Ebook Organic chemistry (7th edition) Part 2

PART
FIVE

Carbonyl Compounds
The three chapters in Part 5 focus on the reactions of compounds that contain a carbonyl group.
Carbonyl compounds can be classified as either those that contain a group that can be replaced by
another group (carboxylic acids and carboxylic acid derivatives) or those that contain a group that cannot
be replaced by another group (aldehydes and ketones).

C H A P T E R 1 6 Reactions of Carboxylic Acids and Carboxylic Acid Derivatives
The reactions of carboxylic acids and carboxylic acid derivatives are discussed in Chapter 16, where
you will see that they all react with nucleophiles in the same way—they undergo nucleophilic addition–
elimination reactions. In a nucleophilic addition–elimination reaction, the nucleophile adds to the
carbonyl carbon, forming an unstable tetrahedral intermediate that collapses by eliminating the weaker
of two bases. As a result, all you need to know to determine the product of one of these reactions—or
even whether a reaction will occur—is the relative basicity of the two potential leaving groups in the
tetrahedral intermediate.
C H A P T E R 1 7 Reactions of Aldehydes and Ketones •

More Reactions of Carboxylic Acid Derivatives •
Reactions of a, b-Unsaturated Carbonyl Compounds
Chapter 17 starts by comparing the reactions of carboxylic acids and carboxylic acid derivatives with the
reactions of aldehydes and ketones. This comparison is made by discussing their reactions with carbon
nucleophiles and hydride ion. You will see that carboxylic acids and carboxylic acid derivatives undergo
nucleophilic addition–elimination reactions with carbon nucleophiles and hydride ion, just as they did
with nitrogen and oxygen nucleophiles in Chapter 16. Aldehydes and ketones, on the other hand, undergo
nucleophilic addition reactions with carbon nucleophiles and hydride ion and nucleophilic addition–
elimination reactions with oxygen and nitrogen nucleophiles (and the species eliminated is always water).
What you learned in Chapter 16 about the partitioning of tetrahedral intermediates is revisited in this
chapter. The reactions of a,b-unsaturated carbonyl compounds are also discussed.
C H A P T E R 1 8 Reactions at the a-Carbon

Many carbonyl compounds have two sites of reactivity: the carbonyl group and the a-carbon.
Chapters 16 and 17 discuss the reactions of carbonyl compounds that take place at the carbonyl group,
whereas Chapter 18 examines the reactions of carbonyl compounds that take place at the a-carbon.

acetamide

acetyl chloride

acetonitrile

acetic anhydride

acetone

acetic acid

acetaldehyde

methyl acetate


16

Reactions of Carboxylic Acids
and Carboxylic Acid Derivatives

Some of the things you will learn in this chapter are the purpose of the large deposit of
fat in a whale’s head, how aspirin decreases inflammation and fever, why Dalmatians
are the only dogs that excrete uric acid, how bacteria become resistant to penicillin, and
why young people sleep better than adults.

W
III
O
R

C

Z

Z = an atom more
electronegative
than carbon

O
R

C

Z

Z = R or H

e have seen that the families of organic compounds can be placed in one of four
groups, and that all the families in a group react in similar ways (Section 5.5). This
chapter begins our discussion of the familes of compounds in Group III—compounds that
contain a carbonyl group.
The carbonyl group (a carbon doubly bonded to an oxygen) is probably the most
important functional group. Compounds containing carbonyl groups—called carbonyl
(“car-bo-neel”) compounds—are abundant in nature, and many play important roles in

biological processes. Vitamins, amino acids, proteins, hormones, drugs, and flavorings
are just a few of the carbonyl compounds that affect us daily. An acyl group consists
of a carbonyl group attached to an alkyl group (R) or to an aromatic group (Ar), such
as benzene.
O
C
a carbonyl group

O

O
R

C

Ar

C

acyl groups

The group (or atom) attached to the acyl group strongly affects the reactivity of
the carbonyl compound. In fact, carbonyl compounds can be divided into two classes
determined by that group. The first class are those in which the acyl group is attached to
a group (or atom) that can be replaced by another group. Carboxylic acids, acyl halides,
esters, and amides belong to this class. All of these compounds contain a group (OH, Cl,
OR, NH2, NHR, NR2) that can be replaced by a nucleophile.
720

Introduction
carbonyl compounds with groups that can be replaced by a nucleophile

O
R

C

O
R

OH

a carboxylic acid

C

O
R

OR′

an ester

C

Cl

R

C

O

O

O
NH2

C

R

an acyl chloride

NHR′

R

C

NR′2

amides

Esters, acyl chlorides, and amides are called carboxylic acid derivatives because they
differ from a carboxylic acid only in the nature of the group or atom that has replaced the
OH group of the carboxylic acid.
The second class of carbonyl compounds are those in which the acyl group is attached
to a group that cannot be readily replaced by another group. Aldehydes and ketones

belong to this class. The H bonded to the acyl group of an aldehyde and the R group
bonded to the acyl group of a ketone cannot be readily replaced by a nucleophile.
carbonyl compounds with groups that cannot be replaced by a nucleophile

O
R

C

O
H

an aldehyde

R¿

C

R

a ketone

We have seen that, when comparing bases of the same type, weak bases are good leaving
groups and strong bases are poor leaving groups (Section 9.2). The pKa values of the conjugate acids of the leaving groups of various carbonyl compounds are listed in Table 16.1.
Table 16.1

The pKa Values of the Conjugate Acids of the Leaving Groups of
Carbonyl Compounds

Carbonyl

compound

Leaving
group

Conjugate acid of
the leaving group

pKa

Carboxylic Acids and Carboxylic Acid Derivatives
a carboxylic acid

O
R

C

Cl−

Cl

HCl

-7

R′OH

~15–16

O
R

C

OR′

−

OR′

O
R

C

an acyl chloride

OH

−

OH

H2O

15.7

NH2

NH3

36*

O
R

C

NH2

−

Aldehydes and Ketones

an ester

O
R

C

H

H−

H2

35

R

R−

RH

> 60

O
R

C

an amide
*

An amide can undergo substitution reactions only when its leaving group is converted to NH3, giving its
conjugate acid (+NH4) a pKa value of 9.4.

721


722

CHAPTER 16

Reactions of Carboxylic Acids and Carboxylic Acid Derivatives

Notice that the acyl groups of carboxylic acids and carboxylic acid derivatives are attached
to weaker bases than are the acyl groups of aldehydes and ketones. (Remember that the

lower the pKa, the stronger the acid and the weaker its conjugate base.) The hydrogen of
an aldehyde and the alkyl group of a ketone are too basic to be replaced by another group.
This chapter discusses the reactions of carboxylic acids and carboxylic acid derivatives.
We will see that these compounds undergo substitution reactions, because they have
an acyl group attached to a group that can be replaced by a nucleophile. The reactions
of aldehydes and ketones are discussed in Chapter 17, where we will see that these
compounds do not undergo substitution reactions because their acyl group is attached to
a group that cannot be replaced by a nucleophile.

16.1 THE NOMENCLATURE OF CARBOXYLIC ACIDS
AND CARBOXYLIC ACID DERIVATIVES
First we will look at how carboxylic acids are named, because their names form the basis
of the names of the other carbonyl compounds.

