a r t i c l e i n f o a b s t r a c t
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 under vacuum to afford (0.67 g, 69%) of N-(2,5-dimethyl-4-
detailed experimental and computational DFT study of N-phenyl- nitrophenyl)-4-methylbenzene-1-sulfonamide as pale yellow
benzenesulfonamide [19]. solid (Scheme-1 supporting information). Suitable single crystals
In this paper we report synthesis, detailed spectroscopic and were grown by slow evaporation solution growth technique at
computational characterization of N-(2,5-dimethyl-4-nitrophenyl)- ambient temperature using chloroform: methanol (1:3) solvent.
4-methylbenzenesulfonamide (NDMPMBS) molecule. In order to
uniquely characterize the title compound we have measured FT-IR, 2.3. X-ray data collection and refinement details
Raman and NMR spectra. Spectral data were also computed within
DFT approach in order to validate the used level of theory. A suitable prism like crystal was selected and mounted on a
Computational investigation within DFT approach has proven to be Bruker APEX-II CCD diffractometer using graphite monochromated
effective tool for investigation of physical and chemical properties MoKa (l ¼ 0.71073 Å) radiation and detector (CCD). The crystal was
of various organic molecules [20e24] and in this study we used it to kept at 273 (2) K during data collection. The structure was solved
study both global and local quantum-molecular descriptors of the using Olex2 software with the olex2. solve [31] structure solution
title compound. Taking into account that organic pharmaceutical program using Charge Flipping and the structure was refined with
molecules such as NDMPMBS represent great threat for water re- the ShelXL [32] refinement package using Least Squares minimi-
sources [25e30], we have also investigated sensitivity of zation. All the non-hydrogen atoms were revealed in the first dif-
NDMPMBS towards autoxidation and hydrolysis, in order to gain an ference Fourier map itself and were refined anisotropically. All the
insight into its possible degradation properties. hydrogen atoms were positioned geometrically. All H atoms were
positioned geometrically, with CeH ¼ 0.96 Å for methyl H,
2. Material and methods CeH ¼ 0.93 Å for aromatic H, and refined using a riding model with
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
FT-IR spectrum (Fig. 1) was recorded in solid state using KBr disc NeH ¼ 0.86 (2) Å. All the geometrical calculations were carried out
in the range of 4000e600 cm1 on ATR module ALPHA-T Bruker FT- using the program PLATON [33] within the WinGX suite [34]. The
IR spectrophotometer. FT-Raman spectrum (Fig. 2) was measured molecular and packing diagrams were generated using the soft-
for solid sample on Bruker RFS 100/s, Germany using Nd:YAG laser ware MERCURY [35]. The crystallographic data and refinement pa-
source, excitation wave length 1064 nm with spectral resolution rameters are summarized in Table 1.
2 cm1 in the region of 0e4000 cm1.1H and 13C NMR chemical
shift values were reported in ppm using TMS as internal standard 2.4. Computational details
on Bruker 400 MHz spectrometer.
Firstly, molecular structure of the title compound was extracted
2.2. Synthesis of N-(2,5-dimethyl-4-nitrophenyl)-4- from the single crystal X-ray structure to be used as a starting ge-
methylbenzenesulfonamide ometry for geometry optimization. The molecular geometry opti-
mization in gas phase together with vibrational analysis, frontier
To a stirred solution of 2,5-dimethyl-4-nitroaniline (0.5 g, orbital analysis (HOMO-LUMO), MEP, surface analysis and Mullikan
3.01 mmol) in pyridine (5 mL), 4-methylbenzene-1-sulfonyl chlo- atomic charges calculation were performed at DFT level of theory
ride (0.86 g, 4.51 mmol) was added. The reaction mixture was with B3LYP [36] hybrid exchange-correlation functional and 6-
stirred for 16 h at room temperature. After completion of reaction 311Gþþ(d,p) (5D, 7 F) basis set, using Gaussian 09 software pack-
by TLC, the reaction mixture was diluted with D.M.water and age [37]. The assignment and PED analysis of wave number were
acidified with dilute HCl solution. Solid was filter, washed with done by GaussView 5.0 program [38] and VEDA4 program [39]. For
D.M.water, MTBE and followed by 1:1 ethyl acetate: hexane. Dried better agreement of calculated wavenumber number with
Fig. 3. ORTEP diagram of N-(2,5-dimethyl-4-nitrophenyl)-4-methylbenzenesulfonamide with thermal ellipsoids drawn at 50% probability with optimized geometry.
