GENERAL  ARTICLE
An Elegant Example of Chemoselective Reaction
The Preparation of Sulfonamide Drugs
Gopalpur Nagendrappa
In a chemoselective reaction, one of the functional groups in
the reactant molecule is selectively attacked by a reagent. The
present article describes this principle by demonstrating that
careful alkaline hydrolysis of N1,N4-diacetylsulfanilamide (7)
removes only the N4-acetyl group from it leaving the N1-acetyl
group intact to yield N1-acetylsulfanilamide (8).
Background
It is an eternal dream of synthetic chemists to prepare a target
molecule with the best yield and highest purity without being
encumbered by side products. That is, the chosen synthetic route
should be able to selectively deliver a single compound. This is
also an important principle of Green Chemistry. Selectivity can
be achieved by choosing suitable starting materials, reagents,
solvents, reaction conditions, and most importantly catalysts.
This saves starting materials, reagents, energy, solvents, time and
effort, and results in the reduction of production cost and environmental pollution. Selectivity aspects are hardly dealt with while
teaching our undergraduate chemistry students, though many
reactions that involve selectivity are dealt with in teaching natural
products synthesis, reagents in organic synthesis, synthesis of
drugs, etc. This omission is even more conspicuous in the laboratory curriculum as no experiment is specifically designed to
demonstrate selectivity aspects.
Three types of selectivity, namely chemoselectivity, regio-selectivity, and stereoselectivity including enantioselectivity, are recognized as important. This article describes the first type, which
is given the least attention in our undergraduate teaching. For this
purpose I have chosen the example of the preparation of sulfona-
RESONANCE  October 2008
G Nagendrappa, after
retiring from Bangalore
University, is now teaching
at the Department of
Medicinal Chemistry, Sri
Ramachandra University,
Porur, Chennai. His
research interests are in
the area of silicon
chemistry, mechanistic
organic and synthetic
chemistry.
Keywords
Chemoselectivity, sulfa drugs,
sulfonamides, amide hydrolysis.
929
GENERAL  ARTICLE
The discovery and
development of
sulfonamides as
medicinal
mide drugs, which made a great impact on health care by controlling bacterial diseases prior to the advent of antibiotics, and are
still in use, though in a limited way.
The Sulfonamides
compounds in the
1930s was a
significant milestone
in the history of
treating diseases
and of modern
pharmaceutical
industry.
The discovery and development of sulfonamides as medicinal
compounds in the 1930s was a significant milestone in the history
of treating diseases and of modern pharmaceutical industry.
Because of their wide spectrum antibacterial activity, sulfonamides were used to treat a variety of illnesses caused by both
Gram-positive and Gram-negative bacteria. Though their importance declined after the introduction of antibiotics and other
drugs from 1950s, they continue to be used for treatment of some
specific diseases.
The discovery of medicinal property of sulfonamides can be
categorized as serendipitous, because it came about as an offshoot of dyes industry in Germany.
1
A pharmacophore is defined
as a set of structural features in
a molecule that is recognized at
a receptor site and is responsible for that molecule’s biological activity.
Sulfonamides are derivatives of 4-aminobenzenesulfonamide (1),
also called sulfanilamide, with one of the two amide hydrogens
being substituted by a variety of substituents that enhance or
modify, in desirable ways, the drug action of 1, which is the
pharmacophore of the class of sulfonamide drugs1.
Sulfonamides are relatively easy to prepare, and most of them are
prepared, with very few exceptions, by a general method given in
Scheme 1.
The mechanistically
R in Scheme 1 is usually a heterocyclic group with a few exceptions such as sulfacetamide (8) in which R is an acetyl (-COCH3)
group. Sulfacetamide is prepared in a slightly different way,
(Scheme 2).
interesting part of this
synthetic sequence is
the selective removal
of N4-acetyl group by
alkaline hydrolysis.
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Why is there Selectivity?
