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An elegant example of chemoselective reaction

Article  in  Resonance · October 2008

DOI: 10.1007/s12045-008-0101-2

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 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).
G Nagendrappa, after
Background
retiring from Bangalore
University, is now teaching
It is an eternal dream of synthetic chemists to prepare a target at the Department of
molecule with the best yield and highest purity without being Medicinal Chemistry, Sri
encumbered by side products. That is, the chosen synthetic route Ramachandra University,
should be able to selectively deliver a single compound. This is Porur, Chennai. His
research interests are in
also an important principle of Green Chemistry. Selectivity can the area of silicon
be achieved by choosing suitable starting materials, reagents, chemistry, mechanistic
solvents, reaction conditions, and most importantly catalysts. organic and synthetic
This saves starting materials, reagents, energy, solvents, time and chemistry.

effort, and results in the reduction of production cost and environ-

mental 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 labora-
tory curriculum as no experiment is specifically designed to
demonstrate selectivity aspects.

Three types of selectivity, namely chemoselectivity, regio-selec-

tivity, and stereoselectivity including enantioselectivity, are rec-
ognized as important. This article describes the first type, which
is given the least attention in our undergraduate teaching. For this Keywords
purpose I have chosen the example of the preparation of sulfona- Chemoselectivity, sulfa drugs,
sulfonamides, amide hydrolysis.

RESONANCE  October 2008 929


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.
1
A pharmacophore is defined
as a set of structural features in
a molecule that is recognized at
a receptor site and is respon-
sible for that molecule’s biologi-
cal activity.
The mechanistically
interesting part of this
synthetic sequence is
the selective removal
of N4-acetyl group by
alkaline hydrolysis.
930
GENERAL  ARTICLE
mide drugs, which made a great impact on health care by control-
ling bacterial diseases prior to the advent of antibiotics, and are
still in use, though in a limited way.
The Sulfonamides
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, sulfona-
mides were used to treat a variety of illnesses caused by both
Gram-positive and Gram-negative bacteria. Though their impor-
tance 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 off-
shoot of dyes industry in Germany.
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.
R in Scheme 1 is usually a heterocyclic group with a few excep-
tions such as sulfacetamide (8) in which R is an acetyl (-COCH3)
group. Sulfacetamide is prepared in a slightly different way,
(Scheme 2).
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
RESONANCE  October 2008
 GENERAL  ARTICLE

3 2 O
4 4 1
H 2N 1
S NH 2
5 6 O
1

NHCOCH 3 NHCOCH 3 NHCOCH 3 NH 2

RNH 2 aq. NaOH

+ HSO3Cl

2 SO2 Cl SO2NHR SO2NHR

3 4 5

S
R= : sulfathiazole
N
O
N
: sulfisoxazole
H 3C CH 3
N
O
: sulfamethoxazole
H 3C
N
: sulf adiazine
N
N
: sulfapyridine

Scheme 1

NH 2 NHCOCH 3 NHCOCH 3 NH 2

(CH3 CO)2O aq. NaOH

or

SO2NH 2 SO2NH 2 SO2 NHCOCH3 SO2NHCOCH3

1 6 7 8
Scheme 2

RESONANCE  October 2008 931

 GENERAL  ARTICLE

Preferential NHCOCH3 NH 2
reaction of a
long
reagent with one + NaOH
reaction time
functional group in
the presence of SO2NHR SO3Na
similar functional Scheme 3
groups is known
as
can undergo hydrolysis under alkaline conditions to ultimately
chemoselectivity.
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 posi-
tions 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 O- O O
R C NH R1 + OH - H 3C C N HR1 H3 C C OH + R 1NH- 1
H3 C C O - + R NH2
OH
9 10
O O O O
R S NH R1 + OH - N HR 1 1 -
H 3C S R S OH + R NH H3 C S O - + R 1NH2
O -
O HO O O
Scheme 4

932 RESONANCE  October 2008

 GENERAL  ARTICLE

O O O-
H -
R S N R1 + OH- R S N R1 R S N R1
O -H 2O O O
12 13
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 elec-

