Combined experimental and theoretical studies on the chemical and spectroscopic properties of an antimicrobial N-(Phenyl)dimethyldisulfonimide

Article abstract of DOI:10.1016/j.molstruc.2018.08.013

A disulfonimide derivative, N-(phenyl)dimethyldisulfonimide, was synthesized by two-step sulfonation of aniline with methane sulfonyl chloride. Antimicrobial activity of the molecule was investigated against some bacteria and fungus species by using the m

Full text of DOI:10.1016/j.molstruc.2018.08.013

Accepted Manuscript
Combined experimental and theoretical studies on the chemical and spectroscopic
properties of an antimicrobial N-(Phenyl)dimethyldisulfonimide
Bilge Eren, Arslan Ünal, Fadime Özdemir-Koçak
PII:
S0022-2860(18)30958-X
10.1016/j.molstruc.2018.08.013
MOLSTR 25534
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 9 February 2018
Revised Date: 27 July 2018
Accepted Date: 5 August 2018
Please cite this article as: B. Eren, A. Ünal, F. Özdemir-Koçak, Combined experimental
and theoretical studies on the chemical and spectroscopic properties of an antimicrobial
N-(Phenyl)dimethyldisulfonimide, Journal of Molecular Structure (2018), doi: 10.1016/
j.molstruc.2018.08.013.
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Graphical Abstract

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Combined experimental and theoretical studies on the chemical and spectroscopic
properties of an antimicrobial N-(Phenyl)dimethyldisulfonimide
Bilge Erena, Arslan Ünalb, *, Fadime Özdemir-Koçakc
a Department of Chemistry, Science and Arts Faculty, Bilecik Seyh Edebali University, 11210
Bilecik, Turkey.
b Department of Physics, Science and Arts Faculty, Bilecik Seyh Edebali University, 11210
Bilecik, Turkey.
c Department of Nursing, School of Health, Bilecik Seyh Edebali University, 11210 Bilecik,
Turkey.
*Corresponding Author. Tel.: +90-228-214-1479; Fax: +90-228-214-1162;
E-mail address: arslan.unal@bilecik.edu.tr (A. Ünal)
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ABSTRACT
A disulfonimide derivative, N-(phenyl)dimethyldisulfonimide, was synthesized by two-step
sulfonation of aniline with methane sulfonyl chloride. Antimicrobial activity of the molecule
was investigated against some bacteria and fungus species by using the microdilution method.
To evaluate the structure-activity relationship, antimicrobial activity test of the two related
sulfonamide derivative was also performed under same conditions. Results showed that the
title disulfonimide have remarkable antibacterial and antifungal activities compared to
sulfonamides tested. The structural characterization of the molecule was performed by using
quantum chemical calculations, single crystal X-ray diffraction, IR and NMR spectroscopies.
Density functional method (DFT) at B3LYP/6-311++G(d,p) theory level was used to
determine some characteristics of the compound such as, relative energies, molecular
geometry, vibrational wavenumbers, frontier molecular orbitals, atomic charges and gauge
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including atomic orbitals (GIAO), H and C-NMR chemical shifts. The crystal structure of
the title compound is monoclinic system. Conformational analysis studies showed that the
molecule has two stable conformers C1 and C2. According to the calculated relative energies
in the gas phase C1 conformer in C1 symmetry is the most stable one. However, X-ray, IR and
NMR values are more compatible with the C1 conformer in C2 symmetry in solid phase.
Keywords: N-(Phenyl)dimethyldisulfonimide; X-ray; IR; DFT; antimicrobial activity.
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1. Introduction
Sulfonamides are important compounds in the area of chemistry and pharmacology. They
known as sulfa drugs since the member of them prontosil, were discovered as the first
antimicrobial agent [1]. Several sulfonamides have been used as pharmacological agent for
their antibacterial [2,3], antifungal [4], antimalarial [5], antitumor [6], hypoglycemic [7],
effects for many years. Some of their derivatives are known with their corrosion inhibition [8]
or carbonic anhydrases (CA) inhibition [9] properties. They are also used in industrial
applications as non-ionic photoacid generators for photo(nano)lithography on sol–gel
materials [10] and utilization of excess of sulfonylating agent [11].
The title compound is one such organic structure that belongs to the disulfonimide group.
Disulfonimides having two sulfone group connected to the nitrogen atom are also used in
medicine for their antitumor effects and CA inhibitory properties [12]. Some complexes of
chiral disulfonimides were used as catalysts in the asymmetric synthesis [13].
