Crystal engineering with pyrazolyl-thiazole derivatives: Structure-directing role of π-stacking and σ-hole interactions

Article abstract of DOI:10.1039/d1ce00256b

The synthesis and X-ray characterization of 1-(2-(3-(4-bromophenyl)-5-(4-methoxyphenyl)-4,5-dihydro-1H-pyrazol-1-yl)-4-methylthiazol-5-yl)ethanone (7), ethyl 2-(5-(4-bromophenyl)-3-(4-chlorophenyl)-4,5-dihydropyrazol-1-yl)thiazole-4-carboxylate (8) and 2-(5-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-N′-(2-hydroxy-3-methoxybenzylidene)thiazole-4-carbohydrazide (10) are described in this manuscript. The structure-directing role of a variety of noncovalent interactions has been analyzed energetically using DFT calculations and Hirshfeld surface analysis. Moreover, the existence and importance of halogen and chalcogen bonding interactions have been analyzed by using the quantum theory of atoms in molecules and the noncovalent interaction index (NCIplot).

Full text of DOI:10.1039/d1ce00256b

Volume 23
Number 18
1
4 May 2021
Pages 3241–3420
CrystEngComm
rsc.li/crystengcomm
ISSN 1466-8033
PAPER
Muhammad Naeem Ahmed, Murtaza Madni,
Antonio Frontera et al.
Crystal engineering with pyrazolyl-thiazole derivatives:
structure-directing role of π-stacking and σ-hole interactions

CrystEngComm
View Article Online
View Journal | View Issue
PAPER
Crystal engineering with pyrazolyl-thiazole
derivatives: structure-directing role of π-stacking
and σ-hole interactions†
Cite this: CrystEngComm, 2021, 23,
276
3
a
b
a
c
Muhammad Naeem Ahmed, * Murtaza Madni,* Shaista Anjum, Saiqa Andleeb,
b
d
e
Shahid Hameed,
Abdul Majeed Khan, Muhammad Ashfaq,
Muhammad Nawaz Tahir, Diego M. Gil
e
f
and Antonio Frontera *g
The synthesis and X-ray characterization of 1-(2-(3-(4-bromophenyl)-5-(4-methoxyphenyl)-4,5-dihydro-
H-pyrazol-1-yl)-4-methylthiazol-5-yl)ethanone (7), ethyl 2-(5-(4-bromophenyl)-3-(4-chlorophenyl)-4,5-
1
dihydropyrazol-1-yl)thiazole-4-carboxylate (8) and 2-(5-(4-chlorophenyl)-3-phenyl-4,5-dihydro-1H-
pyrazol-1-yl)-N′-(2-hydroxy-3-methoxybenzylidene)thiazole-4-carbohydrazide (10) are described in this
manuscript. The structure-directing role of a variety of noncovalent interactions has been analyzed
energetically using DFT calculations and Hirshfeld surface analysis. Moreover, the existence and importance
of halogen and chalcogen bonding interactions have been analyzed by using the quantum theory of atoms
in molecules and the noncovalent interaction index (NCIplot).
Received 22nd February 2021,
Accepted 9th March 2021
DOI: 10.1039/d1ce00256b
rsc.li/crystengcomm
because they are precursors for the synthesis of several drugs,
such as ravuconazole, an antifungal agent, and nizatidine,
Introduction
8
9
Compounds with pyrazole moieties play an important role in
active pharmaceutical drugs and agrochemicals in controlling
an antiulcer agent (Scheme 1). In addition, the thiazole group
is also important in drug designing, since it frequently
appears in the structures of various natural products and
biologically active compounds like thiamine and in some
antibiotic drugs like penicillin, micrococcin and many
metabolic products of fungi and primitive marine animals.
In addition, combined pyrazolyl-thiazole scaffolds are also
relevant for several medical and pharmaceutical applications.
1
–3
infections, diseases and pests.
Several drugs have been
developed in recent years from pyrazole derivatives. For
example, celecoxib demonstrates anti-inflammatory effects
and inhibits COX-2; rimonabant functions as a cannabinoid
4
receptor and is also used to treat obesity. Moreover, pyrazole
derivatives have shown significant biological activities such as
antimicrobial, analgesic, anti-inflammatory, and anticancer
10
11
Their derivatives are potent antiviral and anti-inflammatory
5–7
activities.
The significance of thiazoles is emphasized
a
Department of Chemistry, The University of Azad Jammu and Kashmir,
Muzaffarabad, 13100 Pakistan
b
Department of Chemistry, Quaid-i-Azam University, Islamabad 45320, Pakistan
c
Department of Zoology, The University of Azad Jammu and Kashmir,
Muzaffarabad, 13100 Pakistan
d
Research Laboratory of Bioenergy, Department of Chemistry, Federal Urdu
University of Arts, Science and Technology, Gulshan-e-Iqbal Campus, University
Road, Karachi-75300, Pakistan
e
Department of Physics, University of Sargodha, Sargodha, Pakistan
f
INBIOFAL (CONICET – UNT), Instituto de Química Orgánica, Facultad de
Bioquímica, Química y Farmacia, Universidad Nacional de Tucumán, Ayacucho
471, T4000INI, San Miguel de Tucumán, Argentina.
E-mail: diego.gil@fbqf.unt.edu.ar
g
Department of Quimica, Universitat de les Illes Balears, Crta. De Valldemossa Km
7.5, 07122 Palma de Mallorca, Baleares, Spain
†
Electronic supplementary information (ESI) available: Hirshfeld surfaces of
compounds 7, 8 and 10 mapped over shape index and curvedness properties
Fig. S1). CCDC 1981404, 1009301 and 1009302. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/d1ce00256b
(
Scheme
nizatidine.
1
Structure of celecoxib, rimonabant, ravuconazole and
3276 | CrystEngComm, 2021, 23, 3276–3287
This journal is © The Royal Society of Chemistry 2021