Naming Carboxylic Acids
The functional group of a carboxylic acid is called a carboxyl group.
O
C

CO2H

COOH

OH

carboxyl groups are frequently
shown in abbreviated forms

a carboxyl group

In systematic (IUPAC) nomenclature, a carboxylic acid is named by replacing the
terminal “e” of the alkane name with “oic acid.” For example, the one-carbon alkane is
methane, so the one-carbon carboxylic acid is methanoic acid.
O

O
C
H

O
C

C
OH

CH3

systematic name: methanoic acid
common name:
formic acid

O

OH

ethanoic acid
acetic acid

CH3CH2

C
CH3CH2CH2

OH

propanoic acid
propionic acid

O

O

O

OH

OH
pentanoic acid
valeric acid

hexanoic acid
caproic acid

OH

butanoic acid
butyric acid

C
CH2

CH

OH

propenoic acid
acrylic acid

Carboxylic acids containing six or fewer carbons are frequently called by their common names. These names were chosen by early chemists to describe some feature of the
compound, usually its origin. For example, formic acid is found in ants, bees, and other
stinging insects; its name comes from formica, which is Latin for “ant.” Acetic acid—
contained in vinegar—got its name from acetum, the Latin word for “vinegar.” Propionic acid is the smallest acid that shows some of the characteristics of the larger fatty
acids (Section 16.4); its name comes from the Greek words pro (“the first”) and pion
(“fat”). Butyric acid is found in rancid butter; the Latin word for “butter” is butyrum.
Valeric acid got its name from valerian, an herb that has been used as a sedative since
Greco/Roman times. Caproic acid is found in goat’s milk. If you have ever smelled a
goat, then you know what caproic acid smells like. Caper is the Latin word for “goat.”
In systematic nomenclature, the position of a substituent is designated by a number.
The carbonyl carbon is always the C-1 carbon. In common nomenclature, the position
of a substituent is designated by a lowercase Greek letter, and the carbonyl carbon is not


The Nomenclature of Carboxylic Acids and Carboxylic Acid Derivatives

723

given a designation. Thus, the carbon adjacent to the carbonyl carbon is the a-carbon, the
carbon adjacent to the a-carbon is the b-carbon, and so on.

CH3CH2CH2CH2CH2

6

5

4

3

O

O

C

C

1

OH

2

CH3CH2CH2CH2CH2
e

systematic nomenclature

g

d

b

a = alpha
b = beta
g = gamma
d = delta
e = epsilon

OH

a

common nomenclature

Take a careful look at the following examples to make sure that you understand the
difference between systematic (IUPAC) and common nomenclature:
O

O

O

Br
OH

OH

OH

OCH3

Cl

systematic name: 2-methoxybutanoic acid
common name: a-methoxybutyric acid

3-bromopentanoic acid
b-bromovaleric acid

4-chlorohexanoic acid
g-chlorocaproic acid

Carboxylic acids in which a carboxyl group is attached to a ring are named by adding
“carboxylic acid” to the name of the cyclic compound.
O

O

C

C
OH

cyclohexanecarboxylic acid

COOH
COOH

OH

benzenecarboxylic acid
benzoic acid

1,2-benzenedicarboxylic
acid

Naming Acyl Chlorides
Acyl chlorides have a Cl in place of the OH group of a carboxylic acid. Acyl chlorides
are named by replacing “ic acid” of the acid name with “yl chloride.” For cyclic acids
that end with “carboxylic acid,” “carboxylic acid” is replaced with “carbonyl chloride.”
(Acyl bromides exist too, but are less common than acyl chlorides.)
O
O
CH3

C

C

O
Br

Cl

systematic name: ethanoyl chloride
common name:
acetyl chloride

Cl

3-methylpentanoyl bromide
b-methylvaleryl bromide

cyclopentanecarbonyl
chloride

carbonyl oxygen

O

Naming Esters
An ester has an OR group in place of the OH group of a carboxylic acid. In naming
an ester, the name of the group (RЈ) attached to the carboxyl oxygen is stated first,
followed by the name of the acid, with “ic acid” replaced by “ate.” (The prime on RЈ
indicates that the alkyl group it designates does not have to be the same as the alkyl
group designated by R.) Recall the difference between a phenyl group and a benzyl
group (page 438).
O

O
CH3
systematic name:
common name:

C

OCH2CH3

ethyl ethanoate

ethyl acetate

CH3CH2

C

Br
O

phenyl propanoate
phenyl propionate

CH3CHCH2

C

OR′
carboxyl oxygen

The double-bonded oxygen is the
carbonyl oxygen; the single-bonded
oxygen is the carboxyl oxygen.

O

O
C

R

C
OCH3

methyl 3-bromobutanoate
methyl b-bromobutyrate

OCH2CH3

ethyl cyclohexanecarboxylate


724

CHAPTER 16

Reactions of Carboxylic Acids and Carboxylic Acid Derivatives

Salts of carboxylic acids are named in the same way. That is, the cation is named first,
followed by the name of the acid, again with “ic acid” replaced by “ate.”
O

O

C

O− Na+

H
systematic name:
common name:

C

CH3

sodium methanoate
sodium formate

O
C

O− K+

potassium ethanoate
potassium acetate

O− Na+

sodium benzenecarboxylate
sodium benzoate

Frequently, the name of the cation is omitted.
O

COO−

O

C

O−

O−

CH3

C
H3C

O

acetate

pyruvate

H
OH

(S)-(+)-lactate

Cyclic esters are called lactones. In systematic nomenclature, they are named
as “2-oxacycloalkanones” (“oxa” designates the oxygen atom.) For their common
names, the length of the carbon chain is indicated by the common name of the
carboxylic acid, and a Greek letter specifies the carbon to which the oxygen is
attached. Thus, six-membered ring lactones are d-lactones (the carboxyl oxygen is on
the d-carbon), five-membered ring lactones are g-lactones, and four-membered ring
lactones are b-lactones.
O

O

O

2-oxacyclopentanone
g-butyrolactone
a g-lactone

a

O

b

d

g

O

O

2-oxacyclohexanone
d-valerolactone
a d-lactone

O

O
CH3

3-methyl-2-oxacyclohexanone
d-caprolactone
a d-lactone

CH2CH3
3-ethyl-2-oxacyclopentanone
g-caprolactone
a g-lactone

PROBLEM 1♦

The aromas of many flowers and fruits are due to esters such as those shown in this problem.
What are the common names of these esters? (Also see Problem 66.)
O
a.

O
O

jasmine

a-Hydroxycarboxylic acids are found
in skin products that claim to reduce
wrinkles by penetrating the top layer
of the skin, causing it to flake off.

b.

O
O

banana

c.

O
apple

PROBLEM 2

The word “lactone” has its origin in lactic acid, a three-carbon carboxylic acid with an OH
group on the a-carbon. Ironically, lactic acid (for its structure, see the structure of lactate
near the top of this page) cannot form a lactone. Why not?

Naming Amides
An amide has an NH2, NHR, or NR2 group in place of the OH group of a carboxylic
acid. Amides are named by replacing “oic acid,” “ic acid,” or “ylic acid” of the acid name
with “amide.”