Literature survey has revealed that the DFT calculations using B3LYP method has a great
accuracy in reproducing the experimental values in geometries, dipole moments, vibrational
frequencies, optical properties and molecular electrostatic potentials of organic compounds
[14-22]. Antimicrobial activity, crystal structure parameters and DFT calculation of the title
compound have not been reported in the literature yet. In the present study, N-
(phenyl)dimethyldisulfonimide common named compound -the IUPAC nomenclature N-
(methylsulfonyl)-N-phenylmethanesulfonamide- was synthesized and characterized by using
1
single-crystal X-ray diffraction, FT-IR, 13C and H NMR spectroscopies. Antibacterial
activity of the title disulfonimide was investigated against some bacteria and fungus species
and was compared with those of methanesulfonamide (MSA) and methanesulfonanilide
(MSAN). Theoretical data of the stable two conformers was determined by conformational
analysis using DFT/B3LYP/6-311++G(d,p) theory and were compared with experimental
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spectroscopic data. The vibrational modes were assigned according to literature and compared
with DFT results. Frontier molecular orbitals (FMO), and natural bond orbitals (NBO)
analysis of the molecule were also carried out using same theory. The structural properties
and spectroscopic findings determined in the present work are valuable in order to rule
chemical behavior of the title compound. Also, the results of this study will provide
information about reaction site, structure-activity relationship (SAR) and the probable
biological action mechanism of this kind of important molecules.
2. Experimental
2.1. Instruments
The IR spectrum of the title compound was recorded in 4000-500 cm-1 region with a
Spectrum-100 Frontier spectrometer. The 1H and 13C-NMR spectra were recorded on a Varian
Mercury 300 MHz NMR spectrometer using tetramethylsilane (TMS) as an internal standard
and DMSO-d6 as solvent. Single crystal X-ray data were collected by a Bruker Kappa
APEXII CCD area detector diffractometer using Mo Kα radiation (0,489 mm-1) at T = 293(2)
K.
2.2. Synthesis of N-(Phenyl)dimethyldisulfonimide
The synthetic procedure of N-(Phenyl)dimethyldisulfonimide (C8H11NO4S2) includes
two step sulfonation of aniline with methane sulfonyl chloride [23]; 100 mmol aniline was
dissolved with 20 ml benzene in a reaction flask fitted with a reflux condenser. The solution
of methane sulfonyl chloride (50 mmol) in 15 ml benzene was dribbled from a dropping
funnel and into the aniline solution slowly with stirring. The reaction mixture was refluxed for
two hours. The reaction was terminated and the solvent was evaporated under reduced
pressure. The product was purified by Hinsberg method including base and acid treatment
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respectively in order to obtain methane sulfonanilide as white solid (5.32 g, yield 62 %, m.p.
93-96 °C). Next, the solution of methane sulfonanilide (20 mmol) in 30 ml benzene was
prepared in a reaction flask and threatened with 30 ml benzene solution of the methane
sulfonyl chloride (20 mmol). Potassium tert-butoxide (25 mmol) and catalytic amounts of 18-
crown-6 were added into the reaction mixture in portions, respectively. The system obtained
was refluxed for 3 hours. The reaction was terminated and the solvent was evaporated under
reduced pressure. The crude product was threatened with 20 wt. % NaOH solution to remove
methane sulfonanilide. The solids were collected by suction, washed with DI water and dried
(2.79 g, yield 56%, m.p. 198-200 °C). The product was recrystallized from acetone/water
until the single crystals suitable for X-ray analysis were obtained. The synthesis procedure of
N-(phenyl)dimethyldisulfonimide is shown in Scheme 1.
2.3. X-ray Crystallography
A suitable colorless block-shaped crystal with the size of 0.36 mm x 0.25 mm x 0.11 mm
was used for the crystallography. The measurements of diffraction were carried out at 293(2)
K using graphite monochromated Mo Kα radiation (0,489 mm-1) in ω-scanning mode. See
supplementary material (Table S1) for details of the data collection conditions and parameters
of refinement process.
2.4.Microbial strains and in vitro antimicrobial activity screening
Gram positive bacteria Bacillus cereus ATCC 7064, Staphylococcus aureus ATCC
25923, Gram negative bacteria Escherichia coli ATCC 25922, Pseudomonas aeruginosa
ATCC 27853 and fungus Aspergillus parasiticus NRRL 1957, Candida albicans ATCC
10231 were used in antimicrobial activity studies.
