Convenient synthesis, antibacterial activity, and crystal structure of some biologically important hydrazinecarbonyl benzenesulfonamides

Article abstract of DOI:10.1007/s11164-013-1502-8

Microwave-assisted synthesis of a series of hydrazinecarbonyl benzenesulfonamides (5a-r) is reported, and the products have been characterized by nuclear magnetic resonance and Fourier-transform infrared spectral techniques. A comparison with the conventi

Full text of DOI:10.1007/s11164-013-1502-8

Res Chem Intermed
DOI 10.1007/s11164-013-1502-8
Convenient synthesis, antibacterial activity, and crystal
structure of some biologically important
hydrazinecarbonyl benzenesulfonamides
•
G. Thiyagarajan H. S. P. Rao
•
•
A. Thamaraichelvan Peter Mayer Ashutosh Pandey
•
Received: 27 September 2013 / Accepted: 30 November 2013
Ó Springer Science+Business Media Dordrecht 2013
Abstract Microwave-assisted synthesis of a series of hydrazinecarbonyl ben-
zenesulfonamides (5a–r) is reported, and the products have been characterized by
nuclear magnetic resonance and Fourier-transform infrared spectral techniques. A
comparison with the conventional method for their preparation has also been done.
The crystal and molecular structures of compounds 2-(hydrazinecarbonyl)ben-
zenesulfonamide 3, 2-({(2E)-2-[(3,4-dimethoxy)benzylidene]hydrazine}carbonyl)
benzenesulfonamide 5e, 2-({(2E)-2-[(2,4-dimethoxy)benzylidene]hydrazine}car-
bonyl)benzenesulfonamide 5f, and 2-({(2E)-2-[(4-hydroxy)benzylidene]hydra-
zine}carbonyl)benzenesulfonamide 5k have also been established by single-crystal
X-ray diffraction. Antibacterial activity of prepared compounds (5a–r) is reported
against Staphylococcus aureus, Bacillus firmus, and Escherichia coli. The preemi-
nent antibacterial activity was shown by 2-({(2E)-2-[(2-hydroxy)benzyli-
dene]hydrazine}carbonyl)benzenesulfonamide 5j against all three tested bacterial
organisms.
Keywords Hydrazone Á Benzenesulfonamide Á Crystallography Á
Microwave reaction Á Antibacterial activity
G. Thiyagarajan Á A. Pandey (&)
Department of Chemistry, Motilal Nehru National Institute of Technology,
Allahabad 211 004, India
e-mail: apandey70@yahoo.com
H. S. P. Rao
Department of Chemistry, Pondicherry University, Pondicherry 605 014, India
A. Thamaraichelvan
Department of Chemistry, Thiagarajar College, Madurai 625 020, India
P. Mayer
Department of Chemistry and Biochemistry, Ludwig-Maximilian University Munich,
Butenandtstrasse 5-13, 81377 Munich, Germany
123

G. Thiyagarajan et al.
Introduction
The synergistic effect of growing population and climate change has resulted in the
eruption of several diseases which are affecting humankind [1–4]. There is a
continuous need to synthesize prospective drugs for new diseases by fast and
efficient methods. Therefore, in-depth focus on the discovery of new drugs has
gained tremendous momentum in recent times. Considering the various aspects of
drug design, chemists have synthesized a number of compounds by way of
conventional heating processes [5]. While these processes are too slow to meet the
demand for growing populations, concerns with regards to environmental impact
and energy constraints also compel the search for greener synthetic modes [6–9].
Among the available alternatives that may accelerate these synthetic processes,
green microwave (MW) technology with power and temperature optimization is a
better option which has resulted in dramatic decline in reaction times from days and
hours to minutes and seconds [10, 11].
Saccharin is a polyfunctional ligand with three hydrogen-bond acceptors (one
carbonyl and two sulfonyl O atoms) and one hydrogen-bond donor (imino group
NH). Further, it has been used as an acid in the pharmaceutical industry [12, 13],
and the crystal structures and physical properties of several active saccharinates
used as pharmaceutical ingredients have also been reported recently [14–16].
Additionally, benzenesulfonamides constitute an important class of drugs with a
number of biological activities such as antibacterial [17, 18], hypoglycemic [19],
diuretic [20], anticarbonic anhydrase [21], antithyroidal [22], and anticancer
activities [23]. Hydrazone derivatives which contain highly reactive azomethine
(NH–N=CH) group are also very useful in designing new drugs [24, 25]. Moreover,
hydrazones form an interesting class of chelating ligands linked to a nitrogen atom
and find extensive application in various fields [26]. By virtue of nitrogen–nitrogen–
oxygen (NNO) donor atoms, they have also been introduced into coordination
chemistry for preparation of organometallic complexes [27, 28]. Thus, it is expected
that the synchronized effect of both sulfonamide and hydrazone groups in a certain
stoichiometry should have a strong and manifold effect on the biological
applications of the resulting compounds. Therefore, detailed study on the synthesis
and molecular structure descriptions of these compounds seems to be important for
understanding their biological activities and coordination capabilities.
Herein, we report the synthesis of a series of hydrazinecarbonyl benzenesulf-
1
onamides (5a–r) by MW heating, which have been characterized by H and 13C
NMR, Distortionless enhancement by polarization transfer (DEPT), and FT-IR
spectral studies. The crystal and molecular structures of 2-(hydrazinecarbonyl)
benzenesulfonamide 3, 2-({(2E)-2-[(3,4-dimethoxy)benzylidene]hydrazine}car-
bonyl)benzenesulfonamide 5e, 2-({(2E)-2-[(2,4-dimethoxy)benzylidene]hydra-
zine}carbonyl)benzenesulfonamide 5f, and 2-({(2E)-2-[(4-hydroxy)benzylidene]
hydrazine}carbonyl)benzenesulfonamide 5k have also been described by single-
crystal X-ray crystallography. The antibacterial activities of all the synthesized
compounds (5a–r) were screened against Gram-positive S. aureus and B. firmus
and Gram-negative Escherichia coli bacterial strains.
123

Biologically important hydrazinecarbonyl benzenesulfonamides
Results and discussion
Synthesis
A series of hydrazinecarbonyl benzenesulfonamide derivatives (5a–r) were syn-
thesized by microwave heating (Scheme 1), encompassing two types of mechanistic
pathway. As a consequence of an addition–elimination reaction, saccharin 1 reacts
with hydrazine 2 to form 2-hydrazinecarbonyl-benzenesulfonamide 3 by ring
opening, then the aromatic aldehydes (4a–r) react with 3 to form the corresponding
products (5a–r) by way of ‘‘aldehyde–amine’’ condensation. Notably, we synthe-
sized compound 3 using a new synthetic approach which is greener, easier, and
economical in comparison with earlier synthetic methods [17]. Wang et al.
synthesized 3 by refluxed reaction of 2-methoxycarbonyl benzenesulfonamide with
hydrazine hydrate in excess amount of methanol for 5 h. On the other hand, we
prepared compound 3 within 3 min from saccharin 1 and hydrazine hydrate in
methanol (1 mL) by microwave heating. Similarly, our final products (5a–r) have
also been synthesized by MW heating in higher yields within 2–4 min, while
lacking any additional requirement for complex purification processes such as
column chromatography etc. All the synthesized products were purified simply by
crystallization in methanol. For comparison with microwave-assisted reaction, the
products have also been synthesized by the conventional heating method. Evidently,
the compounds 3 and 5a–r have been prepared in higher yields and lesser reaction
times (Table 1). Therefore, the synthetic procedure adopted in the present work is a
much greener and more economical approach to obtain high-purity products.
NMR spectra
All the synthesized compounds gave the expected spectral data in accordance with
their proposed structures (Scheme 1). The appearance of four aromatic signals in the
1H NMR spectrum of compound 3 in the d 7.59–7.95 region confirms its proposed
molecular structure. Furthermore, the two separate singlets at d 7.09 and 7.02
confirm the presence of exchangeable SNH2 protons. In the 13C NMR spectrum of
compound 3, six carbon signals at d values between 141.2 and 126.9 correspond to
the aromatic carbons, and one peak due to the C=O group at d 167.5 further
substantiates its proposed structure. The aromatic protons of 3 are also confirmed by
DEPT spectra by the four carbon signals appearing at values of d 131.7, 129.9,
129.1, and 126.9.
1
In H NMR of all the final products (5a–r), the two separate singlets for the
exchangeable NH protons were found between d 12.30 and 11.76. The peaks at d
12.24 and 12.22 correspond to the occurrence of exchangeable NH proton of 5l.
Likewise, proton signals at d 11.78 and 11.76 confirm the existence of exchangeable
NH proton of 5h. Similar peaks are also observed in 1H NMR of 5d and 5n; i.e., the
peaks at d 11.89, 11.87 and 12.27, 12.06, respectively, correspond to their
exchangeable NH protons. In addition, the aldehydic proton, which appeared at d
1
*10 in the starting aromatic aldehydes (4a–r), was absent from the H NMR
spectra of our final products (5a–r). The appearance of new single peaks in the d
123

