12

General, Organic, and

Biochemistry, 8e
Bettelheim, Brown,
Campbell, & Farrell

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12-1
12

Reactions of
Organic
Compounds

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12-2
12 Kinds of Organic Reactions
• In general, we look at what occurs and
try to learn how it happens
• Common patterns describe the changes
• Addition reactions – two molecules combine

• Elimination reactions – one molecule splits into two

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12-3
12 Kinds of Organic Reactions
• Substitution – parts from two molecules exchange

• Rearrangement reactions – a molecule undergoes

changes in the way its atoms are connected

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12 Practice:

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12

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12 Reactions of Alkanes
• Reaction with halogens (halogenation)
• Halogenation of an alkane is a substitution reaction.
CH4 + Cl 2 heat CH3 Cl + HCl
or light
Methane Chloromethane
(Methyl chloride)
heat
CH3 Cl + Cl2 CH2 Cl2 + HCl
Dichloromethane
(Methylene chloride)

Cl2 Cl2
CH2 Cl2 CHCl3 CCl4
heat heat
Trichloromethane Tetrachloromethane
(Chloroform) (Carbon tetrachloride)
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12-7
12

Reactions of
Alkenes

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12-8
12 Reactions of Alkenes
• The most common reaction is addition
Reaction Descriptive Name(s )
H Cl
C C + HCl C C hydrochlorination

H OH
C C + H2 O C C hydration

Br Br
C C + Br2 C C bromination

H H
C C + H2 C C hydrogenation
(reduction)
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12-9
12 Reactions of Alkenes
• Most alkene addition reactions are exothermic.
• The products are more stable (lower in energy) than
the reactants.
H H H H
are replaced by
C C + H H H C C H + heat
H H H H
one double bond three single bonds
and one single bond
• Just because they are exothermic doesn’t mean that
alkene addition reactions occur rapidly.
• reaction rate depends on the activation energy
• Many alkene addition reactions require a catalyst.

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12-10
12 Addition of Cl2 and Br2
• Addition takes place readily at room temp.
• reaction is generally carried out using pure reagents,
or mixing them in a nonreactive organic solvent
Br Br
CH3 CH=CHCH3 + Br2 CH3 CH-CHCH3
CH2 Cl2
2-Butene 2,3-Dibromobutane
Br
+ Br2
CH2 Cl2
Br
Cyclohexene 1,2-Dibromocyclohexane

• addition of Br2 is a useful qualitative test for the

presence of a carbon-carbon double bond
• Br2 has a deep red color; dibromoalkanes are
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colorless.
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12-11
12 Addition of H2 - Reduction
• Virtually all alkenes add H2 in the presence of a
transition metal catalyst, commonly Pd, Pt, or Ni.
H3 C H
Pd
C C + H2 CH3 CH2 CH2 CH3
25°C, 3 atm
H CH3 Butane
trans-2-Butene

Pd
+ H2
25°C, 3 atm
Cyclohexene Cyclohexane

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12-12
12 Addition of H2 - Reduction
• Figure 12.2 The addition of hydrogen to an
alkene involving a transition metal catalyst.

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12-13
12 Addition of HX
• Addition of HX (HCl, HBr, or HI) to an alkene
gives a haloalkane.
• H adds to one carbon of the C=C and X to the other.
H Cl
CH2 =CH2 + HCl CH2 -CH2
Ethylene Chloroethane
(Ethyl chloride)
• reaction is regioselective.
• Markovnikov’s rule: H adds to the less substituted
carbon and X to the more substituted carbon.
Cl H H Cl
CH3 CH=CH2 + HCl CH3 CH-CH2 CH3 CH-CH2
Propene 2-Chloropropane 1-Chloropropane
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12-14
12 Addition of HX
• Chemists account for the addition of HX to an
alkene by a two-step reaction mechanism.
• We use curved arrows to show the repositioning of
electron pairs during a chemical reaction.
• The tail of an arrow shows the origin of the electron
pair (either on an atom or in the double bond).
• The head of the arrow shows its new position.
• Curved arrows show us which bonds break and which
new ones form.

