4-(4-Bromophenyl)thiazol-2-amine: Crystal structure determination, DFT calculations, visualizing intermolecular interactions using Hirshfeld surface analysis, and DNA binding studies

Article abstract of DOI:10.1002/poc.3968

2-Aminothiazole is a valuable synthon in organic synthesis and an important structural unit of pharmaceutically active drugs. It is accessible via several synthetic routes. In the current account, compound 4 {4-(4-bromophenyl) thiazol-2-amine} was synthesized by employing a recently reported procedure of Gabriel synthesis using Lawesson reagent. The title compound was characterized through spectro-elemental analytical data, and its crystal structure was determined by single-crystal X-ray diffraction. The torsion angles, bond lengths, and bond strengths between the planes of the thiazole and phenyl rings were optimized by theoretical calculations by applying the B3LYP/6-311++G(d,p) level for the purpose of investigating the conformational effects on the stabilization of the crystal packing. HOMO-LUMO analysis, vibrational analysis, and thermodynamic parameters were also investigated. A detailed analysis of the intermolecular interactions of thiazole moiety bearing the amino and bromophenyl ring has been performed based on the Hirshfeld surfaces and their associated two-dimensional fingerprint plots. The relative contributions of the main intermolecular contacts as well as the enrichment ratios derived from the Hirshfeld surface analysis establish the 2-aminothiazole synthon to be a molecule of great interest. DNA binding studies pointed towards anticancer potency of the synthesized compound via reversible binding.

Full text of DOI:10.1002/poc.3968

Received: 7 January 2019
DOI: 10.1002/poc.3968
Revised: 22 March 2019
Accepted: 30 March 2019
R E S E A R C H A R T I C L E
4‐(4‐Bromophenyl)thiazol‐2‐amine: Crystal structure
determination, DFT calculations, visualizing intermolecular
interactions using Hirshfeld surface analysis, and DNA
binding studies
Pervaiz A. Channar1 | Nasima Arshad2
| Fayaz A. Larik1 | Shahid I. Farooqi2 |
Aamer Saeed1 | Tuncer Hökelek3 | Bakhtawar Batool1 | Rabail Ujan4 | Hafiz Saqib Ali5 |
Ulrich Flörke6
1 Department of Chemistry, Quaid‐i‐Azam
Abstract
University, Islamabad, Pakistan
2‐Aminothiazole is a valuable synthon in organic synthesis and an important
structural unit of pharmaceutically active drugs. It is accessible via several
synthetic routes. In the current account, compound 4 {4‐(4‐bromophenyl)
thiazol‐2‐amine} was synthesized by employing a recently reported procedure
of Gabriel synthesis using Lawesson reagent. The title compound was charac-
terized through spectro‐elemental analytical data, and its crystal structure
was determined by single‐crystal X‐ray diffraction. The torsion angles, bond
lengths, and bond strengths between the planes of the thiazole and phenyl
rings were optimized by theoretical calculations by applying the B3LYP/6‐
311++G(d,p) level for the purpose of investigating the conformational effects
on the stabilization of the crystal packing. HOMO‐LUMO analysis, vibrational
analysis, and thermodynamic parameters were also investigated. A detailed
analysis of the intermolecular interactions of thiazole moiety bearing
the amino and bromophenyl ring has been performed based on the
Hirshfeld surfaces and their associated two‐dimensional fingerprint plots.
The relative contributions of the main intermolecular contacts as well as the
enrichment ratios derived from the Hirshfeld surface analysis establish the
2‐aminothiazole synthon to be a molecule of great interest. DNA binding
studies pointed towards anticancer potency of the synthesized compound via
reversible binding.
2 Department of Chemistry, Allama Iqbal
Open University, Islamabad, Pakistan
3 Department of Physics, Faculty of
Engineering, Hacettepe University,
Beytepe‐Ankara, Turkey
4 Dr. M. A. Kazi Institute of Chemistry,
University of Sindh, Jamshoro, Pakistan
5 School of Chemistry, The University of
Manchester, Manchester, UK
6 Department Chemie, Fakultätfür
Naturwissenschaften, Universität
Paderborn, Paderborn, Germany
Correspondence
Nasima Arshad, PhD, Department of
Chemistry, Allama Iqbal Open University,
44000 Islamabad, Pakistan.
Email: nasimaa2006@yahoo.com; nasima.
arshad@aiou.edu.pk
Aamer Saeed, PhD, Department of
Chemistry, Quaid‐i‐Azam University,
45320 Islamabad, Pakistan.
Email: aamersaeed@yahoo.com
KEYWORDS
2‐aminothiazole, DFT calculations, DNA binding, Hirshfeld surface analysis, X‐ray crystal analysis
1 | INTRODUCTION
Hoffman in 1879.[1] However, a systematic study on the
thiazole moiety of several derivatives was reported in
Thiazole nucleus has been known for a long time.
Earlier work on benzothiazole has been reported by
1887 from Hantzsch laboratory. Since then, the chemistry
of thiazole has enjoyed unprecedented attention and has
J Phys Org Chem. 2019;e3968.
wileyonlinelibrary.com/journal/poc
© 2019 John Wiley & Sons, Ltd.
1 of 15
https://doi.org/10.1002/poc.3968

