Synthesis, Characterization, Thermal and Antimicrobial studies of N-substituted Sulfanilamide derivatives

Article abstract of DOI:10.1016/j.molstruc.2013.12.063

Four sulfanilamide derivatives N-[4-(phenylsulfamoyl)phenyl]acetamide (1), 4-amino-N-phenylbenzenesulfonamide (2), N-[4-(phenylsulfamoyl)phenyl]benzamide (3) and N-{4-[(3-chlorophenyl)sulfamoyl]phenylbenzamide (4) were synthesized and characterized by Infra-Red (IR), Nuclear Magnetic Resonance (NMR) and UV-visible (UV-Vis) spectra. Also Liquid Chromatographic (LCMS) and High Resolution Mass Spectrometric (HRMS) methods were used. Crystal structures of 1-4 were determined by single crystal X-ray diffraction (XRD) and their conformational and hydrogen bond (HB) network properties were examined with survey of the literature data. Compounds 1 and 2 crystallize in the same orthorhombic Pbca symmetry with equivalent molecular conformation (tilted V-shape) but showed distinct packing and hydrogen bonding models. Compounds 3 and 4 crystallize in monoclinic and triclinic crystal systems, albeit exhibiting identical molecular conformation (L-shaped). Same donor acceptor pairs both on 3 and 4 result to different kind of HB network. Thermogravimetric (TG) and differential scanning calorimetric (DSC) methods were used to evaluate thermal properties of the substances. All sulfanilamide derivatives have melting points between195-227 C, initiation of thermal decomposition between 259-271 C and enthalpies of fusion ΔHfusT = 38.96, 36.60, 46.23 and 44.81 kJ mol ^-1 were determined for 1-4, respectively. The derivatives were screened for their antibacterial and antifungal activities against various bacterial and fungal strains. It is observed that there is no significant antibacterial activity with the introduction of the benzene ring to CO-NH group or SO₂-NH moiety, and none of the compounds exhibited antifungal activity.

Full text of DOI:10.1016/j.molstruc.2013.12.063

Journal of Molecular Structure 1060 (2014) 280–290
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstruc
Synthesis, Characterization, Thermal and Antimicrobial studies
of N-substituted Sulfanilamide derivatives
b
c
a
Manu Lahtinen a, Jyothi Kudva b, , Poornima Hegde , Krishna Bhat , Erkki Kolehmainen ,
⇑
Nonappa d, Venkatesh e, Damodara Naral f
a Department of Chemistry, University of Jyväskylä, FI-40014 JY, Finland
b Department of Chemistry, St. Joseph Engineering College, Mangalore, India
c Department of Chemistry, NITK, Surathkal, Mangalore, India
d Aalto University School of Science, Department of Applied Physics, FI-00076 Aalto, Finland
e Department of Chemistry and iNANO, Aarhus University Langelandsgade 140, 8000 Aarhus C, Denmark
f Department of Chemistry, Canara Engineering College, Mangalore, India
h i g h l i g h t s
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Synthesized four sulfanilamide derivatives.
Characterized by IR NMR and Mass spectra.
Single crystal X-ray diffraction study was done.
The thermal behavior study was done by TGA and DSC methods.
Antimicrobial activity was studied.
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 August 2013
Received in revised form 17 December 2013
Accepted 18 December 2013
Available online 31 December 2013
Four sulfanilamide derivatives N-[4-(phenylsulfamoyl)phenyl]acetamide (1), 4-amino-N-phenylben-
zenesulfonamide (2), N-[4-(phenylsulfamoyl)phenyl]benzamide (3) and N-{4-[(3-chlorophenyl)sulfa-
moyl]phenylbenzamide (4) were synthesized and characterized by Infra-Red (IR), Nuclear Magnetic
Resonance (NMR) and UV–visible (UV–Vis) spectra. Also Liquid Chromatographic (LCMS) and High Res-
olution Mass Spectrometric (HRMS) methods were used. Crystal structures of 1–4 were determined by
single crystal X-ray diffraction (XRD) and their conformational and hydrogen bond (HB) network proper-
ties were examined with survey of the literature data. Compounds 1 and 2 crystallize in the same ortho-
rhombic Pbca symmetry with equivalent molecular conformation (tilted V-shape) but showed distinct
packing and hydrogen bonding models. Compounds 3 and 4 crystallize in monoclinic and triclinic crystal
systems, albeit exhibiting identical molecular conformation (L-shaped). Same donor acceptor pairs both
on 3 and 4 result to different kind of HB network. Thermogravimetric (TG) and differential scanning calo-
rimetric (DSC) methods were used to evaluate thermal properties of the substances. All sulfanilamide
derivatives have melting points between195–227 °C, initiation of thermal decomposition between
Keywords:
Synthesis
Sulfanilamides
Antimicrobial activity
X-ray diffraction
Crystal structure
Thermal analysis
259–271 °C and enthalpies of fusion
D
HTfus = 38.96, 36.60, 46.23 and 44.81 kJ molꢁ1 were determined
for 1–4, respectively. The derivatives were screened for their antibacterial and antifungal activities
against various bacterial and fungal strains. It is observed that there is no significant antibacterial activity
with the introduction of the benzene ring to CO–NH group or SO2–NH moiety, and none of the com-
pounds exhibited antifungal activity.
Ó 2013 Elsevier B.V. All rights reserved.
1. Introduction
of tetrahydrofolic acid, which is a basic growth factor essential
for the metabolic process of bacteria. Many biological activities
Sulfonamides represent an important class of medicinally active
compounds which are extensively used as antibacterial agents. It
interferes with PABA (p-aminobenzoic acid) in the biosynthesis
have been recently reviewed that include endothelia, antagonism,
anti-inflammatory, tubular transport inhibition, insulin release and
saluretic activity [1]. It is well documented [2–5] that toxicological
and pharmacological properties are enhanced when sulfonamides
are administered with amide moiety.
⇑
Corresponding author. Tel.: +91 8242232411.
E-mail address: jyothikudva@gmail.com (J. Kudva).
0022-2860/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.molstruc.2013.12.063

M. Lahtinen et al. / Journal of Molecular Structure 1060 (2014) 280–290
281
Hydrogen atoms attached to carbon atoms were calculated to their
‘‘idealized’’ positions as riding atoms, whereas those attached to
nitrogen hosts were located in the difference Fourier map. By this,
the previously reported zwitterion form [32] plausible for com-
pound 2 was ruled out, as hydrogen atoms attached to the amide
and amino groups were possible to locate in the difference Fourier
maps. An isotropic extinction parameter was refined in case of
compounds 1, 3 and 4, whereas for 2 its value was negligible and
therefore was removed from the final refinement. Isotropic dis-
placement parameters of all hydrogen atoms were fixed 1.2–1.5
times higher than those of the attached non-hydrogen atoms.
The programs Mercury (v. 3.0.1) [33] and Olex2 were used for
depicting the crystal structures.
Fig. 1. Molecular structures of compounds 1–4.
