Synthesis, characterization and computational study of the newly synthetized sulfonamide molecule

Article abstract of DOI:10.1016/j.molstruc.2017.10.028

A new compound N-(2,5-dimethyl-4-nitrophenyl)-4-methylbenzenesulfonamide (NDMPMBS) has been derived from 2,5-dimethyl-4-nitroaniline and 4-methylbenzene-1-sulfonyl chloride. Structure was characterized by SCXRD studies and spectroscopic tools. Compound crystallized in the monoclinic crystal system with P2₁/c space group a = 10.0549, b = 18.967, c = 8.3087, β = 103.18 and Z = 4. Type and nature of intermolecular interaction in crystal state investigated by 3D-Hirshfeld surface and 2D-finger print plots revealed that title compound stabilized by several interactions. The structural and electronic properties of title compound have been calculated at DFT/B3LYP/6-311G++(d,p) level of theory. Computationally obtained spectral data was compared with experimental results, showing excellent mutual agreement. Assignment of each vibrational wave number was done on the basis of potential energy distribution (PED). Investigation of local reactivity descriptors encompassed visualization of molecular electrostatic potential (MEP) and average local ionization energy (ALIE) surfaces, visualization of Fukui functions, natural bond order (NBO) analysis, bond dissociation energies for hydrogen abstraction (H-BDE) and radial distribution functions (RDF) after molecular dynamics (MD) simulations. MD simulations were also used in order to investigate interaction of NDMPMBS molecule with 1WKR and 3ETT proteins protein.

Full text of DOI:10.1016/j.molstruc.2017.10.028

Journal of Molecular Structure 1153 (2018) 212e229
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Synthesis, characterization and computational study of the newly
synthetized sulfonamide molecule
a
b
ꢀ c
ꢀ d
P. Krishna Murthy , V. Suneetha , Stevan Armakovic , Sanja J. Armakovic ,
P.A. Suchetan e, L. Giri f, R. Sreenivasa Rao b
,
*
a Department of Chemistry, Bapatla Engineering College (Autonomous), AcharayaNagarjuna University Post Graduate Research Centre, Bapatla-522 102,
A.P., India
b Department of Chemistry, Bapatla College of Arts and Sciences, Baptla-522 101, A.P., India
c
ꢀ
University of Novi Sad, Faculty of Sciences, Department of Physics, Trg D. Obradovica 4, 21000 Novi Sad, Serbia
d
ꢀ
University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg D. Obradovica 3, 21000 Novi Sad,
Serbia
e Department of Studies and Research in Chemistry, University College of Science, Tumkur University, Tumkur-572 103, Karnataka, India
f Solid State & Supramolecular Structural Chemistry Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Bhubaneswar 751
008, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new compound N-(2,5-dimethyl-4-nitrophenyl)-4-methylbenzenesulfonamide (NDMPMBS) has been
derived from 2,5-dimethyl-4-nitroaniline and 4-methylbenzene-1-sulfonyl chloride. Structure was
characterized by SCXRD studies and spectroscopic tools. Compound crystallized in the monoclinic crystal
Received 14 July 2017
Received in revised form
27 September 2017
Accepted 7 October 2017
Available online 8 October 2017
system with P21/c space group a ¼ 10.0549, b ¼ 18.967, c ¼ 8.3087,
b
¼ 103.18 and Z ¼ 4. Type and nature
of intermolecular interaction in crystal state investigated by 3D-Hirshfeld surface and 2D-finger print
plots revealed that title compound stabilized by several interactions. The structural and electronic
properties of title compound have been calculated at DFT/B3LYP/6-311Gþþ(d,p) level of theory.
Computationally obtained spectral data was compared with experimental results, showing excellent
mutual agreement. Assignment of each vibrational wave number was done on the basis of potential
energy distribution (PED). Investigation of local reactivity descriptors encompassed visualization of
molecular electrostatic potential (MEP) and average local ionization energy (ALIE) surfaces, visualization
of Fukui functions, natural bond order (NBO) analysis, bond dissociation energies for hydrogen
abstraction (H-BDE) and radial distribution functions (RDF) after molecular dynamics (MD) simulations.
MD simulations were also used in order to investigate interaction of NDMPMBS molecule with 1WKR
and 3ETT proteins protein.
Keywords:
Sulfonamide
SCXRD
Hirshfeld surface analysis
DFT calculations
Vibrational analysis
© 2017 Elsevier B.V. All rights reserved.
1. Introduction
diseases as well. Besides pharmaceutical applications, sulphona-
mides are also used as reagents in analytical chemistry for con-
SO2eNH group is a key constituent of sulfonamide pharma-
ceuticals, which are promising chemotherapeutic agents used for
treatment of various diseases [1]. Sulfa-drugs possess a wide verity
of medicinal chemistry applications such as antiprotozoal [2],
antibacterial [3], antifungal [4], insecticidal [5], anti-inflammatory
[6], carbonic anhydrase inhibitor [7] and rheumatoid arthritis [8].
Recent literature reports indicate that sulphonamides are also
applied in the cases of Alzheimer's [9], cancer [10,11] and HIV [12]
centration, separation, selective qualitative and quantitative
determination of the 3d transition metal cations [13e15]. Sulfon-
amide compounds have been studied extensively and numerous
experimental and computational reports. Xing et al. reported the
crystal structure of 4-methyl-N-(4-nitrophenyl)benzenesulfona-
mide [16]. Sarojini et al. reported synthesis, structural, spectro-
scopic and computational studies of 4-methyl-N-(3-nitrophenyl)
benzene sulfonamide combining experimental and theoretical ap-
proaches [17]. Rajamani et al. investigated electronic absorption,
vibrational spectra, nonlinear optical properties, NBO analysis and
thermodynamic properties of N-(4-nitro-2-phenoxyphenyl)
methanesulfonamide molecule within the Hartree-Fock and
* Corresponding author.
E-mail address: rsrchemhod@gmail.com (R.S. Rao).
https://doi.org/10.1016/j.molstruc.2017.10.028
0022-2860/© 2017 Elsevier B.V. All rights reserved.

P.K. Murthy et al. / Journal of Molecular Structure 1153 (2018) 212e229
213
density functional approaches [18]. Govindarasu et al. carried out
detailed experimental and computational DFT study of N-phenyl-
benzenesulfonamide [19].
under vacuum to afford (0.67 g, 69%) of N-(2,5-dimethyl-4-
nitrophenyl)-4-methylbenzene-1-sulfonamide as pale yellow
solid (Scheme-1 supporting information). Suitable single crystals
were grown by slow evaporation solution growth technique at
ambient temperature using chloroform: methanol (1:3) solvent.
In this paper we report synthesis, detailed spectroscopic and
computational characterization of N-(2,5-dimethyl-4-nitrophenyl)-
4-methylbenzenesulfonamide (NDMPMBS) molecule. In order to
uniquely characterize the title compound we have measured FT-IR,
Raman and NMR spectra. Spectral data were also computed within
DFT approach in order to validate the used level of theory.
Computational investigation within DFT approach has proven to be
effective tool for investigation of physical and chemical properties
of various organic molecules [20e24] and in this study we used it to
study both global and local quantum-molecular descriptors of the
title compound. Taking into account that organic pharmaceutical
molecules such as NDMPMBS represent great threat for water re-
sources [25e30], we have also investigated sensitivity of
NDMPMBS towards autoxidation and hydrolysis, in order to gain an
insight into its possible degradation properties.
2.3. X-ray data collection and refinement details
A suitable prism like crystal was selected and mounted on a
Bruker APEX-II CCD diffractometer using graphite monochromated
MoKa (
l
¼ 0.71073 Å) radiation and detector (CCD). The crystal was
kept at 273 (2) K during data collection. The structure was solved
using Olex2 software with the olex2. solve [31] structure solution
program using Charge Flipping and the structure was refined with
the ShelXL [32] refinement package using Least Squares minimi-
zation. All the non-hydrogen atoms were revealed in the first dif-
ference Fourier map itself and were refined anisotropically. All the
hydrogen atoms were positioned geometrically. All H atoms were
positioned geometrically, with CeH ¼ 0.96 Å for methyl H,
CeH ¼ 0.93 Å for aromatic H, and refined using a riding model with
2. Material and methods
Uiso(H) ¼ 1.5Ueq(C) for methyl H and Uiso(H) ¼ 1.2Ueq(C) for aro-
2.1. General remarks
matic H. The nitrogen bound H atom was located in a difference
map and was refined isotropically with the bond length restraint
NeH ¼ 0.86 (2) Å. All the geometrical calculations were carried out
using the program PLATON [33] within the WinGX suite [34]. The
molecular and packing diagrams were generated using the soft-
ware MERCURY [35]. The crystallographic data and refinement pa-
rameters are summarized in Table 1.
FT-IR spectrum (Fig. 1) was recorded in solid state using KBr disc
in the range of 4000e600 cmꢀ1 on ATR module ALPHA-T Bruker FT-
IR spectrophotometer. FT-Raman spectrum (Fig. 2) was measured
for solid sample on Bruker RFS 100/s, Germany using Nd:YAG laser
source, excitation wave length 1064 nm with spectral resolution
2 cmꢀ1 in the region of 0e4000 cmꢀ1.1H and 13C NMR chemical
shift values were reported in ppm using TMS as internal standard
on Bruker 400 MHz spectrometer.
2.4. Computational details
Firstly, molecular structure of the title compound was extracted
from the single crystal X-ray structure to be used as a starting ge-
ometry for geometry optimization. The molecular geometry opti-
mization in gas phase together with vibrational analysis, frontier
orbital analysis (HOMO-LUMO), MEP, surface analysis and Mullikan
atomic charges calculation were performed at DFT level of theory
with B3LYP [36] hybrid exchange-correlation functional and 6-
311Gþþ(d,p) (5D, 7 F) basis set, using Gaussian 09 software pack-
age [37]. The assignment and PED analysis of wave number were
done by GaussView 5.0 program [38] and VEDA4 program [39]. For
better agreement of calculated wavenumber number with
2.2. Synthesis of N-(2,5-dimethyl-4-nitrophenyl)-4-
methylbenzenesulfonamide
To a stirred solution of 2,5-dimethyl-4-nitroaniline (0.5 g,
3.01 mmol) in pyridine (5 mL), 4-methylbenzene-1-sulfonyl chlo-
ride (0.86 g, 4.51 mmol) was added. The reaction mixture was
stirred for 16 h at room temperature. After completion of reaction
by TLC, the reaction mixture was diluted with D.M.water and
acidified with dilute HCl solution. Solid was filter, washed with
D.M.water, MTBE and followed by 1:1 ethyl acetate: hexane. Dried
Fig. 1. FT-IR spectrum of N-(2,5-dimethyl-4-nitrophenyl)-4-methylbenzenesulfonamide.