View Article Online
CrystEngComm
agents, AChE inhibitors, antimicrobiotics and EP1 receptor
Paper
12
13
spectra were recorded on
a
Bruker Avance 300 MHz
14,15
antagonists.
pursuing
heterocycles
Motivated by the aforementioned findings and
studies on different five-membered
as well as structural studies,
instrument in deuterated solvents and the chemical shifts are
referenced to TMS. Reactions were monitored using thin layer
chromatography (TLC) on silica gel 60F254 coated aluminium
sheets (Merck, Germany). X-ray diffractometer analysis was
carried out on a Bruker Kappa APEX-IICCD diffractometer.
The synthetic route to compounds 4–10 is shown in
Scheme 2. By following a procedure already reported in the
our
1
6–19
20
we have
designed new derivatives with pyrazolyl-thiazole moieties
Scheme 2). Similarly, in continuation of our recent studies on
(
2
1
antiparallel π–π interactions in isatin-based hydrazides, π-hole
tetrel bonding in 2-triazolyl-2-oxoacetate derivatives
2
2
and
1
2,24–26
recurrent π-stacking motifs in pyrazolyl-thiazole–coumarin
literature
a mixture of substituted acetophenone (5.0
23
hybrids, we report herein synthetic protocols to access aryl-
substituted pyrazolyl-thiazole derivatives. The structures
reported herein exhibit interesting solid-state architectures with
an intricate combination of interactions, including
unconventional π-interactions where the nonaromatic pyrazolyl
ring is stacked over the aromatic thiazole ring and vice versa.
Moreover, the role of halogen and chalcogen bonding
interactions is also analysed using several computational tools,
including molecular electrostatic potential surfaces and a
combination of quantum theory of atoms in molecules (QTAIM)
and NCIplot analyses.
mmol) and 4-substituted benzalaldehyde (5.0 mmol) in 20 mL
of ethanol (EtOH) was stirred at room temperature followed
by the dropwise addition of an aqueous solution of NaOH (10
M). The stirring was continued for 2 h. After reaction
completion verified by TLC, the reaction mixture was poured
into ice-cold water to obtain yellow precipitates. The solid
mass was filtered, washed with excess water and recrystallized
from EtOH to obtain compounds 1–3. Similarly, compounds
1–3 (1 mmol) and thiosemicarbazide (1 mmol) were dissolved
1
2,23
in 20–25 mL of ethanol and stirred vigorously.
Pellets of
NaOH (1.5 mol) were added to the reaction mixture and
heated under reflux. After reaction completion (TLC), the
suspension was poured into ice-cold water. The light yellow
precipitates formed were filtered and recrystallized from
methanol (MeOH) to give compounds 4–6. For the synthesis
of compound 7, 2 mmol of 4 (5-dihydro-3,5-diphenylpyrazole-
1-carbothioamide) and 2 mmol of 3-chloropentane-2,4-dione
were loaded in 100 mL of RBF. Ethanol was used as solvent.
This reaction mixture was stirred for 30 minutes at 50 °C.
After completion of the reaction, the whole mixture was
transferred to a beaker containing crushed ice. The resulting
precipitates were filtered and washed with cold ethanol. After
drying, the solid was recrystallized in EtOH : EtOAc (1 : 1) to
obtain compound 7.
Experimental and theoretical methods
Instrumentation and synthesis
All reagents were commercially available and used without
further purification. Melting points were determined on a
Stuart SMP3 melting point apparatus and are uncorrected. IR
spectra were recorded on a Thermo Scientific Nicolet 6700
1
13
FTIR spectrophotometer using ATR facility. H and C NMR
Compounds 4–6 (1.00 mmol) and α-bromopyruvate (1.0
mmol) were dissolved in ethanol with vigorous stirring at 50–
60 °C for 3–4 h. 2,4-Disubstituted-1,3-thiazole 8 precipitate
was filtered out and the solid mass obtained was washed
1
0
3
with ethanol and recrystallized from CHCl : EtOH (3 : 1).
Compound 9 (1.0 mmol) and the respective benzaldehyde (1
mmol) were added to 20 mL ethanol containing a catalytic
amount of acetic acid. The reaction mixture was refluxed till
completion (TLC). The mixture was poured into ice-cold
water and the precipitate was filtered. The solid formed was
1
0
then recrystallized from CHCl
-(2-(3-(4-Bromophenyl)-5-(4-methoxyphenyl)-4,5-dihydro-
H-pyrazol-1-yl)-4-methylthiazol-5-yl)ethanone (7). Molecular
formula: C22 20BrN S, Mol. wt. = 470.382, yellow solid, m.
p. = 144–146 °C, yield = 82%, R
122 (Ar–H), 2927 (C–H), 1618 (CO), H NMR (300 MHz,
CDCl ) = δ ppm 2.45 (3H, s, CH ), 2.53 (s, 3H, CH ), 3.3 (dd,
H, Jcis = 7.2 Hz, Jgem = 17.4 Hz), 3.8 (s, 3H, –OCH ), 4.03 (dd,
H, Jtrans = 12 Hz, Jgem = 17.4 Hz), 5.65 (dd, 1H, Jcis = 7.2 Hz,
3
: EtOH (3 : 1) to obtain 10.
1
1
H
3 2
O
−
1
f
= 0.45; IR (, ATR, cm ):
1
3
3
3
3
1
1
3
J
trans = 12 Hz), 6.92 (m, 2ArH), 7.25, (m, 2ArH), 7.6 (m, 4ArH);
1
3
C-NMR (75 MHz, CDCl
0.94, 106.8, 114.1, 125.4, 128, 131.4, 131.8, 133, 135.8, 158.7,
151.8, 156.6, 167.6, 189.6.
3
): δ ppm 18.95, 30.06, 43.46, 56.2,
6
Scheme 2 Synthetic route to compounds 4–10.
This journal is © The Royal Society of Chemistry 2021
CrystEngComm, 2021, 23, 3276–3287 | 3277