Compounds possessing amide and sulfonamide functional
groups have been reported to display a wide range of activities like
antibacterial, antifungal [6–9], antiviral [10], anti-tumor [11], anti-
malarial [12], anti-HIV [13], anti-ulcer and anti-inflammatory [14],
anti-convulsant [15], anti-oxidant [16], anti-coccidiostat [17],
hypoglycemic [18], diuretic [19,20], anti-carbonic anhydrase
[19,21] antithyroid agents [22] and in the treatment of Alzheimer’s
disease [23].
2.1.2. Differential scanning calorimetry
Power compensation-type Perkin–Elmer Pyris Diamond
differential scanning calorimeter (DSC) was used to measure DSC
heating–cooling scans. DSC scans were made under high purity
(999.995%) nitrogen atmosphere (flow rate 50 mlꢂminꢁ1) using
50
ll aluminum pan sealed by perforated 30 ll aluminum pan.
Biological and pharmacological properties when coupled with
detailed structural studies that reveal great information to design
potential drug molecules [24,25]. In this context, we have synthe-
sized some organic compounds bearing amide or sulfonamide moi-
eties (compounds 1–4, Fig. 1). The identity of these compounds has
been characterized by IR, NMR, LCMS, HRMS, UV–visible, TG, DSC
and single crystal X-ray diffraction studies. Their antimicrobial
activities were evaluated and the results were compared with
some of the reported compounds.
Temperature calibration was carried out with two standards
(n–decane and In) and energy calibration by an indium standard
(Ref. and meas. value 28.45 and 28.47 Jꢂgꢁ1). Each sample was
heated at a rate of 10 °Cꢂminꢁ1 from ꢁ40 °C to about 10–20 °C
above the last observed thermal transition (predetermined by
TG/DTA), cooled back to ꢁ40 °C at a rate of 5 °Cꢂminꢁ1, and then
heated similarly for a second time. The sample amounts used on
the measurements were about 4–6 mg. The enthalpy of fusion at
298
fus
298 K was calculated by the equation
DH
¼
DHfus
ꢁ
DSfus
ꢁ
ðTm ꢁ 298:15Þ, where in
DSfus
¼
DHfus=Tm.
2. Experimental
2.1.3. Thermogravimetry
Thermogravimetric data were recorded with Perkin–Elmer STA
6000 simultaneous thermal analyzer (measuring both thermo-
gravimetric and differential temperature signals; TG/DTA). Each
measurement was carried out in an open platinum pan under high
purity air (99.999%) atmosphere (flow rate of 45 mlꢂminꢁ1) by
heating a sample from 25 to 700 °C with a heating rate of
10 °Cꢂminꢁ1. Temperature calibration of the instrument was made
using melting points of the Perkin–Elmer indium and zinc stan-
dards (Ref. and measured values: In 156.6 and 156.5; Zn 419.5
and 419.7 °C, respectively). Weight calibration of the instrument
was made at room temperature using amass standard weight
(stainless steel) of 50.00 mg. The sample amounts used in the
measurements were about 7–8 mg.
2.1. Physical and chemical measurements
The IR spectra were recorded on a Perkin Elmer FT/IR Spectrum
BX in the range 4000–400 cmꢁ1 using KBr pellet technique with a
spectral resolution 4 cmꢁ1. 1H and 13C NMR spectra were recorded
with Bruker Avance 400 spectrometer in CDCl3 and DMSO-d6
(400 MHz, 1H and 100 MHz, 13C). Chemical shifts (d) were reported
in ppm from the internal reference tetramethylsilane (TMS). High
resolution mass spectra were measured with Waters Micromass
Q-Tof (ESI-HRMS) spectrometer. LCMS measurements were per-
formed in Agilent technologies 1200w series instrument. UV–Visi-
ble spectra were obtained in Perkin Elmer Lambda 750. TLC was
conducted on 0.25 mm silica gel plates (60F254, Merck). Visualiza-
tion was made by using ultraviolet light. All the reagents were pur-
chased from commercial sources and used without further
purification.
2.1.4. Antimicrobial studies
Antibacterial screening of these samples were made against a
gram +ve (S. Aureus) and a gram –ve (E. Coli), in two different con-
centrations with Ciprofloxacin as reference drug. Testing was done
by zone inhibition method in Agar medium. Antifungal studies
were done against Aspergillus niger and Candida albicuns strains
with Miconazole as reference drug. Toxicity studies were carried
2.1.1. Structure determination by single crystal X-ray diffraction
The intensity data for compounds 1–3 were acquired at –
100 1 °C with
equipped with APEXII detector and using graphite monochroma-
tized Mo K radiation (k = 0.71073 Å). The COLLECT [26] software
a Bruker–Nonius Kappa CCD diffractometer
out as per OECD guidelines by giving an oral dose of 2000 mgꢂkgꢁ1
.
a
All compounds were found non-toxic.
was used for data collection and the data sets were processed with
DENZO-SMN [27] and the multi-scan absorption correction (SAD-
ABS) [28] was used. For compound 4, Agilent Supernova (dual
2.2. Synthesis of the compounds
source) diffractometer was used to acquire the data at
100 1 °C with multilayer optics monochromatized and micro
source generated Cu K radiation (k = 1.54184 Å). Data collection
and reduction, as well as analytical numeric absorption correction
using a multifaceted crystal model were all made by program Cry-
salisPro (v. 1.171.36.24) [29]. All four crystal structures were solved
by direct methods using SHELXS [30] and were refined on F2 using
SHELXL-97 [30] both implemented in program Olex2 (v. 1.2.2) [31].
–
2.2.1. Synthesis of N-[4-(phenylsulfamoyl)phenyl]acetamide (1)
[34,35]
a
Acetanilide (1.35 g, 0.01 mol) was taken in 10 ml chloroform
and cooled to 0 °C. Excess of chlorosulfonic acid (6.7 ml, 0.1 mol)
was added in small aliquots maintaining the temperature. The
mixture was stirred at RT overnight to complete the reaction as
indicated by TLC. Then the reaction mixture was quenched pouring
it into crushed ice. Solid separated was filtered, washed with cold

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M. Lahtinen et al. / Journal of Molecular Structure 1060 (2014) 280–290
water and dried in nitrogen atmosphere. 4-(acetylamino)benzene-
sulfonyl chloride was added to 0.91 ml (0.01 mol) aniline in small
portions at room temperature at pH 8 by the simultaneous addi-
tion of 10% Na2CO3. Progress of the reaction was monitored by
TLC. After the completion of the reaction, the pH was adjusted to
2.0 by dropwise addition of conc. HCl. The precipitate was collected
by filtration, washed with water and dried to afford the compound
1 as white solid. Single crystals suitable for X-ray diffraction stud-
ies were obtained from a dilute ethanol/water solution.
Analytical and physical data: Formula: C14H14N2O3S; Yield:
80–85%; MP: 214–216 °C; LCMS (–ve mode): (M–H) = 289.2
(99.1%), RT – 3.156; HRMS: obtained m/z = 313.0625 (M + Na),
cald. = 313.0630.
