Three Nimesulide Derivatives: Synthesis, Ab Initio Structure Determination from Powder X-ray Diffraction, and Quantitative Analysis of Molecular Surface Electrostatic Potential

Article abstract of DOI:10.1021/acs.cgd.5b01547

Three nimesulide derivatives, N-[4-(2,5-dioxo-pyrrolidin-1-yl)-2-phenoxyphenyl] methanesulfonamide (2), N-[4-(4-methanesulfonylamino-3-phenoxy phenylsulfamoyl) phenyl] acetamide (3), and 4-(4-methanesulfonylamino-3-phenoxyphenyl-carbamoyl)-butanoic acid (4), have been synthesized, and their crystal structures have been determined from laboratory powder X-ray diffraction data. The nature of intermolecular interactions in 2-4 has been analyzed through Hirshfeld surfaces and two-dimensional fingerprint plots and compared with that in the nimesulide polymorphs (1a and 1b). The crystal packing in 2-4 exhibits an interplay of N-H?O, O-H?O (in 4), C-H?O, and C-H?π (in 2) hydrogen bonds, which assemble molecules into a supramolecular framework. Hydrogen-bond based interactions in 2-4 have been complemented by calculating molecular electrostatic potential surfaces. In a competitive molecular recognition situation, the effectiveness of the -NH moiety as a hydrogen bond donor is comparable to that of the -COOH moiety in 4. Hirshfeld surface analyses of 2-4 as well as a few related nimesulide derivatives indicate that about 90% of the Hirshfeld surface areas in these compounds are due to H?H, C?H, and O?H contacts.

Full text of DOI:10.1021/acs.cgd.5b01547

Subscriber access provided by ORTA DOGU TEKNIK UNIVERSITESI KUTUPHANESI
Article
Three Nimesulide Derivatives: Synthesis, Ab-initio Structure
Determination from Powder X-ray Diffraction and Quantitative
Analysis of Molecular Surface Electrostatic Potential
Tanusri Dey, Paramita Chatterjee, Abir Bhattacharya, Sarbani Pal, and Alok K Mukherjee
Cryst. Growth Des., Just Accepted Manuscript • DOI: 10.1021/acs.cgd.5b01547 • Publication Date (Web): 25 Jan 2016
Downloaded from http://pubs.acs.org on January 27, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Crystal Growth & Design is published by the American Chemical Society. 1155
Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 40
Crystal Growth & Design
1
2
3
4
5
6
7
8
9
Three Nimesulide Derivatives: Synthesis, Abꢀinitio Structure Determination
from Powder Xꢀray Diffraction and Quantitative Analysis of Molecular
Surface Electrostatic Potential
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
Tanusri Deya, Paramita Chatterjeea,b, Abir Bhattacharyac, Sarbani Pald and Alok K. Mukherjeea,*
a Department of Physics, Jadavpur University, Jadavpur, Kolkataꢀ700032, India.
b Department of Physics, Lady Brabourne College, Kolkataꢀ700017, India.
c Department of Physics, Amity University, Kolkataꢀ700156, India.
d
Department of Chemistry, MNR Degree and PG College, Kukatpally, Hyderabadꢀ500072,
India.
Abstract
Three nimesulide derivatives, Nꢀ[4ꢀ(2,5ꢀdioxoꢀpyrrolidinꢀ1ꢀyl)ꢀ2ꢀphenoxyphenyl]
methanesulfonamide (2), Nꢀ[4ꢀ(4ꢀmethanesulfonylaminoꢀ3ꢀphenoxy phenylsulfamoyl) phenyl]
acetamide (3) and 4ꢀ(4ꢀmethanesulfonylaminoꢀ3ꢀphenoxyphenylꢀcarbamoyl)ꢀbutanoic acid (4),
have been synthesized and their crystal structures have been determined from laboratory powder
Xꢀray diffraction data. The nature of intermolecular interactions in 2ꢀ4 has been analyzed
through Hirshfeld surfaces and 2D fingerprint plots, and compared with that in the nimesulide
polymorphs (1a and 1b). The crystal packing in 2ꢀ4 exhibits an interplay of NꢀH…O, OꢀH…O
(in 4), CꢀH...O and CꢀH…π (in 2) hydrogen bonds, which assemble molecules into
supramolecular framework. Hydrogenꢀbond based interactions in 2ꢀ4 have been complemented
by calculating molecular electrostatic potential (MEP) surfaces. In a competitive molecular
recognition situation, the effectiveness of ꢀNH moiety as hydrogen bond donor is comparable to
that of ꢀCOOH moiety in 4. Hirshfeld surface analyses of 2ꢀ4 as well as a few related nimesulide
derivatives indicate that about 90% of the Hirshfeld surface areas in these compounds are due to
H…H, C…H and O…H contacts.
Corresponding author
Alok K. Mukherjee
Department of Physics, Jadavpur University, Jadavpur, Kolkataꢀ700032, India.
Eꢀmail: akm_ju@rediffmail.com, Phone No. +919331041417, Fax: 033 24138917
1
ACS Paragon Plus Environment

Crystal Growth & Design
Page 2 of 40
1
2
3
4
5
6
7
8
9
Three Nimesulide Derivatives: Synthesis, Abꢀinitio Structure Determination
from Powder Xꢀray Diffraction and Quantitative Analysis of Molecular
Surface Electrostatic Potential
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
Tanusri Deya, Paramita Chatterjeea,b, Abir Bhattacharyac, Sarbani Pald and Alok K. Mukherjeea,*
a Department of Physics, Jadavpur University, Jadavpur, Kolkataꢀ700032, India.
b Department of Physics, Lady Brabourne College, Kolkataꢀ700017, India.
c Department of Physics, Amity University, Kolkataꢀ700156, India.
d
Department of Chemistry, MNR Degree and PG College, Kukatpally, Hyderabadꢀ500072,
India.
Eꢀmail: akm_ju@rediffmail.com
Abstract
Three nimesulide derivatives, Nꢀ[4ꢀ(2,5ꢀdioxoꢀpyrrolidinꢀ1ꢀyl)ꢀ2ꢀphenoxyphenyl]
methanesulfonamide (2), Nꢀ[4ꢀ(4ꢀmethanesulfonylaminoꢀ3ꢀphenoxy phenylsulfamoyl) phenyl]
acetamide (3) and 4ꢀ(4ꢀmethanesulfonylaminoꢀ3ꢀphenoxyphenylꢀcarbamoyl)ꢀbutanoic acid (4),
have been synthesized and their crystal structures have been determined from laboratory powder
Xꢀray diffraction data. The nature of intermolecular interactions in 2ꢀ4 has been analyzed
through Hirshfeld surfaces and 2D fingerprint plots, and compared with that in the nimesulide
polymorphs (1a and 1b). The crystal packing in 2ꢀ4 exhibits an interplay of NꢀH…O, OꢀH…O
(in 4), CꢀH...O and CꢀH…π (in 2) hydrogen bonds, which assemble molecules into
supramolecular framework. Hydrogenꢀbond based interactions in 2ꢀ4 have been complemented
by calculating molecular electrostatic potential (MEP) surfaces. In a competitive molecular
recognition situation, the effectiveness of ꢀNH moiety as hydrogen bond donor is comparable to
that of ꢀCOOH moiety in 4. Hirshfeld surface analyses of 2ꢀ4 as well as a few related nimesulide
derivatives indicate that about 90% of the Hirshfeld surface areas in these compounds are due to
H…H, C…H and O…H contacts.
2
ACS Paragon Plus Environment

