Synthesis, single crystal X-ray, Hirshfeld surface analysis and characterization of novel 4-(2,4-dichlorophenyl)-N-(2,6-dichlorophenyl)-1,3-thiazol-2-amine

Article abstract of DOI:10.1016/j.molstruc.2017.05.126

In the present study, the spectroscopic characterization of a novel thiazole scaffold was studied. The formation of title compound 4-(2,4-dichlorophenyl)-N-(2,6-dichlorophenyl)-1,3-thiazol-2-amine(6) was evidenced through the changes in FTIR, ¹H NMR, LCMS Data. The X-ray diffraction studies revealed that compound (6) crystallized in monoclinic crystal system with P2₁/c Space group with Z = 4. The percentage of intermolecular contacts contributing to the Hirshfeld surface in thiazole crystal was resolved by Hirshfeld surface analyses with 2D fingerprint plots.

Full text of DOI:10.1016/j.molstruc.2017.05.126

Accepted Manuscript
Synthesis, single crystal X-ray, Hirshfeld surface analysis and characterization of
novel 4-(2,4-dichlorophenyl)-N-(2,6-dichlorophenyl)-1,3-thiazol-2-amine
B.H. Gayathri, Jagadeesh Prasad Dasappa, N.R. Bhavya, Chandra, M. Mahendra
PII:
S0022-2860(17)30745-7
10.1016/j.molstruc.2017.05.126
MOLSTR 23867
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 2 March 2017
Revised Date: 25 May 2017
Accepted Date: 27 May 2017
Please cite this article as: B.H. Gayathri, J.P. Dasappa, N.R. Bhavya, Chandra, M. Mahendra,
Synthesis, single crystal X-ray, Hirshfeld surface analysis and characterization of novel 4-(2,4-
dichlorophenyl)-N-(2,6-dichlorophenyl)-1,3-thiazol-2-amine, Journal of Molecular Structure (2017), doi:
10.1016/j.molstruc.2017.05.126.
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ACCEPTED MANUSCRIPT
Synthesis, single crystal X-ray, Hirshfeld surface analysis and
characterization of novel 4-(2,4-dichlorophenyl)-N-(2,6-dichlorophenyl)-1,3-
thiazol-2-amine
a
a
b
c
b
Gayathri B. H , Jagadeesh Prasad Dasappa *, Bhavya N. R , Chandra and Mahendra M .
a
Dept. of Chemistry, Mangalore University, Mangalore, Karnataka State-574199, India
b
Dept. of Studies in Physics, Manasagangothri, University of Mysore, Mysore, Karnataka State -
5
70006, India
c
Dept. of Physics, National Institute of Engineering, Mysore, Karnataka State- 570008, India
Abstract:
In the present study, the spectroscopic characterization of a novel thiazole
scaffold was studied. The formation of title compound 4-(2,4-dichlorophenyl)-N-
(2,6-dichlorophenyl)-1,3-thiazol-2-amine(6) was evidenced through the changes in
1
FTIR, H-NMR, LCMS Data. The X-ray diffraction studies revealed that
compound (6) crystallized in monoclinic crystal system with P2 /c Space group
1
with Z=4. The percentage of intermolecular contacts contributing to the Hirshfeld
surface in thiazole crystal was resolved by Hirshfeld surface analyses with 2D
fingerprint plots.
Key words: 1, 3-thiazole, crystal structure, Hirshfeld surfaces, 2,6-dichloroaminophenyl.
Corresponding author; jprasad2003@gmail.com; 009448348585, Office: 0824-2287262
1
. Introduction:
Thiazole is a stable heterocyclic compound and has Bird IA value of 79. It
possesses both electron donating and an electron accepting groups (C=N).
Diverse modification of the thiazole ring at various positions led to synthesis of
variety of novel compounds with wide spectrum of pharmacological activities
such as antibacterial[1], antifungal[2]. anti-inflammatory [3], antihypertensive,