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12-15
12 Addition of HCl to 2 Butene
• Step 1:
• reaction of the carbon-carbon double bond with H+
gives a secondary (2°) carbocation intermediate.
+
H
CH3 CH=CHCH3 + H+ CH3 CH-CHCH3
A 2° carbocation intermediate
• Step 2:
• reaction of the carbocation intermediate with chloride
ion completes the addition.

:
: Cl :
- +
: :

: Cl : + CH3 CHCH2 CH3 CH3 CHCH2 CH3

Chloride 2° Carbocation 2-Chlorobutane
ion intermediate
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12-16
12 Addition of H2O
• Addition of water is called hydration
• hydration is acid catalyzed, most commonly by H2SO4.
• hydration follows Markovnikov’s rule; H adds to the
less substituted carbon and OH adds to the more
substituted carbon.
H2 SO4 OH H
CH3 CH=CH2 + H2 O CH3 CH-CH2
Propene 2-Propanol

CH3 CH3
H2 SO4
CH3 C=CH2 + H2 O CH3 C-CH2
HO H
2-Methylpropene 2-Methyl-2-propanol
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12-17
12 Addition of H2O H
+
• Step 1: CH3 CH=CH2 + H+ CH3 CHCH2
A 2° carbocation
intermediate

H H

:
+ O+
• Step 2: CH3 CHCH3 :O-H

:
+ CH3 CHCH3
H An oxonium ion

H H : OH
:

O+ :
• Step 3: CH3 CHCH3 CH3 CHCH3 + H+
2-Propanol
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12-18
12 Catalytic Hydrogenation of Alkyne

cis alkene

trans alkene

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12-19
12

Reactions of
Alcohols

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12-20
12 Dehydration
• Dehydration: elimination of a molecule of water
from adjacent carbon atoms gives an alkene.
• Dehydration is most often brought about by heating
an alcohol with either 85% H3PO4 or concentrated
H2SO4.
• 1° alcohols are the most difficult to dehydrate and
require temperatures as high as 180°C.
• 2° alcohols undergo acid-catalyzed dehydration at
somewhat lower temperatures.
• 3° alcohols generally undergo acid-catalyzed
dehydration at temperatures only slightly above room
temperature.
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12-21
12 Dehydration
H2 SO4
CH3 CH2 OH CH2 =CH2 + H2 O
180°C
Ethanol Ethylene

OH
H2 SO4
+ H2 O
140°C
Cycloh exanol Cyclohexen e

CH3 CH3
H2 SO4
CH3 CCH3 CH3 C=CH2 + H2 O
50°C
OH
2-Meth yl-2-p ropanol 2-Methylpropene
(t ert -Butyl alcoh ol) (Isobutylene)
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12-22
12 Dehydration
• When isomeric alkenes are obtained, the alkene
having the greater number of alkyl groups on the
double bond generally predominates.
• examples:
OH H3 PO4
CH3 CH2 CHCH3 CH3 CH=CHCH3 + CH3 CH2 CH=CH2
-H2 O
2-Butanol 2-Bu tene 1-Butene
(80%) (20%)

CH3 CH3 CH3

H2 SO4
CH3 CHCHCH3 CH3 C=CHCH3 + CH3 CHCH=CH2
-H2 O
OH
3-Meth yl-2-b utanol 2-Methyl-2-b utene 3-Methyl-1-bu tene
(major prod uct)
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12-23
12 Dehydration-Hydration
• Acid-catalyzed hydration of alkenes to give
alcohols (Chapter 12) and acid-catalyzed
dehydration of alcohols to give alkenes are
competing reactions.
• The following equilibrium exists:

dehydration
C C + H2 O C C
h yd ration H OH
An alk ene An alcohol

• In accordance with Le Chatelier's principle, large

amounts of water favor alcohol formation, whereas
removal of water from the equilibrium mixture favors
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alkene formation.
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12-24
12 Oxidation
• Oxidation of a 1° alcohol gives an aldehyde or a
carboxylic acid, depending on the experimental
condition:
• oxidation of a 1° alcohol to a carboxylic acid is
commonly carried out using potassium dichromate,
K2Cr2O7, in aqueous sulfuric acid.
K2 Cr2 O 7 O K Cr O O
2 2 7
CH3 ( CH2 ) 6 CH2 OH CH3 ( CH2 ) 6 CH CH3 ( CH2 ) 6 COH
H2 SO 4 H2 SO 4
1-Octanol Octanal Octanoic acid

• it is often possible to stop the oxidation at the

aldehyde stage by distilling the mixture; the aldehyde
usually has a lower boiling point than either the 1°
alcohol
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12-25
12 Oxidation
• Oxidation of a 2° alcohol gives a ketone.