Page 3 of 40
Crystal Growth & Design
1
2
3
4
Introduction
5
6
7
8
9
Intermolecular interactions, in particular, hydrogen bonds have been a topic of
considerable importance across many scientific disciplines1ꢀ3, and it is indeed the basis of life
due to its structural role, in DNA2, 4, 5, enzymes6ꢀ8 and proteins9ꢀ11. In crystal engineering
perspective, hydrogen bonds play a key role for the assembly and organization of organic
building blocks using the concept of motifs and synthons12, 13. In pharmaceutical science, the
active pharmaceutical ingredients (APIs), which enable the efficacy of drug delivery system, are
inherently amenable to crystal engineering as they contain functional groups with multiple
hydrogen bond donors and acceptors14ꢀ17. Many of the synthons involving N/OꢀH…O/N
hydrogen bonds possess the requisite robustness and reproducibility for the design and synthesis
of new solidꢀstate materials with desirable structure and properties18, 19. In addition to relatively
strong hydrogen bonds, weak interactions such as CꢀH…X (X=O, N), C/NꢀH…π hydrogen
bonds and π…π stacking also influence significantly the selfꢀassembly process in organic
compounds. These interactions are individually weaker and geometrically less wellꢀdefined, their
combined effect, however, can be equally important as strong interactions20, 21. The distance and
directional criteria of specific hydrogen bonds made by the functional groups in molecules have
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
been generally used in describing the crystal packing of molecular solids22ꢀ24
.
Etter25, 26 developed a set of empirical rules useful for determining preferred modes of
hydrogen bonding. However, most hydrogen bonds are primarily electrostatic in nature and vary
in strength according to the different donor/acceptor properties of functional groups and their
environment, thus predicting supramolecular structures driven by hydrogen bonding can be
challenging27ꢀ30. In this context, effective means for ranking hydrogenꢀbond donor and acceptor
groups could provide useful guidelines for designing new materials. Hunter and coꢀworkers31, 32
proposed a strategy for ranking the relative strength of hydrogenꢀbond donors and acceptors
based on molecular electrostatic potential (MEP) surface value. An extensive body of work
correlating MEP with crystal packing via intermolecular interactions has been reported33ꢀ37
.
In general, knowledge of crystal structure is a perquisite for understanding intermolecular
interactions and other properties of crystalline materials. Although single crystal Xꢀray
diffraction (XRD) is the method of choice for determining crystal structures of molecular
compounds, an intrinsic limitation of this approach is the requirement to obtain single crystal of
3
ACS Paragon Plus Environment

Crystal Growth & Design
Page 4 of 40
1
2
3
4
5
6
7
8
9
appropriate size and quality that make them amenable to structure analysis. As many important
materials including the present nimesulide derivatives are available only as microcrystalline
powder, structure determination directly from powder Xꢀray diffraction (PXRD) is highly
desirable. The task of crystal structure determination from Xꢀray powder diffraction is, however,
considerably more challenging than that of its single crystal counterpart38 because, first, the
information content of a powder diffraction is markedly lower and second, it is far more difficult
to extract structural information from a PXRD pattern due to systematic as well as random
overlapping of peaks. Fortunately, there have been significant advances in recent years in the
techniques for carrying out abꢀinitio structure determination of organic molecular solids directly
from PXRD data, particularly through the development of the directꢀspace strategy for structure
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
solution39ꢀ45
.
Nimesulide, Nꢀ(4ꢀnitroꢀ2ꢀphenoxyphenyl) methanesulfonamide (1), is a well known nonꢀ
steroidal antiꢀinflammatory drug (NSAID), which can inhibit cyclooxygenaseꢀ2 (COXꢀ2)
enzyme selectively46. Since the nitro group in 1 is known to be associated with toxic side effects
including gastrointestinal erosions47ꢀ49, several nimesulide derivatives aiming at improving its
tolerability profile and reducing its toxicity have been reported by changing in 1 the nitro group
with an appropriate electron withdrawing moiety49ꢀ51. With this background, we synthesized
three
nimesulide
derivatives,
Nꢀ[4ꢀ(2,5ꢀdioxoꢀpyrrolidinꢀ1ꢀyl)ꢀ2ꢀphenoxyphenyl]
methanesulfonamide (2), Nꢀ[4ꢀ(4ꢀmethanesulfonylaminoꢀ3ꢀphenoxy phenylsulfamoyl) phenyl]
acetamide (3) and 4ꢀ(4ꢀmethanesulfonylaminoꢀ3ꢀphenoxyphenylꢀcarbamoyl)ꢀbutanoic acid (4),
with different aromatic/aliphatic substitutions replacing the nitro group in nimesulide (1) to
analyze differences in crystal packing due to changes in the substituents. Since our attempts to
grow suitable single crystals of 2ꢀ4 for Xꢀray analysis resulted in assemblies of microcrystals,
structure determination was attempted from Xꢀray powder diffraction. Intermolecular hydrogen
bonds facilitating supramolecular structures in 2ꢀ4 have been discussed with a detailed
assessment of molecular electrostatic potential (MEP) surface for ranking different hydrogen
bond donor and acceptor groups. An investigation of close intermolecular interactions in 2ꢀ4,
nimesulide (1) and a few related substituted nimesulide derivatives via Hirshfeld surface analysis
is also presented.
4
ACS Paragon Plus Environment

Page 5 of 40
Crystal Growth & Design
1
2
3
4
Experimental Section
5
6
7
Materials and general methods
8
9
All chemicals were obtained from commercial sources and used without further
purification. Solvents were dried using the standard method, and chromatographic purification
was performed using silica gel (100ꢀ200 mesh). Elemental analysis was carried out with a
PerkinElmer 240 C analyzer. Fourier transform infrared (FTIR) spectra were recorded on a
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
1
Perkin Elmer Spectrum Bx II Spectrometer as KBr pellets. H NMR and 13C NMR were
measured at 22° C using a Bruker DPXꢀ300 Spectrometer using CDCl3 or DMSOꢀd6 as solvent.
Mass spectra were recorded on a Jeol JMC Dꢀ300 instrument with an electron ionization
potential of 70 eV. Melting points were determined by an open glass capillary method and were
uncorrected.
Synthesis
Nꢀ(4ꢀaminoꢀ2ꢀphenoxy phenyl) methanesulfonamide (1′) was prepared by reduction of
Nꢀ(4ꢀnitroꢀ2ꢀphenoxy phenyl) methanesulfonamide (1, nimesulide) using Sn and HCl. The
reaction was carried out at 90° C for 3 hours (Scheme 1). For the synthesis of 2 and 4, the
aromatic amine (1′) (278 mg, 1.0 mmol) was treated with the corresponding cyclic anhydrides,
2a (148 mg, 1.0 mmol) and 4a (100 mg, 1.0 mmol), according to the desired product followed by
refluxing in glacial acetic acid (3 ml) for 1 hour in presence of anhydrous sodium acetate
(Scheme 1). After completion of reaction (monitored by TLC at regular intervals), the reaction
mixture was quenched in crushed ice and stirred. The solid mass separated was filtered and
dried. The crude product on purification by column chromatography on silica gel (100ꢀ200
mesh) using chloroformꢀethyl acetate (3:1) and crystallization from aqueous methanol (1:1)
yielded
microcrystalline
powders
of
Nꢀ[4ꢀ(2,5ꢀdioxoꢀpyrrolidinꢀ1ꢀyl)ꢀ2ꢀ
phenoxyphenyl]methanesulfonamide (2) and 4ꢀ(4ꢀmethanesulfonylaminoꢀ3ꢀphenoxyphenylꢀ
carbamoyl)ꢀbutanoic acid (4). For synthesis of 3, amine (1′) (1g, 3.56 mmol) was dissolved in
dry chloroform and triethylamine (0.6 ml) was added to it. The solution was cooled to 0° C and
sulfonyl chloride (3a, 3.56 mmol) was added drop wise with stirring. The reaction mixture was
further stirred for 15 minutes, poured into water (20 ml) and extracted with chloroform (3×25
ml). Organic layer was collected and washed with 10% HCl (10ml) followed by water (2×10
ml), dried over anhydrous Na2SO4 and concentrated. The residue was crystallized from
5
ACS Paragon Plus Environment