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 group generally appear in the region of 1400e1485 cm1 and 1380-
(bond length (Å), bond angle (º) and torsion angle (º) of investigated 1420 cm1, respectively [64e67]. For title compound, the bands
compound are listed in Table 3). The comparative study shows a calculated at 1449, 1435, 1434, 1432, 1430, 1421 cm1 (B3LYP),
good agreement among the computational and experimental pa- experimentally observed at 1448, 1418 cm1 (IR) (asymmetric
rameters (Supplementary information). The computational deformation) and 1367, 1363, 1362 cm1 (B3LYP) (symmetric
geometrical parameters are slightly more than that of experimental deformation vibrations), shows good agreement with literature
values. Because of, the experimental results were based on mole- values. For the investigated compound, the rocking modes of
cules in the solid state, while the computed values were carried in methyl group are calculated at 1023, 1021, 1017 and
gas phase for isolated molecule. 970 cm1 (B3LYP) and experimentally observed at 970 cm1 in the
Raman spectrum, assigned as expected. The CH3 torsion vibrational
modes are usually appear in the region 185 ± 65 cm1 [62], the
3.4. Vibrational spectral analysis bands assigned at 206, 188, 168 and 28 cm1 (B3LYP).
The stretching vibration modes of aromatic nitro group are ex-
The calculated (scaled) wavenumbers, experimental IR, Raman pected in range, 1570-1485 cm1 (asymmetric stretching) and
bands and assignments are given in Table 4. 1370-1320 cm1 (symmetric stretching) [68]. For in case of inves-
The NeH stretching vibration mode generally measured in re- tigated compound, these modes are assigned at 1521, 1502 cm1
gion 3500-3300 cm1 [60,61]. In the present case, the bands (IR), 1520, 1502 cm1 (Raman), 1541, 1505 cm1 (B3LYP) (asym-
observed at 3277 cm1 (IR), 3276 cm1 (Raman) and 3488 cm1 metric stretching modes); 1300 cm1 (IR and Raman), 1305 cm1
(DFT) is assigned as NH stretching vibration mode. The mode (DFT) (symmetric stretching modes). Both the modes show high IR
(mode no 1) is pure and PED is exactly 100%. The difference be- intensity and Raman activity. The NO2 deformation modes (scis-
tween computational and experimental NeH stretching vibration soring, out-of-plane wagging, in-plane rocking and torsion) are
is 171 cm1 for IR and 172 cm1 for Raman, this may due to the expected in the regions 855 ± 40, 760 ± 30, 540 ± 30 and
NeHeO intermolecular interaction of title molecule in crystal state. 70 ± 20 cm1 respectively [62]. The bands at 858, 734 cm1 in IR
The NeH in-plane bending vibration mode is usually expected spectrum, 857, 734 cm1 in Raman spectrum and 847 and 732 cm1
around 1400 cm1 [17]. In the present case, the bands observed at (DFT) are assigned as deformation modes of NO2 group of title
1386 cm1 in the IR spectrum, 1384 cm1 in the Raman spectrum compound. The reported values of the NO2 deformations modes are
and 1391 cm1 for DFT (B3LYP) are assigned to the NeH in plane 809, 727, 524 cm1 (experimentally), 800, 727, 534 cm1 (DFT) [69].
bending vibration mode, this is good agreement with literature The asymmetric and symmetric stretching vibrational modes
values. The mode number 79 have calculated wave number at fall in region 1330-1295 cm1 and 1150-1125 cm1, respectively for
492 cm1 correlate well with experimental Raman spectrum at SO2 group [70]. In the present case, the bands computed at 1267
493 cm1 assigned as NH out-of-plane bending vibration. and 1082 cm1 (DFT), experimentally observed at 1260, 1086 cm1
The asymmetric and symmetric stretching modes of the methyl in the IR spectrum and 1260 and 1085 cm1 in the Raman spectrum
group are expected in the regions 3000 ± 50 cm1 and are assigned as SO2 asymmetric and symmetric stretching modes.