2 of 15
CHANNAR ET AL.
found multitudinous aspects such as methods of synthe-
sis, physical properties, structure and reactivity, reaction
mechanism, and industrial and biological applica-
tions.[2–5] The structural insights of thiazole units reveal
that it possesses aromatic character, having resonating
double bonds and furthermore its chemical and physical
properties resemble with pyridine unit. However, thiazole
Lawesson reagent (LR) was introduced as an efficient and
high‐yielding versatile thionating reagent. 1,3‐Thiazoles
can be synthesized by using LR, and a plethora of
literature depicts the extensive use of LR in the synthesis
of natural and unnatural organosulfur compounds.[21–24]
In this current account, we envision to synthesize
2‐aminothiazole molecule using LR as an effective
thionating reagent. Moreover, the chemical reactivity,
surface analysis, structural properties, and DNA binding
of the title compound were also explored.
is the weaker base (pKa
= 2.52) than pyridine
(pKa = 5.20), but 2‐aminothiazole (pKa = 5.28) is more
basic than simple thiazole and pyridine.
Thiazole motif is a vital component of many commer-
cial drugs. Dasatinib (antineoplastic agents),[6] ritonavir
(anti‐HIV drug),[7] ravuconazole (antifungal agent),[8]
fanetizole (anti‐inflammatory agents),[9] nizatidine (anti-
ulcer agent),[10] and thiamethoxam (insecticide)[11,12] are
few examples of thiazole bearing products (Figure 1).
1,3‐Thiazole units have achieved an enormous amount
of success in the design of mesogenic liquid crystalline
materials due to their abilities to improve or modify the
mesogenic behaviour and physical properties such as
dielectric anisotropy, polarizability, viscosity, elastic con-
stants, and luminescence. 1,3‐Thiazole displays a linear
structure, and hence, it has the aptitude to exhibit broad
mesophases and polymorphism.[13,14]
2 | EXPERIMENTAL
2.1 | Chemical and reagents
All chemical and reagents used in synthesis and DNA
binding experiments were commercially available and
used as received. Solvents (reagent grade) were dried
and redistilled prior to being used. Autoclave water and
apparatus were used during DNA extraction.
2.2 | Instrumentations
Formidable goals have been achieved in the synthetic
methodologies of heterocycles since the beginning of the
second half of the last century. 2‐Aminothiazoles can be
easily accessed by various approaches such as by
using thiourea and ketones, thiourea and NBS (N‐
bromosuccinimide), thiourea and oxidizing agents, and
alpha‐haloketones. 1,4‐Dicarbonyl compounds are widely
considered precursors for the synthesis of organosulfur
compounds. The thionation can be performed with a vari-
ety of reagents, including phosphorus pentasulfide,[15,16]
hydrogen sulfide,[17,18] thiophosphoryl chloride,[19]
bis(trimethylsilyl)sulfide[20] and rhodanine. In 1956,
Melting points were recorded using a digital Gallenkamp
(SANYO) model MPD.BM 3.5 apparatus and are uncor-
rected. 1H and 13C NMR spectra were determined at
300 MHz using a Bruker AM‐300 spectrophotometer.
FT‐IR spectra were recorded on a Bio‐Rad‐Excalibur
Series Mode FTS 3000 MX spectrophotometer. Elemental
analyses were conducted using a LECO‐183 CHNS
analyser. Thin layer chromatography (TLC) was con-
ducted on 0.25‐mm silica gel plates (60 F254, Merck).
Visualization of chromatograms was made with UV at
365 and 254 nm. R f values were calculated using a
solvent system of petroleum ether: ethyl acetate in 4:1
FIGURE 1 Examples of thiazole bearing drugs

CHANNAR ET AL.
3 of 15
ratio. Shimadzu 1800 spectrophotometer equipped with
temperature controller device was used for DNA binding
experiment, while Schott Gerate viscometer (automated,
Model; AVS 310) was used to measure the viscosity of
DNA without and in the presence of varying compound
concentrations.
and H2 (for OH2) were located in a difference Fourier
map and refined freely. The N‐ and C‐bound H atoms
were positioned geometrically, with N–H = 0.88 Å
(for NH and NH2) and C–H = 0.95 Å for aromatic H
atoms, and constrained to ride on their parent atoms
with Uiso(H) = 1.2 × Ueq (N, C). Full crystallographic data
for compound have been deposited with the Cambridge
Crystallographic Data Centre (CCDC 1871549).
2.3 | Synthesis of 4‐(4‐bromophenyl)
thiazol‐2‐amine
2.6 | Theoretical calculations
2.6.1 | DFT calculations
To the stirring solution of 2‐bromo‐1‐(4‐bromophenyl)
ethanone (0.5 g, 2.016 mmol), in the mixture of tetrahy-
drofuran and ethanol (10 mL), urea (2.016 mmol) was
added with anhydrous potassium carbonate and a cata-
lytic amount of potassium iodide. The system was heated
under reflux for 6 to 7 hours. The solid product (2‐(4‐
bromophenyl)‐2‐oxoethyl) urea 3 was obtained. After
filtration, re‐crystallization of the product was made with
ethanol—chloroform mixture. The compound 3 was
treated with LR using 3 mmol of compound 3 in 3 mL
of toluene with 3 mmol of LR, and the resulting mixture
was heated for 3.5 hours with stirring. On completion, the
reaction mixture was cooled to ambient temperature and
then concentrated in vacuum. A yellow solid of 4‐(4‐
bromophenyl)thiazol‐2‐amine 4 was obtained in good
yield. The final compound was further recrystallized from
ethanol/water (1/1), and the slow evaporation yielded
small crystals suitable for X‐ray analysis.
All quantum chemical calculations were performed with
the GAUSSIAN 09 program package.[27] The initial molec-
ular structures of the title compound were taken from the
X‐ray crystallographic data. Then, the geometry optimiza-
tion of the title compound by density functional theory
(DFT) was carried using Becke three‐parameter hybrid
functional combined with the Lee‐Yang‐Parr correlation
functional (B3LYP) with the 6‐311++G(d,p) basis set.[28]
The vibrational frequencies and thermodynamic parame-
ters were also calculated for the optimized structure at
the same level of theory in the gas phase. Since DFT‐
calculated harmonic vibrational frequencies are usually
larger than those observed experimentally, a frequency
scaling factor was employed for the vibrational analysis.
2.6.2 | Hirshfeld surface calculations
2.4 | Characterization data
Crystal Explorer program 17.5 was employed to carry out
the Hirshfeld surface (HS) analyses.[29] The structural
input file was obtained in the CIF format. HS distance
from the nearest nucleus inside and outside the surface
was measured and represented by di and de, respectively,
while a normalized contact distance was represented as
dnorm. White, red and blue colours have been selected
Yield:80%: M. P 188°C; R f : 0.67; Petroleum ether: ethyl
acetate (6:4) IR; (KBr, cm−1): 3375 (NH2), 3117 (sp2CH),
1624 (C¼N), 1568 (Ar‐C¼C), 1H NMR (300 MHz,
DMSO‐d6): δ (ppm): 7.31 (s, 1H, thiazole H), 6.12 (s, 2H,
NH2), 6.71‐7.20 (m, 4H Ar‐H) 13C NMR (75 MHz,
DMSO‐d6): δ (ppm): 174.4, 153.0, 136.6, 134.8, 129.6,
124.4, 108.3, Anal. Calcd. for C9H7BrN2S: C, 42.37; H,
2.77; N, 10.98; S, 12.57. found: C, 42.39; H, 2.79; N,
10.96; S, 12.58.
for the visualization of dnorm
.
2.7 | DNA binding experiments
Using Falcon method, double‐strand (ds‐) DNA was
extracted from calf thymus gland and checked for its
purity by measuring absorbance at 260 and 280 nm.
A260/A280 was evaluated 1.86, which showed that the
absorbance ratio was satisfactory to assure the DNA
purity.[30] The concentration of stock DNA was evaluated
at λ260 by using the value of the molar extinction
coefficient (ε260 = 6600 cm−1M−1) in Beer law. The
stock concentration of the synthesized compound was
prepared in 1:1 ethanol: water mixture. For DNA binding
2.5 | X‐ray crystallography and structure
refinement
Crystallographic data were recorded on a Bruker AXS
SMART APEX CCD area‐detector diffractometer using
Mo Kα radiation (λ = 0.71073 Å) at T = 130 K. Absorption
correction by multiscan (Bruker, 2005) was applied.[25]
The structure was solved by direct methods and refined
by full‐matrix least squares against F 2 using all data.[26]
All non‐H atoms were refined anisotropically. Atoms H1