G. Thiyagarajan et al.
Scheme 1 Synthesis of hydrazinecarbonyl benzenesulfonamides
8.60–8.04 range in the 1H NMR spectra of compounds 5a–r due to the existence of
azomethene (CH=N) groups confirms their proposed structures (Scheme 1). The
proton signals appearing at d 8.73 and 8.45 in 5l also indicate the presence of
exchangeable azomethene (N=CH) group. In the same way, the two exchangeable
protons at d 7.02, 6.92 in 5g and at d 7.02, 6.84 in 5h also appeared as two singlets
due to the presence of S-NH2 groups. However, two singlets at d 7.15, 7.05 in 5j and
7.13, 6.92 in 5r indicate the exchangeable SNH2 protons.
A singlet peak equivalent to the two methoxy groups in 5e appeared as six
protons at d 3.88, while in 5f the peaks at d 3.86 and 3.66 correspond to the
existence of two methoxy groups. The proton signal in 5d equivalent to the methoxy
group also appeared at d 3.83, integrating as three protons. The OH protons of
compounds 5b and 5c appeared as singlets at d 9.32 and 9.19, while the same for 5j
and 5k were found at d 9.69 and 9.79, respectively. The peaks corresponding to the
123

Biologically important hydrazinecarbonyl benzenesulfonamides
Table 1 Conventional versus microwave heating of 3 and 5a–r
S. no.
Nature
Conventional
Microwave
Time
(h)
Temp.
(°C)
Yield
(%)
Time
(min)
Temp.
(°C)
Yield
(%)
3
White crystalline solid
White solid
5
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
95
85
85
85
85
85
85
85
85
85
85
85
85
85
85
85
85
85
85
86.5
86.4
81.5
84.8
76.2
84.9
79.3
80.7
77.3
89.2
86.1
88.4
84.7
85.3
83.5
89.1
87.9
90.7
86.6
4
2
4
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
85
84
82
79
83
88
89
86
85
83
86
81
87
86
84
87
77
81
92
95.4
93.8
92.6
95.3
96.4
93.2
98.2
94.6
95.2
93.4
94.7
96.3
95.4
94.7
96.4
91.6
97.5
95.3
93.8
5a
5b
5c
5d
5e
5f
Pale-yellow solid
Pale-yellow solid
White crystalline solid
Pale-yellow solid
Pale-yellow solid
White crystalline solid
Orange crystalline solid
White solid
5g
5h
5i
5j
White solid
5k
5l
White solid
White crystalline solid
White solid
5m
5n
5o
5p
5q
5r
White solid
Pale-yellow solid
Pale-yellow solid
Pale-yellow solid
Yellow solid
two methyl groups in 5h are visible at d 2.95 as singlet by integrating six protons.
Compound 5l showed aromatic signals in the d 8.14–7.38 range as multiplet by
integrating eight protons.
The carbon signals due to –CHO group in 4a–r were observed in the range of d
185–180, which disappeared in 5a–r, and new signals due to the presence of N=CH
group originated at d values between 144.0 and 149.7. The carbon signals of C=O
group in all our synthesized products appeared at d *164. Hence, the carbon signals
of C=O group in 5l and 5h appeared at d 164.6 and 164, respectively. The carbon
signal anticipated for methoxy group in 5b appeared at d 55.4. The carbon signal at
d 54.9 also confirms the presence of one methoxy group in 5d, and the peaks
corresponding to the two methyl groups of 5h are observed at d 39.9. In 13C NMR of
5d and 5n, the peaks at d 148.3 and 148.1 appeared, respectively, due to the
presence of N=CH group. The appearance of signals at d 144.4 and 149.2 in 5l and
5h, respectively, is also attributed to the same. All protons of the aromatic rings in
the final compounds were further confirmed by the observed carbon signals in the
range of d 150 and 109 in DEPT spectra. In the DEPT spectrum of compound 5c,
the carbon signal at d 14.6 is due to the methyl group, while another signal at d 63.8
in the reverse direction indicates the presence of methylene (CH2) group. The
carbon signals in 5f at d 55.4 confirm the appearance of two methoxy groups, while
the peaks at d 59.8 and 55.7 in 5g correspond to the three methoxy groups. Thus, the
123

G. Thiyagarajan et al.
proposed molecular structures of all our synthesized compounds were clearly
1
substantiated by H and 13C NMR and DEPT spectral data.
FT-IR spectra
The structures of all the compounds were also examined by IR spectral data.
Compounds 5a–r showed absorption bands at *1,676–1,639 cm-1 due to the
presence of C=O groups, while the IR peak corresponding to the azomethene
(N=CH) group in the region of *1,604–1,558 cm-1 provided confirmatory
evidence for the condensation reaction between aldehyde and hydrazide. IR spectra
of compounds 5e and 5f showed absorption bands at 1,661 and 1,651 cm-1 due to
the presence of C=O group, while the bands observed at 1,603 and 1,568 cm-1
correspond to CH=N linkages, respectively. The peaks between *3,333 and
3,267 cm-1 correspond to the presence of NH and NH2 groups in all the
compounds. The observed IR peaks at 3,245 and 3,318 cm-1 can be attributed to
NH and NH2 groups of 5e and 5f, respectively. In all the compounds, the
absorptions in the 3,091–3,054 cm-1 range are due to CH stretching of aromatic
groups, and the peaks due to O=S=O stretching appeared at 1,169 and 1,161 cm-1
.
Further, the peaks owing to the O=S=O group appeared at 1,160 and 1,168 cm-1 for
5e and 5f, respectively. The absorption bands in the 3,071 cm-1 and 2,991 cm-1
range are due to CH stretching of aromatic rings in 5g and 5h, respectively. The OH
groups of 5b, 5c, 5j, and 5k are confirmed by the absorptions between 3,531 and
3,411 cm-1. In the products 5n, 5o, and 5p the transitions at 1,519, 1,527, and
1,524 cm-1 are attributed correspondingly to the presence of NO2 group.
Single-crystal X-ray analysis
Single crystals of 3, 5e, 5f, and 5k suitable for X-ray diffraction were obtained by
slow evaporation of their solutions in methanol. Crystal data and structure
refinement of all the products are presented in Table 2, while Table 3 presents
selected bond lengths and angles.
The ORTEP diagram for 3 is shown in Fig. 1. It was found in monoclinic form
with eight molecules in the unit cell arrangement, as shown in Fig. 2. Compound 3
has a basal plane which involves the benzene ring, S atom, and C7 atom of the
carbonyl group. The carbon and oxygen atoms of the carbonyl group along with the
two N atoms of the hydrazino group lie in another plane [mean deviation
˚
0.051(2) A] with dihedral angle of 57.5(2)° to the basal plane. The intramolecular
N1–H1ÁÁÁO3 hydrogen bond forces the O atom of carbonyl group and the N atom of
sulfamoyl group to lie on the same side of the basal plane, and thus the molecule
adopts a chiral conformation. The structure is further stabilized by intermolecular
hydrogen bonds and p–p stacking interactions between the phenyl rings. Due to the
repulsion among the lone pairs of electrons at S1 atom in 3, the bond angle O1–S1–
O2 increases to 118.63(7)° while the angles O1–S1–N1 and O2–S1–N1 have to
narrow down to 107.18(9)° and 107.15(8)°, respectively.
ORTEP diagrams for compounds 5e, 5f, and 5k are depicted in Fig. 3. In the unit
cell of 5e, there are eight molecules and intermolecular H-bond was observed
123