K2 Cr 2 O7
OH H2 SO 4 O

2-Isopropyl-5-methyl- 2-Isopropyl-5-methyl-
cyclohexanol cyclohexanone
(Menthol) (Menthone)

• Tertiary alcohols are resistant to oxidation.

CH3 K2 Cr2 O7
(no oxidation )
OH H2 SO4
1-Meth yl-
cyclopen tanol
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12

Reactions of
Aldehydes and
Ketones

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12-27
12 Oxidation
• Aldehydes are oxidized to carboxylic acids by a
variety of oxidizing agents, including potassium
dichromate.
O O
K2 Cr2 O 7
H OH
H2 SO 4
Hexanal Hexanoic acid

• Liquid aldehydes are so sensitive to oxidation by O2 of

the air that they must be protected from contact with
air during storage.
O O
C C
H OH
2 + O2 2

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Benzaldehyde Benzoic acid
12-28
12 Oxidation
• Ketones resist oxidation by most oxidizing
agents, including potassium dichromate and
molecular oxygen.
• Tollens’ reagent is specific for the oxidation of
aldehydes; if done properly, silver deposits on the
walls of the container as a silver mirror.
O
R-C-H + 2 Ag( NH3 ) 2 + + 3 OH-
Aldehyde Tollens'
reagent
O
R-C-O- + 2 Ag + 4 NH3 + 2 H2 O
Carboxylic Silver
anion mirror
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12-29
12 Reduction
• The carbonyl group of an aldehyde or ketone is
reduced to an -CHOH or -CH2OH group by
hydrogen in the presence of a transition-metal
catalyst:
• Reduction of an aldehyde gives a primary alcohol.
• Reduction a ketone gives a secondary alcohol.
O transition
metal catalyst
H + H2 OH
Pentanal 1-Pentanol
transition
metal catalyst
O + H2 OH
Cyclopentanone Cyclopentanol
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12-30
12 Reduction
• The most common laboratory reagent for the
reduction of an aldehyde or ketone is sodium
borohydride, NaBH4.
• This reagent contains hydrogen in the form of hydride
ion, H:-.
• In a hydride ion, hydrogen has two valence electrons
and bears a negative charge.
• In a reduction by sodium borohydride, hydride ion
adds to the partially positive carbonyl carbon which
leaves a negative charge on the carbonyl oxygen.
• Reaction of this intermediate with aqueous acid gives
the alcohol.
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12-31
12 Reduction
H3 O +
H: -
+ C O H C O - H C O-H

Hydride
ion

NaBH4 O- H3 O+ O-H
O
H H

• Reduction by NaBH4 does not affect a carbon-carbon

double bond or an aromatic ring.
O
C 1 . NaBH4 CH2 OH
H
2 . H2 O
Cinnamaldehyde Cinnamyl alcohol
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12-32
12 Reduction
• In biological systems, the agent for the reduction
of aldehydes and ketones is the reduced form of
nicotinamide adenine dinucleotide, abbreviated
NADH (Section 26.3)
• This reducing agent, like NaBH4, delivers a hydride ion
to the carbonyl carbon of the aldehyde or ketone.
• Reduction of pyruvate, the end product of glycolysis,
by NADH gives lactate.
O O- H3 O+ O-H
CH3 -C-COO- NADH CH3 -C-COO- CH3 -C-COO-
H H
Pyruvate Lactate