4 of 15
CHANNAR ET AL.
experiments concentration of synthesized compound was
optimized to 1.25 × 10−4M and kept constant while
adding DNA from 10 to 60μM under physiological tem-
perature (37°C). Conversely, in viscosity experiments,
DNA concentration was kept constant to 1.45 × 10−5M
and compound was added gradually in its increasing
concentration from 10 to 90μM.
3 | RESULTS AND DISCUSSION
3.1 | Synthesis
Thiazole containing scaffold was synthesized by following
a well‐established protocol.[31] In the first step, the nucle-
ophilic substitution reaction was performed by using 1
and 2 to obtain 3. The latter was subjected to LR under
anhydrous conditions to obtain the desired product 4 in
excellent yield (Scheme 1). The mechanism for Gabriel
cyclization reaction is presented as Scheme S1.[22]
FIGURE 2 The molecular structure of the title compound, with
the atom‐numbering scheme for the asymmetric unit
The hydrogen bond geometry and the selected inter-
atomic distances are given in Tables 2 and 3, while the
selected bond lengths, bond angles together with the tor-
sion angles are provided in Table S1.
The asymmetric unit contains one ligand molecule,
one uncoordinated water molecule, and one uncoordi-
nated Br atom. The planar benzene [A (C1‐C6)]
and thiazole [B (S1/N2/C7‐C9)] rings are oriented at
3.2 | Characterization
Synthesized compound was fully characterized by 1H and
13C NMR. In proton NMR, the existence of the thiazole
moiety was confirmed by the two proton singlets lying
in the aromatic region due to being attached with sp2 car-
bon and sulfur and nitrogen electronegative elements. 13C
NMR also confirmed the formation of thiazole moiety.
Quaternary carbon of thiazole ring, which is directly
attached to nitrogen, appeared around 173 ppm, while
the ipso carbons appeared at high ppm values and that
can also be justified from the height of signal. The car-
bons appeared around 140 to 120 ppm values indicated
their aromatic nature.
a
dihedral angle of A/B = 14.82(3)°. Thus, the
molecule is nonplanar as a whole. The uncoordinated
water molecule is bonded to the uncoordinated Br
atom through the intramolecular OW–HW···Brunccord
(W = water, uncoord = uncoordinated) hydrogen bond
(Table 3). In the crystal structure, a significant π···π
interaction between the benzene [A (C1‐C6)] and
thiazole [B (S1/N2/C7‐C9)] rings of the adjacent
molecules with an intercentroid distance of
3.610(2) Å was observed. On the other hand, there
3.3 | Crystal structure description
are intermolecular N–HThz···Brunccord
,
N–HThz···OW,
The molecular structure along with the atom‐numbering
scheme is depicted in Figure 2. The single crystal X‐ray
structure determination of the title compound confirmed
the assignment of its structure from spectroscopic data.
The experimental details including the crystal data, data
collection, and refinement are summarized in Table 1.
C–H···OW and OW–HW···Brunccord (Thz = thiazole)
hydrogen bonds (Table 3 and Figure 3).
The π···π interactions and the hydrogen bonds link
the molecules into a three‐dimensional supramolecular
structure. Hydrogen bonding and van der Waals contacts
are the dominant interactions in the crystal packing.
SCHEME 1 Gabriel synthesis of 1,3‐thiazole through thionation with Lawesson reagent

CHANNAR ET AL.
5 of 15
TABLE 1 Crystallography data for the title compound
TABLE 2 Hydrogen bond geometry (Å, °) for the title compound
D‐H···A
D‐H
H···A
D···A
D‐H···A
Empirical formula
Formula weight
Temperature
C9H8BrN2S.Br. H2O
354.07
N1‐H1A···Br2i
N1‐H1B···Br2vi
N2‐H2B···O10v
O10‐H11···Br2vii
O10‐H12···Br2
C3‐H3A···O1Ov
0.88
2.62
3.442 (2)
3.346 (3)
2.757 (3)
3.353 (3)
3.309 (2)
3.332(3)
155
158
0.88
2.51
130 K
0.88
1.89
170
Wavelength
0.71073 Å
Monoclinic
P 21/c
0.83 (3)
0.83 (3)
0.95
2.54 (3)
2.51 (3)
2.43
164 (3)
161 (3)
158
Crystal system
Space group
Unit cell dimensions a = 13.007(2)Å
b = 9.6097(17) Å
β = 109.5326(3)°
Symmetry codes: (i) –x + 1, −y + 1, −z + 1; (v) –x + 1, y − 1/2,
1/2 − z; (vi) x–1,3/2–y, 1/2+ z; (vii) x, 3/2–y, z–1/2.
c = 9.9436(17) Å
Volume
Z
1171.1(4) Å3
lengths are larger than the experimental values. However,
this can be attributed to the neglect of intermolecular
forces, such as van der Waals interactions and crystal
packing forces in solid state, which make most of the
experimental bond lengths to be shorter than the theoret-
ical ones. Nevertheless, the root means square error
between the experimental and computed values of bond
lengths and bond angles is 8.7% and 1.8%, respectively,
which indicates reasonable consistency. The calculated
torsion angles C3‐C4‐C7‐C8 and C5‐C4‐C7‐N2 were
180.0°, while C3‐C4‐C7‐N2 and C5‐C4‐C7‐C8 were
−180.0° and −0.0°, respectively, and the corresponding
experimental torsion angles obtained from the X‐ray
structure analysis were 163.6(3)°, 169.6(2)°, −13.2(4)°,
and 13.6(4)°, respectively. The torsion angle C3‐C4‐C7‐
C8 has the largest, and the torsion angle C5‐C4‐C7‐C8
has the smallest discrepancy values of 16.4° and 10.4°,
respectively.
4
Density (calculated) 2.008 mg m−3
Absorbtioncocfficient 7.08 mm−1
F (000)
688
Crystal size
0.32 × 0.17 × 0.04 mm3
Ɵ range for data
collection
2.7‐28.3°
Index ranges
−17 ≤ h ≤ 17,
−12 ≤ k ≤ 12,
−13 ≤ l ≤ 13
Reflections collected 10701
Independent
reflections
2793[R (int) = 0.038]
Refinement method Full‐matrix least
squares on F 2
Data/restraints/
parameters
2793/3/144
Goodness‐of‐fit on
1.02
F 2
3.4.2 | Vibrational analysis
Final R indices
[I > 2σ(I)]
R1 = 0.0287
The vibrational analysis plays a significant role in
determining conformational and structural features in
the solid state. The vibrational spectrum of the investi-
gated compound is given in Figure 5. For visual
wR2 = 0.0703
R indices (all data)
R1 = 0.0362
wR2 = 0.0736
Largest diff. Peak
and hole (e Å−3
1.098/−0.443
)
TABLE 3 The selected interatomic distances (Å)
Br2···H1Ai
Br2···H1Bii
2.62
N2···H3A
C3···H2B
2.64 H2B···H11v 2.32
2.70 H2B···H3A 2.14
2.80 H2B···H12v 2.44
2.70 H5A···H8A 2.24
2.47
3.4 | DFT computational analysis
3.4.1 | Molecular geometry
2. 51
Br2···H11iii 2.54 (3) C5···H8A
Br2···H12 2.51 (3) C8···H5A
The ground state optimized the geometry of title com-
pound was found to be almost consistent with the X‐ray
crystal structure results (Figure 4). Some experimental
and computed values of the selected bond lengths, bond
angles, and torsion angles for the title compound are
listed in Table 4. It can be seen that the computed bond
O10···H3Aiv 2.43
O10···H2Biv 1.89
H1A···H2B
H2A···H6Av 2.57
Symmetry codes: (i) 1 − x, 1 − y, 1 − z; (ii) x + 1, 3/2 − y, z − 1/2;
(iii) x, 3/2 − y, z + 1/2; (iv) 1 − x, 1/2 + y, 1/2 − z; (v) 1 − x,
y − 1/2, 1/2 − z.

