Synthesis, characterization and crystal structure of 2-chloroethyl(methylsulfonyl)methanesulfonate

Article abstract of DOI:10.1039/c7nj05138g

The aim of this study was to evaluate the structural and vibrational properties and biological activity of 2-chloroethyl(methylsulfonyl)methanesulfonate, CH₃SO₂CH₂SO₂OCH₂CH₂Cl (clomesone). The solid-state molecular structure has been isolated and characterized using experimental (X-ray diffraction) and theoretical (DFT method) methodologies. The molecules are packed through C-H?O bifurcated interactions and Cl?Cl interactions. The experimental investigations are supplemented by quantum chemical calculations and Hirshfeld surface calculations. Furthermore, the infrared and Raman spectra of the solid phase have been obtained, and the observed bands are assigned to the vibrational normal modes. This study is completed using the atoms-in-molecules (AIM) theory and natural bond orbital (NBO) analysis. Finally, we studied the function of clomesone in biofilm formation and investigated a methanesulfonate complex with respect to QS activity.

Full text of DOI:10.1039/c7nj05138g

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E. Galvan, M. E. Defonsi Lestard, O. E. Piro, G. Echeverria, M. E. Arena, R. Molina, S. E. Ulic and M. E.
Tuttolomondo, New J. Chem., 2018, DOI: 10.1039/C7NJ05138G.
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PAPER
Jason B. Benedict et al.
The role of atropisomers on the photo-reactivity and fatigue of
diarylethene-based metal–organic frameworks
rsc.li/njc

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Synthesis, characterization and crystal structure of
2-chloroethyl (methylsulfonyl) methanesulfonate
J. E. Galván1 M. E. Defonsi Lestard1 O. E. Piro,2 G. Echeverria,2 R. D. I. Molina,3 M.E.
Arena,3 S. E. Ulic,4,5 M. E. Tuttolomondo1*and A. Ben Altabef1
1INQUINOAꢀCONICET, Instituto de Química Física, Facultad de Bioquímica, Química y
Farmacia, Universidad Nacional de Tucumán, R. Argentina.
2Departamento de Física, Facultad de Ciencias Exactas, Universidad Nacional de La Plata
and Institute IFLP (CONICET, CCTꢀLa Plata), C. C. 67, 1900 La Plata, R. Argentina
3INBIOFALꢀCONICET (Instituto de Biotecnología Farmacéutica y Alimentaria)
Universidad Nacional de Tucumán, R. Argentina.
4CEQUINOR (CONICETꢀUNLP), Facultad de Ciencias Exactas, Universidad Nacional de
La Plata, 120 N° 1465 (1900) La Plata, R. Argentina.
5Departamento de Ciencias Básicas, Universidad Nacional de Lujan, Ruta 5 y 7, 6700
Luján, Buenos Aires, R. Argentina.
Abstract
The aim of this work is to evaluate the structural, vibrational properties and the biological
activity of 2ꢀChloroethyl (methylsulfonyl) methanesulfonate, CH3SO2CH2SO2OCH2CH2Cl
(Clomesone). The solid state molecular structure has been isolated and characterized by
experimental (Xꢀray diffraction) and theoretical (DFT method) methodologies. The
molecules are packed through C–H···O bifurcated interactions and Cl···Cl interactions.
The experimental investigations were supplemented by quantum chemical calculation and
Hirshfeld surface calculations. Furthermore, the infrared and Raman spectra for the solid
phase have been recorded and the observed bands assigned to the vibrational normal
modes. The study was completed by The AtomsꢀinꢀMolecules (AIM) theory and natural

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bond orbital (NBO) analysis. Finally, we study the function of Clomesone on biofilm
formation and the study on a methansulfonate complex with respect to QS activity.
∗Corresponding authors: Tel.: +54-0381-4311044; Fax: +54-3081-4248169; E-mail:
altabef@fbqf.unt.edu.ar; metdemunoz@yahoo.com
Keywords: FTIR, Raman spectroscopies / crystal structure/ NBO calculations / DFT
calculations.

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1. INTRODUCTION
The aim of the study is to characterize the crystal structure (Xꢀray diffraction, and Hirshfeld
surface analysis) of 2ꢀChloroethyl (methylsulfonyl) methanesulfonate,
CH3SO2CH2SO2OCH2CH2Cl (Clomesone) besides determining its vibrational properties
(FTIR, Raman).The characterizations of the structural and spectroscopic properties of
Clomesone, was realized with the assistance of theoretical calculations. From these theoryꢀ
experimental data identify the reactive sites of clomesone. The analysis of intermolecular
interactions is focused particularly in O….H and Cl···Cl interactions since they play an
essential role in the molecular selfꢀassembly in crystals. For these reason the dimeric forms
were modeled. Over the past years, the nature of Cl⋯Cl interactions were associated to
specific attractive forces. They were justified in terms of the nonꢀspherical shape of the
halogen charge density, which caused a decrease in the exchange–repulsion interaction.
Halogen bonds are the nature electrostatic with dispersion, polarization, and charge transfer
due the electronic density of the halogen.1ꢀ7The stability of the different dimers in terms of
hyperꢀconjugative and charge transfer interactions have been studied through the Second
Order Perturbation Theory of the Fox Matrix by means of the NBO analysis.8 The AIM
theory9 has been used to analyze the topology of all the optimized structures.
For several years it has been known that halo alkylating agents have antitumor activity
since they produce crossꢀlinking of the DNA strands. In particular, Clomesone, was
evaluated in various types of animal tumors and compared to several agents. The results of
such studies demonstrate that the antitumor activity of Clomesone is similar to that of the
most effective alkylating agents.10ꢀ17
The activity of Clomesone against eukaryotic cells is well known. The compound is toxic
to human cells18 acts as antineoplastic drug19. However, the effect on bacterial biofilm was
not determined. The biofilm is the predominant form in which bacteria is found in the
environment and it is controlled by a chemical system of bacterial communication, called
Quorum sensing (QS). Biofilms have been associated with nonꢀmalignant pathologies such
as inflammatory bowel disease20. However, was determined that biofilms are associated
with human colon cancer and linked to cancer location21. Biofilm emerged as an important
factor in colorectal cancer initiation and progression22. In addition, Quorum sensing
provides a unified model to explain many behaviors of tumor cells at all stages of cancer