214
P.K. Murthy et al. / Journal of Molecular Structure 1153 (2018) 212e229
Fig. 2. FT-Raman spectrum of N-(2,5-dimethyl-4-nitrophenyl)-4-methylbenzene sulfonamide.
Table 1
developed by Johnson et al. [50,51], as implemented in Jaguar
program, was applied for the investigation of intra molecular non-
covalent interactions.
Crystallographic data and structure refinement parameters of NDMPMBS.
CCDC Number
1539743
Empirical formula
Formula weight
Temperature/K
Crystal system
Space group
a/Å
C15H16N2O4S
320.37
273.15
monoclinic
P21/c
10.0549 (13)
18.967 (2)
8.3087 (11)
90
103.184 (4)
90
1542.8 (3)
4
1.3792
0.229
2.5. Hirshfeld surfaces
The 3D-Hirshfeld surfaces [52e54] and the corresponding 2D-
fingerprint plots (de vs di) [55e57], provides summary and quan-
tification of the intermolecular interactions in the crystal structure
[52,58], were generated by using CrystalExplorer3.1 [59] and which
accepts a structure input file in the CIF format. The dnorm values are
mapped onto the Hirshfeld surfaces by using a rainbow colour
scheme (red-white-blue): where a red colour indicates contacts
shorter than sum of van der Waals radii, white colour denotes for
b/Å
c/Å
ꢁ
ꢁ
ꢁ
/
a
b
g
/
/
Volume/Å3
Z
rcalcg/cm3
contacts around the ndW and blue colour specifies contacts longer
than sum of van der Waals radii.
m
/mmꢀ1
F (000)
672.8
Crystal size/mm3
Radiation
0.28 ꢂ 0.25 ꢂ 0.22
Mo K
4.68 to 53.02
a
(
l
¼ 0.71073)
range for data collection/ꢁ
3. Result & discussion
2
Q
Index ranges
ꢀ12 ꢃ h ꢃ 12, ꢀ23 ꢃ k ꢃ 23, ꢀ10 ꢃ l ꢃ 10
Reflections collected
Independent reflections
Data/restraints/parameters
Goodness-of-fit on F2
28527
3.1. Molecular and crystal structure
3199 [Rint ¼ 0.0493, Rsigma ¼ 0.0222]
3199/0/206
The ORTEP view of the molecule of the title compound is shown
in Fig. 3. The dihedral angle between the two benzene rings in the
title compound is 85.54 (6)o. The nitro group is essentially planar
(rmsd ¼ 0.003 Å) and is tilted to the aniline ring by 25.86 (3)o. The
atoms around the sulfonamide S37 atom in the title compound are
1.073
Final R indexes [I ꢄ 2
s
(I)]
R1 ¼ 0.0416, wR2 ¼ 0.1127
R1 ¼ 0.0464, wR2 ¼ 0.1188
0.32/-0.46
Final R indexes [all data]
Largest diff. peak/hole/e Åꢀ3
arranged in
a slightly distorted tetrahedral arrangement as
experimental values, the wave numbers were scaled by a scaling
factor 0.9613 [40]. DFT calculations were also performed with
Jaguar 9.6 [41] program with B3LYP functional and 6e311þþG
(d,p), 6-31 þ G (d,p), 6-311G (d,p) basis sets for calculations of ALIE,
Fukui functions and BDEs, respectively. MD simulations and RDF
calculations were performed with Desmond program [42e45].
Both Jaguar and Desmond programs were used as implemented in
observed generally in sulfonamides. The biggest deviation is in the
angle O33eS37eO34 of 119.34 (1)o, followed by 104.14 (2)o of
O33eS37eN31. The V shaped molecular conformation is stabilized by
intramolecular CeH/O hydrogen bonds involving H18 and O34
atoms (Fig. 3, Table 2) that encloses to form a S (6) motif. In the
crystal, molecules are linked by pairs of NeH/O hydrogen bonds
involving amino nitrogen atom N31 as the hydrogen bond donor
and sulfonyl oxygen atom O33 as the acceptor. These two hydrogen
€
Schrodinger Materials Science Suite 2017e2 [45]. In case of the MD
bonds form inversion related R2 (8) dimers (Fig. 4(a), Table 2).
simulation, one molecule of title compound was placed in the cubic
box with approximately 3000 water molecule. OPLS3 force field
[42,46e48] was used and the model was of NPT ensemble class.
Simulation time was set to 10 ns, temperature to 300 K, pressure to
1.0325 bar, with cut-off radius set to 12 Å. Simple point charge (SPC)
model [49] was used for description of solvent. An approach
2
These dimers are linked by CeH/O hydrogen bonds involving H14
hydrogen atom and the sulfonyl oxygen atom O34 to form a double
C (7) chains propagating along the c-axis direction and forming a
ribbon like architecture (Fig. 4(a)). Neighbouring ribbons are linked
via offset
p
…
p
interactions [Cg
…
Cg ¼ 3.9058 (19) Å; interplanar

P.K. Murthy et al. / Journal of Molecular Structure 1153 (2018) 212e229
215
Fig. 3. ORTEP diagram of N-(2,5-dimethyl-4-nitrophenyl)-4-methylbenzenesulfonamide with thermal ellipsoids drawn at 50% probability with optimized geometry.
observed, first interaction between sulfonamide N31eH38 with O33
of sulphonamide, which can visualize as dark red areas and labelled
as a and aˈ. Another, interaction between O34 of sulfonamide with
the C13eH4 of nitrobenzene, which can be seen as bright red spots
marked as b and bˈ in Fig. 5(a) and (b), on the dnorm mapped sur-
faces. The upper spike denoted with b (Fig. 5(c)) corresponds to the
donor spike (H38 atom in SO2NH group interacting with O33 atom of
the SO2NH group), with the lower spike indicate with a corre-
sponding to an acceptor spike (O33 atom of the SO2NH group with
Table 2
Geometric parameters for hydrogen bonds and other intermolecular contacts (Å, ꢁ
operating in the crystal structures of NDMPMBS.
)
D-H … A
D-H
H … A
D … A
D-H … A
C17eH18/O34a
N31eH38/O33b
C13eH4/O34c
0.93
0.81
0.93
2.45
2.20
2.38
3.0825
2.9772
3.2133
125
160
149
a
Intra.
x,1-y,1-z.
x,y,-1þz.
b
c
H38 atom of the SO2NH group), both are look like sharp spikes with
almost same in length and forming inversion dimers that enclose
R2 (8) loops. Fig. 5(c), depicted H/H contacts appears as spikes,
2
distance ¼ 3.6104 (19) Å; slippage ¼ 1.490 Å; symmetry code: 1-
x,1-y, 1-z] between the nitro aniline rings C11/C12/C13/C15/C16/C18
forming a two dimensional sheet parallel to the ac-plane, as illus-
trated in Fig. 4(b).
indicate with red circle and the wings encircled with black due to
the C/H contacts. From the fingerprint analysis revealed that the
HeH (36.5%) and OeH (36.4%) and CeH (17.6%) contacts appears to
be a predominant contribution in the crystal packing.
3.2. Hirshfeld surface analysis
3.3. Optimized geometry
The Hirshfeld surfaces of title compound display in Fig. 5(a), the
surfaces have been mapped over dnorm (A), shape index (B) and
curvedness (C) in the range of ꢀ0.452 to 1.427 Å, ꢀ1.0 to 1.0 Å
and ꢀ4.0 to 0.4 Å, respectively. Two major interactions are
Full geometry optimization (shown in Fig. 3) of title compound
was carried out for isolated molecules in gas phase at DFT/B3LYP/
6e311þþG (d,p) method, initially coordinates obtained from X-ray
Fig. 4. (a) Ribbon like architecture formed via NeHeO and CeHeO hydrogen bonds in the title compound. (b) A view of the crystal packing of the compound displaying two
dimensional sheets.

