Synthesis, characterization and crystal structure of bis-(methylsulfonylmethyl) sulfone, a symmetric acyclic trisulfone

Article abstract of DOI:10.1016/j.molstruc.2020.129655

Bis - (methylsulfonylmethyl) sulfone, BMSMS, was synthesized and characterized through vibrational (IR, Raman) spectroscopy. The crystal structure of BMSMS, determined by X-ray diffraction methods, together with Hirshfeld surfaces analysis were used to evaluate intermolecular interactions. BMSMS can be considered as one-turn helix of about 7.13 ?, further stabilized by weak intra-molecular CH???O bonds. The experimental results were supplemented by quantum chemical calculations. It was also analyzed the hyperconjugative effects of oxygen atoms lone pairs (LP) on the vibrational behavior of the SO₂ group. Besides, biofilm formation and QS activity were evaluated on this new bis- (methylsulfonylmethyl) sulfone.

Full text of DOI:10.1016/j.molstruc.2020.129655

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Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: www.elsevier.com/locate/molstr
Synthesis, characterization and crystal structure of
bis-(methylsulfonylmethyl) sulfone, a symmetric acyclic trisulfone
J.E. Galvána, O.E. Pirob, G. Echeverriab, R.D.I. Molinac, M.E. Arenac, E. Contreras Aguilard,
S.E. Ulicd,e, M.E. Tuttolomondoa,∗, A. Ben Altabefa,∗
a INQUINOA-CONICET, Instituto de Química Física, Facultad de Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, R. Argentina.
b Departamento de Física, Facultad de Ciencias Exactas, Universidad Nacional de La Plata and Instituto IFLP (CONICET, CCT-La Plata), C. C. 67, 1900 La Plata,
R. Argentina
c INBIOFAL-CONICET (Instituto de Biotecnología Farmacéutica y Alimentaria) Universidad Nacional de Tucumán, R. Argentina.
d CEQUINOR (CONICET-UNLP), Facultad de Ciencias Exactas, Universidad Nacional de La Plata, 120 N° 1465 (1900) La Plata, R. Argentina.
e Departamento de Ciencias Básicas, Universidad Nacional de Lujan, Ruta 5 y 7, 6700 Luján, Buenos Aires, R. Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
Bis - (methylsulfonylmethyl) sulfone, BMSMS, was synthesized and characterized through vibrational (IR,
Raman) spectroscopy. The crystal structure of BMSMS, determined by X-ray diffraction methods, together
with Hirshfeld surfaces analysis were used to evaluate intermolecular interactions. BMSMS can be con-
Received 16 June 2020
Revised 6 November 2020
Accepted 15 November 2020
Available online xxx
˚
sidered as one-turn helix of about 7.13 A, further stabilized by weak intra-molecular CH•••O bonds. The
experimental results were supplemented by quantum chemical calculations. It was also analyzed the hy-
perconjugative effects of oxygen atoms lone pairs (LP) on the vibrational behavior of the SO2 group. Be-
sides, biofilm formation and QS activity were evaluated on this new bis- (methylsulfonylmethyl) sulfone.
Keywords:
Vibrational Spectroscopy
X-ray Crystal Structure
Hyperconjugation Effects
Hirshfeld surface analysis
© 2020 Published by Elsevier B.V.
1. Introduction
treatment of leprosy and tuberculosis [11,12]), agrochemical and
polymer (thermoplastic polysulfone polymers) industry [1]. For a
The aim of the present work was to evaluate the electronic, vi-
brational and structural properties of bis - (methylsulfonylmethyl)
sulfone, BMSMS, and its electronic behavior in relation to the ac-
tion of the BMSMS reactive groups.
long time, sulfones like sulfonamides were used effectively in med-
ical treatment due its antibacterial activity. They can inhibit the di-
hydropteroic acid synthase of diverse parasites like plasmodia [13-
15], and some sulfones present fungicidal activity comparable or
better than the commercial ones used in agriculture. In terms of
structure, sulfones usually present a distorted tetrahedral confor-
mation. In (CH3)2SO2, the adopted values for ࢬC–S–C and ࢬO–S–O
angles are 104° and 116°, respectively [5,6]. The last value, quite far
from the ideal tetrahedral one, is a consequence of the oxygen lone
pairs repulsions and thus decreasing the ࢬC–S–C. Besides, the S=O
has a strong double bond character compared to sulfoxides [16,17].
The SO2 group is also involved in intermolecular interactions, as
acceptor, with donors like amino and hydroxyl groups [18]. How-
ever, non-conventional interactions between C–H and O=S groups
were also observed [19].
Sulfone is an important class of pharmaceutically compounds
because of their wide spectrum of biological activities, such as can-
cer agents, secretase inhibitors for the treatment of Alzheimer’s
disease and antibacterial agents. [1] The synthesis of hybrid
molecules with more than one pharmacological property has re-
cently gained relevance. [2] The use of sulfones, as an auxiliary
group, remains an outstanding synthetic strategy, especially for
the formation of carbon-carbon double bond. [2–4] This functional
group can change the polarity of the molecule, as an electron-
withdrawing group, to stabilize carbanions or as a leaving group.