Crystal Growth & Design
Page 6 of 40
1
2
3
4
chloroformꢀethyl acetate (3:1) to yield microcrystalline powder of Nꢀ[4ꢀ(4ꢀ
5
6
methanesulfonylaminoꢀ3ꢀphenoxy phenylsulfamoyl) phenyl] acetamide (3).
7
8
9
N-[4-(2,5-dioxo-pyrrolidin-1-yl)-2-phenoxyphenyl]methanesulfonamide (2)
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
1
Colorless solid; mp 226(2) ºC; IR (KBr) νmax/cmꢀ1: 1707; HNMR (300 MHz, CDCl3) d 2.7 (s,
13
4H), 3.1 (s, 3H), 6.8 (s, 1H), 7.1( m, 3H,), 7.3 (m, 1H), 7.4 (m, 3H), 9.5 (s, NH,); CNMR (75
MHz, CDCl3) d 28.3 (CH2), 39.8 (CH3), 115.9 (CH), 119.1 (CH), 120.8 (CH), 122.1 (CH),
124.8 (CH), 128.1(C), 128.6 (C), 130.2 (CH), 147.2 (C), 155.1 (C), 175.7 (CO); Mass 361 (M+,
100%); Elemental analysis found: C 56.70, H 4.50, N 7.74%; calculated for C17H16O5N2S; C
56.66, H 4.47, N 7.77%.
N-[4-(4-methanesulfonylamino-3-phenoxy phenylsulfamoyl) phenyl] acetamide (3)
Colorless solid; mp 185(2) ºC; IR (KBr) νmax/ cmꢀ1: 3231, 3315, 1658, 1604; H NMR (200
1
MHz, DMSOꢀd6) δ 9.87 (s, 1H), 9.77 (s, 1H), 8.17 (s, 1H), 6.74ꢀ7.78 (m, 12H), 2.16 (s, 3H),
2.89 (s, 3H), 9.77 (s, 1H), Mass 476 (M+, 100%); Elemental analysis found: C 53.18, H 4.25, N,
8.95%; calculated for C21H21 O6N3S2; C 53.04, H 4.45, N 8.84%.
4-(4-methanesulfonylamino-3-phenoxyphenyl-carbamoyl)-butanoic acid (4)
1
Colorless solid; mp 127(1) ºC; IR (KBr) νmax/cmꢀ1: 1671; HNMR (400 MHz, DMSOꢀd6) d 1.7
(m, 2H), 2.4 (m, 4H), 3.0 (s, 3H), 7.0 (dd, J 8.8 and 1 Hz, 2H), 7.2ꢀ7.3 (m, 4H), 7.42 (m, 2H),
13
10.0 (1H, NH); CNMR (75 MHz, DMSOꢀd6) d 20.2 (CH2), 32.9 (CH2), 35.3 (CH2), 108.6
(CH), 113.8 (CH), 119.1 (CH), 122.3 (C), 123.8 (CH), 127.8 (CH), 129.9 (CH), 138.3 (C), 151.0
(C), 155.9 (C), 170.7 (C), 174.0 (CO); Mass 391 (M+, 100%); Elemental analysis found: C
55.21, H 4.95, N 7.32 %; calculated for C18H20O6N2S; C 55.10, H 5.10, N 7.14%.
Xꢀray Powder Diffraction
Powder Xꢀray diffraction (PXRD) data of 2ꢀ4 were recorded at ambient temperature [293
(2) K] on a Bruker D8 Advance diffractometer operating in the BraggꢀBrentano geometry with
CuKα radiation (λ=1.5418Å) for 2 and 4, and Geꢀmonochromated CuKα1 radiation (λ=1.5406Å)
for 3. The PXRD patterns of 2ꢀ4 were indexed using the NTREOR code52 in the program EXPO
201453 yielding monoclinic unit cells. Given the volume of unit cell and consideration of density,
the number of formula units in the unit cell of 2ꢀ4 turned out as Z=4. Although the correct space
group could not be assigned unambiguously on the basis of systematic absences, statistical
6
ACS Paragon Plus Environment

Page 7 of 40
Crystal Growth & Design
1
2
analysis of PXRD data using the FINDSPACE module of EXPO 201453 indicated the most
probable space group as P21/a for 2 and 4, which were used for structure solution. The unit cell
parameters and space group assignments were validated by a LeꢀBail fit of PXRD data using a
pseudoꢀVoigt peak profile function54 with FOX55. For 3, however, the probable space groups
indicated by EXPO 2014 were P2, P21, Pm, P2/m, P21/m and P21/n. Of these, the frequency of
occurrence of P2, Pm, P2/m and P21/m among the structures in the CSD (version 5.35, 2014
release) is very sparse (0.1ꢀ0.5%), thus the likely space group of 3 was P21/n or P21, and
structure solution was attempted with both space groups. Structure solution of 2ꢀ4 was carried
out by global optimization of structural models in direct space based on a MonteꢀCarlo search
using the simulated annealing technique (in parallel tempering mode), as implemented in the
program FOX55. The optimization of isolated molecules was performed using the energy
gradient method as incorporated in MOPAC 9.056. In 3, the best fit to the experimental data was
found for space group P21/n.
3
4
5
6
7
8
9
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
The best solution (i.e. the structure with lowest Rwp) was used as the initial structural
model of 2ꢀ4 for Rietveld refinement57, which was carried out using the GSAS program58. A
pseudoꢀVoigt peak profile function was used during refinement and the background of the
PXRD patterns in 2ꢀ4 was modeled by a shifted Chebyshev function of the first kind with 20
points regularly distributed over the entire 2θ range. Initially, the lattice parameters, background
coefficients and profile parameters were refined followed by the refinement of the positional
coordinates of all nonꢀhydrogen atoms. Standard restraints were applied to bond lengths and
bond angles, and planar restraints were used for phenyl groups in 2ꢀ4. A common isotropic
displacement parameter was refined for nonꢀhydrogen atoms. Hydrogen atoms in molecules 2ꢀ4
were placed in calculated positions with fixed Uiso values. In the final stages of refinement, a
preferred orientation correction using the generalized spherical harmonic model was applied. The
final Rietveld plots of 2ꢀ4 (Fig. 1) showed good agreement between the observed PXRD profile
and calculated powder pattern, although the observed powder profile of 3 had few very weak
peaks in the 2θ region of 4ꢀ11° (intensity < 1% of the maximum peak) presumably due to
unknown impurity. The molecular views of 2ꢀ4 including the atom labeling scheme are shown
in Fig. 2. A summary of crystal data and relevant refinement parameters for 2ꢀ4 is listed in Table
1.
7
ACS Paragon Plus Environment

Crystal Growth & Design
Page 8 of 40
1
2
3
4
5
6
7
8
Hirshfeld Surface Analysis
Hirshfeld Surfaces59ꢀ61 and associated 2Dꢀfingerprint plots62ꢀ65 were calculated using Crystal
Explorer66, which accepts a structure input file in the CIF format. For each point on the Hirshfeld
isosurface, two distances de, the distance from the point to the nearest nucleus external to the
surface, and di, the distance to the nearest nucleus internal to the surface, are defined. The
normalized contact distance (dnorm) based on de and di is given by
9
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
ꢈꢉꢊ
ꢈꢉꢊ
ꢅ ꢇꢃ
ꢅ ꢇꢃ
ꢋ
ꢋ
ꢆ
ꢆ
ꢀꢁꢂꢃꢄ
=
+
(1)
ꢈꢉꢊ
ꢈꢉꢊ
ꢃ
ꢃ
ꢋ
ꢆ
,where rivdW and revdW being the van der Waals radii of the atoms. The value of dnorm is negative
or positive depending on intermolecular contacts being shorter or longer than the van der Waals
separations. The parameter dnorm displays a surface with a redꢀwhiteꢀblue color scheme, where
bright red spots highlight shorter contacts, white areas represent contacts around the van der
Waals separation, and blue regions are devoid of close contacts.
Computational Study
Density Functional Theory (DFT) calculations were performed in the solid state
(periodic) for 2ꢀ4 with the Dmol3 code67 in the framework of a generalized gradient
approximation (GGA)68. The geometry optimization was carried out using BLYP correlation
functional69,70 with a double numeric plus basis set. The starting atomic coordinates were taken
from the final Xꢀray refinement cycle and geometry optimization was carried out without any
structural constraints.
The molecular electrostatic potential (MEP) is an effective tool for identifying and
ranking the hydrogen bond donating and accepting sites in organic compounds34, 35. The
electrostatic potential at any point ꢌꢍ in the space surrounding a molecule can be expressed by
(
)
ꢒꢒꢒꢍ
ꢖ ꢓꢗ ꢘꢓꢗ
ꢎ
ꢏ
∑
V(rꢍ) =
-
(2)
ꢕ
ꢔ
ꢒꢒꢒꢒꢒꢒꢍ
ꢐꢑ ꢇꢒꢓꢍꢐ
|
ꢒꢒꢒꢍ|
ꢓꢒꢍꢇꢓꢗ
ꢏ
ꢒꢒꢒꢒꢍ
( )
, where zA is the charge of the nucleus A located at ꢙꢚ and ꢛ ꢌꢍ is the molecular electron density
function. The sign of V(rꢍ) at a particular region depends upon whether the effect of the nucleus
or the electrons is dominant there. The MEP surfaces of 2ꢀ4 were generated and the electron
densities including esp charges were evaluated using an isolated molecule DFT calculation
8
ACS Paragon Plus Environment