3. Results and discussion
3.1. IR spectroscopy
The experimental IR frequencies for the compounds are also
given in Table 1 (for sample spectra see Supplementary material
Fig. S1). The spectra of synthesized compounds contains some
characteristic bands of the stretching vibrations of the NAH, C@O
and SO2 groups. The NAH stretching vibration of secondary
amines groups of some aryl sulfonamides occurs in the region
3300–3200 cmꢁ1 [37]. The bands at 3245 – 3145 cmꢁ1 are assigned
to the NAH stretching mode of ASO2NHA. The bands at 3380 –
3291 cmꢁ1 are assigned to the NAH stretching mode of ACONHA.
This NAH bond appears to be somewhat higher than NAH stretch-
ing mode of ASO2NHA, because ACONHA is more electron with-
drawing group. The amides and sulfonamides are strongly
associated with hydrogen bonds. The splitting wave number differ-
ence in the NAH vibrational bands shows the presence of intermo-
lecular hydrogen bonding by the NH group. The SO2 asymmetric
and symmetric stretching vibrations appeared in the range
1327–1317 cmꢁ1 and 1157–1152 cmꢁ1 respectively. Compounds
showed a strong band in the range 1673–1662 cmꢁ1 which is
assigned to C@O stretching vibration.
2.2.2. Synthesis of 4-amino-N-phenylbenzenesulfonamide (2) [36]
2.9 g (0.01 mol) of compound 1 obtained as per the procedure
described above was refluxed with ethanol and conc. HCl till TLC
showed completion of the reaction. Reaction mixture was cooled
and pH of 9 was maintained using ammonia solution. Separated
precipitate was filtered, washed with water and dried. Single crys-
tals of Comp. 2 were grown from water/ethanol solution.
Analytical and physical data: Formula: C12H12N2O2S; Yield:
85–90%; LCMS (+ve mode): M = 248.9 (98.8%), RT – 2.954; HRMS:
obtained m/z = 271.0518 (M + Na), cald. = 271.0517.
2.2.3. Synthesis of N-[4-(phenylsulfamoyl)phenyl]benzamide (3)
[9,15]
3.2. NMR spectroscopy
To a well-stirred solution of compound 2 (2.48 g, 0.01 mol) in
chloroform, benzoyl chloride (1.28 ml, 0.011 mol) in chloroform
was added dropwise at 0 °C and stirring was continued in cold con-
dition. After the completion of reaction (monitored by TLC), the
reaction mixture was poured into ice cold water. White solid was
filtered, washed with acetic acid and sodium bicarbonate solutions,
dried and purified by recrystallization. Single crystals suitable for
diffraction studies were obtained by slow evaporation from
ethanol.
The experimental 1H and 13C NMR chemical shifts for the com-
pounds in DMSO-d6 are given in Table 2 and Table 3, and the num-
bering of atoms in Fig. 2 (for sample spectra see Supplementary
material Fig. S2). The aromatic carbon signals are assigned between
150.86 and 113.14 ppm and the shift of the carbonyl carbon is be-
tween 169 and 166 ppm. Aromatic proton peaks were observed at
about 7.94–6.39 ppm. The NAH proton signals appear in the range
10.57 ppm to 10.21 ppm for 3 and 4, whereas for 1 they appear at
9.52 ppm and 9.26 ppm. But for compound 2, one NAH proton sig-
nal appears at 8.99 ppm and other two NAH proton signals merged
with aromatic proton signals i.e. at 6.99 to 6.91 ppm. Again the dif-
ference in the chemical shift values of NAH proton signal shows
the presence of intermolecular hydrogen bonding by the NH group.
Analytical and physical data: Formula: C19H16N2O3S; Yield:
70–75%; LCMS (+ve mode): (M + H) = 353.0 (99.5%), RT – 4.349;
HRMS: Obtained m/z = 375.0777 (M + Na), cald. = 375.0779.
2.2.4. Synthesis of N-{4-[(3-chlorophenyl)sulfamoyl]phenylbenzamide
(4)
Compound was obtained by the reaction of 4-amino-N-(3-chlo-
rophenyl)benzenesulfonamide with benzoyl chloride following the
same procedure as mentioned earlier. White crystalline solid was
obtained as a final product. Single crystals suitable for diffraction
studies were obtained by slow evaporation from ethanol.
Analytical and physical data: Formula: C19H15ClN2O3S; Yield:
85–90%; LCMS (+ve mode): (M + H) = 387.0(99.5%), RT – 4.868;
HRMS: Obtained m/z = 409.0395 (M + Na), cald. = 409.0390.
3.3. UV–Visible spectroscopy
The spectral band (kmax) values from the recorded UV–Vis
spectra are given in Table 1 and the spectra in Fig. 3. UV–Vis spec-
tra of the synthesized compounds were recorded using ethanol as
solvent. The characteristic UV bands with kmax around 230 and 270
were indicative of the presence of benzene chromophore and
sulfonamide moiety.
Table 1
IR and UV–Vis spectral data.
Comp.
IR data (Å)
NH (str)
UV
SO2 (str)
SO2 (bend)
542.39(m)
C@O(str) (amide I)
NH deform (amide II)
1538.53(s)
NH (out-of-plane)
730.38(w)
kmax (nm)
1
2
3291.72(m)
3240.12(m)
1316.57(s)assy
1153.81(s)sym
1673.39(s)
204, 223, 263
3421.84(m)
3351.21(m)
3244.57(m)
1318.65(s)assy
1151.56(s)sym
545.99(m)
1639.98(s)
(scissoring)
202, 232, 268
3
4
3355.78(m)
3161.19(m)
1321.58(s)assy
1152.57(s)sym
555.52(w)
546.91(w)
1663.01(s)
1661.32(s)
1537.14(s)
1529.49(s)
719.49(w)
726.04(w)
205, 230, 279
204, 230, 277
3380.17(m)
3145.49(m)
1326.45(s)assy
1156.99(s)sym

M. Lahtinen et al. / Journal of Molecular Structure 1060 (2014) 280–290
283
Table 2
1H NMR chemical shift (ppm) values.
Protons
Comp.
1
2
3
4
Ha
9.52
8.99
10.57
10.57
Hb
9.26
10.21
10.48
H2, H6
H3, H5
H8
7.55–7.49
7.55–7.49
7.03–6.87
7.03–6.87
7.03–6.87
7.03–6.87
7.03–6.87
1.98(CH3)
1.98(CH3)
1.98(CH3)
7.32
6.99–6.91
6.39
6.99–6.91
6.81
6.99–6.91
6.39
7.94–7.92
7.94–7.92
7.10
7.23
7.01
7.23
7.10
7.74
7.62–7.51
7.62–7.51
7.96–7.91
7.96–7.91
7.08–7.06
H9
H10
H11
H12
7.12
7.26
7.08–7.06
7.76
7.62–7.58
7.62–7.58
H
H
14, H18
15, H17
H16
Table 3
Fig. 3. UV–Vis absorption spectra of compounds 1–4.
13C NMR chemical shift (ppm) values.