The mechanistically interesting part of this synthetic sequence
(Scheme 2) is the selective removal of N4-acetyl group by alkaline
hydrolysis. In principle, both carboxamides and sulfonamides
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GENERAL  ARTICLE
4
3
2
5
6
O
1
S NH 2
O
4
H 2N
1
1
NHCOCH 3
NHCOCH 3
+
aq. NaOH
RNH 2
HSO3Cl
SO2 Cl
3
2
NH 2
NHCOCH 3
SO2NHR
5
SO2NHR
4
S
R=
: sulfathiazole
N
O
N
H 3C
O
: sulfisoxazole
CH 3
N
: sulfamethoxazole
H 3C
N
: sulf adiazine
N
N
: sulfapyridine
Scheme 1
NH 2
NHCOCH 3
NHCOCH 3
(CH3 CO)2O
or
SO2NH 2
SO2NH 2
1
6
NH 2
aq. NaOH
SO2 NHCOCH3
SO2NHCOCH3
7
8
Scheme 2
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931
GENERAL  ARTICLE
Preferential
NHCOCH3
NH 2
reaction of a
reagent with one
+ NaOH
functional group in
the presence of
long
reaction time
SO2NHR
SO3Na
similar functional
Scheme 3
groups is known
as
chemoselectivity.
can undergo hydrolysis under alkaline conditions to ultimately
give 4- aminobenzenesulfonic acid, as its sodium salt (Scheme 3).
However, if hydrolysis is carried out for a shorter period, only the
N4-acetamide group is hydrolysed as shown in the last step of
Scheme 1. Such preferential reaction of a reagent with one
functional group in the presence of similar functional groups is
known as chemoselectivity. In the case of diacetamide 7, the last
step is even more interesting, because between the two acetyl
groups, it is still the N4-acetyl group that is removed whereas the
N1-acetyl group is left untouched.
What is the reason for the distinctly different behaviour of the
same functional (CH3-CO-NH-) group but in two different positions in the molecule? To understand this variation in the reaction
of similar or same functional groups towards a single reagent, we
have to look at the electronic effects around the reaction sites.
The hydrolysis starts with the attack of the nucleophilic OH– at
the carbonyl carbon of carboxamide or sulfur of sulfonamide, the
respective electrophilic centre, and proceeds further as shown in
Scheme 4.
When both functional groups are present in the same molecule as
O
R C NH R1 + OH 9
O
R S NH R1 + OH O
OH 3C C N HR1
OH
10
O
N HR 1
H 3C S
O
HO
O
H3 C C OH + R 1NH-
O
1
R S OH + R NH
O
O
1
H3 C C O - + R NH2
O
H3 C S O - + R 1NH2
O
Scheme 4
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GENERAL  ARTICLE
O
H
R S N R1 + OH-H 2O
O
OR S N R1
O
13
O
R S N R1
O
12
Scheme 5
in 4, we would expect the OH- to attack sulfur of sulfonamide as
it is more electron deficient than carbonyl carbon. However,
sulfone (-SO2-) moiety is a powerful electron withdrawing group,
which makes the sulfonamide hydrogen slightly acidic. As a
result, when NaOH solution is added the first thing that happens
is the loss of proton at N1 position to form amide anion 12
(Scheme 5), or 14 (Scheme 6). The negative charge so formed on
N1 is shared by the adjacent sulfur by resonance, which repels the
attack by OH– ion.
There are two more possible reasons for slower hydrolysis of
sulfonamide, which are noted below. When OH– adds to sulfur in
4 or 6 the tetrasubstituted sulfur has to expand its valency to five
and become pentasubstituted. This increases valence shell elecO
HN C CH3
O
HN C CH3
+
O
HN C CH3
O
HN C CH 3
OHO S N
O
14
O 2S NH C CH 3
O
C CH 3
O
O S N
O15
C CH 3
O
CH 3
O S N C
O
O16
OHO-
NH -
NH 2
CH 3COO-
+
CH 3COOH +
O 2S NH C CH 3
O
Scheme 6
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CH3
O S N C
O
O-
HN C CH 3
OH
CH 3
O S N C
O
O-
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GENERAL  ARTICLE
When OH– adds to
sulfur in 4 or 6 the
tetrasubstituted
sulfur has to expand
its valency to five
and become
pentasubstituted.
This increases
valence shell
electrons as well as
the steric crowding
around sulfur.
In the case of 7, as
compared to other
sulfonamides, the N1hydrogen is even
more acidic as it is
flanked by two
electron withdrawing
groups (-SO2- and
-CO-). In fact, 7 is
more acidic than most
other sulfonamide
medicinal compounds.