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Minimal inhibitory concentrations (MICs) of the compounds against tested strains
have been monitored by using a broth microdilution method in 96 multi-well microtitre plates
[24-26]. Test strains were incubated in Mueller Hinton broth for 24 h and turbidity of prepared
suspensions has been standardized to 0.5 McFarland. Samples are diluted and dissolved in
dimethyl sulphoxide. We have prepared in which was 96 well microtitre plates that a serial
double dilution of the sample using method of Sarker et al. [25] The stock concentration was
10 mg/ml. The lowest concentration of the compound that inhibited visible growth was
assigned as the MIC value. In order to determine minimal bactericidal concentration (MBC),
the broth was taken from each well which has no visible growth. Then, it was inoculated in
Mueller Hinton agar for 24 hours at 37 °C. The lowest concentration of the tested compound
that killed 99.9% of microorganisms was defined as the MBC value. Tests were repeated for
three times.
3. Calculations
Conformational analysis of the title molecule required to obtain potential energy surfaces
(PESs) at first. The PES of the molecule was obtained by MOPAC2002 geometry
optimization using semi-empirical PM5 Hamiltonian within Fujitsu CAChe WS Pro v.7.5.0
Windows software package [27] on a personal workstation for the possible stable structures of
the title molecule. The torsion angles τ1(C2C1N1S1), τ2(C1N1S1C5) and τ3(N1S1C5H) were
changed by 3°. The adequate nineteen structures whose heat of formation energy (ꢀH) values
were greater than -128.54 kcal/mol were then selected.
By means of Becke’s three-parameter exchange functional [15] and the Lee–Yang–
Parr correlation functional [28] (B3LYP) method with 6-311++G(d,p) basis set, the Gaussian
03W program package [29] was used to examine local minima or transition states on the PES
through geometric optimization and vibrational frequency analysis of the selected structures.
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It was found from the geometry optimization and vibrational frequency analysis computations
that the title molecule has two stable conformers (C1 and C2) which are adopted C1 and C2
point groups containing no symmetry element.
Adequate point groups C1 and C2 were considered and the stability of each conformers
were tested at the same level of theory before calculating vibrational and NMR data of the
conformers. The vibrational wavenumbers were calculated with B3LYP/6-311++G(d,p) and
then scaled by using the scaling factors for nine primitive coordinates proposed by Alyar et al.
[21]. The assignments of each vibrational mode were defined from their potential energy
distributions (PED). The scaling factors were not applied to the infrared and Raman
intensities. Stable three conformers of the title molecule were reoptimized with B3LYP/6-
311++G(d,p) in DMSO-d6 for the NMR calculations using the integral equation formalism
polarizable continuum model (IEFPCM) method [30,31]. 1H and 13C NMR isotropic shielding
tensors of the title compound were calculated by GIAO method [32,33] in DMSO-d6 with the
same theory as implemented in Gaussian 03W. A linear relationship suggested by Alyar et al.
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1
[21] was used to change isotropic shielding tensors of C and H into chemical shifts. Main
atomic charges of non-hydrogen atoms using the natural population analysis (NPA) and
frontier molecular orbitals were obtained at the same level of theory.
4. Results and discussion
4.1. Stability of the conformers
The results of the computations have clearly demonstrated that the title molecule has two
possible stable conformers at room-temperature in gas phase. The relative energies calculated
at B3LYP/6-311++G(d,p) theory level for these possible stable conformers is shown in Table
1. The table points out that the C1 conformer in C1 symmetry is the most stable conformer at
room temperature in gas phase among the others taking into account the energies along with
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the population factors values. However, the crystallographic and vibrational spectral analysis
results are more compatible with the C1 conformer in C2 symmetry in solid phase. For this
reason, the crystal form of title molecule should be in Conformer 1 with C2 symmetry in solid
phase due to the crystal packing.
4.2. Geometrical Structure
Geometrical parameters of the title molecule determined with X-ray and B3LYP/6-
311++G(d,p) are listed in Table 2. The structure of the conformers C1, C2 and X-ray structure
of the title molecule are shown in Fig. 1.
The crystal of the title compound is monoclinic in shape with space group of C2/c and has
four molecules in the unit cell. According to obtained experimental X-ray results, The
molecule composed of two methylsulfonyl groups and an aniline ring. The position of the
benzene ring and the methylsulfonyl group with each other can be deduced from the torsion
angle at the junction, C2-C1-N1-S1. It is found to be -94.3(4)° that indicates methylsulfonyl
groups are nearly at the same region with π-bonds of the benzene ring. Three sigma bonds
attached to nitrogen are nearly coplanar because, the bond angles C1-N1-S1, C1-N1-S1i and
S1-N1-S1i are 119.3(3)°, 119.3(3)°, 121.4(6)° , respectively.
The S=O and S-N bond lengths are in the expected size. In the molecule S1-O1 and amine
S1-N1 bond distances are 1.421(7) Å and 1.675(5) Å respectively. These bond lengths are
compatible with values of ethanesulfonamide-N,N’-pentamethylenebis [1.431(4) and 1.618(4)
Å)] [34], and 4-methyl-N-(naphthalene-1-yl)benzene sulfonamide [1.427(2) and 1.626] [35].