Carbons
Comp.
1
2
3
4
v. 5.33 Aug. 2012) [38]. Six dihedral angles h1-6 were selected
for the survey (Table 4 and Fig. 4), of which for comparability
purposes the first four were set to be analogous to that
of used by Perlovich et al. [39a,39b] and Parkin et al. [40] in
their comparative conformation analyses on number of
sulfonamides. Based on our atomic numbering scheme, dihedral
angles h1–6 were defined as follows: for sulfamoyl group region
C1
C2
C3
C4
C5
C6
C7
C8
133.11
127.64
118.56
142.47
118.56
127.64
137.17
120.38
128.55
124.3
126.34
128.46
113.14
150.86
113.14
128.46
137.63
120.03
128.63
123.39
128.63
120.03
134.42
127.75
119.90
143.05
119.90
127.75
137.79
120.01
129.09
123.94
129.09
120.01
133.69
127.74
128.43
131.92
128.43
127.74
166.07
134.37
127.75
119.97
143.31
119.97
127.75
139.40
118.92
133.2
123.56
130.87
117.86
134.37
127.75
128.40
131.92
128.40
127.75
166.06
h1(N4AS1AC11AC12),
h2(C11AS1AN4AC5)
and
h3(S1AN4
C9
AC5AC6); h4 as acute angle between the least- squared planes
set through the phenyl groups Ph1 (C5AC6AC7AC8AC9AC10)
and Ph2 (C11AC12AC13AC14 AC15AC16); and for amide region
h5(C18AN17AC14AC13) and h6(N17AC18AC20AC21); and
notation analogy with references [39–40] is as follows:
C10
C11
C12
C13
C14
C15
C16
C17
C18
C@O
R
128.55
120.38
h1 = \s1, h2 = \s2, h 3 = \s3, and h4 = \Ph1APh2).
The examined sulfanilamide derivatives 1–4 crystallize without
solvent molecules, in orthorhombic Pbca (1 and 2), monoclinic
P21/c (3), and triclinic P-1 (4) space groups having a single crystal-
lographically independent molecule in their asymmetric units
(Table 4, Fig. 4). Characteristic geometries, typical bond distances
and angles were determined for the main functional groups (e.g.
sulfamoyl, acetamide, phenyl), and the structure models were free
of any disordered atom sites. Due to rigid geometry of a sulfanil-
amide core unit, its conformation turned out to be practically the
same in all cases. Minor differences can generally be observed in
tilting of the phenyl (Ph1) group in relation to the sulfamoyl and
phenyl (Ph2) groups, as well as tilting of benzamide phenyl (Ph3)
group in relation to the amide group (Table 5 and Fig. 5). As can
be seen in Fig. 5, the tilting of Ph1 group on 1 and 2 is equivalent
but clearly different to that found on 3 and 4, where in more
perpendicular positions of phenyl group in relation to the sulfanil-
amide unit is evident. Moreover the conformations of 3 and 4 differ
from each other by tilting of Ph3 phenyl group that is somewhat
closer to a planar orientation on 3. Structural similarity search
from the CSD revealed number of sulfonamide structures having
analogous conformational states for 1 and 2, like in N1-2-chloro-
phenylsulfanilamide [CSD entry: CLPSAM] [41], 4-Amino-N-
(5-chloro-2-methylphenyl)benzenesulfonamide [HUNXUK] [42],
N-(40-nitrophenylsulfonyl)-4-iodoaniline [MEZGON] [43], N1-
phenylsulfanilamide [CEYYAG] [32], and many of those reported
in extensive sulfonamide studies of Perlovich et al. [39a–d]. Similar
molecular conformations with 3 and 4 can be found in N-(4-((4-
methylphenyl)-sulfamoyl)-phenyl)acetamide [DUTDEC] [44], 3-(((4-
acetamidophenyl)-sulfonyl)amino)benzoic acid [QAJMOF] [45],
4-aminoacetyl-N-p-nitrophenylsulfanilamide [SAZJEI] [46] and
in our previously reported N-(4-((3-methylphenyl)-sulfamoyl)
169.22
22.9 (CH3)
Fig. 2. Atom numbering of the core unit in case of NMR data.
3.4. Single crystal X-ray diffraction analysis
Crystal structures of all four sulfanilamide derivatives were
determined by single-crystal X-ray diffraction (XRD). The
crystallographic parameters, selected bond distances and angles,
dihedral angles and hydrogen bonding geometries are shown in
Tables 4–6. In order to properly compare the molecular confor-
mations of the examined compounds, the same numbering
scheme and handedness were used on each compound (Fig. 4).
General trends on the various conformations were further sur-
veyed by performing geometry related searches using CCDC Con-
Quest (v. 1.14) and Cambridge crystallographic database (CSD;

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M. Lahtinen et al. / Journal of Molecular Structure 1060 (2014) 280–290
Table 4
Crystallographic data of compounds 1–4.
Comp.
1
2
3
4
Ref. [47]
Empirical formula
Formula weight
Temperature/°C
Crystal system
Space group
a (Å)
C
14H14O3SN2
C12H12O2SN2
248.30
C19H16O3SN2
352.40
C19H15ClO3S N2
386.84
C20H18N2O3S
366.42
ꢁ100(1)
Triclinic
Pꢁ1
290.33
ꢁ100(1)
ꢁ100(1)
ꢁ100(1)
ꢁ100(1)
Orthorhombic
Pbca
Orthorhombic
Pbca
Monoclinic
P21/c
Triclinic
Pꢁ1
12.5848(7)
9.7577(3)
23.1777(10)
90.00
90.00
90.00
2846.2(2)
8
1.355
0.236
1216
5.9982(3)
15.6227(8)
24.4198(11)
90.00
90.00
90.00
2288.33(19)
8
1.441
0.273
1040
8.9091(9)
8.4554(7)
23.110(2)
90.00
93.035(9)
90.00
1738.4(3)
4
1.346
0.206
736
0.26 ꢄ 0.2 ꢄ 0.12
5.14–58.68°
15798
8.4815(9)
8.5344 (2)
8.8477 (3)
12.4383 (4)
77.924 (2)
75.382 (2)
86.537 (2)
888.67 (5)
2
b (Å)
c (Å)
8.8842(9)
12.5632(16)
76.741(10)
75.174(10)
87.247(8)
890.69(17)
2
1.442
3.185
400
a
(°)
b (°)
(°)
c
Volume (Å3)
Z
qcalc (mg/mm3)
1.369
0.210
384
m (mmꢁ1
F(000)
)
Crystal size (mm3)
0.35 ꢄ 0.28 ꢄ 0.25
0.31 ꢄ 0.26 ꢄ 0.14
5.22–51.98°
5686
0.19 ꢄ 0.16 ꢄ 0.11
7.48–136.94°a
5064
2H range for data collection
5.56–52°
Reflections collected
11962
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
2796 R(int) = 0.0411
2796/2/191
1.034
2249 R(int) = 0.0327
2249/15/166
1.043
4208 R(int) = 0.0402
4208/2/235
1.046
3227 R(int) = 0.0293
3227/2/244
1.062
Final R indexes [I P 2
r
(I)]
R1 = 0.0456, wR2 = 0.1041
R1 = 0.0757, wR2 = 0.1256
0.23/ꢁ0.30
R1 = 0.0483, wR2 = 0.0953
R1 = 0.0803, wR2 = 0.1167
0.20/ꢁ0.29
R1 = 0.0495, wR2 = 0.0968
R1 = 0.0852, wR2 = 0.1136
0.26/ꢁ0.30
R1 = 0.0396, wR2 = 0.1008
R1 = 0.0470, wR2 = 0.1093
0.25/ꢁ0.40
Final R indexes [all data]
Largest diff. peak/hole (e Åꢁ3
)
a
Cu – radiation.