725

The Nomenclature of Carboxylic Acids and Carboxylic Acid Derivatives

O
CH3
systematic name:
common name:

C

O

O
NH2

ethanamide
acetamide

ClCH2CH2CH2

C

C

NH2

NH2

benzenecarboxamide
benzamide

4-chlorobutanamide
g-chlorobutyramide

If a substituent is bonded to the nitrogen, the name of the substituent is stated first (if
there is more than one substituent bonded to the nitrogen, they are stated alphabetically),
followed by the name of the amide. The name of each substituent is preceded by an N to
indicate that the substituent is bonded to a nitrogen.
O
CH3CH2

C

O

O
NH

CH3CH2CH2CH2

C

CH3CH2CH2

NCH2CH3

NCH2CH3
CH2CH3

CH3
N-cyclohexylpropanamide

C

N-ethyl-N-methylpentanamide

N,N-diethylbutanamide

Cyclic amides are called lactams. Their nomenclature is similar to that of lactones. In
systematic nomenclature, they are named as “2-azacycloalkanones” (“aza” designates the

nitrogen atom). For their common names, the length of the carbon chain is indicated by
the common name of the carboxylic acid, and a Greek letter specifies the carbon to which
the nitrogen is attached.
O
a
b

NH
g

d

2-azacyclohexanone
d-valerolactam
a d-lactam

O
NH
2-azacyclopentanone
g-butyrolactam
a g-lactam

O
NH
2-azacyclobutanone
b-propiolactam
a b-lactam

Nature’s Sleeping Pill
Melatonin, a naturally occurring amide, is a hormone synthesized by

the pineal gland from the amino acid tryptophan. An amino acid is an CH3O
a-aminocarboxylic acid. Melatonin regulates the dark–light clock in our
brains that governs such things as the sleep–wake cycle, body temperature,
and hormone production.
Melatonin levels increase from evening to night and then decrease as
morning approaches. People with high levels of melatonin sleep longer
and more soundly than those with low levels. The concentration of the
hormone in our bodies varies with age—6-year-olds have more than
five times the concentration that 80-year-olds have—which is one of
the reasons young people have less trouble sleeping than older people.
Melatonin supplements are used to treat insomnia, jet lag, and seasonal
affective disorder.

H
N

+

NH3

O

O−
O

N
H
melatonin

N

H
tryptophan


726

CHAPTER 16

Reactions of Carboxylic Acids and Carboxylic Acid Derivatives

PROBLEM 3♦

Name the following compounds:
O
a.
C
CH3CH2CH2
O− K+

d.

g.
NH

Cl

O
b.

O

O

COOH

O
e.

O

O

O
c.

h.

OH

O
f.

N

CH3CH2

C

O

i.
NH2

CH3

PROBLEM 4

Draw the structure of each of the following:
a. phenyl acetate
b. g-caprolactam
c. N-benzylethanamide

e. ethyl 2-chloropentanoate
f. b-bromobutyramide
g. cyclohexanecarbonyl chloride

d. g-methylcaproic acid

h. a-chlorovaleric acid

Derivatives of Carbonic Acid
Carbonic acid—a compound with two OH groups bonded to a carbonyl carbon—is
unstable, readily breaking down to CO2 and H2O. The reaction is reversible, so carbonic
acid is formed when CO2 is bubbled into water (Section 1.17).
O
CO2 + H2O

C
HO

OH

carbonic acid

The OH groups of carbonic acid, just like the OH group of a carboxylic acid can be
substituted by other groups.
O

O

C
Cl

O

C
Cl

phosgene

CH3O

O

C
OCH3

dimethyl carbonate

H2N

C
NH2

urea

O

H2N

C
OH

carbamic acid

H2N

OCH3

methyl carbamate

16.2 THE STRUCTURES OF CARBOXYLIC ACIDS
AND CARBOXYLIC ACID DERIVATIVES
The carbonyl carbon in carboxylic acids and carboxylic acid derivatives is sp2 hybridized.
It uses its three sp2 orbitals to form s bonds to the carbonyl oxygen, the a-carbon, and a
substituent (Y). The three atoms attached to the carbonyl carbon are in the same plane, and
the bond angles are each approximately 120°.


The Structures of Carboxylic Acids and Carboxylic Acid Derivatives

727

O
~120°

C
~120°

~120°
p bond

Y

The carbonyl oxygen is also sp2 hybridized. One of its sp2 orbitals forms a s bond
with the carbonyl carbon, and each of the other two sp2 orbitals contains a lone pair.
The remaining p orbital of the carbonyl oxygen overlaps the remaining p orbital of the
carbonyl carbon to form a p bond (Figure 16.1).
Esters, carboxylic acids, and amides each have two resonance contributors. The
resonance contributor on the right makes an insignificant contribution to an acyl chloride
(Section 16.6), so it is not shown here.
−

O

O
C

C
R

OCH3

O

C

C
OH

+

R

OH
−

O

O

C
R

OCH3
−

O
R

+

R

C
NH2

R

+

NH2

The resonance contributor on the right makes a greater contribution to the hybrid in the
amide than in the ester or the carboxylic acid, because the amide’s resonance contributor
is more stable. It is more stable because nitrogen is less electronegative than oxygen, so
nitrogen can better accommodate a positive charge.
PROBLEM 5♦

Which is a correct statement?
A The delocalization energy of an ester is about 18 kcal/mol, and the delocalization energy of an
amide is about 10 kcal/mol.
B The delocalization energy of an ester is about 10 kcal/mol, and the delocalization energy of
an amide is about 18 kcal/mol.
PROBLEM 6♦

Which is longer, the carbon–oxygen single bond in a carboxylic acid or the carbon–oxygen
bond in an alcohol? Why?
PROBLEM 7♦

There are three carbon–oxygen bonds in methyl acetate.
a. What are their relative lengths?
b. What are the relative infrared (IR) stretching frequencies of these bonds?
PROBLEM 8♦

Match the compound to the appropriate carbonyl IR absorption band:
1800 cm - 1
acyl chloride
1640 cm - 1
ester
amide
1730 cm - 1

C

O

s bond

▲ Figure 16.1
Bonding in a carbonyl group. The p bond
is formed by the side-to-side overlap
of a p orbital of carbon with a p orbital
of oxygen.


728

CHAPTER 16

Reactions of Carboxylic Acids and Carboxylic Acid Derivatives

16.3 THE PHYSICAL PROPERTIES OF CARBONYL
COMPOUNDS
The acid properties of carboxylic acids were discussed in Sections 2.3 and 8.15. Recall
that carboxylic acids have pKa values of approximately 5. Carbonyl compounds have the
following relative boiling points:
relative boiling points
amide 7 carboxylic acid 7 nitrile W ester ϳ acyl chloride ϳ ketone ϳ aldehyde
The boiling points of an ester, acyl chloride, ketone, and aldehyde of comparable
molecular weight are similar and are lower than the boiling point of an alcohol of similar
molecular weight because only the alcohol molecules can form hydrogen bonds with
each other. The boiling points of these four carbonyl compounds are higher than the
boiling point of the same-sized ether because of the dipole–dipole interactions between
the polar carbonyl groups.

