Synthesis and supramolecular self-assembly of thioxothiazolidinone derivatives driven by H-bonding and diverse π–hole interactions: A combined experimental and theoretical analysis

Article abstract of DOI:10.1016/j.molstruc.2017.03.046

Two new 3-aryl-5-(4-nitrobenzylidene)-2-thioxothiazolidin-4-one derivatives (1 & 2) were synthesized by the Knoevenagel condensation reaction of 3-(4-aryl)-2-thioxo-1,3-thiazolidin-4-ones with 4-nitrobenzaldehyde. Both products were isolated as orange cry

Full text of DOI:10.1016/j.molstruc.2017.03.046

Journal of Molecular Structure 1139 (2017) 209e221
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Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Synthesis and supramolecular self-assembly of thioxothiazolidinone
derivatives driven by H-bonding and diverse
pehole interactions: A
combined experimental and theoretical analysis
a
a
c
ꢀ b
Hina Andleeb , Imtiaz Khan , Antonio Bauza , Muhammad Nawaz Tahir ,
Jim Simpson d, Shahid Hameed a **, Antonio Frontera b
,
, *
a Department of Chemistry, Quaid-i-Azam University, Islamabad, 45320, Pakistan
b Departament de Química, Universitat de les Illes Balears, Crta. de Valldemossa km 7.5, 07122, Palma de Mallorca, Baleares, Spain
c Department of Physics, University of Sargodha, Sargodha, 40100, Pakistan
d Department of Chemistry, University of Otago, P.O. Box 56, Dunedin, 9054, New Zealand
a r t i c l e i n f o
a b s t r a c t
Article history:
Two new 3-aryl-5-(4-nitrobenzylidene)-2-thioxothiazolidin-4-one derivatives (1 & 2) were synthesized
by the Knoevenagel condensation reaction of 3-(4-aryl)-2-thioxo-1,3-thiazolidin-4-ones with 4-
nitrobenzaldehyde. Both products were isolated as orange crystalline solids in good yields and were
fully characterized by analytical, spectroscopic and structural methods. The interesting supramolecular
assemblies of the title compounds observed in the solid state were analyzed by Density Functional
Theory (DFT) calculations (M06-2X/def2-TZVP), Molecular Electrostatic Potential (MEP) surfaces and
characterized by means of the Bader's theory of “atoms-in-molecules” (AIM) and NCIplot. The compu-
Received 8 November 2016
Received in revised form
6 March 2017
Accepted 11 March 2017
Available online 13 March 2017
Keywords:
Thioxothiazolidinone
Noncovalent interactions
tation of the energy features of the diverse noncovalent interactions including CeH/p, p/p and lp/p-
hole interactions revealed their conspicuous role in the stabilization of the three-dimensional supra-
molecular frameworks for both compounds in addition to the CeH/O/S H-bonding interactions.
© 2017 Elsevier B.V. All rights reserved.
pehole interactions
Theoretical analysis
1. Introduction
applications in the synthesis of compounds with antitumor
[16e18], and anti-HIV properties [19,20]. In addition, rhodanine
Rhodanine, a five-membered heterocyclic skeleton, represents a
very important scaffold in the drug discovery arena with wide-
spread applications [1,2]. This pharmacophore (2-thioxo-1,3-
thiazolidin-4-one) has demonstrated multiple biological inhibi-
tory activities [3] including aldose reductase [4], HCV NS3 protease
derivatives have diverse applications in industry and coordination
chemistry [21]. Moreover, the use of rhodanine compounds as a dye
sensitizer [22], and in the synthesis of non-linear optical (NLO)
materials [23,24] attests to the broad utility of this framework.
The foundation of molecular recognition processes and crystal
growth is a concert of intermolecular interactions. Consequently a
proper understanding of these noncovalent interactions is crucial
to many fields related to supramolecular chemistry and self-
assembly processes. The shared physical basis of well-known
forces such as hydrogen and halogen bonding interactions
[5],
b-lactamase [6], N-acetyltransferase [7], histone acetyl-
transferase [8], and histidine decarboxylase [9]. The 1,3-thiazolidin-
4-one core is also an essential pharmacophore for the treatment of
type 2 diabetes and is found in several drugs such as Epalrestat,
Rosiglitazone, Pioglitazone, and Ciglitazone [10]. Rhodanine de-
rivatives, modified at the methylene group (ylidenerhodanines),
exhibit antibacterial [11], antifungal [12e14], and anticancer ac-
tivities [15]. These versatile building blocks also find potential
[25e28] is that electron rich entities interact with a so-called “s-
hole”, which is defined as a positive electrostatic potential along the
vector of a covalent bond (XeH or XeI) [29e31]. In addition, pos-
itive electrostatic potentials can also be found in electron-deficient
p-systems and these so-called “p-holes” [32e35] can also interact
with electron-rich species in a directional fashion in the solid state
[32,36,37]. In fact some of us have recently shown that this
reasoning applies to p-holes in common nitro-compounds such as
* Corresponding author.
** Corresponding author.
E-mail addresses: shameed@qau.edu.pk (S. Hameed), toni.frontera@uib.es
(A. Frontera).
http://dx.doi.org/10.1016/j.molstruc.2017.03.046
0022-2860/© 2017 Elsevier B.V. All rights reserved.