216
P.K. Murthy et al. / Journal of Molecular Structure 1153 (2018) 212e229
Fig. 5. (a) Hirshfeld surfaces of NDMPMBS (A) dnorm (B) shape index and (C) curvedness. (b) Hirshfeld surfaces mapped with dnorm showing various interactions with surrounding
molecules. (c) Finger print plots of NDMPMBS; (a) total surface area (100%), (b) HeH (36.5%), (c) OeH (36.4%), (d) CeH (17.6%), NeH (1.5%), OeC (1.2%) and NeC (0.9%) interactions
visualized with percentage of contacts.

P.K. Murthy et al. / Journal of Molecular Structure 1153 (2018) 212e229
217
structure without any constraints. Selected geometrical parameters
(bond length (Å), bond angle (º) and torsion angle (º) of investigated
compound are listed in Table 3). The comparative study shows a
good agreement among the computational and experimental pa-
rameters (Supplementary information). The computational
geometrical parameters are slightly more than that of experimental
values. Because of, the experimental results were based on mole-
cules in the solid state, while the computed values were carried in
gas phase for isolated molecule.
group generally appear in the region of 1400e1485 cmꢀ1 and 1380-
1420 cmꢀ1, respectively [64e67]. For title compound, the bands
calculated at 1449, 1435, 1434, 1432, 1430, 1421 cmꢀ1 (B3LYP),
experimentally observed at 1448, 1418 cmꢀ1 (IR) (asymmetric
deformation) and 1367, 1363, 1362 cmꢀ1 (B3LYP) (symmetric
deformation vibrations), shows good agreement with literature
values. For the investigated compound, the rocking modes of
methyl group are calculated at 1023, 1021, 1017 and
970 cmꢀ1 (B3LYP) and experimentally observed at 970 cmꢀ1 in the
Raman spectrum, assigned as expected. The CH3 torsion vibrational
modes are usually appear in the region 185 65 cmꢀ1 [62], the
bands assigned at 206, 188, 168 and 28 cmꢀ1 (B3LYP).
3.4. Vibrational spectral analysis
The stretching vibration modes of aromatic nitro group are ex-
pected in range, 1570-1485 cmꢀ1 (asymmetric stretching) and
1370-1320 cmꢀ1 (symmetric stretching) [68]. For in case of inves-
tigated compound, these modes are assigned at 1521, 1502 cmꢀ1
(IR), 1520, 1502 cmꢀ1 (Raman), 1541, 1505 cmꢀ1 (B3LYP) (asym-
metric stretching modes); 1300 cmꢀ1 (IR and Raman), 1305 cmꢀ1
(DFT) (symmetric stretching modes). Both the modes show high IR
intensity and Raman activity. The NO2 deformation modes (scis-
soring, out-of-plane wagging, in-plane rocking and torsion) are
The calculated (scaled) wavenumbers, experimental IR, Raman
bands and assignments are given in Table 4.
The NeH stretching vibration mode generally measured in re-
gion 3500-3300 cmꢀ1 [60,61]. In the present case, the bands
observed at 3277 cmꢀ1 (IR), 3276 cmꢀ1 (Raman) and 3488 cmꢀ1
(DFT) is assigned as NH stretching vibration mode. The mode
(mode no 1) is pure and PED is exactly 100%. The difference be-
tween computational and experimental NeH stretching vibration
is 171 cmꢀ1 for IR and 172 cmꢀ1 for Raman, this may due to the
NeHeO intermolecular interaction of title molecule in crystal state.
The NeH in-plane bending vibration mode is usually expected
around 1400 cmꢀ1 [17]. In the present case, the bands observed at
1386 cmꢀ1 in the IR spectrum, 1384 cmꢀ1 in the Raman spectrum
and 1391 cmꢀ1 for DFT (B3LYP) are assigned to the NeH in plane
bending vibration mode, this is good agreement with literature
values. The mode number 79 have calculated wave number at
492 cmꢀ1 correlate well with experimental Raman spectrum at
493 cmꢀ1 assigned as NH out-of-plane bending vibration.
expected in the regions 855
40, 760
30, 540
30 and
70 20 cmꢀ1 respectively [62]. The bands at 858, 734 cmꢀ1 in IR
spectrum, 857, 734 cmꢀ1 in Raman spectrum and 847 and 732 cmꢀ1
(DFT) are assigned as deformation modes of NO2 group of title
compound. The reported values of the NO2 deformations modes are
809, 727, 524 cmꢀ1 (experimentally), 800, 727, 534 cmꢀ1 (DFT) [69].
The asymmetric and symmetric stretching vibrational modes
fall in region 1330-1295 cmꢀ1 and 1150-1125 cmꢀ1, respectively for
SO2 group [70]. In the present case, the bands computed at 1267
and 1082 cmꢀ1 (DFT), experimentally observed at 1260, 1086 cmꢀ1
in the IR spectrum and 1260 and 1085 cmꢀ1 in the Raman spectrum
are assigned as SO2 asymmetric and symmetric stretching modes.
The SO2 stretching mode is not pure, but it contains contribution
from other modes. Although the region of the SO2 scissoring
The asymmetric and symmetric stretching modes of the methyl
group are expected in the regions 3000
2900
50 cmꢀ1 and
45 cmꢀ1 [62,63]. For the title compound the stretching
modes are assigned at 2981 cmꢀ1 (Raman), in the range
2999e2940 cmꢀ1 (B3LYP) (asymmetric stretching modes);
2924 cmꢀ1 (IR), 2925 cmꢀ1 (Raman) and in the region 2929-
2895 cmꢀ1 (B3LYP) (symmetric stretching modes) as expected. The
asymmetric and symmetric deformations vibrations of methyl
(560
40 cmꢀ1) and that of SO2 wagging vibration mode
(500 55 cmꢀ1) partly overlap, the two vibrations appear sepa-
rately [62]. The DFT calculation of these bands at 567 cmꢀ1 and
515 cmꢀ1, observed at 566 cmꢀ1 and 515 cmꢀ1 in the Raman
spectrum assigned as wagging and scissoring, respectively. The
twisting vibrational mode of SO2 is fall in region 400 50 cmꢀ1 and
rocking vibrational mode at around 350 cmꢀ1 [62]. For the present
Table 3
Geometrical parameters of the NDMPMBS.
case, these modes are computed at 426 cmꢀ1 and 255 cmꢀ1
respectively.
The SN stretching vibration modes are expected in region
,
Bond length (Å) DFT/XRD
C1eC2
C1eC9
C2eC4
C4eC6
C6eC7
C7eC9
C1eS37
S37eO33
S37eO34
1.393/1.386
1.394/1.386
1.391/1.380
1.399/1.382
1.401/1.385
1.390/1.376
1.794/1.756
1.457/1.435
1.456/1.423
S37eN31
C11eN31
C11eC17
C12eC11
C12eC13
C15eN32
C15eC16
C16eC17
1.706/1.636
1.410/1.414
1.397/1.390
1.411/1.400
1.386/1.381
1.472/1.467
1.406/1.387
1.396/1.392
905 30 cmꢀ1 [62] and in present study, the bands observed at
798 cmꢀ1 (IR), 797 cmꢀ1 (Raman) and 801 cmꢀ1 (B3LYP) assigned
as these modes. The PED is 33% with IR intensity (145.02) and
Raman activity (44.11) respectively. From the references the CN
stretching vibration modes are fall in the region 1275 55 cmꢀ1
[62], for the title compound the vibrational modes expected at
1337, 1017 cmꢀ1(IR), 1336, 1015 cmꢀ1 (Raman) and 1349, 1225,
1017 cmꢀ1 (theoretically). The stretching vibration modes for CS
generally lie in the region 930-670 cmꢀ1 [71]. The CS stretching
vibrational wave number for title compound calculated at
629 cmꢀ1 and experimentally observed at 632 cmꢀ1 (IR and
Raman) as expected [71], PED of 21% and with high IR intensity
(147.45) and low Raman activity (19.42).
Bond angle (º) DFT/XRD
C1eS37eO33
C1eS37eO34
S37eN31eH38
O33eS37eO34
O33eS37eN31
O34eS37eN31
N31eS37eC1
108.510/108.80
S37eC1eC2
S37eC1eC9
C2eC1eC9
C1eC2eC4
C2eC4eC6
C4eC6eC7
119.732/120.56
119.139/118.75
121.127/120.69
118.954/118.86
121.265/121.53
118.424/118.42
107.940/108.54
109.049/111.41
122.550/119.34
102.979/104.14
107.449/108.40
106.296/106.95
The CeH stretching vibrational modes of substituted benzene
ring are generally observed in the region 3000-3100 cmꢀ1 [62]. In
present case, the CeH modes are assigned at 3102, 3084, 3059 cmꢀ1
(IR) and 3101, 3077, 3059, 3045 cmꢀ1 (Raman) and 3088, 3087,
3086, 3075, 3050, 3046 cmꢀ1 (B3LYP) as expected. The stretching
vibration modes (2e7) are pure with PED contribution around
100%. The in-plane and out-of-plane aromatic CH deformation
Torsion angle (º) DFT/XRD
O33eS37eC1eC2 ꢀ155.788/-134.76 N31eS37eC1eC9 ꢀ85.795/-65.94
O33eS37eC1eC9 24.365/45.99
O34eS37eC1eC2 ꢀ20.975/-3.45
O34eS37eC1eC9 159.178/177.30
N31eS37eC1eC2 94.050/113.31
S37eC1eC2eC4
C9eC1eC2eC4
S37eC1eC9eC7
ꢀ179.096/-178.98
0.746/0.3
179.146/179.23