6 of 15
CHANNAR ET AL.
In general, the assignment of C–S band in infrared is
difficult, due to variable intensity band (1250‐250 cm−1).
Moreover, C–S band is less polar compared with carbonyl
group; as a consequence, it falls in lower frequency and
weak band and it is also prone to coupling effects.[33]
The absorption of the C–S group connected with other
groups usually appears between 1250 and 1050 cm−1
Considering these facts, the tentative assignment of the
C–S group was assigned to bands at 1187 to 1040 cm−1
The aromatic amines show C–N stretching absorptions
.
.
in the region of 1382 to 1266 cm−1 [34]
In this study, the
.
band at 1270 cm−1 was assigned to C–N absorption.
The C¼N band is observed at 1726 cm−1 in the FT‐IR
spectrum.
Usually, the N–H stretching vibrations occur in the
region of 3500 to 3300 cm−1. The asymmetric –NH2
stretching vibration appears from 3500 to 3420 cm−1
and the symmetric, –NH2 stretching is observed in the
range of 3420 to 3340 cm−1. In this study, the NH2
asymmetric stretches were captured at 3410 cm−1 in the
FT‐IR spectrum. It was good agreement with HF and
B3LYP/6‐311++G(d,p) calculated values. Generally,
C¼C stretching vibrations occurred in the region of
1430 to 1650 cm−1 [28,35]
Accordingly, in the present
.
FIGURE 3 Part of the crystal structure. N–HThz···Brunccord
N–HThz···OW, C–H···OW, and OW–HW···Brunccord (W = water,
uncoord = uncoordinated and Thz = thiazole) hydrogen bonds are
shown as dashed lines
,
study, the C¼C stretching vibrations of 2‐aminothiazole
were assigned at 1356 and 1276 cm−1 in FT‐IR. The ring
stretching vibrations in FT‐IR were assigned to 821 and
880 cm−1. The experimental frequencies coincided with
B3LYP/6‐311++G(d,p) (DFT) frequencies results.
3.4.3 | HUMO‐LUMO analysis
The energy gap between highest occupied molecular
orbital (HOMO) and lowest unoccupied molecular orbital
(LUMO) is quite helpful in determining electronic
structures and is widely used in the analysis of chemical
reactions.[36,38] According to Koopman theorem, ioniza-
tion potential (IP), electron affinity (EA), and other
reactivity parameters may be defined in terms of the
energy of the HOMO and the LUMO.
FIGURE 4 The optimized molecular structure of the title
compound at B3LYP/6‐311++G(d,p) level of theory
The frontier molecular orbital energies were obtained
using the B3LYP/6‐311++G(d,p) level for the optimized
molecular structure of the title compound. The three‐
dimensional plots of the frontier orbitals, the HOMO,
and the LUMO along with HOMO−1 and LUMO+1 are
shown in Table 5. The positive phase is shown in red
colour, and the negative one is shown in green color.
From the shapes of the orbitals, it is quite clear that the
HOMO is localized over thiazole ring, while the LUMO
is localized over phenyl ring, indicating an efficient elec-
tron transfer from thiazole group of the HOMO to the
phenyl group of the LUMO if electronic transitions occur.
comparison, the simulated spectra computed at the
DFT/B3LYP level using 6‐311++G(d,p) basis set is also
shown. Normally, the vibrational frequencies obtained
by quantum chemical calculations with unscaled ab initio
and DFT force field are greater than the experimental
values due to anharmonicity and basis set deficiencies.
In order to improve the agreement between calculated
and the experimental values, it is necessary to scale down
the calculated harmonic frequencies.[32] In the present
study, a scaling factor of 0.978 was used to obtain a better
agreement.[28]