View Article Online
Paper
CrystEngComm
Ethyl
dihydropyrazol-1-yl)thiazole-4-carboxylate
formula: C21 17BrClN S, Mol. wt. = 490.80, yellow solid, m.
2-(5-(4-bromophenyl)-3-(4-chlorophenyl)-4,5-
formation energies of the assemblies were evaluated by
calculating the difference between the total energy of the
assembly and the sum of the monomers that constitute the
assembly, which were kept frozen. The molecular electrostatic
potential was computed at the same level of theory and plotted
onto the 0.001 a.u. isosurface. The QTAIM (ref. 34) distribution
(8). Molecular
H
3 2
O
−
1
p. = 149–151 °C, yield = 75%, R = 0.51; IR (, ATR, cm ):
f
1
3
033 (CC–H), 2985 (C–H), 1698 (CO), H NMR (300 MHz,
3
CDCl ): δ = 1.34 (t, 3H, J = 7.2 Hz), 3.32 (dd, 1H, Jcis = 5.4 Hz,
35,36
Jgem = 17.4 Hz), 3.90 (dd, 1H, Jtrans = 12.0 Hz, Jgem = 17.7 Hz),
of critical points (CPs) and NCIplot
isosurfaces have been
4
7
.30 (m, 2H), 5.73 (dd, 1H, Jcis = 5.7 Hz, Jtrans = 12 Hz), 7.31–
.45 (m, 6 ArH), 7.54 (s, 1H), 7.75–7.79(m, 2ArH; C NMR (75
used to characterize noncovalent interactions. They correspond
to both favourable and unfavourable interactions, as
differentiated by the sign of the second density Hessian
eigenvalue and defined by the isosurface colour. The colour
1
3
MHz, CDCl ): δ ppm 14.1, 44.4, 61.5, 63.3, 118.9, 126.0,
1
1
3
27.2, 128.9, 129.1, 130.6, 131.2, 133.5, 139.6, 143.8, 152.1,
60.3, 165.8.
2
+
scheme is a red-yellow-green-blue scale with red for ρ cut
−
-(5-(4-Chlorophenyl)-3-phenyl-4,5-dihydro-1H-pyrazol-1-yl)-N′-
2-hydroxy-3-methoxybenzylidene)thiazole-4-carbohydrazide (10).
Molecular formula: C27 22ClN S, Mol. wt. = 532.00, light
yellow solid, m.p. = 220–222 °C, yield = 65%, R = 0.52; IR (,
(repulsive) and blue for ρ
(attractive).
cut
(
H
O
5 3
X-ray data collection and structure refinement
f
Suitable single crystals grown from EtOH:EtOAc of compounds
−1
ATR, cm ): 3242 (NH), 3014 (C–H aromatic), 2926 (C–H
aliphatic), 1702 (CO amidic), 1587 (CN), 1564 (CC); H
NMR (300 MHz, CDCl ) = δ ppm 3.44(dd, 1H, J = 5.7 Hz, Jgem
7
, 8 and 10 were selected for X-ray analyses, and diffraction data
were collected on a Bruker Kappa APEX-II CCD detector with
MoK radiation at 296 K. Semi-empirical correction was applied
1
=
3
cis
α
18.0 Hz), 3.81 (s, 3H, OCH
3
), 3.85 (bs, 1H, OH), 4.12 (dd, 1H,
37
using the SADABS program. All the structures were solved by
Jtrans = 11.7 Hz, Jgem = 18.0 Hz), 5.76 (dd, 1H, Jcis = 5.7 Hz, Jtrans
=
38
direct methods using the SHELX program. The positions and
1
8
4
1
1
1.7 Hz), 6.85–7.51 (m, 9ArH), 7.72, (s, 1H), 7.80–7.83 (m, 3ArH),
2
anisotropic parameters of all non-H atoms were refined on F
13
.67 (1, 1NH), 11.25 (1, 1H); C NMR (75 MHz, DMSO): δ ppm
3.4, 56.3, 63.5, 114.4, 116.7, 119.4, 119.5, 121.3, 127.1, 129.1,
29.2, 129.4, 130.8, 131.0, 132.8, 140.7, 145.0, 147.6, 148.4, 154.5,
49.0, 157.3, 164.8.
using the full matrix least-squares technique. The H atoms were
added at geometrically calculated positions and refined using
the riding model. The details of crystallographic data and
crystal refinement parameters for compounds 7, 8 and 10 are
given in Table 1.
Hirshfeld surface calculations
Results and discussion
Description of crystal structures of compounds 7, 8 and 10
Analysis of the Hirshfeld surfaces (HS) and the corresponding
27
two-dimensional fingerprint plots (full and decomposed) was
carried out employing the CrystalExplorer17.5 (ref. 28) program
to visualize and quantify different intermolecular interactions.
The Hirshfeld surfaces were mapped over dnorm shape index
and curvedness properties. The dnorm is a symmetric function of
distances to the surface from nuclei inside and outside the HS
The molecular structures of compounds 7, 8 and 10 are shown
in Fig. 1. Crystal data and structure refinement are presented in
Table 1. Compounds 7 and 8 crystallize in the triclinic crystal
system with the centrosymmetric P ¯1 space group
accommodating two molecules and one molecule per unit cell,
(d
i
e
and d , respectively), relative to their respective van der Waals
respectively. Compound 10 crystallizes in the orthorhombic
(vdW) radii, which enables identification of the regions of
Pca2 space group with Z = 4 molecules per unit cell.
1
particular importance to intermolecular interactions. The dnorm
surfaces were mapped over a fixed color scale of −0.050 a.u.
In 7, the bromophenyl moiety A (C1–C6/Br1), 4,5-dihydro-
1
H-pyrazole ring B (C7–C9/N1/N2), anisole moiety C (C10–
(red) to 0.750 Å a.u. (blue). The shape index property is based
C16/O1) and 1-(4-methylthiazol-5-yl)ethanone moiety D (C17–
C22/N3/O2/S1) are found to be planar with respective root
mean square (r.m.s.) deviations of 0.0075, 0.0518, 0.0638 and
on the local curvature of the surface, and it is especially useful
27a
to identify planar π-stacking arrangements.
The interaction energies were computed using a dispersion-
corrected CE-B3LYP/6-31G(d,p) level of theory available in the
0
7
.0179 Å. The dihedral angles A/B, B/C and B/D are 7.52(8)°,
4.36(10)° and 6.85(8)°, respectively. The dihedral angles
28
CrystalExplorer17.5 program. The total energy (Etot) is the sum
of four main components, including electrostatic (Eele),
polarization (Epol), dispersion (Edis), and exchange-repulsion
infer that the moieties A and B are nearly planar to each
other and similarly moieties B and D are nearly planar.
In 8 (Fig. 1b and Table 1), the methyl thiazole-4-carboxylate
moiety A (C2–C6/N1/O1/O2/S1), 4,5-dihydro-1H-pyrazole ring B
(Erep) energies, with scale factors of 1.057, 0.740, 0.871 and
29
0.618, respectively.
(C7–C9/N2/N3), bromophenyl ring C (C10–C15/Br1) and
chlorophenyl ring D (C16–C21/Cl1) are found to be planar with
respective root mean square (r.m.s.) deviations of 0.0579,
0.0082, 0.0183 and 0.0108 Å. The central ring B is twisted at
respective dihedral angles of 18.8(2)°, 67.2(1)° and 6.67(3)° with
respect to moiety A and rings C and D. The chloro-substituted
phenyl ring makes a dihedral angle of 64.5(1)° with respect to
Theoretical methods
The DFT calculations presented in the last section of the
manuscript were carried out using the Gaussian-16 program
at the PBE0 (ref. 31)-D3 (ref. 32)/def2-TZVP (ref. 33) level of
theory and using the crystallographic coordinates. The
30
3278 | CrystEngComm, 2021, 23, 3276–3287
This journal is © The Royal Society of Chemistry 2021

View Article Online
CrystEngComm
Paper
Table 1 Crystal data and structure refinement for compounds 7, 8 and 10
Crystal data
7
8
10
1009302
CCDC
1981404
1009301
Chemical formula
C
22
H
20BrN
3 2
O S
C
21
H
3 2
17BrClN O S
C
27
H
22ClN
532.00
Orthorhombic
5 3
O S
M
r
470.38
Triclinic
P¯1
490.80
Triclinic
P1
Crystal system
Space group
Temperature (K)
a (Å)
b (Å)
c (Å)
Pca2
296
23.994(4)
5.0580(9)
20.359(3)
90
90
90
2470.8(7)
4
1
296
296
7.3329(4)
11.3359(7)
13.3196(7)
105.658(3)
92.689(2)
97.255(3)
4.7441(4)
9.5883(9)
12.0770(11)
73.421(5)
89.483(5)
86.045(6)
525.23(8)
1
α (°)
β (°)
γ (°)
V (Å )
3
1053.76(10)
2
Z
Density
1.482
1.552
1.430
F(000)
480
248
1104
Wavelength (λ)
0.71073 Å
2.073
0.71073 Å
2.206
0.71073 Å
0.280
−
1
μ (mm
)
Crystal shape
Crystal colour
Crystal size (mm)
No. of measured, independent
and observed [I > 2s(I)] reflections
Needle
Yellow
0.38 × 0.20 × 0.18
15 423
Needle
White
0.40 × 0.18 × 0.16
8109
Needle
Light yellow
0.42 × 0.22 × 0.16
20 066
4064
4306
5563
2568
3367
2853
R
int
0.037
0.027
0.089
Theta range for data collection
Index ranges
2.788 to 26.000
−8 ≤ h ≤8
2.222 to 27.502
−5 ≤ h ≤6
−12 ≤ k ≤12
−15 ≤ l ≤15
0.650
0.035
0.077
1.03
1.697 to 27.481
−30 ≤ h ≤31
−5 ≤ k ≤6
−26 ≤ l ≤25
−
13 ≤ k ≤13
16 ≤ l ≤16
−
−
1
(
sin θ/λ)max (Å
)
0.617
0.040
0.098
1.02
2
2
R[F > 2σ(F )]
0.047
0.078
0.92
2
wR(F )
S
No. of reflections
No. of parameters
No. of restraints
4064
265
—
0.43, −0.44
4306
263
3
0.17, −0.30
5563
336
1
0.23, −0.27
−3
Δρmax, Δρmin (e Å
)
the bromo-substituted ring. This dihedral angle inspection
infers that ring B and D are almost parallel. The terminal C
atom (C1) is at a distance of 1.3589(7) Å from the plane of
moiety A.
The crystal packing of compound 7 is stabilized by both
classical and non-classical noncovalent interactions including
C–H⋯O, C–H⋯Br, C–H⋯π and π⋯π stacking interactions,
as shown in Fig. 2. The strong dimer D2 (Etot = −22.3 kcal
−
1
In 10 (Fig. 1c and Table 1), the chlorophenyl ring A (C1–
mol ) is further stabilized by C–H⋯π interactions involving
the H6 atom from the bromophenyl ring and the Cg4
centroid of the anisole ring [d(H6⋯Cg4) = 3.83 Å]. In
addition, this dimer is stabilized by offset π⋯π stacking
interactions between the centroid of the thiazole ring Cg1
and the centroid of the bromophenyl moiety Cg3, with an
inter-centroid separation of 3.8853(2) Å (symmetry: 1 − x, 2 −
y, −z) corresponding to a ring offset of 1.573 Å. The
contribution of dispersion energy was calculated to be 75.1%
towards the stabilization of this structural dimer. The dimer
C6/Cl1), 4,5-dihydro-1H-pyrazole ring
B
(C7–C9/N1/N2),
phenyl ring C (C10–C15), thiazole ring D (C16–C18/N3/S1)
and (E)-N′-(2-hydroxy-3-methoxybenzylidene)formohydrazide
group E (C19–C27/N4/N5/O1–O3) are found to be planar with
respective r.m.s. deviations of 0.0069, 0.0666, 0.0090, 0.0028
and 0.0156 Å. The thiazole ring D is twisted at a dihedral
angle of 8.02(3)° and 1.32(2)° with respect to ring B and
group E, respectively. These dihedral angles infer that
thiazole ring D and group E are almost parallel. Chlorophenyl
ring A makes dihedral angles of 80.04(1)° and 86.7(9)° with
respect to ring C and group E, respectively.
−
1
D1 (Etot = −20.6 kcal mol ) is stabilized by intermolecular
C8–H8B⋯O2 hydrogen bonds involving the O2 atom from
the carbonyl group as an acceptor and the H8B atom from
the 4,5-dihydro-1H-pyrazole ring. The electrostatic and
dispersion energies contribute 33.7% and 66.3%, respectively,
towards the stabilization of this dimer.
Crystal packing and interaction energy analysis
The intermolecular interactions which are responsible for the
crystal packing of compounds 7, 8 and 10 are reported in
Table 2 along with the respective interaction energies.
Intermolecular C2–H2⋯O1 and C8-H8A⋯O1 hydrogen
bonding interactions are responsible for the stabilization of
This journal is © The Royal Society of Chemistry 2021
CrystEngComm, 2021, 23, 3276–3287 | 3279