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antiHIV [4], antitumor, antifilarial [5], anticonvulsant [6], antiulcer [7],
herbicidal, insecticidal, schistosomicidal and anthelmintic [8]. Prompted by
these literature we synthesized the title compound 4-(2,4-dichlorophenyl)-N-
(2,6-dichlorophenyl)-1,3-thiazol-2-amine containing electron donating two
chloro groups on both the phenyl rings. The recent interest in building new
dynamic catalytic structure containing 1,3-thiazole heterocycle stood as an
additional lever for the development. Title compound was well characterized
1
by the, H NMR, FT-IR, LC-Mass, UV-Visible Spectra, TGA and elemental
analysis .The lattice parameters, bond lengths, bond angles, dihedral angles,
torsion angles, hydrogen bonding and intermolecular interactions of the grown
crystals were obtained from single crystal diffraction(XRD) technique.
2
2
. Experimental:
.1. Materials and methods:
2
.1.1 Materials and physical measurements
The chemicals used in the study was of standard quality and obtained from
Alfa-aesar(U.K). The novel synthesized 4-(2,4-dichlorophenyl)-N-(2,6-
dichlorophenyl)-1,3-thiazol-2-amine were confirmed by the spectral data. Melting
points of novel compounds were determined in open capillary tubes and were
uncorrected. The purity of synthesized compound was checked by TLC on Merck
silica gel 60 F254 precoated alumina plates in chloroform/methanol mixture and
spots were developed using ultraviolet light as visualizing agent. The IR spectrum
1
was recorded on a Shimadzu-FTIR 577. The H-NMR spectrum was recorded on a
Bruker (400 MHz) spectrometer using DMSO-d6 as solvent and TMS as the
standard. All the chemical shift values were reported in
δ scale downfield from
TMS. The LC-MS spectrum was recorded and molecular ion peak (m/z) were

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equivalent to the molecular weights of the newly synthesized compound. The
elemental analysis (C, H, N) was carried out on a Elementar Vario EL III analyzer.
2
.2. Synthetic procedure for 4-(2,4-dichlorophenyl)-N-(2,6-dichlorophenyl)-
1
,3-thiazol-2-amine (6).
2-bromo-1-(2,4-dichlorophenyl)ethanone (2) was synthesized via bromination
0
(
1 eq) of 2,4-dichloroacetophenone (1eq) in chloroform at 0 C [9]. N-(2,6-
dichlorophenyl)thiourea (5) was prepared by the reaction of benzoyl chloride (1
eq.) with 2,6-dichloroaniline (3) (1 eq) in the presence of NH SCN(1eq.) and
4
acetone. Debenzoylation of the N-(2,6-dichlorophenyl)thiourea takes place with
aqueous sodium hydroxide(1M) [10]. The target compound was synthesized by
condensation of 2-bromo-1-(2,4-dichlorophenyl)ethanone (2) and N-(2,6-
dichlorophenyl)thiourea (5) in ethanol was heated for 10h . The precipitated white
hydrobromide salt was collected, washed with H O and cold ethanol.
2
Recrystallized from methanol[11]. Yield: 76%
2
.3. General procedure for the preparation of 2-bromo-1-(2,4-dichloro phenyl
)ethanone(2)[1].
To a solution of 2,4-dichloro acetophenone (1) (8.40 mL , 64.70 mmol) in 40
ml chloroform, bromine(3.33 ml, 64.7 mmol) in 30 ml chloroform were added
drop wise at ambient temperature. The mixture was stirred at room temperature for
2
h and was washed with H O and saturated Na S O solution. The organic phase
2
2
2
3
was dried over Na SO , filtered and the solvent was removed in vacuum. The
2
4
crude product, 2-bromo-1-(2,4-dichlorophenyl)ethanone (2) was recrystallized
from petroleum ether. Yield: 73%

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2
.4. General procedure for the preparation of N-[(2,6-dichlorophenyl)
carbamothioyl] benzamide(4)[2].
Benzoyl chloride (1.75 mL, 15.2 mmol) was added over 5 min to a freshly
prepared solution of NH SCN (1.27 g, 16.68 mmol) in 20 mL acetone and the
4
mixture was heated to reflux for 15 min. The insitu generated benzoyl
isothiocyanate reacted with 2,6-dichloro aniline(2.08 g,15.20 mmol) in 20 ml
acetone. The mixture was heated to reflux for 30 min, and then poured on ice with
vigorous
stirring.
The
resulting
solid,
N-[(2,6-
dichlorophenyl)carbamothioyl]benzamide, was collected and washed with cold
acetone. Yield: 69%
2
.5. General procedure for the preparation of N-(2,6-dichloro phenyl) thio
urea(5)[2].
A solution of N-[(2,6-dichlorophenyl)carbamothioyl]benzamide(4) (1g , 3.33
0
mmol) in 5 mL aqueous sodium hydroxide (2 M) was heated to 100 C for 5h. The
precipitating solid N-(2,6-dichlorophenyl)thiourea (5), was collected and washed
with H O. Yield: 70%
2
2
.6. X-ray data collection, structure determination, and refinement:
A single crystal of the molecule (6) with dimensions of 0.30 × 0.25 × 0.20 mm was
chosen for X-ray diffraction studies. The crystallographic data were collected at
2
93K on a Rigaku XtaLAB Mini X-ray diffractometer operating at 50 kV and 12
mA with MoK radiation of wavelength = 0.71073 Å. Raw data was processed
α
λ
and reduced by using CRYSTAL CLEAR [12]. All the frames were indexed with
primitive monoclinic lattice. The crystal structure was solved by direct methods