4.3. Infrared Spectrum
The vibrational assignments of the title compound in comparison with the calculated
data of Conformer1 in C2 symmetry was listed in Table 3. The FT-IR spectrum of the title
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compound was also seen in Fig. 2. The aromatic structure shows a couple of C-H stretching
modes (3073, 3060, 3033 cm-1) in the region 3100-3000 cm-1 which is the characteristic
region for the ready identification of C-H stretching vibrations [36, 37]. The aromatic C-H in-
plane bending modes of benzene and its derivatives are observed as weak intensity peaks in
the region 1300-1000 cm-1 in the vibrational spectra. The C-H out-of-plane bending vibrations
occur in the range 1000-750 cm-1 in the aromatic compounds [21, 38, 39]. The weak or
medium bands occur at the spectrum of the compound at 991 and 942 cm-1 are assigned to C-
H out-of-plane bending modes. Also, the bands observed at 1165 and 1079 cm-1 in are
assigned to aryl C-H in-plane bending vibrations for the compound. In general, the calculated
aromatic C-H vibrations (stretching, in-plane and out-of-plane bending) are in good
agreement with experimentally expected values given in literature [36-41]. The C-H
asymmetric and symmetric stretching vibrations of the CH3 group are seen at 3013 and 2932
cm-1 as expected.
When evaluated in terms of SO2 vibrations, the asymmetric and symmetric SO2
stretching vibrations appear in the range 1330±30 cm-1 and 1160±30 cm-1, both with strong
intensity [42, 43]. The asymmetric stretching mode was recorded at 1345, 1328 cm-1, while
the symmetric mode was obtained at 1155 cm-1. These are the strongest peaks at the defined
region from the literature. These vibrations were calculated by B3LYP/6-311++G(d,p) at
1346, 1329 cm-1 for asymmetric stretching and 1155 cm-1 symmetric stretching with excellent
consistency.
The aromatic carbon-carbon stretching vibrations generally occur in the region of
1625-1430 cm-1. The bands are variable in intensity and observed at, 1625-1590, 1590-1575,
1540-1470, 1460-1430 and 1380-1280 cm-1 wavenumbers ranges for the five bands in the
region [21, 39]. The bands observed in the FT-IR spectrum of the title compound at 1593,
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1484, and 1458 cm-1 were assigned to aromatic C-C stretching vibrations. These bands were
calculated by B3LYP/6-311++G(d,p) at 1608, 1487, and 1448 cm-1.
The assignments of the C-N stretching wavenumbers were made from analogy with
the similar molecules in the literature [36, 39, 44]. The peaks observed at 1224 and 1210 cm-1
are attributed to the C-N stretching vibrations. The S-N stretching vibration exhibits a
medium band in the range 905±70 cm-1 [42]. The infrared studies of some arylsulfonamide
[45] and N-aryl-methanesulfonamide derivatives [46] are also assigned in the region of, 924-
906 cm-1 and 926-833 cm-1. The bands occur at the spectrum of the title compound at 926 (m)
and 887 cm-1(s) are assigned to S-N stretching vibration. The assignment of the C-S stretching
vibrations are difficult, due to masking or mixing by the bending modes easily. Despite this,
789-740 cm-1 region was reported for C-S stretching vibrations of some methanesulfonamide
derivatives [46]. The bands observed at 762 (s) and 749 cm-1 (m) were assigned to C-S
stretching vibration. As shown in the Table 3, considering the vibrational frequencies the
results of B3LYP method have exhibited better coherence with the experimental ones in
general.
4.4. NMR Spectra
The 13C and 1H NMR spectra of the title molecule in DMSO-d6 are shown in Fig. 3. The
experimental 13C and 1H NMR chemical shifts (ppm) together with the calculated data for the
stable conformers of the title compound are given in Table 4. The table apparently shows that
calculated data for C1(C2) are almost compatible with the experimental data.
The singlet signal at the highest field (3.50 ppm) accounting for six protons was easily
assigned to equivalent protons of the two methyl groups (H-C5 and H-C5i). Aromatic protons
of the benzene ring appeared together as a singlet signal at 7.49 ppm. The peak at 43.42 ppm
calculated as 48.72 ppm for C1(C2) is certainly belongs to methyl group (C5 and C5i) which
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is the single aliphatic carbon atom in the structure. The assignments of the experimental C
NMR signals of the benzene ring were made from analogy with aniline [47] and N-substituted
aniline rings [44,48]. The weak signal at the lowest field (134.36 ppm) was assigned to
quaternary C1 carbon which was connected to the electronegative nitrogen atom. The strong
peak 131.37 ppm assigned to C2 and C2i carbons of the benzene ring which are both in the
same environment. However, by B3LYP, C1 and C2 carbons were calculated as 132.68 ppm
and 134.15 ppm, respectively. The reason for this was thought to be the spatial interactions
between the electronegative oxygen atoms of sulfonyl groups and C2 carbons. As shown in
Table 5, all the other carbons in the benzene ring appear at the expected regions and in
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accordance with the calculated data for C1(C2) Consequently, the experimental H and C
spectra data also support the structure of the title compound and the reported values [44, 47,
48].