934
trons as well as the steric crowding around sulfur, both of which
are unfavourable to OH– attack. For acetyl carbonyl carbon, on
the other hand, the attachment of OH– brings about a change from
trisubstitution (sp2-planar) to tetrasubstitution (sp3-tetrahedral),
but no change in the number of valence electrons. These changes
do not hinder the OH– attack on carbonyl carbon and takes place
far more easily than that on sulfonamide sulfur.
In the case of 7, as compared to other sulfonamides, the N1hydrogen is even more acidic as it is flanked by two electron
withdrawing groups (-SO2- and -CO-). In fact, 7 is more acidic
than most other sulfonamide medicinal compounds, and has a pKa
= 5.4, which is almost the lowest among them. The anion formed
on N1 after the loss of its proton is shared by the neighbouring
carbonyl group as well as by -SO2- group by resonance effect
(Scheme 6). As this carbonyl group acquires negative charge
(16), it will prevent the attack of hydroxide anion. In comparison,
the N4-carbonyl is not hampered by this restriction, and hence it
undergoes hydrolysis much faster to lose acetyl group, while N1acetyl remains intact, (Scheme 6). Thus, we witness a smooth
chemoselective hydrolysis of one carboxamide in preference to
the other carboxamide as well as sulfonamide.
The sodium salt of sulfacetamide is neutral and is used as an
ointment or drops in the treatment of eye infections, for topical
application for skin infections, and other similar situations.
A brief procedure for the preparation of sulfacetamide is given
below. It is a simple experiment and can be included in MSc
practicals as an example of chemoselective reaction, and to
discuss mechanistic aspects of amide hydrolysis.
Preparation of Sulfacetamide
First Step – Preparation of N1,N4-Diacetylsulfanilamide (7)
To 8.6 g of 4-aminobenzenesulfonamide (1) in a 250 ml round
bottomed flask are added 40 ml of acetic anhydride carefully.
Initially the solid dissolves, but within minutes a solid forms with
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GENERAL  ARTICLE
evolution of heat which is controlled by holding the flask under
tap water. The mixture is then refluxed on a heating mantle (or a
Bunsen burner) for 2-3 h, cooled to room temperature and poured
into ice-water (30-40 ml with crushed ice pieces). The solid
N1,N4-diacetylsulfanilamide (7) formed is filtered and washed
with cold water (3-4 times); the yield is about 70-75%. A small
amount of this is recrystallized from isopropyl alcohol (3-4 ml)
containing a few drops of methanol for checking mp (found,
253 oC; literature [1] mp 254 oC).
IR (neat, cm–1): 3575 (NH), 3469 (NH), 1703 (CO), 1668 (CO),
1638, 1589, 1538, 1469, 1374, 1325 (sym. SO2), 1233, 1155
(asym. SO2), 1089, 1002, 842, 715, 635, 611, 540.
H NMR (DMSO-D6, 400 MHz):  1.89 (s, 3H), 2.07 (s, 3H), 7.73
(d, J = 8.80 Hz, 2H), 7.82 (d, J = 8.96 Hz, 2H), 10.37 (s, 1H), 11.95
(s, 1H).
1
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Figure 1a. FT-IR spectrum
of diacetyl sulfonamide 7.
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GENERAL  ARTICLE
Figure 1b. 1H NMR (400 MHz,
DMSO-D 6 ) spectrum of
diacetyl sulfonamide 7.
ppm
C NMR (DMSO-D6, 400 MHz):  23.17, 24.13, 118.35, 128.85,
132.68, 143.77, 168.63, 169.10.
13
Second Step – Hydrolysis of 7 to Sulfacetamide (N1-Acetylsulfanilamide, 8)
The crude product 7 (9.2 g) is treated with a solution of 3.59 g of
NaOH in 40 ml of water. The mixture is boiled for 1.5 h on a
heating mantle, cooled, and neutralized to pH 8 with 4N HCl. The
solution on cooling and standing deposits a little sulfanilide (1)
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GENERAL  ARTICLE
Figure 1c. 13C NMR (400
MHz, DMSO-D6 ) spectrum
of diacetyl sulfonamide 7.
ppm
which is removed by filtration. The filtrate is further treated with
4N HCl till its pH is 4 and kept in a refrigerator for 24 h, when
sulfacetamide separates out as a white solid. It is collected by
filtration and recrystallized from hot water. The yield is 2.3 g
(30%) and the m.p. is 180 oC (literature [1] m.p. 181 oC).