Biologically important hydrazinecarbonyl benzenesulfonamides
Table 2 Crystal data and structure refinement of crystals 3, 5e, 5f, and 5k
Compound
3
5e
5f
5k
Net formula
C7H9N3O3S
215.231
C16H17N3O5S
363.389
C16H17N3O5S
363.389
C14H13N3O4S
319.337
Mol. weight (Mr)
(g/mol)
Crystal size (mm)
Temperature (K)
Radiation
0.46 9 0.40 9 0.25 0.35 9 0.23 9 0.19 0.25 9 0.19 9 0.11 0.35 9 0.28 9 0.20
173(2)
173(2)
173(2)
173(2)
Mo Ka
Monoclinic
C2/c
Mo Ka
Monoclinic
P21/n
Mo Ka
Monoclinic
P21/c
Mo Ka
Crystal system
Space group
Orthorhombic
P212121
Unit cell dimensions
˚
a (A)
11.8661(8)
11.5910(6)
14.5859(15)
90
18.8205(18)
9.6272(7)
19.6232(19)
90
16.3030(2)
12.6915(2)
8.2361(1)
90
8.0359(9)
11.6060(12)
15.0251(19)
90
˚
b (A)
˚
c (A)
a (°)
b (°)
c (°)
117.650(6)
90
110.675(11)
90
90.1813(9)
90
90
90
3
˚
Volume (A )
1,777.0(2)
8
3,326.5(5)
8
1,704.12(4)
4
1,401.3(3)
4
Z (molecules/cell)
D (calc) (g/cm3)
l (mm-1
1.60902(18)
0.349
1.4512(2)
0.228
1.41640(3)
0.222
1.5137(3)
0.254
)
Absorption
correction
Multiscan
Multiscan
None
Multiscan
Transmission factor 0.83183–1.00000
range
0.67716–1.00000
–
0.60102–1.00000
Refls. measured
Rint
4,764
17,571
14,444
7,731
0.0166
0.0705
0.0238
0.0424
0.0442
4.33-26.37
Mean r(I)/I
0.0206
0.0623
0.0212
h range for data
collection
4.55–26.37
4.22–26.30
3.20–27.54
Observed refls.
1,667
5,049
6,710
473
3,360
3,901
237
2,608
2,845
211
Refls. in refinement 1,815
Parameters
Restraints
142
0
6
3
4
R(Fobs
Rw(F2)
)
0.0323
0.0881
1.034
0.001
0.333
0.0479
0.1289
1.043
0.001
0.269
0.0356
0.0922
1.042
0.001
0.265
0.0434
0.1133
1.077
0.001
0.730
S
Shift/errormax
Max. electron
˚
3
density (e/A )
Min. electron
-0.503
-0.571
-0.450
-0.351
3
˚
density (e/A )
123

G. Thiyagarajan et al.
Table 3 Selected bond lengths and angles of crystals 3, 5e, 5f, and 5k
Atoms
3
5e
5f
5k
˚
Bond length (A)
N2–N3
1.417(2)
–
1.378(2)
1.278(3)
1.610(3)
1.409(3)
1.215(3)
1.390(3)
1.405(3)
1.375(3)
1.425(2)
1.429(2)
1.503(3)
1.466(3)
1.3831(16)
1.2875(18)
1.6139(14)
1.4014(19)
1.2328(16)
1.3856(18)
1.389(2)
1.385(3)
1.277(3)
1.595(3)
1.400(3)
1.253(3)
1.383(4)
1.387(3)
1.378(5)
1.430(2)
1.439(2)
1.493(4)
1.452(4)
N3–C8
S1–N1
1.6119(17)
1.409(2)
1.229(2)
–
C1–C6
O3–C7
C10–C11
C11–C12
C3–C4
–
1.374(3)
1.4324(13)
1.4344(12)
1.504(2)
–
1.377(2)
S1–O1
1.4302(11)
1.4317(11)
1.5034(18)
1.4533(18)
S1–O2
C6–C7
C8–C9
Bond angle (°)
C2–C3–C4
N2–C7–O3
N2–N3–C8
C7–N2–N3
C10–C9–C14
O1–S1–C1
O2–S1–C1
C1–C6–C7
C11–C12–C13
O1–S1–O2
O1–S1–N1
O2–S1–N1
120.01(15)
123.89(15)
–
120.4(2)
122.7(2)
114.9(2)
119.91(17)
121.1(2)
107.1(1)
106.8(1)
123.0(2)
120.1(2)
119.70(12)
108.74(13)
105.91(12)
119.63(14)
125.56(12)
113.19(11)
121.79(11)
117.95(12)
107.76(7)
107.30(6)
124.16(12)
121.13(14)
119.35(6)
108.07(7)
106.48(7)
120.0(3)
122.0(2)
115.6(2)
123.11(15)
–
118.5(15)
118.5(2)
108.12(8)
107.15(8)
122.74(15)
–
107.20(12)
107.58(13)
123.3(2)
120.5(2)
118.63(7)
107.18(9)
107.15(8)
119.38(14)
106.87(14)
106.54(13)
among NH group with the carbonyl and sulfonyl O atom of a neighboring molecule
as well as intramolecular H-bond with NH2 group and carbonyl O atom (Fig. 4).
Crystals 5f and 5k encompass four molecules of the compounds, as shown in Figs. 5
and 6. In 5f, the NH group of a molecule is intermolecularly H-bonded with the
oxygen of the carbonyl group and sulfonamide H atom of adjacent molecule, which
is extended further. Intermolecular H-bond was also observed in 5k between NH
group and the carbonyl O atom of a neighboring molecule. The crystal system of 5k
is orthorhombic, while 5e and 5f occurred in monoclinic form. The N2–N3 bond
˚
distance [1.417(2) A] in 3 is longer than the corresponding lengths in 5e, 5f, and 5k
˚
(avg. 1.3835 A). This may be due to the existence of active NHNH2 group in
˚
compound 3. The S1–N1 bond lengths in 3 (1.6119 A) and in 5e, 5f, and 5k (avg.
˚
1.6067 A) are almost similar, which may be a reason for the presence of stable
SO2NH2 group.
The N2–N3–C8 bond angles observed in 5e [113.3(2)°] and 5f [113.19(11)°]
encompass nearly the same values, although being lesser than in 5k [115.6(2)°].
123

Biologically important hydrazinecarbonyl benzenesulfonamides
Fig. 1 ORTEP diagram of single-crystal 3
Fig. 2 Crystal packing of 3 showing inter- and intramolecular hydrogen bonding
123

G. Thiyagarajan et al.
Fig. 3 ORTEP views of 5e, 5f, and 5k
Fig. 4 Inter- and intramolecular hydrogen bonding in crystal packing of 5e
This may be a result of the respective positions of the functional groups in 5e, 5f,
and 5k. The O1–S1–C1 bond angle was found to be less in 5e (105.56°) in
comparison with compounds 5k and 5f (avg. 107.35°). The C2–C3–C4 bond angle
in all the compounds (*120°) shows the planarity of the aromatic rings. A similar
pattern is also noticed around C12 atom in molecules of 5e, 5f, and 5k. In all the
˚
compounds, N3–C8 bond distances (avg. 1.2826 A) indicate the double-bond nature
123