O

O

C

C
CH3CH2CH2OH
bp = 97.4 °C

H

O

CH3

OCH3

bp = 32 °C

O

C
Cl

bp = 51 °C

C
CH3

CH3

bp = 56 °C

O
N

CH3

bp = 97 °C

H

bp = 49 °C

CH3CH2OCH3
bp = 10.8 °C

O

C
CH3CH2C

CH3CH2

C
OH

CH3

bp = 118 °C

NH2

bp = 221 °C

The strong dipole–dipole interactions of a nitrile give it a boiling point similar to that of
an alcohol. Carboxylic acids have relatively high boiling points because each molecule
has two groups that can form hydrogen bonds. Amides have the highest boiling points
because they have strong dipole–dipole interactions, since the resonance contributor
with separated charges contributes significantly to the overall structure of the compound
(Section 16.2). In addition, if the nitrogen of an amide is bonded to a hydrogen, hydrogen
bonds can form between the molecules.
R

d−

dipole–dipole
interactions

N
R

C

d+

d+

C

N

d−

R

O
R

HO
C

C
OH

O

R

R

+

N

intermolecular
hydrogen bonds

R
dipole–dipole
interactions

C

O−
C
R

O−
R
N
+

R

Carboxylic acid derivatives are soluble in solvents such as ethers, chloroalkanes, and
aromatic hydrocarbons. Like alcohols and ethers, carbonyl compounds with fewer than
four carbons are soluble in water. Tables of physical properties can be found in the Study
Area of MasteringChemistry.
Esters, N,N-disubstituted amides, and nitriles are often used as solvents because they are
polar but do not have reactive OH or NH2 groups. We have seen that dimethylformamide
(DMF) is a common aprotic polar solvent (Section 9.2).


Fatty Acids Are Long-Chain Carboxylic Acids

16.4 FATTY ACIDS ARE LONG-CHAIN CARBOXYLIC ACIDS
Fatty acids are carboxylic acids with long hydrocarbon chains that are found in nature
(Table 16.2). They are unbranched and contain an even number of carbons because they
are synthesized from acetate, a compound with two carbons. The mechanism for their
biosynthesis is discussed in Section 18.20.
Table 16.2 Common Naturally Occurring Fatty Acids

Melting
point
(°C)

Number
of carbons Common name

Systematic name

Saturated
lauric acid

12

dodecanoic acid

COOH

44

Structure

14

myristic acid

tetradecanoic acid

COOH

58

16

palmitic acid

hexadecanoic acid

COOH

63

18

stearic acid

octadecanoic acid

COOH

69

20

arachidic acid

eicosanoic acid

COOH

77

Unsaturated
COOH
16

palmitoleic acid

(9Z)-hexadecenoic acid

18

oleic acid

(9Z)-octadecenoic acid

18

linoleic acid

(9Z,12Z)-octadecadienoic acid

18

linolenic acid

(9Z,12Z,15Z)-octadecatrienoic acid

20

arachidonic acid (5Z,8Z,11Z,14Z)-eicosatetraenoic acid

20

EPA

0
COOH
13
COOH
−5

COOH
−11

COOH

(5Z,8Z,11Z,14Z,17Z)-eicosapentaenoic acid

Fatty acids can be saturated with hydrogen (and therefore have no carbon–carbon
double bonds) or unsaturated (and have carbon–carbon double bonds). Fatty acids with
more than one double bond are called polyunsaturated fatty acids.

−50

COOH
−50

729


730

CHAPTER 16

Unsaturated fatty acids have
lower melting points than
saturated fatty acids.

Reactions of Carboxylic Acids and Carboxylic Acid Derivatives

The melting points of saturated fatty acids increase with increasing molecular weight

because of increased van der Waals interactions between the molecules (Section 3.9).
The melting points of unsaturated fatty acids with the same number of double bonds also
increase with increasing molecular weight (Table 16.2).
The double bonds in naturally occurring unsaturated fatty acids have the cis configuration and are always separated by one CH2 group. The cis double bond produces a
bend in the molecule, which prevents unsaturated fatty acids from packing together as
tightly as saturated fatty acids. As a result, unsaturated fatty acids have fewer intermolecular interactions and therefore have lower melting points than saturated fatty acids
with comparable molecular weights (Table 16.2).

stearic acid

oleic acid

an 18-carbon fatty acid
with no double bonds

an 18-carbon fatty acid
with one double bond

Omega Fatty Acids
Omega indicates the position of the first double bond in an unsaturated fatty acid,
counting from the methyl end. For example, linoleic acid is an omega-6 fatty acid
because its first double bond is after the sixth carbon, and linolenic acid is an
omega-3 fatty acid because its first double bond is after the third carbon. Mammals
lack the enzyme that introduces a double bond beyond C-9, counting from the
carbonyl carbon. Linoleic acid and linolenic acids are therefore essential fatty acids
for mammals: mammals cannot synthesize them, but since they are needed for
normal body function, they must be obtained from the diet.
Omega-3 fatty acids have been found to decrease the likelihood of sudden death
due to a heart attack. When under stress, the heart can develop fatal disturbances in
its rhythm. Omega-3 fatty acids are incorporated into cell membranes in the heart and

apparently have a stabilizing effect on heart rhythm. These fatty acids are found in
fatty fish such as herring, mackerel, and salmon.

COOH
omega-6
fatty acid

Linoleic and linolenic acids are essential fatty acids
for mammals.

omega-3
fatty acid

linoleic acid

COOH

linolenic acid

PROBLEM 9

Explain the difference in the melting points of the following fatty acids:
a. palmitic acid and stearic acid
b. palmitic acid and palmitoleic acid
PROBLEM 10

What products are formed when arachidonic acid reacts with excess ozone followed by treatment
with dimethyl sulfide? (Hint: See Section 6.11.)

How Carboxylic Acids and Carboxylic Acid Derivatives React

731

16.5 HOW CARBOXYLIC ACIDS AND CARBOXYLIC ACID
DERIVATIVES REACT
The reactivity of carbonyl compounds is due to the polarity of the carbonyl
group,  which  results from oxygen being more electronegative than carbon. The
carbonyl carbon  is therefore electron deficient (an electrophile), so it reacts with
nucleophiles.
d−

O carbonyl carbon
C

R

d+

Y

When a nucleophile adds to the carbonyl carbon of a carboxylic acid derivative, the
weakest bond in the molecule—the p bond—breaks, and an intermediate is formed. It is
called a tetrahedral intermediate because the sp2 carbon in the reactant has become an
sp3 carbon in the intermediate.
the π bond
reforms and
a group is
eliminated
−

O sp2
C
R

Y

sp3 O

+ Z

−

R

C

O sp2
Y

C
R

Z

Z

+ Y

−

A compound that has an sp3
carbon bonded to an oxygen atom
generally will be unstable if the
sp3 carbon is bonded to another
electronegative atom.

a tetrahedral
intermediate

the nucleophile adds
to the carbonyl carbon

The tetrahedral compound is an intermediate rather than a final product because it is not
stable. Generally, a compound that has an sp3 carbon bonded to an oxygen atom will be
unstable if the sp3 carbon is bonded to another electronegative atom. The tetrahedral
intermediate, therefore, is unstable because Y and Z are both electronegative atoms.
A lone pair on the oxygen re-forms the p bond, and either Y - or Z - is eliminated along
with its bonding electrons. (Here we show Y - being eliminated.)
Whether Y - or Z - is eliminated from the tetrahedral intermediate depends on their
relative basicities. The weaker base is eliminated preferentially, making this another
example of the principle we first saw in Section 9.2: when comparing bases of the
same type, the weaker base is a better leaving group. Because a weak base does not
share its electrons as well as a strong base does, a weaker base forms a weaker bond—
one that is easier to break.
If Z - is a much weaker base than Y - , then Z - will be eliminated.
−

O

O
−

+ Z

C
R

Y

R

C

Y

Z
a tetrahedral
intermediate

Z − is a weaker
base than Y −,
so Z − is
eliminated and
the reactants
are re-formed

In this case, no new product is formed. The nucleophile adds to the carbonyl carbon, but
the tetrahedral intermediate eliminates the nucleophile and re-forms the reactants.
On the other hand, if Y - is a much weaker base than Z - , then Y - will be eliminated

and a new product will be formed.

