
?CHOH) isomerizes to
acetaldehyde. Vinyl acetate, however, does not rearrange and can be polymerized to poly(vinyl
acetate). How could you make use of this fact to prepare poly(vinyl alcohol)?
20.41 Lucite is a polymer of methyl methacrylate.
(a) Assuming the first step in the polymerization of methyl methacrylate is as shown,
write a structural formula for the free radical produced after the next two propagation
steps.
(b) Outline a synthesis of methyl methacrylate from acetone, sodium cyanide, and any nec-
essary organic or inorganic reagents.
20.42 A certain compound has a molecular weight of 83 and contains nitrogen. Its infrared spec-
trum contains a moderately strong peak at 2270 cm
H110021
. Its
1
H and
13
C NMR spectra are shown in
Figure 20.10. What is the structure of this compound?
H11001OR CCOCH
3
O
CH
3
H
2
C
Methyl methacrylate
ROCH
2
CCOCH
3
O
CH
3
CH
2
CHCH
2
CH
OH OH
n
H20898H20899
Poly(vinyl alcohol)
CH
2
CHCH
2
CH
CH
3
CO
O O
OCCH
3
n
H20898H20899
Poly(vinyl acetate)
Compound BHO NHC NO
2
O
Compound A
H
H11001
NO
2
RNHCH
2
CH
2
OC
O
Compound A
Compound B
828 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
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2
4
3
2.0 1.0 0.03.04.0
Chemical shift (δ, ppm)
(a)
C
60708090100110120130 50 40 30 20 10
Chemical shift (δ, ppm)
(b)
CH
2
CH
2
CH
2
CH
3
FIGURE 20.10 The 200-MHz
(a)
1
H and (b)
13
C NMR spec-
tra of the compound in
problem 20.42.
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20.43 A compound has a molecular formula of C
8
H
14
O
4
, and its infrared spectrum contains an
intense peak at 1730 cm
H110021
. The
1
H NMR spectrum of the compound is shown in Figure 20.11.
What is its structure?
20.44 A compound (C
4
H
6
O
2
) has a strong band in the infrared at 1760 cm
H110021
. Its
13
C NMR spec-
trum exhibits signals at H9254 20.2 (CH
3
), 96.8 (CH
2
), 141.8 (CH), and 167.6 ppm (C). The
1
H NMR
spectrum of the compound has a three-proton singlet at H9254 2.1 ppm along with three other signals,
each of which is a doublet of doublets, at H9254 4.7, 4.9, and 7.3 ppm. What is the structure of the
compound?
20.45 Excluding enantiomers, there are three isomeric cyclopropanedicarboxylic acids. Two of
them, A and B, are constitutional isomers of each other, and each forms a cyclic anhydride on
being heated. The third diacid, C, does not form a cyclic anhydride. C is a constitutional isomer
of A and a stereoisomer of B. Identify A, B, and C. Construct molecular models of the cyclic anhy-
drides formed on heating A and B. Why doesn’t C form a cyclic anhydride?
830 CHAPTER TWENTY Carboxylic Acid Derivatives: Nucleophilic Acyl Substitution
2.0 1.0 0.03.04.05.0
Chemical shift (δ, ppm)
4
4
6
FIGURE 20.11 The 200-MHz
1
H NMR spectrum of the
compound C
8
H
14
O
4
in prob-
lem 20.43.
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| 课件名称： | 有机化学（英文原版） |
| 课件分类： | 化学 |
| 课件类型： | 电子图书 |
| 文件大小： | 28.97MB |
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- 11. 有机化学（英文原版）：Chapt11
- 12. 有机化学（英文原版）：Chapt12
- 13. 有机化学（英文原版）：Chapt13
- 14. 有机化学（英文原版）：Chapt14
- 15. 有机化学（英文原版）：Chapt15
- 16. 有机化学（英文原版）：Chapt16
- 17. 有机化学（英文原版）：Chapt17
- 18. 有机化学（英文原版）：Chapt18
- 19. 有机化学（英文原版）：Chapt19
- 20. 有机化学（英文原版）：Chapt20
- 21. 有机化学（英文原版）：Chapt21
- 22. 有机化学（英文原版）：Chapt22
- 23. 有机化学（英文原版）：Chapt23
- 24. 有机化学（英文原版）：Chapt24
- 25. 有机化学（英文原版）：Chapt25
- 26. 有机化学（英文原版）：Chapt26
- 27. 有机化学（英文原版）：Chapt27
- 28. 有机化学（英文原版）：End of Book
- 29. 有机化学（英文原版）：Glossary