Biologically important hydrazinecarbonyl benzenesulfonamides
Fig. 5 Molecular packing structure of 5f showing inter- (N2HÁÁÁO3ÁÁÁ1HÁÁÁO2) and intramolecular
(NH2ÁÁÁO=C) hydrogen bonding
of the N=CH group, in accordance with reported values [29]. Furthermore, the
˚
observed C7=O3 bond length (avg. 1.2313 A) also falls in the range of a double
bond. The C10–C9–C14 bond angle in 5f [117.95(12)°] is smaller than the angle in
5e [119.8(2)°], which may be due to the difference in positions of the two methoxy
˚
groups. In 5k the O4–H bond length [0.82(3) A] and the C12–O4–H angle [115(2)°]
are slightly different from reported values [29]. The two phenyl rings connected
with hydrazone and benzenesulfonamide of 5e, 5f, and 5k have boat-like
conformation. Moreover, the hydrazide group displays a trans configuration about
the C=N double bond in all the studied crystals.
Antibacterial activity
The in vitro antibacterial activity of the aforementioned compounds against Gram-
positive S. aureus and B. firmus and Gram-negative E. coli was tested at four
different doses, viz. 200, 100, 50, and 25 lg/mL, prepared in dimethyl sulfoxide
(DMSO). There was no inhibition of growth in DMSO. The results for all the tested
compounds were compared with the well-known marketable antibacterial drug
123

G. Thiyagarajan et al.
Fig. 6 Molecular packing structure of 5k showing inter- (NHÁÁÁO=C) and intramolecular (NH2ÁÁÁO=C)
hydrogen bonding
norfloxacin at the same concentrations. There was significant difference in activity
between higher and lower doses of compounds. The results, presented in Table 4,
indicate that some of the synthesized compounds have efficient antibacterial activity
against all three bacterial strains, but were less potent when compared with the
standard drug norfloxacin. Among all the tested compounds, 5j showed the highest
activity against S. aureus (32 mm), B. firmus (28 mm), and E. coli (26 mm) at
200 lg/mL, albeit considerably less than that of the standard drug norfloxacin
against S. aureus (36 mm), B. firmus (30 mm), and E. coli (34 mm) at 200 lg/mL.
Compound 5j also displayed significant activity against S. aureus (10 mm at 25 lg/
mL), B. firmus (9 mm at 25 lg/mL), and E. coli (13 mm at 50 lg/mL). Compounds
5a and 5p also showed moderate activity against all the tested bacterial strains,
whereas 5r had significant effect on S. aureus (17 mm at 200 lg/mL) and E. coli
(14 mm at 200 lg/mL) but no effect on B. firmus. Compounds 5b and 5n showed
significant activity (14 and 15 mm at 200 lg/mL, respectively) against S. aureus,
123

Biologically important hydrazinecarbonyl benzenesulfonamides
while compounds 5k and 5o also showed noteworthy effect (16 and 14 mm at
200 lg/mL, respectively) against E. coli. Compound 5f had considerable activity
(15 mm at 200 lg/mL) against B. firmus. Compounds 5b and 5e exhibited
significant activity (14 and 10 mm at 200 lg/mL, respectively) against S. aureus,
but had no effect on B. firmus or E. coli. Likewise, compound 5k had no impact on
S. aureus or B. firmus but showed reasonable performance (16 mm at 200 lg/mL)
against E. coli. In addition, compounds 5d, 5g, 5h, 5i, 5l, and 5m had no activity
against all the tested organisms.
The effective antibacterial activity of our final products was also confirmed by
their minimum inhibitory concentration (MIC) values (Table 5). The moderate
antibacterial activity of compound 5j was confirmed by its MIC values of 25 lg/mL
for S. aureus and B. firmus and 50 lg/mL for E. coli. The MIC value of 5a and 5p
against all three tested bacterial strains was 50 lg/mL, further indicating the
effectiveness of these compounds in medicinal chemistry research. Therefore, it
may be concluded that the tested compounds containing hydroxyl group in o-
position and nitro group in p-position of second phenyl ring along with azomethine
and benzenesulfonamide group exhibited maximum zones of inhibition. The
Table 4 Antibacterial activity of synthesized compounds
X
S. aureus
B. firmus
E. coli
200
100
50
25
200
100
50
25
200
100
50
25
5a
5b
5c
18
14
13
–
14
12
10
–
10
9
–
–
12
–
8
–
–
–
–
–
–
–
–
–
–
–
9
–
–
–
–
–
–
–
–
8
–
16
–
13
–
7
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
18
–
–
–
–
12
–
9
–
–
–
–
5d
5e
–
–
–
–
–
–
–
10
11
–
–
–
–
–
–
–
–
–
–
5f
–
–
–
15
–
12
–
9
–
–
–
5g
5h
5i
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
5j
32
–
26
–
19
–
10
–
28
–
20
–
16
–
26
16
–
21
13
–
13
8
5k
5l
–
–
–
–
–
–
–
–
5m
5n
5o
5p
5q
5r
–
–
–
–
–
–
–
–
–
–
15
–
12
–
9
–
–
–
–
10
14
15
12
14
34
–
7
–
–
–
–
–
–
11
12
9
8
16
–
14
–
10
–
–
14
–
11
–
9
9
–
–
–
17
36
–
15
32
–
11
24
–
–
8
–
–
8
–
N
16
–
30
–
26
–
18
–
31
–
25
–
DMSO
– No activity, N norfloxacin
123

G. Thiyagarajan et al.
Table 5 MIC (lg/mL) values
of 5a–r
X
S. aureus
B. firmus
E. coli
5a
5b
5c
5d
5e
5f
50
50
100
–
100
–
50
–
100
–
–
–
200
200
–
–
–
50
–
–
5g
5h
5i
–
–
–
–
–
–
–
5j
25
–
25
–
50
50
–
5k
5l
–
–
5m
5n
5o
5p
5q
5r
–
–
–
50
–
–
100
50
50
–
–
50
–
50
–
50
200
100
decreasing order of activity of our products towards the bacterial strains was found
to be: S. aureus [ E. coli [ B. firmus.
Experimental
Materials and methods
For all the syntheses, the used solvents were of reagent grade and dried by standard
procedures [30]. Saccharin 1, hydrazine hydrate 2, and various aromatic aldehydes
(4a–r) were obtained from Sigma-Aldrich Chemicals. MW irradiation was carried
out in a modified domestic Samsung microwave oven (model no. GE 83HDT,
2,450 MHz, 850 W). An infrared thermometer was used for recording temperature
during the MW reactions. The synthesized products were frequently checked by
thin-layer chromatography (TLC) on silica gel GF-254 using hexane/ethyl acetate or
else chloroform/methanol as eluents, and the spots were visualized by short
exposure to iodine vapor, UV light, and KMnO4 solution. Infrared (IR) spectra were
measured from potassium bromide pellets using a Nicolet 6700 spectrophotometer
series Fourier-transform infrared (FT-IR) spectrometer. NMR spectra were recorded
in DMSO-d6:CCl4 (2:3) with tetramethylsilane (TMS) (0 ppm) as internal standard
on a Bruker AVANCE-DRX-400 MHz NMR spectrometer. Carbon tetrachloride
(CCl4) was used along with DMSO-d6 to reduce the cost of expensive deuterated
NMR solvent.
123