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12-33
12 Addition of Alcohols
• Addition of a molecule of alcohol to the carbonyl
group of an aldehyde or ketone forms a
hemiacetal (a half-acetal).
• The functional group of a hemiacetal is a carbon
bonded to one -OH group and one -OR group.
• In forming a hemiacetal, H of the alcohol adds to the
carbonyl oxygen and OR adds to the carbonyl carbon.
O H O-H
C + O-CH2 CH3 C OCH2 CH3
H H
Benzaldehyde Ethanol A hemiacetal

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12-34
12 Addition of Alcohols
• Hemiacetals are generally unstable and are only minor
components of an equilibrium mixture except in one
very important type of molecule:
• When a hydroxyl group is part of the same molecule
that contains the carbonyl group and a five- or six-
membered ring can form, the compound exists almost
entirely in a cyclic hemiacetal form.
redraw to
O show the -OH 3 2
5
4
3
2
1 and -CHO close 1 H H
H to each other 4
C
5 O O-H
O-H O O
4-Hydroxypentanal H A cyclic hemiacetal

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12-35
12 Addition of Alcohols
• A hemiacetal can react further with an alcohol to
form an acetal plus water.
• This reaction is acid catalyzed.
• The functional group of an acetal is a carbon bonded
to two -OR groups.
O-H H OCH2 CH3
H+
C OCH2 CH3 + OCH2 CH3 C OCH2 CH3 + H- OH
H H
A hemiacetal Ethanol An acetal
(from benzaldehyde)

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12-36
12 Addition of Alcohols
O-H H
H+ OCH2 CH3
+ OCH2 CH3 + H2 O
OCH2 CH3 OCH2 CH3
A hemiacetal Ethanol An acetal
(from cyclohexanone)

• All steps in hemiacetal and acetal formation are

reversible.
• As with any other equilibrium, we can drive this one in
either direction by using Le Chatelier's principle.
• To drive it to the right, we either use a large excess of
alcohol or remove water from the equilibrium mixture
• To drive it to the left, we use a large excess of water.
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12

Reactions of
Amines

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12-38
12 Reactions of Amines
• The most important chemical property of amines
is their basicity.
• Amines, whether soluble or insoluble in water, react
quantitatively with strong acids to form water-soluble
salts.
HO H HO H
+ -
HO NH2 HO NH3 Cl
H2 O
+ HCl
HO HO
(R)-Norepinephrine (R)-Norepinephrine hydrochloride
(only slightly soluble in water) (a water-soluble salt)

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12-39
12 Reactions of Amines
• example: Complete each acid-base reaction and name
the salt formed.
(a) ( CH3 CH2 ) 2 NH + HCl

(b) + CH3 COOH

N

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12-40
12 Reactions of Amines
• example: Complete each acid-base reaction and name
the salt formed.
• solution:
(a) (CH3 CH2 ) 2 NH + HCl (CH3 CH2 ) 2 NH2 + Cl-
Diethylammonium
chloride

(b) + CH3 COOH CH3 COO-

N N+
H Pyridinium acetate

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12-41
12

Reactions of
Carboxylic Acid
and Its
Derivatives

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12-42
12 Reaction With Bases
• All carboxylic acids, whether soluble or
insoluble in water, react with NaOH, KOH, and
other strong bases to form water-soluble salts.
H2 O - +
COOH + NaOH COO Na + H2 O

Benzoic acid Sodium benzoate

(slightly soluble in water) (60 g/100 mL water)

• They also form water-soluble salts with ammonia and

amines.
H2 O - +
COOH + NH3 COO NH4
Benzoic acid Ammonium benzoate
(slightly soluble in water) (20 g/100 mL water)
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12-43
12 Reaction With Bases
• Like inorganic acids, carboxylic acids react with
sodium bicarbonate and sodium carbonate to form
water-soluble sodium salts and carbonic acid.
• Carbonic acid then decomposes to give water and
carbon dioxide, which evolves as a gas.
H2 O - +
CH3 COOH + NaHCO3 CH3 COO Na + CO2 + H2 O
Acetic acid Sodium acetate

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12-44
12 Fischer Esterification
• Fischer esterification is one of the most
commonly used preparations of esters.
• In Fischer esterification, a carboxylic acid is reacted
with an alcohol in the presence of an acid catalyst,
most commonly concentrated sulfuric acid.
O H2 SO4 O
CH3 C-OH + H-OCH2 CH3 CH3 COCH2 CH3 + H2 O
Ethanoic acid Ethanol Ethyl ethanoate
(Acetic acid) (Ethyl alcohol) (Ethyl acetate)

• Fischer esterification is reversible.

