Synthesis of a novel methyl(2E)-2-{[N-(2-formylphenyl)(4-methylbenzene) sulfonamido]methyl}-3-(2-methoxyphenyl)prop-2-enoate: Molecular structure, spectral, antimicrobial, molecular docking and DFT computational approaches

Article abstract of DOI:10.1016/j.molstruc.2016.08.001

The title compound methyl(2E)-2-{[N-(2-formylphenyl)(4-methylbenzene)sulfonamido] methyl}-3-(2-methoxyphenyl)prop-2-enoate (MFMSM) has been synthesized and single crystals were grown by slow evaporation solution growth technique at room temperature. XRD,

Full text of DOI:10.1016/j.molstruc.2016.08.001

Accepted Manuscript
Synthesis of a novel methyl(2E)-2-{[N-(2-formylphenyl)(4-methylbenzene)
sulfonamido]methyl}-3-(2-methoxyphenyl)prop-2-enoate:molecular structure, spectral,
antimicrobial, molecular docking and DFT computational approaches
S. Murugavel, V. Vetri velan, Damodharan Kannan, Manickam Bakthadoss
PII:
S0022-2860(16)30829-8
10.1016/j.molstruc.2016.08.001
MOLSTR 22827
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 17 May 2016
Revised Date: 1 August 2016
Accepted Date: 1 August 2016
Please cite this article as: S. Murugavel, V. Vetri velan, D. Kannan, M. Bakthadoss, Synthesis of a novel
methyl(2E)-2-{[N-(2-formylphenyl)(4-methylbenzene) sulfonamido]methyl}-3-(2-methoxyphenyl)prop-2-
enoate:molecular structure, spectral, antimicrobial, molecular docking and DFT computational
approaches, Journal of Molecular Structure (2016), doi: 10.1016/j.molstruc.2016.08.001.
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ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT
Synthesis of a novel methyl(2E)-2-{[N-(2-formylphenyl)(4-methylbenzene)
sulfonamido]methyl}-3-(2-methoxyphenyl)prop-2-enoate:molecular structure,
spectral, antimicrobial , molecular docking and DFT computational
approaches .
c
S.Murugavela* V.Vetri velana Damodharan Kannanb, Manickam Bakthadossb,
, ,
aDepartment of Physics, Thanthai Periyar Government Institute of Technology, Vellore-632 002.
Tamilnadu, India.
bDepartment of Organic Chemistry, University of Madras, Guindy Campus, Chennai-600025,
Tamilnadu, India.
cDepartment of Chemistry, Pondicherry University, Pondicherry – 605 014, India.
Abstract
The title compound methyl(2E)-2-{[N-(2-formylphenyl)(4-methylbenzene)sulfonamido]
methyl}-3-(2-methoxyphenyl)prop-2-enoate (MFMSM) has been synthesized and single crystals
were grown by slow evaporation solution growth technique at room temperature. XRD, FT-IR
and NMR spectra of MFMSM in the solid phase were recorded and analyzed. The optimized
geometry and vibrational wave numbers were computed using DFT method. The NLO,
Mulliken, MEP, HOMO-LUMO energy gap and thermodynamic properties were theoretically
predicted. The NBO analysis explained the intramolecular hydrogen bonding. The global
chemical reactivity descriptors are calculated for MFMSM and used to predict their relative
stability and reactivity. All the calculations were carried out by B3LYP/6-311G (d,p) method.
MFMSM has been screened for its antimicrobial activity and found to exhibit antifungal and
antibacterial effects. Docking simulation has been performed.
Keywords: Single crystal analysis, DFT, NLO, Antimicrobial activity, Molecular docking
*
Corresponding author. Tel.: +919790084145. Email address: smurugavel27@gmail.com
(S.Murugavel)
1. Introduction
Benzene sulfonamides form an important class of compounds in pharmaceutical
chemistry and medicinal by means of numerous biological applications [1-4]. The chemistry of
the carbon–nitrogen double bond plays a essential role in the progresses of chemistry science [5].
Although benzene sulfonamides are best known as bacterio-static [6] and anti malarial agents [7]
there is now a variety of drugs acquiring extremely diverse pharmacological activities, wherein
the sulfonamide group is present [8]. Several of these drugs suffer from adverse secondary
effects or bioavailability problems [9,10]. In analytical area, benzene sulfonamides have been
investigated as reagents for the separation, concentration and selective determination of many of
the first row transition metal cations [11–13]. It is known that coordination with metals can
modify the pharmacological and toxicological properties of free sulfonamides [14–17]. The
chemistry of sulfonamides has been well-known as synthons in the preparation of different
valuable biologically active compounds used as protease inhibitor, antibacterial, anti-tumor,
diuretic and hypoglycemic [18–25]. As a consequence of the wide range of the biological
significance of the benzene sulfonamides, the synthesis of several substituted sulfonamides, the
study of their molecular structure and other chemical, biochemical and physical studies has

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become attractive field in research. The MFMSM is one similar organic compound that goes to
the sulfonamide family. Nowadays, organic materials are widely used for nonlinear optical
(NLO) devices, frequency converters, electro-optical modulators, operating as second
harmonic generators, etc. The organic compound showing high hyperpolarizability are those
containing an electron withdrawing group and an electron donating group interacting in the
course of a system of associated double bonds. In the case of benzene sulfonamides, the
electron with drawing group is the sulfonyl group [26,27]. The density functional theory (DFT)
method has employed for the analysis of molecular structure and vibrational spectra.
Supplemented by a visualization program, the assignments can exactly be made.
S.Murugavel et al. [28, 29] analyzed synthesis, crystal structure analysis, spectral
investigations, DFT computations, Biological activities and molecular docking studies of
sulfonamide derivative compounds. Sarojini et al. [30] reported synthesis, structural,
spectroscopic studies, NBO analysis, NLO and HOMO-LUMO of 4-methyl-N-(3-nitrophenyl )
benzene sulfonamide with experimental and theoretical approaches. Karabacak et al.[31]
reported theoretical investigation on the molecular structure and spectra of para - halogen
benzene sulfonamides, 4-X-C6H4SO2NH2 (X=Cl, Br or F ).
Literature survey reveals that to the best of our knowledge, there is no synthesis, single
crystal structure analysis, DFT studies, vibrational assignments, antibacterial activity, anti fungal
activity and molecular docking studies for title compound MFMSM.
It is very difficult to analyze all the properties by experimental methods. But, the
theoretical and computational analysis of the molecular structure of compounds will provide
complete information about the molecule and the obtained results may be used effectively in the
medical field. Analyzing the properties like geometrical structure, electron distribution, anti-
bacterial, anti-fungal, pharmacological and molecular docking for the compound MFMSM will
motivate the present work. To design new drug compounds, we need the knowledge of biological
activity, toxicity molecular structured based properties, interaction of drug with protein in the
body for the compounds.
The present work aims to explain synthesis, single crystal structure analysis, vibrational
assignments, natural bond orbital (NBO), non-linear optical (NLO) properties, molecular
electrostatic potential (MEP), HOMO-LUMO analysis, thermodynamic properties, antibacterial
activities and molecular docking studies of MFMSM.
The computed results of XRD, vibrational assignments and NMR spectra of compound
MFMSM shows good agreement with observed data. Stability of the molecule arising from
hyper conjugative interactions and charge delocalization has been analyzed by using NBO
analysis. The calculated HOMO and LUMO energies showed that charge transfer occurs within
the molecule. The calculated first order hyperpolarizability was found to be greater than that of
standard NLO material. The present study concludes that the compound exhibited good to
moderate antimicrobial activity on comparing with the standard drug.
To find out the drug ability of the standard drug and MFMSM, the pharmacological
parameters such as molecular properties rooted in Lipinski rule of five [32], drug-likeness and
Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) properties were
executed by molinspiration online tool kit [33], OSIRIS property explorer [34] and pre-
ADMET[35] online servers, respectively. This pharmacological analysis of compounds will help
pharmaceutical scientists to go for the best candidates for development as well as to discard
those with a low probability of success. Based on pharmacological investigation, in silico

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binding mode of MFMSM ligand into the penicillin-binding protein [36] in comparison with
cefuroxime as reference drug by docking route is also examined in this paper.
2. Experimental and Computational Methods
2.1 Materials and instruments
All of the chemical reagents and solvents were purchased from commercially available
suppliers and used without further purification. Thin-layer chromatography (TLC) was executed
on aluminum packed sheets of silica gel F254(0.2mm, Merck) and visualized under UV chamber.
1
The 13C NMR and H spectra were evaluated with a Bruker 300 MHz spectrometer and the
chemical shifts are expressed in ppm relatively to TMS with J values in Hertz. The splitting
1
patterns in H NMR spectra are reported as follows s = singlet, d = doublet, m = multiplet. 13C
NMR data are reported with the solvent peak (CDCl3= 77.0MHz) as the internal standard. FT-IR
spectra of the compound were recorded in the range of 4000- 400 cm-1 regions with a shimadzu
FT-IR 8400 spectrophotometer.
2.2 Synthesis
General synthesis method of MFMSM was characterized schematically in Scheme 1.
To a stirred solution of 2-aminobenzyl alcohol in chloroform, 1.5 equiv of pyridine and
1.5 equiv of 4-methylbenzene-1-sulfonyl chloride were added at room temperature over a period
of 18 h. The resulting brown colored solution was quenched with aqueous HCl. After workup a
pale brownish solid was obtained. The combined organic fractions were dried over Na2SO4 and
partially concentrated under reduced pressure at 25°C. The product was precipitated with
diethylether. Further, MnO2 was added to a solution of N-(2-(hydroxymethyl)phenyl)-4-
methylbenzenesulfonamide in dry 1,2-dichloroethane solvent under nitrogen atmosphere. The
suspension was stirred at 80°C in reflux condition for 5 h and filtered through celite. The filtrate
was partially concentrated on a rotary evaporator at 25°C and the product was precipitated with
diethylether. Recystallization of the product from CH2Cl2 yielded pale yellow crystals of the N-
(formylphenyl)(4-methylbenzene)sulfonamide (Yield: 86%).
A solution of N-(formylphenyl)(4-methylbenzene)sulfonamide (1 mmol, 0.275 g) and
potassium carbonate (1.5 mmol, 0.207 g) in acetonitrile was stirred for 15 minutes at room
temperature. To this solution, (Z)-methyl 2-(bromomethyl)-3-(2-methoxyphenyl)acrylate (1.2
mmol, 0.342 g) was added drop wise until the addition was completed. After the completion of
the reaction, as indicated by TLC, acetonitrile was evaporated off. Ethylacetate (15 ml) and
water (15 ml) were added to the crude mass. The organic layer was dried over anhydrous sodium
sulfate. The pure methyl (2E)-2-{[N-(2-formylphenyl)(4-methylbenzene)sulfonamido]methyl}-
3-(2-methoxy phenyl)prop-2-enoate (MFMSM)compound was obtained as a colorless solid (0.45
g, 94% yield). Single crystals suitable for XRD were obtained by slow evaporation of an
ethylacetate solution at room temperature.
Experimental Section
1
Yield: 97%; M. Pt: 110-112oC; H NMR (CDCl3, 300 MHz): δ 2.41 (s, 3H), 3.69 (s, 3H), 4.45
(d, 1H, J = 13.5 Hz), 5.01 (d, 1H, J = 13.8 Hz), 6.38 - 7.87 (m, 13H), 9.85 (s, 1H). 13C NMR
(CDCl3, 75 MHz)
: δ 21.58, 46.74, 52.19, 55.29, 110.71, 120.31, 123.11, 126.35, 127.43,
127.74, 128.04, 128.24, 129.47, 129.99, 130.95, 133.21, 133.32, 136.05, 140.87, 141.47, 144.14,
157.35, 167.43, 190.04. IR(KBr) 3059, 2938, 2760, 1931, 1703, 1595, 1456, 1352, 1256,
− 3402
1165, 1103, 1032, 820, 770, 729, 662, 565, 480 cm-1.
ν
,

