Chlorosulfonation of Acetanilide to Obtain an Intermediate and

Preparation of a Sulfa Drug

Dr. P. Shashikala, D. shruthi keerthi*

University College of Technology, Osmania University, Hyderabad, India.

Anurag group of Institutions, Venkatapur(V), Ghatkesar(M), Hyderabad, India

Email address: - shashikala_patangay@yahoo.co.in, shruthi.keerthi77@gmail.com

ABSTRACT

Sulphonamides were the first effective chemotherapeutic agents employed

systematically for the prevention and cure of bacterial infections in humans. They are called
as wonder drugs of their times. Though their usage has been limited they are still been used
for burns, bacterial infections in stomach. Here the yields of sulfathiazole has been increased
by using new modified method based on the available literature from which high yields with
reduced time periods has been successfully achieved. Here sulfathiazole is prepared by
Chlorosulfonation of Acetanilide to obtain an intermediate is reacted with corresponding
amine. Three samples of Sulfathiazole with different ratios (3:1, 1:1, and 1:3 intermediate
to amine ratio) and with different acid acceptors like Pyridine, Sodium bi-carbonate, Di-
methyl aniline and Ammonium hydroxide are studied. The analysis was done by using IR
spectroscopy in FT – IR which is found to be best method for identification of samples.

Keywords

Acetanilide, Sulfathiazole, sulfonation, Pyridine, Sodium Bi-Carbonate, Cholorsulfonation,

P-Acetamidobenzenesulfonyl chloride, FT – IR Spectroscopy.

1
INTRODUCTION

For preparation of sulfathiazole many methods are available in present day trend but many of
the processes don’t offer maximum efficiency. The main aim of the work is to develop and a
method which gives maximum yields with reduced time and cost efficient. The intermediate
p-acetamido benzene sulfonyl chloride is prepared from chlorosulfonation of acetanilide at
different temperatures up till 114oC till the best sample is obtained. Then sulfathiazole is
prepared from the obtained intermediate by varying the quantities of intermediate and amine
and varying different acid acceptors like pyridine, etc. One best sample is selected out of the
samples based on their properties.

The sulfathiazole can be prepared to high yields with economical cost. All the identification of
samples was done using IR Spectroscopy with FT-IR

2
 PROCESS MECHANISM

The first step of synthesis is the chlorosulfonation of acetanilide using chlorosulfonic acid.
Chlorosulfonic acid will react violently with water to produce sulfuric acid and hydrogen chloride gas.
When a bottle of chlorosulfonic acid is opened the fumes observed are HCl gas formed by the
hydrolysis that occurs due to the moisture in air.

Chlorosulfonic acid

The Chlorosulfonation is an electrophilic substitution reaction that will occur predominantly in the para
position because of steric hindrance by the acetylamino group. The chlorosulfonation occurs in 2 stages
and requires two moles of Chlorosulfonic acid per mole of acetanilide.

Preparation of p-acetamidobenzenesulfonamide. Amidation (ammonolysis): Here the sulfonyl

chloride group is converted to the sulfonamide group by treating with excess of ammonia. The 'cl'
atom reacts with "NH3" group resulting in the formation of hydrogen chloride. Ammonia is a better
nucleophile than water and ammonolysis prevails over hydrolysis.

Controlled hydrolysis (Formation of sulfanilamide):

The protective acetyl group is removed by a controlled hydrolysis reaction by boiling with dilute
hydrochloric acid. There are 2 amide groups in the molecule the acetamido group and the sulfonamide

3
group. The objective is to bring about hydrolysis of acetamido group without affecting the sulfonamide
group.

Fig1 Reaction mechanism of Sulfanilamide

Neutralizing the reaction with sodium bicarbonate the free sulfanilamide will precipitate from the
solution.

1-Acetanilide, 2- Chlorosulfonic acid, 3- p-acetamidobenzenesulfonic acid,

4- p-acetamidobenzenesulfonyl chloride, 5-p-acetamidobenzenesulfonamide

MATERIALS

Analytical Grade chemicals were used for the experimentation. P-acetamidobenzenesulfonyl

chloride was procured from virchow Labs, Hyderabad. Sulfathiazole was procured from SD-
Fine Chemicals, Mumbai. Acetanilide, chlorosulfonic acid, 2-aminothiazole and all other
chemicals were purchased fromLoba –Chemie Pvt Ltd, Mumbai.

METHODOLOGY

 Chlorosulfonation of acetanilide (preparation of p-acetamidobenzenesulfonyl chloride)

 Preparation of {4-amino-N-(1, 3-thiazol-2-yl) benzene sulfonamide}.
 Re-crystallization of obtained Sulfa drug (Sulfathiazole).