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development.23 Taylor et al.24 suggesting that the metastasis formation could be mediated
by a signaling circuit of quorum sensing type analogous to those previously identified in
bacteria. For this reason, actually, knows cancer therapeutics are modified an assayed as
antiꢀbacterial, antiꢀbiofilm as well as antiꢀcancer efficacy.25
2. EXPERIMENTAL
2.1. Synthesis of 2-chloroethyl (methylsulfonyl) methanesulfonate
2ꢀChloroethyl (methylsulfonyl) methanesulfonate was prepared as reported in the
literature26 with slight modifications. In a roundꢀbottom flask, 3mL of methanesulfonyl
chloride dissolved in 3mL acetonitrile was added dropꢀwise under stirring to a solution of
triethylamine (8 mL) and acetonitrile (17.5 mL). The mixture was kept at ꢀ30°C for 1 hour.
After that, a solution of 2ꢀchloroethanol (1.3 mL) in 1.3 mL of acetonotrile was added and
stirred for two hours. The mixture was filtered at room temperature, to separate
triethylamine hydrochloride and the solution was washed with NaCl 0.1M, dried over
MgSO4 and evaporated in vacuum to give an oil product (red oil). These oil was dissolved
in a solvents mixture (dichloromethane:hexane) and stored overnight at ꢀ5ºC. The solid
product was filtered, washed with cold hexane and recrystallized twice from hot
chloroform. The obtained white crystalline solid was suitable for spectroscopic and
structural studies.
2.2. X-ray data collection and structure refinement.
The measurements were performed on an Oxford Xcalibur, Eos, Gemini CCD diffractometer
with graphiteꢀmonochromated CuKα (λ=1.54184 Å) radiation. Xꢀray diffraction intensities
were collected (ω scans with ϑ and κꢀoffsets), integrated and scaled with CrysAlisPro27suite
of programs. The unit cell parameters were obtained by leastꢀsquares 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 corrected
empirically for absorption employing the multiꢀscan method implemented in CrysAlisPro.
The structure was solved by direct methods with SHELXS of the SHELX suite of programs28
and the initial molecular model was refined by fullꢀmatrix leastꢀsquares procedure with
SHELXL of the same package. The hydrogen atoms were positioned on stereoꢀchemical

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basis a refined with the riding model. The methyl Hꢀatoms were refined as rigid groups
allowed to rotate around the SꢀCH3 bonds such as to maximize the sum of the observed
residual electron density at their calculated positions. As a result, the –CH3 group converged
to a staggered conformation (Tables S1-S4).
2.3. Infrared and Raman spectroscopy
The FTIR spectrum was recorded in the 4000ꢀ400 cmꢀ1 region with a spectral resolution of
2 cmꢀ1 using a PerkinꢀElmer GX1 FTIR spectrometer. The Raman spectrum of the solid was
measured in the 4000–100 cmꢀ1 interval with a Thermoscientific DXR Raman microscope.
The Raman data were collected using a diodeꢀpump, solid state laser of 532 nm. The
resolution of the equipment employed was 1 cmꢀ1. A total of 64 scans were done in each
condition and the spectra were analyzed using the OMNIC v.8.0 mathematical software
provided by the manufacturer.
2.4. Computational details
The Gaussian 0329 set of programs was used to carry out the DFT calculations. Full
optimizations were performed with standard gradient techniques at the DFT levels of
theory. Three types of basis sets were employed: Pople´s 6ꢀ31G(d), 6ꢀ311(3df) and 6ꢀ
311++G**30ꢀ34 basis sets were used. Becke’s hybrid exchange B335 was the exchange
functional, and the Lee–Yang–Parr nonꢀlocal functional, LYP36 was employed for
correlation. In addition, Natural Bond Orbital (NBO) calculations were performed at the
B3LYP/6ꢀ311G(3df) level of theory using the NBO 3.1 program.37,38 AIM calculations
were performed by means of AIM2000 program.39 The atomic displacements given by the
Gaussian program for each vibrational mode were used to understand qualitatively the
nature of the molecular vibrations and, for that purpose; the corresponding data were
represented graphically using the GaussView program.40
2.5. Hirshfeld surface calculations
Hirshfeld surfaces and their associated twoꢀdimensional fingerprint plots41ꢀ44 were obtained
using CrystalExplorer 3.1 software45 using the structural information obtained from Xꢀray
diffraction. The dnorm (normalized contact distance) surface and the breakdown of twoꢀ

