EXP.

48
SULFA DRUGS: PREPARATION OF SULFANILAMIDE
LEARNING OBJECTIVES: To illustrate some key concepts of organic synthesis and mechanisms. These concepts
are the following.
1. MULTISTEP SYNTHESIS
2. PROTECTING GROUPS
3. THE SULFONIC ACID FUNCTIONAL GROUP AND ITS DERIVATIVES
4. ELECTROPHILIC AROMATIC SUBSTITUTION

QUIZ PREPARATION: Recitation notes and readings assigned in the syllabus.

Have your textbook ready for quick reference to pages 388-396

MULTISTEP SYNTHESIS
Multistep synthesis refers to a sequence of reactions designed to produce a specific molecule as the final outcome.
The sequence of reactions shown on p. 392 of your textbook is an example. The starting material is acetanilide.
The sequence consists of three steps or reactions. Each reaction produces a product that is used in the next one,
until the target molecule is obtained as the final product. The target molecule in this experiment is a sulfa drug called
sulfanilamide.

PROTECTING GROUPS
An abbreviated representation of this synthesis is shown below. Both the starting material and the product contain
a benzene ring as the basic carbon skeleton. There are nitrogen-containing groups attached to both molecules. In
the starting material this group is an amide. In the product it is an amine.

O
H

amide

CH3

NH 2

amine

SO 2NH2
Notice that the amide group is carried all the way through the synthesis. It is not modified into amine until the very
end, when the final step is reached. The question then is, why not start the synthesis with an amine group in the
first place? The amide group can be thought of as a protected amine. Amines are very reactive, whereas amides
are not. The amide group is preferred because there is less probability of side reactions through the synthesis with
a less reactive group than with a more reactive one. The CH3CO portion of the amide (called acetyl group) can
be thought of as a protective group for the amine that keeps it from undergoing side reactions. Protecting groups
are widely used in organic synthesis for better control during the intermediate steps. They are typically removed at
the end of the synthesis when they are no longer needed.

THE SULFONIC ACID GROUP AND ITS DERIVATIVES

Sulfonic acids are organic analogs of sulfuric acid, an inorganic compound that is a very strong acid. Like sulfuric
acid, sulfonic acids are highly corrosive, they react vigorously with water, and can cause skin burns.

O
H

Cl

Chlorosulfonic acid,
also a strong acid.

Sulfuric acid, H 2SO4.

Strong acid, highly corrosive

The amide
functional group.

O
O

O
Cl

NH 2

Benzenesulfonyl chloride. An
organic analog of chlorosulfonic acid.

Benzene sulfonic acid, an

organic analog of sulfuric acid.

NH 2

The sulfonamide
functional group

Because they are highly reactive towards water, some of these substances are also lachrymators. They react with
water in the eye to produce hydrochloric acid (HCl), another corrosive and irritant substance.
HANDLE ALL OF THESE SUBSTANCES WITH CARE AND IN THE HOOD.
ALWAYS WEAR GLOVES AND SAFETY GLASSES.

Sulfonyl chlorides contain a good leaving group (Cl). That is what makes them highly reactive towards water and
other nucleophiles such as ammonia (NH3). These reactions are used in this synthesis, but they can also cause
problems. For example, the second step of the synthesis transforms p-acetamidobenzenesulfonyl chloride into
p-acetamidobenzenesulfonamide by reaction with ammonia.

CH 3

CH3
O

O
N
H

S
O

NH 3

Cl

N
H

NH 2

LIkewise, on p. 395 at the top, the textbook recommends that the organic sulfonyl chloride be handled expeditiously
after pouring it into ice to avoid the slow decomposition that results from contact with water.

This makes it apparent why aniline cannot be used as the starting material in the synthesis. The amino group of
aniline is a strong electrophile. This would cause undesirable side reactions in the first and second steps because
the molecule would tend to react as a base or as a nucleophile to form undesirable products.
O

O
HO

Cl

H2 N

Cl

H 3N

O
aniline

Aniline is a strong base. It can react with chlorosulfonic acid in a proton exchange in the first step.