2900 ± 45 cm1 [62,63]. For the title compound the stretching The SO2 stretching mode is not pure, but it contains contribution
modes are assigned at 2981 cm1 (Raman), in the range from other modes. Although the region of the SO2 scissoring
2999e2940 cm1 (B3LYP) (asymmetric stretching modes); (560 ± 40 cm1) and that of SO2 wagging vibration mode
2924 cm1 (IR), 2925 cm1 (Raman) and in the region 2929- (500 ± 55 cm1) partly overlap, the two vibrations appear sepa-
2895 cm1 (B3LYP) (symmetric stretching modes) as expected. The rately [62]. The DFT calculation of these bands at 567 cm1 and
asymmetric and symmetric deformations vibrations of methyl 515 cm1, observed at 566 cm1 and 515 cm1 in the Raman
spectrum assigned as wagging and scissoring, respectively. The
Table 3
twisting vibrational mode of SO2 is fall in region 400 ± 50 cm1 and
Geometrical parameters of the NDMPMBS. rocking vibrational mode at around 350 cm1 [62]. For the present
case, these modes are computed at 426 cm1 and 255 cm1,
Bond length (Å) DFT/XRD
respectively.
C1eC2 1.393/1.386 S37eN31 1.706/1.636 The SN stretching vibration modes are expected in region
C1eC9 1.394/1.386 C11eN31 1.410/1.414
905 ± 30 cm1 [62] and in present study, the bands observed at
C2eC4 1.391/1.380 C11eC17 1.397/1.390
C4eC6 1.399/1.382 C12eC11 1.411/1.400 798 cm1 (IR), 797 cm1 (Raman) and 801 cm1 (B3LYP) assigned
C6eC7 1.401/1.385 C12eC13 1.386/1.381 as these modes. The PED is 33% with IR intensity (145.02) and
C7eC9 1.390/1.376 C15eN32 1.472/1.467 Raman activity (44.11) respectively. From the references the CN
C1eS37 1.794/1.756 C15eC16 1.406/1.387 stretching vibration modes are fall in the region 1275 ± 55 cm1
S37eO33 1.457/1.435 C16eC17 1.396/1.392
S37eO34 1.456/1.423
[62], for the title compound the vibrational modes expected at
1337, 1017 cm1(IR), 1336, 1015 cm1 (Raman) and 1349, 1225,
1017 cm1 (theoretically). The stretching vibration modes for CS
Bond angle (º) DFT/XRD
C1eS37eO33 108.510/108.80 S37eC1eC2 119.732/120.56 generally lie in the region 930-670 cm1 [71]. The CS stretching
C1eS37eO34 107.940/108.54 S37eC1eC9 119.139/118.75
vibrational wave number for title compound calculated at
S37eN31eH38 109.049/111.41 C2eC1eC9 121.127/120.69
O33eS37eO34 122.550/119.34 C1eC2eC4 118.954/118.86
629 cm1 and experimentally observed at 632 cm1 (IR and
O33eS37eN31 102.979/104.14 C2eC4eC6 121.265/121.53 Raman) as expected [71], PED of 21% and with high IR intensity
O34eS37eN31 107.449/108.40 C4eC6eC7 118.424/118.42 (147.45) and low Raman activity (19.42).