• It is possible to drive it in either direction by the
choice of experimental conditions (Le Chatelier’s
principle).
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12-45
12 Fischer Esterification
• In Fischer esterification, the alcohol adds to the
carbonyl group of the carboxylic acid to form a
tetrahedral carbonyl addition intermediate.
• The intermediate then loses H2O to give an ester.

O H H2 SO4 O-H
CH3 C + OCH2 CH3 CH3 C OCH2 CH3
OH OH
A tetrahedral carbonyl
addition intermediate

H2 SO4 O
CH3 COCH2 CH3 + H2 O

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12-46
12 Phosphoric Esters
• Phosphoric acid forms mono-, di-, and triphosphoric
esters.
• In more complex phosphoric esters, it is common to
name the organic molecule and then indicate the
presence of the phosphoric ester by either the word
"phosphate" or the prefix phospho-.
• Dihydroxyacetone phosphate and pyridoxal
phosphate are shown as they are ionized at pH 7.4,
the pH of blood plasma.
CH2 OH CHO O
O CO O HO CH2 O-P-O-
CH3 O-P-OH CH2 -O-P-O- O-
OCH3 O- H3 C N
Dimethyl phosphate Dihydroxyacetone Pyridoxal phosphate
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phosphate
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12-47
12 Decarboxylation
• Decarboxylation: the loss of CO2 from a carboxyl
group.
O
decarboxylation
RCOH RH + CO 2
• Almost all carboxylic acids, when heated to a
very high temperature, will undergo thermal
decarboxylation.
• Most carboxylic acids, however, are resistant to
moderate heat and melt and even boil without
undergoing decarboxylation.
• An exception is any carboxylic acid that has a
carbonyl group on the carbon b to the COOH
group.
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12-48
12 Decarboxylation
• Decarboxylation of a b-ketoacid.
O O O
warm
b  OH + CO 2
3-Oxobutanoic acid Acetone
(Acetoacetic acid)
• The mechanism of thermal decarboxylation
involves (1) redistribution of electrons in a cyclic
transition state, (2) followed by keto-enol
tautomerism. enol of
a ketone
H H
O O O O O
(1) (2) +
C CO 2
O
O
(A cyclic six-membered
transition state)
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12-49
12 Decarboxylation
• An important example of decarboxylation of a b-
ketoacid in biochemistry occurs during the
oxidation of foodstuffs in the tricarboxylic acid
(TCA) cycle. Oxalosuccinic acid, one of the
intermediates in this cycle, has a carbonyl group
(in this case a ketone) b to one of its three
carboxyl groups.

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12-50
12 Preparation of Amides
• In principle, we can form an amide by treating a
carboxylic acid with an amine and removing -OH
from the acid and an -H from the amine.
• In practice what occurs if the two are mixed is an acid-
base reaction to form an ammonium salt.
• If this salt is heated to a high enough temperature,
water is eliminated and an amide forms.
O O +
-
CH3 C-OH + H2 NCH2 CH3 CH3 C-O H3 NCH2 CH3
Acetic Ethanamine An ammonium
acid (Ethylamine) salt
O
heat
CH3 C-NHCH2 CH3 + H2 O
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12-51
12 Preparation of Amides
• It is much more common, however, to prepare amides
by treating an anhydride with an amine.
O O O O
CH3 C-O-CCH3 + H2 NCH2 CH3 CH3 C-NHCH2 CH3 + CH3 COH
Acetic anhdyride An amide

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12-52
12 Hydrolysis of Anhydrides
• Hydrolysis is a chemical decomposition involving
breaking a bond and the addition of the elements of
water.
• Carboxylic anhydrides, particularly the low-molecular-
weight ones, react readily with water (hydrolyze) to
give two carboxylic acids.
O O O O
CH3 COCCH3 + H2 O CH3 COH + HOCCH3
Acetic anhydride Acetic acid Acetic acid