Experimental procedure for preparation of intermediate p-acetamodobenzenesulfonylchloride:

In this method by using sulfonation process chlorosulfonation of acetanilide was performed for
different range of temperatures up to 113oC. All the samples obtained are compared with the pure
form of p-acetamidobenzenesulfonyl chloride by using IR spectroscopy out of which a best sample is
selected for further experimentation.

Preparation of sulfathiazole: the obtained p-acetamodobenzenesulfonyl chloride is reacted

with corresponding amine 2-aminothiazole with pyridine as acid acceptors (they provide
neutralization removal of hydrochloric acid from degreasing operation). The mixture is then
allowed to react in presence of heating and once an oily mixture is obtained it is collected in
a beaker and crushed ice is added and filtered using Buchner funnel. Then the collected
precipitate is dried and re-crystallized using pre-heated ethyl alcohol. After re-crystallization
the pure sample is dried and further proceeded for melting point test. Similarly the same
procedure is applied for different compositions of intermediate and amine in presence of
different acid acceptors like sodium bi-carbonate, Di-methyl hydroxide and ammonium

4
hydroxide. All the obtained samples are checked using melting point test and then the samples
are compared with the original Sulfathiazole (IP) and identified using FT-IR spectrometry.

In the similar way a series of samples were prepared for different compositions of intermediate
to amine changing the acid acceptors.

The following melting point tests were carried out for each single sample obtained.

I. Melting point test for p-acetamodobenzenesulfonyl chloride

Melting point of re-crystallized p-acetamodobenzenesulfonyl chloride is observed in the

range of standard p-acetamodobenzenesulfonyl chloride.

Melting point observed is 146oC which is equal to the theoretical melting point.

II. Melting point test of Sulfathiazole (with 3:1, 1:1, 1:3 ratios of p-
acetamodobenzenesulfonyl chloride to 2-Aminothiazole)

Table 1: Melting points of re-crystallized sulfathiazole observed (with 3:1, 1:1, 1:3 ratio of p-
acetamodobenzenesulfonyl chloride to 2-Aminothiazole)

Acid Melting 3:1 ratio 1:1 ratio 1:3 ratio

acceptors point
observed

Pyridine 201oC 199oC 204 o C

Sodium bicarbonate 195oC 202oC 195oC

Ammonium hydroxide 189oC 209oC 185oC

Di-methyl aniline 208oC 185oC 190oC

From the above observation, it was found that pyridine is proved to be the best acid acceptor when
compared to other acid acceptors because melting point of the product obtained by this method is very
close to the theoretical melting point of sulfathiazole. Therefore the product obtained from these
samples (with pyridine as acid acceptor) is of good quality.

Further the percentage yields of the samples were calculated

Based on the theoretical yield the weight of crude sulfathiazole crude is calculated then the product
is re-crystallized and dried. The dried product is weighed and the percent yield is calculated.

Percent recovery = (weight of re-crystallized product/weight of crude product)*100

Percent yield = (weight of the re-crystallized product/theoretical weight)*100

Calculation:

For I: Yields of p-acetamidobenzenesulfonyl chloride at varied temperatures

5
Table.4 yields of P-acetamidobenzenesulfonyl chloride observed at varied temperatures of
acetanilide

Sl.no Varied temperatures % yields obtained for p-

for acetanilide acetamido
benzenesulfonyl
Chloride(re-crystalised)

1. At 98oC 81.08%

2. At 102oC 82.63%

3. At 106oC 84.27%

4. At 110oC 86.59%

5. At 114oC 90.05%

Here from this observation, when acetanilide is completely melted to its melting point and then
reacted with Chlorosulfonic acid then increase in yield of p-acetamidobenzenesulfonyl chloride
is possible rather than melting it to just semi-solid or mixing acetanilide and chlorosulfonic acid
together and proceeding with reaction.

92
90
88
PERCENT YEILD

86
84
82
80
78
76
98 102 106 110 114
DIFFERENT TEMPERATURES oC FOR
ACETANILIDE

Yields of P-acetamidobenzenesulfonyl chloride observed at varied temperatures of acetanilide

Here from the above observation it shows that at 114oC Acetanilide melts completely. Reaction
between acetanilide and chlorosulfonic acid is completed and at this temperature maximum yields are
obtained when compared to those at low temperatures.