View Article Online
Paper
CrystEngComm
for the stabilization of the crystal lattice. The strongest dimer
−
1
D1 (Etot = −20.1 kcal mol with the contribution of 81%
dispersion energy) is stabilized by C11–H11⋯O1 [d(H11⋯O1)
=
2.68 Å] and C11–H11⋯N1 [d(H11⋯N1) = 2.83 Å] hydrogen
bonds. This structural dimer is also stabilized by π⋯π
stacking interactions involving bromophenyl rings (Cg3) of
adjacent molecules with a centroid-to-centroid distance of
4
4
.7441(4) Å (symmetry: 1 + x, y, z) and between the
,5-dihydro-1H-pyrazole ring (Cg2) and the chlorophenyl ring
(
Cg4), with an inter-centroid distance Cg2⋯Cg4 of 4.1285(4)
Å (symmetry: −1 + x, y, z). Interestingly, (Cl1)⋯π interactions
involving the Cl1 atom and the chlorophenyl ring (Cg4)
[
d(Cl1⋯Cg4) = 4.020 Å, <(C19–Cl1⋯Cg4) = 82.2°] stabilize
−
1
the dimer D1. The dimer D2 (E : −7.3 kcal mol ) is mainly
tot
stabilized by intermolecular C–H⋯O hydrogen bonds
involving the O2 atom of the carbonyl group as an acceptor
and the H8B of the 4,5-dihydro-1H-pyrazole ring. In addition
to the hydrogen bond, this structural motif is also stabilized
by C–H⋯π interactions involving the H5 atom of the thiazole
ring and the chlorophenyl ring (Cg4). The electrostatic and
dispersion energies contribute 60% and 40%, respectively,
towards the stabilization of this dimer. The carbonyl group is
also involved as an acceptor for the intermolecular C15–
H15⋯O2 hydrogen bond (dimer D3), with a total interaction
−
1
energy of −5.7 kcal mol . It is important to emphasize that
the contribution of electrostatic (58.2%) and dispersion
(
41.8%) energies are similar. Further, dimer D4 is mainly
Fig. 1 Molecular structure of compounds 7 (a), 8 (b) and 10 (c). The
atom numbering scheme is also given.
stabilized by weak C17–H17⋯Br1 hydrogen bonds and
Br1⋯S1 chalcogen bond. The classification of the Br⋯S
contact has been analyzed by using NBO analysis (see the
Theoretical methods section).
The crystal structure of compound 10 is mainly stabilized by
intermolecular C–H⋯N, C–H⋯O, C–H⋯π and π⋯π
interactions, as shown in Fig. 4. The most stabilized molecular
dimer D1 (Etot = −24.2 kcal mol ) is formed by C5–H5⋯N3 and
C27–H27A⋯O2 hydrogen bonds and C–H⋯π contacts [C27–
H27A⋯Cg5, C20–H20⋯Cg3 and C8–H8B⋯Cg4].
In addition, π⋯π stacking interactions between 4,5-dihydro-
1H-pyrazole (Cg2) and the phenyl ring (Cg4) are also responsible
for the dimer stabilization. The dispersion energy (81%) is
contributing more than 4-fold that of electrostatic energy (19%)
towards the stabilization. The dimer D2 is generated by
intermolecular C–H⋯O hydrogen bonding interactions
involving the H8A of the 4,5-dihydro-1H-pyrazole ring and the
O3 atom of the methoxy group as an acceptor [d(H8A⋯O3) =
2.66 Å]. This structural motif is also stabilized by C–H⋯π
contacts involving the H27B atom of the methoxy group and the
chlorophenyl ring (Cg3), with H27B⋯Cg3 distance of 3.03 Å. It
is important to emphasize that the contribution of electrostatic
energy (60.3%) is higher than that of dispersion energy (39.7%)
towards the stabilization of dimer D2.
−
1
dimer D3 (Etot = −12.4 kcal mol ) with 41.8% electrostatic
energy contribution towards the stabilization.
Interestingly, the crystal packing of 7 is further stabilized
by (Br1)⋯π interactions involving the Br1 atom and the
centroid Cg4 of the anisole ring [d(Br1⋯Cg4) = 3.6279(2) Å;
−1
<
(C4–Br1⋯Cg4) = 167.80(1)°, symmetry: x, y, −1 + z] and
weak C–H⋯Br hydrogen bonds involving the H19B of the
-(4-methylthiazol-5-yl)ethanone moiety and the bromine
atom of the bromophenyl ring (dimer 4). The intermolecular
1
−
1
interaction energy for dimer D4 is −2.9 kcal mol and the
dispersion energy contributes 84% towards the stabilization
of this structural dimer. Further analysis of this dimer is
discussed below regarding the physical nature of the Br⋯π
interaction (lone pair⋯π vs. halogen bond).
−
1
The energetically weakest dimer D5 (Etot = −2.7 kcal mol
with 58% contribution of electrostatic energy) is mainly
stabilized by C12–H12⋯O2 hydrogen bonds involving the O2
atom of the 1-(4-methylthiazol-5-yl)ethanone moiety as an
acceptor and the H12 atom from the anisole ring.
The crystal packing of 8 shows four molecular dimers and
the intermolecular interaction energy of these dimers are
As shown in Fig. 4, the structural dimer D3 (E = −5.6
tot
−
1
−1
between −20.1 and −1.5 kcal mol , as shown in Table 2.
These dimers are mainly stabilized by C–H⋯O, C–H⋯N and
C–H⋯Br hydrogen bonds (Fig. 3). In addition, C–H⋯π, lone
pair (Cl)⋯π and π⋯π stacking interactions are responsible
kcal mol ) is stabilized by two C11–H11⋯O1 and C12–
H12⋯O1 hydrogen bonds. The electrostatic and dispersion
energies contribute 49.7% and 50.3%, respectively, towards
the stabilization of this dimer.
3280 | CrystEngComm, 2021, 23, 3276–3287
This journal is © The Royal Society of Chemistry 2021