218
P.K. Murthy et al. / Journal of Molecular Structure 1153 (2018) 212e229
Table 4
Calculated scaled wave numbers, observed IR and Raman bands and assignment of NDMPMBS.
B3LYP/6e311þþG (d,p) IR
(cmꢀ1
Raman
(cmꢀ1
)
Assignmentsa
n
)
IRI
RA
n
(cmꢀ1
)
n
3448
3088
3087
3086
3075
3050
3046
2999
2995
2990
2986
2964
2940
2929
2909
2895
1596
1571
1549
1541
1505
1469
1463
1449
1435
1434
1432
1430
1421
1391
1372
1367
1363
1362
1349
1305
1289
1283
1278
1267
1236
1225
1181
1165
1160
1124
1095
1082
1036
1023
1021
1017
1017
1006
991
46.4581
0.5718
3.3703
0.9234
1.4139
7.0118
9.4734
15.0176
10.2853
11.0976
5.5996
15.5323
13.0716
11.5999
16.7402
20.7788
72.8545
23.4981
2.4327
130.8072
223.5909
69.7658
9.1238
11.8096
11.8435
14.2335
10.021
22.3058
8.0846
21.8701
8.3958
7.9481
10.179
3.3186
30.6472
479.1206
20.1009
3.887
91.8182
96.5058
9.074
3277
3102
e
3276
3101
e
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
n
NH(100)
CHII(74)
CHII(69)
CHI(90)
CHI(93)
CHI(95)
CHI(93)
asyCH3
asyCH3
asyCH3
asyCH3
asyCH3
asyCH3
syCH3
42.5747
82.2193
78.9474
104.0429
55.4886
57.2905
68.4502
78.0916
86.467
65.2499
210.3946
282.9166
210.3411
123.5693
71.5686
6.3037
150.8671
57.7494
12.3407
1.7324
3.2022
6.6691
9.1215
9.273
5.4629
7.661
3084
e
e
3077
3059
3045
3000
e
3059
e
e
e
e
e
e
2981
e
e
e
e
2924
e
2925
e
syCH3
syCH3
PhII(25)
e
e
e
1595
1573
e
1572
e
PhI(30),
PhI(27),
d
d
PhI(10)
PhI(13)
1521
1502
e
1520
1502
e
asyNO2(11),
asyNO2(30)
nPhII(23)
d
d
d
d
d
d
d
d
d
d
d
d
d
CHII(26)
CHI(20)
1453
1448
e
e
e
asyCH3(29)
asyCH3(30),
asyCH3(40),
asyCH3(58),
asyCH3(27)
asyCH3(53),
HNC (39), dasCH3 (12), nPhII(12)
CH(10), PhI(17)
syCH3(53)
e
t
t
t
CH3(13)
CH3(12)
CH39110
e
e
e
e
e
e
1418
1386
e
e
t
CH3(16)
1.2362
1.4436
1384
e
17.2254
8.8532
22.9263
12.2288
466.0533
4.1237
11.5492
3.9597
5.4774
122.7941
260.7209
17.4604
2.0068
4.3912
10.3407
0.1308
57.5833
12.0904
4.1252
3.4665
52.8199
0.872
23.1076
2.0952
7.7547
0.2327
0.3556
0.3669
0.3834
1.8665
23.6678
0.262
44.1127
13.1022
9.2131
57.6339
1.4291
4.593
7.6921
1.0984
15.7566
19.4248
e
e
e
e
HNC (10),
syCH3(28)
dsyCH3(41)
e
e
1337
1301
e
1336
1300
e
n
n
n
CN(10), PhII(18)
syNO2(36),
PhII(12)
dNO2(11)
1283
1278
1260
e
e
d
d
CHI(13),
CHI(13),
n
n
PhI(14)
PhI(10)
2.8038
92.2633
57.3095
159.3669
2.706
1278
1260
e
nSO2(24),
nSO2(27),
nPhII(13),
n
CHII(16)
nCHII(26)
e
e
nCN(14)
e
e
d
d
d
d
d
PhI(12),
CHII(13)
CHI(17), CC(10)
PhII(10), CN(13),
CH(15), PhI(14)
nCC(39)
9.701
e
e
4.3426
5.4554
6.9218
228.657
49.2109
21.2059
25.9912
138.9511
1.868
23.1045
8.8863
5.1592
0.1598
0.0298
0.3507
33.6547
5.5845
2.6101
0.179
145.0279
53.2133
38.8255
6.191
5.1162
6.0197
19.2976
3.337
1156
e
1151
1124
1089
1085
e
n
nCC(12)
1089
1086
e
n
n
n
SO2(27),
SO2(17),
n
n
CS(12)
PhI(18)
e
e
d
d
d
d
t
d
CH3(16)
CH3(16)
CH3(11),
CH3(11),
HCCC(20)
PhI(22)
e
e
e
e
n
n
CN(13),
CN(13)
nCC(15)
1017
e
1015
e
e
e
971
970
954
935
896
879
847
818
801
795
780
777
732
712
697
688
e
e
nPh(11),
t
HCCC(19)
CH3(10), tHCCC(36)
e
971
e
dCH3(10),
dCHI(23)
dCHI(18),
dCHII(40)
dCHII(43)
dNO2(30)
dCHI(26)
d
e
e
e
tPhI(10)
895
e
895
e
858
818
798
e
857
817
797
e
nSN(33)
d
d
d
d
d
t
t
CHI(24)
e
e
NO2(25),
PhI(30)
NO2
NO2
PhII(16)
PhI(31)
dCC(19), dPhII(19)
e
e
734
706
e
734
e
698
684
e
e
635
629
17.125
147.4525
e
n
n
PhII(15)
CC(14), dPhI(10), nCS(21)
632
632