1. P-acetamidobenzenesulfonyl chloride

Percent yield P-acetamidobenzenesulfonyl chloride =90.05%

For II: Yields of sulfathiazole for each sample with different acid acceptors

6
 SAMPLE 1(preparation of sulfathiazole with 3:1, 1:1, 1:3 ratios of intermediate to amine with
different acid acceptors)

Table 5 Yields of sulfathiazole with 3:1, 1:1, 1:3 ratios of p-acetamidobenzenesulfonyl chloride to 2-
aminothiazole with different acid acceptors given in percentages

Acid acceptors Percentage recovered =(impure weight/re-crystallized wt)

3:1 1:1 1:3

Pyridine 97.55% 94.56% 91.93%

Sodium bicarbonate 94.80% 95.71% 89.33%

Ammonium hydroxide 92.38% 93.06% 87.38%

Di-methyl aniline 94.26% 94% 88.03%

OBSERVATIONS

 Here the (3:1 ratio) sample with acid acceptor pyridine gave good recovery (97.55%) and
yield. (91.814%)
 Here the (1:1 ratio) sample with acid acceptor sodium-bicarbonate gave good recovery
(95.71%) and yield. (81.73%)
 Here the (1:3 ratio) sample with acid acceptor pyridine gave good recovery (91.93%) and
yield. (68.9%)

3 good samples are selected from the samples and further identification is carried out by using
FT-IR analysis.

Here the selected samples are

I. P-acetamidobenzenesulfonyl chloride sample.

II. Sulfathiazole sample (3:1 ratio of p-acetamidobenzenesulfonyl chloride to 2-aminothiazole

with pyridine as acid acceptor).

III. Sulfathiazole sample (1:1 ratio of p-acetamidobenzenesulfonyl chloride to 2-aminothiazole

with sodium bicarbonate as acid acceptor).

IV. Sulfathiazole sample (1:3 ratio of p-acetamidobenzenesulfonyl chloride to 2-aminothiazole

with pyridine as acid acceptor).

Results:-

Sample preparation for FT-IR analysis Sample/KBr ratio: the concentration of the sample in KBr
should be in the range of 0.2% to 1%. The pellet is much thicker than a liquid film, hence a lower
concentration in the sample is required (Beer's Law). Transfer some KBr into a mortar. Add about

7
1 to 2 % of your sample, mix and grind to a fine powder. Take two stainless steel disks out of the
desiccators. Place a piece of the precut cardboard on top of one disk and fill the cutout hole with
the finely ground mixture. Put the second stainless steel disk on top and transfer onto the pistil in
the hydraulic press. Remove the film, which should be homogenous and transparent in appearance.
Insert into the IR sample holder and attach with scotch tape. Run the spectrum.

FT-IR FOR P-ACETAMIDOBENZENESULFONYL CHLORIDE

FT-IR Spectra of standard p-acetamidobenzenesulfonyl chloride

X-axis indicates the wave number (cm-1) and Y-axis indicates percent transmission the identified
wave numbers are given below. The spectrum is observed for series of samples of concentrations
10mcg, 20mcg, 30mcg, 40mcg of pure p-acetamidobenzenesulfonyl chloride.

FT-IR spectra of sample (p-acetamidobenzenesulfonyl chloride):

Here the x axis indicates the wave number and the y axis indicates percent transmission. The sample
inserted into the spectrometer is 20mcg. Absorbance can be calculated by
A = log10 (1 /%T).

A = log10 (1 /0.24)

A = log10 (4.116) =0.621

Table9 Calibration curve for p-acetamidobenzenesulfonyl chloride

Conc. of p-Absorbance (A)

acetamidobenzene sulfonyl
chloride (mcg )

8
 0 0

10 0.315

20 0.621

30 0.823

40 0.988

calibration curve for p-

acetamidobenzenesulfonylchloride

1
0.9 calibration
0.8 curve for p-
ABSORBANCE

0.7 acetamidobenz
0.6 R² = 0.9846 enesulfonylchl
0.5 oride
0.4
0.3
0.2 Linear
0.1 (calibration
0 curve for p-
acetamidobenz
0 10 20 30 40
enesulfonylchl
CONCENTRATION(MCG) oride)

Calibration curve for p-acetamidobenzenesulfonyl chloride

Generalized R2

Where L (0) is the likelihood of the model with only the intercept, is the likelihood of the
estimated model and n is the sample size.

The absorbance obtained for sample at 20mcg is 0.601. The absorbance for standard sample of p-
acetamidobenzenesulfonyl chloride at 20mcg is 0.621. Hence from the above graph, it is shown
that at 20 mcg the standard and sample values are same and the fit showed maximum accuracy.