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dimensional fingerprint plots are used for decoding and quantifying intermolecular
interactions in the crystal lattice.
The dnorm (normalized contact distance) surface and the breakdown of twoꢀdimensional
fingerprint plots are used for decoding and quantifying intermolecular interactions in the
crystal lattice.
The dnorm is a symmetric function of distances to the surface from nuclei inside and
outside the Hirshfeld 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) – 0.6
Å au(blue), Shape index in the color range of –1.0 au (concave) –1.0 au (convex) Å, and
Curvedness in the range of –4.0 au (flat) – 0.01 au (singular) Å. The 2D fingerprints plot
are displayed by using the translated 0.6–2.6 Å range and including reciprocal contacts.
2.6. Bacterial growth
Overnight cultures of Pseudomonas aeruginosa PAO1, Pseudomonas aeruginosa PA14
and Staphylococcus aureus ATCC 6528 were diluted to reach an optical density (OD) of
0.125 ± 0.01 at 560 nm in LuriaꢀBertani (LB) and Müeller Hinton (MH) medium,
respectively. The diluted culture (195 µL) was placed in one of the 96 wells of a microtitre
polystyrene plate. Solutions of compound in dimethyl sulphoxide (DMSO, Sigma–Aldrich)
were prepared separately, and 5 µl of each one was pipetted to the microtitre plate wells
individually (5 replicates) to reach final concentrations of 200, 100, and 10 µg/mL.
Control wells (5 replicates) contained the diluted culture (195 µL) and 5 µL of DMSO,
in which the final concentration of DMSO was 2.5%. Bacterial cultures were grown at
37°C for 24 h and growth was detected as turbidity (560 nm) using a microtitre plate reader
(Thermo Fisher Multiscan Go, Finland). Ciprofloxacin was incorporated in the same
bioassay as a positive control at 1 µg/mL.
2.7. Biofilm formation assay
For biofilm quantification, a micro method based on a protocol previously reported was
employed.46 The supernatants of bacterial cultures prepared as described previously, was
discarded after 24 h incubation and the material that remained fixed to the polystyrene
(containing biofilm) was washed with water. Biofilms formed were stained with 200 µL of

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an aqueous solution of crystal violet, (0.1% w/v) for 30 min. After washing with water,
crystal violet bound to biofilm was removed from each, employing 200 µl of absolute
ethanol and shaking for 30 min at 37°C with shaking. Absorbance (580 nm) of ethanol
solutions of crystal violet was determined using the microtitre plate reader.
2.8. Biosensor assay
Detection of QS inhibition was carried out by a diffusion assay using the biosensor strain
Chromobacterium violaceum CV026 Wells placed in the center of the surfaces of LB agar
plates previously inoculated with C. violaceum CV026 and supplemented with 5 µg of the
QS autoinducers, NꢀhexanoylꢀLꢀhomoserine lactone (HHL) (Sigma) were loaded with 50
µl of a 4 mg / mL solution of the compounds in DMSO to obtain 200 µg per well. DMSO
was included as vehicle solvent control. After incubation for 18 h at 28 ° C, inhibition of
QS was visualized by the presence of a clear halo on a violet background, where the
presence of viable cells without the production of violacein around the well was disrupted.
The strains C. violaceum Tn5ꢀmutant CV026 is unable to produce the pigment violacein per
se, because it does not produce auto inducers. However, it is able to form violacein and its
production depends on autoꢀinducer exogenous addition. 47
The antiꢀQS compounds inhibit the production of violacein due to the antagonist molecules
that bind instead of the natural autoinducers ligands and prevent the DNA from binding to
the pigment transcription, considered an important virulence factor of C. violaceum.48 In the
C. violaceum CV026 bioassay, the presence of turbid halos on a violet background
indicated QS inhibition without affecting microbial growth.
2.9. Statistical data analysis
All experiments were conducted in quintuplicates at least three times. Differences in the
mean values were evaluated by analysis of variance (ANOVA). The Tukey test was used
for all pairꢀwise multiple comparisons of groups. In all analyses, values of p < 0.05 were
considered statistically different.49,50

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3. RESULTS AND DISCUSSION
3.1. Structural X-ray diffraction
Figure 1 is an ORTEP51 drawing of the solid state molecule and intra/interꢀmolecular
bonds distance and angles are in Table 1. These geometrical data for
CH3SO2CH2SO2OCH2CH2Cl molecule agree with Organic Chemistry’s rules. Sulfur atoms
acts with a sixꢀvalence bond capability showing S=O double bond distances in the range
from 1.410(5) to 1.429(5) Å, SꢀC single bond lengths in the 1.746(8)ꢀ1.801(5) Å range, and
d(SꢀO) = 1.566(4) Å. All carbon atoms show the expected sp3 bonding structure with d(Cꢀ
O) = 1.432(8) Å, d(CꢀC) = 1.475(8) Å, and d(CꢀCl) = 1.775(8) Å. The molecule
conformation is stabilized by intramolecular Hꢀbonds, involving a C(1)ꢀH(1A)···O(22)
interaction [d(C···O)= 3.225Å, < C(1)ꢀH(1A)···O(22)= 123.1°].
The optimized structural parameters of CH3SO2CH2SO2OCH2CH2Cl were calculated like
isolated and dimer structures at B3LYP method with different basis sets, these result are
shows in Table S5 in comparison with the experimental data with their RMSD
corresponding. As a result, the dimer optimized parameters obtained by B3LYP/6ꢀ
311G(3df) are in good agreement with experimental data. The deviation of dihedral angles
C(2)S(2)O(3)C(3) and S(2)O(3)C(3)C(4) (approximately 20°) between the values of RX
and those calculated for the monomer are corrected when calculating the dimer (~1°). This
is because the geometry optimization of the dimer is performed considering the hydrogen
bond interactions present in the crystal (Table S6).
The crystal structure is stabilized by strong intramolecular hydrogen bonds, resulting the
strongest ones C(2)ꢀH(2B)...O(12)#3 and C(3)ꢀH(3B)...O(12)#3. This interaction is
modeled by quantum methods as a dimer and the calculations show small deviations from
Xꢀray structure.