Table 5
Selected bond distances (Å) and angles (°) of 1–4 with dihedral angles h1–6
.
Comp.
1
2
3
4
Ref. [47]
Mean angle
No. of entriesa
Distances
S1AO2
S1AO3
S1AN4
S1AC11
N4AC5
1.4235(18)
1.4299(17)
1.643(2)
1.748(3)
1.439(3)
1.346(3)
1.218(3)
1.4325(19)
1.431(2)
1.631(2)
1.749(3)
1.439(3)
1.4360(14)
1.4232(14)
1.6219(18)
1.7590(19)
1.417(3)
1.4375(14)
1.4399(13)
1.4328(14)
1.6281(17)
1.7642(19)
1.428(3)
1.4296(15)
1.6314(18)
1.7607(19)
1.424(3)
1.360(3)
1.225(2)
N17AC18
C18AO19
1.352(2)
1.220(2)
1.360(2)
1.231(2)
Angles
O3AS1AO2
N4AS1AC11
C5AN4AS1
N17AC18AO19
119.04(11)
106.34(11)
117.38(15)
122.2(2)
119.04(13)
108.27(12)
119.10(19)
119.27(9)
107.88(9)
125.79(15)
121.98(19)
119.02(9)
107.27(9)
124.09(15)
122.88(18)
118.60(8)
107.99(8)
124.74(13)
122.61(17)
Dihedral angles
h1(N4AS1AC11AC12)
h2(C11AS1AN4AC5)
h3(S1AN4AC5AC6)
h4(Ph1ꢂ ꢂ ꢂPh2)
ꢁ82.4(2)
ꢁ59.8(2)
ꢁ77.1(3)
41.36(10)
30.1(4)
ꢁ77.7(2)
ꢁ57.6(3)
ꢁ80.0(3)
53.49(9)
ꢁ74.35(18)
ꢁ62.69(18)
ꢁ18.8(3)
89.03(8)
ꢁ73.41(18)
ꢁ62.66(18)
ꢁ28.6(3)
95.44(7)
ꢁ69.07(17)
ꢁ60.65(17)
ꢁ24.1(3)
86.07
63.29
538
538
538
538
81
3312
10
1522
112.30
68.10
93.84(6)
h5(C18AN17AC14AC13)
h5(C18AN17AC14AC13)c
h6(N17AC18AC20AC21)
h6(N17AC18AC20AC21)c
12.3(3)
19.2(3)
21.41(19)
15.03b
30.20b
28.62b
28.19b
ꢁ161.9(2)
ꢁ144.6(2)
ꢁ150.49(18)
a
Searches were limited to structures having 3D coordinates determined and R-value 6 10%.
b
Two population exist on angular ranges of ꢃ0–50° and 140–180° depending on the bearing of the carbonyl group in relation to the attached phenyl group (Ph2) and
whether above plane or below plane torsion angle was retrieved by the ConQuest. To have comparable value, absolute angles were reduced to be independent of carbonyl
direction by setting angle range to vary from 0 to 90°.
c
Data retrieved with a fragment not having SO2NH group attached to the para-position of Ph2 group.
phenyl)benzamide [YAGBOZ] [47], to mention few. Overlays of 1–4
with selected sulfonamide conformations can be seen in Fig. 5 (see
also Supplementary material Fig. S4).
The conformational modes were inspected further using above
described dihedral angles h1 - h6, of which statistical variations re-
trieved from the CSD are shown in Supplementary Fig. S5. Based on
the survey dihedral angle h1, describing the orientation of the NH
group in relation to a Ph2 group, varies generally about from 45°
to 135° with mean average of 86.7°, thereby indicating the almost
perpendicular to be the most preferable conformational state for
phenyl group Ph1. In contrast to h1, angular variation for dihedral
angle h2 is clearly less and ‘‘rotation angle’’ (S1AN4 bond as rota-
tion axis) of about 60° (mean angle 63.29°) between the Ph1 and
Ph2 phenyl groups is strongly favored. Broader range of variation
occurs in dihedral angle h3, describing the rotational angle of Ph1
group in relation to the NH group, as it varies more or less equally
across a semicircle; dihedral angles above ꢃ75° being somewhat
more favored (mean 112.3°) among others. It should also be noted
that on the amidated sulfonamides, the lower end of the angular
range is favored instead; as in the case of 3, 4, [SAZJEI] [46] and

M. Lahtinen et al. / Journal of Molecular Structure 1060 (2014) 280–290
285
Table 6
Hydrogen bonding geometry for compounds 1–4.
D–Hꢂ ꢂ ꢂA
D–H
Hꢂ ꢂ ꢂA
Dꢂ ꢂ ꢂA
D–Hꢂ ꢂ ꢂA No. of entries
1
N4–H4ꢂ ꢂ ꢂO3 (i)
0.87 (2) 2.13 (2) 2.983 (3) 169 (3)
N17–H17ꢂ ꢂ ꢂO19 (ii) 0.89 (2) 1.96 (2) 2.847 (3) 174 (2)
2
N4–H4ꢂ ꢂ ꢂN17 (iii)
0.83(2) 2.46(2) 3.202(4) 151(3)
N17–H17Aꢂ ꢂ ꢂO2 (iv) 0.87(2) 2.47(3) 3.104(4) 131(3)
N17–H17Bꢂ ꢂ ꢂO3 (v) 0.87(2) 2.30(2) 3.089(4) 151(3)
3
N4–H4ꢂ ꢂ ꢂO19 (vi)
0.85 (2) 2.03 (2) 2.846 (2) 162 (2)
N17–H17ꢂ ꢂ ꢂO2 (vii) 0.86 (2) 2.18 (2) 3.002 (2) 159 (2)
4
N4–H4ꢂ ꢂ ꢂO19 (viii)
0.86 (2) 2.01 (2) 2.824 (2) 158 (2)
0.87 (2) 2.30 (2) 3.017 (2) 139 (2)
N17–H17ꢂ ꢂ ꢂO2 (ix)
Ref. [47]
N4–H4ꢂ ꢂ ꢂO19a
0.86(2) 1.99(2) 2.813(2) 160(2)
0.84(2) 2.38(2) 3.062(2) 140(2)
N17–H17ꢂ ꢂ ꢂO2a
Survey
Fig. 5. Molecular conformations of 1–4 shown with few comparable structures
found in the CSD. (a) 1 and 2; (b) 3 and 4; (c) 2 (red line) [h4 = 53.49°] with I
[CLPSAM; yellow, h4 = 49.65°] [41], II [HUNXUK; green, h4 = 67.61°] [42], III
[MEZGON; blue, h4 = 31.37°] [43] and IV [CEYYAG; pink, h4 = 50.67°] [32]; and (d)
3 (red line) [89.03°] with I [DUTDEC; yellow, h4 = 67.03°] [44], II [QAJMOF; green,
h4 = 63.21°] [45], III [SAZJEI; blue, h4 = 88.89°] [46] and IV [YAGBOZ; pink, 86.17°]
[47]. h4 = acute angle between the planes running through Ph1 and Ph2 phenyl
rings. (For interpretation of the references to color in this figure legend, the reader is
referred to the web version of this article.)