FT-IR FOR SAMPLE 1(sulfathiazole with 3:1 ratio of intermediate to amine)

FT-IR spectra of standard sulfathiazole

9
The spectrum is observed for series of samples of concentrations 10mcg, 20mcg, 30mcg, 40mcg
of pure sulfathiazole.

FT-IR of sulfathiazole sample 1:

Conc. of sulfathiazole(mcg ) Absorbance(A)

0 0
10 0.102
20 0.387
30 0.657
40 0.844

Calibration curve for sulfathiazole

1

0.8 R² = 0.9824
ABSORBANCE

0.6 Calibration
curve for
sulfathiazole
0.4

0.2 Linear
(Calibration
0 curve for
0 10 20 30 40 sulfathiazole
-0.2 )
CONCENTRATON (MCG)

The absorbance obtained for sample at 20mcg is 0.365. The absorbance obtained for pure
sulfathiazole at 20mcg is 0.387. Hence from the above graph, it is shown that at 20 mcg the standard
and sample values are same and the fit showed maximum accuracy.

FT-IR FOR SAMPLE 2(sulfathiazole with 1:1 ratio of intermediate to amine)

10
Table11 Calibration curve for sulfathiazole

Conc. of sulfathiazole(mcg ) Absorbance(A)

0 0
10 0.102
20 0.387
30 0.657
40 0.844
Calibration curve for sulfathiazole

calibration curve for sulfathiazole

1
0.8 R² = 0.9824
calibration
Absorbance

0.6 curve for

sulfathiazole
0.4
0.2 Linear
(calibration
0 curve for
sulfathiazole )
-0.2 0 10 20 30 40
concentration(mcg)

The absorbance obtained for sample at 20mcg is 0.259. The absorbance obtained for original
sulfathiazole at 20mcg from calibration graph is 0.387.

FT-IR FOR SAMPLE 3(sulfathiazole with 1:3 ratio of intermediate to amine)

Table15 Calibration curve for sulfathiazole

11
 Conc. of sulfathiazole(mcg ) Absorbance(A)
0 0
10 0.102
20 0.387
30 0.657
40 0.844
Calibration curve for sulfathiazole

calibration curve for sulfathiazole

0.9
0.8 R² = 0.9824
0.7
0.6 calibration
Absorbance

curve for
0.5 sulfathiazole
0.4
0.3 Linear
0.2 (calibration
curve for
0.1
sulfathiazole )
0
-0.1 0 10 20 30 40
concentration(mcg)

The absorbance obtained for sample at 20mcg is 0.880. The absorbance obtained for original
sulfathiazole at 20mcg from calibration graph is 0.387.

DISCUSSION:

Here the identification was conducted for intermediate p-acetamidobenzenesulfonyl chloride and
all the samples of sulfathiazole [with 3:1 ratio of intermediate to amine (sample 1), with 1:1 ratio
of intermediate to amine (sample 2) and 1:3 ratio of intermediate to amine (sample3)]. The
obtained graphs were compared to standard graphs.

Functional groups were identified for all the samples at similar wave lengths to that of standard
graphs and structures were identified.

Here from plots of p-acetamidobenzenesulfonyl chloride and Sulfathiazole sample 1much

deviations were not observed which resulted in appropriate structures. Though the structures
identified from the two plots (Sulfathiazole sample 2 and sample 3) were appropriate but, the
deviations were also observed to a higher extent.

The calibration plots were plotted for standard p-acetamidobenzenesulfonyl chloride and
sulfathiazole at different concentrations to corresponding absorbance. The absorbance at 20mcg
for the standard p-acetamidobenzenesulfonyl chloride and Sulfathiazole were compared to the
absorbance at 20mcg for corresponding samples.

This resulted in best quality of p-acetamidobenzenesulfonyl chloride (90.05%) and sulfathiazole

sample1 (91.184%) (with 3:1 ratio of intermediate to amine) and poor quality of sulfathiazole
sample2(with 1:1 ratio of intermediate to amine) and sample3(with 1:3 ratio of intermediate to
amine) due to deviations in corresponding plots resulting in bi-products.

12
R2 plotted for all the graphs showed that the method followed for experimentation gave maximum
accuracy and best results.

CONCLUSIONS

 Amongst the reaction ratios studied for sulfathiazole sample with 3:1 ratio of p-
acetamidobenzenesulfonyl chloride to 2-Aminothiazole with pyridine as acid acceptor is
proved to be best reactant ratio.
 The process employed for experimentation proved to be a cheaper, efficient and time saving
process when compared to general processes.
 Pyridine is the best acid acceptor as compared to other acid acceptors like Sodium bi-
carbonate, Di-methyl aniline, Magnesium hydroxide.
 Maximum percent yield obtained is 91.34%.
 A FT-IR spectrum is a reliable technique for establishing the identity of sulfathiazole as
well as the intermediate.

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