P.K. Murthy et al. / Journal of Molecular Structure 1153 (2018) 212e229
219
Table 4 (continued )
B3LYP/6e311þþG (d,p)
IR
Raman
(cmꢀ1
)
Assignmentsa
n
(cmꢀ1
)
IRI
RA
n
(cmꢀ1
)
n
621
584
567
537
515
492
474
457
443
426
409
398
383
355
320
316
306
275
255
244
227
212
206
188
168
156
142
101
91
2.5455
14.7141
80.959
88.1423
78.0052
25.7815
2.3793
1.7323
10.9643
6.5447
0.3637
0.0749
0.0748
1.4186
1.1514
1.0446
1.7845
2.1131
3.0132
1.7079
0.6907
1.7256
0.7871
1.3078
0.5755
0.7665
0.3113
3.3054
1.9723
2.9088
0.0972
0.1761
0.0845
1.3962
6.1092
0.8446
10.0026
7.5126
2.5205
14.2137
3.7152
10.4594
2.065
2.3866
1.7107
0.0283
1.8542
0.4892
0.8876
0.3568
0.1186
5.4593
3.4884
2.4539
3.3657
1.5674
0.4177
1.3333
0.8188
0.569
615
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
e
n
PhI(36)
e
t
d
d
d
d
d
HCCC(12), dCCCC(14)
SO2 wag (10)
ONC(14)
SO2 sci (14)
NHCC(54)
CCCC(15)
566
e
515
493
e
e
nCC(10),
d
PhII(17)
CCCC(12)
CCC(10)
e
t
d
d
t
d
d
d
d
PhII(24),
SO2(28),
CCC(11)
PhI(28),
ONC(10),
NSC(12)
NSC(11),
CCC(49)
d
d
e
e
e
t
HCCC(12)
e
dCCC(15)
e
e
dCCCC(10)
e
301
e
n
n
CN(12),
CS(32)
dPhII(13)
e
d
d
n
SO2 rock (10), OSN(10)
CCN(14), OSN(19)
PhII(10), CCC(20), nSN(14)
nCS(12),
d
e
d
d
227
e
dNCC(42),
tCH3(25),
tCH3(11),
tCH3(18),
dSCC(56),
tPhII(12),
dCNS(31),
tPhII(13)
tPhII(21)
tNO2(53)
tCH3(34)
tNO2(22)
tNO2(10)
d
d
d
d
OSN(10)
e
CCCC(14)
NCCC(15),
NSC(10)
e
dNSC(14)
e
e
d
ONCS(24)
NCCC(12)
dCCN(23)
0.1023
1.2104
0.6841
1.2039
1.5942
0.9245
3.4964
6.4671
e
d
e
92
e
57
34
28
26
e
e
e
19
e
a
n-stretching; d-in-plane deformation and out-of-plane deformation; t-torsion; 2,5-dimethyl 4-nitrophenyl and tosyl ring are represented as PhI and PhII; potential energy
distribution is given in brackets (%) in the assignment column.
modes are expected above and below 1000 cmꢀ1 [62] and for in the
case of investigated compound these modes assigned at 1283,1278,
1260, 1156, 1089 cmꢀ1 (IR), 1278, 1260, 1089 cmꢀ1 (Raman), 1283,
1278, 1267, 1236, 1095 cmꢀ1 (B3LYP) (in-plane deformation) and at
895, 818 cmꢀ1 (IR), 895, 817 cmꢀ1 (Raman), 896, 818 cmꢀ1 (B3LYP)
(out-of-plane deformation). The aromatic ring stretching vibra-
tional modes expected in the region 1615-1260 cmꢀ1 [62]. For the
investigated compound, the bands experimentally observed at
1572, 1502, 1386, 1278 cmꢀ1 (IR), 1595, 1573, 1502, 1384, 1278 cmꢀ1
(Raman) and in the range of 1596e1278 cmꢀ1 (B3LYP) assigned as
these modes.
and 20.95 ppm and calculated at 16.85, 24.07, 22.09 ppm was
assigned to methyl carbon atoms at C23, C27 and C19. The signals for
aromatic carbons (tosyl ring and nitrobenzene ring) were observed
at 126.57e145.12 ppm and calculated at 124.86e154.11 ppm for
DFT. The C15 carbon of nitrobenzene ring appears 145.12 ppm due
to nitro substitution, calculated as 150.35 ppm. The signal at C1 and
C6 carbons of tosyl ring appears at 137.31 ppm (147.51 ppm) and
139.89 ppm (154.11 ppm) (experimental/calculated) due to methyl
group as well as sulfonyl group substitution. The signal at
143.59 ppm is assigned as C11 carbon of nitrobenzene ring due to
amine group substitution, which was calculated at 149.61 ppm,
show good agreement.
The title compound have 16 protons occur in three regions, out
of which 9 protons attached to methyl groups, one protons is
attached nitrogen (NeH proton) and 6 protons are aromatic pro-
3.5. NMR spectral analysis
NMR spectroscopy is one of the important and valuable tool for
identification of structural and functional groups of the molecules.
13C and 1H NMR chemical shifts values of title compound were
recorded in DMSO solvent (TMS as internal standard), calculated in
DMSO at GIAO method [72] using DFT/6-311Gþþ(d,p) basic set,
which provide information about the number of different types of
carbon atoms and the number of different types of protons present
in the molecule, respectively. The 13C and 1H NMR spectra are given
in Fig. 6(a) and (b). Correlated results of experimental and calcu-
lated 13C and 1H NMR chemical shifts values are given in Table 5.
The result in Table 5 shows that the range of 13C NMR chemical
shift of typical organic molecule usually is > 100 ppm [73,74] the
accuracy ensures reliable interpretation of spectroscopic parame-
ters. In 13C NMR spectrum, upfield signal observed at 16.92, 19.68
tons. The 9 methyl protons are occur in the upfield region at d 2.04,
2.37, 2.42 ppm (experimental) and calculated at 2.01, 2.35,
2.64 ppm, shows good agreement. The NeH proton observed
experimental at 10.01 ppm and computed at 6.07 ppm. The phenyl
ring protons are observed around at 7.20e7.82 ppm (experimental)
which shows good agreement with calculated value
7.45e8.17 ppm.
3.6. Electronic spectra and frontier molecular orbital analysis
Electronic spectra of title compound calculated in DMSO as well
as methanol solution by TD-DFT/PCM model using B3LYP/6-
311Gþþ(d,p) basic set (Table 6). The electronic spectra of the title

220
P.K. Murthy et al. / Journal of Molecular Structure 1153 (2018) 212e229
Fig. 6. 13C NMR (a) and 1H NMR (b) spectrum of N-(2,5-dimethyl-4-nitrophenyl)-4-methylbenzenesulfonamide.

P.K. Murthy et al. / Journal of Molecular Structure 1153 (2018) 212e229
221
Table 5
Experimental and calculated (13C and 1H) NMR chemical shifts (ppm) of NDMPMBS.
Atom
Experimental (ppm)
TMS B3LYP/6-311 þ G (2d,p) GIAO (ppm)
13C-NMR
C23
16.92
16.85
C27
19.68
24.07
C19
20.95
22.09
C17
C13
C12
C2, C9
C4, C7
C16
C1
C6
126.57
126.76
126.90
129.81
130.72
131.41
137.31
139.89
143.59
145.12
124.86
133.47
131.86
131.04
134.71
144.83
147.19
154.11
149.61
150.35
C11
C15
1H-NMR
H24eH26
H20eH22
H28eH30
H5, H8
H18
H3, H10
H14
H38
2.04
2.37
2.42
7.38
7.20
7.66
7.82
10.01
2.01a
2.35a
2.64a
7.45a
8.10
7.82a
8.17
6.07
a
Average.
compound (in Figure S2 and S3 supporting information) illustrate
an electronic absorption band with maxima at 349 nm (DMSO) and
347 nm (methanol), is due to the electronic transition from the
ground state to the first excited state. It is mainly described by one-
electron excitation from the HOMO (characterizes by the ability of
electron donating) to LUMO (characterizes by the ability of electron
accepting). Diagrammatic representation of HOMO-LUMO proved
in Fig. 7, HOMO (MO 84) is confined on eNHeSO2 group and
delocalized over nitrobenzene; LUMO (MO 85) is confined on nitro
group, delocalized on benzene ring of nitrobenzene. Consequently,
HOMO/LUMO transition implies an electron cloud transfer from
eSO2 group to nitro group through the benzene ring of title com-
pound. In case of title compound, the calculated energy values of
HOMO and LUMO are ꢀ7.01 eV and ꢀ2.7 eV, respectively and the
energy separation between HOMO and LUMO is 4.31 eV.
Fig. 7. HOMO-LUMO plots of N-(2,5-dimethyl-4-nitrophenyl)-4-methylbenzene
sulfonamide.
Single point calculation was performed at DFT at 6e311þþG (d,p)
method. The difference in energies gave the vertical ionization
potential (I) and vertical electron affinity (A) defined by equations,
I ¼ EN-1 e EN, A ¼ EN-ENþ1, where ENþ1, EN and EN-1 are the energies
of the Nþ1, N and N-1 electron systems respectively [75]. The
magnitude of global reactivity descriptor values as tabulated in
Table 7 were calculated with the help of energies of Ionization
potential (I) and electronic affinity (A) utilizing equations provided
in the supplementary material.
In order to understand the chemical reactivity of title com-
pound, global reactivity parameters were calculated DFT method.
Table 6
Theoretical electronic absorption spectra of title compound (absorption wavelength
l
(nm), excitation energies E (eV) and oscillator strengths (f)) using TD-DFT/B3LYP/
6311þþG (d,p) method.
Excitation
CI expansion
Energy Coefficient (eV)
Wavelength (nm)
Oscillator Strength (f)
DMSO
84 / 85
80 / 85
82 / 85
83 / 85
80 / 85
82 / 85
83 / 85
84 / 85
Methanol
84 / 85
80 / 85
82 / 85
83 / 85
80 / 85
82 / 85
83 / 85
84 / 85
0.68391
0.23487
ꢀ0.12971
0.63785
0.61136
ꢀ0.12639
ꢀ0.25811
0.15724
3.5498
3.7555
349
330
0.3372
0.0277
3.9266
315
0.0317
0.68231
0.24398
ꢀ0.12914
0.63440
0.60688
ꢀ0.12481
ꢀ0.26620
0.16292
3.5631
3.7605
347
329
0.3240
0.0255
3.9277
315
0.0330