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Figure 1. View of CH3SO2CH2SO2OCH2CH2Cl Xꢀray structure showing the labeling of
the nonꢀH atoms and their displacement ellipsoids at the 30% probability level.
Table 1. Inter / intramolecular hydrogen bonds in the crystal structure of Clomesone.
X-Raya
d(DꢀH)
0.96
0.97
0.97
0.96
0.96
0.96
0.96
0.97
d(H...A)
2.60
d(D...A)
3.23(9)
3.17(9)
3.51(8)
3.19(1)
3.372(9)
3.314(8)
3.448(8)
3.305(7)
<(DHA)
123.1
151.2
158.7
138.9
144.4
130.6
150.9
124.7
C(1)ꢀH(1A)...O(22)
C(2)ꢀH(2B)...O(12)#3
C(3)ꢀH(3B)...O(12)#3
C(1)ꢀH(1B)...O(11)#1
C(1)ꢀH(1B)...O(21)#1
C(1)ꢀH(1C)...O(22)#2
C(2)ꢀH(2A)...O(21)#1
C(3)ꢀH(3A)...O(22)#4
2.28
2.59
2.41
2.54
2.61
2.57
2.66
aSymmetry transformations used to generate equivalent atoms: (#1) x, y+1, z;
(#2) ꢀx+1, y+1/2, ꢀz+1; (#3) ꢀx+2, yꢀ1/2, ꢀz+1; (#4) ꢀx+1, yꢀ1/2, ꢀz
3.2. Hirshfeld Surface calculations
In Figure 2 is observed a schematic view along bꢀaxis, as bilayers. The Cl atoms are not
involved in the hydrogen bonding and in each bilayer, chlorine atoms are arranged

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perpendicular to the bꢀaxis and facing to each other at a distance of 3.7 Å(θCl···Cl···Cl =
95.8°). According to angular approach of halogens, the halogenꢀhalogen interaction shave
been classified as Type I (cis and trans geometry) and Type II (electrophileꢀnucleophile
model or Lꢀ geometry). This interaction (θ1≈ 180°, θ2 ≈ 90°) represents a chemical model
with each halogen atom polarized positively in the polar region and negatively in the other
region. In the Clomesone crystal the bond angles are θ1=165.53°and θ2=75.26° around two
Cl atoms (θC–Cl···Cl) therefore correspond to the TypeꢀII interactions.2
Figure 2. A view of packing diagram of CH3SO2CH2SO2OCH2CH2Cl
The bilayer is stabilized by Cl···Cl interactions and CH···O bifurcated interactions, leading
to the formation of
rings stacked perpendicular to the bꢀ axis (Figure 3(A)). In turn,
the biꢀlayers stabilize each other by means of the H(1C)···O (22) interaction.
Figure 3(B) shows one of the sheets along aꢀaxis, where the molecules are stabilized by
bifurcated CH···OR interactions giving rise to the formation of 2 adjacent 6ꢀmembered
rings
and
(6)) arranged along the bꢀaxis.

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Figure 3.View of structure of CH3SO2CH2SO2OCH2CH2Cl: (A) along the bꢀaxis and (B)
along the aꢀaxis.
The analysis of the Hirshfeld surface allowed to know the nature of the intermolecular
interactions and their contributions to the crystal packing. The CH(2B)···O(12) and
CH(3B)···O(12) hydrogen interactions (Figure 4(A)) are represented on the Hirshfeld
surface as intense red color points (Figure 4(B)).
Hirshfeld surface analysis shows the highest proportion of H···O interactions (63.8%) and
is displayed on the fingerprint plot with a blue circle (see Figure 4(C)).
The zigzag (Figure 4(D)) chain of Cl atoms observed in the crystal structure is displayed
on the 2Dꢀfingerprint plot as a bright streak circled in purple in Figure 4(C), representing
only 1.2% of the surface. This low percentage does not reflect the strength and structureꢀ
directing effect that such an interaction has on the solidꢀstate behavior of the molecule.
The contacts H ··H constitute 14.4% of the surface, with a short contact between a methyl
proton and a methyl proton of a nearby molecule (2.77) Å, ∠= 118.4°, highlighted in black
in Figure 4(D), giving rise a zigzag chain of CH3 groups.

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Figure 4. (a) Packing diagram with short contacts highlighted: Cl···Cl (purple), pairꢀwise
O···H (blue). (b) CH(2B)···O(12) and CH(3B)···O(12) interactions are represented on the
surface of Hirshfeld as intense red color points. (c) dnorm surfaces displaying the pairꢀwise
O···H interaction. (d) Fingerprint plot with circled characteristic interactions: Cl···Cl
(purple), O···H (blue), and H···H (black).
3.3. NBO analysis
Natural bond orbital (NBO) analysis has often been used in the evaluation of the anomeric
effect and to explain the origin of the internal rotation barrier. The NBO analysis allows to
estimate the energy of the molecule with the same geometry but in the absence of electronic
delocalization. Moreover, only the steric and electrostatic interactions through ELewis are
taken into account:
(equation 1)
where ꢁELewis represents the energy of the hypothetical localized species described by a
determinant of nearly doubly occupied NBOs comprising the core electrons, lone pairs and