Page 9 of 40
Crystal Growth & Design
1
2
starting with the geometry optimized models as input in the Dmol3 code with the same set up as
earlier. The electrostatic potentials were plotted on 0.017 au electron density isosurface71. The
MEP surfaces have been mapped with a rainbow color scheme with red representing the highest
negative potential region while blue representing the highest positive potential region.
3
4
5
6
7
8
9
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
Result and discussion
The essential difference between nimesulide (1) and compounds (2ꢀ4) is that the nitro
group at the Cꢀ3 position in 1 has been replaced by different electron donating moieties, a
pyrrolidineꢀ2,5ꢀdione in 2 and substituted benzosulfonamide and acetamide derivatives in 3 and
4, respectively. The overall conformation of molecules in 2ꢀ4 can be described by relative
orientations of oxoꢀbridged phenyl rings (A: C1ꢀC6 atoms and B: C8ꢀC13 atoms) as well as the
substituents at Cꢀ3 position (Fig. 1). The dihedral angles between the least squares planes
through rings A and B in 2ꢀ4 are 86.46(12), 68.74(13) and 68.77(13)°, respectively; the
corresponding angles in two polymorphs of nimesulide, WINWUL(1a)72 and WINWUL01(1b)73
are 74.9(2)° and 72.3(2)/76.4(2)°, respectively. While in 2, the pyrrolidin ring at Cꢀ3 position is
twisted about the C3ꢀN2 bond with respect to the phenyl ring A by 69.7(2)°, the benzene
sulfonamide (N2/S2/O4/O5/C14ꢀC19) fragment in 3 exhibits a syn configuration with respect to
ring A; the torsion angle C3ꢀN2ꢀS2ꢀC14 is ꢀ51.6(5)°. The conformation of carbamoylbutanoic
acid moiety in 4 is established by torsion angles C3ꢀN2ꢀC14ꢀC15 of 176.0(4)°, C14ꢀC15ꢀC16ꢀ
C17 of ꢀ53.6(5)° and C16ꢀC17ꢀC18ꢀO6 of ꢀ142.1(7)°. The difference in orientation of the
methanesulfonamide group in compounds is revealed by torsion angle C6ꢀN1ꢀS1ꢀC7 of 65. 5(5)°
in 2, ꢀ53.1(4)° in 3 and 74.9(5)° in 4; the corresponding values in the nimesulide polymorphs are
59.2(3)° in 1a, ꢀ61.1(5)° and ꢀ60.2(5)° in 1b, respectively. An overlay of molecular
conformations of the title compounds as determined by Xꢀray powder diffraction analysis and
theoretical calculations (solid state DFT) is shown in Fig. 3. The r.m.s. deviations of the
geometrically optimized bond lengths and bond angles from the corresponding
crystallographically determined values are 0.02Å, 1.6° in 2, 0.03Å, 2.2° in 3 and 0.03Å, 2.6° in
4. Close agreement between the Xꢀray analyzed structure and that obtained via quantumꢀ
mechanical calculations probably indicates that the compounds studied are stable conformers.
The crystal packing in 2ꢀ4 exhibits an interplay of intermolecular NꢀH…O, OꢀH…O, Cꢀ
H..O and CꢀH…π (arene) hydrogen bonds (Table 2). A pair of intermolecular NꢀH…O hydrogen
9
ACS Paragon Plus Environment

Crystal Growth & Design
Page 10 of 40
1
2
3
4
bonds in 2 (Table 2) with sulfonamide N1 atom in the molecule at (x, y, z) acting as a donor to
5
6
7
8
sulfonyl O2 atom in the molecule at (1ꢀx, 1ꢀy, ꢀz) produces a centrosymmetrtic dimeric ring (M)
with an R2 (8) graphꢀset motif74. Similarly, the C7ꢀH7B…O1 hydrogen bonds (Table 2) form
2
another type of R2 (8) ring (N). Two types of R2 (8) rings are spiroꢀfused to generate a C2 (8)
2
2
2
9
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
chain along the [001] direction with a MNMN… sequence (Fig. 4). Intermolecular C2ꢀH2…O4
hydrogen bonds in 2 connect parallel C2 (8) chains along the [010] direction to form twoꢀ
2
dimensional molecular sheets parallel to the (200) plane, which on further linking through C16ꢀ
H16A…O4 hydrogen bonds results into a three dimensional supramolecular architecture (Fig. 4).
Additional reinforcement within the three dimensional framework in 2 is provided by C17ꢀ
H17B…π (C8ꢀC13) hydrogen bond (Table 2).
Among the three available NH donors in 3, N1H and N2H groups participate in
intramolecular NꢀH…O interaction while the remaining N3H group takes part in intermolecular
NꢀH…O hydrogen bonding. Intermolecular N3ꢀHN3…O6 and C7ꢀH7C…O1 hydrogen bonds in
3 (Table 2) connect molecules into two C1 (4) chains propagating along the [010] direction,
1
which in turn combine to form a oneꢀdimensional molecular strip built with edgeꢀfused R2 (32)
2
synthon of dimension 9.9Å × 5.1Å (Fig. 5). The parallel strips are further joined through C7ꢀ
H7B…O6 hydrogen bonds producing R3 (12) rings into a twoꢀdimensional framework (Fig 5)
3
ꢜ
parallel to the (101) plane. In 4, while O6ꢀHO6…O4 hydrogen bonds between the
centrosymmetrically related molecules facilitate formation of R2 (18) rings, N2ꢀHN2…O2
2
hydrogen bonds generate C2 (18) chains propagating along the [100] direction. A combination of
2
C2 (18) chains and R2 (18) rings produces a columnar architecture. The molecular columns in 4
2
2
with axis parallel to the [010] direction are edgeꢀfused along the crystallographic aꢀaxis (Fig. 6).
Finally, C10ꢀH10…O5 hydrogen bonds expand the columnar assembly in 4 along the [001]
direction into a three dimensional supramolecular framework.
The Hirshfeld surfaces of 2ꢀ4 are illustrated in Fig. 7 (i), showing surfaces that have been
mapped over a dnorm range of 0.5 to 1.5 Å. The dominant interaction between the amine NH
group and the sulfonyl O atom in 2 and 4 (carbonyl O atom in 3) can be seen in the Hirshfeld
surface (Fig. 7 (i)) as bright red spots labeled as ‘a’ and ‘a'’, while almost equally bright red
spots (b/b') in Fig. 5(i) are due to the OꢀH…O hydrogen bond in 4. The light red areas marked as
c/c' in Fig. 7 (i) can be attributed to the CꢀH…O hydrogen bonds in 2ꢀ4. Other visible red
patches (d and e) in Fig. 7 (i) for 2 and 3 correspond to C…O and H…H interactions,
10
ACS Paragon Plus Environment

Page 11 of 40
Crystal Growth & Design
1
2
3
4
5
6
7
8
9
respectively.In the 2D fingerprint plots (Fig. 7 (ii)), two sharp spikes (labeled as ’a’ and ‘a'’) of
almost equal length in the region 2.1<de+di<2.5 Å are characteristics of NꢀH…O interactions.
The spikes (labeled as b/b' and c/c') due to OꢀH…O and CꢀH…O hydrogen bonds in 2ꢀ4 are
masked within the corresponding NꢀH…O spikes (a/a') in Fig. 7 (ii).The wings marked with
black circles in Fig. 7 (ii) represent the CꢀH…π interaction in 2. The central spikes (Fig. 7 (ii))
extending upto (di, de) region of (1.1Å, 1.1Å) in 2, (0.9Å, 0.9Å) in 3 and (0.95Å, 0.95Å) in 4
reveal relatively high percentages of H…H contacts in 2ꢀ4. The sharpness of central spike in Fig.
7 (ii) is a consequence of close H…H contacts (~ 2.02 Å) in 3. The subtle differences among the
molecular interactions in 2ꢀ4 are reflected in the distribution of scattered points in both high and
low (di, de) regions in the fingerprint plots (Fig. 7 (ii)). The relative contribution of different
interactions to the Hirshfeld surfaces of 2ꢀ4 as well as the two nimesulide polymorphs (1a, 1b)
and a few nimesulide derivatives with different substitutions at the C3 position (Fig. 2) retrieved
from the CSD is shown in Fig. 8. It is evident from Fig. 8 that H…H, O…H and C…H
interactions in 2ꢀ4 can account for more than 90% of the Hirshfeld surface area (92. 1% in 2, 91.
9% in 3 and 93.5% in 4), whereas the corresponding values are 84.2% in 1a, 84.4% in 1b, and
86.2% in 2,5ꢀdioxodihydropyrrolꢀ1ꢀyl derivative (MUTJUH) 75 of nimesulide, which has a close
structural resemblence with 2. Due to replacement of the nitro group in nimesulide by different
cyclic and acyclic substituents in 2ꢀ4, the contribution of H…H interactions increased steadily
from 31.7% in 1b to 42.3% in 2 with a corresponding decrease in the contribution of C…O
contacts from 6.9% in 1a to 1.0% in 4. A possible explanation for enhanced H…H interaction
contribution to the Hirshfeld surface area in 2ꢀ4 is the increased percentage of hydrogen atoms in
the molecular formula (39ꢀ43%) in comparison to that of nimesulide (36%).
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
The effect of substitutions in the nimesulide skeleton on the formation of supramolecular
synthon has been summarized in Table 3. In nimesulide polymorphs (1a and 1b) with a strong
electron withdrawing nitro (NO2) group at the trans position with respect to the
methanesulfonamide moiety, the N(sulfonamide) ꢀH…O(sulfonyl) hydrogen bond generates oneꢀ
2
dimensional molecular tapes comprising of C2 (16) synthon. When the nitro group in 1 is
replaced by a strong electron donating amino (NH2) group in OPEKOK50 , the N atom acts as a
2
double donor to two sulfonyl O atoms to produce two C2 (18) chains which combine together
2
2
into a twoꢀdimensional supramolecular assembly built with fused R2 (12) and R2 (36) rings. The
replacement of NO2 group in 1 by bulky cyclic substituents, such as dioxopyrrolidinꢀ1ꢀyl in 2,
11
ACS Paragon Plus Environment