210
H. Andleeb et al. / Journal of Molecular Structure 1139 (2017) 209e221
nitromethane and nitroaromatics [32], and also other less common
nitro-bearing molecules such as nitrate esters [38].
2.3. Synthesis
In this manuscript, we report the convenient synthesis (four
steps) and X-ray characterization of two thioxothiazolidinone de-
rivatives (Scheme 1) that exhibit interesting solid state architec-
tures. Apart from the conventional CeH/O/S H-bonding
2.3.1. Preparation of 3-(4-substituted phenyl)-2-thioxothiazolidin-
4-one (9 & 10)
Carbon disulfide (0.2 mol) in diethyl ether (50 mL) was added
dropwise to a suspension of the corresponding aniline (3 & 4)
(0.1 mol) and triethylamine (0.2 mol) in a 250 mL round bottom
flask at 0 ꢀC. The reaction mixture was stirred at the same tem-
perature for 5e6 h. After complete precipitation, the corresponding
triethylammonium dithiocarbamate (5 & 6) was filtered in vacuo
and washed with diethyl ether. The solid product was used in the
next step without further purification.
interactions (s-hole interactions), p-hole interactions involving the
p-acidic five-membered ring and the nitro groups are also relevant
to rationalize the overall crystal packing of compounds 1 and 2.
These interactions have been studied using high level DFT calcu-
lations (M06-2X/def2-TZVP) and the Bader's theory of atoms in
molecules. The computations and crystal structures reported in this
work support the concept that
compounds are directional and relevant in crystal engineering.
p
-hole interactions with nitro-
A solution of the corresponding triethylammonium dithiocar-
bamate (5 & 6) (0.1 mol) in water/ethanol (1:1) was added slowly to
a stirred solution of sodium chloroacetate (0.1 mol) in H2O (35 mL)
and the resulting mixture was stirred at 70 ꢀC. After completion of
the reaction (monitored by TLC), the mixture was cooled to room
temperature and slowly poured into boiling hydrochloric acid
(12 M, 40 mL). After 5 min, the solution was allowed to cool slowly
to room temperature to precipitate the desired 3-(4-substituted
2. Experimental and theoretical methods
2.1. Substrates and reagents
phenyl)-2-thioxothiazolidin-4-one derivatives (9
& 10). The
p-Anisidine, p-toluidine and ethylenediamine were from Merck.
4-Nitrobenzaldehyde was purchased from Sigma Aldrich. The re-
agents used were of analytical grade. Ethanol, chloroform and
methanol were supplied by Lab scan (Patuman, Bankok).
Dichloromethane and diethyl ether were products from Riedel de
Haen (Seezle) while ethyl acetate and acetone were obtained from
local commercial sources. All solvents used were either anhydrous
or dried and purified by passage through activated alumina col-
umns under nitrogen pressure.
precipitated solid was filtered and washed with water followed by
cold ethanol, dried and recrystallized from ethanol [39]. The
spectroscopic data were consistent with those reported in litera-
ture [40].
2.3.2. Preparation of 3-aryl-5-(4-nitrobenzylidene)-2-
thioxothiazolidin-4-one (1 & 2)
To a stirred solution of an appropriate 3-(4-substituted phenyl)-
2-thioxothiazolidin-4-one (9 & 10) (1.0 mmol) in chloroform/
methanol (8:1; 18 mL), glacial acetic acid (40 mmol, 2.28 mL) was
added followed by ethylenediamine (0.2 mmol,11 mL). The resulting
2.2. Instrumentation
mixture was stirred for 15 min followed by the addition of 4-
nitrobenzaldehyde (1.2 mmol) at ambient temperature. After
completion of the reaction (TLC; 40% acetone/petroleum ether), the
excess solvent was removed to afford a bright yellow solid. The
crude solid was washed with methanol/water (10:1), filtered, dried
and recrystallized (chloroform/methanol; 1:6) to yield the title
compounds (1 & 2) [39].
Unless specified otherwise, all reactions were carried out using
oven-dried glassware. The reaction progress was monitored by thin
layer chromatography (TLC) using Merck DF-Alufoilien 60F254
0.2 mm precoated plates. Compounds were visualized by exposure
to UV light at 254 nm. Melting points were recorded in open cap-
illaries using a Gallenkamp melting point apparatus (MP-D) and are
uncorrected. FTIR spectra were recorded on a Thermoscientific
Fourier Transform Infra-Red Spectrophotometer USA model Nicolet
6700 using the attenuated total refraction (ATR) technique. NMR
spectra were acquired on Bruker AV300 spectrometer at room
temperature. 1H and 13C NMR spectra were referenced to external
tetramethylsilane via the residual protonated solvent (1H) or the
solvent itself (13C). All chemical shifts are reported in parts per
million (ppm). For CDCl3, shifts are referenced to 7.27 ppm for 1H
NMR spectroscopy and 77.0 ppm for 13C NMR spectroscopy. For
DMSO-d6, shifts are referenced to 2.50 ppm for 1H NMR spectros-
copy and 39.97 ppm for 13C NMR spectroscopy. Coupling constant
(J) values are reported to the nearest 0.5 Hz. Elemental analyses
were performed on a Leco CHNS-932 Elemental Analyzer, Leco
Corporation (USA).
2.3.2.1. (Z)-3-(4-methoxyphenyl)-5-(4-nitrobenzylidene)-2-
thioxothiazolidin-4-one
(1). Orange
crystals
(79%):
m.p
268e269 ꢀC; Rf: 0.31 (40% acetone/n-hexane); IR (ATR, cmꢁ1): 3085
(AreH), 2994, 2853 (CH3), 1598 (C]O),1565,1521 (C]C), 1363 (C]
S); 1H NMR (300 MHz, DMSO-d6):
d
8.38 (2H, d, J ¼ 8.7 Hz, ArH),
7.96 (2H, d, J ¼ 8.7 Hz, ArH), 7.95 (1H, s, ]CHeArNO2), 7.36e7.32
(2H, m, ArH), 7.12e7.09 (2H, m, ArH), 3.83 (3H, s, OCH3); 13C NMR
(75 MHz, DMSO-d6):
d 194.29 (C]S), 167.30 (C]O), 160.28, 148.08,
139.72, 131.91, 130.32, 129.86, 128.21, 127.78, 124.94, 115.03, 55.91.
Anal. Calcd. for C17H12N2O4S2 (372.02): C, 54.83; H, 3.25; N, 7.52; S,
17.22%; found: C, 54.66; H, 3.04; N, 7.30; S, 17.05%.
2.3.2.2. (Z)-5-(4-nitrobenzylidene)-2-thioxo-3-(p-tolyl)thiazolidin-
4-one (2). Orange crystals (83%): m.p 273e274 ꢀC; Rf: 0.45 (40%
acetone/n-hexane); IR (ATR, cmꢁ1): 3076 (AreH), 2989, 2832 (CH3),
1597 (C]O), 1564, 1519 (C]C), 1365 (C]S); 1H NMR (300 MHz,
CDCl3):
d
8.38 (2H, d, J ¼ 8.7 Hz, ArH), 7.81 (1H, s, ]CHeArNO2),
7.76 (2H, d, J ¼ 8.7 Hz, ArH), 7.40 (2H, d, J ¼ 8.1 Hz, ArH), 7.19 (2H, d,
J ¼ 8.1 Hz, ArH), 2.47 (3H, s, CH3); 13C NMR (75 MHz, DMSO-d6):
d
192.29 (C]S), 172.30 (C]O),167.28,140.28,139.30,131.73,130.98,
130.46, 129.55, 128.00, 127.90, 124.53, 21.44. Anal. Calcd. for
17H12N2O3S2 (356.03): C, 57.29; H, 3.39; N, 7.86; S, 17.99%; found:
C, 57.03; H, 3.20; N, 7.62; S, 17.71%.
C
Scheme 1. Compounds 1e2.