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localized bonds of the Lewis structure and the delocalization energy change, ꢁEdeloc
,
represents the hyperconjugative stabilization contribution to the rotational barrier that arises
from bond→antibond charge transfer.
Table 2. Calculated (B3LYP/6ꢀ311G(3df)]) contributions to the total energy of
CH3SO2CH2SO2OCH2CH2Cl from Lewis energy (ELewis), because of the localized electron
density, and hyperconjugation energy (Edeloc) due to the delocalized electron density.
a
a
a
b
b
b
dimer Etotal
ELewis
Edeloc
ꢀEtotal
ꢀELewis
ꢀEdeloc
ꢀ3581.5427 0.00 ꢀ3577.5377
0.00
4.005 0.00
Cl···Cl ꢀ3581.5389 9.96 ꢀ3577.9380 ꢀ1049.80 3.601 1060.5
ꢀ3581.3104 609.21 ꢀ3577.3211 ꢀ568.04 3.989 41.3
a Absolute energies in Hartrees
b Relative energies in kJ mol–1
NBO calculation in Clomesone was performed for dimers generated by intermolecular
interactions: CH(2B)···O(12) and CH(3B)···O(12)(
); C(1)ꢀH(1B)···O(21) and C(2)ꢀ
H(2A)···O(21) (R6) and Cl···Cl at the B3LYP/6ꢀ311(3df) level of theory. Table 2 presents
the contributions due to the localized (ELewis) and delocalized (Edeloc) electron density for
dimers of the crystal structure. The results show that the delocalization energy plays a
significant role in the stabilization of
interactions for Cl···Cl dimer.
and
dimer and the electrostatic
To complement the structural and conformational study of Clomesone, energy donor →
acceptor interaction analysis was performed by approximating Natural Bond Orbital
(NBO). For the
delocalization is greater for
hydrogen bonds of (~ 160 °) allow a better superposition of the orbitals involved in
and
dimers stabilization, the electronic LP O → σ*CꢀH
than for , since the angles established in the
the hyperconjugative interactions (Table 3).
The LPπO(3) → σ*C(2)ꢀS(2) and LPπO(11/12) →σ*S(1)ꢀC(1)/σ*S(1)ꢀC(2) electronic
delocalizations influence the value of the dihedral angles C(2)S(2)O(3)C(3) and C(1)S(1)

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C(2)S(2), respectively. These values correspond to gauche forms, characteristic of
sulfonates and sulfones, where the mesomeric effect is responsible of the adopted structure.
This behavior has already been reported for these systems.52ꢀ54
The largest delocalization in each unit of the dimer is caused by LPπO(21/22) → σ*S(2)ꢀ
O(3) charge transfer, increasing the stability to the SO2ꢀO group. Therefore, these
sulfonates are good groups of donors bound to SO2ꢀOꢀ, these results agree with the
experimental results of Kenedy et al.19 This group found that at pH values below the pKa of
clomesone, the main degradation products were chloroethanol and (methylsulfonyl)
methanesulfonate I produced by cleavage of a CꢀO bond instead of an SꢀO clomesone.26,55
This delocalization is at its highest value for the Cl···Cl dimer (Table 3), which shows that
the Cl ... Cl interaction is purely electrostatic but also due to the effect of polarization and
dispersion that occurs in the electron density around the Cl.2
Table 3. Report of the most important hyperconjugative interaction contributions (kJ molꢀ
1).
Donor → Acceptor
Cl···Cl
ꢀ
ꢀ
LP σ O(3) →σ*C(3)ꢀ C(4) 3.4
15.1
4.6
13.4
10.0
31.4
5.9
13.5
→σ* S(2)ꢀO(21)
→σ* S(2)ꢀO(22) 10.0
20.1
6.0
LPπO(3) →σ* C(2)ꢀ S(2) 29.4
→σ* C(2)ꢀ S(1) 6.5
19.7
ꢀ
12.5
7.4
11.6
7.4
→σ* S(2)ꢀO(21)
→σ* S(2)ꢀO(22)
11.0
3.0
ꢀ
→σ*C(3)ꢀ C(4) ꢀ
0.8
LP σ O(11/12) →σ* S(1)ꢀC(1) 3.4
2.5
2.8
2.6
4.9
→σ* S(1)ꢀC(2)
5.5
4.4
→σ* S(1)ꢀO(11/12)
72.2
89.5
88.3
84.0
108.1
96.4
LPπO(11/12) →σ* S(1)ꢀC(1) 77.0
→σ* S(1)ꢀC(2) 93.3
→σ* S(1)ꢀO(11/12) 92.4

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4.0
4.3
LP σ O(21/22) →σ* S(2)ꢀC(2) 4.1
→σ* S(2)ꢀO(21/22) 6.0
5.9
5.6
80.3
95.2
130.4
90.2
2.51
0.63
0.88
1.55
0.54
LPπO(21/22) →σ* S(2)ꢀC(2) 86.0
126.5
126.9
→σ* S(2)ꢀO(3)
85.9
→σ* S(2)ꢀO(21/22) 88.0
LP σ O(11A) →σ*C(1)ꢀ H(1B) ꢀ
LP σ O(21A) →σ*C(1)ꢀ H(1B) ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
LP σ O(21A) →σ*C(2)ꢀ H(2A)
LP π O(21A) → C(1)ꢀH(1B) ꢀ
LP π O(21A) → σ*C(2)ꢀ H(2A) ꢀ
6.48
LPσO(12) →σ* C(2)ꢀ H(2B)
→σ* C(3)ꢀ H(3B)
1.0
LPπO(12) →σ* C(2)ꢀ H(2B) 5.4
→σ* C(3)ꢀ H(3B) 3.1
a
LP is a lone pair on the specified atom. See Figure 1 for atom numbering.
bCalculated using the B3LYP/6ꢀ311G(3df) method
3.4. AIM analysis
One final attempt was made to rationalize the structure of Clomesone. Bader’s Atomsꢀinꢀ
Molecules (AIM) quantum theory9 has repeatedly shown to be helpful in bond
characterization, through a topological analysis of the electronic charge density and its
Laplacian at the bond critical point. The nature of the bonding interaction can be
determined analyzing the charge density ρ(r) and its Laplacian ∇2(ρ) at the bond critical
point (BCP), and through the atoms properties, which are obtained integrating the charge
density over the atomic basin. The results predict a stabilizing intramolecular bonding
involving O(22) and H(1A)ꢀC (1) and intermolecular contacts previously described as
Cl···Cl and hydrogen bond type.