[5,6]
Sulfone derivatives are compounds with several bioactivities [7–
10], and the SO2 group plays an remarkable role in many com-
pounds of the pharmaceutical (as Daps, an antibiotic used in the
In this work a comparison between experimental and theo-
retical geometric parameters, computed with different DFT hybrid
functionals methods, was carried out for BMSMS and different sul-
fones (CF3SO2X (X = F, OH, NH2, CH3)) [20-27]. The analysis of
intermolecular interactions is focused particularly in OꢀꢀꢀH bonds,
since they play an essential role in the molecular self-assembly in
crystals. The study was complemented by The Atoms-in-Molecules
∗
Corresponding authors.
E-mail
addresses:
metdemunoz@yahoo.com
(M.E.
Tuttolomondo),
aida.benaltabef@fbqf.unt.edu.ar (A.B. Altabef).
https://doi.org/10.1016/j.molstruc.2020.129655
0022-2860/© 2020 Published by Elsevier B.V.
Please cite this article as: J.E. Galván, O.E. Piro, G. Echeverria et al., Synthesis, characterization and crystal structure of bis-
(methylsulfonylmethyl) sulfone, a symmetric acyclic trisulfone, Journal of Molecular Structure, https://doi.org/10.1016/j.molstruc.2020.
129655

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(AIM) [28–30] theory and Natural Bond Orbital (NBO) [31,32]
analysis. In vitro bacterial growth inhibition and biofilm forma-
tion were tested, considering that BMSMS has similar structure to
Clomesone (2- chloroethyl(methylsulfonyl)methanesulfonate) [16],
which inhibits biofilm formation.
2.4. Computational details
Gaussian 03 and 09 [36,37] set of programs was used to carry
out the DFT calculations. Full optimizations were performed with
standard gradient techniques at DFT levels of theory. Three types
of basis sets were employed: Poples´ 6-31G(d), 6-311(3df) and 6-
311++G∗∗ [38–42], . Quantum chemical calculations of stable con-
formations of BMSMS molecule were performed using three hybrid
functionals B3LYP, wB97XD and BVP86 [42-46]. In addition, Natural
Bond Orbital (NBO) calculations were performed at the B3LYP/6-
311G(3df) level of theory, using the NBO 3.1 program [30-32]. AIM
calculations were carried out with AIM2000 program [29,30]. The
atomic displacements, from the Gaussian program for each vibra-
tional mode, were used to understand qualitatively the nature of
the molecular vibrations and they were visualized with GaussView
program [47]. The calculated frequencies were scaled using the
Yoshida [48] methodology, and the potential energy distribution
(PED) was calculated using the VEDA program [49].
2. Experimental
2.1. Synthesis of bis (methylsulfonylmethyl) sulfone
The synthesis of BMSMS was carried out according to the liter-
ature [33 a-b] with some modifications. BMSMS was obtained from
solutions of Et3N (triethylamine), CH3SO2Cl (methanesulfonyl chlo-
ride) and CF3CH2OH (2-trifluoroethanol) in acetonitrile (0.66 M,
0.44 M and 0.44 M, respectively). The temperature was hold in the
range of −30°C to −40°C. The CH3SO2Cl solution was added drop-
wise to a triethylamine solution with continuous stirring avoiding
exceeding −30°C, since this temperature is essential for the for-
mation of CH3SO2CH2 = SO2Cl intermediate. After two hours, a
white solid of triethylamine hydrochloride (Et3NHCl) was removed
by filtration. The solvent of the orange-reddish supernatant was
extracted using a rotary evaporator, and the obtained white solid
was washed with hexane and recrystallized from chloroform.
1H NMR (400 MHz, CDCl3) δ = 4.94 (s, 4H, CH2), 3.26 (s, 6H,
CH3); 13C NMR (101 MHz, CDCl3) δ = 69.26 (CH2), 42.73 (CH3).
The measurements were performed on an RMN Bruker AVANCEIII
Ascend 400 (400 MHz).
2.5. Hirshfeld surface calculations
Hirshfeld surfaces of BMSMS and their associated two-
dimensional fingerprint plots [50-53] were obtained using Crys-
tal Explorer 3.1 software [53], using the structural information ob-
tained from X-ray diffraction. The dnorm (normalized contact dis-
tance) surface and the breakdown of two- dimensional fingerprint
plots were used for decoding and quantifying intermolecular inter-
actions in the crystal lattice. The dnorm is a symmetric function
of distances to the surface from nuclei inside and outside the Hir-
shfeld surface (di and de, respectively), relative to their respective
van der Waals radii. 3D dnorm surfaces are mapped over a fixed
color scale of −0.08 au (red) to 0.60 au (blue), Shape index in the
color range of –1.0 au (concave) to 1.0 au (convex), and Curvedness
in the range of –4.0 au (flat) to 0.01 au (singular). The 2D finger-
print plots are displayed using the translated 0.6–2.6 A range and
including reciprocal contacts.
2.2. X-Ray data collection and structure refinement
The measurements were performed on an Oxford Xcalibur, Eos,
Gemini CCD diffractometer with graphite-monochromated CuKα
˚
(λ=0.71073A) radiation. X-Ray diffraction intensities were collected
(ω scans with ϑ and κ-offsets), integrated and scaled with CrysAl-
isPro [34] suite of programs. The unit cell parameters were ob-
tained by least-squares refinement (based on the angular settings
for all collected reflections with intensities larger than seven times
the standard deviation of measurement errors) using CrysAlisPro.