View Article Online
CrystEngComm
Paper
−1
Table 2 Interaction energies (kcal mol ) of the main intermolecular interactions for various molecular pairs observed in the crystal structure of
compounds 7, 8 and 10
c
Geometry
a
b
Dimer
R
Symmetry
Involved interactions
H⋯A/<(D–H⋯A)
E
ele
E
pol
E
dis
E
rep
E
tot
Compound 7
D1
6.38
−x, −y, −z
C8–H8B⋯O2
C19–H19C⋯Cg3
Cg1⋯Cg2
2.53/149
3.42
4.2636(3)
3.83
3.8853(2)
2.57/174
2.67/127
3.6279(2)
3.35/146
2.54/143
−9.3
−2.4
−23.0
13.8
−20.6
D2
D3
D4
D5
3.43
−x, −y, −z
−x, −y, −z
x, y, z
C6–H6⋯Cg4
Cg1⋯Cg3
−7.2
−5.7
−0.7
−1.4
−3.6
−2.5
−2.0
−0.2
−0.9
−2.4
−29.1
−10.7
−5.1
15.8
5.5
−22.3
-12.4
−2.9
9.20
C2–H2⋯O1
C8–H8A⋯O1
Br1⋯Cg4
13.32
11.34
3.3
C19–H19B⋯Br1
C12–H12⋯O2
x, y, z
−1.7
1.0
−2.7
Compound 8
D1
4.74
x, y, z
C11–H11⋯O1
C11–H11⋯N1
Cg3⋯Cg3
2.68/136
2.83/160
4.7441(4)
4.1285(4)
4.02
2.51/157
3.50
2.75/159
3.75
−25.6
10.2
−20.1
Cg2⋯Cg4
Cl1⋯Cg4
D2
10.99
x, y, z
C8–H8B⋯O2
C5–H5⋯Cg4
C15–H15⋯O2
Br1⋯S1
−3.3
−1.2
−6.8
3.5
−7.3
D3
D4
9.59
12.08
x, y, z
x, y, z
−1.8
−0.4
−1.1
−6.5
−2.4
3.3
1.4
−5.7
−1.5
0.0
C17–H17⋯Br1
3.49/126
Compound 10
D1
5.06
x, y, z
C5–H5⋯N3
2.71/155
2.85/130
3.51
3.22
2.56
3.71
2.66/149
3.03
2.68/119
2.80/114
−5.1
−3.4
−36.9
20.3
−24.2
C27–H27A⋯O2
C27–H27A⋯Cg5
C20–H20⋯Cg3
C8–H8B⋯Cg4
Cg2⋯Cg4
D2
D3
12.66
12.04
x + 1/2, −y, z
x + 1/2, −y, z
C8–H8A⋯O3
C27–H27B⋯Cg3
C11–H11⋯O1
C12–H12⋯O1
−6.0
−2.4
−2.0
−1.3
−5.3
−3.8
1.8
1.5
−10.7
−5.6
a
b
R: centroid-to-centroid distance (Å) of the molecular pair (main atomic position). Cg1, Cg2, Cg3, Cg4 and Cg5 are the centroids of the rings
c
S1/C17/N3/C18/C20, N1/N2/C7–C9, C1–C6, C10–C15 and C21–C26, respectively. Geometry of intermolecular contacts (Å, °).
Fig. 2 View of the different dimers observed in the crystal structure of
. Intermolecular interactions are shown as dashed lines. Cg1: S1/C17/
N3/C18/C20 centroid (violet), Cg2: N1/N2/C7–C9 centroid (yellow),
Cg3: C1–C6 centroid (green), Cg4: C10–C15 centroid (orange).
Fig. 3 Partial view of the different structural dimers observed in the
crystal structure of 8. The intermolecular interactions are shown as
dashed lines. Cg2: N1/N2/C7–C9 centroid (yellow), Cg3: C1–C6
centroid (green) and Cg4: C10–C15 centroid (orange).
7
This journal is © The Royal Society of Chemistry 2021
CrystEngComm, 2021, 23, 3276–3287 | 3281

View Article Online
Paper
CrystEngComm
Fig. 4 Partial view of the different structural dimers observed in the crystal
structure of 10. The intermolecular interactions are shown as dashed lines.
Cg2: N1/N2/C7–C9 centroid (yellow), Cg3: C1–C6 centroid (green), Cg4:
C10–C15 centroid (orange), and Cg5: C21–C26 centroid (pink).
Fig. 5 Hirshfeld surfaces of compounds 7, 8 and 10 mapped over the
dnorm function in two orientations (the second molecule is rotated 180°
around the horizontal axis of the plot). The labels are discussed in the
main text.
Hirshfeld surface analysis
Hirshfeld surface analyses were carried out to understand the
nature of packing motifs and the contribution of the main
intermolecular interactions which are responsible for the
supramolecular architectures in crystalline solids 7, 8 and 10.
Fig. 5 shows Hirshfeld surfaces mapped over the dnorm
function, where arrows with numbers indicate close contacts.
Graphical plots of the molecular Hirshfeld surfaces mapped
over the dnorm property use a red-white-blue color scheme,
where red indicates shorter contacts, white is used for
contacts around the van der Waals (vdW) separation, and
blue is used for longer contacts. Full and decomposed two-
dimensional fingerprint (FP) plots of the main intermolecular
contacts are presented in Fig. 6.
In compound 7, the largest and red regions labeled 1, 2
and 3 in Fig. 5 are attributed to C8–H8B⋯O2, C2–H2⋯O1
and C12–H12⋯O3 hydrogen bonds, respectively. These
contacts are represented as a pair of spikes at (d
e
+ d
i
) ≈ 2.4
Å in the fingerprint plot (Fig. 6) with a contribution of 12.2%
to the total Hirshfeld surface area. Two red spots labeled 4
and 5 (Fig. 5) represent H⋯C/C⋯H contacts with a large area
fraction of 12.3%.
These contacts are attributed to C19–H19C⋯Cg3 and C6–
H6⋯Cg4 interactions, which appear in the form of “wings”
Fig. 6 Full and decomposed two-dimensional fingerprint plots for
compounds 7, 8 and 10. Close contacts are labeled as follows: (1)
H⋯O/O⋯H, (2) H⋯Br/Br⋯H, (3) H⋯N/N⋯H and (4) H⋯Cl/Cl⋯H.
3282 | CrystEngComm, 2021, 23, 3276–3287
This journal is © The Royal Society of Chemistry 2021