H. Andleeb et al. / Journal of Molecular Structure 1139 (2017) 209e221
211
2.4. Crystal growth development
level of theory. To evaluate the interactions in the solid state, we
have used the crystallographic coordinates. This procedure and
level of theory have been successfully used to evaluate similar in-
teractions [48]. We have also computed two assemblies using the
MP2/def2-TZVP level of theory and the binding energies are com-
parable to those computed using the M06-2X functional, thus
giving reliability to the level of theory used herein. The interaction
energies were computed by calculating the difference between the
energies of isolated monomers and their assembly. The interaction
energies were corrected for the Basis Set Superposition Error (BSSE)
using the counterpoise method [49]. The Bader's “Atoms in mole-
cules” theory [50] has been used to study the interactions discussed
herein by means of the AIMall calculation package [51]. For the
calculation of the MEP (Molecular Electrostatic Potential) surfaces
we have used the SPARTAN10 software [52]. The NCI plot is a
visualization index based on the electron density and its de-
rivatives, and enables identification and visualization of non-
covalent interactions efficiently. The isosurfaces correspond to
both favorable and unfavorable interactions, as differentiated by
the sign of the second density Hessian eigenvalue and defined by
the isosurface color. NCI analysis allows an assessment of host-
guest complementarity and the extent to which weak in-
teractions stabilize a complex. The information provided by NCI
plots is essentially qualitative, i.e. which molecular regions interact.
Good quality single crystals of compounds 1 and 2 suitable for X-
ray diffraction analysis were grown from 10% CHCl3:EtOH solutions
by slow evaporation at ambient temperature.
2.5. Single crystal data collection and structure solution
The X-ray measurements for compounds 1 and 2 (Table 1) were
carried out on a Bruker APEXII Kappa CCD single crystal diffrac-
tometer equipped with a graphite monochromator. Mo-K
a radia-
tion (
l
¼ 0.71073 Å) was used for the collection, which was
controlled by APEX2 [41] with data collected at 296(2)K. Data were
corrected for Lorentz and polarization effects using SAINT [41] and
multi-scan absorption corrections were applied using SADABS [41].
The structures were solved by direct methods using SHELXS-97
[42] and refined using full-matrix least-squares procedures with
SHELXL-2014 [43]. All non-hydrogen atoms were refined aniso-
tropically and all hydrogen atoms bound to carbon were placed in
the calculated positions, and their thermal parameters were refined
isotropically with Ueq ¼ 1.2 or 1.5 Ueq(C). The molecular plots and
packing diagrams were drawn using Mercury [44] and additional
metrical data were calculated using PLATON [45]. Tabular material
was prepared using WINGX [46].
The color scheme is a red-yellow-green-blue scale with red for rþ
cut
(repulsive) and blue for rꢁcut (attractive). Yellow and green surfaces
correspond to weak repulsive and weak attractive interactions,
respectively [53].
2.6. Theoretical methods
Calculations of the noncovalent interactions were carried out
using TURBOMOLE version 7.0 [47] using the M06-2X/def2-TZVP
Table 1
Crystal data and structure refinement for (1) and (2).
Data
Compound 1
Compound 2
Empirical formula
Formula weight
Temperature
C17H12N2O4S2
372.41
296(2) K
C17H12N2O3S2
356.41
296(2) K
Wavelength
Crystal system
Space group
0.71073 Å
Triclinic
P -1
0.71073 Å
Triclinic
P -1
Unit cell dimensions
a ¼ 4.2172(4) Å
a ¼ 7.3942(8) Å
b ¼ 12.3528(11) Å
c ¼ 16.6547(16) Å
b ¼ 8.0203(9) Å
c ¼ 15.2417(18) Å
a
b
g
¼ 106.097(5)ꢀ
¼ 94.489(5)ꢀ
¼ 95.340(5)ꢀ
a
b
g
¼ 78.332(4)ꢀ
¼ 83.687(4)ꢀ
¼ 66.940(4)ꢀ
Volume
Z
Density (calculated)
Absorption coefficient
F(000)
825.05(14) Å3
2
814.00(16) Å3
2
1.499 Mg/m3
0.348 mmꢁ1
384
1.454 Mg/m3
0.345 mmꢁ1
368
Crystal size
Theta range for data collection
Index ranges
0.42 ꢂ 0.18 ꢂ 0.16 mm3
1.728e27.475ꢀ
ꢁ5 ¼ h<¼5,
ꢁ15 ¼ k<¼14,
ꢁ20 ¼ l<¼21
12988
0.40 ꢂ 0.32 ꢂ 0.16 mm3
2.803e27.000ꢀ
ꢁ9 ¼ h<¼9,
ꢁ10 ¼ k<¼10,
ꢁ19 ¼ l<¼19
12986
Reflections collected
Independent reflections
Completeness to theta ¼ 25.242ꢀ
Refinement method
3703 [R(int) ¼ 0.0423]
3524 [R(int) ¼ 0.0447]
99.8%
99.5%
Full-matrix least-squares on F2
3703/0/227
1.024
Full-matrix least-squares on F2
3524/0/218
1.068
Data/restraints/parameters
Goodness-of-fit on F2
Final R indices [I > 2sigma(I)]
R1 ¼ 0.0475,
wR2 ¼ 0.1057
R1 ¼ 0.0793,
wR2 ¼ 0.1195
0.291 and ꢁ0.210 e.Åꢁ3
1491798
R1 ¼ 0.0675,
wR2 ¼ 0.1848
R1 ¼ 0.0882,
wR2 ¼ 0.2090
0.848 and ꢁ0.292 e.Åꢁ3
1491799
R indices (all data)
Largest diff. peak and hole
CCDC