Data were empirically corrected for absorption, employing the
multi-scan method implemented in CrysAlisPro. The structure was
solved by intrinsic phasing with SHELXT of the suite of programs
SHELX [35] and the molecular model refined by full-matrix least-
squares with SHELXL of the same package. Most hydrogen atoms
were located in a difference Fourier map phased on the heavier
atoms. The methylene hydrogen atoms were refined at their found
positions with isotropic displacement parameters. The hydrogen
atoms were positioned on stereo-chemical basis a refined with the
riding model. The methyl H-atoms were refined as rigid groups
allowed to rotate around the S-CH3 bonds, such as to maximize
the sum of the observed residual electron density at their calcu-
lated positions (Table S1). The CIF file, with details of the crys-
tal structure, reported in this work has been deposited with the
Cambridge Crystallographic Data Centre, under deposition number
CCDC 2005284.
2.6. Biofilm formation assay
For biofilm quantification, a previously reported micro method
based on a protocol was employed [54]. The supernatants of
bacterial cultures, prepared as described earlier [54], was dis-
carded after 24 h incubation and the material that remained fixed
to polystyrene (containing biofilm) was washed with water. The
formed biofilms were stained with 200 μL of an aqueous solution
of crystal violet (0.1% w/v) for 30 min. After washing with water,
crystal violet bounded to biofilm was removed employing 200 μl
of absolute ethanol for 30 min at 37°C with continuous shaking.
Absorbance (580 nm) of crystal violet ethanol solutions was deter-
mined using the microtitre plate reader.
3. Results and discussion
3.1. X-ray diffraction and structure refinement
The crystal structure of BMSMS was elucidated by X-ray diffrac-
tion methods. The compound crystallizes in the monoclinic P21/n
˚
2.3. Vibrational spectroscopy
space group, with a = 5.6950(5), b = 19.660(2), c = 8.6184(9) A,
β = 96.076(8)° and Z = 4 molecules per unit cell (Figure S1). The
The FTIR spectrum was recorded in the 4000-400 cm−1 region,
with a spectral resolution of 2 cm−1, using a Perkin-Elmer GX1
FTIR spectrometer. The Raman spectrum of the solid was measured
in the 3500–100 cm−1 interval with a Thermo Scientific DXR Ra-
man microscope, and a resolution of 5 cm−1. The Raman data were
collected using a diode-pump solid state laser of 532 nm.
molecule can be considered as a single-turn helix of about 7.13
˚
A pitch. Corresponding bond distances and angles are in Table S2
and conforms the Organic Chemistry rules. In particular, C-S single
˚
bond lengths are in the range from 1.738(3) to 1.789(3) A. Sulfox-
˚
ide S=O double bonds distances are from 1.423(2) to 1.432(2) A
and O=S=O bond angles are in the 117.6(1)-119.5(1)° range.
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3.2. Theoretical calculations
The solid experimental geometric parameters obtained by X-ray
diffraction and the calculated ones (B3LYP, wB97XD and RBVP86
with 6-311(3df)) for the BMSMS dimer structure (Figure S2) are
presented in Table S2. The smallest standard deviations for the cal-
culated distances were found with wB97XD, but only with a dif-
˚
ference of 0.003 A from B3LYP. However, for both angles and di-
hedrals, B3LYP predicts the smallest deviations, so for this sulfone
the best level of calculation is achieved with B3LYP / 6-311G (3df).
For the computed dihedral angles, the lowest standard devia-
tion (RMS) value was found with the B3LYP / 311G (3df) level, and
the largest discrepancy was observed for the C1-S1-C2-S2 and C2-
S2-C3-S3 angles, since only a single possible dimer was considered
to calculate the geometric parameters (Table S2). Particularly, these
dihedral angles are affected by intermolecular hydrogen bonds as
shown in Table 1, (C(1)-H ••O (11) hydrogen bond affects the di-
hedral angles involving the C1 atom), which were not considered
due to computational cost reasons. However, in the case of the
Clomesone, they have been analyzed in order to explain the dis-
crepancy in the value of certain dihedral angles [16].
Fig. 1. View of the asymmetric unit content of BMSMS crystal, showing the labeling
of the non-H atoms and their displacement ellipsoids at the 30% probability level.
•••
Weak intra-molecular CH
O bonds are indicated by dashed lines.
Table 1
˚
Distances (A) and angles (°) for intramolecular and intermolecular hydro-
gen bonds observed for BMSMS.
D-HꢀꢀꢀA
d(D-H)
d(HꢀꢀꢀA)
d(DꢀꢀꢀA)
ࢬ(DHA)
C(1)-H(1A)ꢀꢀꢀO(11)#1
C(1)-H(1B)ꢀꢀꢀO(21)
C(1)-H(1C)ꢀꢀꢀO(11)#2
C(4)-H(4B)ꢀꢀꢀO(22)
C(2)-H(2A)ꢀꢀꢀO(31)
C(2)-H(2B)ꢀꢀꢀO(12)#3
C(3)-H(3A)ꢀꢀꢀO(31)#4
C(3)-H(3B)ꢀꢀꢀO(12)
C(3)-H(3B) ꢀꢀꢀO(22)#5
0.96
2.58
3.396(4)
3.265(4)
3.438(4)
3.124(5)
3.175(4)
3.117(3)
3.192(4)
3.081(4)
3.315(3)
142.5
3.3. Hirshfeld Surfaces
0.96
2.57
129.5
0.96
2.66
138.5
The analysis of the intermolecular interactions in the crystal
packing allowed justifying the deviations of the calculated C1-S1-
C2-S2 and C2-S2-C3-S3 (≈ 5 °) dihedral angles for the isolated
molecule respect to the X-ray diffraction data.