222
P.K. Murthy et al. / Journal of Molecular Structure 1153 (2018) 212e229
3.7. Local reactivity properties of NDMPMBS e MEP and ALIE
surfaces, Fukuifunction surfaces and non-covalent interactions
In order to locate possibly important reactive sites of the newly
synthetized NDMPMBS molecule, in this study we have also
investigated frequently used quantum-molecular descriptors such
as MEP, ALIE and Fukui functions. Values of the aforementioned
quantities have been mapped to the electron density surface in
order to visualize their distribution within NDMPMBS molecule,
Figs. 8e10.
We begin with the identification of possibly important reactive
(electrophilic and nucleophilic) sites by the molecular electrostatic
potential (MEP) surface, which is a very useful descriptor in studies
of biological recognition and hydrogen-bonding interactions
[76,77]. The pictorial representation with rainbow colour scheme of
electrostatic potential for title compound has been shown in Fig. 8,
in the range of ꢀ6.012 a. u. to þ6.012 a. u. The darkest red colour
denotes electron rich regions (V(r) <-6.012 a. u.) that could be
sensitive towards electrophilic attacks. According to Fig. 8 these
regions are localized over oxygen atoms O33 and O34 (belonging to
sulfonyl group) and oxygen atoms O35 and O36 (belonging to the
nitro group). The darkest blue colour indicates electron poor re-
gions (V(r) > þ6.012 a. u.), and therefore the molecule sites that
could be sensitive towards the nucleophilic attacks.
Fig. 8. MEP plot of N-(2,5-dimethyl-4-nitrophenyl)-4-methylbenzenesulfonamide.
Also, the electrostatic potential mapped over the dnorm surface
of the neighbouring molecules (Figure S4 supporting information)
clearly showed that the electrostatic potential on the hydrogen
bond donors and acceptors in the neighbouring molecules are to
one another (red spots close to H-acceptor and blue spots close to
H-bond donors), thus provide further evidence to the R2 (8)
2
hydrogen bond pattern formed by NeHeO hydrogen bonds
(Figure S4 supporting information). indicates the occurrence of
N31eH38eO33, C13eH14eO34 and C17eH18eO34 interactions in title
compound. ALIE surface is even more reliable tool than MEP for the
identification of molecule sites sensitive towards electrophilic at-
tacks, since ALIE values show molecule areas where electrons are
least tightly bound [78e81]. Representative ALIE surface (Fig. 9) of
NDMPMBS molecule emphasizes the importance of oxygen atoms
O35 and O36, when it comes to the sensitivity to electrophilic at-
tacks. These molecule sites are characterized by the lowest ALIE
values of ~217 kcal/mol. Intramolecular noncovalent interactions
have also been visualized in Fig. 9. Two noncovalent interactions
were formed between oxygen and hydrogen atoms (O34eH18 and
Fig. 9. Representative of ALIE surface of N-(2,5-dimethyl-4-nitrophenyl)-4-
methylbenzenesulfonamide.
O
36eH30), with very similar strength of ~0.015 electron/bohr3.
The importance of oxygen atoms O35 and O36 from the aspect of
reactivity has been also confirmed by Fukui functions as well,
Fig. 10. Fukui functions give information about the changes in
electron density as a consequence of charge addition or removal.
Purple color in Fig. 10(a) gives information about where electron
density increased after the charge addition, while negative color in
Fig. 10(b) gives information where electron density decreased after
the charge addition. According to the results presented in Fig. 10(a),
electron density could increase in the near vicinity of oxygen atoms
O36 and O37 after the charge addition. On the other side, results in
Fig. 10(b) indicate that electron density decreases in the near vi-
cinity of oxygen atoms O33 and O34 after the charge removal.
3.8. Nonlinear optical properties
Table 7
The energy values of global reactivity descriptors (Ionization po-
Nonlinear optical materials occupy a foremost function in
nonlinear optics and in particular they have a great impact on in-
formation technology and industrial applications. NLO properties
find applications in optical communication, telecommunications,
optical phase conjugation, frequency mixing, optical mixing, dy-
namic image processing, signal processing and second harmonic
wave generation [82e84]. Total dipole moment (mo), anisotropy of
the polarizability (atot), mean polarizibility (Da), and first-order
tential (IP), electron affinity (EA), electro negativity (
potential ( ), global hardness ( ), global softness (
)) for title compound.
c), chemical
) and global
m
h
s
electrophilicity (
u
Parameter
Value (eV)
Ionization potential (IP)
Electron affinity (EA)
8.48
1.09
4.78
ꢀ4.78
3.69
0.13
3.09
Electronegativity (
Chemical potential (
Global hardness (
Global softness (
Electrophilicity index (
c)
m
)
h)
hyperpolarizibilitiy(b) of NDMPMBS were calculated at DFT/
s
)
B3LYP/6-311Gþþ(d,p) method and listed in Table 8. The dipole
u
)
moment and mean polarizability of the title compound are 2.2670

P.K. Murthy et al. / Journal of Molecular Structure 1153 (2018) 212e229
223
Fig. 10. Fukui functions of N-(2,5-dimethyl-4-nitrophenyl)-4-methylbenzenesulfonamide.
Debye and 7.4165
polarizibilitiy(
ꢂ
10ꢀ24 esu. The is first-order hyper-
) of NDMPMBS calculated and is found to be
3.10. Mulliken atomic charge analysis
b
12.02 ꢂ 10ꢀ30 esu which is 92.46 times greater than that of the
The Mulliken atomic charges of investigated compound calcu-
lated at DFT/B3LYP/6-31 þ G (d,p) method in gaseous state are
given in Table 11. It is based on the linear combination of atomic
orbitals and therefore the wave function of the molecule are ob-
tained from Mulliken population analysis [89]. The charge distri-
bution on the molecule has an important role in the application of
quantum chemistry calculations for the molecular system.
standard NLO material urea (0.13 ꢂ 10ꢀ30 esu) [85]. The highest
value of first-order hyperpolarizibilitiy(b) may be due transfer of p-
electron cloud from donor (sulphonamide group) to acceptor (nitro
group) which makes molecule highly polarized and the possibility
of intra molecular charge transfer (ICT).
From the analysis of Table 11, hydrogen atoms of title compound
shows atomic charges with positive values in the range of
0.138e0.308 and but some H atoms exhibit more positive atomic
charges H38 (0.308), H14 (0.247) and H18 (0.266) comparative other
hydrogen atoms and possess acidic nature. Due to the presence of
more negative atomic charges values on oxygen atom O33 (ꢀ0.131),
O34 (ꢀ0.100) and nitrogen atom N31 (ꢀ0.215), net positive atomic
charge values on hydrogen atom H38 (0.308), H14 (0.247) and H18
(0.266) may support the formation of hydrogen bonding
3.9. NBO analysis
The natural bond orbital (NBO) calculations were performed
using NBO 3.1 program [86] as executed in the Gaussian09 suite at
the B3LYP/6e311þþG (d,p) (5D, 7 F) basic set which offers a suit-
able basis for examining the various interactions in both filled and
virtual orbital spaces that could enhance the analysis of inter and
intramolecular interactions. The second-order Fock-matrix was
carried out to evaluate the donoreacceptor interactions in the NBO
basis [87,88]. In NBO analysis large E (2) value shows the intensive
interaction between electron-donors and electron-acceptors, and
greater the extent of conjugation of the whole system, the possible
intensive interaction are given in Tables 9 and 10.
N31eH38eO33, C13eH14eO34 and C17eH18eO34.
3.11. Sensitivity towards autoxidation and stability in water
Modern water purification methods in the case of organic
pharmaceutical pollutants are based on the oxidation reactions
[90e92]. In terms of computational molecular modelling tech-
niques, the concept of bond dissociation energies (BDE) can be
useful for predicting molecule's weak spots where degradation
could start. Particularly, bond dissociation energies for hydrogen
abstraction (H-BDE) resemble the molecule's sensitivity towards
autoxidation mechanism [93e95], while in the same time BDEs for
the remaining single acyclic bonds can be very useful for predicting
The strong interaction n3(O35) /
(2) value 155.95 kJ/mol and an another interaction has been in
n1(N31)/ *(C11eC17) with an energy of 23.39 kJ/mol. Table 10
p*(N32eO36) has the highest E
p
gives the occupancy of electrons and p-character in significant
NBO natural atomic hybrid orbital. Almost, a very close to pure p-
character was observed in
pairs of n2O33, n2O34, n2O35, n3O35, n2O36, n1N31
p-bonding of C11eC17, N32eO36 and lone
.
Table 8
The electric dipole moment (
m), polarizability (Da) and first order hyper polarizability (
b) of title compound by B3LYP/6-311Gþþ(d,p).
Parameter
Value
Parameter
a.u.
esu (ꢂ10ꢀ24
)
Parameter
a.u.
esu (ꢂ10ꢀ33
)
mx
my
mz
mo
ꢀ1.7249
1.1390
0.9312
2.2670
axx
axy
ayy
axz
ayz
azz
atot
Da
265.9277
13.2483
217.2198
ꢀ24.6687
1.0165
214.6588
232.6021
50.0441
39.4104
1.9633
32.1919
3.6559
0.1506
31.8124
34.4716
7.4165
bxxx
bxxy
bxyy
byyy
bxxz
bxyz
byyz
bxzz
byzz
bzzz
btot
966.0397
718.7733
322.1631
29.1894
ꢀ137.3283
ꢀ28.2303
ꢀ24.3833
ꢀ120.6461
4.6938
8345.9067
6209.6981
2783.2636
252.1759
1186.4203
243.89
210.6546
1042.2978
40.5511
77.0165
665.3686
12023.3906
1391.7089
btot ¼ 12.02 ꢂ 10ꢀ30 esu