4.5. Molecular electrostatic potential (MEP) and natural population analysis
MEP maps give information about the electronic density distribution. So that it is very
beneficial tool in defining the regions of a molecule for an electrophilic and a nucleophilic
attack in the reactions [49, 50]. MEP plot of the molecule obtained by the B3LYP/6-
311++G(d,p) method was shown in Fig. 4. Additionally, main atomic charges (i.e. the charges
on non hydrogen atoms computed by natural population analysis) were calculated at the same
theory level and were given in Table 5. Fig. 4 shows that the negative (red) regions in the
plots is about to electrophilic attack and the positive (blue) ones to nucleophilic attack in a
reaction for the title molecule. The nitrogen atom and oxygen atoms of the sulfon groups
carry the negative charges with a maximum value of -0.043 a.u. On the other hand, the methyl
groups has the positive charges as shown in MEP plots. The atomic charges indicated that the
possible site for an electrophilic attack is the nitrogen atom with a maximum value of NBO
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charge (-0.993 e). These results provide information concerning the region where the
compound can interact with another molecule or a metal. Also, it confirms the absence of a
certain inter-molecular H-bonding between the molecules of the title molecule. As given in
Table 5. sulfur atoms S1 and S1i are the most possible sites for a nucleophilic attack on the
the title molecule. The common atoms in the isomers such as N1, O1, O1i, O2 and O2i has
richly negative charges contributing the bioactivity according to atomic charge distributions
[20].
4.6. Frontier molecular orbitals (FMOs)
FMOs could provide valuable information to determine molecular dynamics and
describing the chemical transformations [51]. FMOs with the frontier electron density are also
important tools for estimating the most reactive region of a molecule and explaining many
reactions including conjugated systems. The value of the highest occupied molecular orbital
(HOMO) energy of a molecule identifies the capacity of donating an electron and lowest
unoccupied molecular orbital (LUMO) energy identifies the capacity of accepting an electron.
The difference between HOMO and LUMO energies is a crucial factor for defining the
optical properties [52], molecular chemical stability [51] and biological activity [20]. The
energies of the FMOs of tautomers: HOMO, HOMO-1, LUMO and LUMO+1 were calculated
by B3LYP/6-311++G(d,p). The energy levels and distributions of the FMOs for the tautomers
are given in Table 6. The schemes of the FMOs are shown in Fig. 5. The figure clearly shows
that both of the HOMO and LUMO are generally delocalized on nearly all the atoms of the
molecule. The HOMO-1 and LUMO+1 are comparatively localized on the benzene ring. The
majority of the both of the FMOs are p-antibonding-type orbitals. The energy difference
between HOMO and LUMO is determined about 6 eV for the both tautomers C1 and C2. This
value indicates that the title molecule has chemical stability and prone to have biological
reactivity.
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4.7 Antibacterial and antifungal properties
Antimicrobial activity results of the title disulfonimide in comparison with MSA
(Methane sulfonamide) and MSAN (Methanesulfonanilide) against some clinical type strains
in terms of MIC and MBC were given in Table 7. The MIC values determined in the range of
500-1000 µg/ml clearly showed that the title disulfonimide has considerable capability of
inhibiting the metabolic growth of tested microorganisms even more than tested
sulfonamides. The sulfonamides MSA and MSAN can inhibit the metabolic growth of
microorganisms at the concentrations of 2000 µg/ml and higher. On the other hand MBC
values of the title disulfonimide on aforementioned species was determined between the dose
of 1000-2000 µg/ml. The corresponding values of MSA and MSAN measured as higher than
2000 µg/ml.
The remarkable activity was observed by the title disulfonimide against S. aureus
(MIC=500 µg/ml) and C. albicans (MIC=500 µg/ml). It was equally effective against A.
parasiticus, E. coli, B. cereus and P. aeroginosa (MIC= 1000 µg/ml). This value is also at the
level that can be considered well.