0.96
2.41
131.1
0.94(3)
0.93(3)
0.88(3)
0.94(3)
0.94(3)
2.43(3)
2.40(3)
2.50(3)
2.37(3)
2.64(3)
136(2)
134(3)
136(3)
132(3)
129(2)
In Fig. 2, a helical bilayer structure is observed along a, b and c
crystal axes, where H atoms are involved in intra- and intermolec-
ular hydrogen bonding. The bilayer is stabilized mainly by bifur-
cated CH ••O interactions (Fig. 3).
Symmetry transformations used to generate equivalent atoms: (#1) -x+1,
-y+1, -z+2; (#2) -x, -y+1, -z+2;(#3) x+1,y,z; (#4) x-1/2,-y+3/2,z-1/2; (#5)
x-1,y,z.
The fingerprint plots of the hydrogen atom interactions are
shown in Fig. 4, where 38% corresponds to OꢀꢀꢀH, with an aver-
˚
age distance of 2.50 A. The larger contribution is focused in C ••H
contacts (43,6%), whereas that the H ••S interactions are negligible.
The crystal structure of bis- (methylsulfonylmethyl) sulfone is
shown in Fig. 1. The helical structure is further stabilized by weak
intra-molecular CH•••O bonds [C•••O distances from 3.081(4) to
3.4. Vibrational analysis
˚
3.265(4) A] and the lattice, besides van der Waals interaction, by
The BMSMS infrared and Raman spectra in solid state are
shown in Figure S3. The DFT calculations reproduced the vibra-
tional frequencies with the following RMSD (root mean square
deviation) values for each basis set: 68 cm−1 (B3LYP), 53 cm−1
inter-molecular CH•••O bonds [C•••O distances in the 3.117(3)-
˚
3.396(4) A range] (Table 1). The H-bonding structure is further de-
tailed in Table S3-S5.
Fig. 2. Schemes of the crystal structure along axis a, b and c.
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rent results with those previously obtained for related molecules.
In fact, the combination B3LYP/6-311G(3df) is being extensively
used for vibrational calculations as a good compromise between
economy of computational resources, accuracy and applicability to
many-atoms systems. [5,6,16,26,27,55].
The experimental and computed (B3LYP/6-311G (3df)) spectra
for the isolated dimer are displayed in Figures S5 (IR) and Figures
S6a-b (Raman). BMSMS belongs to C1 symmetry group with 63
normal vibrational modes. The IR and Raman observed band po-
sitions together with calculated wavenumbers and PED mode as-
signments are collected in Table 2. The complete assignment of
the fundamental vibration modes was performed with the assis-
tance of theoretical calculations and by comparison with related
molecules [5,6,16,26,27,55].
The C-H stretching modes are observed in the region of
3000
cm−1
.
In the Raman spectrum, the asymmetric and symmet-
ric stretching of the CH3 groups appear at 3040/3020 and 2917
cm−1, respectively, and at 2981/2974 cm−1 and 2937/2937 cm−1
for the CH2 asymmetric and symmetric stretching modes, respec-
tively. The observed frequency difference between the symmet-
ric stretching modes of both CH2 groups may be due to hydro-
gen bonding interactions with the SO2 groups. The bands observed
at 1344, 1327, 1315 cm−1 in the IR spectrum were assigned to
the S(2)O2, S(1)O2 and S(3)O2 asymmetric stretching modes, and
the bands at 1174, 1141 and 1128 cm−1 to the S(2)O2, S(1)O2 and
S(3)O2 symmetric stretching ones. The frequency differences be-
tween asymmetric and symmetric bands are 170, 186 and 187
cm−1, respectively. The SO2 stretching modes are very sensitive
to the electrostatic environment, and when increasing the elec-
•••
Fig. 3. CH
O interactions are represented on the surface of Hirshfeld as intense
red color points.
(RBVP86) and 85 cm−1 (wB97XD). Although the RBVP86 hybrid
functional reproduces somewhat better the experimental frequen-
cies, however B3LYP better predicts the intensities. Although the
frequencies can be scaled, the intensity better represents the ex-
perimental behavior (Table S6-Figure S4). Therefore, the results ob-
tained with the B3LYP functional were used for the vibrational
analysis, also in order to facilitate the comparison of the cur-
Fig. 4. Fingers print plots for hydrogen atom interactions of BMSMS (top) and full 2D fingerprint plot (bottom).
4

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Table 2
Experimental and theoretical (harmonic and scaled) infrared and Raman spectra (cm−1) and PED (%) mode assignments for BMSMS.