212
H. Andleeb et al. / Journal of Molecular Structure 1139 (2017) 209e221
3. Results and discussion
were further identified by 13C NMR spectroscopy where diagnostic
chemical shifts around 194e192 ppm were attributed to the pres-
ence of C]S groups in the rhodanine rings, whereas the C]O
functional group resonance was found at 172e167 ppm. Finally, the
purity of the synthesized compounds 1 and 2 was determined by
elemental analysis.
3.1. Synthesis and spectroscopic characterization
Synthesis of rhodanine compounds (1 & 2) was accomplished by
the synthetic route illustrated in Scheme 2. Triethylammonium N-
aryl dithiocarbamates (5 & 6) were prepared by reaction of the
corresponding aniline (p-anisidine/p-toluidine) (3 & 4) (1.0 equiv)
with carbon disulfide (2.0 equiv) in diethyl ether under basic con-
ditions (triethylamine; 2.0 equiv) which subsequently afforded the
sodium 2-(N-4-substituted phenylcarbamothioylthio)acetates (7 &
8) from a reaction with sodium chloroacetate in ethanol/water
(1:1). The 3-aryl-2-thioxo-1,3-thiazolidin-4-ones (9 & 10) were
synthesized by cyclization of 7 and 8 in boiling hydrochloric acid
[39].
3.2. Molecular structures of (Z)-3-(4-methoxyphenyl)-5-(4-
nitrobenzylidene)-2-thioxothiazolidin-4-one (1) and (Z)-5-(4-
nitrobenzylidene)-2-thioxo-3-(p-tolyl)thiazolidin-4-one (2)
The molecular structures of both compounds (Fig. 1) are suffi-
ciently similar to be discussed together, with each molecule
comprising a central 2-thioxo-1,3-thiazolidin-4-one ring system
with phenyl substituents on the thiazolidine N3 atoms and 4-
nitrobenzylidene substituents on C5. The molecules differ only in
the nature of the substituents on the 4-positions of the two phenyl
rings with a methoxy group in 1 and a methyl group for 2. Selected
bond distances and angles are shown in Table S1 (ESI). Both mol-
ecules adopt a Z-configuration about the C5]C6 double bond. In
both molecules, the 4-nitrobenzylidene-2-thioxo-1,3-thiazolidin-
4-one segments of the molecules are surprisingly planar, no doubt
imposed in part by intramolecular C8eH8/S1 hydrogen bonds in
both molecules, Tables 2 and 3. The root mean square deviations are
0.0678 Å for 1 and 0.0728 Å for 2 from the best fit planes through all
17 non-hydrogen atoms of these moieties. This planarity is under-
scored further by the fact that the 1,3-thiazolidine and its adjacent
phenyl ring are inclined at angles of 6.21(13)ꢀ for 1 and 7.90(8)ꢀ for
2. Additional evidence is provided by the corresponding in-
clinations of this phenyl ring and its nitro substituent, which are
4.1(4)ꢀ and 5.2(3)ꢀ respectively.
Knoevenagel condensation reactions of 3-(4-aryl)-2-thioxo-1,3-
thiazolidin-4-ones (9 & 10) with 4-nitrobenzaldehyde gave 3-aryl-
5-(4-nitrobenzylidene)-2-thioxothiazolidin-4-ones (1 & 2) in good
yield [39].
The structures of the synthesized compounds (1 & 2) were
characterized by the usual analytical techniques including FT-IR, 1H
and 13C NMR spectroscopy. In the IR spectra, typical stretching vi-
brations for the C]O and C]S moieties were found around
1598e1597 and 1365e1363 cmꢁ1, respectively. Distinct Csp2-H
stretching vibrations were observed in the region 3085e3076 cmꢁ1
.
In 1H NMR spectra, the lone olefinic proton (]CeH) resonated
as a singlet at 7.95e7.81 ppm confirming the Z-configuration for the
exocyclic double bond as evident from literature [54e57]. In
addition, M06-2X/def2-TZVP calculations confirm that the Z isomer
is 5.7 kcal/mol more stable than the E one. The reason for this
deshielding is attributed to the cis position of the carbonyl oxygen
of the rhodanine ring to the ]CH and hence the Z configuration.
The cis positioning is due to the high degree of thermodynamic
stability of these compounds because of the intramolecular
hydrogen bond that can be formed between the hydrogen atom of
]CH and the oxygen atom in rhodanine [52].
In contrast, the N bound phenyl ring subtends an angle of
60.13(6)ꢀ to the thiazolidine ring for 1 and is almost orthogonal to it
in 2 with a dihedral angle 82.75(11)ꢀ. The methoxy substituent in 1
lies close to the plane of its benzene ring with an angle of 1.5(3)ꢀ
between the benzene ring plane and the plane containing C16, O16
and C161.
This distinctive feature was further confirmed by the single
crystal X-ray diffraction analysis (vide infra). The structures (1 & 2)
Nine structures of molecules with a central 2-thioxo-1,3-
Scheme 2. Synthesis of 3-aryl-5-(4-nitrobenzylidene)-2-thioxothiazolidin-4-ones (1 & 2).