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Table 4. Local topological properties of the electron charge density (in au) at the bond,
ring, and cage critical points in the intermolecular region for Clomesone.
∇2(ρ) V/G λ1/λ3
Contact
Bond
ρ(r)
Eint (cal)
Intramolecular C(1)ꢀH(1A)...O(22)
Intermolecular
0.00841 0.02926 0.832 0.1656 1.63
C(2)ꢀH(2B) ··O(12)#3 0.01199 0.04900 0.755 0.1680 2.33
C(3)ꢀH(3B) ··O(12)#3 0.00625 0.02238 0.772 0.1663 1.10
C(2)ꢀH(2A) ··O(21)#1 0.00615 0.02337 0.756 0.1625 1.11
C(1)ꢀH(1B) ··O(21)#1 0.00697 0.02630 0.761 0.1638 1.26
C(1)ꢀH(1B) ··O(21)#1 0.00697 0.02630 0.761 0.1638 1.26
C(1)ꢀH(1B) ··O(11)#1 0.00910 0.03712 0.739 0.1631 1.70
2
R1 (6)
1
R2 (6)
Cl···Cl
Cl···Cl
0.003141 0.00872 0.695 0.1494 0.36
Table S7 shows the properties of the electronic charge density in some selected BCP´s of
the studied molecule. The values of ρ(r) and ∇2ρ(r) for the CꢀC, CꢀS, SꢀO, CꢀH and CꢀCl
bonds are typical of a shared or covalent interaction, which is dominated by a contraction of
ρ(r) towards the bond path, leading to its accumulation in the internuclear region. The ρ(r)
values are within the (0.177 ꢀ 0.323) au range and ∇2ρ(r) are in the (−0.130 ꢀ −0.860) au
range.
Table 4 shows topological and energetic properties for six intermolecular and one
intramolecular hydrogen bonds localized in the motive: ρ(r) and ∇2ρ(r) values are in the
(0.00625 ꢀ 0.01199) and (0.2238 ꢀ 0.04900) au ranges and are both positive being typical of
weak hydrogen bonds. The charge density and Laplacian are within the range proposed by
Koch and Popelier56 for Hꢀbond interactions that is 0.002–0.034 au and 0.024–0.139 au for
charge density and Laplacian, respectively.
For Cl ··Cl interaction, the ρ(r) and ∇2ρ(r) values are 0.003141 and 0.00872 au,
respectively. Furthermore, the magnitudes of the kinetic energy density are greater than
those of the potential energy density for all these interactions leading to |V|/G < 1 and H >
0,showing that these mainly electrostatic (δ+···δ−) interactions are very weak.

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The lower energy (Eint=1/2V) corresponds to the Cl ··Cl interaction and the higher to the
C(2)ꢀH(2B) ··O(12)#3 interaction of the R(7) ring.
3.5. Vibrational analysis
The experimental Raman and infrared spectra of CH3SO2CH2SO2OCH2CH2Cl are shown in
Figure S1. The observed and calculated wavenumbers, relative intensities and tentative
assignment of fundamental vibration modes are given in Table S8. The experimental
spectra were measured in solid phase, while calculated ones were performed as monomer
and dimer at the B3LYP/6ꢀ311G(3df) level (Figure 5).
Figure 5. Infrared spectra of Clomesone between 1550 and 400 cmꢀ1: (upper trace) solid
state; (resolution 2 cmꢀ1, path length 10 cmꢀ1); calculated dimer (medium trace); calculated
monomer (lower trace). The theoretical spectra are obtained from the frequencies
(B3LYP/6ꢀ311G (3df)) calculated from the force field scales.
CH3 modes. The bands at 3038 and 2938 cmꢀ1 in IR and Raman spectra is assigned to the
CH3 asymmetric and symmetric stretching mode respectively. The weak intense bands at
1414 and 1390 cmꢀ1 are assigned to the CH3 asymmetric bending, while the symmetric

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mode is attributed to the medium band at 1301 cmꢀ1. The CH3 rocking modes are assigned
to the weak and the medium band at 982 and 956 cmꢀ1, respectively.
CH2 modes. In the infrared and Raman spectra, the C(2)H2 asymmetric and symmetric
stretching modes appear at 3038 and 2990 cmꢀ1, respectively. The bands at 3022 and 2990
cmꢀ1 are assigned to the C(4)H2 asymmetric and symmetric stretching modes, respectively.
(Figure 6) C(3)H2 symmetric stretching mode can be attributed to the absorption at 2928
cmꢀ1. The CH2bending modes are assigned at 1462 cmꢀ1 (δC(3)H2), 1430 cmꢀ1 (δC(4)H2)
and 1361 cmꢀ1 (δ C(2)H2).The shoulders at 1354 and 1253 cmꢀ1 are attributed to wagging of
the C(3)H2 and C(4)H2 groups, respectively. The medium intense band at 1200 cmꢀ1 is
associated with the ωC(2)H2 mode. The twisting mode of the C(3)H2, C(4)H2 and
C(2)H2groups appear at 1237, 1186 and 1125cmꢀ1, respectively.
Figure 6. Experimental (lower trace) and theoretical Raman spectra (monomer and dimer)
in the 3500ꢀ2500 cmꢀ1 region.