N–Hꢂ ꢂ ꢂX (O, N)b
N–Hꢂ ꢂ ꢂX (O, N)c1
N–Hꢂ ꢂ ꢂX (O, N)c2
2.13
2.10
2.08
2.93
2.95
2.90
161
168
161
328
79
2329
Symmetry codes: (i) ꢁx + 1/2, y + 1/2, z; (ii) ꢁx ꢁ 1/2, y ꢁ 1/2, z; (iii) ꢁx ꢁ 1/2, y + 1/
2, z; (iv) ꢁx ꢁ 1/2, y ꢁ 1/2, z; (v) ꢁx + 1/2, y ꢁ 1/2, z; (vi) ꢁx + 1, ꢁy + 2, ꢁz; (vii) x,
y ꢁ 1, z; (viii) ꢁx ꢁ 1, ꢁy, ꢁz; (ix) x ꢁ 1, y, z.
a
The labeling used here is different to that of found in Ref. [47].
Data retrieval with SO2NH donor. Amide fragment withc1 and withoutc2 SO2NH
b
attached to the para-position of Ph2 group.
[YAGBOZ] [47] with h3 varying merely from ꢃ15° to 24°. The distri-
bution of h4 angles show an increasing trend towards higher angles
(varying about from 30° to 90°) and having average of 68.10°
among ꢃ530 sulfonamide entries found in the database (Table 5).
Further analysis of the distribution reveals local ‘‘maximum’’ that
exist in the angular range (40–50°) representing the tilted Ph1 con-
formations found in 1 (h4 = 41.4°), 2 (h4 = 53.5°), and for instance in
N-(4-chlorophenyl)-benzenesulfonamide (h4 = 54.4°) [39b]. The
second maximum is located around the mean value range
ꢃ65–70° to which structural examples are for instance 4-amino-
N-(4-methoxyphenyl)-benzenesulfonamide
(h4 = 60.7°)
and
N-phenyl-benzenesulfonamide (h4 = 64.4°) [39b]. The third and
more populated maximum is located closer to angular range 80–
90°, that includes many of the amidated sulfonamides such as 3,
Fig. 4. Asymmetric units of (a) 1, (b) 2, (c) 3 and (d) 4 along with the atomic numbering. Thermal displacement ellipsoids are shown at 50% probability.

286
M. Lahtinen et al. / Journal of Molecular Structure 1060 (2014) 280–290
4 and those reported in the references [47–50]. As expected the
dihedral angles h5 and h6 show clearly the low mobility of
the amide group, as both angles vary within narrow range of 0
to about 30° (either below or above the NCO plane) among
over 3300 reported amide containing structures found in
the CSD. It also appears that the angular range of h5 is some-
what affected by the fact whether the sulfamoyl
(SO2NH) group is located in the para-position of phenyl Ph2 group
or not, as closer to planar orientation (ꢃ15°) is preferred when
the para-position is occupied. However, no significant change
can be observed in h6 with or without sulfamoyl group, as the
mean angle is about 28°in both cases.
tions present in the crystal lattice (e.g. hydrogen and halogen
bonding; vander Waals, and CH– interactions). As described
p
–p
p
above, 1 and 2 exhibit practically the same molecular conforma-
tion (tilted V-shape), crystallize in orthorhombic Pbca space group,
have same number of hydrogen bonding (HB) donors, and have rel-
atively similar unit cell dimensions but due to different proton do-
nor–acceptor groups the molecular packing and intermolecular
interaction networks are clearly dissimilar. In case of 1, hydrogen
bonding (HB) network is formed from sulfonamide and amide
donors (N4AH4 and N17AH17) to the same functional groups on
nearby molecules acting as acceptors (O3 and O19), thus HBs exist
between amide–amide and sulfonamide–sulfonamide groups with
Dꢂ ꢂ ꢂA distances varying from ꢃ2.8 to 3.0 Å (Fig. 6 and Table 6). The
presented HB geometry can also be categorized using so-called
graph set notations described by Etter [51]. With given notations
Despite of conformational similarities prevailing among various
sulfonamides, the molecular packing schemes can differ consider-
ably depending on the available palette of intermolecular interac-
Fig. 6. Depictions of HB networks (dashed blue lines) viewed along crystallographic a-, b- and c-axes, (a) 1, (b) 2, (c) 3 and (d) 4. Hydrogen atoms are removed for clarity. (For
interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

M. Lahtinen et al. / Journal of Molecular Structure 1060 (2014) 280–290
287
parallel C(4) type of HB chains (ꢂ ꢂ ꢂHANACAOꢂ ꢂ ꢂ and
ꢂ ꢂ ꢂHANASAOꢂ ꢂ ꢂ mediated; see [52]) are running orthogonally
through layers of molecules packed parallel to ac-plane.
Combination of basic HB geometries form a larger second level
R44ð26Þ type HB rings mediated by four molecules. The molecules
are packed so that phenyl groups Ph1 are showing face-to-edge
sulfanilamide derivative [47], having N-substituted chlorophenyl
and methylphenyl groups respectively, follow resembling packing
modes than on 3 (Figs. 6 and S6 for [47]), despite of crystallizing in
a lower triclinic symmetry. The same donor–acceptor groups form
HB network showing again orthogonally linked R22ð20Þ and R44ð16Þ
type HB geometries with analogous Dꢂ ꢂ ꢂA distances of about
like arrangement but the
p–p
contact distance is rather long
2.8–3.0 Å. Analogous p–p interactions can be identified in the
(ꢃ5.7 Å) indicating only weak interaction between these phenyl
groups. In compound 2, more complex HB network is formed via
amino (N17AH17a and N17AH17b) donors and sulfamoyl group
acceptors (O2 and O3), as well as from sulfonamide donor
(N4AH4) to amino (N17) acceptor. By this, parallel HB chains of
C22ð6Þ type (ꢂ ꢂ ꢂHANAHꢂ ꢂ ꢂOASAOꢂ ꢂ ꢂ) are running through a-axis
(Dꢂ ꢂ ꢂA = ꢃ3.1 Å), whereas zigzag HB chains of C(8) type (mediated
by 4-aminophenyl-sulfamoyl groups) goes along b-axis. Also sec-
ond level R44ð22Þ and R22ð6Þ HB rings exist in the structure as
structures in form of face-to-face and several face-to-edge contacts
with an average ring centroid distances of 3.6 and 4.7–5.0 Å,
respectively. It is also noticeable that the chlorophenyl in
compound 4 is not participating to the hydrogen bonding but
instead forms face-to-face
p–p contacts that is geometrically
identical to that of found in methylphenyl substituted sulfanil-
amide. In a broader view majority of HB geometries observed on
compounds 1–4 are frequently found in other sulfonamides, of
which the C(8), C22ð6Þ and R44ð22Þ type HB geometries (on 2–4)
are one of the most common ones [39a–d]. The observed R22ð20Þ
and R44ð16Þ type HB geometries seem to be somewhat more
common for amidated sulfonamides, as in addition to the exam-
ined ones resembling HB geometries were also found in amidated
sulfonamides, such as DUTDEC [44], QAJMOF [45] and SAZJEI [46].