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2.3 X-ray Crystallography
A Crystal of MSMSM with approximate dimension of 0.35×0.30×0.25 mm3 was
mounted on a glass fiber using cyanoacrylate adhesive. The crystal measurement were performed
on a Bruker AXS Kapppa Apex II single crystal X-ray diffractometer using graphite mono-
chromated MoKα (λ = 0.71071 Å) radiation and CCD detector. Diffraction data were collected
at room temperature by the ω-scan technique. Using least-squares fit of multiple high angle
reflections in the ranges 2.86o < θ < 28.28o, orientation matrix and accurate unit cell parameters
were arrived for MFMSM. The unit cell parameters were resolved for 36 frames measured
(0.5ophi-scan) from three different crystallographic zones and employing the method of
difference vectors. The final result of intensity data were collected with an average four-fold
redundancy per reflection and most favorable resolution (0.75 Å). Using SAINT-NT (version
7.06a) software, the intensity data collection, frames integration, Lorentz-polarization correction
and decay correction were completed. By SADABS [37] program, empirical absorption
correction (multi-scan) was performed. The molecular structure was worked out by direct
methods employing SHELXS-97 implemented in WINGX [38] program suit. The refinement
was adept by full-matrix least-square method on the positional and anisotropic temperature
parameters of the non-hydrogen atoms, using SHELXL-97 [39]. All the Hydrogen(H) atoms
were located geometrically and constrained to rely on their parent atom with C-H = 0.93–0.97 Å
and with Uiso(H) = 1.5 Ueq for methyl hydrogen(H) atoms and 1.2Ueq(C) for other hydrogen(H)
atoms. The reflection [0 1 0], was expunged from the final cycles of refinement due to poor
agreement. For structure analysis and presentation of the results the following crystallography
tools PLATON [40], ORTEP [41] and MERCURY [42] were utilized.
2.4 Antimicrobial test
The ultimate intention of structure-activity relationship (SAR) studies is to connect the
biological activity of a series of compounds with some suitable descriptors in order to help the
design of best active new compounds. The mechanism of antimicrobial action of sulfonamides is
well expressed at the enzyme level. Their antibacterial properties are connected to the inhibition
of the enzyme dihydropteroate synthase (DHPS) [43]. Antimicrobial agents consist of any of
several synthetic organic compounds competent of inhibiting the growth of bacteria that require
para amino benzoic acid which is structurally similar to sulphanilamide. In bacteria, sulfonamide
exhibits a bacteriostatic rather than bactericidal effect [36]. Antimicrobial susceptibility test was
carried out using Kirby-bauer disk diffusion method as per CLSI M38-A guidelines [44]. The
synthesized compound was dissolved in DMSO at various concentrations (25, 50 and 75 µg/ml)
and tested against selected bacterial and fungal pathogens. Suspension of bacterial isolates was
adjusted to 0.5 McFarland standards in 0.85% saline (suspension will accommodate
approximately 4 x 108 CFU/ml) and lawn culture was spread using sterile swabs on Muller
Hinton agar media (Hi-media, Mumbai). The wells having 6mm were created in the media with
the help of sterile metallic borer with centre at least 20mm apart. Test compound (25, 50,
75µg/ml) were loaded to the wells covered by purifying conditions and the plates were at 37°C
for 24 hours. Existence of inhibition zones encompassing each well evidenced antimicrobial
activity. The antimicrobial activity was evaluated by measuring the inhibition zones diameter in
millimeters. The bacterial assays were performed in triplicate and the mean of inhibitory zones
were recorded.
Tests strains were purchased from MTCC, INTECH and Chandigarh, India. They include
Gram positive such as Staphylococcus aureus, Bacillus cerus and Gram negative such as

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Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumonia, Acinetobacter baumanni and
Proteus vulgaris for bacteria, Aeromonas hydrophila, Candida albicans, Epidermophyton
floccosum and Aspergillus fumigates for fungus. Standard antibiotic ciprofloxacin (25µg) was
used as positive control to execute the test for antibacterial studies and standard antibiotic
amphotericin-B (20µg) was used as positive control to execute the test for antifungal activity.
2.5 Computational details
2.5.1 DFT
The molecular structure of MFMSM in the ground state (in vacuo) was optimized by
DFT/B3LYP method with the 6-311G (d,p) [45] basis set. All the calculations were carried out
without specifying and symmetry for MFMSM using Gauss view molecular visualization
program [46] and Gaussian 03 program package [47] for modeling the initial guess of the
compound was first obtained from the X ray coordinates. The harmonic vibrational frequencies
were computed at the B3LYP /6-311G (d,p) level of theory for the optimized structure the
obtained frequencies were scaled by 0.961 [48]. Frequency calculations at the same levels of
theory disclosed no imaginary frequencies, indicating that an optimal geometry at these levels of
approximation was found for MFMSM. Additionally, the calculated vibrational frequencies
were clarified by way of the potential energy distribution (PED) analysis and assignments of all
the fundamental vibrational modes using VEDA 4 programs [49]. The geometry of the
compound MFMSM, together with that of tetra methyl silane (TMS) was fully optimized. 1H and
13C NMR chemical shifts were computed within G1AO approach applying the same method and
1
13
the basis set as used for geometry optimization. The predicted H and C NMR chemical shifts
x
iso
x
x
TMS
were derived from the equation
δ
=
-
where
δ
is the chemical shift,
is the
σ iso
σ iso
σ
iso
TMS
absolute shielding and
is the absolute shielding of TMS. Whose values are 31.99 ppm and
σ
iso
186.4 ppm for B3LYP/6-311G(d,p). The effect of solvent on the theoretical NMR parameters
was integrated using the default model IEF-PCM (Integral Equation Formulation – Polarizable
Continuum Model) [50] given by Gaussian 03. Finally, the natural bonding orbitals (NBOs)
calculation [51] were achieved using NBO 3.1 program as applied in the Gaussian 03W [47]
package at the B3LYP/6-311G (d,p) level so as to understand various second order interactions
between the filled orbitals of one subsystem and virtual orbitals of another subsystem, which is a
measure of the inter molecular delocalization or hyper conjugation. The first order hyper
polarizability (β) of MFMSM was calculated using B3LYP/6-311G(d,p) basis set, based on the
finite- field approach [52]. And also, HOMO-LUMO, molecular electrostatic potential (MEP),
Mulliken charges, Global reactivity descriptors and thermodynamic properties were performed
with the same level of theory.
2.5.2 Pharmacological investigation
The molecular properties and Lipinski rule of five for compounds MFMSM and
cefuroxime (standard drug) were determined by Mol inspiration online server.
The drug-likeness of the compound can be identified by OSIRIS computer programmer.
The computer programmer OSIRIS is used to predict Mutagenic, Turmeric, Irritant and
Reproductive effect. This programmer gives overall drug score values to consider the compound
as drug. It is used to screen compounds that are most likely to have high binding affinities
represented as drug score.

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ADME-Toxicity was executed for the compounds MFMSM and cefuroxime using Pre
ADMET online server. Caco-2 cell permeability, Plasma protein binding (PPB), Blood-brain
penetration (BBB), Skin permeability, Human intestinal absorption (HIA) and Madin-Darby
canine kidney (MDCK) cell permeability properties of above compounds were calculated.
Toxicity parameters such as carcinogenicity prediction in mouse & rat and mutagenic prediction
were done by Pre ADMET online server.
2.5.3 Molecular Docking
Docking is a method that predicts the desired orientation of two molecules bound to each
other to form a stable complex in three dimensional (3D) space. Docking is helpful to compare
the binding strength between groups of derivatives or compounds. Prediction of binding affinity
will be useful to synthesis preferred compounds. As a result of its ability of predicting binding
interactions and orientation, docking is being extensively used in rational drug design and
structure based drug designing processes. Docking is also useful to find the orientation that
capitalizes on the interaction as diminishing the total energy of the complex. The extensive use
of common antibiotics leads to a growing number of defiant bacteria through gene transfer and
mutation. Penicillin-binding proteins (PBPs), the key targets for bacterial antibiotics, are
periplasmic membrane-attached proteins held responsible for the maintenance and construction
of the cell wall of bacterial. PBPs are the main reason in the finishing stages of the synthesis of
peptidoglycan, the major component of bacterial cell walls. The synthesis of bacterial cell wall is
vital for cell division (thus reproduction), growth, and maintaining the structure of the bacterial
cell. Inhibition of PBPs gives rise to irregularities in cell wall structure such as elongation, loss
of selective permeability, lesions, and eventual cell death and lyses. Hence the crystal structure
of penicillin-binding protein 2X (PDB ID: 1QMF in complex with cefuroxime) from human
pathogen streptococcus pneumonia [33], which is one of the most important contributory agents
of respiratory tract infections, has been selected as a target of interest. Hence, MFMSM was
docked into the active sites of PBP-2X and the result shows very good binding and docking
energy that makes MFMSM capable lead for the design of PBP-2X inhibitor.
Molecular docking was performed as to shed light on the binding modalities of
investigated ligands towards its target PBP-2X (PDB code: 1QMF). The molecular docking
program Autodock 4.2 was used to determine the potential binding mode between the compound
and the selected PBP-2X. Preparation of the 1QMF protein structure prior to docking was
performed by adding essential hydrogen atoms using Kollman united atom charges and solvation
parameters as provided by AutoDock Tools [53]. Ligand structures were planned for docking by
blend non-polar hydrogen atoms, adding Gasteiger partial charges and defining rotatable bonds.
A maximum grid box size of 40×40×40 Å was generated to cover the entire protein using Auto
Grid. The grid box was allocated at the centre of the protein using x, y, z coordinates of 99.86,
58.75, 49.12, respectively. Docked structures were visualized and a 2-dimensional schematic
representation of protein-ligand interaction was generated using Discovery studio visualizer 3.5.
3. Results and discussion
3.1 Description of crystal structure
The displacement ellipsoid plot and theoretical optimized geometric structure with the
atom numbering scheme for MFMSM is shown in Fig.1. The compound crystallizes in the
triclinic, space group P with cell constants: a = 7.8851(5) Å, b = 11.6612(9) Å, c = 13.437(11)
1
Å, α =84.181(4)o, β =84.490(4)o, γ = 76.246(3)˚, V = 1190.61(15) Å3, Z = 2 (at 296(2) K) and µ
= 0.178 mm-1. Details of the crystal parameters, data collection and refinement process of