N31eS37eC1 106.296/106.95 The CeH stretching vibrational modes of substituted benzene
Torsion angle (º) DFT/XRD ring are generally observed in the region 3000-3100 cm1 [62]. In
O33eS37eC1eC2 155.788/-134.76 N31eS37eC1eC9 85.795/-65.94 present case, the CeH modes are assigned at 3102, 3084, 3059 cm1
O33eS37eC1eC9 24.365/45.99 S37eC1eC2eC4 179.096/-178.98 (IR) and 3101, 3077, 3059, 3045 cm1 (Raman) and 3088, 3087,
O34eS37eC1eC2 20.975/-3.45 C9eC1eC2eC4 0.746/0.3 3086, 3075, 3050, 3046 cm1 (B3LYP) as expected. The stretching
O34eS37eC1eC9 159.178/177.30 S37eC1eC9eC7 179.146/179.23 vibration modes (2e7) are pure with PED contribution around
N31eS37eC1eC2 94.050/113.31
100%. The in-plane and out-of-plane aromatic CH deformation
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.
Table 4 (continued )
modes are expected above and below 1000 cm1 [62] and for in the and 20.95 ppm and calculated at 16.85, 24.07, 22.09 ppm was
case of investigated compound these modes assigned at 1283, 1278, assigned to methyl carbon atoms at C23, C27 and C19. The signals for
1260, 1156, 1089 cm1 (IR), 1278, 1260, 1089 cm1 (Raman), 1283, aromatic carbons (tosyl ring and nitrobenzene ring) were observed
1278, 1267, 1236, 1095 cm1 (B3LYP) (in-plane deformation) and at at 126.57e145.12 ppm and calculated at 124.86e154.11 ppm for
895, 818 cm1 (IR), 895, 817 cm1 (Raman), 896, 818 cm1 (B3LYP) DFT. The C15 carbon of nitrobenzene ring appears 145.12 ppm due
(out-of-plane deformation). The aromatic ring stretching vibra- to nitro substitution, calculated as 150.35 ppm. The signal at C1 and
tional modes expected in the region 1615-1260 cm1 [62]. For the C6 carbons of tosyl ring appears at 137.31 ppm (147.51 ppm) and
investigated compound, the bands experimentally observed at 139.89 ppm (154.11 ppm) (experimental/calculated) due to methyl
1572, 1502, 1386, 1278 cm1 (IR), 1595, 1573, 1502, 1384, 1278 cm1 group as well as sulfonyl group substitution. The signal at
(Raman) and in the range of 1596e1278 cm1 (B3LYP) assigned as 143.59 ppm is assigned as C11 carbon of nitrobenzene ring due to
these modes. amine group substitution, which was calculated at 149.61 ppm,
show good agreement.
The title compound have 16 protons occur in three regions, out
3.5. NMR spectral analysis
of which 9 protons attached to methyl groups, one protons is
attached nitrogen (NeH proton) and 6 protons are aromatic pro-
NMR spectroscopy is one of the important and valuable tool for
tons. The 9 methyl protons are occur in the upfield region at d 2.04,
identification of structural and functional groups of the molecules.
13 2.37, 2.42 ppm (experimental) and calculated at 2.01, 2.35,
C and 1H NMR chemical shifts values of title compound were
2.64 ppm, shows good agreement. The NeH proton observed
recorded in DMSO solvent (TMS as internal standard), calculated in
experimental at 10.01 ppm and computed at 6.07 ppm. The phenyl
DMSO at GIAO method [72] using DFT/6-311Gþþ(d,p) basic set,
ring protons are observed around at 7.20e7.82 ppm (experimental)
which provide information about the number of different types of
which shows good agreement with calculated value
carbon atoms and the number of different types of protons present
7.45e8.17 ppm.
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. 3.6. Electronic spectra and frontier molecular orbital analysis
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 Electronic spectra of title compound calculated in DMSO as well
accuracy ensures reliable interpretation of spectroscopic parame- as methanol solution by TD-DFT/PCM model using B3LYP/6-
ters. In 13C NMR spectrum, upfield signal observed at 16.92, 19.68 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
13
Fig. 6. C 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.