CHANNAR ET AL.
7 of 15
TABLE 4 Experimental and computed (B3LYP/6‐311++G(d,p) geometric parameters of the title compound
Bond Lengths, Å
Bond Angles, °
Torsion Angles, °
Parameters
B3LYP X‐ray
Parameters
B3LYP X‐ray
Parameters
B3LYP X‐ray
Br1‐C1
S1‐C9
S1‐C8
N1‐C9
N2‐C9
N2‐C7
C1‐C2
C1‐C6
C2‐C3
C3‐C4
C4‐C5
C4‐C7
C5‐C6
C7‐C8
1.954
1.813
1.848
1.409
1.301
1.361
1.391
1.393
1.396
1.406
1.407
1.474
1.394
1.080
1.895(3)
C9‐S1‐C8
C9‐N2‐C7
C2‐C1‐C6
C2‐C1‐Br1
C6‐C1‐Br1
C3‐C2‐C1
C2‐C3‐C4
C3‐C4‐C5
C3‐C4‐C7
C5‐C4‐C7
C6‐C5‐C4
C5‐C6‐C1
C8‐C7‐N2
C8‐C7‐C4
N2‐C7‐C4
C7‐C8‐S1
N1‐C9‐N2
N1‐C9‐S1
N2‐C9‐S1
86.2
113.2
120.9
119.6
119.5
119.4
121.0
118.2
119.8
122.0
121.1
119.3
114.0
126.7
120.7
111.4
125.4
120.7
114.0
90.2(1)
C6‐C1‐C2‐C3
Br1‐C1‐C2‐C3
C1‐C2‐C3‐C4
C2‐C3‐C4‐C5
C2‐C3‐C4‐C7
C3‐C4‐C5‐C6
C7‐C4‐C5‐C6
C4‐C5‐C6‐C1
C2‐C1‐C6‐C5
Br1‐C1‐C6‐C5
C9‐N2‐C7‐C8
C9‐N2‐C7‐C4
C3‐C4‐C7‐C8
C5‐C4‐C7‐C8
C3‐C4‐C7‐N2
C5‐C4‐C7‐N2
N2‐C7‐C8‐S1
C4‐C7‐C8‐S1
C9‐S1‐C8‐C7
C7‐N2‐C9‐N1
C7‐N2‐C9‐S1
C8‐S1‐C9‐N1
C8‐S1‐C9‐N2
−0.0
180.0
−0.0
0.0
−1.2(5)
176.8(2)
−0.5(5)
1.9(4)
1.730(3)
1.731(3)
1.323(3)
1.329(3)
1.406(3)
1.386(4)
1.388(4)
1.386(4)
1.400(4)
1.404(4)
1.463(4)
1.378(4)
1.345(4)
114.8(2)
120.7(3)
119.2(2)
120.1(2)
119.4(3)
121.1(3)
118.0(3)
122.4(2)
119.6(2)
121.2(2)
119.5(3)
111.3(2)
127.7(2)
120.9(2)
112.5(2)
125.0(2)
123.8(2)
111.2(2)
−180.0
−0.0
0.0
−175.3(3)
−1.6(4)
175.7(3)
0.0(4)
−0.0
−0.0
−180.0
0.0
1.5(4)
−176.5(2)
0.1(3)
180.0
180.0
−0.0
−180.0
180.0
0.0
177.4(2)
163.6(3)
−13.6(4)
−13.2(4)
169.6(2)
0.6(3)
−180.0
0.0
−176.4(2)
−0.9(2)
179.6(3)
−0.8(3)
−179.5(3)
1.0(2)
180.0
0.0
−180.0
0.0
By analysing HOMO and LUMO energy values, the
global chemical reactivity descriptors, ie, the chemical
potential (μ), electronegativity (χ), hardness (η), softness
(S), and electrophilicity index (ω) were obtained and
incorporated in Table 6. Since a strong nucleophile is
characterized by a lower value of chemical potential
and electrophilicity index, the obtained values point
towards the reactive nature of the title compound. The
chemical potential (μ) was computed negative which
indicated that this compound does not decompose
spontaneously into the compounds from which it is
made up of.[33] The small value of hardness (η) and a
large value of softness (S) indicated that the system is
polarizable, which was further confirmed by the large
value of computed dipole moment.[33] These values
together with small HOMO‐LUMO gap (ΔE) and nega-
tive binding energy confirmed that the title compound
is polarizable and reactive in nature, hence could bind
with DNA.[34]
3.4.4 | Molecular electrostatic potential
The molecular electrostatic potential (MEP) plays a cru-
cial role in understanding the chemical reactivity of any
structure, molecular interactions, biophysical recognition,
hydrogen bonding interactions, molecular cluster, and
crystal behaviour. Moreover, it helps to predict the regio-
selectivity such as sites of nucleophilic and electrophilic
attacks. In addition to this, it provides correlations
between chemical reactivity and the partial charges,
dipole moments, and electronegativity of a molecule.
The three‐dimensional plot of the MEP of the crystal
based on the title compound was obtained from the
optimized molecular structure (Figure 6). It is clear from
the figure that areas related to phenyl ring atoms are
showing slightly positive electrostatic potential (yellow
colour) and hydrogen atoms of –NH2 attached to the
thiazole moiety are representing the regions of sharply
positive electrostatic potential (blue colour). The low

8 of 15
CHANNAR ET AL.
FIGURE 5 Experimental (top) and
simulated [B3LYP/6‐311++G(d,p)]
(bottom) vibrational spectrum of the
title compound
charge densities on the phenyl ring and hydrogen atoms
of –NH2 attached to thiazole moiety indicating the
possible sites in the title compound for interactions via
hydrogen bonding.
thermodynamics parameters have shown an increasing
trend by increasing the temperature range from 10 to
500 K due to the fact that the vibrational intensities of
the titled compound were changed with temperature.[39]
The variations in H, S, and G with temperature were plot-
ted and shown in Figure 7. Since increase in temperature
increases the internal energy of the system, hence
justified the rise in the values of H and S. Further, the
contributions of S to G were found more at higher
temperatures; the Gibbs free energy G values have shown
a prominent decreasing trend at high temperatures.
3.4.5 | Thermodynamic parameters
The thermodynamic data of a compound help in
predicting and estimating the reactivity and feasibility of
a chemical reaction. Furthermore, such data can be used
to calculate many other inter‐dependent thermodynamic
parameters. The statistical thermo‐chemical analysis of
the title compound was carried out considering the mole-
cule to be at standard temperature and pressure (298.15 K
and 1 atm). The thermodynamic properties like heat
capacity (Cp), enthalpy (H), Gibbs free energy (G), and
entropy (S) were calculated using the DFT/B3LPY with
6‐311G++(d,p) basis set. The thermodynamic quantities
of the titled compound for various ranges (10‐500 K) of
temperatures were calculated using the Moltran software
and the data is provided in Table S2. Most of the
3.5 | HS analysis
Visualization and exploration of intermolecular close
contacts in the crystal structure of the title compound
are invaluable. Thus, an HS analysis[40,41] was carried
out by using Crystal Explorer 17.5 to investigate the loca-
tions of atoms···atom short contacts with potential to
form hydrogen bonds and the quantitative ratios of these
interactions besides of the π‐stacking interactions. In the

CHANNAR ET AL.
9 of 15
TABLE 5 Molecular orbital surfaces and energy levels for the HOMO−1, HOMO, LUMO, and LUMO+1, of the title molecule
Type
LUMO
LUMO+1
Energy
−0.16822 eV
−0.16527 eV
HOMO−1
Type
HOMO
Energy
−0.26156 eV
−0.29478 eV
Abbreviations: HOMO, highest occupied molecular orbital; LUMO, lowest unoccupied molecular orbital.
TABLE 6 The calculated other parameters derived from HOMO‐
LUMO energy values
IP
χ
0.26156
0.21489
0.04667
0.49473
7.1034
EA
μ
0.16822
−0.21489
10.71
η
S
Ψ
D
BE
−3425.52
Abbreviations: D, dipole moment (Debye); EA, electron affinity (eV);
HOMO, highest occupied molecular orbital; IP, ionization potential (eV);
LUMO, lowest unoccupied molecular orbital; χ, electronegativity; μ, chemi-
cal potential; ?, chemical hardness; S, chemical softness; Ψ, (electrophilicity
index); BE, binding energy (hartrees).
FIGURE 7 Effect of temperature on enthalpy, entropy, and
Gibbs free energy values calculated by DFT method
HS plotted over dnorm (Figure 8), the white surface
indicates contacts with distances equal to the sum of
van der Waals radii, and the red and blue colours indicate
distances shorter (in close contact) or longer (distinct
contact) than the van der Waals radii, respectively.[42]
The bright‐red spots appearing near uncoordinated
Br2 and hydrogen atoms H1A, H1B, H2B, H11, H12,
and H3A indicate their roles as the respective donors
and acceptors in the dominant N–H···O, N–H···Br,
O–H···Br, and C–H···O hydrogen bonds. The shape
FIGURE 6 Molecular electrostatic potential (MEP) map of the
title molecule calculated at B3LYP/6‐311++G(d,p) level