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MFMSM are shown in Table 1. The supplementary information in the CIF form is available
from Cambridge Crystallographic Database Centre, No. CCDC 1471011.
In our molecule 2-formylphenyl, tosyl group and 4-methylbenzene methoxy phenyl prop-
2-enoate are attached at N1 atom. Atom S1 of the sulfonyl group has a distorted tetrahedral
configuration commonly observed in sulfonamides [54, 55]. The widening of angle O1-S1-O2
[120.4 (1)°] and the narrowing of angle N1-S1-C8 [108.3 (1)°] from the ideal tetrahedral value
are ascribed to the Thorpe–Ingold effect [56]. The significant difference in length of the
C24-O5 = 1.333(3) Å and C25-O5 = 1.443(2) Å bonds is characterized to a partial contribution
from the O––C = O+– C resonance structure of the O4-C24–O5–C25 group [57]. This future is, in
general, examined in the carboxylic ester group of the substituent in various compounds gives
mean values of 1.340 Å and 1.447 Å respectively for these bonds [58]. The sum of bond angles
around N1 (349.4o) indicates that N1 is in sp2 hybridization. The S1-C8 distance of 1.757(2) Å is
normal single bond values and conforms to those observed in other sulfonamides [59]. The
torsion angle C-S-N-C defining the conformation of the sulfonamide group is reported to lie in
the range 60-90o [60]. In the present crystal structure, the torsion angle C15-N1-S1-C8 is -
67.3(1)o. The position of the methyl group C14 is defined by the torsion angle C9-C10-C11-C14
and C14-C11-C12-C13 are -176.7(2)o and 177.7(2)o. The sulfonyl bound benzene (C8-C13) ring
forms dihedral angles of 43.1(1)o and 70.6(1)o respectively, with the 2-formylpheneyl (C1-C6)
and methoxy phenyl (C18-C23) rings. The dihedral angle between methoxy phenyl (C18-C23)
ring and 2-formylphenyl (C1-C6) ring is 38.8(1)o. The structural parameter of MFMSM
conforms to those reported for similar structure [61].
It is significance to note that, the molecular structure is stabilized by an intramolecular
C-H…π interaction between a H9 atom and a phenyl (C18-C23) ring with a C9-H9…Cg1
(Table 2, Cg1 is the centroid of the C18-C23 phenyl ring). In addition, the molecular structure is
stabilized by three weak intramolecular C7-H7…N1, C17-H17…O5 and C13-H13…O2
hydrogen bonds, each producing S(5) ring motifs [62] (Table 2). In the crystal structure, C(6)
supramolecular chain along a axis is achieved by intermolecular C2-H2…O1i contacts. These
chains are connected into a double layer via intermolecular C-H···π interactions between a
H26A atom and the sulfonyl bound benzene ring (C8-C13) of a neighbouring molecule as an
acceptor, with a C26-H26A…Cg2ii separation of 2.97 Å (Cg2 is the centroid of the C8-C13
benzene ring, symmetry codes: (i) = 1+x, y, z and (ii) = 2-x, -y, 2-z).The resulting double layer
stacks along the b axis without any specific interactions (Table 2 and Fig. 2).
3.2 Optimized structure
The geometric parameters of MFMSM were calculated at the B3LYP/6-311G (d,p) level
by DFT method and listed in Table 3 jointly with corresponding experimental values.
As seen in Table 3, the most of the optimized bond lengths are slightly different from the
experimental results, since the molecular states are different during the experimental and
theoretical processes. Many packing molecules are treated in condensed phase during
experimental (XRD) measurements, while one isolated molecule is considered in gas phase
during the theoretical (DFT) calculation. By grant the relaxation of all parameters, the
calculations assemble to optimized geometries, which coincide to true energy minima as
conceded by the lack of imaginary frequencies in the vibrational mode calculation. This
molecule has twenty four C-C bond lengths, twenty five C-H bond lengths, four C-O lengths,

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two C-N bond lengths, two S-O bond lengths and one C-S, N-S bond lengths. Loughrey et
al.[62] reported the bond lengths S31-O32= 1.4337, S32-O33=1.4256, S31-N34=1.6051, S31-
C28=1.7737 and C21-N20=1.4212
1.430, 1.704, 1.660 and 1.760 . The above said bond lengths O2 –S1, O3-S1, N1-S1, C8-S1,
and C1-N1 are in good agreement with experimental values (1.456, 1.457, 1.702, 1.797 and
1.438 ). Panicker et al.[63] and Petrov et al.[64] recorded the crystal structure and
Å, whereas the corresponding values for MFMSM are 1.430,
Å
Å
conformations of benzene sulfonamide by gas electron diffraction and quantum chemical
computations. According to their results, the bond lengths C-S, S-N and S-O vary in the range of
1.7756-1.7930, 1.6630-16925 and 1.4284- 1.4450 Å, respectively. Binil et al.[65] reported the
C=O bond length as 1.2145, 1.2146 Å (DFT), 1.2000, 1.23 Å (XRD). In the present case, the
C=O bond length is 1.210, 1.212 Å (DFT) , 1.199(2), 1.192(2) Å (XRD) and the C-O bond
length is 1.348, 1.356 Å ( DFT) and 1.333(3), 1.367(3) Å (XRD) which was in agreement with
the reported values [66,67].
In this study we observed that methoxy phenyl ring shows to be a little distorted on
account of the electronegative oxygen atom added to C19 position as seen from the bond angles,
C18-C19-C20 which are calculated as 120.3o by DFT method 120.6(2)o by experimental (XRD)
value which is greater than typical hexagonal angle of (120o) at the point of substitution. The
sulfonyl bound ring was also appears to be a little distorted because of the SO2 group
substitutions at C8 position as seen from the bond angles C9-C8-C13 which are calculated as
120.9o by theoretical method which is greater than typical hexagonal angle of 120o and
experimentally by 120.0(2)o. With the electron donating substituents on the benzene ring the
symmetry of the ring is an imperfect, resigned ring angles smaller than 120o at the point of
substitution [68]. Similarly due to N1 atom attached at C1 position of 2-formylphenyl ring
appears a little distorted. It is evident from the bond angles C2-C1-C6 = 119.5o by DFT method
which is smaller than typical hexagonal angle of 120o and XRD by 120.0(2)o. At C24 position,
the bond angles are O4-C24-C16 = 123.2o, O5-C24-C16=113.9 o, 04-C24-O5=122.8 o and this
asymmetry shows the repulsion between C=O. Here the value of C-S and S-N bond length is
found to be high compared to other bond length values. The torsion angle τ (C15-N1-S1-C8) is
calculated as 75.5o for which falls within the expected range (70-120o). The torsion angles τ1
o
(C9-C10-C11-C14) and τ2 (C14-C11-C12-C13) are -179.4o and 179.6 respectively for DFT.
These torsion angles are in agreement with the XRD data. Further, the results of our calculations
showed that S1-O2 and S1-O3 bonds show typical double bond characteristics and all other bond
lengths fall within the expected range. The experimental bond lengths are slightly lower than
that of theoretical values. Theoretical bond lengths vary ± 0.85
Å where comparing with the
XRD data and these differences are probably due to intra molecular interaction in the solid state.
As seen from Table 3 the difference between the XRD and DFT values for the bond
lengths C8-S1, N1-S1, O2-S1 and O3-S1 are 0.037, 0.042, 0.026 and 0.027Å, respectively.
Similarly, the difference bond angles O1-C7-C6, O3-S1-O2, N1-S1-C8 and C1-N1-C15 are 1.2,
2.3, 1.7 and 1.5o respectively. This difference is more not only because of intra molecular C9-
H9…Cg1, C7-H7…N1, C17-H17…O5 and C13-H13…O2 hydrogen bond but also due to
intermolecular C2-H2...O1i, and C26–H26A…Cg2ii interactions (Cg1 and Cg2 are the centroids
of the C18-C23 and C8-C13 benzene rings, respectively; symmetry codes: i = 1+x, y, z and
ii = 2-x, -y, 2-z). According to theoretical values, the sulfonyl bound benzene ring forms dihedral
angles of 36.96o and 62.65 o respectively, with the 2-formylphenyl and methoxyphenyl rings. The
o
dihedral angle between 2-formylphenyl and methoxyphenyl ring is 30.76 . In spite of the