Finally, brief literature search on HB distances using various
donor–acceptor combinations [NAHꢂ ꢂ ꢂX (O, N)] revealed typical
HB distances to have statistical mean values of 2.90–2.95 Å, which
are also consistent with now reported parameters.
combination of the basic HB units. Moreover, weak
p–p interac-
tions exists between adjacent phenyl groups having face-to face
and face-to-edge distances of 3.838(2) and 5.318(2) Å, respectively.
As a result layer like molecular packing is formed in the crystal
lattice wherein HB network and aromatic phenyl group regions
alternate. On compound 3, the L-shaped molecules are packed
alongside each other in antiparallel manner. Amide and sulfamoyl
groups act both as HB donors and acceptors forming C(8) type HB
chain parallel to b-axis. These HBs participate to two larger almost
orthogonally linked two- and four-molecule membered HB rings
with R22ð20Þ and R44ð16Þ geometry types in which amide-
sulfonamide donor–acceptor pairs alternate. In addition, face-
3.5. Thermal analysis
to-edge (5.309(1) Å) and twisted parallel type of p–p interactions
(4.771(1) Å via the phenyl groups are also visible in the crystal
structure (Fig. 6c). Compound 4 as well as our previously published
Thermoanalytical results obtained by differential scanning calo-
rimetric (DSC) and simultaneous thermogravimetric and differen-
tial temperature (TG/DTA) analyzers are summarized in Tables 7
Table 7
Thermodynamic characteristic of 1–4 with the literature data.
1
2
3
4
R1 [39b]
R2 [39b]
R3 [39b]
R4 [53]
R5 [53]
R6 [53]
Tm (°C)
Tm (K)
211.5
484.6
38.96
195.2
468.3
36.60
227.9
501.1
46.23
225.2
498.4
44.81
188
461.0
39.6
204
477.6
45.6
175
448.4
32.4
259
532.2
40.7
236
519.2
36.4
244
517.2
45.2
D
D
D
HTfus
a
298
a
23.97
80.38
23.29
78.16
27.51
92.27
26.81
89.91
25.6
85.9
28.5
95.5
21.5
72.3
22.8
76.6
20.9
70.1
26.1
87.4
H
fus
T
b
Sfus
D
STfus
=
D
HTfus=T3; R1 = 4-amino-N-(2-bromo-4-nitro-phenyl)-benzene-sulfonamide; R2 = 4-amino-N-(3-chloro-4-methylphenyl)-benzene-sulfon-amide; R3 = 4-amino-N-(3-
methoxy-pyrazinyl)-benzene-sulfonamide; R4 = sulfadiazine; R5 = sulfamerazine; and R6 = sulfisomidine. kcal values reported in Ref. [53] were changes to kJ molꢁ1 and not
298
fus
reported
DH
values were calculated.
a
D
D
H = kJ molꢁ1
S = J molꢁ1 Kꢁ1
.
b
.
Table 8
Thermoanalytical results of 1–4.
Step
Decomp. onset T
Tdec. (°C)
T range
(°C)
Weight loss/step
(%)
Weight loss, overall
(%)
DTGmax
(°C)
DTAmax
(°C)
1
1
2
3
271
265–303
303–423
423–679
6.07
52.95
40.94
283
332
567
289 (exo)
335 (endo)
527 (exo)
99.96
99.83
99.29
99.86
2
1
2
3
257
261
261
238–306
306–352
352–676
22.85
28.11
48.87
279
322
542
279 (endo)
322 (endo)
496 (exo)
3
1
2
3
254–309
309–367
367–678
5.97
47.39
45.93
277
335
585
275 (exo)
337 (endo)
596 (exo)
4
1
2
3
249–314
314–365
365–685
24.41
32.49
42.96
294
328
576
266 (exo)
329 (endo)
572 (exo)

288
M. Lahtinen et al. / Journal of Molecular Structure 1060 (2014) 280–290
transition occurs first at 49.7, 64.3 and 75.1 °C, respectively, fol-
lowed by a re-crystallization from 100 to 140 °C on 1 and 3, and
from 130 to 170 °C on 4. Subsequently above crystallization the
melting of original structure form is observed on 1 (see Supple-
mentary material Table S1 for Tms of 2nd heating scans), whereas
weak melting endotherm appeared at 219.6 and 199.6 °C for 3
and 4, respectively, thus indicating melting of a polymorphic form
instead of the original one. Compound 2 exhibit sharp crystalliza-
Tm
1
Tc
Tg
Tm
2
Tc
tion exotherm already on cooling (153.5 °C;
D
H = –31.52 kJꢂmolꢁ1
)
Tm
and on a second heating scan, sharp melting transition of the ori-
ginal structure form is observed.
3
4
Inspection of thermodynamical characteristics reveals that sul-
fanilamide derivatives 1 and 2 have rather analogous Tms with clo-
Tc
Tm
Tc
Tg
sely matching
D D
HfTus and SfTus values even though they are
chemically different and hold clearly different HB geometries.
Same trend, but with higher values, is observed also for benzamide
derivatives 3 and 4 (Table 7). The amidation of sulfanilamide and
the change of phenyl (3) to chlorophenyl group (4) appear to in-
duce only minor change to the observed thermodynamic values.
Based on the literature similar enthalpies of fusion and melting
points have been reported to several sulfonamide derivatives, of
which few are gathered to Table 7 for a comparison.
40
60
80 100 120 140 160 180 200 220 240
Temp. (°C)
Fig. 7. DSC scans of 1–4. For each compound: top = 1st heating; middle = cooling,
and bottom scan = 2nd heating. Tm = melting, Tc = crystallization, Tg = glass
transition.