Obviously as indicated in the literature antimicrobial activity of the title disulfonimide
may easily be attributed to the sulfonamide pharmacophore (-SO2N-) [1-4]. The sulfonamide
mechanism of effect was explained before by replacing with PABA (p-aminobenzoic acid)
owing to its structural similarity and inhibiting the folic acid biosynthesis of the
microorganism. Whereas several factors have influence on the bioactivity of sulfonamide
derivatives. Molecular dynamics, electronic and steric factors, groups which increase
hydrophobic character and liposolubility that enhances the biological absorbance, structural
factors increase the dipolarity of S=O bond etc. [4]. In the present work the title disulfonimide
having two sulfone groups is more active against both bacteria and fungus comparing to
MSAN. This finding supports that sulfone group is the fundamental component which
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responsible from bioactivity. At the disulfonimide molecule two sulfone group is attached to
the same nitrogen and are sterically interact with each others. This can also affect the
dipolarity of S=O bond and increase the activity. Different than the other two molecule, MSA
is sterically small molecule and lacks the hydrophobic phenyl ring. Relating to this molecule
low liposolubility that reduces the biological absorbance is thought to cause a decrease in the
bioactivity. As can be seen that valuable findings regarding to structure-activity relationship
of that kind of molecules was introduced by the antimicrobial activity studies.
5. Conclusion
N-(Phenyl)dimethyldisulfonimide, was synthesized and analyzed by experimental and
1
theoretical methods. The single-crystal X-ray diffraction, FT-IR, 13C and H NMR
spectroscopies and DFT/B3LYP/6-311++G(d,p) calculations were performed for the
molecular characterization. X-ray results show that the crystal of the title compound was in
the monoclinic form. Conformational analysis studies showed that the molecule has two
stable conformers C1 and C2 which are adopted C1 and C2 point groups. According to the
calculated relative energies in the gas phase C1 conformer in C1 symmetry is the most stable
one in gas phase. However, X-ray, IR and NMR values are more compatible with the C1
conformer in C2 symmetry in solid phase. There was well consistency with the experimental
and theoretical structural parameters, FT-IR and NMR data for C1(C2) of the title molecule.
The antimicrobial screening of the title disulfonimide in comparison with MSA and MSAN
was performed against some bacteria and fungus species. The result showed that the title
disulfonimide have remarkable antibacterial and antifungal activities compared to tested
sulfonamides. It is particularly effective against S. aureus (MIC=500 µg/ml) and C. albicans
(MIC=500 µg/ml). Also, the necessity of the sulfon group and lipophilicity for the
antimicrobial activity of a sulfonamide derivative is clear. As another criteria to understand
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the impact of the structural and biological properties, main atomic charges, molecular
electrostatic potential (MEP) and energies of the frontier molecular orbitals (FMOs) HOMO,
HOMO-1, LUMO, LUMO+1 were determined at B3LYP/6-311++G(d,p) theory level. The
electrostatic dynamics and molecular orbital energies was also indicating the stability and
biological reactivity of the title disulfonimide.
Acknowledgement
This study was supported financially by Bilecik Seyh Edebali University (project No: 2013-
01-BİL.04-03). CCDC 939032 contains the supplementary crystallographic data (excluding
structure factors) for the structure reported in this article. These data can be obtained free of
charge via http://www.ccdc.cam.ac.uk/data request/cif, by e-mailing or by contacting The
Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax:
+44 1223 336033.
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ACCEPTED MANUSCRIPT
Scheme and Figure Captions
Scheme 1. Synthesis of N-Phenyl-N,N-dimethylsulfonimide
Fig. 1. The molecular structure of N-(Phenyl)dimethyldisulfonimide: (a) Conformer1,
calculated; (b) Conformer2, calculated; (c) XRD, experimental.
Fig. 2. The ATR-IR spectrum of N-(Phenyl)dimethyldisulfonimide.
Fig. 3. The NMR spectra of N-(Phenyl)dimethyldisulfonimide in DMSO-d6: (a) 13C; (b) 1H.
Fig. 4. Molecular electrostatic potential (MEP) map plotted on the surface of N-
(Phenyl)dimethyldisulfonimide with an isodensity value of 0.0004 a.u. calculated at the
B3LYP/6-311++G(d,p) theory level.
Fig. 5. HOMO-1, HOMO, LUMO and LUMO+1 molecular orbital surfaces for the
conformers of N-(Phenyl)dimethyldisulfonimide. The positive phase is red and the negative
phase is green.
Table Captions
Table 1. The selected molecular properties of the possible stable conformers of N-
(Phenyl)dimethyldisulfonimide at DFT-B3LYP method with 6-311++G(d,p) basis set.
Table 2. The experimental geometrical parameters of N-(Phenyl)dimethyldisulfonimide and
comparison with calculated data of the conformers at B3LYP/6-311++G(d,p) theory level.