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differences, calculated geometric parameters signify good approximation and there are the bases
for calculating other parameters like vibrational frequencies and thermodynamic properties.
By superimposing the molecular skeletons obtained from experimental (XRD) and
theoretical (DFT) calculations atom by atom, a global comparison was made (Fig. S1), obtaining
RMSE’s values of 0.004 Å for B3LYP/6-311G(d,p) method. This degree of RMSE can be
elucidated by the fact that intermolecular coulombic interaction with the adjacent molecules are
not available in gas phase, whereas the experimental result corresponds to interacting molecule
in the crystal lattice.
3.3 Vibrational assignments
Vibrational spectroscopy is used extensively in organic chemistry for the identification of
functional groups of organic compounds, the study of molecular confirmations, kinetics, reaction
etc. Assignment of complex system can be expected on the basis of frequency agreement
between the observed fundamental modes and computed harmonies. The complete vibrational
assignments of fundamental modes of MFMSM along with the PED are given in Table S1
(Supporting information). The molecule consists of 59 atoms and expected to have 171 normal
modes. Normal coordinate analyses were carried out to provide the entire assignment of
fundamental vibrational wavenumbers of the molecule. DFT force fields which were computed
theoretically was transformed to the final set of vibrational coordinates and applied in all
succeeding calculations. Potential energy distribution (PED) was computed for each normal
mode among the symmetry coordinates of the molecule. Based on the computed PED values and
FT-IR band intensities a detailed assignment of the fundamentals was proposed. The unscaled
vibrational wavenumbers are normally greater than the experimental value. Since the theoretical
calculations were made for a free molecule in vacuum and the experimental calculations were
performed for liquid sample, there is the disagreement between computed and observed
vibrational wavenumbers. The reason is also relatively due to the neglecting of anharmonicity
and partly due to approximate nature of the quantum mechanical methods. However, for
dependable information on the vibrational properties the use of selective scaling is necessary.
The calculated wavenumbers are scaled using the scaling factor 0.961 [48].
The experimental and theoretical FT-IR spectra are shown in Fig.S2 (Supporting information)
for comparative purposes, in which the calculated intensity and activity are plotted against the
harmonic vibrational frequencies. The experimental wavenumbers, calculated wavenumbers and
IR intensities are given in Table S1 along with detailed assignments.
3.3.1 C-H ring vibrations
In aromatic compounds, the C-H stretching wavenumbers fall in the range 3100 - 3000
cm-1, and the C-H in-plane and out-of-plane bending vibrations lie in the range 1300 - 1000 and
1000 - 750 cm-1, respectively [69,60]. This is the distinguishing region for the identification of
C-H stretching vibration. In this region the bands are not affected appreciably by the nature of
the substitutions. In the same way, in the present study, the twelve adjacent hydrogen atoms left
around the rings of the title compound give rise to twelve C-H stretching vibrations, which
correspond to stretching modes of C2-H2, C3-H3, C4-H4, C5-H5, C9-H9, C10-H10, C12-H12,
C13-H13, C20-H20, C21-H21, C22-H22 and C23-H23 units respectively. The aromatic C-H
stretching of the compound give bands at 3059 cm-1 in the FT-IR spectrum. All the aromatic C-H
stretching bands are found to be weak, and this is owing to reduction of negative charge on the
carbon atom. This reduction takes place as a result of the electron withdrawal on the carbon atom

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by means of the substituent owing to the decrease in the inductive effect, which in turn is rooted
by the increase in the chain length of the substituent [70]. As estimated, these twelve modes are
pure stretching modes as is evident from PED column of Table S1, they almost contribute 95%
The C-H stretching vibrations of aromatic and hetero aromatic structures mostly occur in
the region 3100 - 2800cm-1 [71]. This permits the ready identification of the structure. The bands
in this region are not much affected by the nature and position of the substituents. Because of
low intensity of C-H stretching modes, the theoretical description for this region is somewhat
difficult. The C-H stretching ring vibrations are lies at 3123 - 3035 cm-1 and observed
experimentally at 3059 cm-1. The scaled theoretical values of ring C-H stretching mode agree
well with that of experimental data as listed in Table S1. The percentage of PED predicts that C-
H modes of MFMSM are very pure, as their percentage is almost 100%. However, C-H
stretching modes also satisfy harmonic oscillator equation [72].
The C-H in-plane bending vibrations in the benzene ring are commonly weak and
appeared in the regions 1300-1000cm-1 as the C-H out-of-plane bending vibrations occur in the
region 900-650 cm-1 [71]. In-plane C-H bending vibrations are expected in the range of 1600 -
1030 cm-1 for MFMSM in the FT-IR spectrum. The in-plane bending vibrations of MFMSM are
observed at1595 and 1032cm-1 in FT-IR and the corresponding calculated values are 1574, 1573,
1572, 1548, 1464, 1454, 1424, 1411, 1286, 1277, 1268, 1244, 1186, 1181, 1165, 1163, 1139,
1127, 1096, 1094, 1040 and 1023 cm-1. These vibrations are mixed with stretching C-C
vibrations. The C-H out-of-plane bending of phenyl rings are calculated at 969, 942, 938, 936,
919, 858, 825, 771, 748, 738 714, and 689cm-1. The computed C-H in-plane and out-of- plane
bending vibrations are well coincide to experimental ones.
3.3.2 C-C ring vibrations
The aromatic ring C-C stretching vibrations are very important in the spectrum of
aromatic compound and are highly characteristic of the aromatic ring itself. However, observed
assignments of vibrational modes of peaks are complicated. Bands between 1650 and 1400 cm-1
in benzene derivatives are assigned to ring vibrations. In particular the variable intensity five
bands in the fingerprint region are observed at 1625-1590, 1590-1575, 1540-1470, 1460-1430
and 1380-1280 cm-1 from the frequency ranges given by Varsanyi [73]. For our case the different
intensity bands are observed at 1595 and 1256 cm-1 in FT-IR and has been assigned to C=C
stretching vibrations. Theoretically calculated values at 1574, 1573, 1572, 1555, 1553, 1548,
1464, 1433, 1424, 1294, 1281, 1277 and 1266 cm-1 by B3LYP /6-311G (d,p) method shows
excellent agreements with experimental data. Sarojini et al. [30] calculated the wave number for
C-C-C in-plane bending vibrations experimentally at 991,770, 818 and 665 cm-1 in FT-IR
spectrum and theoretically calculated wave numbers at 1475, 992, 796, 782, 623, 392 and 303
cm-1 by DFT method. In this study, C-C-C in-plane bending vibrations are computed at 1572,
1555, 1464, 1454, 1000, 994, 847, 782, 771, 623, 616 and 497 cm-1. The C-C-C-C out-of- plane
bending vibration is observed at 480 cm-1 and calculated at 461, 402, 306, 289 and 89 cm-1. The
mode numbers 83, 81, 78, 61, 59, 50, 45, 40, 35, 23, 18, 12, 7 and 3 were recognized as torsional
deformation τCCCC modes and shown in Table S1.
3.3.3 Methylene group vibration
The C-H stretching of the methylene group is at lower frequencies than those of the
aromatic C-H ring stretching. The CH2 asymmetirc stretching vibrations are mostly expected in
the region 3000-2900 cm-1 while CH2 symmetric stretch will appear between 2900 and 2800cm-1
[74, 75]. In our case the band observed at 2938 cm-1 has been assigned to CH2 asymmetric

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vibrations in FT-IR spectrum and computed theoretically at 3003 cm-1. The computed PED
confirms that CH2 stretching modes are pure mode and they almost give 100% as it is evident
from the Table S1. The wagging vibration of CH2 computed at 1419cm-1 with contribution of
PED is 47%.
3.3.4 Methyl group vibrations
The methyl group vibrations are generally assign to as electron contributing substituent in
the aromatic ring system. The title compound MFMSM possesses three CH3 groups. Vibrations
of each CH3 system in title molecule should be expressed by 12 normal modes. The nine modes
can be described as three stretching; 2υas (CH3) and υs (CH3); three bending; 2 asymd (CH3) and
symd (CH3); 2 rocking r (CH3) and one torsion mode of the CH3 group τ (CH3). The remaining
three modes describes vibrations of the whole C- CH3 group which has two bending and one
stretching modes of the C- CH3 bonds.
The C-H stretching in CH3 group happens at lower frequencies than those of aromatic C-
H stretching (3100-3000 cm-1). The asymmetric C-H stretching mode of CH3 group will fall in
the region around 2980 cm-1 and symmetric [72, 76-78] one is predictable around the region
2870 cm-1. The first of these results from the asymmetric stretching of CH3 mode in which the
two C-H bonds of the method group are expanding while the third one is shrinking. In case of
symmetric stretching in which all the three C-H bonds expand and shrink in-phase. The
asymmetric stretching for the CH3 has magnitude higher than the symmetric stretching [79-81].
In the present study the C14H3, C25H3 and C26H3 of asymmetric stretching vibration
theoretically calculated at 3033, 3019, 2999, 2998 and 2958 cm-1.
The symmetric stretching modes of CH3 are calculated at 2951, 2930, 2910 and 2891 cm-1
(mode numbers 151, 150, 149, 147). In general, the asymmetric and symmetric deformation
vibrations of methyl substituted benzene derivatives appear in the regions 1465-1440 cm-1 and
1390-1370 cm-1, respectively [82-85]. Rooted in the above literature data, in the present study
the medium strong band observed in FT-IR spectrum at 1465 cm-1 is assigned to C26H3
asymmetric deformation vibration. In our calculations, the asymmetric deformation vibrations
are predicted in the range 1462-1434 cm-1(mode numbers 136 - 131).
The theoretically calculated value by B3LYP/6-311G(d,p) method at 1430 and 1424cm-1
(mode numbers 129, 128) are assigned to C14H3 and C25H3 symmetric deformation vibrations
in CH3 groups also in congruent with the above literature data as well as in the FT-IR spectrum .
The wagging vibration of C14H3 is observed at 1352 cm-1 in FT-IR spectrum is agree well with
calculated value. The rocking vibrations of CH3 group of C14H3, C25H3 and C26H3 unit appear
as independent vibrations. These modes usually occur [86] in the region 1070 - 1010 cm-1. In
comparison with the above literature data, the band observed at 1103 cm-1 in FT-IR spectrum is
assigned to C26H3 rocking vibration. The theoretically predicted values at 1127 cm-1(mode no
99) assigned to CH3 rocking vibration accurately agrees with literature as well as recorded FT-IR
spectrum. Other CH3 rocking vibration of C26H3 and C14H3 are calculated at 1125 and 968 cm-1.
The computed wave numbers at 251, 125, 115 and 12 cm-1 (mode numbers 27, 17, 16 and 2) are
assigned to CH3 torsional mode. These modes are not pure as evident from Table S1.
3.3.5 Aldehyde group vibrations
The aldehyde C-H stretching vibration can be possibly observed in FT-IR spectra by its
band position in the small wave number region, compared to other stretching C-H vibrations. On
account of low intensity, the overtone band expected below 2796 cm-1 cannot be observed