H. Andleeb et al. / Journal of Molecular Structure 1139 (2017) 209e221
213
Fig. 1. The molecular structures of (a) compound 1 and (b) compound 2 with displacement ellipsoids drawn at the 50% probability level. Intramolecular hydrogen bonds are drawn
as dotted lines.
Table 2
Crystallographic Database [58] including the archetypal 3-phenyl-
5-(phenylmethylidene)-2-thioxo-1,3-thiazolidin-4-one [59]. The
Hydrogen bonds for 1 [Å and ꢀ].
other related structures had substituents on either the benzene
ring of the phenylmethylidene moiety [60,61] or on both benzene
rings [62e66] with one instance of a phenylethylidene substituent
at C5 [67].
DeH … A
d(DeH)
d(H … A)
d(D … A)
<(DHA)
C(8)eH(8) … S(1)
0.93
0.93
0.93
0.93
0.93
0.93
0.96
0.93
2.51
2.47
2.56
2.92
2.99
2.49
2.63
2.52
3.223(3)
3.354(3)
3.416(3)
3.580(3)
3.608(3)
3.417(3)
3.151(4)
3.294(3)
134
C(6)eH(6) … O(4)#1
C(12)eH(12) … O(4)#1
C(8)eH(8) … S(2)#2
C(9)eH(9) … S(2)#2
C(15)eH(15) … O(16)#3
C(161)-H(16B) … O(101)#4
C(18)eH(18) … O(4)#5
159.8
152.7
129.0
125.0
174.6
114.7
140.4
3.3. Crystal packing for compound 1
Compound 1 crystallizes in the triclinic space group P-1 with
Z ¼ 2. In the crystal structure of 1, C161eH16B/O101 hydrogen
bonds (Table 2) link molecules into chains. These chains are linked
in an obverse fashion by C8eH8/S2 and C9eH9/S2 hydrogen
bonds with S2 acting as a bifurcated acceptor and these contacts
link adjacent molecules forming inversion dimers, simultaneously
generating R22(18), R22(16) and R12(5) ring motifs. Similar inversion
dimers are generated on the opposite side of the molecule by
C6eH6/O4 and C12eH12/O4 contacts with O4 acting as the
bifurcated acceptor in this case, with the generation of R22(14),
R22(10) and R12(5) rings and again link to an adjacent chain in an
obverse fashion. This array of contacts generates layers of molecule
in a plane approximately parallel to (-1 -1 3) (Fig. 2).
Symmetry transformations used to generate equivalent atoms: #1 ꢁxþ1,ꢁy,-zþ1
#2 ꢁx,ꢁyþ1,-zþ1 #3 ꢁx,ꢁy,ꢁz #4 xꢁ2,yꢁ1,zꢁ1 #5 xꢁ1,y,z.
Table 3
Hydrogen bonds for 2 [Å and ꢀ].
DeH … A
d(DeH)
d(H … A)
d(D … A)
<(DHA)
C(8)eH(8) … S(1)
0.93
0.93
0.93
0.93
0.93
2.54
2.53
2.52
2.71
2.64
3.250(3)
3.432(4)
3.293(4)
3.569(4)
3.186(4)
133
C(18)eH(18) … O(102)#2
C(9)eH(9) … O(4)#3
C(14)eH(14) … O(102)#4
C(12)eH(12) … O(4)#5
163.2
141.1
154.8
118.4
Symmetry transformations used to generate equivalent atoms: #1 ꢁxþ2,ꢁy,ꢁzþ1
#2 ꢁxþ2,ꢁyþ1,ꢁz #3 xꢁ1,yþ1,z #4 ꢁxþ1,ꢁyþ1,ꢁz #5 ꢁxþ2,ꢁy,ꢁz.
C15eH15/O16 contacts form additional inversion dimers and
generate R22(8) rings and these dimers are linked by C18eH18/O4
hydrogen bonds into layers in the ac plane (Fig. 3). This extensive
series of contacts combines to stack the molecules along the a axis
direction (Fig. 4).
thiazolidin-4-one ring system with similar phenyl and benzylidene
substituents were found in
a
search of the Cambridge