O
H2N

Cl

H 2N

O
Cl

H2N

NH

SO2Cl

Even if this product could be prepared in the first step, it would react with itself in the second one as a nucleophile.

ELECTROPHILIC AROMATIC SUBSTITUTION

The first reaction in this sequence is an electrophilic aromatic substitution (EAS). This reaction is used to place the
second group (SO2Cl) on the benzene ring. This is not intended to be a full discussion of EAS mechanisms. For a
comprehensive treatment please consult your organic chemistry textbook.
The most important steps in the mechanism are presented below.
1. GENERATION OF THE ELECTROPHILE
O
Cl

O
OH

Cl

Cl

OH2

O
Cl

OH2

H2O

strong
electrophile

2. POSSIBLE SITES FOR ELECTROPHILIC ATTACK ON THE BENZENE RING

NHCOCH3

ring substituent

ortho (o) position

meta (m) position

para (p) position

S
O

H2O is good
leaving group

O
S

S
O

strong acid
(sulfuric acid analog)

Cl

Cl

3. FORMATION OF THE ACTIVATED -COMPLEX, A RESONANCE-STABILIZED REACTION

INTERMEDIATE (structures I-IV).

NHCOCH3

NHCOCH3

NHCOCH3

NHCOCH3

p-attack

Cl

Cl

Cl

II

III

Cl

electron donor

NHCOCH3

NHCHOCH3

resonance structure II
has extra stability
O

Cl

Cl

II

IV

4. REGENERATION OF THE AROMATIC BENZENE RING.

NHCOCH3

ClO2S

adjacent positive charge

makes this proton acidic

NHCOCH3

NHCOCH3

base

O
O

Cl

S
O

O
ClO2S

HO

SO2Cl

Cl

5. REACTION OF SULFONYL CHLORIDE GROUP WITH A NUCLEOPHILE (AMMONIA).

Aryl (aromatic) group (Ar)

H3COCHN

O
Ar

Cl

NH3

Ar

NH3
Ar
Cl

Ar

SO2Cl

SO2Cl

-H

Ar

NH3

leaving group

6. HYDROLYSIS OF THE AMIDE GROUP.

CH3
H

amide group
N

SO2NH2

CH3
H

CH3
H

Ar

OH

Ar

H2O
H

OH + H2O

OH

Ar

CH2
H

CH2

Ar

HO

CH3
OH

Ar

CH3
H2N

OH

Ar

HO
CH3
H2N

OH
ArNH2

OH

+
H3C

OH

ArNH3 +

Ar
NaHCO3
ArNH3

ArNH2 + H2O + CO2 + Na

H3C

OH

NH2

7. PROTECTING GROUP STRATEGY - Acetanilide is used as the starting material in these reactions, but at the
end the amide group gets hydrolyzed into an amine group. Why not start the reaction sequence with aniline (below)
rather than acetanilide, and save the last step? The answer is that the amino group in aniline is too reactive and it
can react at several stages in the course of the reaction sequence.

amino group

NH2
aniline

For example, the amine can react in step 5 (reaction of the sulfonyl chloride group with ammonia), just like ammonia
does, since they are both nucleophiles of similar structure. At the beginning of the reaction, the free amino group
would get protonated by the strong acid (chlorosulfonic acid) to become a meta-directing group, rather than a paradirecting group.

H
NH2

NH3

meta-directing

By using the amide, instead of the free amine, the nucleophilic properties of the nitrogen get reduced by resonance
stabilization of the lone pair of electrons. In addition, the bulk of the amide group in acetanilide favors para-substitution
over ortho-substitution due to steric hindrance.

O
Ar

NH2

Ar

the free amine is a

strong nucleophile

O
NH2

Ar

NH2

resonance delocalization of the lone electron pair

reduces the nucleophilic ability of nitrogen in the amide

O
H

H
N

CH3
o-attack

p-attack

CH3