10 of 15
CHANNAR ET AL.
pair of thin edges at de + di ~ 3.36 Å result from
short interatomic H···C/C···H contacts. The H···S/S···H
contacts in the structure with 8.3% contribution to the
HS has an asymmetric distribution of points (Figure 10
E), with the tips at de + di ~ 3.16 Å. In the fingerprint
plot delineated into H···O/O···H contacts (Figure 10F),
the 7.5% contribution to the HS arises from the inter-
atomic H···O/O···H contacts listed in Table 3 and is
waived as a pair of spikes with the tips at de + di ~ 1.77 Å.
The C ···C contacts assigned to short interatomic C···C
contacts with 5.8% contribution to the HS appear as an
arrow‐shaped distribution of points in Figure 10G, with
the vertex at de = di ~ 1.70 Å. The symmetrical distribu-
tion of points in the fingerprint plot delineated into
C···Br/Br···C contacts (Figure 10H); the 4.0% contribu-
tion to the overall crystal packing is viewed as a pair
of spikes with the tips at de + di ~ 3.67 Å. Finally, the
S···Br/Br···S (Figure 10I) and N···C/C···N (Figure 10J)
contacts in the structure with 2.6% and 2.1% contribu-
tions to the HS, respectively, have a nearly symmetric
distribution of points, with the scattered points of low
densities.
FIGURE 8 View of the three‐dimensional Hirshfeld surface of
the title compound plotted over dnorm in the range of −0.6597 to
1.0672 au
The HS representations with the function dnorm plotted
onto the surface are shown for H···Br/Br···H, H···H,
H···C/C···H, H···S/S···H, H···O/O···H, and C···C interac-
tions in Figure 11A‐F. The HS analysis confirms the
importance of H‐atom contacts in establishing the
packing. The large number of H···Br/Br···H, H···H,
H···C/C···H, H···S/S···H, and H···O/O···H interactions
suggest that van der Waals interactions and hydrogen
bonding play the major roles in the crystal packing.
FIGURE 9 Hirshfeld surface of the title compound plotted over
shape index
index of the HS is a tool to visualize the π···π stacking by
the presence of adjacent red and blue triangles; if there
are no adjacent red and/or blue triangles, then there are
no π···π interactions. Figure 9 clearly suggest that there
are π···π interactions in the title compound.
The overall two‐dimensional fingerprint plot
(Figure 10A) and those delineated into H···Br/Br···H,
H···H, H···C/C···H, H···S/S···H, H···O/O···H, C···C,
C···Br/Br···C, S···Br/Br···S, and N···C/C···N contact[43]
are illustrated in Figure 10B‐J, respectively, together with
their relative contributions to the HS. The most important
interaction is H···Br/Br···H contributing 30.4% to the
overall crystal packing due to the interatomic H···Br
contacts (Tables 3 and 4), which is reflected in
Figure 10B as a pair of spikes with the tips at
de + di ~ 2.42 Å. In the fingerprint plot delineated into
H ···H contacts (Figure 10C), the 25.1% contribution to
the HS is viewed as widely scattered points of high den-
sity due to the large hydrogen content of the molecule.
The small single spike in the centre at de = di = 1.2 Å in
Figure 10C is due to the short interatomic H···H contacts
(Table 4). In the absence of C–H···π interactions in the
crystal, the tiny pair of characteristic wings resulting in
the fingerprint plot delineated into H···C/C···H contacts
with 10.2% contribution to the HS (Figure 10D) and the
3.6 | DNA binding studies
Reactivity and possible binding sites in the compound's
structure as investigated by DFT were further explored
experimentally for its binding with calf thymus (ct‐) dou-
ble strand (ds‐) DNA by UV‐visible spectroscopy and vis-
cometry. Initially, spectroscopic experiments were run
separately to obtain an individual spectrum of DNA and
the test compound. DNA peak appeared at 260 nm, while
for the test compound, a single peak appeared at
290.40 nm. Then, titrations were carried out by adding
DNA in aliquots into fixed compound's concentration so
that each addition gradually raised the DNA concentra-
tion into the reaction mixture from 10 to 60μM. Upon
DNA additions, compound's peak shifted progressively
towards shorter wavelength (blue shift) along with a
gradual decrease in the absorbance maxima (Figure 12,
left). The peak shifting was measured 5.2 nm from its ini-
tial position, which was quite significant to authenticate
that the compound has interacted with DNA. The

CHANNAR ET AL.
11 of 15
FIGURE 10 The full two‐dimensional fingerprint plots for the title compound, showing A, all interactions, and delineated into B,
H···Br/Br···H, C, H···H, D, H···C/C···H, E, H···S/S···H, F, H···O/O···H, G, C···C, H, C···Br/Br···C, I, S···Br/Br···S, and J, N···C/C···N
interactions. The di and de values are the closest internal and external distances (in Å) from given points on the Hirshfeld surface contacts
observed hypochromism was evaluated as 23.24% by
using Equation (1):
changes. The observed hypochromism and blue shift
have been reported for intercalative binding of a com-
pound with DNA.[44,45] Such binding possibility usually
observed due to complete/or partial insertion of a com-
pound into the DNA pocket and its chromophore's
electronic state interact with DNA base pairs via
overlapping; the coupling π orbital is partially filled by
electrons and results in the reduction of transition
A
free − Abound
H% ¼
× 100:
(1)
Afree
The binding possibility of the compound with DNA
could further be explained on the bases of UV‐spectral

12 of 15
CHANNAR ET AL.
FIGURE 11 The Hirshfeld surface representations with the function dnorm plotted onto the surface for A, H···Br/Br···H, B, H···H, C,
H···C/C···H, D, H···S/S···H, E, H···O/O···H, and F, C···C interactions
FIGURE 12 The UV‐visible spectrum of the test compound on adding increasing concentrations of DNA (10 to 60μM) in a fixed
concentration of compound (1.25 × 10−4M) in (1:1) ethanol water at 37°C