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 0.68391 3.5498 349 0.3372
80 / 85 0.23487 3.7555 330 0.0277
82 / 85 0.12971
83 / 85 0.63785
80 / 85 0.61136 3.9266 315 0.0317
82 / 85 0.12639
83 / 85 0.25811
84 / 85 0.15724
Methanol
84 / 85 0.68231 3.5631 347 0.3240
80 / 85 0.24398 3.7605 329 0.0255
82 / 85 0.12914
83 / 85 0.63440
80 / 85 0.60688 3.9277 315 0.0330
82 / 85 0.12481
83 / 85 0.26620
84 / 85 0.16292
222 P.K. Murthy et al. / Journal of Molecular Structure 1153 (2018) 212e229
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.
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 R22 (8)
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.
O36eH30), 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,
the charge addition. According to the results presented in Fig. 10(a),
Fig. 10. Fukui functions give information about the changes in
electron density could increase in the near vicinity of oxygen atoms
electron density as a consequence of charge addition or removal.
O36 and O37 after the charge addition. On the other side, results in
Purple color in Fig. 10(a) gives information about where electron
Fig. 10(b) indicate that electron density decreases in the near vi-
density increased after the charge addition, while negative color in
cinity of oxygen atoms O33 and O34 after the charge removal.
Fig. 10(b) gives information where electron density decreased after
Debye and 7.4165 1024 esu. The is first-order hyper- 3.10. Mulliken atomic charge analysis
polarizibilitiy(b) of NDMPMBS calculated and is found to be
12.02 1030 esu which is 92.46 times greater than that of the The Mulliken atomic charges of investigated compound calcu-
standard NLO material urea (0.13 1030 esu) [85]. The highest lated at DFT/B3LYP/6-31 þ G (d,p) method in gaseous state are
value of first-order hyperpolarizibilitiy(b) may be due transfer of p- given in Table 11. It is based on the linear combination of atomic
electron cloud from donor (sulphonamide group) to acceptor (nitro orbitals and therefore the wave function of the molecule are ob-
group) which makes molecule highly polarized and the possibility tained from Mulliken population analysis [89]. The charge distri-
of intra molecular charge transfer (ICT). bution on the molecule has an important role in the application of
quantum chemistry calculations for the molecular system.
From the analysis of Table 11, hydrogen atoms of title compound
shows atomic charges with positive values in the range of
3.9. NBO analysis 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
The natural bond orbital (NBO) calculations were performed hydrogen atoms and possess acidic nature. Due to the presence of
using NBO 3.1 program [86] as executed in the Gaussian09 suite at more negative atomic charges values on oxygen atom O33 (0.131),
the B3LYP/6e311þþG (d,p) (5D, 7 F) basic set which offers a suit- O34 (0.100) and nitrogen atom N31 (0.215), net positive atomic
able basis for examining the various interactions in both filled and charge values on hydrogen atom H38 (0.308), H14 (0.247) and H18
virtual orbital spaces that could enhance the analysis of inter and (0.266) may support the formation of hydrogen bonding
intramolecular interactions. The second-order Fock-matrix was N31eH38eO33, C13eH14eO34 and C17eH18eO34.
carried out to evaluate the donoreacceptor interactions in the NBO
basis [87,88]. In NBO analysis large E (2) value shows the intensive 3.11. Sensitivity towards autoxidation and stability in water
interaction between electron-donors and electron-acceptors, and
greater the extent of conjugation of the whole system, the possible Modern water purification methods in the case of organic
intensive interaction are given in Tables 9 and 10. pharmaceutical pollutants are based on the oxidation reactions
The strong interaction n3(O35) / p*(N32eO36) has the highest E [90e92]. In terms of computational molecular modelling tech-
(2) value 155.95 kJ/mol and an another interaction has been in niques, the concept of bond dissociation energies (BDE) can be
n1(N31)/ p*(C11eC17) with an energy of 23.39 kJ/mol. Table 10 useful for predicting molecule's weak spots where degradation
gives the occupancy of electrons and p-character in significant could start. Particularly, bond dissociation energies for hydrogen
NBO natural atomic hybrid orbital. Almost, a very close to pure p- abstraction (H-BDE) resemble the molecule's sensitivity towards
character was observed in p-bonding of C11eC17, N32eO36 and lone autoxidation mechanism [93e95], while in the same time BDEs for
pairs of n2O33, n2O34, n2O35, n3O35, n2O36, n1N31. the remaining single acyclic bonds can be very useful for predicting
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 (1024) Parameter a.u. esu (1033)
Table 9
Second-order perturbation theory analysis of Fock matrix in NBO basis corresponding to the intramolecular bonds of the title compound.