The weaker the base,
the better it is as a leaving group.


732

CHAPTER 16

Reactions of Carboxylic Acids and Carboxylic Acid Derivatives
Y− is a weaker base
than Z −, so Y − is
eliminated and the
products are formed
−

O

O
−

+ Z

C
R

R

Y

C

O
Y

+ Y

C
R

Z

−

Z

a tetrahedral
intermediate

This reaction is a nucleophilic acyl substitution reaction because a nucleophile (Z - )
has replaced the substituent (Y - ) that was attached to the acyl group in the reactant. It is
also called an acyl transfer reaction because an acyl group has been transferred from
one group to another. Most chemists, however, prefer to call it a nucleophilic addition–
elimination reaction to emphasize the two-step nature of the reaction: a nucleophile
adds to the carbonyl carbon in the first step, and a group is eliminated in the second step.
If the basicities of Y - and Z - are similar, some molecules of the tetrahedral intermediate will eliminate Y - and others will eliminate Z - . When the reaction is over, both
the reactant and the product will be present.
the basicities of Y− and Z−
are similar, so a mixture

of reactants and products
will be obtained

O

O
+ Z

C
R

−

R

Y

C

−

O
Y

+ Y

C
R

Z

Z

−

a tetrahedral
intermediate

We can therefore make the following general statement about the reactions of carboxylic acid derivatives:
A carboxylic acid derivative will undergo a nucleophilic addition–elimination
reaction, provided that the newly added group in the tetrahedral intermediate is
not a much weaker base than the group attached to the acyl group in the reactant.
A carboxylic acid derivative will
undergo a nucleophilic addition–
elimination reaction if the newly
added group in the tetrahedral
intermediate is not a much weaker
base than the group attached to the
acyl group in the reactant.

Let’s compare this two-step addition–elimination reaction with a one-step SN2 reaction.
When a nucleophile attacks a carbon, the weakest bond in the molecule breaks. The
weakest bond in an SN2 reaction is the bond to the leaving group, so this is the bond that
breaks in the first and only step of the reaction (Section 9.1). In contrast, the weakest
bond in an addition–elimination reaction is the p bond, so this bond breaks first and the
leaving group is eliminated in a subsequent step.

CH3CH2

−

Y + Z

CH3CH2

−

Z + Y

an SN2 reaction

Let’s now look at a molecular orbital description of how carbonyl compounds
react. In Section 1.6, which first introduced you to molecular orbital theory, you saw
that because oxygen is more electronegative than carbon, the 2p orbital of oxygen
contributes more to the p bonding molecular orbital (it is closer to it in energy) and
the 2p orbital of carbon contributes more to the p* antibonding molecular orbital
(see Figure 1.6). As a result, the p* antibonding orbital is largest at the carbon atom,
so that is where the nucleophile’s nonbonding orbital, in which the lone pair resides,
overlaps. This allows the greatest amount of orbital overlap, and greater overlap
means greater stability. When two orbitals overlap, the result is a molecular orbital—
in this case, a s molecular orbital—that is more stable than either of the overlapping
orbitals (Figure 16.2).


The Relative Reactivities of Carboxylic Acids and Carboxylic Acid Derivatives
empty p∗
antibonding
orbital

C

O
Z

a filled
nonbonding
orbital

O-

Energy

C

C Z s∗
antibonding
molecular orbital

new C Z
s bond

C O p∗
antibonding
orbital
nonbonding
orbital of the
lone pair

these orbitals
overlap

C Z s
bonding
molecular orbital

Z
▲ Figure 16.2

The filled nonbonding orbital containing the nucleophile’s lone pair overlaps the empty p* antibonding orbital of the carbonyl group,
forming the new s bond in the tetrahedral intermediate.

PROBLEM-SOLVING STRATEGY

Using Basicity to Predict the Outcome of a Nucleophilic Addition–Elimination Reaction

What is the product of the reaction of acetyl chloride with CH3O - ? The pKa of HCl is –7; the
pKa of CH3OH is 15.5.
To identify the product of the reaction, we need to compare the basicities of the two groups in
the tetrahedral intermediate so that we can determine which one will be eliminated. Because HCl
is a stronger acid than CH3OH, Cl– is a weaker base than CH3O–. Therefore, Cl– will be eliminated from the tetrahedral intermediate and methyl acetate will be the product of the reaction.
O−

O
CH3

C

Cl

+ CH3O−

CH3

O

C

Cl

CH3

OCH3

C

OCH3

+ Cl−

methyl acetate

acetyl chloride

Now use the strategy you have just learned to solve Problem 11.

PROBLEM 11♦

a. What is the product of the reaction of acetyl chloride with HO–? The pKa of HCl is –7; the
pKa of H2O is 15.7.

b. What is the product of the reaction of acetamide with HO–? The pKa of NH3 is 36; the pKa
of H2O is 15.7.

16.6 THE RELATIVE REACTIVITIES OF CARBOXYLIC
ACIDS AND CARBOXYLIC ACID DERIVATIVES
We have just seen that there are two steps in a nucleophilic addition–elimination reaction:
formation of a tetrahedral intermediate and collapse of the tetrahedral intermediate. The
weaker the base attached to the acyl group (Table 16.1), the easier it is for both steps of
the reaction to take place.
relative basicities of the leaving groups

weakest
base

Cl− <

−

OR ≈

−

OH <

−

NH2

strongest
base

733


734

CHAPTER 16

Reactions of Carboxylic Acids and Carboxylic Acid Derivatives

Therefore, carboxylic acid derivatives have the following relative reactivities:
relative reactivities of carboxylic acid derivatives

O
most
reactive

R

C

O
>
Cl

R

acyl chloride

O

C

≈

OR′

ester

R

C

O
>

OH

carboxylic acid

C

R

NH2

least
reactive

amide

How does having a weak base attached to the acyl group make the first step of the
addition–elimination reaction easier? The key factor is the extent to which the lone-pair
electrons on Y can be delocalized onto the carbonyl oxygen.
Weak bases do not share their electrons well, so the weaker the basicity of Y, the
smaller will be the contribution from the resonance contributor with a positive charge on
Y. In addition, when Y = Cl, delocalization of chlorine’s lone pair is minimal due to the
poor orbital overlap between the large 3p orbital on chlorine and the smaller 2p orbital on
carbon. The less the contribution from the resonance contributor with the positive charge
on Y, the more electrophilic the carbonyl carbon. Thus, weak bases cause the carbonyl
carbon to be more electrophilic and, therefore, more reactive toward nucleophiles.
−

O

O

relative reactivity: acyl chloride >
ester ~ carboxylic acid > amide

C
R

C
Y

R

Y

+

resonance contributors of a carboxylic acid or carboxylic acid derivative

PROBLEM 12♦

a. Which compound will have the stretching vibration for its carbonyl group at the highest
frequency: acetyl chloride, methyl acetate, or acetamide?
b. Which one will have the stretching vibration for its carbonyl group at the lowest frequency?