IR
Raman
Calculateda
Scaledb
IIR
ARaman
PED (%)c
1
3040 w
3040 w
3020 w
3020 w
3020 w
2981 m
2972 m
2937 sh
2926 m
2916 m
1480 vw
1460 vw
1434 vw
1434 vw
1415 w
1415 w
1344 s
1327 s
1315 s
1303 f
1303 f
1225 m
1186 m
1174 m
1141 m
1128 vs
1104 w
1104 m
988 w
988 w
975 sh
975 sh
871 w
844 s
806 w
775 w
751 w
712 w
-
3040(13)
3181
3181
3156
3156
3148
3148
3077
3077
3064
3063
1461
1461
1451
1449
1405
1402
1374
1372
1366
1348
1342
1235
1232
1190
1165
1157
1124
1113
985
3042
3042
3021
3021
3014
3014
2950
2950
2945
2940
1440
1440
1435
1428
1395
1387
1355
1355
1348
1330
1326
1228
1220
1178
1158
1146
1114
1000
977
3
25
25
58
71
24
30
165
24
134
126
5
100 υas C(1)H3
2
3.0
0.2
0.1
9
90 υas C(4)H3+ 10 υas C(1)H3
3
3020(20)
89 υas C(1)H3 + 11 υas C(4)H3
4
89 υas C(4)H3+ 11 υs C(3)H2
5
100 υasC(2)H2
6
2981(20)
2974(18)
2938(60)
2926(51)
2917(36)
-
30
7
100 υasC(3)H2
7
89 υsC(2)H2 + 11 υasC(2)H2
8
32
1.3
1.3
2
100 υsC(3)H2
9
84 υs C(1)H3+ 16 υs C(2)H3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
90 υs C(4)H3+ 10 υs C(1)H3
55 δas C(1)H3 + 45 δas C(4)H3
-
6
1
45 δas C(1)H3 + 55 δas C(4)H3
-
0.4
0.0
6
1.4
10
1
55 δas C(1)H3 + 45 δas C(4)H3
-
45 δas C(1)H3 + 55 δas C(4)H3
1415 sh
1407 (13)
1363(16)
1347(14)
1321(6)
1297(10)
-
65 δ C(2)H2 + 35 δ C(3)H2
0.4
242
23
242
11
273
43
23
26
5
17
6
70 δ C(3)H2 + 30 δ C(2)H2
50 υas S(2)O2 + 15 υas S(1)O2 + 15 υas S(3)O2 +10 δs C(3)H3 + 10 δas C(4)H3
40 υas S(1)O2 + 40 υas S(3)O2 +10 wag C(2)H2 + 10 wag C(3)H2
30 υas S(1)O2 + 30 υas S(3)O2 +20 υas S(2)O2 + 10 δ C(2)H2 + 10 δ C(3)H2
50 δs C(3)H3 + 50 δas C(4)H3
1.3
7
0.4
6.0
3
50 δs C(3)H3 + 50 δas C(4)H3
1225(3)
-
90 wag C(3)H2+ 10 wag C(2)H2
10 wag C(3)H2 + 90 wag C(2)H2
30 υas S(1)O2 + 30 υas S(3)O2 +20 υas S(2)O2 +10 tw C(3)H2 + 10 tw C(2)H2
40 υas S(1)O2 + 40 υas S(3)O2 + 10 tw C(3)H2 + 10 tw C(2)H2
60 υas S(2)O2 + 20 υas S(3)O2 +20 υas S(1)O2
50 tw C(3)H2 + 50 tw C(2)H2
1.9
31
2
1166(38)
-
1125(18)
1112(45)
-
300
4
5
14
1
20
12
44
2
50 tw C(3)H2 + 50 tw C(2)H2
985(3)
-
2
50 ρ C(1)H3 + 50 ρ C(4)H3
985
977
0.2
1
50 ρ C(1)H3 + 50 ρ C(4)H3
972(4)
-
977
963
100 ρ C(1)H3
977
963
2
1.5
1
100 ρ C(4)H3
870(3)
-
872
870
4
50 ρ C(3)H3 + 50 ρ C(4)H3
845
844
242
21
8
0
50 ρ C(3)H2 + 50 ρ C(2)H2
803(2)
777(11)
753(13)
713(17)
685(100)
-
789
788
9
50 ρ C(3)H2 + 50 ρ C(2)H2
748
747
2
40 C(1)-S(1)+ 40 S(3)-C(4)+10C(3)-S(3)+10 C(2)-S(1)
60 S(3)-C(4)+ 30 C(3)-S(3)
726
725
36
17
1
5
694
691
5
50 C(3)-S(3)+50 C(2)-S(1)
676
668
4
50 C(1)-S(1)+ 50 S(2)-C(3)
681 w
530 w
500 m
460 m
450 sh
-
660
657
3
40
2
50C(2)-S(2)+50 C(4)-S(3)
535(10)
499(14)
465(13)
443 (7)
419 (8)
419 (8)
363sh
355(11)
322(2)
300(13)
284(22)
256(8)
241(8)
241 (8)
205(12)
182 (3)
168(9)
168 (9)
145(7)
145(7)
-
535
532
0
50C(1)-S(2)+50 C(2)-S(2)
525
525
24
72
17
4
0.5
3
73 δ S(2)O2 +17 δ S(1)O2 + 10 δ S(3)O2
52 δ S(1)O2 + 20 δ S(3)O2 +10 δ S(2)O2
20 δ S(1)O2 + 37 δ S(3)O2 +20 δ S(2)O2
80 wag S(2)O2 +10 δ S(1)O2 + 10 δ S(3)O2
45 δ S(1)O2 + 44 δ S(3)O2
493
494
476
475
1
459
455
3
-
456
450
101
1.6
0
2
-
341
343
2
53 δ S(1)O2 + 35 δ S(3)O2
-
340
1.8
1
40 δ C(3)S(3)C(4)+ 14 ρ S(3)O2
52 δ C(2)S(2)C(3) + 34 δ C(3)S(3)C(4)+15 δ C(1)S(1)C(2)
96 ρ S(2)O2
-
320
321
293
280
265
242
224
200
190
181
155
144
144
60
5
-
291
4
5
-
283
1.3
0
1