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manifestly. However, the doublet of Fermi resonance can be observed evidently in solution
spectrum. The C-H stretching absorption in aldehyde normally takes place in the region 2830-
2695cm-1. The creation of Fermi resonance between the first overtone of the C-H in- plane
bending and fundamental C-H stretching appear near 2985 cm-1. This formation is owing to
doublet. Consequently, in the present study the aldehyde C-H stretching vibration for MFMSM
was observed at 2760 cm-1 in the FT-IR spectrum. The theoretically calculated value at 2896cm-1
by B3LYP/6-311G (d,p) method shows excellence with characteristic data [87]. The other
aldehyde group vibrations acquired and assigned in this study were found to be in congruent with
those in the literature [88, 89]. In general, aromatic aldehydes have a strong absorption at 700-80
cm-1 due to in-plane deformation vibrations of the C-CHO group [90]. Many studies of
benzaldehyde derivatives have been encouraged by the internal rotation of the aldehyde moiety
with respect to the aromatic ring [91]. Therefore in the present work, the calculated wave number
at 1165 cm-1 is assigned to C-CHO stretching mode. A pure mode cannot be expected for this
vibration as it lies in a complicated region of vibration spectrum. The C-H in-plane bending
vibration of the aldehyde group is calculated at 1365 cm-1 (mode no.122).
The carbonyl (C=O) stretching in aldehydes [87, 92] usually appear in the region 1740-
1720 cm-1. In the present case, strong band observed at 1931 cm-1 in FT-IR spectrum and
theoretically calculated wave number at 1703 cm-1 (mode no.146) corresponds to C=O stretching
vibration mode which is pure mode with PED contribution of 89%.
Inter and intramolecular factors affect the carbonyl absorption in general organic
compounds. Mesmeric and inductive effects are associated with the groups attached to the
carbonyl compounds such as aldehydes. The carbonyl group depends mainly on the force
constant consecutively depends upon conjugative effect, inductive effect, field effect and steric
effect. This is due to the wave number of absorption. The inductive effect reduces the length of
the C=O bond and therefore increases its force constant and the wave number of absorption.
3.3.6 Ester group of vibrations
The carbonyl C=O stretching mode [93, 94] is expected to fall in the region 1750-1600
cm-1 and for MFMSM this mode is observed with very strong band at 1703 cm-1 in FT-IR, which
coincide exactly with theoretical value with contribution of PED is 86%. A weak infrared band at
3402 cm-1 (not list in Table S1) assigned to the overtone of C=O stretching vibration of ester was
also observed [92]. Methyl ester has the strong absorption bands about the C-O asymmetric
stretching modes at 1315-1195 cm-1 and symmetric stretching modes at 1096-900 cm-1 [95]. The
theoretically computed wave numbers at 1244, 1237cm-1(mode numbers 109,110) are assigned
to the asymmetric stretching modes which in combination of other modes. The computed wave
number at 1012 cm-1(mode no.88) is designated to O-CH3 stretching mode which is a pure mode
with PED contribution of 69%. The in-plane and out-of-plane deformations of C=O are appear in
the regions 625±70cm-1and 540±80 cm-1, respectively [79]. The bands at 820, 729 cm-1 in the IR
spectrum and 801, 771, 749, 673 cm-1(DFT) is represented to C=O deformation mode.
The methyl ester has also two distinguished vibration modes in 530-340cm-1 and 390-250
cm-1 region [92] corresponding to the CO-O rocking and CO-C deformation. The computed
modes at 441,346, 325, 305, 220 and 181 cm-1 represent CO-C deformation.
3.3.7 SO2 vibrations
The asymmetric stretching vibrations for the SO2, NH2, NO2, CH2 and CH3 etc, has
magnitude larger than the symmetric stretching [95, 31]. The symmetric and asymmetric SO2

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stretching vibrations lie in the region 1150-1125cm-1 and 1330-1295 cm-1, respectively [96].
According to Alvareza et al., [97] for sulfamoil fluoride substance, the intense signals showing at
1418 and 1217cm-1 (FT-IR) were ascribed to the SO2 anti symmetric and symmetric stretching
fundamental modes. The symmetric stretching mode at 1150cm-1 as strong peak, and the
antisymmetric modes at 1341 and 1351 cm-1 in infrared spectrum for N-3 pridinal methane
sulfonamide was recorded by Dodoff [98]. In MFMSM, a band in FT-IR spectrum at 1165 cm-1
is designated to SO2 stretching mode and computed wave number at 1160cm-1 (mode no.103)
with PED contribution of 14%. The region of the SO2 scissoring (560±40 cm-1) and that of SO2
wagging vibration (500±55 cm-1) partly overlap; the two vibrations show separately [92]. In the
present study, the FT-IR band observed at 565 is assigned to SO2 scissoring. The band observed
at 480 cm-1 is assigned to SO2 wagging. The theoretically calculated values at 551, 520 and
461cm-1 (mode numbers 51, 47, 43) are designated to SO2 scissoring and wagging vibrations,
respectively.
3.3.8 C-S, S-N and N-C vibrations
Normally, the C-S stretching bands occur in the range 930-670 cm-1 [99] with a moderate
intensity. In the present work, the computed wave number at 629 cm-1(mode no.56) is assigned
as C-S stretching vibration. The C-S in-plane and out-of-plane bending vibrations are fall in the
regions 600-420 cm-1 and 420-320 cm-1, respectively [100]. In MFMSM, the calculated
frequency at 209, 141 157 cm-1 by DFT method gives the C-S out-of-plane bending vibration.
The S-N stretching vibration is expected to fall in the region 905±30 cm-1 [100]. In MFMSM,
S-N stretching vibration is observed at 662 cm-1 in FT-IR and the corresponding calculated value
at 674 cm-1. On account of the mixing of several bands, the identification of C-N vibrations is a
very complicated. Sen et al. [101] assigned C-N stretching absorption in the region 1266 -1382
cm-1. In the present study, the mode no. 109 calculated at 1225 cm-1 is recognized as C-N
stretching vibration. The PED of this mode is 22%. The calculated wave numbers at 610 and
497cm-1 listed in Table S1 is assigned as C-C-N in-plane bending vibration. The calculated wave
numbers at 391 cm-1 is assigned as C-C-N out-of-plane bending vibration. The C-N-S out-of-
plane bending vibrations are calculated at 209, 141 and 64 cm-1 (mode numbers 24, 19, 11).
The comparison of theoretical observations with the experimental observation is given as
the correlation graph in Fig. S3 (Supporting information) based on the calculation. As can be
seen from the correlation graph, the correlation coefficient (CC) R2 is 0.993 for B3LYP/6-311G
(d,p).
3.4 13C and 1H NMR Spectral analysis
The NMR spectrum proves to be of great utility in structure elucidation because, the
properties it displays can be related to the chemist’s perception of molecular structure. This
technique enables us to study the shape and structure of molecules. Chemical shifts presented in
NMR spectra are most important section of the information on molecular geometry along with
they are imperative for structural analysis as a result of their sensitivity to conformational
deviations. A prime way to predict and recognize the structure of large molecules is to add in
computer simulation and NMR methods. Outstanding predictions of molecular geometries are
necessary for good calculations of magnetic properties [102]. So complete geometry
optimization of MFMSM was carried out by the B3LYP/6-311G (d,p) method. Later, Gauge
13
1
Independent Atomic Orbital (GIAO) C and H chemical shift computations of MFMSM have
been completed by same level. The G1AO applications [103] come close to molecular systems

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was considerably improved by an efficient application of the method to the ab initio SCF
calculations, utilizing techniques borrowed from analytic derivative methodologies. The G1AO
method is noticeably better because it exhibits a faster convergence of the computed properties
upon addition of the basis set used. By considering the effectiveness of calculation and the
computational rate, the G1AO method seems to be attractive from many features currently.
Otherwise, the density functional methodologies propose an efficient alternative to the
conventional correlated methods, owing to their significantly lower computational cost. The
chemical shifts were measured in chloroform (CDCl3). The isotropic chemical shifts δ with
respect to tetra methyl silane (TMS) was calculated by isotropic shielding values
1
13
x
iso
x
TMS
TMS
(
δ
=
-
σ iso ). The value of
are 31.99and 184.79 ppm for H and C NMR spectra,
σ
σ
iso
iso
13
respectively. Taking into account that the range of C NMR chemical shift for similar organic
molecules usually is >100ppm [80, 81]. The accuracy ensures reliable interpretation of
spectroscopic specifications. The recorded NMR spectra of 13C and H using chloroform
1
(CDCl3) are depicted in Fig.S4 and Fig.S5 (Supporting information).
The present work, the MFMSM also lie down with above literature data. In general,
highly shielded electrons appear down field and vice versa. The computed chemical shift values
by the theoretical (DFT) values coincide well with the experimental values. In the 13C NMR
spectrum, the highly shielded tosyl, methyl carbon of the ester carbonyl and methoxyphenyl
group show signals at 21.58, 46.74 and 55.29 ppm and calculated as 23.75, 55.19 and 57.05 ppm.
The aromatic carbons of the tosyl, 2-formylphenyl and methoxy phenyl group are appeared as
multiplet in the range of 110.71-144.14 ppm and are found to be in the range of 114.17-155.43
ppm for DFT. The signal at 190.04 ppm is assigned to C7 carbon atom of the carbonyl group
computed as 196.05 ppm. The signal at 167.43 ppm assigned to the C24 carbon of the ester
carbonyl group is computed as 175.73 ppm. The signal at 144.14 ppm assigned to the C1 carbon
of the formylphenyl ring which is bonded with nitrogen is calculated as 155.43 ppm. The signal
at 141.47 ppm assigned to the C11 carbon of the tosyl ring which is bonded with methyl (CH3)
group, is computed as 152.44 ppm. The signal at 144.14 assigned to the C17 carbon which is
bonded with C18 carbon of the methoxy phenyl ring, is calculated as 151.25 ppm. The signal at
140.87 ppm assigned to the C8 carbon of the tosyl phenyl ring which is bonded with sulfonyl
group, is calculated as 144.17 ppm. The signal at 133.21 ppm assigned to the C6 carbon of the
2-formyl phenyl ring which is bonded with aldehyde carbon C7, is calculated as 143.16 ppm.
The signal at 136.05, 127.74, 127.43 and 126.35 ppm are assigned to the (C3, C2, C5 and C4)
carbons of the 2-formylphenyl ring. The above said carbons are calculated as 140.83, 134.74,
134.26 and 134.13 ppm. The meta carbons (C12, C10) of the tosyl phenyl ring are accountable
for the signal at 128.24 and 128.04 ppm, calculated as 135.47 and 135.25 ppm. The ortho
carbons (C13, C9) of the tosyl ring are responsible for the signal at 129.99 and 123.11 ppm,
computed as 133.97 and 133.34 ppm. The ortho carbons (C19, C23) of the methoxy phenyl ring
are responsible for the signal at 157.35, and 130.95 ppm, calculated as 167.46 and 137.07 ppm.
The meta carbons (C20, C22) of the methoxy phenyl ring are responsible for the signal at 110.71
and 120.31 ppm for B3LYP calculated as 114.17 and 124.77 ppm. A signal at 76.66-77.51 ppm
indicates the carbon atom of CDCl3 (Solvent).
In the 1H NMR spectrum, a singlet at 2.41, 3.69 and 4.61 ppm indicates the three protons
of methyl group. The above said methyl group protons are calculated at 2.38, 3.86 and 4.04 ppm
for DFT. The twelve aromatic protons of 2-formylphenyl, tosyl and the methoxy phenyl ring are
appeared as multiplet in the range of 6.38-7.86 ppm and are calculated in the range of 6.56-8.50
ppm. It is another possible result that among the 1H isotropic chemical shifts, the H proton (H7)