224
P.K. Murthy et al. / Journal of Molecular Structure 1153 (2018) 212e229
Table 9
Second-order perturbation theory analysis of Fock matrix in NBO basis corresponding to the intramolecular bonds of the title compound.
Donor(i)
Type
ED/e
Acceptor(j)
Type
ED/e
E (2)a
E(j)-E(i)b
F (i,j)c
C1eC2
s
e
1.97716
C1eC9
C2eC4
s
s
*
*
0.02400
0.01496
3.90
2.13
1.27
1.30
0.063
0.047
e
e
O33eS37
s
*
0.14580
0.58
0.99
0.022
e
C1eC9
s
e
1.97704
1.97568
C1eC2
C7eC9
s
s
*
*
0.02395
0.01480
3.89
2.18
1.28
1.30
0.063
0.048
e
e
O34eS37
s
*
0.15553
0.61
0.99
0.023
e
C2eC4
s
e
C1eC2
C1eS37
s
s
*
*
0.02395
0.20548
2.83
3.50
1.25
0.86
0.053
0.051
e
e
e
e
C4eC6
s
s
*
*
0.02239
0.01388
2.55
3.33
1.27
1.11
0.051
0.054
C6eC19
e
C4eC6
s
e
1.97692
1.97678
1.97587
C2eC4
C6eC7
s
s
*
*
0.01496
0.02266
2.33
2.53
1.27
1.26
0.049
0.050
e
e
C6eC19
s
*
0.01388
1.31
1.11
0.034
e
C6eC7
s
e
C4eC6
C6eC19
s
s
*
*
0.02239
0.01388
2.52
1.27
1.26
1.11
0.050
0.034
e
e
C7eC9
s
*
0.01480
2.34
1.27
0.049
e
C7eC9
s
e
C1eC9
C1eS37
s
s
*
*
0.02400
0.20548
2.88
3.38
1.25
0.87
0.054
0.051
e
e
e
e
C6eC7
s
s
*
*
0.02266
0.01388
2.54
3.28
1.27
1.12
0.051
0.054
C6eC19
e
C11eC17
s
e
1.97383
1.63339
1.97050
1.97351
C11eC12
C11eN31
s
s
*
*
0.03083
0.03005
3.62
0.93
1.25
1.12
0.060
0.029
e
e
C12eC23
s
*
0.01497
3.23
1.11
0.054
e
C11eC17
p
e
C11eC17
C12eC13
p
p
*
*
0.37633
0.30516
0.76
15.53
0.28
0.29
0.013
0.061
e
e
C15eC16
p
*
0.41191
21.46
0.28
0.075
e
C12eC13
s
e
C11eC12
C11eN31
s
s
*
*
0.03083
0.03005
3.03
4.14
1.25
1.12
0.055
0.061
e
e
C12eC23
s
*
0.01497
1.70
1.11
0.039
e
C15eC16
s
e
C13eC15
C16eC17
s
s
*
*
0.01906
0.01780
3.79
2.11
1.27
1.28
0.062
0.047
e
e
C16eC27
s
*
0.01377
1.71
1.12
0.039
e
N32eO36
s
e
1.99561
1.98387
1.80373
C13eC15
C15eN32
s
s
*
*
0.01906
0.09523
0.80
0.55
1.62
1.36
0.032
0.025
e
N32eO36
p
e
C15eC16
N32eO36
p
p
*
*
0.41191
0.63887
3.35
7.42
0.46
0.31
0.039
0.052
e
LP N31
s
e
C1eS37
C11eC17
s
p
*
*
0.20548
0.37633
7.63
23.39
0.47
0.33
0.053
0.082
e
e
O34eS37
s
*
0.15553
3.69
0.57
0.042
e
LP O33
s
e
1.98241
1.81651
1.98051
1.81923
1.9813
C1eS37
O34eS37
s
s
*
*
0.20548
0.15553
0.81
2.20
0.96
1.07
0.026
0.045
e
LP O33
p
e
C1eS37
N31eS37
s
s
*
*
0.20548
0.27315
17.99
8.97
0.45
0.40
0.081
0.055
e
LP O34
s
e
C1eS37
O33eS37
s
s
*
*
0.20548
0.14580
0.77
2.08
0.96
1.07
0.026
0.043
e
LP O34
p
e
C1eS37
N31eS37
s
s
*
*
0.20548
0.27315
17.63
10.34
0.45
0.40
0.080
0.059
e
LP O35
s
e
C15eN32
N32eO36
s
s
*
*
0.09523
0.63887
4.27
2.27
1.09
1.21
0.062
0.047
e
LP O35
p
e
1.89823
C15eN32
N32eO36
s
s
*
*
0.09523
0.05723
11.51
19.09
0.58
0.70
0.073
0.104
e
LP O35
LP O36
n
p
e
1.46754
1.90136
e
N32eO36
C15eN32
N32eO35
p
*
0.63887
0.09523
0.05831
155.95
10.94
19.69
0.14
0.58
0.70
0.136
0.071
0.106
s
s
*
*
e
a
E (2) means energy of hyper-conjugative interactions (stabilization energy in kJ/mol).
Energy difference (a.u) between donor and acceptor i and j NBO orbitals.
F (i,j) is the Fock matrix elements (a.u) between i and j NBO orbitals.
b
c
where degradation mechanism could start.
useful for the identification of atoms with pronounced interactions
with water molecules. The results regarding BDEs are presented in
Fig. 11, while Fig. 12 contains information on the most important
RDFs.
Results presented in Fig. 11 indicate the absence of H-BDE values
lower than at least 90 kcal/mol. This indicates that the title
Since majority of pharmaceutical pollutants eventually end up
in the water resources, it is also of great importance for predictions
of degradation properties to understand the stability of molecules
in water. This can be done thanks to the molecular dynamics (MD)
simulations and radial distribution functions (RDF), which are very