Biologically important hydrazinecarbonyl benzenesulfonamides
Synthesis of 2-hydrazinecarbonyl-benzenesulfonamide 3
Conventional heating method
To a dry RB flask, hydrazine hydrate 2 (1.36 g, 27.3 mmol) was added to a stirred
solution of saccharin 1 (1 g, 5.46 mmol) in 10 mL methanol. The resulting mixture
was refluxed at 95 °C for 5 h. The solvent was evaporated under reduced pressure,
and this crude upon washing with 5 mL 2-propanol:ethanol (7:3) solvent yielded a
white crystalline solid, which was filtered and dried in vacuum. The product 3 was
further purified by crystallization from methanol.
Microwave heating method
In a dry sealed tube, saccharin (1 g, 5.46 mmol) was added to hydrazine hydrate
(1.36 g, 27.3 mmol) and mixed with methanol (1 mL). The resulting mixture was
heated under microwave irradiation at *95 °C for 4 min to give a waxy yellow
liquid. This liquid upon washing with 5 mL 2-propanol:ethanol (7:3) solvent
mixture yielded a white crystalline solid, which was filtered and dried in vacuum.
Crystallization of this product from methanol gave compound 3. m.p. 179–81 °C,
1H NMR (400 MHz, DMSO-d6:CCl4): d 9.87 (s, 1H, NH), 7.95 (m, 1H, Ar–CH),
7.65 (m, 2H, Ar–CH), 7.59 (m, 1H, Ar–CH), 7.09 and 7.02 (ss, 2H, SNH2), 3.87 (d,
2H, J = 2.8 Hz, NNH2); 13C NMR (400 MHz, DMSO-d6:CCl4): d 167.5 (C=O),
141.2 (Ar–C–S), 133.2 (Ar–C), 131.7, 129.9, 129.1 and 126.9 (Ar–CH); DEPT
(400 MHz, DMSO-d6:CCl4): d 131.7, 129.9, 129.1, 126.9 (Ar–CH); IR (KBr):
3,341.3 (NH, NH2), 3,068.7 (Ar–CH), 1,662.8 (C=O), 1,170.1 cm-1 (O=S=O).
General procedure for syntheses of 5a–r
Conventional heating
The appropriate aromatic aldehydes (12 mmol) were added to solution of compound
3 (10 mmol) in 10 mL methanol/acetic acid (9:1 mL). The resulting mixtures were
refluxed at 85 °C in a sealed tube for 8 h. The crude products were concentrated
under reduced pressure and poured into ice-cold distilled water (10 mL). The
resulting precipitates were filtered and dried in vacuum. After that, all the
derivatives (5a–r) were purified by crystallization from methanol.
Microwave heating
In a dry sealed tube, the appropriate aromatic aldehydes (12 mmol) were added to a
mixture of compound 3 (10 mmol) and 1 mL methanol:acetic acid (9:1). The
resulting mixture was subjected to microwave irradiation for 2–4 min at *85 °C.
At the end of this period, the crude products were cooled to RT and poured into ice-
cold distilled water (10 mL). The resulting products (5a–r) were filtered and dried
in vacuum. After that, all the derived products were purified by crystallization from
methanol.
123

G. Thiyagarajan et al.
2-({(2E)-2-[Benzylidene]hydrazine}carbonyl)benzenesulfonamide 5a
M.p. 158–160 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 12.03 and 12.00 (ss, 1H,
NH), 8.64 and 8.31 (ss, 1H, N=CH), 8.07–7.30 (m, 9H, Ar–CH), 7.02 and 6.87 (ss,
2H, SNH2); 13C NMR (400 MHz, DMSO-d6:CCl4): d 164.5 (C=O), 148.4 (N=CH),
144.2, 141.5 (Ar–C–S), 134.0 and 133.3 (Ar–C), 131.7, 130.1, 129.9 and 129.0 (4C,
Ar–CH), 128.4, 128.4, 127.1 and 126.7 (5C, Ar–CH); DEPT (400 MHz, DMSO-
d6:CCl4): d 148.4 (N=CH), 144.3, 131.7, 130.1, 129.9, 129.0, 128.4, 127.1 and
126.7 (9C, Ar–CH); IR (KBr): 3,247.9 (NH, NH2), 3,053.3 (Ar–CH), 1,660.8
(C=O), 1,573 (C=N), 1,162.7 (O=S=O) cm-1
.
2-({(2E)-2-[(4-Hydroxy-3-methoxy)benzylidene]hydrazine}carbonyl)
benzenesulfonamide 5b
M.p. 188–190 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 11.92 and 11.87 (ss, 1H,
NH), 9.32 (br s, 1H, OH), 8.17 (s, 1H, N=CH), 7.98–6.67 (m, 7H, Ar–CH), 7.06 and
7.04 (ss, 2H, SNH2), 3.88 (s, 3H, OCH3); 13C NMR (400 MHz, DMSO-d6:CCl4): d
164.2 (C=O), 149.2 (N=CH), 147.8 (Ar–C–O), 141.4 (Ar–C–S), 133.4 (Ar–C),
131.6, 129.0, 127.0, 125.2, 122.3, 115.1 and 108.9 (Ar–CH), 55.4 (OCH3); DEPT
(400 MHz, DMSO-d6:CCl4): 149.3 (N=CH), 131.6, 130.1, 129.0, 127.0, 122.3,
115.1 and 108.8, 55.5 (OCH3); IR (KBr): 3,531.5 (OH), 3,271.3 (NH, NH2), 3,091.3
(Ar–CH), 1,643.1 (C=O), 1,597.6 (C=N), 1,164.8 (O=S=O) cm-1
.
2-({(2E)-2-[(3-Ethoxy-4-hydroxy)benzylidene]hydrazine}carbonyl)
benzenesulfonamide 5c
M.p. 163–164 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 11.83 and 11.81 (ss, 1H,
NH), 9.19 (br s, 1H, OH), 8.15 (s, 1H, N=CH), 7.99–6.68 (7H, Ar–CH), 7.04 and
7.01 (ss, 2H, SNH2), 4.14 (q, 2H, J = 8.0 Hz, CH2), 1.44–1.41 (m, 3H, CH3); 13C
NMR (400 MHz, DMSO-d6:CCl4): d 164.1 (C=O), 149.4 and 149.0 (2C, Ar–C–O),
147.0 (N=CH), 141.5, 133.5, 131.6, 130.0, 129.0, 127.0, 125.2, 122.2, 115.1, 110.3,
63.8 (CH2), 14.6 (CH3); DEPT (400 MHz, DMSO-d6:CCl4): d 147.0 (N=CH),
131.6, 130.0, 129.0, 127.1, 122.2, 115.2 and 110.3 (Ar–CH), 63.8 (CH2), 14.6
(CH3); IR (KBr): 3,530.3 (OH), 3,268.8 (NH, NH2), 3,065.6 (Ar–CH), 1,648.3
(C=O), 1,595.2 (C=N), 1,168.5 (O=S=O) cm-1
.
2-({(2E)-2-[(4-Methoxy)benzylidene]hydrazine}carbonyl)benzenesulfonamide 5d
M.p. 182–184 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 11.89 and 11.87 (ss, 1H,
NH), 8.35 and 8.24 (ss, 1H, N=CH), 8.0–7.98 (m, 2H, Ar–CH), 7.70–7.63 (m, 4H,
Ar–CH), 7.02 and 6.97 (ss, 2H, S-NH2), 6.97–6.8 (m, 2H, Ar–H), 3.83 (s, 3H,
OCH3); 13C NMR (400 MHz, DMSO-d6:CCl4): d 164.3 (C=O), 160.9 (Ar–C–O),
148.3 (N=CH), 141.5 (Ar–C–S), 133.4 (Ar–C), 130.6, 129.0, 128.7, 128.2, 127.1,
126.5, 113.7, 54.9 (OCH3); DEPT (400 MHz, DMSO-d6:CCl4): d 148.3 (N=CH),
130.5, 129.0, 128.8, 128.2, 127.1, 115.5, 54.8 (OCH3); IR (KBr): 3,263.9 (NH),
3,067.4 (Ar–CH), 1,647.3 (C=O), 1,604.9 (C=N), 1,169.2 (O=S=O) cm-1
.
123