View Article Online
CrystEngComm
Paper
on the sides of the fingerprint plots (Fig. 6), characteristic of
The Hirshfeld surfaces mapped over shape index and
C–H⋯π contacts with the shortest value at (d + d ) ≈ 3.2 Å.
curvedness properties (Fig. S1, ESI†) are a very useful tool to
e
i
3
9
The red spots labeled 6 in the dnorm surface are attributed to
lone pair (Br1)⋯π interactions, as was described previously.
These contacts are also visible in the FP plots as two broad
identify planar π⋯π stacking interactions. The pattern of
touching red and blue triangles on the shape index surfaces
(highlighted as black circles in Fig. S1, ESI†) is characteristic
4
0
spikes at (d
e
+ d
i
) ≈ 3.4 Å with 3.00% contribution to the
of π⋯π stacking arrangements and they are visible in the
surfaces of all structures. The mentioned interactions are
also visible as relatively large and green flat regions
delineated by blue circles on the corresponding curvedness
surfaces (Fig. S1, ESI†).
Hirshfeld surface area. The white spot labeled 7 in the d
norm
map shows weak H⋯Br/Br⋯H contacts attributed to C19-
H19B⋯Br1 hydrogen bonds, which are viewed as broad
spikes at (de + d ) ≈ 3.0 Å in the fingerprint plot with a
i
contribution of 9.4% to the Hirshfeld surface area.
In compound 8, the H⋯O/O⋯H contacts labeled 1 in
Fig. 5 are attributed to C8–H8B⋯O2 hydrogen bonds. These
contacts appear as sharp spikes in FP with short (d + d ) ≈
DFT calculations
e
i
2
.3 Å and a contribution of 8.60% to the total Hirshfeld
The theoretical study is devoted to analyzing two types of
motifs found in the solid state of these compounds, on the
one hand, the formation of stacked dimers that present
numerous interactions due to the nonaromatic nature of the
dihydropyrazolyl ring. On the other hand, we focus on the
existence of halogen bonding interactions involving the Br
and Cl atoms. In the case of compound 8, the formation of a
Br⋯S interaction is further analyzed in terms of
competition between halogen (XB) and chalcogen (ChB)
bonding.
We have computed the dimerization energies (PBE0-D3/
def2-TZVP) and performed the QTAIM and NCIplot index
analyses of several dimers of compounds 7, 8 and 10
retrieved from the X-ray structures. Both computational tools
(QTAIM and NCIplot) are very convenient to reveal
noncovalent interactions. The existence of a bond path and
bond critical point (CP) connecting two atoms is an
unambiguous indicator of an interaction. Moreover, the
NCIplot analysis gives information regarding the spatial
regions between molecules where the interaction is
established. Moreover, the color of the isosurface gives
valuable information regarding the attractive (blue and
green) or repulsive (yellow and red) nature of the interaction.
First of all, we have computed the MEP surfaces of
compounds 7, 8 and 10 in order to investigate the existence
of σ-holes in the halogen atoms and the S atom of the
thiazole group. The MEP surfaces are shown in Fig. 7 and it
can be observed that the MEP maximum is located at the
surface. The white spot labeled 2 in the dnorm map is
attributed to weak C11–H11⋯N1 hydrogen bonds, which are
viewed as a pair of broad spikes at (d
e
+ d
i
) ≈ 2.6 Å in FP with
a contribution of 5.4% to the total Hirshfeld surface area.
The occurrence of small red spots (labeled 3) on the
Hirshfeld surfaces (Fig. 5) is associated to weak C–H⋯π
contacts involving the H5 atom and the Cg4 centroid with a
high contribution of 17.8%. The sharp spikes observed in the
decomposed FP plot (Fig. 6) with 2.10% contribution to the
total Hirshfeld surface area confirm the relevance of Br⋯S/
S⋯Br in the supramolecular assembly of compound 8.
a
In compound 10, the small red spots labeled 1 and 2 in
the dnorm map is attributed to C8-H8A⋯O3 and C11–
H11⋯O1 hydrogen bonds, respectively. These H⋯O/O⋯H
contacts are visible in the FP plots as two broad spikes at (d
e
+
d ) ≈ 2.5 Å, comprising a 12.3% contribution to the
i
Hirshfeld surface area. The red regions labeled 3 in the dnorm
surfaces (Fig. 5) are attributed to C5–H5⋯N3 hydrogen bonds
(Fig. 4), and represented as a pair of broad spikes at (d + d )
e i
≈
2.5 Å in FP, with a contribution of 4.00%. Like in structure
, the small red spots labeled 3, 4 and 5 indicate weak H⋯C/
7
C⋯H contacts corresponding to C–H⋯π interactions
Table 2) which also appear as two types of “wings” in the FP
(
plots with 25.1% contribution to the Hirshfeld surface area.
The spots labeled 6 in Fig. 5 are attributed to π⋯π stacking
interactions between Cg2 and Cg4 centroids. The Hirshfeld
surface of compound 10 also shows two red spots labeled 7
attributed to vdW H1⋯H127B interactions.
H⋯H contacts are also responsible for the crystal packing
of the three studied compounds. These interactions are
highlighted in the middle of scattered points of FP plots with
CH group of the 4,5-dihydropyrazolyl ring in compounds 7
2
−
1
and 8 (+28 kcal mol ) and it is located at the NH bond of
−
1
the hydrazido group (+34 kcal mol ) in compound 10. The
MEP minima are located in the O atoms of the keto (7), ester
(8) or hydrazido (10) substituents of the thiazole ring. By
using a much reduced energy scale, the existence of σ-holes
at the halogen atoms is revealed, as highlighted in Fig. 7.
The MEP values at the σ-holes range from 6.5 kcal mol at
Cl of compound 10 to 12 kcal mol at Br of compound 7.
The MEP value at the σ-hole of the S atom is significantly
more intense (+20 kcal mol ) than those at the halogen
atoms. Moreover, this σ-hole overlaps with the σ-hole of the
adjacent H atom (see Fig. 7B, left), and consequently, it is
more intense than the σ-hole at the Br atom.
minimum values of (d
e i
+ d ) in the range 2.05–2.30 Å and
highest contributions of 43.4%, 30.4% and 35.3% to the total
Hirshfeld surface area for compounds 7,
8 and 10,
−
1
respectively.
−
1
In addition to the hydrogen bonds described previously,
the crystal structure of the three compounds are stabilized by
π⋯π stacking interactions, as shown in Table 2. The C⋯C
contacts appear as a distinct pale blue to green area
highlighted by a circle at around d = d = 1.8 Å in the FP
−
1
e
i
plots of the three compounds.
This journal is © The Royal Society of Chemistry 2021
CrystEngComm, 2021, 23, 3276–3287 | 3283

View Article Online
Paper
CrystEngComm
Fig. 7 MEP surfaces (0.001 a.u.) of compounds 7 (A), 8 (B) and 10 (C).
−
1
The MEP values at selected of the surfaces are indicated in kcal mol
.
Fig. 8 Combined QTAIM/NCIplot analyses of the stacked dimer (A)
and the σ-hole complex (B) for compound 7. Only bond critical points
are represented (as red spheres) for the sake of clarity. For the NCIplot
Fig. 8 shows the energetic results for the dimers of
compound 7 analyzed herein, which consist of the stacked
dimer and the halogen bonding complex. The QTAIM
analysis of the stacked dimer shows a large number of bond
CPs (represented as small red spheres) and bond paths
isosurface (0.5 a.u.), the −0.35 < sign(λ
2
)ρ < 0.35 color scale was used.
Gradient cut-off = 0.04 a.u.
(dashed lines) interconnecting several atoms of both
monomers. Moreover, the NCIplot shows extended
isosurfaces located between the aromatic, nonaromatic and
C–H bonds, thus justifying the large dimerization energy
energies using the QTAIM potential energy density (V
r
)
predictor measured at the bond CP, as described in the
4
1,42
literature (see red numbers in Fig. 8B).
that the XB is stronger than the HB.
It can be observed
−
1
(−21.7 kcal mol ) and confirming its importance as a strong
binding motif in the solid state of 7. Fig. 8B shows the
halogen bonding contact where the electron donor moiety is
the electron-rich π-system of the methoxybenzene ring. The
XB is characterized by a bond CP and bond path connecting
the Br atom to one carbon atom of the ring. Moreover, the
presence of a green NCIplot isosurface between the Br atom
and the aromatic ring further confirms the existence of the
XB interaction (Br⋯π). The combined QTAIM/NCIplot
analysis also reveals the existence of a weak HB between the
methyl group and the negative belt of the Br atom. The
The sum of the individual energies computed using the V
r
−
1
predictor (−4.0 kcal mol ) is very similar to the dimerization
−
1
energy (−3.9 kcal mol ) computed using the supramolecular
approach (energy difference between the complex and the
sum of the energies of the monomers), thus giving reliability
to the QTAIM energy predictor.
Fig. 9 shows the results for compound 8 that are similar
to those of compound 7 regarding the interaction energies of
−
1
the stacked dimer (−21.4 kcal mol ) and the σ-hole complex
−
1
(−2.3 kcal mol ). The combined QTAIM/NCIplot analysis
shows that several bond CPs and bond paths interconnect
both monomers and extended NCIplot isosurfaces located
between the aromatic, nonaromatic and C–H bonds. Fig. 9B
shows the halogen/chalcogen bonding contact where it is not
−
1
dimerization energy is very modest (ΔE
2
= −3.9 kcal mol ), in
line with the small MEP value at the σ-hole (see Fig. 8A). In
order to investigate the relative importance of both
interactions, we have evaluated the individual interaction
3284 | CrystEngComm, 2021, 23, 3276–3287
This journal is © The Royal Society of Chemistry 2021