where degradation mechanism could start. useful for the identification of atoms with pronounced interactions
Since majority of pharmaceutical pollutants eventually end up with water molecules. The results regarding BDEs are presented in
in the water resources, it is also of great importance for predictions Fig. 11, while Fig. 12 contains information on the most important
of degradation properties to understand the stability of molecules RDFs.
in water. This can be done thanks to the molecular dynamics (MD) Results presented in Fig. 11 indicate the absence of H-BDE values
simulations and radial distribution functions (RDF), which are very lower than at least 90 kcal/mol. This indicates that the title
P.K. Murthy et al. / Journal of Molecular Structure 1153 (2018) 212e229 225
Table 10 Table 11
NBO results showing the formation of Lewis and non-Lewis orbitals. 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
sC1-C2 1.97716 51.40 48.60 0.7169 (sp1.61)Cþ 38.33 61.63 S37 0.134 H3 0.208
e 0.74770 e e 0.6971 (sp1.97)C 33.65 66.30 N31 0.215 H5 0.182
sC1-C9 1.97704 51.34 48.66 0.7165 (sp1.63)Cþ 38.05 61.91 N32 0.203 H8 0.184
0.74669 e e 0.6975 (sp1.97)C 33.66 66.29 O33 0.131 H10 0.249
e
O34 0.100 H14 0.247
sC2-C4 1.97568 50.33 49.67 0.7094 (sp1.81)Cþ 35.52 64.44
O35 0.013 H18 0.266
e 0.72622 e e 0.7048 (sp1.86)C 35.00 64.96
O36 0.004 H20 0.185
sC4-C6 1.97692 49.28 50.72 0.7020 (sp1.85)Cþ 35.03 64.93 C1 0.204 H21 0.151
e 0.72233 e e 0.7121 (sp1.94)C 34.00 65.96 C2 0.285 H22 0.156
sC6-C7 1.97678 50.68 49.32 0.7119 (sp1.95)Cþ 33.84 66.12 C4 0.610 H24 0.175
e 0.72114 e e 0.7023 (sp1.86)C 34.97 64.99 C6 0.496 H25 0.182
sC7-C9 1.97587 49.65 50.35 0.7046 (sp1.85)Cþ 35.09 64.87 C7 0.495 H26 0.153
0.72850 e e 0.7096 (sp1.80)C 35.66 64.30 C9 0.164 H28 0.195
e
C11 0.199 H29 0.138
sC11-C17 1.97383 51.47 48.53 0.7174 (sp1.71)Cþ 36.88 63.08
C12 0.955 H30 0.212
e 0.73082 e e 0.6966 (sp1.97)C 33.65 66.30
C13 0.442 H38 0.308
pC11-C17 1.63339 47.40 52.60 0.6885 (sp99.99)Cþ 0.01 99.99 C15 2.057
e 0.28039 e e 0.7252 (sp99.99)C 0.01 99.95 C16 1.860
sC12-C13 1.97050 50.80 49.20 0.7127 (sp1.86)Cþ 35.00 64.96 C17 0.683
e 0.72910 e e 0.7014 (sp1.80)C 35.76 64.20 C19 0.479
sC15-C16 1.97351 50.44 49.56 0.7102 (sp1.60)Cþ 38.44 61.52 C23 0.471
0.73156 e e 0.7040 (sp2.03)C 33.01 66.95 C27 0.326
e
sN32-O36 1.99561 49.06 50.94 0.7004 (sp2.15)Nþ 31.66 68.23
e 1.08213 e e 0.7138 (sp3.13)O 24.18 75.68
pN32-O36 1.98387 39.14 60.86 0.6256 (sp99.99)Nþ 0.02 99.72 with water molecules. This hydrogen atom with the most impor-
e 0.45651 e e 0.7801 (sp99.99)O 0.06 99.71
tant RDF curve is located adjacent to the bond with the lowest BDE
14.60
n1 N31 1.80373 e e sp 6.41 93.56
value, indicating that the influence of water could be of importance
e 0.32731 e e e e e
for the degradation of NDMPMBS.