Biologically important hydrazinecarbonyl benzenesulfonamides
2-({(2E)-2-[(3,4-Dimethoxy)benzylidene]hydrazine}carbonyl)benzenesulfonamide
5e
M.p. 168–170 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 11.93 and 11.89 (ss, 1H,
NH), 8.34 and 8.21 (ss, 1H, N=CH), 7.99–7.95 (m, 1H, Ar–CH), 7.72–7.60 (m, 3H,
Ar–CH), 7.50–7.15 (m, 2H, Ar–CH), 7.03 and 7.01 (ss, 2H, SNH2), 6.95–6.81 (m,
2H, Ar–CH), 3.88 (s, 6H, OCH3); 13C NMR (400 MHz, DMSO-d6:CCl4): d 164.3
(C=O), 150.9 (Ar–C–O), 149.1 (Ar–C–O), 148.7 (N=CH), 141.5 (Ar–C–S), 133.4
(Ar–C), 131.7, 130.1, 129.0, 127.1, 126.6, 122.1, 111.0, 108.3, 55.3 (2C, OCH3);
DEPT (400 MHz, DMSO-d6:CCl4): 148.6 (N=CH), 131.7, 130.1, 129.0, 127.1,
122.1, 111.0 and 108.2 (Ar–CH), 55.3 (OCH3); IR (KBr):tmax 3,245.7 (NH, NH2),
3,082 (Ar–CH), 1,661.5 (C=O), 1,603 (C=N), 1,160.9 (O=S=O) cm-1
.
2-({(2E)-2-[(2,4-Dimethoxy)benzylidene]hydrazine}carbonyl)benzenesulfonamide
5f
M.p. 191–193 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 11.87 and 11.82 (ss, 1H,
NH), 8.56 and 8.29 (ss, 1H, N=CH), 7.99–7.87 (m, 2H, Ar–CH), 7.70–7.46 (m, 3H,
Ar–CH), 7.02 and 6.84 (ss, 2H, S-NH2), 6.58–6.35 (m, 2H, Ar–CH), 3.89 and 3.84
(s, 6H, OCH3); 13C NMR (400 MHz, DMSO-d6:CCl4): d 164.2 (C=O), 162.5 (Ar–
C–O), 159.1 (Ar–C–O), 144.3 (N=CH), 141.5 (Ar–C–S), 133.4 (Ar–C), 131.6,
130.0, 129.0, 127.1, 126.9, 114.8, 106.0, 97.8, 55.4 (OCH3), 55.0 (OCH3); DEPT
(400 MHz, DMSO-d6:CCl4): 144.3 (N=CH), 131.6, 130.0, 129.0, 127.1, 106.0 and
97.8 (Ar–CH), 55.4 (OCH3), 55.1 (OCH3); IR (KBr): 3,318.2 (NH, NH2), 3,071.7
(Ar–CH), 1,651.6 (C=O), 1,568 (C=N), 1,168.6 (O=S=O) cm-1
.
2-({(2E)-2-[(3,4,5-Trimethoxy)benzylidene]hydrazine}carbonyl)
benzenesulfonamide 5g
M.p. 196–197 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 12.03 and 11.99 (ss, 1H,
NH), 8.20 (s, 1H, N=CH), 8.00–7.92 (m, 1H, Ar–CH), 7.73–7.47 (m, 4H, Ar–CH),
7.02 and 6.92 (ss, 2H, SNH2), 6.92–6.67 (m, 1H, Ar–CH), 3.86–3.69 (9H, OCH3);
13C NMR (400 MHz, DMSO-d6:CCl4): d 164.5 (C=O), 153.0 and 152.8 (3C, Ar–C–
O), 148.5 (N=CH), 141.5 (Ar–C–S), 133.3 (Ar–C), 131.7, 130.2, 129.4, 129.0,
127.2, 104.0 (Ar–CH), 126.8 (Ar–C), 59.9 and 55.8 (3C, OCH3); DEPT (400 MHz,
DMSO-d6:CCl4): 148.4 (N=CH), 131.7, 130.2, 129.0, 127.1, 126.8 and 104.4 (Ar–
CH), 59.8 and 55.7 (3C, OCH3); IR (KBr): 3,282.8 (NH, NH2), 3,073.2 (Ar–CH),
1,676.4 (C=O), 1,579 (C=N), 1,169.5 (O=S=O) cm-1
.
2-({(2E)-2-[4-(Dimethylamino)benzylidene]hydrazine}carbonyl)
benzenesulfonamide 5h
M.p. 191–193 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 11.78 and 11.76 (ss, 1H,
NH), 8.16 (s, 1H, N=CH), 7.99-7.93 (m, 2H, Ar–CH), 7.71–7.48 (m, 6H, Ar–CH),
7.03 and 6.85 (ss, 2H, SNH2), 6.76–6.71 (m, 2H, Ar–CH), 2.95 (s, 6H, N(CH3)2);
13C NMR (400 MHz, DMSO-d6:CCl4): d 164.0 (C=O), 149.2 (N=CH), 141.5 (Ar–
123

G. Thiyagarajan et al.
C–S), 133.7 (Ar–C), 131.7, 130.2, 129.0, 128.9, 128.0, 127.1 and 111.8 (Ar–CH),
126.7 (Ar–C), 39.9 (2C, NCH3); DEPT (400 MHz, DMSO-d6:CCl4): d 149.2, 131.7,
130.02, 129.0, 128.9, 128.0, 127.1, 111.8 (Ar–CH), 39.9 (2C, NCH3); IR (KBr):
3,359.7 (NH, NH2), 2,991.6 (Ar–CH), 1,654.2 (C=O), 1,526.8 (N=CH), 1,168.9
(O=S=O) cm-1
.
2-({(2E)-2-[(4-Diethylamino)benzylidene]hydrazine}carbonyl)benzenesulfonamide
5i
M.p. 187–189 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 11.67 and 11.58 (ss, 1H,
NH), 8.34 and 8.16 (ss, 1H, N=CH), 7.86–7.90 (m, 2H, Ar–CH), 7.65–7.39 (m, 6H,
Ar–CH), 7.02 and 6.95 (ss, 2H, SNH2), 6.69–6.63 (m, 2H, Ar–CH), 3.18 (m, 4H,
2-NCH2), 1.29 (m, 6H, CH3); 13C NMR (400 MHz, DMSO-d6:CCl4): d 165.7
(C=O), 148.6 (N=CH), 141.4 (Ar–C–S), 133.9 (Ar–C), 131.2, 130.4, 129.1, 128.8,
128.2, 127.0, 110.9 9 (Ar–CH), 126.5 (Ar–C), 48.6 (CH2), 40.1 (CH3); DEPT
(400 MHz, DMSO-d6:CCl4): d 148.5 (N=CH), 131.2, 130.4, 129.1, 128.8, 128.2,
127.0, 110.9 (Ar–CH), 48.6 (CH2), 40.1 (CH3); IR (KBr): 3,360.1 (NH, NH2),
2,998.9 (Ar–CH), 1,659.8 (C=O), 1,525.4 (N=CH), 1,166.3 (O=S=O) cm-1
.
2-({(2E)-2-[(2-Hydroxy)benzylidene]hydrazine}carbonyl)benzenesulfonamide 5j
M.p. 195–197 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 12.30 and 12.12 (ss, 1H,
NH), 9.69 (s, 1H, OH), 8.47 and 8.24 (ss, 1H, N=CH), 8.02–6.70 (m, 8H, Ar–CH),
7.15 and 7.05 (ss, 2H, SNH2); 13C NMR (400 MHz; DMSO-d6:CCl4): d 164.3
(C=O), 157.9 (Ar–C–O), 149.7 (N=CH), 141.6 (Ar–C–S), 132.8 (Ar–C), 132.0,
131.3, 130.5, 129.3, 128.1, 119.0, 118.0 and 116.4 (Ar–CH), 126.4 (Ar–C); DEPT
(400 MHz, DMSO-d6:CCl4): d 149.7 (N=CH), 132.7, 132.1, 131.2, 130.8, 129.7,
128.0,118.9 and 116.3 (Ar–CH); IR (KBr): 3,523.1 (OH), 3,316.9 (NH, NH2),
2,995.5 (Ar–CH), 1,648.1 (C=O), 1,570 (C=N), 1,162.6 (O=S=O) cm-1
.
2-({(2E)-2-[(4-Hydroxy)benzylidene]hydrazine}carbonyl)benzenesulfonamide 5k
M.p. 186–188 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 11.82 and 11.78 (ss, 1H,
NH), 9.79 (br s, 1H, OH), 8.27 and 8.17 (ss, 1H, N=CH), 7.96 (m, 2H, Ar–CH),
7.67–7.55 (m, 4H, Ar–CH), 7.01 and 6.81 (ss, 2H, SNH2), 6.81–6.66 (m, 2H, Ar–
CH); 13C NMR (400 MHz, DMSO-d6:CCl4): d 164.3 (C=O), 159.7 (Ar–C–O),
148.9 (N=CH), 141.5 (Ar–C–S), 133.5 (Ar–C), 131.7, 130.1, 129.1, 128.3, 127.1,
124.7 and 115.5 (Ar–CH), 126.2 (Ar–C); DEPT (400 MHz, DMSO-d6:CCl4): d
148.8 (N=CH), 131.7, 130.0, 129.0, 128.3, 127.1 and 115.5 (Ar–CH); IR (KBr):
3,410.7 (OH), 3,236 (NH, NH2), 3,068.4 (Ar–CH), 1,638.9 (C=O), 1,600 (C=N),
1,163.6 (O=S=O) cm-1
.
2-({(2E)-2-[(2-Chloro)benzylidene]hydrazine}carbonyl)benzenesulfonamide 5l
M.p. 185–187 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 12.24 and 12.22 (ss, 1H,
NH), 8.45 and 8.73 (ss, 1H, N=CH), 8.14–7.38 (m, 6H, Ar–CH), 7.01 and 6.90 (ss,
123