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12-53
12 Hydrolysis of Esters
• Esters hydrolyze only very slowly, even in boiling
water.
• Hydrolysis becomes considerably more rapid,
however, when the ester is heated in aqueous acid or
base.
• Hydrolysis of esters in aqueous acid is the reverse of
Fischer esterification.
• A large excess of water drives the equilibrium to the
right to form the carboxylic acid and alcohol (Le
Chatelier's principle).
O + O
H
CH3 COCH2 CH3 + H2 O CH3 COH + CH3 CH2 OH
Ethyl acetate Acetic acid Ethanol
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12-54
12 Hydrolysis of Esters
• We can also hydrolyze an ester using a hot aqueous
base, such as aqueous NaOH.
• This reaction is often called saponification, a
reference to its use in the manufacture of soaps.
• The carboxylic acid formed in the hydrolysis reacts
with hydroxide ion to form a carboxylic acid anion.
• Each mole of ester hydrolyzed requires one mole of
base.
O O
H2 O
CH3 COCH2 CH3+ N aOH CH3 CO - N a++ CH3 CH2 OH
heat
Ethyl acetate Sodium Sodium Ethanol
hydroxide acetate

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12-55
12 Hydrolysis of Amides
• Amides require more vigorous conditions for
hydrolysis in both acid and base than do esters.
• Hydrolysis in hot aqueous acid gives a carboxylic acid
and an ammonium ion.
• Hydrolysis is driven to completion by the acid-base
reaction between ammonia or the amine and the acid
to form an ammonium ion.
• Each mole of amide hydrolyzed requires one mole of
acid.
O O
H2 O + -
CH3 CH2 CH2 CNH2 + H2 O + HCl CH3 CH2 CH2 COH + NH4 Cl
heat
Butanamide Butanoic acid

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12-56
12 Hydrolysis of Amides
• Hydrolysis of an amide in aqueous base gives a
carboxylic acid salt and ammonia or an amine.
• Hydrolysis is driven to completion by the acid-base
reaction between the carboxylic acid and base to form
a salt.
• Each mole of amide hydrolyzed requires one mole of
base.
O O
H2 O
CH3 CNH + NaOH CH3 CO-Na+ + H2 N
heat
Acetanilide Sodium Aniline
acetate

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12-57
12 Reaction with Alcohols
• Anhydrides react with alcohols and phenols to
give an ester and a carboxylic acid.
O O O O
CH3 COCCH3 + HOCH2 CH3 CH3 COCH 2 CH 3 + HOCCH3
Acetic anhydride Ethanol Ethyl acetate Acetic acid

• Aspirin is prepared by the reaction of salicylic

acid with acetic anhydride.
COOH COOH
O O O
OH + CH3 C- O-CCH3 + CH3 C- OH
OCCH 3
Salicylic acid Acetic anhydride O Acetic acid
Acetylsalicylic acid
(Aspirin)

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12-58
12 Reaction with Amines
• Anhydrides react with ammonia and with 1° and
2° amines to form amides.
• Two moles of amine are required; one to form
the amide and one to neutralize the carboxylic
acid by-product.
O O O O
CH3 C- O-CCH3 + N H3 CH3 CN H2 + CH3 C- OH

O O
CH3 C- OH + N H3 CH3 CO - N H4 +

O O O O
CH3 C- O-CCH3 + 2 N H3 CH3 CN H2 + CH3 CO - N H4 +
Acetic Acetamide Ammonium
anhydride acetate
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12-59
12 Reaction with Amines
• Esters react with ammonia and with 1° and 2°
amines to form amides.
O O
OCH2 CH3 + N H3 N H2 + CH3 CH2 OH
Ethyl 2-phenyl acetate 2-Phenylacetamide

• Thus, an amide can be prepared from a

carboxylic acid by first converting the carboxylic
acid to an ester by Fischer esterification and
then reaction of the ester with an amine.

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12-60
12 Reaction with Amines
• Amides do not react with ammonia or with
amines.

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12 Chapter 12

End
Chapter 12
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12-62