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has the maximum chemical shift of 9.85 ppm due to the closer to the electro negative oxygen
atom in the 2-formylphenyl. The methylene protons (H15A, H15B) assigned to C15 and
methylene proton (H17) assigned to C17 shows a doublet at 4.99 and 5.03 ppm. The above said
protons are calculated at 3.87 and 4.75 ppm. The chemical shifts of the hydrogen (H) atom
would be more vulnerable to intermolecular interactions as they are the smallest of all the atoms
and mostly confined to a small area on the periphery of molecules. Because of non availability of
individual hydrogen atoms of methyl (CH3) groups in the experimental 1H chemical shift values,
we have presented the average of the computed values for these hydrogen atoms.
1
As can be seen from Table 4, the calculated 13C and H chemical shift results for
MFMSM are generally closer to the experimental data. For comparison with experimental
observations, correlation graph in Fig. S6 (Supporting information) is presented based on the
calculations. As can be seen from the graph, the correlation co-efficient (CC) R2 for 13C is 0.995.
3.5 NBO analysis
The molecular stability and bond strength were investigated by applying the natural bond
orbital analysis (NBO). Stability of the molecule arising from hyper conjugative interactions and
charge delocalization has been analyzed using natural bond orbital (NBO) analysis. By means of
the second order donor–acceptor (bond – antibond) NBO analysis, observation into the most
important delocalization schemes was collected. The alteration in electron density (ED) in the
(σ*, π*) antibonding orbitals and E(2) energies have been calculated by natural bond orbital
(NBO) analysis [104] using DFT/B3LYP method to give clear confirmation of stabilization
arising from various molecular interactions. The hyperconjugative interaction energy was
withdraw from the second-order perturbation approach [51]
2
F(i, j)
(
)
E(2) = ∆Eij = qi
−
j
i
where qi is the donor orbital occupancy,
diagonal NBO Fock matrix element.
and i are diagonal element, and F (i, j) is the off
j
The enhanced E(2) value, the more in-depth is the interaction between electron donors and
acceptor, i.e. the more donation affinity from electron donors to electron acceptors and the higher
the level of conjugation of the complete system [51] . The stabilizing donor–acceptor interaction
was established by way of delocalization of electron density between occupied Lewis’s type
(lone pair or bond) NBO orbital and properly unoccupied (Rydberg or anti bond) non-Lewis
NBO orbital. NBO analysis has been performed on the MFMSM molecule at the B3LYP/6-311G
(d,p) level to simplify the intra-molecular rehybridization and delocalization of electron density
within the molecule. The strong intramolecular hyperconjugation interaction of the π and σ
electrons of C–C to the anti C–C bond to the ring leads to stabilization of some part in the ring as
evident from Table S2 (Supporting information).
The electron density of six conjugated bonds of phenyl ring (~1.98e) evidently
demonstrates strong delocalization. In addition, observed that there is no deviation in charge
distribution on all other carbon atoms. The strong intermolecular hyperconjugative interactions
are formed by orbital overlap between π(C-C), π*(C-C) and σ(C-C), σ*(C-C) bond orbitals,
which results in intermolecular charge transfer, causing stabilization of the system. These
interactions are observed as an increase in the electron density(ED) in the C-C antibonding
orbital that deteriorates the respective bonds [105]. The ED at the conjugated σ bonds (1.96e)
and σ*(0.02e) of the aromatic ring clearly demonstrates weak/strong delocalization. The strong
intermolecular hyperconjugation interaction of the π electrons from (C8-C9) to the π*

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antibonding orbitals of (C12-C13) and (C10-C11) bond shows an ED of 1.69366e, leading to the
stabilization of 21.29 and 15.77 kJ/mol respectively. As shown in Table 5, these interactions are
observed as increase in ED in C10-C11 anti-bonding orbital that weakens the respective bonds.
Another important hyperconjugation interaction is for the lone pair atoms, in the present study of
our molecule there is a strong intermolecular hyper-conjugative interaction of S1-N1 from O2 of
LP (2) O2→ σ*( S1-N1) which increases ED(0.26747e) that weakens the respective bond S1-N1
(1.77979e) leading to stabilization of 16.05 kJ/mol. The hyper conjugative interaction of S1-C8
from O3 of LP (2) O3 → σ*(S1-C8) which increases ED (0.20054e) that weakens the respective
bond S1-C8(1.82236e) leading to stabilization of 16.86 kJ/mol and also the hyperconjugation of
O5-C24 from O4 of LP (2) O4 → σ*(O5-C24) which increases ED (0.09821e) that weakens the
respective bonds O5-C24 (1.85395e) leading to stabilization of 31.29 kJ/mol. Then the
hyperconjugative interaction of O4-C24 from O5 of LP (2) O5→ π* (O4-C24) which increases
ED (0.26066e) weakens the respective bond O4-C24 (1.79720e) leading to stabilization of 46.18
kJ/mol and also the hyperconjugation of C19-C20 from O6 of LP (2) O6 → π*(C19-C20) which
increases ED (0.37365e) that weakens the respective bonds C19-C20 (1.83132e) leading to
stabilization of 32.41 kJ/mol. The most important highest energy, related to the molecule is
electron donating from π* (C8-C9) to the antibonding acceptor π* (C10-C11) and π* (C12-C13)
with stabilization energy 180.23 and 185.02 kj/mol, respectively. Similarly, electron donating
from π* (C2-C3) to the antibonding acceptor π* (C4-C5) leads to strong delocalization of 243.78
kJ/mol. The highest interaction around the ring can stimulate the large bio activity in the
compound.
3.6 Non-linear optical (NLO) effects
Non linear optical materials play a major role in nonlinear optics and in particular they
have a great impact on information technology and industrial applications. NLO relates with the
interaction of applied electromagnetic fields in various materials to produce new electromagnetic
fields, modified in frequency, phase, amplitude or other physical properties [106]. Organic
molecules able to maneuver photonic signals efficiently are of significance in recent trend
technologies such as optical computing, optical communication and dynamic image processing
[107,108] .
In an electric field E
achieved using Taylor series expansion:
µtot µ0 ij Ej + ijk Ej Ek +....
i
(x), the total dipole moment µtot of an isolated molecule can be
=
+
α
β
Where αij is the linear polarizability, µ0 is the permanent dipole moment and βijk are the first
hyperpolarizability tensor components. The isotropic (or average) linear polarizability is defined
as [109]:
α xx
+
α yy +α zz
α tot
=
3
Total polarizability is
1/2
∆α
= 2−1/2 α yy )2 + (α yy α zz )2 + (α zz α xx )2 + 6α x2x
(
α xx − − )
−
First hyperpolarizability is a third rank tensor that can be described by 3 ×3 ×3 matrix. The 3D
matrix of 27 components can be abridged to 10 components because of the Kleinman symmetry
[76] (βxyy = βyxy = βyyx = βyyz = βyzy = βzyy, etc. similarly other permutations also take same value).
By means of the following equation the components of the first hyperpolarizability can be
calculated [110]:

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1
βi
=
βiii
+
(β + β jij + βα jji )
ijk
∑
3 i≠ j
By means of the x, y and z components of β, the magnitude of the first hyperpolarizaability
tensor can be calculated by:
2
2
2 1/2
βz )
βtot = (βx
+
βy
+
where
βx = (βxxx
βy = (βyyy
βz = (βzzz
+
βxyy
βyzz
βxxz
+
+
+
βxzz
βxxy
)
+
)
+
βyyz )
The output form Gaussian03W, the complete equation for calculating the magnitude of βtot is
given in this way
2 1/2
βtot =[(βxxx
+ βxyy + β + βyzz + β + βxxz + β ) ]
xzz )2 +(βyyy xxy )2 + (βzzz
yyz
As the values of the polarizability (α) and the hyperpolarizability (β) of the Gaussian output are
reported in atomic units (a.u.), the calculated values have been converted into electrostatic units
(e.s.u.) (For α: 1a.u. = 0.1482X10-24esu; for β: 1a.u. = 8.6393X10-33esu).
The output form of Gaussian03W such as total molecular dipole moment (µ), linear
polarizability(α) and first order hyperpolarizability(β) of the computations have been elucidated
in detail previously [111] and DFT has been broadly used as an competent method to examine
the organic NLO materials [110, 116-115].
The computed hyper polarizability values of MFMSM are listed in Table S3 (Supporting
information). In our calculations, the dipole moment µ and mean polarizability αtot of MFMSM
were found to be 3.0375D and 49.22x10-24esu, respectively, and also the highest value of dipole
moment is observed in the direction µz which is equal to -2.7658D. The first order hyper
polarizability β of calculated value is found to be 4.135x10-30esu (Table S3). Since the values
tot
of the first hyper polarizability tensors of Gaussian 03W output are reported in atomic units (a.u),
the theoretically computed values were converted into electro static units
(For α: 1a.u. = 0.1482X10-24esu; for β: 1a.u. = 8.6393X10-33esu). The ideal molecule of urea is
employed in the investigating of the NLO properties of the molecular bodies. Thus urea was used
frequently as a threshold value for comparative purpose. The total polarizability ∆α and first
order hyper polarizability β
are 63.80X10-24 esu and 41.35X10-31esu respectively. The
tot
MFMSM molecule of total dipole moment is approximately 2.13 times greater than that of urea
and with first order hyper polarizability is 6.8 times larger than that of urea [µ, αtot and βtot of
,
urea are 1.42515 Debye, 4.154X10-24 esu and 6.069X10-31esu computed by B3LYP/6-311G(d,p)
method]. Excellence of particular compound enumerate on a large delocalization of charges in
that direction. It is noticed that in βxxx and βzzz direction, the largest values of hyper
polarizability are observed and subsequence delocalization of electron cloud is high in that
direction. The high value of hyperpolarizability βtot which is a measure of NLO activity of the
molecular system is associated with the intra molecular charge transfer (ICT), resulting from the
movement of electron cloud through π conjugated structure from electron donor to electron
acceptor groups. The physical properties of these conjugated molecules are managed by the low
band gaps and by the high degree of electronic charge delocalization along the charge transfer