Table 3. The experimental vibrational assignments of N-(Phenyl)dimethyldisulfonimide and
comparison with the calculated data of Conformer1 (C2).
1
Table 4. The experimental 13C and H NMR chemical shifts (ppm) together within the
calculated data for the conformers of N-(Phenyl)dimethyldisulfonimide in DMSO-d6.
Table 5. NBO charges (in e) for the conformers of N-(Phenyl)dimethyldisulfonimide.
Table 6. Energy (in eV) of frontier molecular orbitals for the conformers of N-
(Phenyl)dimethyldisulfonimide.
Table 7. The antimicrobial activity of N-(Phenyl)dimethyldisulfonimide in comparison with
MSA and MSAN against some clinical type strains in terms of MIC and MBC.
23

ACCEPTED MANUSCRIPT
Table 1. The selected molecular properties of the possible stable conformers of N-
(Phenyl)dimethyldisulfonimide molecule at DFT-B3LYP method with 6-311++G(d,p) basis set.
DFT/B3LYP/6-311++G(d,p)a
Conformers
Ni
(%)
µtotal
(Debye)
1.563
1.624
6.119
∆Etotal
kcal/mol kcal/mol
0.044
-
4.140
∆E0
δ∆G
kcal/mol
-
0.451
4.359
Symmetry
C1
C1
C2
C1
C2
C1
-
68.18
31.82
0.00
0.020
4.042
a
The relative energies of the conformers were given in respect to the total electronic energy (Etotal), zero point
corrected total energy (E0) and Gibbs free energy (∆G). Ni, is the Boltzmann weighting factors for population
analysis.

ACCEPTED MANUSCRIPT
Table 2. The experimental geometrical parameters of N-(Phenyl)dimethyldisulfonimide and comparison with
calculated data of the conformers at B3LYP/6-311++G(d,p) theory level.
DFT/B3LYP/6-311++G(d,p)
Parametera
Exp.
C1(C2)
C1 (C1)
C2 (C1)
Bond length (Å)
C1-C2
C2-C3
C3-C4
C1-N1
S1-N1
S1-O1
S1-O2
C5-S1
1.395
1.392
1.394
1.441
1.735
1.455
1.459
1.798
1.396
1.392
1.394
1.443
1.732
1.454
1.459
1.799
1.397
1.392
1.395
1.448
1.739
1.456
1.461
1.802
1.378(10)
1.385(13)
1.369(12)
1.443(13)
1.675(5)
1.421(7)
1.418(7)
1.738(11)
Bond angle (º)
C1-C2-C3
C2-C3-C4
C3-C4-C3i
C2-C1-C2i
C2-C1-N1
C2i-C1-N1
C1-N1-S1
C1-N1-S1i
N1-S1-O1
N1-S1-O2
O1-S1-O2
N1-S1-C5
O1-S1-C5
O2-S1-C5
S1-N1-S1i
119.67
120.09
120.06
120.42
119.79
119.79
120.08
120.08
105.77
106.91
120.87
104.29
108.97
108.77
119.84
119.66
120.08
120.06
120.44
120.54
119.02
119.36
119.33
105.87
106.21
120.95
105.08
108.94
108.65
119.63
119.79
119.93
120.09
120.52
117.90
121.58
116.60
114.68
105.78
111.64
120.44
100.42
105.78
111.64
118.43
118.6(9)
120.3(9)
120.5(12)
121.6(11)
119.2(5)
119.2(5)
119.3(3)
119.3(3)
105.4(4)
107.3(4)
119.5(5)
104.1(4)
109.6(5)
109.8(5)
121.4(6)
Torsion angle (º)
C1-C2-C3-C4
C2-C3-C4-C3i
C2i-C1-C2-C3
N1-C1-C2-C3
C2-C1-N1-S1
C2i-C1-N1-S1
C2-C1-N1-S1i
C2i-C1-N1-S1i
O1-S1-N1-C1
O2-S1-N1-C1
C5-S1-N1-C1
O1-S1-N1-S1i
O2-S1-N1-S1i
C5-S1-N1-S1i
-0.40
0.20
0.20
-179.80
-102.83
77.17
-0.46
0.34
0.11
-179.77
-96.32
83.35
0.01
0.25
-0.48
-2.0(13)
1.0(6)
1.0(6)
-179.70
-114.81
65.98
100.50
-78.72
179.09
-48.12
66.10
-179.0(6)
-94.3(4)
85.7(4)
85.7(4)
-94.3(4)
-22.4(4)
-150.7(4)
92.9(4)
157.6(4)
29.3(4)
-87.1(4)
77.17
68.82
-102.83
-11.53
-141.55
103.33
168.47
38.45
-111.51
-26.10
-155.85
89.11
168.81
39.06
-37.57
95.15
-150.56
-76.67
-75.98
a Coordinate descriptions are carried out by the numbers in Fig. 1.