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SO2 modes.
Figure 7 shows the experimental and calculated infrared spectrum of the Clomesone in the
stretching region of the SO2 group. They are clearly observed four intense bands
corresponding to both SO2 groups present in the molecule, sulfonate (S(2)O2) and sulfone
(S(1)O2). Two intense bands at 1370 and 1177 cmꢀ1 are assigned to the ν S(2)O2
asymmetric and symmetric modes, respectively. The very strong band at 1318 cmꢀ1 and the
intense band at 1166 cmꢀ1 are assigned to the ν S(1)O2 asymmetric and symmetric modes,
respectively. At 1334 and 1187 cmꢀ1 appear two weak absorptions that correspond to the
asymmetric and symmetric stretching modes of S(1)O(12) ··H(2)ꢀC(2) (Figure 7 ꢀ stars).
Figure 7. Experimental and theoretical infrared spectra in the 1500ꢀ1000 cm ꢀ1 region. The
stars correspond to the asymmetric and symmetric stretching modes of S(1)O(12) ··H(2)ꢀ
C(2).
The remaining bands corresponding to the vibrations of the whole S(2)O2 group appear at
relatively low frequencies: 598 cmꢀ1 (wagging); 528 cmꢀ1 (bending) and 352 cmꢀ1 (twisting).
Besides, the infrared bands at 507 cmꢀ1 (bending), 464 cmꢀ1 (wagging) and the Raman band

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at 271 cmꢀ1 (twisting) are assigned to the S(1)O2 group, which are also supported by
computed and previous results.52ꢀ55
Figure 8. Experimental (lower trace) and theoretical (upper trace) Raman spectra in the
1500ꢀ100 cmꢀ1 region.
Skeletal modes. The C(2)ꢀS(2), C(1)ꢀS(1),and C(2)ꢀS(1) stretching modes are associated
with the bands located at 790, 766 and 699 cmꢀ1, respectively. The medium band in the
infrared spectrum at 667 cmꢀ1 is assigned to the C(3)ꢀCl stretching. In addition, the C(3)ꢀ
O(3), C(4)ꢀC(3) and S(2)ꢀO(3) stretching modes are located at 988, 1072, and 758 cmꢀ1,
respectively (Figure 8).
3.6. Biological results
This is the first study on the methansulfonate complex different to the
Colistinmethansulfonate (CMS), as well as the first study on a methansulfonate complex
with respect to QS activity.

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The results showed that Clomesone is unable to inhibit the bacterial growth of P.
aeruginosa or S. aureus in the range of assayed concentrations. However, it produces
significant inhibition on the biofilm formation, mainly in P. aeruginosa. The biofilm
formation of the strain of P. aeruginosa PAO1 diminished 63% in presence of 200 µg/mL
of Clomesone and the inhibition of the strain PA14 was 22% at the same concentration.
Considering that PAO1 and PA14 are the main studied strains for the biofilm inhibition due
to their higher capacity to form biofilm with different strategies of virulence and since
biofilm formation of both strains was inhibited by Clomesone, this suggests the possibility
to use this compound as antipathogenic one.
Antipathogenic compounds do not kill bacteria or inhibit bacterial growth, but they rather
control bacterial QS and biofilm formation, preventing the development of resistant
strains.57
There is a linear correlation between growth inhibition and biofilm formation for P.
aeruginosa strain PA14. Moreover, the biofilm inhibition was greater than the inhibition of
bacterial development in the other two studied strains; indicating that Clomesone not only
affects the growth but also the formation of biofilm (Figures 9-11).
Figure 9: Growth (ꢀ) and biofilm production (ꢁ) by P. aeruginosa PAO1 cultures grown
in LB broth in absence and presence of 10, 100, and 200 µg/mL of Clomesone. The

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inhibitor control used was CIP (Ciprofloxacin) 1 µg/mL. The error bars indicate standard
deviation (n=8).
Figure 10: Growth (ꢀ) and biofilm production (ꢁ) by P. aeruginosa PA14 cultures
grown in LB broth in absence and presence of 10, 100, and 200 µg/mL of Clomesone. The
inhibitor control used was CIP (Ciprofloxacin) 1 µg/mL. The error bars indicate standard
deviation (n=8).
Figure 11: Growth (ꢀ) and biofilm production (ꢁ) by S. aureus cultures ATCC
6528grown in MH broth in absence and presence of 10, 100 and 200 µg/mL of Clomesone.

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The inhibitor control used was CIP (Ciprofloxacin) 1 µg/mL. The error bars indicate
standard deviation (n=8).
According to the obtained results, the potential QS inhibitory effect of the compound was
studied using the biosensor Chromobacteriumviolaceum CV026. The inhibition halo was
9.9 ± 0.5 cm for Clomesone and it showed bacterial growth indicating the QS inhibition
(Figure 12). The observed decrease was significant and comparable with previously
reported QS inhibitors at the same concentration.58
Figure 12.Competitive inhibition of violacein production induced by NꢀhexanoylꢀLꢀ
homoserine lactone in C. violaceum CV026 by CLMSMS (b).Control (a)
A complex of methansulfonate is used for the administration of colistin. Colistin
methansulfonate (CMS) is a prodrug that is hydrolyzed after intravenous administration to
produce several derivatives, predominantly the active drug colistin. This complex is used to
control P. aeruginosa colonization of the airway to prevent the pneumonia development
because toxicity decreased significantly with respect to colistin.50 This was the only
methansulfonate complex previously studied with respect to biofilm target. The bactericidal
effect of CMS on biofilmꢀforming cells of strain multidrugꢀresistant P aeruginosa was poor
compared with those on the planktonic cells. These in vitro obtained results indicated that
the efficacy of administered CMS depends on the resistance of the biofilm formed.49