Crystal Growth & Design
Page 12 of 40
1
2
dioxopyrrolꢀ1ꢀyl in MUTJUH75, dioxoisoindoleꢀ2ꢀyl in OPEKUQ50, phenylꢀ1Hꢀtriazolꢀ1ꢀyl in
QOJSAL76, tolylꢀ1Hꢀtriazolꢀ1ꢀyl in QOJSEP76 and chloromethyl phenoxymethylꢀ1Hꢀtriazolꢀ1ꢀyl
in QOJSIT76 leads to different hydrogen bonding patterns. The molecular assembly in these
3
4
5
6
7
8
9
2
compounds exhibits cyclic R2 (8) ring generated by N(sulfonamide) ꢀH…O(sulfonyl) hydrogen
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
2
bonds. The propagation of R2 (8) rings via C(aryl)ꢀH…O(sulfonyl) and C(aryl)ꢀ
H…O(oxopyrrol) hydrogen bonds results in different supramolecular framework in these
structures. In 3 and 4, with acyclic substituents having multiple NH donors replacing the NO2
n
group in 1, the molecular aggregation, however, reveals Cm (x) chains formed by N(amide)ꢀ
H…O(amide) and N(amide)ꢀH…O(sulfonyl) hydrogen bonds. The ranking of different donor
and acceptor groups in intermolecular hydrogen bonding in 2ꢀ4 and other NO2 substituted
nimesulide derivatives has been further confirmed by MEP calculations.
The MEP surfaces of 2ꢀ4 (Fig. 9) as well as the nimesulide polymorphs (1a and 1b) and a
few NO2 substituted nimesulide derivatives containing different hydrogen bond donors such as ꢀ
NH, ꢀOH and ꢀCH groups have been analyzed successfully in relation to their hydrogen bonding.
The MEP derived charges at the BLYP level using DMol3 for atoms in 2ꢀ4 indicated high
negative charges on the oxygen (O1ꢀO5 in 2, O1ꢀO6 in 3 and 4) as well as the nitrogen
(excepting the pyrrolidin ring N2 in 2) atoms. The sulfur (S1 in 2, 4 and S1, S2 in 3) and carbon
(C5, C8, C14, C15 in 2, C3, C5, C8, C20 in 3, C3, C5, C8, C14, C18 in 4) atoms carry
substantial positive charge due to electron withdrawing nature of adjacent oxygen and nitrogen
atoms. Significant positive charge accumulation on the hydrogen atoms (HN1 in 2; HN1, HN2,
HN3 in 3; HN1, HN2, HO6 in 4) of amino and hydroxyl moieties in 2ꢀ4 suggests that these
groups are likely to act as donors in intraꢀ and interꢀmolecular DꢀH…X hydrogen bonds. Due to
this charge reꢀdistribution the dipole moments of 2ꢀ4 become 2.64, 3.75 and 4.26 a.u.,
respectively. The magnitudes of electrostatic potential maxima (Vs,max) associated with the
hydrogen atoms of 1ꢀ4 can serve as indicators of a fairly realistic ranking of hydrogen bond
donating ability, and the corresponding Vs,min values can be used to identify and rank hydrogen
bond acceptor sites. The magnitudes of Vs,max and Vs,min values associated with the
donor/acceptor groups of 1ꢀ4 and other related compounds are related to the relative strength of
NꢀH..O, OꢀH…O and CꢀH…O hydrogen bonds (Table 4). In the nimesulide polymorphs (1a and
1b), the hydrogen atoms of sulfonamide NH and oxygen atoms of the nitro group are associated
with the maximum (51ꢀ56 Kcal molꢀ1) and minimum (ꢀ37 to ꢀ39 Kcal molꢀ1) MEP values (Table
12
ACS Paragon Plus Environment

Page 13 of 40
Crystal Growth & Design
1
2
3
4
5
6
7
8
9
4). This is consistent with the crystallographic observation which indicates that N(sulfonamide)ꢀ
H…O(nitro) is the strongest intermolecular hydrogen bond in nimesulide72,73.Three most positive
potentials in 2 correspond to hydrogen atoms of the amino group, HN1 (Vs,max51 Kcal molꢀ1),
and pyrrolidin ring, H16 and H17 (Vs,max 36ꢀ37 Kcal molꢀ1), which participate in hydrogen
bonding (Table 2). The hydrogen bond acceptors in 2, on the other hand are characterized by
three strong negative potentials around the oxygen atoms of sulfonyl and oxo groups with O1
and O2 (Vs,min ꢀ39 Kcal molꢀ1) and O4 and O5 (Vs,min ꢀ35 Kcal molꢀ1), respectively. The
electrostatic potentials near the bridging oxygen atom O3 in 2ꢀ4 lie in the range ꢀ2 to ꢀ10 Kcal
molꢀ1. The presence of different electron withdrawing substituents can significantly modify the
molecular electrostatic potential around phenyl rings37. While regions of negative electrostatic
potentials of ꢀ9 Kcal molꢀ1 above and below the terminal benzene ring (C8ꢀC13 atoms) in 2
reflect the π electrons taking part in CꢀH… π hydrogen bond, no such local minima could be
observed for other aryl rings in 2ꢀ4.
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
In 3, the amino hydrogen (HN3) is localized in the most positive potential region, Vs,max
of 75 Kcal molꢀ1, while the carbonyl oxygen atom (O6) assumes the top ranked negative surface
potential of Vs,min ꢀ40 Kcal molꢀ1. This indicates that among different NH donors and oxygen
acceptors, the acetamide N/O part (N3 and O6 atoms) is favored for a relatively strong NꢀH…O
hydrogen bond. The Vs,max values associated with HN1 and HN2 atoms participating in
intramolecular NꢀH…O interaction in 3, are 53 and 62 Kcal molꢀ1, respectively. The N2ꢀ
HN2…O2 and O6ꢀHO6…O4 intermolecular hydrogen bonds in 4 are characterized by two top
ranked positive molecular electrostatic potentials associated with HO6 (Vs,max 79 Kcal molꢀ1) and
HN2 (Vs,max 65 Kcal molꢀ1) atoms and corresponding most negative potentials around O2 and
O4 (Vs,min ꢀ46 Kcal molꢀ1) atoms. Other strong negative potential near O5 (Vs,min ꢀ45 Kcal molꢀ1)
and a moderate positive potential of 32 Kcal molꢀ1 around H10 can be attributed to C10ꢀ
H10…O5 intermolecular hydrogen bond in 4. Similar correlation between the MEP values of
donor/acceptor atoms and intermolecular hydrogen bond interaction can also be established for
other NO2 substituted nimesulide derivatives (Table 4), where most positive and most negative
potential values correspond to strongest hydrogen bonds.
13
ACS Paragon Plus Environment

Crystal Growth & Design
Page 14 of 40
1
2
3
4
5
6
7
Conclusions
8
9
In summary, crystal structures of three nimesulide derivatives (2ꢀ4), in which pyrrolidinꢀ
2,5ꢀdione (in 2), substituted benzosulfonamide (in 3) and acetamide (in 4) moieties replacing the
nitro group at the Cꢀ3 position in nimesulide (1), have been determined using powder crystal Xꢀ
ray diffraction (PXRD). The subtleties of crystal packing are illustrated by an interplay of Nꢀ
H…O, OꢀH…O, CꢀH...O and CꢀH…π (in 2) hydrogen bonds, which assemble molecules in
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
n
n
compounds 2ꢀ4 into supramolecular architecture via the formation of Rm (x) rings and Cm (x)
polymeric chains. The results also emphasize that a reliable ranking of hydrogen bond donor
strength in 2ꢀ4 can be achieved by using molecular electrostatic potential (MEP) surfaces and for
competing hydrogen bond donors, the selection depends strongly on the MEP values of the
acceptor. The MEP based selectivity of hydrogen bonding can be used for designing tailorꢀmade
nimesulide derivatives with desired biological activity. A comparison of the relative contribution
of different interactions to the Hirshfeld surfaces of 2ꢀ4 and a few related nimesulide derivatives
indicated that H…H, O…H and C…H interactions can account for more than 80% of the
Hirshfeld surface area. Finally, the present work clearly demonstrates the potential of PXRD for
determining the crystal structure of complex organic materials with considerable molecular
flexibility directly from the bulk powder without the need to grow single crystals.
Acknowledgements:
Financial support from the Council for Scientific and Industrial Research (CSIR), New Delhi,
India, for a senior research fellowship (SRF) to T.D, is gratefully acknowledged.
Supporting Information: Crystallographic data for the structures C17H16O5N2S (2),
C21H21O6N3S2 (3) and C18H20O6N2S (4) reported in this article have been deposited to the
Cambridge Crystallographic Data Centre with publication numbers CCDC 1430581ꢀ1430583.
Copies of the data can be obtained free of charge on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ, UK (fax: +44 1223 336033; email: (deposit@ccdc.cam.ac.uk). Values of
selected bond distances, bond angles and torsion angles are given in Table S1. This material is
available free of charge via the Internet at http://pubs.acs.org.
14
ACS Paragon Plus Environment