214
H. Andleeb et al. / Journal of Molecular Structure 1139 (2017) 209e221
Fig. 2. Layers of molecules of 1 parallel to (-1 -1 3). In this and subsequent Figures, hydrogen bonds are drawn as blue dashed lines. (For interpretation of the references to colour in
this figure legend, the reader is referred to the web version of this article.)
Fig. 3. Layers of inversion dimers of (1) in the ac plane.
3.4. Crystal packing for compound 2
enclosing an R22(26) ring motif (Fig. 5). C9eH9/O4 hydrogen
bonds form chains of molecules along the ab diagonal (Fig. 6).
C12eH12/O4 hydrogen bonds form inversion dimers and
generate R22(14) rings. The dimers are linked by short intermo-
lecular S2/S22V contacts, 3.4477(16) Å (2v ¼ 2-x,-y,1-z), forming
chains along c (Fig. 7). Overall, these contacts combine to stack the
molecules along the b axis direction (Fig. 8).
Compound 2 also crystallizes in the triclinic space group P -1
with Z ¼ 2. In the crystal structure of 2, atom O102 acts as a
bifurcated acceptor forming C14eH14/O102 and C18eH18/O102
hydrogen bonds (Table 3) and linking molecules in a head-to-tail
fashion into sheets approximately parallel to (0 3 4). Each of
these contacts also generate inversion dimers with each dimer
A striking feature of the crystal structures of both molecules is

H. Andleeb et al. / Journal of Molecular Structure 1139 (2017) 209e221
215
Fig. 4. Overall packing for 1 viewed along the a axis direction.
Fig. 5. Sheets of molecules of 2 parallel to (0 3 4).