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axis. As a result, we conclude that the title molecule MFMSM is an attractive object for NLO
properties.
3.7 Mulliken atomic charges
The atomic charge distribution of the molecule has computed on the root of Mulliken
method [116] using B3LYP level with 6-311G(d,p) basis set are listed in Table S4 (Supporting
information). This calculation explains the charges of the every atom in the molecule. Allocation
of positive and negative charges is the necessary to decreasing or increasing of bond length
between the atoms. The literature survey reveals that effective atomic calculations gave a
important role in the application of quantum chemical calculation of molecular system because
of dipole moment, molecular polarizability, atomic charges, electronic structure, acidity–basicity
nature and more properties of molecular system [116].
In our title compound MFMSM, the sulfonyl S1 atom has the maximum positive charge
(1.1379e) compare to other atoms on account of highly electronegative oxygen atoms
(O2= -0.4928e and O3= -0.4907e) present in the nearest position. The carbon atom involved with
hydrogen atom is negative whereas the remaining carbon atoms are positively charged in
MFMSM. The nitrogen and oxygen atoms have more negative charge whereas all the hydrogen
atoms have the positive charges. The more positive charge of carbon is found for the atoms C1,
C7 and C24. It is mainly due to the substitution of negative charge of an oxygen and nitrogen
atoms. The presence of large negative charge on N1,O5, O2 and net positive charge on H7, H17,
H13 atoms may confirm the formation of C7-H7…N1, C17-H17…O5 and C13-H13…O2 intra
molecular interaction in solid state.
3.8 Frontier molecular orbitals (FMOs)
HOMO–LUMO orbitals are also named frontier orbitals as they fall at the outmost
boundaries of the electrons of the molecules. The FMOs impose in a imperative role in the
electric and optical properties in addition to UV–Vis spectra and quantum chemistry [117]. The
HOMO–LUMO gap helps explain the kinetic stability and the chemical reactivity of the
molecule. A molecule with a small HOMO–LUMO gap is usually related with a low kinetic
stability, high chemical reactivity and is also called as soft molecule [117]. The three
dimensional (3D) formats of the frontier orbitals HOMO and LUMO figures for the MFMSM are
shown in Fig.3. The in-phase and out of phase overlap combination of different atomic orbitals
makes the bonding molecular orbital and the anti-bonding molecular orbital (designated with an
*) respectively. The π bonding and π* anti-bonding orbitals result by reason of the lateral in
phase and out of phase overlap of π atomic orbitals respectively. The enhance in bonding
character of molecular orbital is caused by the hyper-conjugation effect and is reflected as large
overlapping of molecular orbitals, because the electrons are spread over many orbitals. The π*
anti-bonding orbitals direct to a decrease in electron density between the nuclei, reaching a value
of zero (node) at the midpoint between the nuclei where there is a nodal plane. The nodes state
the anti-bonding character of the molecular orbital. The larger the number of nodes in a
molecular orbital, the higher is the anti-bonding character of the molecular orbital. The computed
energy values of HOMO and LUMO are -6.2477 eV and -1.6573 eV and the frontier orbital
energy gap value is - 4.5904 eV for MFMSM. Smaller value in the HOMO and LUMO energy
gap elucidates the ultimate charge transfer interactions happening within the molecule, which
manipulates the biological activity of the molecule. In order to get the material to be NLO active,
the intramolecular charge transfer should be taking place between HOMO and LUMO which is
possible by means of narrow energy gap between them. Investigation of the wave function
specifies that the electron absorption be in contacts to the transition from the ground state to the

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first excited state and is mainly described as a result of one-electron excitation from HOMO to
LUMO.
3.9 Global and local reactivity descriptors
The energy gap between HOMO and LUMO is a major parameter to decide molecular
electrical transport properties. The global chemical reactivity descriptors of molecules for
example chemical potential, softness, hardness, electronegativity and electrophilicity index as
well as local reactivity have been explained through HOMO and LUMO energy values for a
molecule [118–122]. The concept of electronegativity was introduced by Pauling. Hardness (η),
chemical potential (µ) and electronegativity (χ) and softness (S) are defined follows.




∂2 E
1
1 ∂
µ


η
=
V r =
( )
V r
( )




2 ∂N2
2 ∂N


∂E
∂N


η
χ
=
V r
( )




∂E
∂N


= −
µ
= −
V r
( )




where V(r) and E are external potential and electronic energy of an N-electron system,
respectively. Softness(S) is a property of molecule that estimates the extent of chemical
reactivity. It is the reciprocal of hardness (η).
S = 1/2η
Using Koopman’s theorem for closed-shell molecules, η, µ and χ can be defined as
The hardness of the molecule η = (I-A)/2
The chemical potential of the molecule µ = - (I+A)/2
The electronegativity of the molecule χ = (A+I)/2
where I and A are the ionization potential and electron affinity of the molecules respectively. The
ionization energy (I) and electron affinity (A) can be expressed by HOMO and LUMO orbital
energies as I = - EHOMO and A = - ELUMO. Electron affinity (A) relate to the efficiency of a ligand
to accept in particular one electron from a donor. The ionization potential I and an electron
affinity A of our molecule MFMSM calculated by B3LYP/6-311G(d,p) method is 6.2477 eV and
1.6573 eV respectively. Considering the chemical hardness, large frontier orbital gap (HOMO–
LUMO) means a hard molecule and small frontier orbital gap (HOMO– LUMO) means a soft
molecule. A molecule with small frontier gap is generally associates with a low kinetic stability
and high chemical reactivity. Parr et al. [118] defined a new descriptor electrophilicity index (ω),
which describes a quantitative classification of the global electrophilic nature of a molecule.
They defined electrophilicity index (ω) as follows:
ω = µ2/2η
Using the above equations, the chemical potential, hardness and electrophilicity index
have been calculated for MFMSM and their values are shown in Table S7 (Supporting
information). The value of this new reactivity quantity has been recently proved in understanding
the toxicity of various pollutants concerning their site selectivity and reactivity [123–125]. The
calculated value of electrophilicity index describes the biological activity of MFMSM.

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The computed self - consistent field (SCF) energy of MFMSM is - 1910.4299 a.u.
Besides lowering in the HOMO and LUMO energy gap make clear the possible charge transfer
interactions that occur within the molecule.
3.10 Molecular electrostatic potential (MEP)
MEP is interrelated to the electronic density and is very valuable descriptor in
understanding locations for electrophilic attack and nucleophilic reactions over and above
hydrogen-bonding interactions [126,127]. Being a real physical property, V(r) can be determined
experimentally by diffraction or by computational methods [128]. To project reactive positions
for electrophilic and nucleophilic attack for MFMSM, MEP was computed by utilizing the
DFT/B3LYP method with using 6-311G(d,p) basis set for the optimized geometry. The red
(negative) regions of MEP were connected to electrophilic reactivity and the blue (positive)
regions to nucleophilic reactivity sites shown in Fig.4. As can be seen in from the Fig.4, the
maximum values of negative and positive regions are – 0.062 and 0.062 a.u. respectively. The
positive region is mainly localized on C2-H2, C26-H26A and C13-H13 bond has a value of
+0.028 a.u, +0.019 a.u. and +0.023 a.u. The negative regions are mainly around O1 and O2
atoms. These outcomes furnish information regarding the region where the compound have intra
or inter molecular interaction and metallic bonding. So, the MEP map confirms the existence of
intra and inter molecular interactions observed in the solid state. These significances obtained in
MEP analysis evidently consistent with the X-ray experimental results given in Table 2.
3.11 Thermodynamic properties
On the basis of Vibrational analysis, the statistical thermodynamic properties for instance
heat capacity at constant pressure (Cpom ), entropy ( Smo ) and the enthalpy changes ( ∆Hmo ) for the
MFMSM have been determined by B3LYP/6-311G(d,p) method in temperature range 100 -500K
and listed in Table S6 (Supporting information) . The values of thermodynamic parameters for
example thermal energy, dipole moment and zero-point vibrational energy of MFMSM by DFT
method with 6-311G(d,p) basis set at 298.15K and 1 atm pressure were computed and listed in
Table S5 (Supporting information). From Table S5, the high value of dipole moment of
MFMSM indicates large charge delocalization, resulting in the formation of charge separated
species, relatively loose structured,.
The correlation graph for the thermodynamic properties with respect to the temperature
(T) in Kelvin unit are plotted and shown in Fig.S7 (Supporting information). When observed
from Fig.S7, it can be seen that these thermodynamic functions are increasing with temperature
caused by the enhancement of the molecular vibrational intensities with temperature. The
relationship between heat capacities, entropies, enthalpy changes with temperatures was fitted by
quadratic formulas and the corresponding fitting factors (R2) for these thermodynamic properties
are 0.99999, 0.99892 and 0.99923, respectively. The corresponding fitting equations are as
follows:
Cpom = 17.147 + 0.34203T + 0.070863 X10-5T2 (R2 = 0.99999)
Smo = 78.972 + 0.44335T – 10.938X10-4T2
(R2 = 0.99892)
∆Hmo = 287.54 + 0.03461T + 1.3246 X10-4T2 (R2= 0.99923)
These equations could be used for further studies on the title compound MFMSM. for
example, when the interaction of MFMSM with another compound is considered, these
thermodynamic properties could be obtained from the above equation and then can be used to
calculate the change.
3.12 Interpretation of antimicrobial activity