A weak base attached to the acyl group also makes the second step of the addition–
elimination reaction easier, because weak bases are easier to eliminate when the tetrahedral intermediate collapses.
O
R

−

C

Y

the weaker the base, the
easier it is to eliminate

Z

In Section 16.5 we saw that in a nucleophilic addition–elimination reaction, the
nucleophile that adds to the carbonyl carbon must be a stronger base than the substituent
that is attached to the acyl group. This means that a carboxylic acid derivative can be
converted into a less reactive carboxylic acid derivative in a nucleophilic addition–

elimination reaction, but not into one that is more reactive. For example, an acyl chloride
can be converted into an ester because an alkoxide ion is a stronger base than a chloride ion.
O
R

C

O
Cl

+

CH3O−

R

C

OCH3

+

Cl−

An ester, however, cannot be converted into an acyl chloride because a chloride ion is a
weaker base than an alkoxide ion.


The Relative Reactivities of Carboxylic Acids and Carboxylic Acid Derivatives

O
R

C

OCH3

+

Cl−

no reaction

Reaction coordinate diagrams for nucleophilic addition–elimination reactions with
nucleophiles of varying basicity are shown in Figure 16.3 (where TI is the tetrahedral
intermediate).

Free energy

Free energy

TI

better
leaving group

b.

TI
more reactive

(less stable)
carbonyl compound

Progress of the reaction

c.

same leaving propensity

Free energy

poorer
leaving group

a.

TI

same reactivity

Progress of the reaction

Progress of the reaction

less reactive
(more stable)
carbonyl compound

▲ Figure 16.3
(a) The nucleophile is a weaker base than the group attached to the acyl group in the reactant.

(b) The nucleophile is a stronger base than the group attached to the acyl group in the reactant.
(c) The nucleophile and the group attached to the acyl group in the reactant have similar basicities.

1. To synthesize a more reactive compound from a less reactive compound, the new
group in the tetrahedral intermediate will have to be a weaker base than the group
attached to the acyl group in the reactant. The lower energy pathway will be for the
tetrahedral intermediate (TI) to eliminate the newly added group and re-form the
reactants, so no reaction takes place (Figure 16.3a).
2. To synthesize a less reactive compound from a more reactive compound, the new
group in the tetrahedral intermediate will have to be a stronger base than the group
attached to the acyl group in the reactant. The lower energy pathway will be for the
tetrahedral intermediate (TI) to eliminate the group attached to the acyl group in the
reactant and form a substitution product (Figure 16.3b).
3. If the reactant and product have similar reactivities, then both groups in the tetrahedral intermediate will have similar basicities. In this case, the tetrahedral intermediate can eliminate either group with similar ease, so a mixture of the reactant
and the substitution product will result (Figure 16.3c).
PROBLEM 13♦

Using the pKa values listed in Table 16.1, predict the products of the following reactions:
O
O
a.

CH3

C

OCH3

+ NaCl

c.

CH3

C
CH3

NH2

+ NaCl

O

O
b.

C

Cl

+

NaOH

d.

C
CH3

NH2

+

NaOH

735


736

CHAPTER 16

Reactions of Carboxylic Acids and Carboxylic Acid Derivatives
PROBLEM 14♦

Is the following statement true or false?
If the newly added group in the tetrahedral intermediate is a stronger base than the group
attached to the acyl group in the reactant, then formation of the tetrahedral intermediate is the
rate-limiting step of a nucleophilic addition–elimination reaction.

16.7 THE GENERAL MECHANISM FOR NUCLEOPHILIC
ADDITION–ELIMINATION REACTIONS
All carboxylic acid derivatives undergo nucleophilic addition–elimination reactions by
the same mechanism. If the nucleophile is negatively charged, the mechanism shown
here and described on pages 731–732 is followed:
MECHANISM FOR A NUCLEOPHILIC ADDITION–ELIMINATION REACTION
WITH A NEGATIVELY CHARGED NUCLEOPHILE

O

O

C
R

Y

+

CH3O

−

R

■

C

O
−

C

Y

OCH3

negatively charged
nucleophile adds to

the carbonyl carbon
■

−

R

OCH3

+ Y

elimination of the
weaker base from the
tetrahedral intermediate

The nucleophile adds to the carbonyl carbon, forming a tetrahedral intermediate.
The weaker of the two bases is eliminated—either the group that was attached to the
acyl group in the reactant or the newly added group—and the π bond re-forms.

If the nucleophile is not charged, then the mechanism has an additional step.
MECHANISM FOR A NUCLEOPHILIC ADDITION–ELIMINATION REACTION
WITH A NEUTRAL NUCLEOPHILE

O

O

C
R

Y

+ CH3OH

neutral nucleophile
adds to the carbonyl
carbon

R

C
+

−

O
R

Y

O

C Y
OCH3

OCH3
H

−

B

removal of
a proton from
the tetrahedral
intermediate

HB+

C
R

−

+ Y
OCH3

elimination of the
weaker base from the
tetrahedral intermediate

:B represents any species in the solution that is capable of removing a proton, and HB+
represents any species in the solution that is capable of donating a proton.
■
■

■

The nucleophile adds to the carbonyl carbon, forming a tetrahedral intermediate.
A proton is removed from the tetrahedral intermediate, resulting in a tetrahedral intermediate like the one formed by a negatively charged nucleophile. (Proton transfers to

and from oxygen are extremely fast steps.)
The weaker of the two bases is eliminated—either the newly added group after it has
lost a proton or the group that was attached to the acyl group in the reactant—and the
p bond re-forms.

The remaining sections of this chapter show specific examples of these general principles. Keep in mind that all the nucleophilic addition–elimination reactions follow the


The Reactions of Acyl Chlorides

737

same mechanism. Therefore, you can always determine the outcome of the reactions of
carboxylic acids and carboxylic acid derivatives presented in this chapter by examining the tetrahedral intermediate and remembering that the weaker base is preferentially
eliminated (Section 16.5).
PROBLEM 15♦

What will be the product of a nucleophilic addition–elimination reaction—a new carboxylic
acid derivative, a mixture of two carboxylic acid derivatives, or no reaction—if the new group
in the tetrahedral intermediate is the following?
a. a stronger base than the substituent that was attached to the acyl group
b. a weaker base than the substituent that was attached to the acyl group
c. similar in basicity to the substituent that was attached to the acyl group

16.8 THE REACTIONS OF ACYL CHLORIDES
Acyl chlorides react with alcohols to form esters, with water to form carboxylic acids,
and with amines to form amides because, in each case, the incoming nucleophile is a
stronger base than the departing halide ion (Table 16.1).
O

O
+

C
R

Cl

CH3OH

C
R

O
Cl

+ H2O

OH
O

C
Cl

acetyl chloride

+ HCl

C
R

O
R

+ HCl

O

C
R

OCH3

+ 2 CH3NH2

C
R

+

NHCH3

+ CH3NH3 Cl−

All the reactions follow the general mechanism described on page 736.
MECHANISM FOR THE REACTION OF AN ACYL CHLORIDE WITH AN ALCOHOL

the weaker base is eliminated

O−

O
C
R

Cl

+ ROH

R

C

■

■

■

Cl

R C

+

OR
H

formation of a tetrahedral
intermediate

O−

O
Cl
R

OR
B

+ Cl−

C
OR

HB+

a proton is removed

The nucleophilic alcohol adds to the carbonyl carbon of the acyl chloride, forming a
tetrahedral intermediate.
Because the protonated ether group is a strong acid, the tetrahedral intermediate loses
a proton. (Proton transfers to and from oxygen are diffusion controlled, so they occur
very rapidly.)
The chloride ion is eliminated from the deprotonated tetrahedral intermediate because
chloride ion is a weaker base than the alkoxide ion.