216
H. Andleeb et al. / Journal of Molecular Structure 1139 (2017) 209e221
the marked tendency to form inversion dimers through non-
classical CeH/S and CeH/O hydrogen bonds for 1 and CeH/O
contacts for 2.
3.5. Theoretical (DFT) study
The theoretical study is devoted to an analysis of the non-
covalent interactions that are present the crystal packing of com-
pounds 1 and 2, excluding the H-bonding interactions that have
been described in the previous section. In particular, we have
focused our attention to the remarkable CeH …
teractions and lp … -hole interactions. The importance of the CeH
interaction in the solid state has been studied in depth by
Nishio [68] and, as aforementioned, these -hole interactions
p, p … p in-
p
…
p
p
(especially those involving the nitro group) are also increasingly
taken into consideration by the scientific community due to their
relevance to crystal engineering and supramolecular chemistry
[32e38]. Moreover, the physical nature of this type of
p-hole
interaction has been investigated theoretically also [69e73].
As a first approximation to rationalize the different assemblies
observed in the solid state of compounds 1 and 2, we have
Fig. 6. C9 chains of molecules of 2 along the ab diagonal.
Fig. 7. Chains of inversion dimers of 2 along c.
Fig. 8. Overall packing of 2 viewed along the b axis direction.

H. Andleeb et al. / Journal of Molecular Structure 1139 (2017) 209e221
217
and the p-methoxy(or methyl)-phenyl ring is
p
-basic (ꢁ10 kcal/
mol). Additional details of the H-bond acceptor ability of the
different groups of the ligand are given in the ESI (Fig. S1).
In Fig. 10a, we illustrate a partial view of the crystal packing of
compound 1 that is governed by several interactions. Basically, 2D
layers are formed by H-bonding interactions that stack forming the
final 3D architecture (see also Fig. 3). We have examined first the
stacking mode that can be defined as
a parallel-displaced
arrangement (Fig. 10b). The displacement minimizes the electro-
static repulsion between the aromatic rings (the electrostatic po-
tential over the five membered ring is very positive, Fig. 9). In fact
the distance between the six membered ring centroids is large
(4.21 Å) and the stacking complex formation is likely governed by
other interactions involving the
p-acidic regions. These include, S
…
p
(3.69 Å) and O … (3.57 Å) interactions involving the five
p
membered ring and the nitro group (Fig. 10b). Moreover, a CeH/O
H-bonding interaction between the methoxy groups further con-
tributes to the stabilization of this assembly. This intricate combi-
nation of noncovalent interactions explains the large interaction
energy computed for this dimer (
two types of self-assembled H-bonded dimers are found in the 2D
layers (Fig. 10c,e). The dimer shown in Fig. 10c also presents
D
E1 ¼ ꢁ12.6 kcal/mol). In addition,
ancillary CeH/
arene (most positive H-atoms) and the
p
interactions involving the H atoms of the nitro-
-system of the p-
p
Fig. 9. Open MEP surfaces (isosurface 0.002 e/Å3) of compounds 1 and 2. Energies at
selected points of the surfaces are given in kcal/mol.
methoxyphenyl ring (electron-rich ring) in good agreement with
the MEP analysis. The interaction energy of this self-assembled
dimer (Fig. 10c) is
computed the interaction energy of a theoretical dimer where the
D
E2 ¼ ꢁ10.2 kcal/mol. Furthermore we have
computed their Molecular Electrostatic Potential (MEP) surfaces
that are shown in Fig. 9. As expected, in both compounds the most
negative regions (red surface) correspond to the oxygen atoms. The
most positive region corresponds to the H atoms of the nitroarene.
p-methoxyphenyl rings have been replaced by H atoms. Conse-
quently the CeH/
energy is reduced to
level) that can be attributed to the contribution of the H-bonding
network (two bifurcated H-bonds) and the difference ( E2
p
interactions are not formed and the interaction
DE3 ¼ ꢁ5.4 kcal/mol (ꢁ6.2 kcal/mol at the MP2
However, there are two
positive ( -acidic regions). One is the five membered thio-
xothiazolidine ring and the other one is the -hole over the nitro
p-systems that also show significantly
D
e
p
D
E3 ¼ ꢁ4.8 kcal/mol) is a rough estimation of both symmetrically
p
equivalent CeH …
p interactions. This energetic study confirms the
group. Interestingly, the MEP surfaces indicate that the aromatic
rings present opposite electronic characteristics. That is, the p-
importance of these interactions to the formation of the dimer.
Finally, the other H-bonded dimer that participates in the
nitrophenyl ring is
p-acidic (þ7 kcal/mol over the ring centroid)
Fig. 10. (a) X-ray fragment of 1, H-atoms omitted for clarity. (bee) Theoretical models used to evaluate the
distance has been measured using the ring centroids.
pep, H-bonding, lpep and CeH … p interactions. Distances in Å. The
pep