n1 O33 1.98241 e e sp0.32 75.47 24.50
e 0.82036 e e e e e
n2 O33 1.81651 e e sp99.99 0.08 99.61 3.12. Drug likeness and molecular docking
e 0.31360 e e e e e
n1 O34 1.98051 e e sp0.33 75.20 24.76 Drug likeness properties associated to the Lipinski's rule of five
e 0.81948 e e e e e
[96,97] for the newly synthetized NDMPMBS molecule have been
99.99
n2 O34 1.81923 e e sp 0.11 99.58
calculated and summarized in Table 12. According to all parameters
e 0.31566 e e e e e
provided in Table 12 it can be concluded that newly synthetized
n1O35 1.98139 sp0.32 75.71 24.28
0.81272 e e e e e
NDMPMBS molecule could be considered as a candidate for prac-
e
n2 O35 1.89823 e e sp99.99 0.25 99.64
tical applications in some pharmaceutical formulation. Namely, the
e 0.29882 e e e e e AlogP value is 3.67, which is far below the desired threshold of 5. In
n3O35 1.46754 e e sp99.99 0.07 99.73 the same time, prospective drug candidates should have less than 5
e 0.28319 e e e e e and 10 HBD and HBA, respectively. These prerequisites are also
n2O36 1.90136 e e sp99.99 0.41 99.48 fulfilled by the NDMPMBS molecule. Ghose et al. [98], have stated
e 0.30047 e e e e e that the molar refractivity should be in the range between 40 and
a
ED/e is expressed in a. u. 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.
molecule is not sensitive towards the autoxidation mechanism. NDMPMBS molecule is also very close to satisfy the Congreeve's
Namely, all of the H-BDE values are much higher than the desired rule of three [100]. Namely, the Congreeve's rule of three is just
threshold of 90 kcal/mol, with the lowest H-BDE values calculated slightly violated by the NDMPMBS molecule in terms of somewhat
for hydrogen atoms of methyl groups, thanks to which it is expected higher AlogP value and one more rotatable bond.
that the title molecule is stable in the presence of oxygen. The Drug likeness parameters motivated us to further investigate
lowest BDE value of the rest of the single acyclic bonds have been NDMPMBS molecule from the aspect of pharmaceutical properties.
calculated in the case of NeS bond, with BDE value of just 41 kcal/ In order to identify in which direction NDMPMBS molecule could
mol, indicating that degradation could start precisely by breaking of exhibit its biological activity we have employed the Prediction of
this bond. Other significantly low BDE values have been calculated Activity Spectra for Substances (PASS) online software [101], which
in the cases of CeN bond (N belonging to the NO2 group) and CeS screens the biologically activity spectrum of the potential drug
bond, with BDE values of around 70 kcal/mol, indicating that candidates taking into account the large training set. The results
detachment of benzene or NO2 group could occur during the concerning the predicted biological activities have been summa-
degradation. rized in Table 13, where Pa represents the probability for molecule
Calculations of RDFs indicate that six atoms of NDMPMBS have to be active, while Pi represents the probability for molecule to be
high and sharp RDF curves. However, five of six of the aforemen- inactive. Table 13 contains information about activities that are
tioned atoms have their maximal g(r) values located at distances of higher than 0.7.
around 4 Å. Certainly, the most important RDF has been calculated According to the screening of biological activities by PASS it can
in the case of hydrogen atom H38, with its maximal g(r) value be seen that NDMPMBS molecule has significantly high probabili-
located at distance of 2 Å, which indicates significant interactions 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
Table 12
Drug likeness parameters for the NDMPMBS molecule.
Descriptor Value
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