11 ρ S(3)O2 +11 δ C(2)S(2)C(3) + 12 S(2)C(3)S(3)+ 22 tw S(2)O2
40 ρ S(3)O2 + 10 τ C(4)H3 + 17 tw S(3)O2
35 δ C(2)S(2)C(3) + 29 S(2)C(3)S(3)+ 11 10 τ C(4)H3
50 10 τ C(1)H3 + 50 10 τ C(4)H3
50 10 τ C(1)H3 + 50 10 τ C(4)H3
50 10 τ C(1)H3 + 50 10 τ C(4)H3
50 10 τ C(1)H3 + 50 10 τ C(4)H3
92 τ C(2)S(2)C(3)S(3)
-
267
9
-
242
3
1
-
224
0.4
1.4
6
1.7
1
-
202
-
198
0.3
1
-
184
0
-
156
0
1
-
145
4
0
66 τ HC(1)S(1)C(2) + 20 ρ C(1)H3 + 19 100 ρ C(4)H3
74 τ C(1)S(1)C(2)S(2) + 10 ρ C(3)H3 + 10 ρ C(4)H3
74 τ S(1)C(2)S(2)C(3) + 12 ρ C(3)H3 + 10 ρ C(4)H3
88 τ C(2)S(2)C(3)S(3)
-
145
31
0
0
-
62
0
-
59
55
6
0
-
48
44
0.5
0.4
66 τ S(2)C(3)S(3)C2(4)
a
Calculated at B3LYP/6-311G(3df)
Scaled with Yoshida equation [48]
b
c
See Table S7 for definition of natural internal coordinates; ds, strong; m, medium; w, weak; sh, shoulder; v, very; eRelative intensity in parentheses; fν,
stretching; δ, bending; ρ, rocking; wag, wagging; tw, twisting.
tronegativity of the CX3 neighboring group a greater shifting be-
tween symmetric and asymmetric stretching frequencies is ex-
pected. In this case, the smallest observed difference corresponds
to the SO2 group bounded to two sp2 hybridized CH2 groups.
[56,57].
Skeletal modes. The ν CH2-SO2-CH2, ν CH2-SO2-CH3, ν SO2-CH3
stretching modes are associated to the bands at 775, 751, 712 and
681 cm−1, respectively. As observed, both C1-S1 and S3-C4 stretch-
ing are located at higher wave numbers based on their shorter
bond distances.
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2
Table 3
The ρ(r) and ∇ ρ(r) values are within 0.206-0.321 au and -0.408
NBO analysis of selected hyperconjugative interactions, cal-
–0.860 au range.
culated at B3LYP/6-311G(3df) level.
Table 4 shows topological and energy properties of selected
intramolecular and intermolecular hydrogen bonds. The ρ(r) val-
ues are in the ranges of 0.0114-0.0163 au (intramolecular hydrogen
bond) and 0.0058-0.0082 au (intermolecular hydrogen bond). The
Donor (i) → Acceptor (j)a
ꢀE / kJ/mol
LP π O (11/39) → σ∗ C(1/30) –H(4/32)
LP(σ)O(12/38) →σ∗ C(6/28)-H(23/43)
LP(π)O(12/38) →σ∗ C(6/28)-H(23/43)
LP(σ)O(13/36) → σ∗ C(28/5)-H(44/21)
LP(π)O(13/36) → σ∗ C(28/5)-H(44/21)
LP(σ)O(14/37) → σ∗ C(24/1)-H(26/3)
LP(π)O(13/37) → σ∗ C(24/1)-H(26/3)
3.76
4.09
5.23
0.79
2.47
1.05
2.42
2
gradient, ∇ ρ(r), varies between 0.040-0.060 au and 0.019-0.032
(intermolecular hydrogen bond, in each case are positive values),
typical for weak hydrogen bonds. The charge density and Laplacian
are within the range proposed by Koch and Popelier [58] for H-
bond interactions, which are 0.002–0.034 a.u. and 0.024–0.139 a.u.,
respectively. Intramolecular bonds are stronger than intermolecular
ones; according to the results obtained by NBO.
a
LP: lone pair on the specified atom. For atom number-
ing, see Figure S23.
Fig. 5a shows the Laplacian contour map and the large circles
in Fig. 5b correspond to attractor groups or (3, -3) nuclear critical
points (NCP), attributed to the positions of the atomic nuclei. The
lines that connect the nuclei are the PAs (points where the density
gradient is cancelled, ꢀρ = 0) and the small circles are the BCP or
(3, -1) bond critical points, obtained from the topological analysis
of electronic density.