P.K. Murthy et al. / Journal of Molecular Structure 1153 (2018) 212e229
225
Table 10
NBO results showing the formation of Lewis and non-Lewis orbitals.
Table 11
Mulliken atomic charge of title compound by DFT/B3LYP/6-311G (d,p).
Bond (A-B) ED/ea
EDA% EDB% NBO
s%
p%
Atoms
Atomic charges
Atoms
Atomic charges
s
C1-C2
1.97716
ꢀ0.74770
1.97704
ꢀ0.74669
1.97568
ꢀ0.72622
1.97692
ꢀ0.72233
1.97678
ꢀ0.72114
1.97587
ꢀ0.72850
1.97383
ꢀ0.73082
1.63339
ꢀ0.28039
1.97050
ꢀ0.72910
1.97351
ꢀ0.73156
1.99561
ꢀ1.08213
1.98387
ꢀ0.45651
1.80373
ꢀ0.32731
1.98241
ꢀ0.82036
1.81651
ꢀ0.31360
1.98051
51.40 48.60 0.7169 (sp1.61)Cþ
38.33 61.63
33.65 66.30
S37
N31
N32
O33
O34
O35
O36
C1
C2
C4
C6
C7
0.134
H3
H5
H8
0.208
0.182
0.184
0.249
0.247
0.266
0.185
0.151
0.156
0.175
0.182
0.153
0.195
0.138
0.212
0.308
e
e
0.6971 (sp1.97)C
ꢀ0.215
ꢀ0.203
ꢀ0.131
ꢀ0.100
0.013
e
s
C1-C9
51.34 48.66 0.7165 (sp1.63)Cþ
38.05 61.91
33.66 66.29
0.6975 (sp1.97)C
H10
H14
H18
H20
H21
H22
H24
H25
H26
H28
H29
H30
H38
e
e
e
s
C2-C4
50.33 49.67 0.7094 (sp1.81)Cþ
35.52 64.44
35.00 64.96
e
e
0.7048 (sp1.86)C
e
0.004
0.204
s
C4-C6
49.28 50.72 0.7020 (sp1.85)Cþ
35.03 64.93
34.00 65.96
e
e
0.7121 (sp1.94)C
e
ꢀ0.285
ꢀ0.610
0.496
ꢀ0.495
ꢀ0.164
ꢀ0.199
0.955
ꢀ0.442
ꢀ2.057
1.860
ꢀ0.683
ꢀ0.479
ꢀ0.471
ꢀ0.326
s
C6-C7
50.68 49.32 0.7119 (sp1.95)Cþ
33.84 66.12
34.97 64.99
e
e
0.7023 (sp1.86)C
e
s
C7-C9
49.65 50.35 0.7046 (sp1.85)Cþ
35.09 64.87
35.66 64.30
0.7096 (sp1.80)C
C9
e
e
e
C11
C12
C13
C15
C16
C17
C19
C23
C27
s
C11-C17
51.47 48.53 0.7174 (sp1.71)Cþ
36.88 63.08
33.65 66.30
e
e
0.6966 (sp1.97)C
e
p
C11-C17
47.40 52.60 0.6885 (sp99.99)Cþ 0.01
99.99
99.95
e
e
0.7252 (sp99.99)C
0.01
e
s
C12-C13
50.80 49.20 0.7127 (sp1.86)Cþ
35.00 64.96
35.76 64.20
e
e
0.7014 (sp1.80)C
e
s
C15-C16
50.44 49.56 0.7102 (sp1.60)Cþ
38.44 61.52
33.01 66.95
e
e
0.7040 (sp2.03)C
e
s
N32-O36
49.06 50.94 0.7004 (sp2.15)Nþ
31.66 68.23
24.18 75.68
e
e
0.7138 (sp3.13)O
e
p
N32-O36
39.14 60.86 0.6256 (sp99.99)Nþ 0.02
99.72
99.71
with water molecules. This hydrogen atom with the most impor-
tant RDF curve is located adjacent to the bond with the lowest BDE
value, indicating that the influence of water could be of importance
for the degradation of NDMPMBS.
e
e
0.7801 (sp99.99)O
0.06
e
n1 N31
e
e
e
e
sp14.60
e
6.41
93.56
e
e
e
n1 O33
e
e
e
e
sp0.32
e
75.47 24.50
e
e
e
n2 O33
e
e
e
e
sp99.99
e
0.08
99.61
3.12. Drug likeness and molecular docking
e
e
e
n1 O34
e
e
e
e
sp0.33
e
75.20 24.76
Drug likeness properties associated to the Lipinski's rule of five
[96,97] for the newly synthetized NDMPMBS molecule have been
calculated and summarized in Table 12. According to all parameters
provided in Table 12 it can be concluded that newly synthetized
NDMPMBS molecule could be considered as a candidate for prac-
tical applications in some pharmaceutical formulation. Namely, the
AlogP value is 3.67, which is far below the desired threshold of 5. In
the same time, prospective drug candidates should have less than 5
and 10 HBD and HBA, respectively. These prerequisites are also
fulfilled by the NDMPMBS molecule. Ghose et al. [98], have stated
that the molar refractivity should be in the range between 40 and
130, while PSA should take values less than 140 Å2. Inspection of
Table 12 clearly indicates that these criteria are satisfied by the
NDMPMBS molecule, including the criteria by Veber et al. [99], for
the number of rotatable bonds, which should be lower than 10.
NDMPMBS molecule is also very close to satisfy the Congreeve's
rule of three [100]. Namely, the Congreeve's rule of three is just
slightly violated by the NDMPMBS molecule in terms of somewhat
higher AlogP value and one more rotatable bond.
Drug likeness parameters motivated us to further investigate
NDMPMBS molecule from the aspect of pharmaceutical properties.
In order to identify in which direction NDMPMBS molecule could
exhibit its biological activity we have employed the Prediction of
Activity Spectra for Substances (PASS) online software [101], which
screens the biologically activity spectrum of the potential drug
candidates taking into account the large training set. The results
concerning the predicted biological activities have been summa-
rized in Table 13, where Pa represents the probability for molecule
to be active, while Pi represents the probability for molecule to be
inactive. Table 13 contains information about activities that are
higher than 0.7.
ꢀ0.81948
1.81923
ꢀ0.31566
1.98139
ꢀ0.81272
1.89823
ꢀ0.29882
1.46754
e
e
e
n2 O34
e
e
e
e
sp99.99
e
0.11
99.58
e
e
e
n1O35
sp0.32
75.71 24.28
e
e
e
e
e
e
n2 O35
e
e
e
e
sp99.99
e
0.25
99.64
e
e
e
n3O35
e
e
e
e
sp99.99
e
0.07
99.73
ꢀ0.28319
1.90136
ꢀ0.30047
e
e
e
n2O36
e
e
e
e
sp99.99
e
0.41
99.48
e
e
e
a
ED/e is expressed in a. u.
molecule is not sensitive towards the autoxidation mechanism.
Namely, all of the H-BDE values are much higher than the desired
threshold of 90 kcal/mol, with the lowest H-BDE values calculated
for hydrogen atoms of methyl groups, thanks to which it is expected
that the title molecule is stable in the presence of oxygen. The
lowest BDE value of the rest of the single acyclic bonds have been
calculated in the case of NeS bond, with BDE value of just 41 kcal/
mol, indicating that degradation could start precisely by breaking of
this bond. Other significantly low BDE values have been calculated
in the cases of CeN bond (N belonging to the NO2 group) and CeS
bond, with BDE values of around 70 kcal/mol, indicating that
detachment of benzene or NO2 group could occur during the
degradation.
Calculations of RDFs indicate that six atoms of NDMPMBS have
high and sharp RDF curves. However, five of six of the aforemen-
tioned atoms have their maximal g(r) values located at distances of
around 4 Å. Certainly, the most important RDF has been calculated
in the case of hydrogen atom H38, with its maximal g(r) value
located at distance of 2 Å, which indicates significant interactions
According to the screening of biological activities by PASS it can
be seen that NDMPMBS molecule has significantly high probabili-
ties to be active as inhibitor of arylsulfatesulfotransferase and

226
P.K. Murthy et al. / Journal of Molecular Structure 1153 (2018) 212e229
Table 13
PASS predicted biological activities of NDMPMBS.
Pa
Pi
Activity
0.889
0.888
0.860
0.850
0.766
0.757
0.744
0.758
0.731
0.724
0.734
0.004
0.007
0.005
0.003
0.011
0.010
0.003
0.023
0.004
0.011
0.056
Arylsulfate sulfotransferase inhibitor
Polyporopepsin inhibitor
Glutamyl endopeptidase II inhibitor
Phospholipid-translocating ATPase inhibitor
Omptin inhibitor
Venombin AB inhibitor
Antiprotozoal (Coccidial)
Benzoate-CoA ligase inhibitor
Aspergillopepsin I inhibitor
2-Hydroxymuconate-semialdehyde hydrolase inhibitor
Ubiquinol-cytochrome-c reductase inhibitor
Fig. 11. BDE of all single acyclic bonds of N-(2,5-dimethyl-4-nitrophenyl)-4-
methylbenzenesulfonamide.
actions including: removal of water molecules, addition of
hydrogen atoms and addition of charges according to Gasteiger-
Marsili approach. Protein sites which contained docked molecules
from the experimentally obtained results were used as a target
search space for docking studies. Fig. 13 contains illustration of the
docked NDMPMBS molecule to the surface of the two selected
proteins, while binding energies of several representative docking
modes have been summarized in Table 14.
Results provided in Fig. 13 and Tables 12e14 indicate great po-
tential of the newly synthesized NDMPMBS molecule for applica-
tion in pharmaceutical applications. Fig. 13 and Table 14 illustrate
that NDMPMBS molecule binds to 1WKR and 3ETT proteins with
significantly high binding energies. In both cases binding energy of
the most representative docking mode had the value of ꢀ7.20 kcal/
Fig.
12. RDF's
of
atoms
of
N-(2,5-dimethyl-4-nitrophenyl)-4-
methylbenzenesulfonamide with significant interactions with water.
Table 12
Drug likeness parameters for the NDMPMBS molecule.
Descriptor
Value
Hydrogen Bond Donor (HBD)
Hydrogen Bond Acceptor (HBA)
Mass
1
2
320.40
3.67
97.69
85.34
38
AlogP
Polar surface area (PSA) [Å2]
Molar refractivity
Number of atoms
Number of rotatable bonds
4
polyporopepsin. Since probabilities for these two activities are very
similar, we have decided to investigate how NDMPMBS molecule
binds to the representatives of proteins related to arylsulfate-
sulfotransferase and polyporopepesin. Using the RCSB protein
databank and taking into account the arylsulfatesulfotransferase
and polyporopepesin inhibitor acitivites we have chosen to inves-
tigate docking of NDMPMBS to proteins with PDB IDs: 1WKR and
3ETT, respectively.
Molecular docking has been performed with Autodock4 tools,
while preparation of ligand and proteins has been performed with
AutoDock tools [102]. After being imported from the protein
databank, proteins have been firstly prepared by the set of the
Fig. 13. Docked NDMPMBS molecule at the surface of a) 1WKR and b) 3ETT proteins.

P.K. Murthy et al. / Journal of Molecular Structure 1153 (2018) 212e229
227
Table 14
€
the support received from Schrodinger Inc. Part of this study was
conducted within the projects supported by the Ministry of Edu-
cation, Science and Technological Development of Serbia, grant
numbers OI 171039 and TR 34019.
The binding energies of several modes for docking of NDMPMBS against 1WKR and
3ETT
Mode Binding energy with 1WKR (kcal/
mol)
Binding energy with 3ETT (kcal/
mol)
1
2
3
4
5
6
7
8
9
10
ꢀ7.20
ꢀ6.96
ꢀ6.90
ꢀ5.77
ꢀ5.76
ꢀ5.70
ꢀ5.62
ꢀ5.61
ꢀ5.46
ꢀ5.45
ꢀ7.20
ꢀ7.12
ꢀ7.12
ꢀ7.01
ꢀ6.97
ꢀ6.85
ꢀ6.78
ꢀ6.66
ꢀ6.97
ꢀ6.79
Appendix A. Supplementary data
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.molstruc.2017.10.028.
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