View Article Online
CrystEngComm
Paper
Fig. 9 Combined QTAIM/NCIplot analyses of the stacked dimer (A)
and the σ-hole complex (B) for compound 8. Only bond critical points
are represented (as red spheres) for the sake of clarity. For the NCIplot
isosurface (0.5 a.u.), the −0.35 < sign(λ
2
)ρ < 0.35 color scale was used.
Gradient cut-off = 0.04 a.u.
Fig. 10 Combined QTAIM/NCIplot analyses of the stacked dimer (A)
and the σ-hole complex (B) for compound 10. Only bond critical points
are represented (as red spheres) for the sake of clarity. For the NCIplot
evident which atom is acting as an electron donor and which
one is the σ-hole donor. This contact is characterized by a
bond CP and bond path connecting the Br atom to the S
atom of the thiazole ring. Moreover, the presence of a green
NCIplot isosurface between both atoms further confirms the
existence of an interaction (XB or ChB). The combined
QTAIM/NCIplot analysis also reveals the existence of a weak
HB between one aromatic H atom and the negative belt of
isosurface (0.5 a.u.), the −0.35 < sign(λ
Gradient cut-off = 0.04 a.u.
2
)ρ < 0.35 color scale was used.
bond CP and bond path interconnecting the Cl and O atoms.
Moreover, the QTAIM also shows the existence of an ancillary
H-bond where the negative belt of Cl acts as electron donor.
the Br atom. The dimerization energy is very modest (ΔE
4
=
r
This HB is weaker than the XB, as evidenced by the V energy
predictor.
−
1
−
2.3 kcal mol ) and the evaluation of the individual
interaction energies using the V predictor demonstrates that
r
the HB is the weakest interaction.
Concluding remarks
In order to classify the Br⋯S contact we have performed
4
3
the natural bond orbital (NBO) analysis, focusing on the
second-order perturbation analysis, since it is very convenient
to explore donor–acceptor interactions. Remarkably, we have
not found any contribution involving the σ*(Br–C) orbital as
acceptor, thus ruling out the halogen bond. In contrast, we
have found an orbital donor–acceptor interaction from the
LP at the Br atom to the antibonding S–C orbital of the
thiazole ring, that is Lp(Br) → σ*(S–C) with a concomitant
Three new derivatives of 4,5-dihydropyrazolylthiazole have
been synthesized and characterized. The supramolecular
assemblies observed in their solid-state structures have been
analyzed using Hirshfeld surface analysis, DFT calculations
and a combination of QTAIM and NCIplot computational
tools. All methods suggest that π⋯π stacking interactions are
the most dominant interactions and they have a prominent
role in directing the X-ray packing in all complexes. The
existence of weak σ-hole halogen bonds has been evidenced
in these compounds, and in the case of compound 8, where
an ambiguous Br⋯S is established, the NBO analysis
confirms that the interaction is a chalcogen bond where the
Br atom acts as an electron-rich atom [Lp(Br) → σ*(S–C)].
−
1
stabilization energy of 0.30 kcal mol . Therefore, around
2
0% of the ChB energy is due to orbital effects.
Finally, a similar study was performed for compound 10
and the results are shown in Fig. 10. Again the stacked dimer
presents a very large binding energy due to the large overlap
of both molecules, as revealed by the NCIplot. In fact, the
interaction energy is stronger than those observed for the
dimers of 7 and 8 commented above due to the presence of
the additional methoxyphenol ring. However, the halogen
bonding complex is weaker than those of 7 and 8, likely
because Cl instead of Br acts as a σ-hole donor, in agreement
with the MEP surface analysis. The XB is characterized by a
Author contributions
M. M., S. A., S. H., A. M. K., M. A. and M. M. T.: experimental
work, investigation and formal analysis. D. M. G.: Hirshfeld
surface analysis; visualization; writing – review and editing;
funding acquisition. M. N. A. and A. F.: formal analysis;
This journal is © The Royal Society of Chemistry 2021
CrystEngComm, 2021, 23, 3276–3287 | 3285