CHANNAR ET AL.
13 of 15
probability (ie, hypchromism) of compound's chromo-
phore after DNA addition.[41] The appearance of an
isosbestic point in the UV spectra further suggested
compound‐DNA complex formation via intercalation
and absence of other species except free and DNA bound
complex.[46]
Intrinsic binding constant (Kb) and Gibbs free energy
change (ΔG) for compound‐DNA complex were calcu-
lated by using Benesi‐Hildebrand and classical Vant Hoff
equations (Equations 2 and 3, respectively).[44]
Ao
εG
εG
1
¼
þ
ε
;
(2)
(3)
A − Ao
ε
H−G − εG
H−G − εGKb½DNAꢀ
FIGURE 13 The plot of relative specific viscosity vs compound to
DNA concentrations ratio, on adding increasing concentrations of
the compound from 10 to 90 μM into 1.45 × 10−5M DNA
ΔG ¼ −RT lnKb
4 | CONCLUSIONS
In Equation (2)), Ao and A are compound's absorption in
the absence and presence of DNA, respectively; ɛG and ɛH‐
Gabriel cyclization reaction was employed to synthesize
the title compound 4 using LR as an effective thionating
reagent that provides high yield and the results are repro-
ducible. The single crystal X‐ray structure determination
of the title compound confirmed the structural assign-
ment from spectroscopic data. X‐ray crystal analysis sug-
gested dominant interactions in the crystal packing via
hydrogen bonding and van der Waals contacts. HOMO‐
LUMO analysis by DFT revealed delocalization of elec-
tronic clouds over thiazole ring and the electronic trans-
port properties from thiazole to phenyl ring. Theoretical
studies on quantum parameters, vibrational analysis,
and thermodynamic properties further provided detailed
insights about the chemical reactivity, conformational
details, and temperature effect. For the visualization and
exploration of the intermolecular close contacts in the
crystal structure of the title compound, a detailed HS
analysis was carried out to investigate the locations of
atoms···atom short contacts with potential to form hydro-
gen bonds and the quantitative ratios of these interactions
besides of the π‐stacking interactions. Spectroscopic and
viscometric DNA binding studies revealed that the test
compound has a potency to bind with DNA via intercala-
tion. However, further work on this compound from bio-
logical and pharmaceutical aspects could help to explore
it as a potential anticancer drug agent.
are molar extinction coefficient of pure compound and
G
compound‐DNA complex, respectively. By plotting Ao/A‐
Ao vs 1/[DNA], the value of binding constant, Kb, was
obtained from the intercept to slope ratio (Figure 12,
right). Binding constant was calculated to the value of
1.18 × 104M−1. The binding order (104) was evaluated
greater than the reported intercalator isoxazocucumine
(6.3 × 103M−1) and more or less parallel to the values
reported for typical intercalators lumazine (1.74 × 104M
−1), proflavine (K = 2.32
0.41 × 104M−1), epirubicin
(K = 3.4 × 104M−1), anthracycline molecules (K ≈ 104–
105M−1), and other intercalators including methylene
blue, acridine orange, and ethidium bromide (K = 104M
order for all).[47,48] Kb value of the test compound
−1
was further utilized in Equation (3), and ΔG were evalu-
ated to the value of −24.16 kJ mol−1, which showed spon-
taneity in the compound‐DNA binding.
DNA binding by UV spectroscopy was further verified
by measuring the viscosity of DNA in the presence of
compound's concentrations. Viscosity measurements
were made by adding 10 to 90μM compounds' concentra-
tion gradually into 1.45 × 10−5M DNA solution. A plot
was drawn between the cube root of relative specific vis-
cosity and compound/DNA concentration ratio and is
given in Figure 13. A linear rise in the relative viscosity
of the DNA was observed until the additions of 60μM
compound's concentrations into the DNA solution. After
that, no significant change in the DNA viscosity was
observed and seemed to be constant after 60μM additions
of compound's concentration. This trend pointed towards
a mixed mode of the compound‐DNA binding and has
been reported intercalative mode along with the possibil-
ity of minor groove binding.[49]
ACKNOWLEDGEMENTS
The authors would like to thank all the mentioned depart-
ments of national and international universities/institutes
for the accomplishment of research explored in this paper.