Biologically important hydrazinecarbonyl benzenesulfonamides
2H, SNH2), 6.81–6.66 (m, 2H, Ar–CH); 13C NMR (400 MHz, DMSO-d6:CCl4): d
164.6 (C=O), 156.4 (Ar–C–Cl), 146.4 (N=CH), 141.6 (Ar–C–S), 133.5 (Ar–C),
133.1, 131.6, 131.1, 130.3, 129.5, 128.9, 127.2 and 127.0 (Ar–CH), 126.6 (Ar–C);
DEPT (400 MHz, DMSO-d6:CCl4): d 144.4 (N=CH), 140.4, 131.6, 131.1, 130.3,
129.5, 128.9, 127.2, 127.0; IR (KBr): 3,332.1 (NH, NH2), 3,056.3 (Ar–CH), 1,657.4
(C=O), 1,555.9 (N=CH), 1,166.1 (O=S=O) cm-1
.
2-({(2E)-2-[(4-Chloro)benzylidene]hydrazine}carbonyl)benzenesulfonamide 5m
M.p. 193–195 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 12.08 and 12.04 (ss, 1H,
NH), 8.28 and 8.04 (ss, 1H, N=CH), 8.0–7.27 (m, 8H, Ar–CH), 7.05 and 7.01 (ss,
2H, SNH2); 13C NMR (400 MHz, DMSO-d6:CCl4): d 164.5 (C=O), 154.2 (Ar–C–
Cl), 147.0 (N=CH), 141.5 (Ar–C–S), 134.9 (Ar–C), 132.8, 131.6, 130.8, 130.2,
129.4, 128.9 and 127.2 (Ar–CH), 126.2 (Ar–C); DEPT (400 MHz, DMSO-d6:CCl4):
d 147.0 (N=CH), 131.6, 130.8, 130.2, 129.4, 128.9 127.2; IR (KBr): 3,345.9 (NH,
NH2), 3,057.5 (Ar–CH), 1,645.6 (C=O), 1,602.1 (CH=N), 1,166.7 (O=S=O) cm-1
.
2-({(2E)-2-[(2-Nitro)benzylidene]hydrazine}carbonyl)benzenesulfonamide 5n
M.p. 179–80 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 12.27 and 12.06 (ss, 1H,
NH), 8.57 and 8.41 (ss, 1H, N=CH), 8.23–7.46 (m, 8H, Ar–CH), 7.05 and 7.0 (ss,
2H, SNH2); 13C NMR (400 MHz, DMSO-d6:CCl4): d 164.7 (C=O), 148.1 (N=CH),
147.9, 145.8 (Ar–C–N), 141.6 (Ar–C–S), 136.0, 133.0 (Ar–C), 131.7, 130.0, 128.9,
126.9 (Ar–C), 124.0, 123.5, 121.3; DEPT (400 MHz, DMSO-d6:CCl4): d 164.7
(C=O), 148.1 (N=CH), 133.0, 131.7, 130.0, 129.0, 127.1, 123.6, and 121.3 (Ar–
CH); IR (KBr): 3,266.7 (NH, NH2), 3,066.7 (Ar–CH), 1,675.1 (C=O), 1,519.3
(NO2), 1,558.7 (CH=N), 1,160.2 (O=S=O) cm-1
.
2-({(2E)-2-[(3-Nitro)benzylidene]hydrazine}carbonyl)benzenesulfonamide 5o
M.p. 188–190 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 11.38 and 11.25 (ss, 1H,
NH), 8.23 and 8.20 (ss, 1H, N=CH), 8.18–7.46 (m, 8H, Ar–CH), 7.04 and 7.01 (ss,
2H, SNH2); 13C NMR (400 MHz, DMSO-d6:CCl4): d 164.7 (C=O), 148.1 (N=CH),
145.8 (Ar–C–NO2), 141.6 (Ar–C–S), 136.0, 133.0 (Ar–C), 132.4, 131.7, 130.3,
129.2, 128.9, 127.2, 124.0, 121.3; DEPT (400 MHz, DMSO-d6:CCl4): d 148.2
(N=CH), 136.0, 131.7, 130.0,129.2, 128.9, 124.1 and 121.2 (Ar–CH); IR (KBr):
3,271.3 (NH), 3,065.4 (Ar–CH), 1,661.4 (C=O), 1,527.9 (NO2), 1,590.6 (C=N),
1,171.8 (O=S=O) cm-1
.
2-({(2E)-2-[(4-Nitro)benzylidene]hydrazine}carbonyl)benzenesulfonamide 5p
M.p. 183–184 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 12.31 and 12.26 (ss, 1H,
NH), 8.39 and 8.28 (ss, 1H, N=CH), 8.28–7.45 (m, 8H, Ar–CH), 7.01 and 6.94 (ss,
2H, SNH2); 13C NMR (400 MHz, DMSO-d6:CCl4): d 164.8 (C=O), 147.9 (N=CH),
141.5 (Ar–C–NO2), 140.3 (Ar–C–S), 133.0 (Ar–C), 131.7, 130.3, 129.2, 128.6,
128.0, 127.2, 123.6; DEPT (400 MHz, DMSO-d6:CCl4): d 147.8 (N=CH), 133.1,
123

G. Thiyagarajan et al.
131.6, 130.2, 128.5, 127.2, 123.6; IR (KBr): 3,333.5 (NH, NH2), 3,065.1 (Ar–CH),
1,659.7 (C=O), 1,524.7 (NO2), 1,590.2 (C=N), 1,166 (O=S=O) cm-1
.
2-({(2E)-2-[(Furan-2-yl)methylene]hydrazine}carbonyl)benzenesulfonamide 5q
M.p. 163–65 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 11.98 and 11.92 (ss, 1H,
NH), 8.19 (s, 1H, N=CH), 7.99–7.94 (m, 2H, Ar–CH), 7.73–7.45 (m, 3H, Ar–CH),
7.04 and 7.0 (ss, 2H, SNH2), 6.89–6.46 (m, 2H, Ar–CH); 13C NMR (400 MHz,
DMSO-d6:CCl4): d 164.5 (C=O), 149.3 (N=CH), 144.7 (Ar–C–O), 141.5 (Ar–C–S),
138.1, 133.2 (Ar–C), 131.7, 130.8, 129.0, 127.2, 113.2, 111.8; DEPT (400 MHz,
DMSO-d6:CCl4): d 149.2 (N=CH), 138.1, 131.7, 130.9, 127.2, 113.2, 111.8; IR
(KBr): 3,255.6 (NH), 3,060.9 (Ar–CH), 1,653.9 (C=O), 1,589.2 (CH=N), 1,168.8
(O=S=O) cm-1
.
2-({(2E)-2-[2-(Anthracen-9-yl)benzylidene]hydrazine}carbonyl)
benzenesulfonamide 5r
M.p. 157–159 °C, 1H NMR (400 MHz, DMSO-d6:CCl4): d 12.26 and 12.22 (ss, 1H,
NH), 8.81 (m, 1H, Ar–H), 8.60 and 8.48 (ss, 1H, N=CH), 8.42 (d, 1H, J = 8.4, Ar–
CH), 8.09–7.82 (m, 3H, Ar–CH), 7.76–7.39 (m, 7H, Ar–CH), 7.13 and 6.92 (ss, 2H,
S-NH2); 13C NMR (400 MHz, DMSO-d6:CCl4): d 164.5 (C=O), 147.7 (N=CH),
141.7 (Ar–C–S), 140.5, 133.9, 133.3 (Ar–C), 130.8, 129.8, 129.0, 128.5, 126.8,
126.4, 125.1, 124.9; DEPT (400 MHz, DMSO-d6:CCl4): d 147.7 (N=CH), 130.8,
129.8, 129.0, 128.5, 126.8, 126.4, 125.1, 124.8; IR (KBr): 3,302.4 (NH), 3,073.7 (Ar
CH), 1,658.8 (C=O), 1,603.6 (C=N), 1,168.7 (O=S=O) cm-1
.
Antibacterial assay
All the synthesized compounds were dissolved in dimethyl sulfoxide (DMSO) and
tested for their antibacterial activity against Gram-positive S. aureus and B. firmus
and Gram-negative E. coli bacterial organisms by the hole diffusion method.
DMSO was chosen as a control because it has no effect on these bacterial strains.
The culture media for the growth of bacterial strains S. aureus and E. coli were
prepared by using peptone (3.0 g), NaCl (1.0 g), yeast (1.5 g), and agar (6.0 g) in
300 mL distilled water at pH 7.0. However, the culture medium intended for
B. firmus was prepared by the reported procedure [31]. Sterilization of the medium
was done by autoclaving at 15 Pa for 20 min, and after keeping at 85 °C for 30 min
it was poured into sterilized Petri plates in a laminar flow environment.
Solidification of the medium was achieved at 30 °C in 15 min. The bacterial
strains were inoculated over the media with the help of a micropipette followed by
poking with a 5-mm hollow glass tube to create holes. The four different tested
doses, viz. 200, 100, 50, and 25 lg/mL, of each of the synthesized compounds (5a–
r) and norfloxacin were loaded into these holes separately through bacteria-free
micropipettes in different Petri dishes. After 24 h, the antibacterial activity was
determined by measuring the zone of inhibition in millimeters (mm) and compared
with the results obtained from the standard drug norfloxacin. The lowest
123