Page 15 of 40
Crystal Growth & Design
1
2
3
4
5
6
7
8
9
References
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
(1)
(2)
Steiner, T., Angew. Chem., Int. Ed. 2002, 41, 48ꢀ76.
Glowacki, E. D.; IrimiaꢀVladu, M.; Bauer, S.; Sariciftci, N. S., J. Mater. Chem. B 2013,
1, 3742ꢀ3753.
(3)
Sweetman, A. M.; Jarvis, S. P.; Sang, H.; Lekkas, I.; Rahe, P.; Wang, Y.; Wang, J.;
Champness, N. R.; Kantorovich, L.; Moriarty, P., Nat. Commun. 2014, 5.
(4)
Parkinson, G.; Gunasekera, A.; Vojtechovsky, J.; Zhang, X.; Kunkel, T. A.; Berman, H.;
Ebright, R. H., Nat. Struct. Mol. Biol. 1996, 3, 837ꢀ841.
(5)
(6)
(7)
(8)
(9)
11.
Kool, E. T., Annu. Rev. Biophys. Biomol. Struct. 2001, 30, 1ꢀ22.
Cleland, W.; Kreevoy, M., Science 1994, 264, 1887ꢀ1890.
Cleland, W. W.; Frey, P. A.; Gerlt, J. A., J. Biol. Chem. 1998, 273, 25529ꢀ25532.
Gerlt, J. A.; Kreevoy, M. M.; Cleland, W. W.; Frey, P. A., Chem. Biol. 1997, 4, 259ꢀ267.
Pauling, L.; Corey, R. B.; Branson, H. R., Proc. Natl. Acad. Sci. U. S. A.1951, 37, 205ꢀ
(10) Cordier, F.; Grzesiek, S., J. Am. Chem. Soc. 1999, 121, 1601ꢀ1602.
(11) Hooft, R. W. W.; Sander, C.; Vriend, G., Proteins Struct., Funct., Bioinf. 1996, 26, 363ꢀ
376.
(12) Desiraju, G. R., Acc. Chem. Res. 2002, 35, 565ꢀ573.
(13) Frontiers in Crystal Engineering.; Tiekink, E. R. T., Vittal, J., Eds.; John Wiley & sons:
2006.
(14) Brittain, H. G., J. Pharm. Sci. 2012, 101, 464ꢀ484.
(15) Serajuddin, A. T. M., Adv. Drug Delivery Rev. 2007, 59, 603ꢀ616.
(16) Vishweshwar, P.; McMahon, J. A.; Bis, J. A.; Zaworotko, M. J., J. Pharm. Sci. 2006, 95,
499ꢀ516.
(17) Schultheiss, N.; Newman, A., Cryst. Growth Des. 2009, 9, 2950ꢀ2967.
(18) Desiraju, G. R., Nature 2001, 412, 397ꢀ400.
(19) Allen, F. H.; Motherwell, W. D. S.; Raithby, P. R.; Shields, G. P.; Taylor, R., New J.
Chem. 1999, 23, 25ꢀ34.
15
ACS Paragon Plus Environment

Crystal Growth & Design
Page 16 of 40
1
2
3
4
5
6
(20) Desiraju, G. R.; Steiner, T., The Weak Hydrogen Bond in Structural Chemistry and
Biology.; Oxford University Press: 2001.
7
8
9
(21) Moulton, B.; Zaworotko, M. J., Chem. Rev. 2001, 101, 1629ꢀ1658.
(22) Jeffrey, G. A., An Introduction to Hydrogen Bonding.; Oxford University Press: New
York, 1997.
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
(23) Braga, D.; Grepioni, F.; Biradha, K.; Pedireddi, V. R.; Desiraju, G. R., J. Am. Chem. Soc.
1995, 117, 3156ꢀ3166.
(24) Spek, A. L., Acta Crystallogr. D 2009, 65, 148ꢀ155.
(25) Etter, M. C., Acc. Chem. Res. 1990, 23, 120ꢀ126.
(26) Etter, M. C., J. Phys. Chem. 1991, 95, 4601ꢀ4610.
(27) Aakeröy, C. B.; Baldrighi, M.; Desper, J.; Metrangolo, P.; Resnati, G., Chem. - Eur. J.
2013, 19, 16240ꢀ16247.
(28) Duggirala, N. K.; Wood, G. P. F.; Fischer, A.; Wojtas, Ł.; Perry, M. L.; Zaworotko, M.
J., Cryst. Growth Des. 2015, 15, 4341ꢀ4354.
(29) Dey, A.; Bera, S.; Biradha, K., Cryst. Growth Des. 2015, 15, 318ꢀ325.
(30) Lü, J.; Han, L.ꢀW.; Alsmail, N. H.; Blake, A. J.; Lewis, W.; Cao, R.; Schröder, M., Cryst.
Growth Des. 2015, 15, 4219ꢀ4224.
(31) Hunter, C. A., Angew. Chem., Int. Ed. 2004, 43, 5310ꢀ5324.
(32) Musumeci, D.; Hunter, C. A.; Prohens, R.; Scuderi, S.; McCabe, J. F., Chem. Sci.2011, 2,
883ꢀ890.
(33) Murray, J. S.; Politzer, P., J. Org. Chem. 1991, 56, 6715ꢀ6717.
(34) Politzer, P.; Murray, J. S., Cryst. Growth Des. 2015, 15, 3767ꢀ3774.
(35) Aakeroy, C. B.; Wijethunga, T. K.; Desper, J., New J. Chem. 2015, 39, 822ꢀ828.
(36) Aakeröy, C. B.; Epa, K.; Forbes, S.; Schultheiss, N.; Desper, J., Chem.- Eur. J.2013, 19,
14998ꢀ15003.
(37) Bulat, F. A.; ToroꢀLabbe, A.; Brinck, T.; Murray, J. S.; Politzer, P., J. Mol. Model 2010,
16, 1679ꢀ91.
(38) Harris, K. D. M.; Tremayne, M.; Kariuki, B. M., Angew. Chem., Int. Ed. 2001, 40, 1626ꢀ
1651.
(39) David, W. I. F.; Shankland, K., Acta Crystallogr. A 2008, 64, 52ꢀ64.
(40) Structure Determination from Powder Diffraction Data.; David, W. I. F.,Shankland, L.,
McCusker, L. B., Baerlocher, Ch., Eds.; Oxford University Press: New York, 2002.
16
ACS Paragon Plus Environment