3.5. NBO Analysis
To complement the structural and conformational study of
BMSMS, the donor → acceptor interaction energies analysis es-
tablished between the orbitals was carried out by means of the
Natural Bond Orbitals (NBO) approximation, calculated at B3LYP/6-
311G(3df) level for the dimer structure (Table 3; for atom number-
ing see Figure S2).
3.7. Biofilm formation analysis
The LP(σ/π)O→ σ∗S-O delocalization is the most important in-
teraction (~92 kJ mol−1), and the highest values correspond to the
sulfone groups attached to sp3 hybridized carbon atoms.
S. aureus has become the main cause of infections in the blood-
stream and food intoxications. The pathogenicity of S. aureus in-
fections is related to various components of the bacterial surface
[59]. In general, the components are peptidoglycans and teichoic
acids, in addition to protein A. Thus, the pathogenesis caused by
this microorganism arises when the combination of virulence fac-
tors occurs with the decrease of host defenses [59]. These condi-
tions favor that S. aureus possesses quite particular virulence char-
acteristics [60,61]. Additionally, the situation becomes more seri-
ous since the pathogen has developed multiple resistance against
antibiotics, making it increasingly difficult to treat the diseases
caused by them [61]. There are many strains of S. aureus with re-
sistance to antibiotics, the most worrisome is the infectious preva-
lence of methicillin-resistant strains (MRSA).
The electronic delocalization of LP(π)O→σ∗C-S (~82 kJ mol−1
)
affects the value of all dihedral angles of the molecule that cor-
respond to the gauche orientation, characteristic of sulfonates and
sulfones, and the mesomeric effect is responsible of the adopted
structural form. This behavior has already been reported in numer-
ous works on these systems. [16,26,27]
Furthermore, oxygen atoms lone pairs of one unit of the dimer
transfer electronic charge to the C-H bond virtually empty σ∗ or-
bital of other dimer molecule. The magnitude of the interaction is
~2 kJ mol−1 (Table S8). For CH•••O delocalization, intramolecular
hydrogen bonds have higher energy values than intermolecular hy-
drogen bonds.
In the last ten years, biofilms were recognized in dental plaque,
caries, periodontal infection, cystic fibrosis, chronic cystitis, bac-
terial endocarditis, osteomyelitis and chronic prostatitis. Likewise,
it was observed that biofilms developed in a variety of medical
implants, causing associated infections, including sepsis by intra-
venous and arterial catheters, as well as in urinary catheters, sig-
moidoscopes and contact lenses. They are also a serious problem
in artificial heart valves, pacemakers and orthopedic prostheses
which, once infected, they generate infections that are exception-
ally difficult to solve with antibiotics [59-65].
3.6. AIM Analysis
Bader’s Atoms in Molecules (AIM) quantum theory performs a
topological analysis of electronic charge density and its Laplacian,
at the bond critical point (BCP), allowing to know the nature of
the interactions. The results predict several intra and intermolec-
ular hydrogen bonds, which give rise to the formation of various
five-members rings.
Table S9 shows the properties of the electronic charge density
Bis- (methylsulfonylmethyl) sulfone (BMSMS) showed no sig-
nificant difference with the control in the performed tests (Fig-
ure S7), and consequently it does not inhibit the biofilm forma-
tion. The structure-biological activity relationship is highlighted
in the present work. BMSMS possesses a similar structure to 2-
2
in some selected BCPs´ for BMSMS. The values of ρ(r) and ∇ ρ(r)
for C-C, C-S and S=O bonds are typical of shared or covalent inter-
actions, which are dominated by a contraction of ρ(r) towards the
bond path, leading to its accumulation in the internuclear region.
Table 4
Local topological properties of the electron charge density (in au) at the bond, ring, and cage critical
points for intermolecular region of BMSMS.
2
Contact
Bond
ρ(r)
∇ (ρ)
|V|/G
|λ1|/λ3
Eint (cal)
Intramolecular
C(6)-H(23)…O(12)
C(7)-H(9)ꢀꢀꢀO(14)
C(30)-H(32)ꢀꢀꢀO(37)
C(28)-H(43)ꢀꢀꢀO(38)
0.0163
0.0114
0.0114
0.0126
0.060
0.040
0.040
0.044
0.837
0.839
0.834
0.832
0.182
0.180
0.177
0.183
0.0040
0.0036
0.0036
0.0038
Intermolecular
C(1)-H(3)ꢀꢀꢀO(37)#2
C(5)-H(21)ꢀꢀꢀO(36)#2
C(28)-H(44)ꢀꢀꢀO(13)#1
C(24)-H(26)ꢀꢀꢀO(14)#1
0.0089
0.0058
0.0058
0.0089
0,031
0.019
0.019
0,032
0.805
0.807
0.807
0.805
0.174
0.180
0.180
0.175
0.0026
0.0015
0.0016
0.0027
6

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Journal of Molecular Structure xxx (xxxx) xxx
Fig. 5. a) Laplacian contour map; b) Topological graph showing bond and ring routes (solid lines that join adjacent atoms and also those involved in hydrogen bonding
interactions) and critical bond and ring points.
chloroethyl (methylsulfonyl) methanesulfonate (Clomesone) how-
ever, Clomesone inhibits biofilm formation [16]. Molecular charge
distribution is a factor that changes the biological activity of struc-
turally similar compounds [63-67]. Molecules with an electroneg-
ative zone close to oxygen atoms are reported to be more active
against biofilm formation [65]. The presence of a chlorine close to
two oxygen atoms in Clomesone could be the reason for its differ-
ent behavior against biofilm formation compared to BSMSM.