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According to our results, Clomesone acts in the same way as CMS, inhibiting
biofilm more than growth and its significant effect on biofilm could be explained by the QS
inhibition.
The competitive inhibition of the Clomosone with HHL could be because they have
similar electronic delocalization in their active sites. In addition, it was observed that
Clomesone is more active than CMS although both have a sulfonate group in their
structure.
At pH 5, Clomesone ionization takes place with the release of a chloroethyl cation
and a highly electrophilic site in the sulfonate group. The greater biofilm inhibition´s ability of
Clomosome compared to that reported for CMS, in spite of having the same active site
(sulfonate group), it can be attributed to the different electronegativity of the environment.
Besides, the much larger size of the CMS would be responsible of the low competitive
inhibition with HHL due to steric hindrance (Figure S2), whereas that in Clomesone the
active site where the autoinducer joins is favored due to its smaller size.
The stretching bands of the Clomesone sulfonate group are observed at 1370, 1177
and 758 cmꢀ1 (assigned to νas S=O, νs S=O and ν SꢀO, respectively). These vibrational
frequencies are suitable to characterize and identify Clomesone when it is part of a
biological matrix. The band position of sulfonate group is directly related to the
electronegativity of the neighboring groups. A greater electronic delocalization around this
group turns it into a more attractive electrophilic site.54
CONCLUSIONS
2ꢀchloroethyl (methylsulfonyl) methanesulfonate, Clomesone, was prepared as reported in
the literature with slight modifications. Its solid state molecular structure was determined
by Xꢀray diffraction methods. The crystal is stabilized by strong intermolecular Hꢀbonds
and Cl ··Cl interactions and the molecule conformation stabilized by an intraꢀmolecular Hꢀ
bonds. As this compound presents strong intermolecular Hꢀbond interactions, the quantum
chemical calculation was performed on its dimeric form. These computations were in very
good agreement with the experimental results concerning both geometric and vibrational
features.

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The delocalization in each unit of the dimer is produced from LPπO(21/22) →σ*S(2)ꢀO (3)
transition, stabilizing the SO2ꢀO moeity, this is the reason why these sulfonates are good
donating groups attached to the SO2ꢀOR. These results are complemented by AIM study
which predicts that the lower energy (Eint=1/2V) corresponds for the Cl ··Cl interaction
and the higher to the C(2)ꢀH(2B)...O(12)#3 interaction of the R(7) ring.
IR and Raman spectra were obtained for Clomesone and the vibrational data were used as a
basis to perform an approximate description of the modes. The spectroscopic
characterization of Clomesone results useful for its identification in pharmaceuticals and
biological matrices and may be valuable in the standardization of Clomesone formulations,
in pharmacokinetics studies, and potentially in therapeutic drug monitoring. In covalent
sulfones, the SO2 stretching modes are very sensitive to intermolecular hidrogen bonds.
In addition, Clomesone tests were performed with different biological media. The results
showed that Clomesone is unable to inhibit the bacterial growth of P. aeruginosa or S.
aureus in the range of assayed concentrations, but produces significant inhibition on the
biofilm formation mainly in P. aeruginosa. The fact that Clomesone inhibits the
mechanism of bacterial communication, Quorum sensing, analogous to the mechanism of
metastasis formation, suggests the possibility of some other mechanism of action of this
antineoplastic, which should be studied.
The greater biofilm inhibition of Clomosone suggests that sulfonate anion, remainig after
ionization, is possibly the active group. This novel result supports that the spectroscopic
characterization is fundamental in pure Clomosone, and the next target will be the
spectroscopic characterization of the biological system.
Acknowledgements
The authors wish to thank Consejo de Investigaciones de la Universidad Nacional de
Tucumán (CIUNT), Consejo Nacional de Investigaciones Científicas y Técnicas, PIP 002
and PIP 0359 (CONICET), ANPCyT (PICT2013ꢀ 0697), Universidad Nacional de La Plata
(UNLP) and Departamento de Ciencias Básicas de la Universidad Nacional de Luján
(UNLu) for financial support. S.E.U especially thanks Deutscher Akademischer
Austauschdienst Germany (DAAD) for the FTIR spectrometer grant and financial support.

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Supporting Information available:
The supporting information includes:
Crystal data and structure refinement results for 2ꢀchloro (methylsulfonyl) methanesulfonate
4
(Table S1); Atomic coordinates (x 10 ) and equivalent isotropic displacement parameters
2
3
(Å x 10 ) for 2ꢀchloro (methylsulfonyl) methanesulfonate. To be deposited (Table S2);
2
3
Anisotropic displacement parameters (Å x 10 ) for 2ꢀchloro (methylsulfonyl)
4
methanesulfonate. To be deposited (Table S3); Hydrogen coordinates (x 10 ) and isotropic
2
3
displacement parameters (Å x 10 ) for the 2ꢀchloro (methylsulfonyl) methanesulfonate. To
be deposited (Table S4);Theoretical and experimental geometric parameter of the
Clomesone (Table S5); Theoretical Inter / intramolecular hydrogen bonds of the dimer
form for Clomesone, calculated at B3LYP/6ꢀ311(3df) level (Table S6); Observed and
Calculated Frequencies, Infrared and Raman Intensities for Clomesone (Table
S7);Topological properties of Clomesone calculated at B3LYP/6ꢀ311G(3df) level (Table
S8); Infrared and Raman spectra of Clomesone in solid state (Figure S1). View of
Clomesone, NꢀhexanoylꢀLꢀhomoserine lactone, CH3SO2CH2SO2Oꢀ and Colistin
methansulfonate (CMS) (Figure S2).
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