Thermal decomposition of compounds was examined with
simultaneous TG/DTA analyzer. The resulted curves and thermal
parameters are shown in Fig. 8 and Table 8, respectively. In all four
cases three main degradation steps analogously to number of sul-
fonamides reported in the literature [54,55] can be observed. The
first step indicative to thermal decomposition begins slowly at
240 °C(ꢃ20–40 °C above Tm) accelerating gradually from decompo-
sition onsets temperatures (Td = 261, 257 261 and 271 °C for 1–4,
respectively). Thermal decomposition continues in the second step
(temperature onsets about at 310–320 °C) with a higher weight
and 8. The corresponding DSC and TG/DTA curves are illustrated in
Figs. 7 and 8. The first DSC heating scans of 1–4 show single sharp
melting endotherms at onset temperature of 211.5, 195.2, 227.9
and 225.2 °C, respectively. In addition, on 4 also an additional se-
quence of weak exo- and endothermic transitions are visible con-
secutively after the melting endotherm. These transitions appears
to be originating as a result of partial re-crystallization of melt to
a short-lived high temperature structure form that melts at
232.5 °C (
D
H = 5.55 kJꢂmolꢁ1). On ensuing cooling scan, com-
pounds 1, 3 and 4 vitrify, and when heated for a second time a glass
75
50
25
0
75
50
25
0
100
80
60
40
20
0
100
80
60
40
20
0
DTG
DTG
0
0
-20
-40
-20
-40
DTA
DTA
TG
TG
1
2
-25
-25
100 200 300 400 500 600 700
100 200 300 400 500 600 700
75
75
100
80
60
40
20
0
100
80
60
40
20
0
DTG
DTG
0
0
50
25
0
50
25
0
-20
-40
-20
-40
DTA
DTA
TG
TG
3
4
-25
-25
100 200 300 400 500 600 700
100 200 300 400 500 600 700
Temp. (°C)
Temp. (°C)
Fig. 8. TG, DTG and DTA curves of 1–4.

M. Lahtinen et al. / Journal of Molecular Structure 1060 (2014) 280–290
289
Table 9
The benzamide containing sulfonamides 3 and 4 show L-shaped
molecular conformation crystallizing in monoclinic P21/c and tri-
clinic P-1 space groups, respectively. The molecular conformations
determined in this study can also be found in number of previously
reported sulfonamides, of which the tilted V-shape appears to be
somewhat more common one among the surveyed structures. On
1, only ꢂ ꢂ ꢂHANACAOꢂ ꢂ ꢂ and ꢂ ꢂ ꢂHANASAOꢂ ꢂ ꢂ mediated hydrogen
bond (HB) geometries with graph set notation of C(4) can be ob-
served. These HBs form parallel HB chains running along b-axis.
Also larger R44ð26Þ type HB rings are formed as a combination of
the simple basic C(4) HB units. The benzamidated derivatives 3
and 4 manifest L-shaped molecular conformation and have analo-
gously C(8) type HB units that forms second level HB rings of
R22ð20Þ and R44ð16Þ types. The only amide – free sulfanilamide deriv-
ative 2 exhibits C(8) HB basic units but in contrast to 3 and 4 dif-
ferent HB network of R44ð22Þ and R22ð6Þ type geometries are
formed. Many of the observed HB geometries, such as C(8), C22ð6Þ
and R44ð22Þ are also manifested frequently in other sulfonamides
reported in the literature. Thermal characteristics of the examined
compounds varied slightly in relation to the range of the substitu-
ents used. The melting points increased in order of 2 < 1 < 4 < 3
(195.2, 211.5, 225.2 and 227.9 °C, respectively), whereas 1 and 2
had enthalpies of fusion in the same order of magnitude (ꢃ37–
38 kJꢂmolꢁ1), as in the case of 3 and 4 albeit with somewhat higher
enthalpies (ꢃ45–46 kJꢂmolꢁ1). Thermal decomposition onset tem-
peratures increased in order of 2 < 3 = 4 < 1 (257, 261, 261,
271 °C, respectively), thus the amide – free derivative 2 being the
least and the acetamidated being the most thermally stable com-
pound under the conditions used. Finally the antibacterial studies
suggested that the introduction of the benzene ring to COANH
group or SO2ANH moiety hinders the significant antimicrobial
activity.
Zone inhibition values (in mm) of compounds with two concentrations (mg/ml).
Comp.
S. Aureus
E. Coli
A. Niger
C. Albicans
10
100
10
100
10
10
1
2
17
21
40
26
24
40
23
40
Ciprofloxacin
Miconazole
40
11
11
loss rate, that gradually slows down when proceeding to the third
and final weight loss step (ranging from about 350–650 °C). Gener-
ally above 650 °C TG curves settle to near zero values (ꢃ1%) indi-
cating nearly ashless residue. On 1 and 3 the first weight loss
step is better resolved and clearly smaller in contrast to 2 and 4
in which the reactions of consecutive steps are significantly more
overlapped. By combining first two steps, rather similar overall
weight losses (ꢃ51–59%) can be obtained for all compounds. It is
obvious that major degradation occurs on these steps but with
slightly different kinetics and variation of reaction paths per sub-
stance. The third step is caused by further carbonization processes
and slow combustion of the resulted molecular fragments. The
decomposition products cannot be explicitly identified per step
but it can be expected that various components like H2O, NH3, aro-
matic fragments (some halogenated on 4), SO2 and/or amines may
be formed on the first two steps while CO and CO2 are the main
products of the last step. It is noticeable that the first weight loss
step on amidated compounds 1, 3 and 4 is exothermic (see DTA
signals). Exothermic processes were also observed by Khattab
et al. on decomposition of sulfonamides, such as sulfapyridine, sul-
fadiazine, sulfanilamide, sulfaphenazole and sulfathiazole [54]. As
the range of functional groups in above molecules varies, it is as-
sumed that the exothermic decomposition reactions may originate
from a sulfamoyl core unit. This is further supported by the only
amide-free compound 2 that at first show endothermic peak on
first weight loss step but which turns exothermic in latter part of
the step, thus the potential exothermic deamination on 1, 3, and
4 cannot be the only reason. Second step is uniformly endothermic
(DTA peak maximum around at 330 °C) on all four compounds due
the energy consuming fragmentation reactions occurring at the
shown temperature range (Table and Fig. 8). Similarly the first part
of the third step is endothermic due the carbonization but while
the combustion processes gradually increase the DTA signal
changes to exothermic.
Appendix A. Supplementary material
IR, NMR spectra, additional structure model figures and figure
for the statistical distributions of various (dihedral) angles are in-
cluded in the supplementary material. Crystallographic data for
the compounds 1–4 have been deposited at the Cambridge Crystal-
lographic Data Centre with the deposition numbers CCDC 947892-
947895. Copies of the data can be obtained free of charge via exter-
nal link http://ccdc.cam.ac.uk/retrieving.html. Supplementary data
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.molstruc.2013.12.063.
3.6. Antimicrobial activity
References
The inhibition zones of the compounds are listed in Table 9.
Compounds 1 and 2 have shown significant zone of inhibition for
gram positive bacteria. But compounds 3 and 4 did not show any
activity. No sample has shown antibacterial activity against gram
negative bacteria except compound 1. The results indicate that
there is no significant antibacterial activity with the introduction
of the benzene ring to COANH group or SO2ANH moiety. None of
the samples have shown antifungal activity.
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