ACCEPTED MANUSCRIPT
Table 3. The experimental vibrational assignments of N-(Phenyl)dimethyldisulfonimide and comparison with
the calculated data of Conformer1 (C2).
ATR-IR
(cm-1)
Unscaled wavenumber
(cm-1)
3061
3052
3046
3027
2931
1608
1487
1448
1417
1414
1346
1329
1298
1208
1208
1168
1155
1080
1033
991
Scaled wavenumber
(cm-1)
3197
3188
3183
3162
3062
1626
1520
1481
1463
1460
1326
1307
1324
1221
1221
1195
1117
1101
1048
1003
990
IR Intensity Assignment a
(km.mol-1)
3073 vw
3060 vw
3033 vw
3013 vw
2932 vw
1593 vw
1.3
7.6
7.4
0.7
3.8
νC-H, aromatic
νC-H, aromatic
νC-H, aromatic
νasC-H, methyl
νsC-H, methyl
νC=C
1.9
1484
1458
1421
1413
w
w
w
w
30.0
5.3
νC=C
νC=C
4.6
4.5
δasC-H, methyl
δasC-H, methyl
νasS-O
νasS-O
δsC-H, methyl
νC-N
νC-N
δC-H, aromatic
νsS-O
δC-H, aromatic
νsC=C=C
1345 vs
342.0
151.4
2.7
15.8
15.8
0.9
267.9
15.7
8.7
1328
1284
1224
1210
s
w
w
w
1165 s sh
1155 vs
1079
1029
991
979
964
942
926
887
762
749
693
662
w
w
w
m
w
m
m
s
6.6
33.3
0.2
19.7
30.8
166.0
65.1
70.0
35.7
0.2
γC-H, aromatic
C-H rock, methyl
C-H rock, methyl
γC-H, aromatic
νS-N
νS-N
νC-S
νC-S
γC=C=C
977
967
938
914
834
735
723
698
986
948
927
842
733
721
705
657
s
m
m
w
641
δC=C=C + νC-S
a ν: bond stretching, δ: in-plane angle bending, γ: out-of-plane angle bending, as: antisymmetric, s: symmetric.

ACCEPTED MANUSCRIPT
1
Table 4. The experimental 13C and H NMR chemical shifts (ppm) together within the calculated data for the
conformers of N-(Phenyl)dimethyldisulfonimide in DMSO-d6.
DFT/B3LYP/6-311++G(d,p)a
Nucleus
Experimental
C1 (C2)
132.68
134.15
134.15
132.06
129.30
129.30
48.72
48.72
7.77
7.63
7.63
7.44
7.44
3.27
3.27
C1 (C1)
132.38
132.84
134.79
132.11
129.18
129.62
50.11
46.46
7.76
7.66
7.66
7.40
7.47
3.19
3.33
C2 (C1)
132.94
133.66
135.00
132.82
129.38
130.14
47.01
50.76
7.82
7.66
7.71
7.86
7.46
2.70
3.53
C-1
C-2
C-2i
C-4
C3
C3i
C5
C5i
H-C4
H-C3
H-C3i
H-C2
H-C2i
H-C5i
H-C5
134.36
131.37
131.37
130.61
129.98
129.98
43.42
43.42
7.49
7.49
7.49
7.49
7.49
3.50
3.50
a σ transform into δ using equations given in Ref. [19] δ13C=175.7-0.963 σ13C and δ1H= 30.9-0.970 σ1H.

ACCEPTED MANUSCRIPT
Table 5. NBO charges (in e) for the conformers of N-(Phenyl)dimethyldisulfonimide.
DFT/B3LYP/6-311++G(d,p)
Nucleus
C1 (C2)
0.124
C1 (C1)
0.123
C2 (C1)
0.102
C-1
C-2
C-2i
C-3
C-3i
C-4
C-5
C-5i
N-1
O-1
O-1i
O-2
O-2i
S-1
-0.176
-0.176
-0.195
-0.195
-0.183
-0.774
-0.774
-0.993
-0.885
-0.885
-0.911
-0.911
2.202
-0.186
-0.170
-0.195
-0.194
-0.183
-0.778
-0.771
-0.986
-0.885
-0.884
-0.914
-0.910
2.204
-0.184
-0.183
-0.192
-0.200
-0.182
-0.776
-0.772
-0.967
-0.882
-0.875
-0.919
-0.886
2.195
S-1i
2.202
2.194
2.177