Biologically important hydrazinecarbonyl benzenesulfonamides
concentration that inhibited the growth of bacteria was noted and considered as the
MIC value for each of the tested compounds.
Crystallography
Data collection from crystals of 3 and 5k was performed on an Oxford Diffraction
Xcalibur 3 diffractometer (Mo Ka radiation, graphite monochromator) and on a
Nonius Kappa CCD diffractometer for crystals of 5e and 5f (Mo Ka radiation,
multilayer X-ray optics) at temperature of 173 K. The structures were solved by
direct methods with SIR97 [32] and refined by full-matrix least-squares methods on
F2 with SHELXL-97 [33]. All nonhydrogen atoms were refined anisotropically. The
C-bound hydrogen atoms were added geometrically and treated as riding on their
parent atoms. The O-bound hydrogen atoms for crystal 5k were refined to a fixed
˚
distance of 0.82(1) A with Uiso(H) = 1.2Ueq(N/H). The thermal parameters of the
N-bound hydrogen atoms were in all cases refined as U(H) = 1.2U(N). The
˚
N-bound hydrogen atoms for 3 and 5f were refined to a fixed distance of 0.86(1) A,
while in 5e this distance was refined freely. Multiscan absorption corrections were
performed with SCALE 3 ABSPACK [34] for the crystals of 3, 5e, and 5k, while
the crystal data of 5f were not corrected for multiscan absorption.
Conclusions
A series of hydrazinecarbonyl benzenesulfonamides (5a–r) have been synthesized
by microwave heating in shorter reaction times and higher yields in small amounts
of solvents. A comparison with synthesis of the products by the conventional
method has also been undertaken. The obtained products have been characterized by
NMR and IR spectral techniques. The crystal and molecular structures of 3, 5e, 5f,
and 5k have also been elucidated by single-crystal X-ray crystallography. The
in vitro antibacterial activities of the derived products were evaluated against Gram-
positive S. aureus and B. firmus along with Gram-negative E. coli bacterial strains.
The zone of inhibition of compounds 5a, 5j, 5p, and 5r showed that these
compounds exhibit moderate bioactivities against all tested organisms.
Supplementary information
The crystallographic information file (CIF) data of 3 (CCDC 853352), 5e (CCDC
863707), 5f (CCDC 863710), and 5k (CCDC 863353) can be obtained free of
charge via http://www.ccdc.cam.ac.uk/conts/retrieving.html (or from the Cambridge
Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: ?44
1223 336033).
References
1. C. Rooney, A.J. McMichael, R.S. Kovats, M. Coleman, J. Epidemiol. Community Health 52, 482
(1998)
123

G. Thiyagarajan et al.
2. T. Kosatsky, Eurosurveillance 10, 148 (2005)
3. A. Woodward, S. Hales, P. Weinstein, Clim. Res. 11, 31 (1998)
4. A. Haines, R.S. Kovats, L.D. Campbell, D. Corvalan, Lancet 367, 1 (2006)
5. A.S. William, F.B. Aleksel, C. Ron, Organic Synthesis: The Science Behind Art (Royal Society of
Chemistry, Cambridge, 1998)
6. R.S. Varma, R. Dahiya, R.K. Saini, Tetrahedron Lett. 386, 7029 (1997)
7. R. Strauss, R.W. Trainor, Aust. J. Chem. 48, 1665 (1995)
8. N.B. Ondruschka, W. Lautenschlager, Synth. Commun. 31, 1277 (2001)
9. R.S. Varma, Green. Chem. 1, 43 (1999)
10. D.R. Baghurst, D.M.P. Mingos, Chem. Soc. Rev. 20, 1 (1991)
11. C.O. Kappe, Angew. Chem. Int. Ed. 43, 6250 (2004)
12. K. Rader, P. Stoss, U.S. Patent US4362730, 7 Dec 1982
13. J.W. Rayburn, WO Patent 00/12067, 9 Mar 2000
14. P.M. Bhatt, N.V. Ravindra, R. Banerjee, G.R. Desiraju, Chem. Commun. 1073 (2005)
15. R. Banerjee, P.M. Bhatt, N.V. Ravindra, G.R. Desiraju, Cryst. Growth Des. 5, 2299 (2005)
16. R. Banerjee, P.M. Bhatt, G.R. Desiraju, Cryst. Growth Des. 6, 1468 (2006)
17. S.Y. Wang, W.C. Guo, N. Ma, Acta Cryst. E 63, o3192 (2007)
18. J. Drews, Science 287, 1960 (2000)
19. A.E. Boyd 3rd, Diabetes 37, 847 (1988)
20. T.H. Maren, Annu. Rev. Pharmacol. Toxicol. 16, 309 (1976)
21. C.T. Supuran, A. Scozzafava, Curr. Med. Chem. Immunol. Endocr. Metabol. Agents 1, 61 (2001)
22. C.W. Thornber, Chem. Soc. Rev. 8, 563 (1979)
23. L. Yin, L. Yao, Q. Ke-Ming, L. Xiang, F. Jie, Z. Hai-Liang, Bioorg. Med. Chem. 19, 6069 (2011)
24. S. Rollas, S.G. Kucukguzel, Molecules 12, 1910 (2007)
25. G. Thiyagarajan, P. Nithiya, A. Pandey, A. Pandey, Int. J. Org. Chem. 1, 71 (2011)
26. S.K. Sridhar, A. Ramesh, Biol. Pharm. Bull. 24, 1149 (2001)
27. J.X. Wang, X.Z. Li, L.N. Zhu, J.Y. Wang, H.J. Qu, J. Chem. Crystallogr. 40, 726 (2010)
28. S. Naskar, R.J. Butcher, S.K. Chattopadhyay, Inorg. Chim. Acta 363, 3641 (2010)
29. G.N. Lewis, J. Am. Chem. Soc. 38, 772 (1916)
30. W.L.F. Armarego, L.L.C. Christina, Purification of Laboratory Chemicals, 5th edn. (Elsevier,
Amsterdam, 2003)
31. J. Szumigaj, Z. Zakowska, L. Klimek, Pol. J. Microbiol. 57, 281 (2008)
32. A. Altomare, M.C. Burla, M. Camalli, G.L. Cascarano, C. Giacovazzo, A. Guagliardi, G.G. Moli-
terni, G. Polidori, R. Spagna, J. Appl. Cryst. 32, 115 (1999)
33. G.M. Sheldrick, Acta Cryst. A 64, 112 (2008)
34. L.J. Farrugia, J. Appl. Cryst. 32, 837 (1999)
123