Dr. Oscar E. Piro, Dr. Gustavo Echeverria, X-Ray data collection
and structure refinement.
Dr. Rocío Molina, Dr. Mario Arena, Biofilm formation assay,
Biofilm formation analysis.
Dr. María Eugenia Tuttolomondo, Theoretical calculations. Hir-
shfeld Surfaces. Vibrational spectroscopy.
Dr. Sonia E. Ulic, Dr. Aida Ben Altabef, Responsables of the re-
search studies and the financial supports.
Supporting Information Available
4. Conclusions
The supporting information includes:
The CH3 and CH2 groups of BMSMS are involved in intramolec-
ular hydrogen bonds, and the C(3)-HꢀꢀꢀO(12) bond exhibits a bet-
ter overlap because of its shorter distance and a more favorable an-
gle between the involved atoms. The various C-S bonds have differ-
ent distances according to their position in the molecular structure
and the shortest distance found corresponds to the H3C(1)-S bond.
The crystal structure is arranged as bilayers along the a, b and c
axes, showing a helical structure in the crystal, mainly stabilized
by CHꢀꢀꢀO bifurcated interactions. Hydrogen atoms are involved in
both intra- and intermolecular hydrogen bonding. AIM and NBO
results agree that the intramolecular bonds are stronger than in-
termolecular ones. The lone pairs delocalization of the SO2 oxygen
atoms towards the neighboring CH2 group is ~ 82 kJ mol−1, and
consequently an increase in the population of the antibonding or-
bital of CS(CH2) and a longer bonding distance are observed. This
is also evidenced in the vibrational spectra, since the shifting of
the C-S stretching bands (νH2C-S (657 cm−1)) highlights this de-
localization. BMSMS was tested on S. aeureus, and no significant
differences were found respect to the control, regarding to the in-
hibition of biofilm formation. The BMSMS exhibits a strong delo-
calization on the lone pairs of the sulfone oxygen atoms towards
the CS bonds, making the molecule very stable with no sites of re-
activity, and showing a different behavior to that observed for its
analogous Clomesone. It could be explained because of the lack of
electronegative groups in the vicinity of the oxygen atoms.
Crystal data and structure refinement results for BMSMS, (Ta-
ble S1), Theoretical and experimental geometrical parameters of
BMSMS, (Table S2); Atomic coordinates (x 104) and equivalent
˚
isotropic displacement parameters (A2 × 103) for tris-(methyl
sulfonyl). U(eq) is defined as one third of the trace of the or-
thogonalized Uij tensor (Table S3), Atomic anisotropic displace-
ment parameters (Table S4), Hydrogen coordinates and isotropic
displacement parameters for Bis - (methylsulfonylmethyl) sulfone
(Table S5); Definition of natural internal coordinates for BMSMS
(Table S6); Comparison of theoretical wavenumbers (cm−1) with
DFT(differents Hybrid Functionals) / 6-311G(3df) for BMSMS. (Ta-
ble S7); Hyperconjugative interactions calculated with B3LYP/6-
311G(3df) level, using the NBO analysis, (Table S8); Local topolog-
ical properties of the electron charge density (in au) at the bond
critical points for intermolecular region of BMSMS dimer, (Table
S9).
View of the BMSMS crystal packing, showing the unit cell with
the four corresponding molecules (Figure S1); Calculated structure
for BMSMS dimer (Figure S2); Infrared (above) and Raman (below)
spectra of bis-(methylsulfonylmethyl) sulfone in solid state, (Fig-
ure S3); Experimental (bottom) and calculated (top) FTIR spectra
of bis- (methylsulfonylmethyl) sulfone (Figure S4); Experimental
(botton) and calculated (top) infrared spectra of bis- (methylsul-
fonylmethyl) sulfone, showing also a tentative assignment (Figure
S5); Experimental (bottom) and calculated (top) Raman spectra of
bis- (methylsulfonylmethyl) sulfone, showing also a tentative as-
signment in the range of: a) 3300-2800 cm−1; b) 1500-100 cm−1
(Figure S6); Growth (ꢀ) and (ꢁ) production of biofilm by S. aureus
ATCC 6538 (39%) on cultures produced in LB broth in absence and
presence of BMSMS (10 and 100 μg / mL). CIP (Ciprofloxacin) (1
μg / mL) is the inhibitor control used. The error bars indicate the
standard deviation (n = 8), (Figure S7).
Credit Author Statement
Dr. Jorge Galvan, Synthesis of bis (methylsulfonylmethyl) sul-
fone, Vibrational spectroscopy.
Dr. E. Contreras Aguilar, RMN measurements.
7

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Journal of Molecular Structure xxx (xxxx) xxx
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11220130100651CO (CONICET), ANPCyT (PICT 0697), UNLP (Grants
11/X709, 11/X673 and 11/X830) and Departamento de Ciencias
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Supplementary materials
Supplementary material associated with this article can be
found, in the online version, at doi:10.1016/j.molstruc.2020.129655.
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