IR (neat, cm–1): 3468 (NH), 3376 (NH), 1682 (CO), 1638, 1590,
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937
GENERAL  ARTICLE
Figure 2a. FT–IR spectrum
of sulfacetamide 8.
1464, 1316 (sym. SO2), 1243, 1144 (asym. SO2), 1084, 991, 853,
823, 676, 626, 589, 532.
H NMR (Methanol-D4, 400 MHz):  1.93 (s, 3H), 6.66 (d, J =
8.76 Hz, 2H), 7.64 (d, J = 8.76 Hz, 2H). (NH protons are
exchanged for deuterium in CD3OD; therefore, no NH2 proton
signals are seen).
1
C NMR (Methanol-D4, 400 MHz):  23.23, 113.87, 125.88,
131.28, 155.19, 170.97.
13
Conclusion
The experiment shows that an amide functional group behaves
chemically differently when it is present in slightly different
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GENERAL  ARTICLE
ppm
2b
2c
chemical environments. Here one acetamide group finds itself to
be hydrolyzing faster than the other one, in spite of being the same
functional group, only because the chemical environments around
the two groups are different. Such selectivity is a very common
phenomenon and is observed for many other functional groups in
a wide variety of transformations (see, Ref [4]).
ppm
Figure 2b. 1H NMR (400 MHz,
CD3OD) spectrum of sulfacetamide 8.
Figure 2c. 13C NMR (400
MHz, CD3OD) spectrum of
sulfacetamide 8.
Acknowledgment
The author thanks R Senthil Kumar for preparing the compounds
7 and 8.
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939
GENERAL  ARTICLE
Suggested Reading
[1]
M L Crossley, E H Northey and M E Hultquist, J. Am. Chem. Soc.,
Vol.61, pp.2950–2955, 1939. (Preparation of sulfonamides)
[2]
J March, Advanced Organic Chemistry, 4th Edition, John Wiley & Sons,
pp.440-911, 1992. (Chemoselectivity)
[3]
M A Weidner-Wells and M J Macielag, Kirk-Othmer Encyclopedia of
Chemical Technology, Fifth Edition, Vol.23, pp.493–513, 2007. (Sulfa
drugs – description)
[4]
D J Abraham (Ed.) Burger’s Medicinal Chemistry & Drug Discovery, 6th
Edition, Vol.1, pp.252–3, 2007. (Pharmacophore definition)
[5]
Bentley and Driver’s Text book of Pharmaceutical Chemistry, 8th Edition, Oxford University Press 20th impression, pp.688–693, 2003. (Sulfa
drugs – general)
Porur, Chennai 600 116
[6]
Email:
[email protected]
[7]
R T Morrison and R N Boyd, Organic Chemistry, 6th Edition, Prentice
Hall of India, pp.585–860, 2007. (Sulfonamide hydrolysis, mechanism)
M Dohrn and P Diedrich, US patent No. 2, 411, 495 (1946, applied, 1939)
(Preparation of sulfonamides)
Address for Correspondence
G Nagendrappa
Department of Medicinal
Chemistry
Sri Ramachandra University
How to Add a Molecule of Water to
Molecular Formula?
This happened during the time of my doctoral work. One of
my fellow doctoral colleagues was working in the area of
inorganic complexes. The work involved the preparation
and characterization of new complexes, which required
elemental analysis data in addition to other pieces of information. On one occasion his research guide, finding some
discrepancy between the analysis data calculated for an
assumed molecular formula and the experimentally found
values, asked him to add a molecule of water in calculating
the percentage values to match the experimental values.
My friend took some compound in a test tube and asked his
guide how he might add one molecule of water to it! I do not
remember what the guide’s reaction was, but this is one of
the memorable episodes of my PhD days that lingers on.
G Nagendrappa
940
RESONANCE  October 2008