View Article Online
Paper
CrystEngComm
funding acquisition; methodology; project administration;
resources; supervision; validation; visualization; writing –
original draft; writing – review and editing.
16 M. N. Ahmed, K. A. Yasin, K. Ayub, T. Mahmood, M. N.
Tahir, B. A. Khan, M. Hafeez and M. Ahmed, J. Mol. Struct.,
2016, 1106, 430–439.
1
7 M. N. Ahmed, K. A. Yasin, S. Hameed, K. Ayub, I.-u. Haq, M. N.
Tahir and T. Mahmood, J. Mol. Struct., 2017, 1129, 50–59.
8 M. N. Ahmed, B. Sadiq, N. A. Al-Masoudi, K. A. Yasin, S.
Hameed, T. Mahmood, K. Ayub and M. N. Tahir, J. Mol.
Struct., 2018, 1155, 403–413.
Conflicts of interest
1
There are no conflicts to declare.
Acknowledgements
1
2
2
9 B. Wang, M. N. Ahmed, J. Zhang, W. Chen, X. Wang and Y.
Hu, Tetrahedron Lett., 2013, 54, 6097–6100.
0 M. N. Ahmed, K. Ahmad, K. A. Yasin, T. Farooq, B. A. Khan
and S. K. Roy, New J. Chem., 2019, 43, 11316–11333.
1 M. N. Ahmed, M. Arif, F. Jabeen, H. A. Khan, K. A. Yasin,
M. N. Tahir, A. Franconetti and A. Frontera, New J. Chem.,
MNA and MM are thankful to The University of Azad Jammu
and Kashmir and Quaid-i-Azam University Islamabad
Pakistan for financial support. DMG thanks the ANPCyT
(PICT 2016-0226) and SCAIT-UNT (Project 683) and AF thanks
the MICIU/AEI, grant number CTQ2017-85821-R, FEDER for
funding.
2
019, 43, 8122–8131.
2
2 M. N. Ahmed, K. A. Yasin, S. Aziz, S. U. Khan, M. N. Tahir,
D. M. Gil and A. Frontera, CrystEngComm, 2020, 22, 3567–3578.
3 M. Madni, M. N. Ahmed, M. Hafeez, M. Ashfaq, M. N. Tahir,
D. M. Gil, B. Galmés, S. Hameed and A. Frontera, New J.
Chem., 2020, 44, 14592–14603.
Notes and references
2
1
N. Bakthavatchala Reddy, G. V. Zyryanov, G. Mallikarjuna
Reddy, A. Balakrishna, A. Padmaja, V. Padmavathi, C. Suresh
Reddy, J. R. Garcia and G. Sravya, J. Heterocyclic Chem.,
24 M. Madni, S. Hameed, M. N. Ahmed, K. A. Yasin and M. N.
Tahir, Chin. J. Struct. Chem., 2015, 7, 1013–1018.
2
019, 56, 589–596.
2
P. Sharma, K. R. Senwar, M. K. Jeengar, T. S. Reddy, V.
Naidu, A. Kamal and N. Shankaraiah, Eur. J. Med. Chem.,
25 Y.-M. Lin, Y. Zhou, M. T. Flavin, L.-M. Zhou, W. Nie and F.-C.
Chen, Bioorg. Med. Chem., 2002, 10, 2795–2802.
2
015, 104, 11–24.
26 B. F. Abdel-Wahab, H. A. Abdel-Aziz and E. M. Ahmed, Eur. J.
Med. Chem., 2009, 44, 2632–2635.
3
4
5
6
V. Kumar, K. Kaur, G. K. Gupta and A. K. Sharma, Eur. J.
Med. Chem., 2013, 69, 735–753.
A. Ansari, A. Ali and M. Asif, New J. Chem., 2017, 41,
27 (a) J. J. McKinnon, M. A. Spackman and A. S. Mitchell, Acta
Crystallogr., Sect. B: Struct. Sci., 2004, 60, 627–668; (b) J. J.
McKinnon, D. Jayatilaka and M. A. Spackman, Chem.
Commun., 2007, 3814–3816; (c) M. A. Spackman and D.
Jayatilaka, CrystEngComm, 2009, 11, 19–32; (d) M. A.
Spackman, Chem. Rev., 1992, 92, 1769–1797; (e) M. A.
Spackman, Phys. Scr., 2013, 87, 048103.
1
6–41.
A. M. Isloor, B. Kalluraya and P. Shetty, Eur. J. Med. Chem.,
009, 44, 3784–3787.
2
A. Isloor, B. Kalluraya, M. Rao and A. Rahiman, J. Saudi
Chem. Soc., 2000, 4, 265–270.
7
8
D. Sunil and P. Shetty, Der Pharma Chem., 2009, 1, 19–26.
M. Cuenca-Estrella, A. Gomez-Lopez, E. Mellado, G. Garcia-
Effron and J. L. Rodriguez-Tudela, Antimicrob. Agents
Chemother., 2004, 48, 3107–3111.
28 M. J. Turner, J. J. McKinnon, S. K. Wolf, D. J. Grimwood,
P. R. Spackman, D. Jayatilaka and M. A. Spackman,
CrystalExplorer17, University of Western, Australia, 2017.
29 C. F. Mackenzie, P. R. Spackman, D. Jayatilaka and M. A.
Spackman, IUCrJ, 2017, 4, 575–587.
9
R. M. Mohareb, M. Y. Zaki and N. S. Abbas, Steroids,
2
015, 98, 80–91.
30 M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, G. A.
Petersson, H. Nakatsuji, X. Li, M. Caricato, A. V. Marenich, J.
Bloino, B. G. Janesko, R. Gomperts, B. Mennucci, H. P.
Hratchian, J. V. Ortiz, A. F. Izmaylov, J. L. Sonnenberg, D.
Williams-Young, F. Ding, F. Lipparini, F. Egidi, J. Goings, B.
Peng, A. Petrone, T. Henderson, D. Ranasinghe, V. G.
Zakrzewski, J. Gao, N. Rega, G. Zheng, W. Liang, M. Hada,
M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T.
Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, K.
Throssell, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. J.
Bearpark, J. J. Heyd, E. N. Brothers, K. N. Kudin, V. N.
Staroverov, T. A. Keith, R. Kobayashi, J. Normand, K.
Raghavachari, A. P. Rendell, J. C. Burant, S. S. Iyengar, J.
Tomasi, M. Cossi, J. M. Millam, M. Klene, C. Adamo, R.
Cammi, J. W. Ochterski, R. L. Martin, K. Morokuma, O.
Farkas, J. B. Foresman and D. J. Fox, Gaussian 16, Revision
C.01, Gaussian, Inc., Wallingford, CT, 2016.
1
1
1
0 M. Madni, S. Hameed, M. N. Ahmed, M. N. Tahir, N. A. Al-
Masoudi and C. Pannecouque, Med. Chem. Res., 2017, 26,
2
653–2665.
1 P. Kumar, N. Chandak, P. Kaushik, C. Sharma, D. Kaushik,
K. R. Aneja and P. K. Sharma, Med. Chem. Res., 2012, 21,
3
396–3405.
2 M. Madni, M. N. Ahmed, S. Hameed, S. W. A. Shah, U.
Rashid, K. Ayub, M. N. Tahir and T. Mahmood, J. Mol.
Struct., 2018, 1168, 175–186.
3 H. Patel, V. Ugale, A. Ingale and S. Bari, Lett. Drug Des.
Discovery, 2012, 9, 840–847.
4 M. Atobe, K. Naganuma, M. Kawanishi, A. Morimoto, K.-i.
Kasahara, S. Ohashi, H. Suzuki, T. Hayashi and S. Miyoshi,
Bioorg. Med. Chem. Lett., 2013, 23, 6569–6576.
5 M. Atobe, K. Naganuma, M. Kawanishi, A. Morimoto, K.-i.
Kasahara, S. Ohashi, H. Suzuki, T. Hayashi and S. Miyoshi,
Bioorg. Med. Chem. Lett., 2013, 23, 6064–6067.
1
1
1
3286 | CrystEngComm, 2021, 23, 3276–3287
This journal is © The Royal Society of Chemistry 2021

View Article Online
CrystEngComm
Paper
3
3
1 C. Adamo and V. Barone, J. Chem. Phys., 1999, 110, 6158–6169.
2 S. Grimme, J. Antony, S. Ehrlich and H. Krieg, J. Chem. Phys.,
37 G. M. Sheldrick, SADABS, Program for empirical X-ray
absorption correction, Bruker-Nonius, Madison, WI, 1990.
38 G. M. Sheldrick, Acta Crystallogr., Sect. C: Struct. Chem.,
2015, 71, 3–8.
2
010, 132, 154104.
3
3 (a) F. Weigend and R. Ahlrichs, Phys. Chem. Chem. Phys.,
2
2
005, 7, 3297–3305; (b) F. Weigend, Phys. Chem. Chem. Phys.,
006, 8, 1057–1065.
39 A. Di Santo, G. A. Echeverría, O. E. Piro, H. Pérez, A. Ben
Altabef and D. M. Gil, J. Mol. Struct., 2017, 1134,
492–503.
3
3
4 R. F. W. Bader, Chem. Rev., 1991, 91, 893–928.
5 J. Contreras-Garcia, E. R. Johnson, S. Keinan, R. Chaudret,
J. P. Piquemal, D. N. Beratan and W. Yang, J. Chem. Theory
Comput., 2011, 7, 625–632.
40 M. A. Spackman and D. Jayatilaka, CrystEngComm, 2009, 11,
19–32.
41 E. Espinosa, E. Molins and C. Lecomte, Chem. Phys. Lett.,
1998, 285, 170–173.
42 A. Bauzá and A. Frontera, ChemPhysChem, 2020, 21, 26–31.
43 F. Weinhold, J. Comput. Chem., 2012, 33, 2363–2379.
3
6 E. R. Johnson, S. Keinan, P. Mori-Sanchez, J. Contreras-
Garcia, A. J. Cohen and W. Yang, J. Am. Chem. Soc.,
2
010, 132, 6498.
This journal is © The Royal Society of Chemistry 2021
CrystEngComm, 2021, 23, 3276–3287 | 3287