O O O O
HN C CH3 HN C CH3 HN C CH3 HN C CH 3

+ OH-

- CH 3
O 2S NH C CH 3 O S N C CH 3 O S N C CH 3 O S N C
O O O O- O O O-
14 15 16
OH-

O-
NH 2 NH - HN C CH 3
OH
CH 3COO- + CH 3COOH +
CH3 CH 3
O 2S NH C CH 3 O S N C O S N C
O O O- O O-
Scheme 6

RESONANCE  October 2008 933

 GENERAL  ARTICLE

trons as well as the steric crowding around sulfur, both of which

When OH– adds to
are unfavourable to OH– attack. For acetyl carbonyl carbon, on
sulfur in 4 or 6 the
the other hand, the attachment of OH– brings about a change from
tetrasubstituted
trisubstitution (sp2-planar) to tetrasubstitution (sp3-tetrahedral),
sulfur has to expand
but no change in the number of valence electrons. These changes
its valency to five
do not hinder the OH– attack on carbonyl carbon and takes place
and become
far more easily than that on sulfonamide sulfur.
pentasubstituted.
This increases In the case of 7, as compared to other sulfonamides, the N1-
valence shell hydrogen is even more acidic as it is flanked by two electron
electrons as well as withdrawing groups (-SO2- and -CO-). In fact, 7 is more acidic
the steric crowding than most other sulfonamide medicinal compounds, and has a pKa
around sulfur. = 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 N1-
acetyl 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
In the case of 7, as application for skin infections, and other similar situations.
compared to other
A brief procedure for the preparation of sulfacetamide is given
sulfonamides, the N1-
below. It is a simple experiment and can be included in MSc
hydrogen is even
practicals as an example of chemoselective reaction, and to
more acidic as it is
discuss mechanistic aspects of amide hydrolysis.
flanked by two
electron withdrawing Preparation of Sulfacetamide
groups (-SO2- and
-CO-). In fact, 7 is First Step – Preparation of N1,N4-Diacetylsulfanilamide (7)
more acidic than most
To 8.6 g of 4-aminobenzenesulfonamide (1) in a 250 ml round
other sulfonamide
bottomed flask are added 40 ml of acetic anhydride carefully.
medicinal compounds.
Initially the solid dissolves, but within minutes a solid forms with

934 RESONANCE  October 2008

 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.
1
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 Figure 1a. FT-IR spectrum
(s, 1H). of diacetyl sulfonamide 7.

RESONANCE  October 2008 935

 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,

13

132.68, 143.77, 168.63, 169.10.

Second Step – Hydrolysis of 7 to Sulfacetamide (N1-Acetylsul-

fanilamide, 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)

936 RESONANCE  October 2008

 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,

RESONANCE  October 2008 937

 GENERAL  ARTICLE

Figure 2a. FT–IR spectrum 1464, 1316 (sym. SO2), 1243, 1144 (asym. SO2), 1084, 991, 853,
of sulfacetamide 8.
823, 676, 626, 589, 532.
1
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).

C NMR (Methanol-D4, 400 MHz):  23.23, 113.87, 125.88,

13

131.28, 155.19, 170.97.

Conclusion

The experiment shows that an amide functional group behaves

chemically differently when it is present in slightly different

938 RESONANCE  October 2008

 GENERAL  ARTICLE

ppm

2b 2c ppm

chemical environments. Here one acetamide group finds itself to Figure 2b. 1H NMR (400 MHz,
be hydrolyzing faster than the other one, in spite of being the same CD3OD) spectrum of sulfac-
functional group, only because the chemical environments around etamide 8.
the two groups are different. Such selectivity is a very common Figure 2c. 13C NMR (400
MHz, CD3OD) spectrum of
phenomenon and is observed for many other functional groups in
sulfacetamide 8.
a wide variety of transformations (see, Ref [4]).

Acknowledgment

The author thanks R Senthil Kumar for preparing the compounds

7 and 8.

RESONANCE  October 2008 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)
Address for Correspondence [4] D J Abraham (Ed.) Burger’s Medicinal Chemistry & Drug Discovery, 6th
G Nagendrappa Edition, Vol.1, pp.252–3, 2007. (Pharmacophore definition)
Department of Medicinal [5] Bentley and Driver’s Text book of Pharmaceutical Chemistry, 8th Edi-
Chemistry tion, Oxford University Press 20th impression, pp.688–693, 2003. (Sulfa
Sri Ramachandra University drugs – general)
Porur, Chennai 600 116 [6] R T Morrison and R N Boyd, Organic Chemistry, 6th Edition, Prentice
Email: Hall of India, pp.585–860, 2007. (Sulfonamide hydrolysis, mechanism)
gnagendrappa@gmail.com [7] M Dohrn and P Diedrich, US patent No. 2, 411, 495 (1946, applied, 1939)
(Preparation of sulfonamides)

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 infor-
mation. 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

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