Page 17 of 40
Crystal Growth & Design
1
2
3
4
5
6
(41) Pagola, S.; Stephens, P. W.; Bohle, D. S.; Kosar, A. D.; Madsen, S. K., Nature 2000, 404,
307ꢀ310.
7
8
9
(42) Harris, K. D. M.; Cheung, E. Y., Chem Soc. Rev. 2004, 33, 526ꢀ538.
(43) Hammond, R. B.; Roberts, K. J.; Docherty, R.; Edmondson, M., J. Phys. Chem. B 1997,
101, 6532ꢀ6536.
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
(44) FavreꢀNicolin, V.; Černý, R., Z. Kristallogr. Cryst. Mat.2004, 219, 847–856.
(45) Brodski, V.; Peschar, R.; Schenk, H., J. Appl. Crystallogr. 2005, 38, 688ꢀ693.
(46) Griswold, D. E.; Adams, J. L., Med. Res. Rev. 1996, 16, 181ꢀ206.
(47) Traversa, G.; Bianchi, C.; Da Cas, R.; Abraha, I.; MennitiꢀIppolito, F.; Venegoni, M., Br.
Med. J. 2003, 327, 18ꢀ22.
(48) Hawkey, C. J., Gastroenterology 2000, 119, 521ꢀ35.
(49) Durgadas, S.; Chatare, V. k.; Mukkanti, K.; Pal, S., Appl. Org. Chem. 2010, 24, 680ꢀ684.
(50) Bhattacharya, A.; Ghosh, S.; Kankanala, K.; Reddy, V. R.; Mukkanti, K.; Pal, S.;
Mukherjee, A. K., Chem. Phys. Lett. 2010, 493, 151ꢀ157.
(51) Karakuꢁ, S.; Güniz Küçükgüzel, ꢂ.; Küçükgüzel, Đ.; De Clercq, E.; Pannecouque, C.;
Andrei, G.; Snoeck, R.; ꢂahin, F.; Faruk Bayrak, Ö., Eur. J. Med. Chem. 2009, 44, 3591ꢀ3595.
(52) Altomare, A.; Giacovazzo, C.; Guagliardi, A.; Moliterni, A. G. G.; Rizzi, R.; Werner, P.ꢀ
E., J. Appl. Crystallogr. 2000, 33, 1180ꢀ1186.
(53) Altomare, A.; Cuocci, C.; Giacovazzo, C.; Moliterni, A.; Rizzi, R.; Corriero, N.;
Falcicchio, A., J. Appl. Crystallogr. 2013, 46, 1231ꢀ1235.
(54) Thompson, P.; Cox, D. E.; Hastings, J. B., J. Appl. Crystallogr. 1987, 20, 79ꢀ83.
(55) FavreꢀNicolin, V.; Cerny, R., J. Appl. Crystallogr. 2002, 35, 734ꢀ743.
(56) Stewart, J. J., J. Mol. Model. 2007, 13, 1173ꢀ213.
(57) Rietveld, H., Acta Crystallogr. 1967, 22, 151ꢀ152.
(58) Larson, A. C.; Von Dreele, R. B. General Structure Analysis System (GSAS); Los Alamos
Laboratory Report, LAUR: 2000; pp 86ꢀ748.
(59) Hirshfeld, F. L., Theor. Chim. Acta 1977, 44, 129ꢀ138.
(60) Spackman, M. A.; Jayatilaka, D., CrystEngComm 2009, 11, 19ꢀ32.
(61) Clausen, H. F.; Chevallier, M. S.; Spackman, M. A.; Iversen, B. B., New J. Chem. 2010,
34, 193ꢀ199.
(62) Spackman, M. A.; McKinnon, J. J., CrystEngComm 2002, 4, 378ꢀ392.
17
ACS Paragon Plus Environment

Crystal Growth & Design
Page 18 of 40
1
2
3
4
5
6
7
8
9
(63) Parkin, A.; Barr, G.; Dong, W.; Gilmore, C. J.; Jayatilaka, D.; McKinnon, J. J.;
Spackman, M. A.; Wilson, C. C., CrystEngComm 2007, 9, 648ꢀ652.
(64) Rohl, A. L.; Moret, M.; Kaminsky, W.; Claborn, K.; McKinnon, J. J.; Kahr, B., Cryst.
Growth Des. 2008, 8, 4517ꢀ4525.
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
(65) McKinnon, J. J.; Spackman, M. A.; Mitchell, A. S., Acta Crystallogr. B 2004, 60, 627ꢀ
668.
(66) Wolff, S.; Grimwood, D.; McKinnon, J.; Jayatilaka, D.; Spackman, M., Crystal Explorer
2.1, University of Western Australia, Perth 2007.
(67) Delley, B., J. Chem. Phys. 1990, 92, 508ꢀ517.
(68) Perdew, J.P.; Burke, K.; Ernzerhof, M., Phys. Rev. Lett. 1996, 77, 3865ꢀ3868.
(69) Becke, A. D., Phys. Rev. A 1988, 38, 3098ꢀ3100.
(70) Lee, C.; Yang, W.; Parr, R. G., Phys. Rev. B 1988, 37, 785ꢀ789.
(71) Bader, R. F. W.; Carroll, M. T.; Cheeseman, J. R.; Chang, C., J. Am. Chem. Soc. 1987,
109, 7968ꢀ7979.
(72) Dupont, L.; Pirotte, B.; Masereel, B.; Delarge, J.; Geczy, J., Acta Crystallogr. C 1995, 51,
507ꢀ509.
(73) Sanphui, P.; Sarma, B.; Nangia, A., J. Pharm. Sci. 2011, 100, 2287ꢀ2299.
(74) Bernstein, J.; Davis, R. E.; Shimoni, L.; Chang, N.ꢀL., Angew. Chem., Int. Ed. 1995, 34,
1555ꢀ1573.
(75) Bhattacharya, A.; Kankanala, K.; Pal, S.; Mukherjee, A. K., J. Mol. Struct. 2010, 975, 40ꢀ
46.
(76) Dey, T.; Ghosh, S.; Mareddy, J.; Anireddy, J.; Pal, S.; Mukherjee, A. K., CrystEngComm
2015, 17, 764ꢀ774.
18
ACS Paragon Plus Environment

Page 19 of 40
Crystal Growth & Design
1
2
3
4
Tables
5
6
7
8
Table 1 Crystal data and structure refinement parameters of C17H16O5N2S (2), C21H21O6N3S2 (3)
and C18H20O6N2S (4).
9
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
Compound
Formula weight
Temperature (K)
Crystal system
Wavelength (Å)
Space group
a (Å)
b (Å)
c (Å)
α (º)
β (º)
C17H16O5N2S (2)
360.39
293(2)
Monoclinic
1.5418
P21/a
32.7832(5)
5.8150(2)
8.8234(1)
90
90.450(2)
90
C21H21O6N3S2 (3)
475.55
293(2)
Monoclinic
1.5406
P21/n
23.5927(7)
5.1184(2)
17.7026(5)
90
93.745(3)
90
2133.1(1)
4
1.4808
4ꢀ90
0.02
20
191
20
14
0.0198
0.0276
0.1096
2.119
C18H20O6N2S (4)
392.43
293 (2)
Monoclinic
1.5418
P21/a
18.791(4)
8.967(2)
11.339(3)
90.000
104.525(2)
90.000
1849.5(8)
4
1.4094
6ꢀ100
0.02
20
219
25
18
0.0255
0.0349
0.0936
2.374
γ (º)
Volume (Å3)
Z
1682.0(1)
4
Density (calculated) g cmꢀ3 1.4232
2θ interval (º)
Step size (º)
Counting time (sec)
No. of variable parameters 209
No. of background points
Spherical harmonics
Rp
4ꢀ96
0.02
20
20
18
0.0412
0.0585
0.0569
2.334
Rwp
2
RF
χ2 /S
19
ACS Paragon Plus Environment

Crystal Growth & Design
Page 20 of 40
1
2
3
4
Table 2 Hydrogen bonds in C17H16O5N2S (2), C21H21O6N3S2 (3) and C18H20O6N2S (4).
5
6
7
8
9
Interaction
DꢀH…A/ º Symmetry code
DꢀH/ Å H…A/ Å D…A/ Å
C17H16O5N2S (2)
N1ꢀHN1···O2
C2ꢀH2···O4
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
0.86
0.93
0.96
0.97
0.96
2.20
2.55
2.53
2.52
2.77
2.913(6)
3.449(11) 164
3.407(6) 152
139
1ꢀx, 1ꢀy, ꢀz
x, 1+y, z
C7ꢀH7B···O1
C16ꢀH16A···O4
C17ꢀH17B···Cg(2)
C21H21O6N3S2 (3)
N1ꢀHN1…O2
N2ꢀHN2…O4
N3ꢀHN3···O6
C7ꢀH7B···O6
C7ꢀH7C···O1
C18H20O6N2S (4)
N2ꢀHN2···O2
O6ꢀHO6···O4
C10ꢀH10···O5
C17ꢀH17A···O6
N1ꢀHN1···N2
1ꢀx, 1ꢀy, 1ꢀz
1/2ꢀx, 1/2+y, 1ꢀz
1/2ꢀx, 1/2+y, ꢀz
3.203(13) 128
140
0.87
0.86
0.86
0.95
0.96
2.47
2.49
2.19
2.54
2.53
2.459(7)
2.460(6)
3.041(6)
79
x, y, z
78
x, y, z
169
x, ꢀ1+y, z
1/2+x, 5/2ꢀy, 1/2+z
x, ꢀ1+y, z
3.419(13) 154
3.344(6)
142
0.86
0.83
0.93
0.96
0.86
1.98
2.00
2.33
2.54
2.64
2.806(9)
159
ꢀ1/2+x, 1/2ꢀy, z
ꢀx, 1ꢀy, ꢀz
2.804(12) 163
3.204(10) 156
ꢀx, ꢀy, 1ꢀz
3.494(6)
3.452(5)
176
157
ꢀx, 1ꢀy, ꢀz
1/2ꢀx, ꢀ1/2+y, 1ꢀz
Cg(2) = C8ꢀC13 atoms for 2
20
ACS Paragon Plus Environment