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Each zone size is interpreted as a consequence of reference to the Table 2G [129]. Results
recorded that target compound revealed good to moderate antimicrobial activity against preferred
organisms such as Bacillus cerus, Staphylococcus aureus, Staphylococcus epidermidis, Escherichia
coli, Pseudomonas aeruginosa, Acinetobacter baumanni, and Klebsiella pneumoniae with respect to
the standard antibiotic ciprofloxacin (25 µg).
The compound MFMSM displays good antibacterial activity against Bacillus cerus,
Escherichia coli and Acinetobacter baumanni and exhibit moderate activity against Staphylococcus
aureus, Klebsiella pneumonia, Pseudomonas aeruginosa and Proteus vulgaris as shown in Table 6.
Fig.5 explains a bar diagram for the antibacterial activity. Compound under study confirmed a mean
biological activity because of the existence of sulfonamide moiety. Normally, nitrogenated
sulfonamide derivative displayed potent antimicrobial activity [130]. The present study concludes
that the compound reveals good to moderate antibacterial activity against all screened organisms.
The mainly susceptible organisms among fungus were, Candida albicans (30mm) and
Aeromonas hydrophila (28mm) at concentration 75µg/ml of the compound, exhibiting good
antifungal activity against these organisms when compared to other organisms studied, while 50
and 25µg/ml concentrations of the compound exhibited moderate activity ranging from
10-25mm in diameter for about all organisms as shown in Table 7. Fig. 6 explains a bar diagram
for the antifungal activity. The present study concludes that the compound exhibited good to
moderate antifungal activity against all tested organisms.
3.13 Pharmacological investigation Results
Table S7 (Supporting information) gives an idea about the molecular properties
(Molecular weight, miLogP, TPSA and n rotb) of compounds MFMSM and cefuroxime. By
investigating Table S7, the compound MFMSM and cefuroxime were found in agreement with
Lipinski’s rule of five recommendations for novel chemical entity to have good oral
bioavailability with one violation. In MFMSM, the value of miLogP was found to be slightly
higher than five, implying that the molecule will have less permeability across the cell
membrane. The TPSA value for compound MFMSM is lower than 160Å, which authenticates
that the compound is fulfilling the optical requirement for drug absorption. On the other hand,
TPSA value for cefuroxime is 173.77 Å, suggesting less permeability across cell membrane. In
MFMSM, number of hydrogen bond acceptors was within Lipinski’s limit i.e. less than 10 and
number of hydrogen bond donors was also within Lipinski’s limit i.e. less than 5. Number of
rotatable bonds is a simple topological parameter and is an assess of molecular flexibility.
The drug-likeness and toxicity properties for MFMSM and cefuroxime were computed
using OSIRIS property explorer and has been listed in Table S8 (Supporting information).
Colour codes are utilized to value toxicity prediction such as mutagenicity, tumerogenicity, skin
irritancy and reproductive effects. If the compound is not toxic, it is represented by green colour.
Orange and red colour indicates moderate and severe toxicity of the compound, respectively.
From Table S8, it is obvious that the compound MFMSM is toxic in reproductive effect
and the standard drug cefuroxime shows severe mutagenic effect. Both compounds display a
positive value for drugs likeness. The compound MFMSM will have a drug score value of 0.18
which is almost comparable with drug score value of cefuroxime.
The prediction of ADME and Toxicity parameters for the compounds MFMSM and
cefuroxime are shown in Table S9 and Table S10 (Supporting information), respectively. It has
been found that the compound MFMSM will be having better absorption through intestine for

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HIA, better permeability for CaCo-2 cells and slightly low permeability for mdck cells when
compared with standard drug cefuroxime.
BBB penetration is an essential pharmacokinetic property as CNS-active compounds
must pass across it to evade CNS side effects. It is obvious from Table S9, the BBB penetration
capability was expected to have middle absorption to CNS (Central Nervous System) for
MFMSM and poor absorption to CNS for standard drug cefuroxime.The degree of plasma
protein binding (PPB in percentage) of a drug controls on the drug’s action, its disposition and
efficacy. Also, 100% PPB value specifies strong binding to plasma protein for MFMSM and
17.33% PPB value for cefuroxime substantiates a very weak binding to plasma protein.
From Table S10, the standard drug cefuroxime shows positive result for carcinogenicity
prediction in mouse. Alternatively, MFMSM shows negative result for both carcinogenicity
prediction in mouse and rat. Consequently, MFMSM has lower carcinogenic risk than the
standard drug cefuroxime .
On the strength of pharmacological parameters such as drug score, drug-likeness and
ADMET property, MFMSM was look upon as a possible candidate for drug development. Since,
sulfonamide derivatives has already regarded as a good inhibitor of PBP-2X, the compound
MFMSM will be considered as a competent drug candidate for treating contagious disease by
molecular docking studies and binding interactions.
3.14 Molecular docking results
Out of 10 conformations acquired by docking sulfonamide derivative MFMSM into the
active site of penicillin binding protein, the best conformation was chosen depending on the
binding energy. The high score pose was chosen and compared with cefuroxime, which was re-
docked with the target protein by similar protocol. Fig.7 shows the molecular binding mode of
MFMSM and cefuroxime at the binding site of PBP-2X. The ligand-protein interaction of
MFMSM and cefuroxime to PBP-2X binding site is shown in Fig. 8. The hydrogen bond
interactions and binding energy of MFMSM and standard drug cefuroxime on binding with
1QMF protein are given in Table 8.
The docking results implied that MFMSM could compactly occupy the active site of
PBP-2X with binding energy -6.07kcal/mol, compared to −4.58kcal/mol of cefuroxime. Five
hydrogen bond interactions were observed in the 1QMF- MFMSM complex in such a way that
the atom NZ of residue LYS420 has trifurcated hydrogen bond donar interactions with ligand
atoms of O2, O4 and O5 with distances 2.739 Å, 3.471 Å and 2.981 Å, respectively, and the
atom N of residue GLY664 has bifurcated hydrogen bond donar interactions with the ligand
atoms O3 and O1 at a distance of 2.639 Å and 3.27 Å, respectively (Table 8). Also, the residues
GLU695 (CB) and THR665 (CG2) forms sigma-π interactions with formyl phenyl and sulfonyl
bound phenyl rings at a distance of 3.998 Å and 3.846 Å, respectively.
Four hydrogen bond interactions were maintained in the 1QMF- cefuroxime complex.
The O4 and O2 atoms of cefuroxime have hydrogen bond acceptor interactions with the active
residues of LYS420 (NZ). The ASP698 (NH) has one hydrogen bond interaction with atom O3
of cefuroxime. A hydrogen bond donor interaction is viewed between the ligand N13 atom and
the active site residue of ASN735 (OD1) (Table 8). The residue ARG426 (NH2) generates a
cation-π interaction with furan ring at a distance of 6.152 Å.
It is a well known fact that, if the number of interactions is more in the docked complex,
it will enrich the bioactive of the compound. The noteworthy part of the observation is that five
hydrogen bond interactions and two sigma- π interaction were obtained in 1QMF- MFMSM
complex and four hydrogen bond interactions and one cation- π interaction in 1QMF-

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cefuroxime complex. Moreover, the docked 1QMF-MFMSM complex has comparatively better
binding energy -6.07kcal/mol than the binding energy −4.58kcal/mol of 1QMF- cefuroxime
complex. In addition, hydrogen bond interactions of MFMSM have explained favorable
interactions with active site residues. As a result, the compound MFMSM may be deemed as a
budding and capable inhibitor of PBP-2X.
4. Conclusion
Methyl(2E)-2-{[N-(2-formylphenyl)(4-methylbenzene)sulfonamido]methyl}-3-(2-
methoxyphenyl)prop-2-enoate has been synthesized and grown as single crystals by slow
evaporation solution growth technique. They were characterized by FTIR, NMR and X-ray
1
single crystal diffraction. The geometric parameters, vibrational frequencies, H NMR and 13C
NMR chemical shifts of MFMSM have been computed using density functional theory method
with 6-311G(d,p) as basis set, and are in good agreement with the experimental results. NBO
analysis result shows that electron density(ED) in the π* and σ* antibonding orbitals and second
order delocalization energies E(2) prove the occurrence of intramolecular charge transfer (ICT)
within the molecule and causing stability of the molecule. Since, the calculated first order
hyperpolarizability was found to be 6.8 times greater than that of standard NLO material urea,
MFMSM is a good candidate as second order NLO material. The obtained Mulliken atomic
charges of the MFMSM suggests that the presence of large negative charge on N1, O5, O2and
net positive charge on H7, H17, H13 atoms may confirm the formation of C7-H7…N1,
C17-H17…O5 and C13-H13…O2 intra molecular interaction in solid state. The lowering of the
HOMO-LUMO energy gap value has extensive influence on the intra molecular charge transfer
and bioactivity of the molecules. The MEP map verifies the existence of an intermolecular
C2-H2…O1 and C26-H26A…Cg2 interaction. Molecular docking of the title compound is also
reported due to the different biological activity of MFMSM. Therefore, we hope the results of
this present study will facilitate researchers to explore and synthesize of new sulfonamide
derivatives.
Acknowledgment
The authors thank Dr. Shibu M. Eapen, SAIF, Cochin University of Science and Technology, for
the single-crystal XRD measurements.
Supplementary Materials
CCDC 1471011 contains the supplementary crystallographic data for this paper. This data can
be obtained free of charge at http://www.code.cam.ac.uk/data_request/cif, by e-mailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB21EZ, UK; fax: +44(0)1223-336033.
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Figure caption
Scheme 1. Synthetic strategy of MFMSM
Fig. 1. (a) The theoretical optimized geometric structure of MFMSM(B3LYP/6-311G (d,p)
level). (b) View of MFMSM showing the atom-numbering scheme. Displacement ellipsoids for
the non-hydrogen atoms are drawn at the 20% probability level. Hydrogen atoms are presented
with spheres with arbitrary radii.
Fig. 2. Part of the crystal structure showing C–H…π intermolecular hydrogen bonds generating
[110] ladder network [symmetry code: i = 1+x, 1+y, z].
Fig. 3. The molecular orbitals and energy levels for the HOMO and LUMO of MFMSM.
Fig. 4. Molecular electrostatic potential map calculated at B3LYP/6-311G (d,p) level.
Fig. 5. A bar diagram for the antibacterial activity of MFMSM.
Fig. 6. A bar diagram for the antifungal activity of MFMSM.
Fig. 7. Binding mode of (a) MFMSM and (b) cefuroxime at the binding site of PBP-2X.
Fig. 8. Interaction of (a) MFMSM and (b) cefuroxime to PBP-2X binding site
Supplementary Figure caption
Fig. S1. Atom-by-atom superimposition of the calculate structure (red) on the experimental
structure (blue) for MFMSM.
Fig. S2. Theoretical (Top) and experimental (Bottom) FT-IR spectra of MFMSM.
Fig. S3. Correlation graph between experimental and calculated wave number at B3LYP level.
Fig. S4. Experimental spectrum of 13C NMR of MFMSM.
Fig. S5. Experimental spectrum of 1H NMR of MFMSM.
Fig. S6. Correlation graph between the experimental and theoretical 13C NMR chemical shift
values of MFMSM.
Fig. S7. Correlation graphic of heat capacity, entropy, enthalpy at different temperature for
MFMSM.
Table caption