218
H. Andleeb et al. / Journal of Molecular Structure 1139 (2017) 209e221
formation of the 2D layer (Fig. 10e) presents a modest interaction
energy
because less basic S instead of O atoms participate in the formation
of the bifurcated H bonds.
A similar study has been also carried out for compound 2. In
Fig. 11a, we represent a partial view of the crystal packing of this
compound that is significantly different compared to that for 1.
Interestingly, the self-assembled dimer shown in Fig. 10c governed
We have used Bader's theory of “atoms in molecules” (AIM) to
characterize the noncovalent bonds described above for complex 1
as a model system. A bond critical point (CP) and a bond path
connecting two atoms is unambiguous evidence of interaction. The
AIM distribution of critical points and bond paths computed for two
dimers of compound 1 is shown in Fig. 12. The distribution in the
D
E4 ¼ ꢁ4.8 kcal/mol (ꢁ4.4 kcal/mol at the MP2 level)
self-assembled H-bonded dimer (with ancillary CeH …
p in-
teractions) reveals that each bifurcated H-bond is characterized by
two CPs (red spheres) and bond paths connecting the O atom with
by H-bonding interactions (augmented by CeH …
p interactions) in
1 is also observed in compound 2; however, the relative importance
two H atoms (Fig. 12a). The CeH … p interaction is characterized by
of these two interactions is reversed. The interacting molecules are
two CPs (red spheres) and bond paths connecting the CeH bonds to
two C atoms of the arene. Finally, the AIM analysis also reveals the
formation of two symmetrically equivalent H-bonds between the
nitro and methoxy groups characterized by a bond CP and a bond
path. The distribution of CPs and bond paths for the parallel dis-
not coplanar in 2, favoring the CeH …
the H-bonds that are seen to be considerably longer (Fig. 11b). The
interaction energy of this dimer is
E5 ¼ ꢁ9.4 kcal/mol (similar to
E5) but this is reduced to
p interaction and weakening
D
D
D
E6 ¼ ꢁ2.8 kcal/mol when an additional
theoretical model is used, replacing the p-methylphenyl moiety by
an H atom. This result confirms that this dimer is mainly governed
placed
p-stacking complex is shown in Fig. 12b. All interactions
described above in the energetic study (
pe
p
, lpe and H-bonding
p
by the CeH …
bonding interactions is only ꢁ2.8 kcal/mol. An important difference
with compound 1 is the stacking arrangement. In 2, an anti-
p
interaction since the contribution of the H-
interactions) are confirmed by the AIM analysis. They are charac-
terized by the presence of a bond CP and a bond path connecting
the electron-rich atom with the corresponding H atom in the case
pep
parallel displaced arrangement (Fig. 11c) is observed instead of the
parallel one described above. This is likely due to the absence of the
methoxy group in 2 (the H-bond shown in Fig. 10b cannot be
of H-bonding interactions or with a C/S atom for the
or lpe ).
Finally, we have used the noncovalent interaction plot (NCIplot)
p-interactions
(pe
p
p
formed). Similar to 1, the
lows the formation of two symmetrically related lpe
involving the -hole of the nitro group (3.61 Å). Moreover, this
dimer is also stabilized by two H-bonds involving the aromatic H
atoms and the O atoms of the nitro groups (2.53 Å). The interaction
p
-stacking antiparallel displacement al-
analysis for the dimers analyzed above. As described in the litera-
ture, this approach is a computational tool based on the electron
density and its derivatives [53]. The peaks that appear in the
reduced density gradient (s) at low densities correspond to the
different noncovalent interactions. The sign of the second eigen-
value (l2) of the electron-density Hessian matrix is used to
distinguish bonded (l2 < 0) from nonbonded (l2 > 0) interactions
and its strength can be derived from the density values of the low-
gradient spikes. An advantage of this method is the visualization in
real space of the gradient isosurfaces. Fig. 13 displays the NCI
p
interactions
p
energy of this assembly is
E8 ¼ ꢁ8.4 kcal/mol when the p-methylphenyl moieties are
eliminated. Thus, the H-bonding interactions contribute ꢁ2.3 kcal/
mol and the main contribution is due to a combination of lpe and
interactions.
DE7 ¼ ꢁ10.7 kcal/mol that is reduced to
D
p
pep
Fig. 11. (a) X-ray fragment of 2. (bec) Theoretical models used to evaluate the CeH …
p, lp … p and H-bonding interactions. Distances in Å.

H. Andleeb et al. / Journal of Molecular Structure 1139 (2017) 209e221
219
Fig. 12. Distribution of bond, ring and cage critical points (red, yellow and green spheres, respectively) and bond paths for two dimers of compound 1. (For interpretation of the
references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 13. NCI analysis of complexes 1, (a,b) and 2 (c,d). The gradient isosurfaces are colored on a BGR scale according to the sign (l2
)
r
over the range ꢁ0.015 to 0.015 a.u.

220
H. Andleeb et al. / Journal of Molecular Structure 1139 (2017) 209e221
€
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to visualize the H-bonding, lpe and CeH … interactions.
p,
pe
p
p
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than 0.01 a.u., which corresponds to the region of weak in-
teractions, characterized by the green color at the isosurfaces. In all
dimers the color observed for the isosurface area is green,
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s-hole interactions found
Acknowledgements
H.A. is grateful to the Higher Education Commission, Pakistan
for financial support under Indigenous 5000 Ph.D Fellowship pro-
gram. J.S. thanks the Chemistry Department, University of Otago for
support of his work. A.B. and A.F. thank DGICYT of Spain (project
CTQ2014-57393-C2-1-P) for funding. We thank the CTI (UIB) for
free allocation of computer time.
Appendix A. Supplementary data
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