Page 21 of 40
Crystal Growth & Design
1
2
3
4
Table 3 Supramolecular assemblies formed by hydrogen bonds in nimesulide and its derivatives
5
6
7
8
9
10
11
12
13
Compounds
Type of hydrogen bond
D…A (Å)
Graph Set
Notation
∠DHA (°)
2
N(sulfonamide)ꢀH…O(nitro)
C(aryl)ꢀH…O(sulfonyl)
3.092(3)
3.459(4)
151
154
C22(16)
WINWUL (1a)
C2 (14)
2
N(sulfonamide)ꢀH…O(nitro) 3.000(6)/3.079(6) 151/138
C22(16)
WINWUL01 (1b)
MUTJUH
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
C(aryl)ꢀH…O(sulfonyl)
3.420(6)/3.463(6) 160/156
C2 (14)
2
N(sulfonamide)ꢀH…O(sulfonyl)
C(methyl)ꢀH…O(sulfonyl)
3.166(2)
3.428(2)
157
145
R22(8)
R2 (8)
2
N(amine)ꢀH…O(sulfonyl)
N(amine)ꢀH…O(sulfonyl)
3.274(4)
3.179(4)
162
147
C22(18)
OPEKOK
C2 (18)
2
N(sulfonamide)ꢀH…O(sulfonyl)
C(aryl)ꢀH…O(diꢀOxoꢀPyrrol)
C(methyl)ꢀH…O(sulfonyl)
3.060(2)
3.441(2)
3.510(2)
147
145
152
R2 (8)
OPEKUQ
2
R2 (10)
2
R2 (8)
2
N(sulfonamide)ꢀH…O(sulfonyl)
C(methyl)ꢀH…O(sulfonyl)
C(triazole)ꢀH…N(triazole)
2.997(3)
3.516(3)
3.585(4)
147
167
163
R22(8)
QOJSAL
C22(8)
C2 (8)
2
N(sulfonamide)ꢀH…O(sulfonyl)
C(aryl)ꢀH…O(oxoꢀBridge)
2.985(9)
3.330(3)
144
161
R2 (8)
QOJSEP
QOJSIT
2
C2 (12)
2
N(sulfonamide)ꢀH…O(sulfonyl)
C(methyl)ꢀH…O(sulfonyl)
3.174(7)
2.978(9)
157
156
R22(8)
C2 (8)
2
N(sulfonamide)ꢀH…O(sulfonyl)
C(methyl)ꢀH…O(sulfonyl)
2.913(6)
3.407(6)
139
152
R22(8)
Compound 2
Compound 3
Compound 4
R2 (8)
1
N(amide)ꢀH…O(amide)
C(methyl)ꢀH…O(amide)
3.041(6)
3.344(6)
169
142
C11(4)
C1 (4)
2
N(amide)ꢀH…O(sulfonyl)
O(carboxilic acid)ꢀH…O(amide)
2.804(9)
2.800(12)
159
163
C22(18)
R2 (18)
21
ACS Paragon Plus Environment

Crystal Growth & Design
Page 22 of 40
1
2
3
4
5
Table 4 Selected Vs,max and Vs,min values for MEP surfaces of 1ꢀ4 and few other nimesulide
derivatives.
6
7
8
9
Compound
Selected area
VS,max/VS,min
(Kcal/mol)
ꢀ39
Sulfonyl oxygens (O1, O2)
C17H16O5N2S (2)
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
Pyrrolidin oxo group (O4, O5)
Pyrrolidin hydrogens (H16A, H16B, H17A,
H17B)
ꢀ35
36
Sulfonamide hydrogen (HN1)
51
ꢀ40
ꢀ38
ꢀ36
53
Carbonyl oxygen (O6)
Sulfonyl oxygens (O4, O5)
Sulfonyl oxygens (O1, O2)
Sulfonamide hydrogen (HN1)
Sulfonamide hydrogen (HN2)
Amide hydrogen (HN3)
C21H21O6N3S2 (3)
62
75
Sulfonyl oxygen (O2), Carbonyl oxygen (O4)
Carbonyl oxygen of COOH (O5)
Sulfonyl oxygen (O1)
ꢀ46
ꢀ45
ꢀ44
46
C18H20O6N2S (4)
Sulfonamide hydrogen (HN1)
Amide hydrogen (HN2)
65
Carboxylic acid hydrogen (HO6)
Nitro oxygen (O3, O4)
79
ꢀ37
56
WINWUL (1a)
WINWUL01 (1b)
MUTJUH
Sulfonamide hydrogen (HN1)
Nitro oxygen (O3, O4)
ꢀ39
52
Sulfonamide hydrogen (HN1, HN3)
Sulfonyl oxygen (O2, O3)
Sulfonamide hydrogen (HN2)
Sulfonyl oxygen (O2, O3)
Amino hydrogen (HN1)
ꢀ45
56
ꢀ48
58
OPEKOK
Sulfonyl oxygen (O3)
ꢀ43
52
OPEKUQ
Sulfonamide hydrogen (HN2)
Sulfonyl oxygen (O2)
ꢀ33
55
ꢀ34
51
QOJSAL
Sulfonamide hydrogen (HN1)
Sulfonyl oxygen (O2, O3)
Sulfonamide hydrogen (HN1)
Sulfonyl oxygen (O2)
QOJSEP
ꢀ34
56
QOJSIT
Sulfonamide hydrogen (HN1)
22
ACS Paragon Plus Environment

Page 23 of 40
Crystal Growth & Design
1
2
3
4
Scheme and figures
5
6
7
8
9
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
Scheme 1
23
ACS Paragon Plus Environment

Crystal Growth & Design
Page 24 of 40
1
2
3
4
5
6
7
8
9
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
Fig. 1: Final rietveld plot for C17H16O5N2S (2), C21H21O6N3S2 (3) and C18H20O6N2S (4). The
intensity in the high angle region has been multiplied by a factor 10.
24
ACS Paragon Plus Environment

Page 25 of 40
Crystal Growth & Design
1
2
3
4
5
6
7
8
9
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
Fig. 2: Molecular views with atom labeling scheme for C17H16O5N2S (2), C21H21O6N3S2 (3) and
C18H20O6N2S (4).
Fig. 3: Superposition of molecular conformations as obtained from Xꢀray structure analysis
(violet) and solid state DFT calculation (blue) for C17H16O5N2S (2), C21H21O6N3S2 (3) and
C18H20O6N2S (4). Hydrogen atoms of 4 have been omitted for clarity.
25
ACS Paragon Plus Environment

Crystal Growth & Design
Page 26 of 40
1
2
3
4
5
6
7
8
9
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
Fig. 4: (a) Three dimensional architecture (b) polymeric MNMN… chain formed by NꢀH…O
and CꢀH…O hydrogen bonds in C17H16O5N2S (2).
Fig. 5: Two dimensional network formed by NꢀH…O and CꢀH…O hydrogen bonds in
C21H21O6N3S2 (3).
26
ACS Paragon Plus Environment

Page 27 of 40
Crystal Growth & Design
1
2
3
4
5
6
7
8
9
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
Fig. 6: Two dimensional columnar framework by OꢀH…O and NꢀH…O hydrogen bonds in
C18H20O6N2S (4).
Fig. 7: (i) Hirshfeld surfaces and (ii) fingerprint plots for C17H16O5N2S (2), C21H21O6N3S2 (3)
and C18H20O6N2S (4).
27
ACS Paragon Plus Environment

Crystal Growth & Design
Page 28 of 40
1
2
3
4
5
6
7
8
9
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
Fig. 8: Relative contribution of different interactions to the Hirshfeld surfaces of C17H16O5N2S
(2), C21H21O6N3S2 (3) and C18H20O6N2S (4), and a few related structures from the CSD.
Fig. 9: MEP surfaces of C17H16O5N2S (2), C21H21O6N3S2 (3) and C18H20O6N2S (4).
28
ACS Paragon Plus Environment

Page 29 of 40
Crystal Growth & Design
1
2
3
4
5
For Table of Contents Use Only
6
7
8
9
Three Nimesulide Derivatives: Synthesis, Abꢀinitio Structure Determination
from Powder Xꢀray Diffraction and Quantitative Analysis of Molecular
Surface Electrostatic Potential
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
Tanusri Deya, Paramita Chatterjeea,b, Abir Bhattacharyac, Sarbani Pald and Alok K. Mukherjeea,*
Three nimesulide derivatives have been synthesized, and their crystal structures are
determined from Xꢀray powder diffraction. The nature of intermolecular interactions and relative
hydrogenꢀbond donor strengths has been analyzed through Hirshfeld surface analysis and
molecular electrostatic potential surface calculation.
29
ACS Paragon Plus Environment