14 of 15
CHANNAR ET AL.
[26] a) V. R. Hartwar, M. Sist, M. R. V. Jorgensen, A. H. Mamakhel,
X. Wang, C. M. Hoffmann, K. Sugimoto, J. Overgaard, B. B.
Iversen, IUCr J. 2015, 2, 563. b) G. M. Sheldrick, ActaCryst.
2008, 64, 112.
CONFLICT OF INTEREST
Authors declare no conflict of interest.
[27] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A.
Robb, J. R. Cheeseman, H. Nakatsuji, M. Caricato, X. Li, H. P.
Hratchian, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, R.
Nakajima, Y. Honda, O. Kilao, H. Nakai, T. Verven, J. A. Mont-
gomery Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E.
Brothers, K. N. Kudin, V.N. Staroveror, R. Kobayashi, J.
Normand, K. Ragavachari, A. Rendell, J.C. Burant, S. J.
Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox,
J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R.
E. Strattmann, O. Yazyev, A. J. Austin, R. Cammi, J. W.
Ochetrski, R. L. Martin, K. Morokuma, V. G. Zakrazawski, G.
A. Votn, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Dan-
iels, O. Farkas, J. B. Foresman, O. G. Gaussian, Revision A.O2,
Gaussian Inc.,Wallingford, CT 2009.
ORCID
Nasima Arshad https://orcid.org/0000-0002-4257-9909
REFERENCES
[1] a) A. W. Hofmann, Ber. 1879, 12, 1126. b) A. W. Hofmann, Ber.
1880, 13, 8; c) A. Hantzsch, J. H. Weber, Ber. 1887, 3118, 3336.
[2] N. Siddiqui, M. F. Arshad, W. Ahsan, M. S. Alam, Int. J. Pharm.
Sci., Drug Res. 2009, 1, 136.
[3] A. Dondoni, A. Marra, Chem. Rev. 2004, 104, 2557.
[4] N. A. A. Elkanzi, J. Chin. Chem. Soc. 2018, 65, 189.
[5] A. Saeed, P. A. Channar, G. Shabir, F. A. Larik, J. Fluoresc.
2006, 26, 1067.
[28] Y. Erdogdu, D. Manimaran, M. T. Güllüo lu, M. Amalanathan,
I. Hubert Joe, S. Yurdakul, Opt. Spectrosc. 2013, 114, 525.
[6] J. Das, P. Chen, D. Norris, R. Padmanabha, J. Lin, R. V.
Moquin, Z. Shen, L. S. Cook, A. M. Doweyko, S. Pitt, S. Pang,
J. Med. Chem. 2006, 49, 6819.
[29] M. J. Turner, J. J. McKinnon, S. K. Wolff, D. J. Grimwood, P. R.
Spackman, D. Jayatilaka, M. A. Spackman, Cryt. Exp. 2017, 17.
[30] S. S. Babkina, N. A. Ulakhovich, Anal. Chem. 2005, 77, 5678.
[7] M. V. N. D. Souza, M. V. D. Almeida, Química Nova 2003, 26,
366.
[31] S. V. Giofre, R. Romeo, R. Mancuso, N. Cicero, N. Corriero, U.
Chiacchio, G. Romeo, B. Gabriele, RSC Adv. 2016, 6, 20777.
[8] A. C. Pasqualotto, K. O. Thiele, L. Z. Goldani, Curr. Opin.
Investig. Drugs 2010, 11, 165.
[32] L. Legnani, L. Toma, P. Caramella, M.A. Chiacchio, S. Giofre, I.
Delso, T. Tejero, P. Merino, J. Org. Chem. 2016, 81, 7733.
[9] L. M. Fox, L. D. Saravolatz, Clin. Infect. Dis. 2005, 40, 1173.
[33] A. Bendjeddou, T. Abbaz, S. Maache, A. Gouasmia, D.
[10] M. Zia‐ur‐Rehman, J. A. Choudary, S. Ahmad, Bull. Korean
Chem. Soc. 2005, 26, 1771.
Villemin, Int. J. Pharm. Sci. Rev. Res. 2016, 39, 136.
[34] C. S. Abraham, J. C. Prasana, S. Muthu, M. Raja, J. Mol. Struct.
2018, 1160, 393.
[11] M. P. Knadler, R. F. Bergstrom, J. T. Callaghan, A. L. A. N.
Rubin, Drug Metab. Dispos. 1986, 14, 175.
[35] M. Karaback, M. Cinar, M. Kurt, J. Mol. Struct. 2008, 885, 28.
[36] R. J. Xavier, E. Gobinath, Spectrochim. Acta A. 2012, 86, 242.
[12] R. Nauen, U. Ebbinghaus‐Kintscher, V. L. Salgado, M.
Kaussmann, Pestic. Biochem. Physiol. 2003, 76, 55.
[13] A. J. Seed, P. Sampson, Liq. Cryst. 2017, 44, 1894.
[37] A. U. Rani, N. Sundaraganesan, M. Kurt, M. Cinar, M.
Karabacak, Spectrochim. Acta A. 2010, 75, 1523.
[14] J. W. Goodby, R. J. Mandle, E. J. Davis, T. Zhong, S. J. Cowling,
Liq. Cryst. 2015, 42, 593.
[38] H. Gökce, S. Bahçeli, Spectrochim. Acta A 2013, 114, 61.
[15] V. Polshettiwar, M. P. Kaushik, Liq. Cryst. 2004, 45, 6255.
[16] T. J. Curphey, J. Org. Chem. 2002, 67, 6461.
[39] V. Balachandran, G. Santhi, V. Karpagam, A. Lakshmi,
Spectrochim. Acta Part A: Mol. Biomol. Spectrosc. 2013, 110,
130.
[17] B. Böttcher, F. Bauer, Eur. J. Org. Chem. 1951, 574, 218.
[40] F. L. Hirshfeld, Theor. Chim. Acta 1977, 44, 129.
[18] T. T. Nguyen, T. N. Le, P. E. Hansen, F. Duus, Tetrahedron Lett.
2006, 47, 8433.
[41] M. A. Spackman, D. Jayatilaka, Cryst. Eng. Comm. 2009, 11, 19.
[19] R. M. Elofson, L. A. Baker, F. F. Gadallah, R. A. Sikstrom,
[42] P. Venkatesan, S. Thamotharan, A. Ilangovan, H. Liang, T.
Sundius, Spectrochim. Acta A 2016, 153, 625.
J. Org. Chem. 1964, 29, 1355.
[20] U. Pathak, L. K. Pandey, R. Tank, J. Org. Chem. 2008, 73, 2890.
[43] J. J. McKinnon, D. Jayatilaka, M. A. Spackman, Chem.
Commun. 2007, 37, 3814.
[21] A. Degl'Innocenti, A. Capperucci, G. Mordini, G. Reginato, A.
Ricci, F. Cerreta, Tetrahedron Lett. 1993, 34, 873.
[44] N. Arshad, S. I. Farooq, M. H. Bhatti, S. Saleem, B. Mirza,
J. Photochem. Photobiol. B: Biol. 2013, 125, 70.
[22] F. A. Larik, A. Saeed, U. Muqadar, P. A. Channar, J. Sulphur
Chem. 2017, 38, 206.
[45] Z. Rehman, A. Shah, N. Muhammad, S. Ali, R. Qureshi, A.
Meetsma, I. S. Butler, Eur. J. Med. Chem. 2009, 44, 3986.
[23] F. A. Larik, A. Saeed, U. Muqadar, H. El‐Seedi, M. Faisal, P. A.
Channar, H. Mehfooz, Phosphorus, Sulfur Silicon Relat. Elem.
2017, 192, 490.
[46] K. W. Kohn, M. J. Waring, D. Glaubiger, C. A. Friedman, Can-
cer Res. 1975, 35, 71.
[24] A. Saeed, H. Mehfooz, F. A. Larik, M. Faisal, P. A. Channar,
[47] N. Arshad, M. H. Bhatti, S. I. Farooq, S. Saleem, B. Mirza, Arab.
J. Chem. 2016, 9, 451.
J. Asian Nat. Prod. Res. 2017, 19, 1114.
[25] Bruker, SADABS, Bruker AXS Inc. Madison, Wisconsin, USA,
[48] N. Arshad, M. Ahmad, M. Z. Ashraf, H. Nadeem, J. Photochem.
Photobiol B: Biol. 2014, 138, 331.
2009.

CHANNAR ET AL.
15 of 15
[49] N. K. Janjua, A. Shaheen, A. Yaqub, F. Perveen, S. Sabahat, M.
Mumtaz, C. Jacob, L. A. Ba, H. A. Mohammed, Spectrochim.
Acta Part A. 2011, 79, 1600.
How to cite this article: Channar PA, Arshad N,
Larik FA, et al. 4‐(4‐Bromophenyl)thiazol‐2‐amine:
Crystal structure determination, DFT calculations,
visualizing intermolecular interactions using
Hirshfeld surface analysis, and DNA binding
studies. J Phys Org Chem. 2019;e3968. https://doi.
org/10.1002/poc.3968
SUPPORTING INFORMATION
Additional supporting information may be found online
in the Supporting Information section at the end of the
article.