The weaker base is eliminated
from the tetrahedral intermediate.

738

CHAPTER 16

Reactions of Carboxylic Acids and Carboxylic Acid Derivatives

Notice that the reaction of an acyl chloride with an amine (on page 737) or with
ammonia (shown next) to form an amide is carried out with twice as much amine or
ammonia as acyl chloride because the HCl formed as a product of the reaction will
protonate any amine or ammonia that has yet to react. Once protonated, it is no longer
a nucleophile, so it cannot react with the acyl chloride. Using twice as much amine or
ammonia as acyl chloride guarantees that there will be enough unprotonated amine to
react with all the acyl chloride.
one equivalent

O

O
C
R

one equivalent

Cl

+ NH3

+ HCl

C
R

NH2

NH3

+

NH4 Cl−

PROBLEM 16

Starting with acetyl chloride, what neutral nucleophile would you use to make each of the
following compounds?
O

O
a.

CH3

C

OCH2CH2CH3

d.

C
CH3

O
b.

CH3

C

O
e.

NH2

CH3

O
c.

CH3

C

OH

C

O

O
f.

N(CH3)2

CH3

C

O

NO2

P R O B L E M 1 7 Solved

a. What two amides are obtained from the reaction of acetyl chloride with an equivalent of
ethylamine and an equivalent of propylamine?
b. Why is only one amide obtained from the reaction of acetyl chloride with an equivalent of
ethylamine and an equivalent of triethylamine?
Solution to 17a Either of the amines can react with acetyl chloride, so both N-ethylacetamide

and N-propylacetamide are formed.
O
CH3

C

O

O
Cl

+

NH2

+

NH2

CH3

C

N
H

N-ethylacetamide

+

CH3

C

N
H

N-propylacetamide

Solution to 17b Two compounds are formed initially. However, the compound formed by
triethylamine is very reactive because it has a positively charged nitrogen, which is an excellent

leaving group. Therefore, the compound will react immediately with any unreacted ethylamine, so
N-ethylacetamide is the only amide product of the reaction.


The Reactions of Esters

O
CH3

O
+

C

NH2

Cl

+

N
CH3

C

O
+

N
H

CH3

C

+

N

N-ethylacetamide

NH2
O
CH3

C

N
H

N-ethylacetamide

PROBLEM 18

Write the mechanism for each of the following reactions:
a. the reaction of acetyl chloride with water to form acetic acid
b. the reaction of benzoyl chloride with excess methylamine to form N-methylbenzamide

16.9 THE REACTIONS OF ESTERS
Esters do not react with chloride ion because it is a much weaker base than the RO– group

of the ester, so Cl– (not RO–) would be the base eliminated from the tetrahedral intermediate (Table 16.1).
An ester reacts with water to form a carboxylic acid and an alcohol. This is an example of a hydrolysis reaction. A hydrolysis reaction is a reaction with water that converts
one compound into two compounds (lysis is Greek for “breaking down”).
a hydrolysis reaction

O

O

C
R

OCH3

+ H2O

HCl

C
R

OH

+ CH3OH

An ester reacts with an alcohol to form a new ester and a new alcohol. This is an example
of an alcoholysis reaction—a reaction with an alcohol that converts one compound into
two compounds. This particular alcoholysis reaction is also called a transesterification
reaction because one ester is converted to another ester.
a transesterification reaction

O
C
R

O
OCH3

+

CH3CH2OH

HCl

C
R

OCH2CH3

+ CH3OH

Both the hydrolysis and the alcoholysis of an ester are very slow reactions because
water and alcohols are poor nucleophiles and the RO– group of an ester is a poor leaving
group. Therefore, these reactions are always catalyzed when carried out in the laboratory.

methyl acetate

739

740

CHAPTER 16

Reactions of Carboxylic Acids and Carboxylic Acid Derivatives

Both hydrolysis and alcoholysis of an ester can be catalyzed by acids (Section 16.10).
The rate of hydrolysis can also be increased by hydroxide ion and the rate of alcoholysis
can be increased by the conjugate base (RO–) of the reactant alcohol (Section 16.11).
Esters react with amines to form amides. A reaction with an amine that converts one
compound into two compounds is called aminolysis. Notice that the aminolysis of an
ester requires only one equivalent of amine, unlike the aminolysis of an acyl halide,
which requires two equivalents (Sections 16.8). This is because the leaving group of
an ester (RO–) is more basic than the amine, so the alkoxide ion—rather than unreacted
amine—picks up the proton generated in the reaction.
an aminolysis reaction

O
+ CH3NH2

C
R

O

Δ

OCH2CH3

R

C

+ CH3CH2OH
NHCH3

The reaction of an ester with an amine is not as slow as the reaction of an ester with
water or an alcohol because an amine is a better nucleophile. This is fortunate because the
reaction cannot be catalyzed by an acid. The acid would protonate the amine, and a protonated amine is not a nucleophile. The rate of the reaction, however, can be increased by heat.
In Section 8.15, we saw that phenol is a stronger acid than alcohol.
OH

CH3OH

pKa = 10.0

pKa = 15.5

Therefore, a phenolate ion (ArO- ) is a weaker base than an alkoxide ion (RO- ), so a
phenyl ester is more reactive than an alkyl ester.
O

O

C

C
CH3

O

is more reactive than

CH3

OCH3

methyl acetate

phenyl acetate

Waxes Are Esters That Have High-Molecular Weights
Waxes are esters formed from long-chain carboxylic acids and long-chain alcohols. For example,
beeswax, the structural material of beehives, has a 26-carbon carboxylic acid component and
a 30-carbon alcohol component. The word wax comes from the Old English weax, meaning
“material of the honeycomb.” Carnauba wax is a particularly hard wax because of its relatively
high molecular weight; it has a 32-carbon carboxylic acid component and a 34-carbon alcohol
component. Carnauba wax is widely used as a car wax and in floor polishes.
O
CH3(CH2)24

C

O
O(CH2)29CH3

a major component of
beeswax
structural material
of beehives

CH3(CH2)30

C

O
O(CH2)33CH3

a major component of
carnauba wax
coating on the leaves
of a Brazilian palm

CH3(CH2)14

C

layers of honeycomb in a beehive

O(CH2)15CH3

a major component of
spermaceti wax
from the heads of
sperm whales

Waxes are common in the biological world. The feathers of birds are coated with wax to make
them water repellent. Some vertebrates secrete wax in order to keep their fur lubricated and water
repellent. Insects secrete a waterproof, waxy layer on the outside of their exoskeletons. Wax is also
found on the surfaces of certain leaves and fruits, where it serves as a protectant against parasites

and minimizes the evaporation of water.

raindrops on a feather


Acid-Catalyzed Ester Hydrolysis and Transesterification

PROBLEM 19

We have seen that it is necessary to use excess amine in the reaction of an acyl chloride with an
amine. Explain why it is not necessary to use excess alcohol in the reaction of an acyl chloride
with an alcohol.

PROBLEM 20

Write a mechanism for each of the following reactions:
a. the noncatalyzed hydrolysis of methyl propionate.
b. the aminolysis of phenyl formate, using methylamine.

PROBLEM 21♦

a. State three factors cause the uncatalyzed hydrolysis of an ester to be a slow reaction.
b. Which is faster, the hydrolysis of an ester or the aminolysis of the same ester? Explain your
answer.

P R O B L E M 2 2 Solved

List the following esters in order from most reactive to least reactive toward hydrolysis:
O
C

CH3

O
O

C
CH3

O
O

C

NO2

CH3

O

OCH3

Solution We know that the reactivity of a carboxylic acid derivative depends on the basicity

of the group attached to the acyl group—the weaker the base, the easier it is for both steps
of the reaction to take place (Section 16.6). So now we need to compare the basicities of the
three phenolate ions.
The nitro-substituted phenolate ion is the weakest base because the nitro group withdraws
electrons inductively and by resonance (see page 363), which decreases the concentration of
negative charge on the oxygen. The methoxy-substituted phenolate ion is the strongest base
because the methoxy group donates electrons by resonance more than it withdraws electrons

inductively (see page 364), so the concentration of negative charge on the oxygen is increased.
Therefore, the three esters have the following relative reactivity toward hydrolysis.
O

O
C
CH3

O

NO2

>

C
CH3

O
O

>

C
CH3

O

OCH3

16.10 ACID-CATALYZED ESTER HYDROLYSIS AND

TRANSESTERIFICATION
We have seen that esters hydrolyze slowly because water is a poor nucleophile and esters
have relatively basic leaving groups. The rate of hydrolysis can be increased by either
acid or hydroxide ion. When you examine the mechanisms for these reactions, notice the
following features that hold for all organic reactions:
All organic intermediates and products in acidic solutions are positively charged or
neutral; negatively charged organic intermediates and products are not formed in
acidic solutions.
All organic intermediates and products in basic solutions are negatively charged or
neutral; positively charged organic intermediates and products are not formed in
basic solutions.

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CHAPTER 16

Reactions of Carboxylic Acids and Carboxylic Acid Derivatives

Hydrolysis of An Ester with a Primary or Secondary Alkyl Group
When an acid is added to a reaction, the first thing that happens is the acid protonates
the atom in the reactant that has the greatest electron density. Therefore, when an acid is
added to an ester, the acid protonates the carbonyl oxygen.
+

H

O

O
C
OCH3

R

+ HCl

+ Cl−

C
R

OCH3

The resonance contributors of the ester show why the carbonyl oxygen is the atom
with the greatest electron density.

O

O

C

this atom has the
greatest electron
density

−

C

R

OCH3

R

OCH3
+

resonance contributors of an ester

The mechanism for the acid-catalyzed hydrolysis of an ester is shown next. (HB+
represents any species in the solution that is capable of donating a proton and :B represents any species that is capable of removing a proton.)
MECHANISM FOR ACID-CATALYZED ESTER HYDROLYSIS

the acid
protonates
the carbonyl
oxygen

+

O
H

C
R

OCH3

O

B+

C
R

H
OH
OCH3 + H2O

the nucleophile
adds to the
carbonyl carbon

Pay attention to the three tetrahedral
intermediates that occur in this
mechanism:

C

R
+

OCH3

OH

B

H
tetrahedral intermediate I
equilibration of the 3
tetrahedral intermediates;
either OH or OCH3 can
be protonated

OH

protonated tetrahedral intermediate I →
neutral tetrahedral intermediate II →
protonated tetrahedral intermediate III.

R C

This pattern will be repeated in many
more acid-catalyzed reactions.

removal of a
proton from the
carbonyl oxygen

O

+

HB+

O
C

C
R

H

OH

R

OH

B
+ CH3OH

OCH3

OH

H

B+

tetrahedral intermediate II

OH
R C

+

OCH3
H

OH

elimination of
the weaker base

tetrahedral intermediate III
■
■

■

The acid protonates the carbonyl oxygen.
The nucleophile (H2O) adds to the carbonyl carbon of the protonated carbonyl group,
forming a protonated tetrahedral intermediate.
The protonated tetrahedral intermediate (I) is in equilibrium with its nonprotonated
form (II).


Acid-Catalyzed Ester Hydrolysis and Transesterification
■

■

■

The nonprotonated tetrahedral intermediate can be re-protonated on OH, which
re-forms tetrahedral intermediate I, or protonated on OCH3, which forms tetrahedral intermediate III. (From Section 2.10, we know that the relative amounts of the
three tetrahedral intermediates depend on the pH of the solution and the pKa values of
the protonated intermediates.)
When tetrahedral intermediate I collapses, it eliminates H2O in preference to CH3O–
(because H2O is a weaker base), and re-forms the ester. When tetrahedral intermediate
III collapses, it eliminates CH3OH rather than HO– (because CH3OH is a weaker base)
and forms the carboxylic acid. Because H2O and CH3OH have approximately the
same basicity, it will be as likely for tetrahedral intermediate I to collapse to re-form
the ester as it will for tetrahedral intermediate III to collapse to form the carboxylic
acid. (Tetrahedral intermediate II is much less likely to collapse because both HO– and
CH3O– are strong bases and, therefore, poor leaving groups.)
Removal of a proton from the protonated carboxylic acid forms the carboxylic acid
and re-forms the acid catalyst.

Because tetrahedral intermediates I and III are equally likely to collapse, both ester and
carboxylic acid will be present when the reaction has reached equilibrium. Excess water
can be used to force the equilibrium to the right (Le Châtelier’s principle; Section 5.7). Or,
if the boiling point of the product alcohol is significantly lower than the boiling points of
the other components of the reaction, the reaction can be driven to the right by distilling
off the alcohol as it is formed.
O
R

C

O
OCH3

+

H2O

HCl

R

excess

C

OH

+ CH3OH

In Section 16.14, we will see that the mechanism for the acid-catalyzed reaction of a
carboxylic acid and an alcohol to form an ester and water is the exact reverse of the mechanism for the acid-catalyzed hydrolysis of an ester to form a carboxylic acid and an alcohol.
PROBLEM 23♦

What products would be formed from the acid-catalyzed hydrolysis of the following esters?
O
O
O
a.

C

b.
OCH2CH3

c.

C
OCH3

O

PROBLEM 24

Using the mechanism for the acid-catalyzed hydrolysis of an ester as your guide, write the
mechanism—showing all the curved arrows—for the acid-catalyzed reaction of acetic acid and
methanol to form methyl acetate. Use HB+ and :B to represent the proton-donating and protonremoving species, respectively.

Now let’s see how the acid catalyst increases the rate of ester hydrolysis. For a catalyst
to increase the rate of a reaction, it must increase the rate of the slow step of the reaction
because changing the rate of a fast step will not affect the rate of the overall reaction.
Four of the six steps in the mechanism for acid-catalyzed ester hydrolysis are proton transfer steps. Proton transfer to or from an electronegative atom such as oxygen or nitrogen
is always a fast step. The other two steps in the mechanism—namely, formation of the
tetrahedral intermediate and collapse of the tetrahedral intermediate—are relatively slow.
The acid increases the rates of both these steps.
The acid increases the rate of formation of the tetrahedral intermediate by protonating
the carbonyl oxygen. Protonated carbonyl groups are more susceptible than nonprotonated

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