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using SHELXS-97 [12-13]. All the non-hydrogen atoms were revealed in the first
Fourier map itself and subjected to Full-matrix least squares refinement using
SHELXL-97 [12-13]. Anisotropic refinement of non-hydrogen atoms was started
at this stage. Subsequent refinements were carried out with anisotropic thermal
parameters for non-hydrogen atoms and isotropic temperature factors for the
hydrogen atoms which were placed at chemically acceptable positions, finally
converged with residual value of R = 0.0546 and wR = 0.1419, respectively.
1
2
The thermal ellipsoid plot[14] at 50% probability of the molecule (6) is represented
in Figure 1. All geometrical calculations were performed using PLATON [15]. The
molecular packing diagrams were plotted using MERCURY [16]. A summary of
experimental and crystallographic data for (6) is given in Table 1. The details of
crystallographic information of the molecule (6) have been deposited at the CCDC
with the NO. 1524786 (CCDC NO. 1524786 - Contains the supplementary
crystallographic data for the molecule (6). These data can be obtained free of
charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK;
fax: +44(0)1223 762911; email: deposit@ccdc.cam.ac.uk]).
Figure 1: ORTEP [3] diagram of the molecule (6 )at 50 % probability.

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Figure 2: Packing of the molecule (6) viewed along c-axis. Hydrogen bonds are represented as
dashed lines.
Table 1: Crystal data and structure refinement for Molecule(6).
Empirical formula
Formula weight
Temperature
C H Cl N S
1
5
8
4
2
3
2
0
90. 09
93(2)K
Wavelength
.71073Å
Crystal system
Space group
Monoclinic
P2 /c
1
Cell dimensions
a = 13.166(2) Å, b = 9.8986(11) Å, c = 13.788(2) Å,
°
β = 116.297(5)
3
Volume
1
4
1
0
7
0
2
611.0(4) Å
Z
3
Density(calculated)
Absorption coefficient
.608 Mg/m
-
1
.859 mm
84
F0
00
3
Crystal size
.30 × 0.25 × 0.20 mm
5º
θmax
Index ranges
−
15 ≤ h ≤ 10, −11 ≤ k ≤ 9, −16 ≤ l ≤ 16

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Reflections collected
5958
Independent reflections
Refinement method
2819 [R(int) = 0.0416]
2
Full-matrix least-squares on F
2819 / 0 / 199
Data / restraints / parameters
2
Goodness-of-fit on F
1.038
Final R indices [I > 2σ(I)]
R indices (all data)
R = 0.0546, wR = 0.1419
1
2
R = 0.0646, wR = 0.1602
1
2
-3
Largest diff. peak and hole
CCDC Deposition No
0.735 and -0.646 e. Å
1524786
3
3
. Results and Discussion
.1. Chemistry
The synthetic route for target thiazole was carried out as outlined in Scheme 1.The
key intermediate of N-(2,6-dichloro phenyl) thiourea (5)[2] was synthesized by the
reaction of N-[(2,6-dichlorophenyl)carbamothioyl]benzamide(4) and aqueous
sodium hydroxide. The resulted N-(2,6-dichloro phenyl) thiourea (5) derivative
was treated with 2-bromo-1-(2,4-dichloro phenyl )ethanone (2)[1] to afford the
target compound. The thiazole ring was formed on the basis of nucleophilic
intermolecular attack from the sulfur atom of the 2,6-dichloro phenyl) thiourea
group to the electron deficient center bromoethyl carbon of 2-bromo-1-(2,4-
dichloro phenyl) ethanone (2) generating isothiourea intermediate. Further this
undergoes cyclization via intramolecular nucleophilic attack of the amine nitrogen
to the electrophilic centre of the carbonyl carbon leading to the formation of
desired 4-(2,4-dichlorophenyl)-N-(2,6-dichlorophenyl)-1,3-thiazol-2-amine with
the elimination of H O molecule.
2

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0
Scheme 1: Reagents and conditions: i) Bromine, acetic acid, 0 C , RT , 2 h , ii) Benzoyl
0
0
0
chloride, NH SCN , acetone , 60 C , 45 min , iii) NaOH 100 C, 1h iv) Ethanol, 80 C
4
3
.2. Spectral Study
For the identification of Target compound spectroscopic techniques such as,
1
FTIR spectroscopy, H-NMR spectroscopy, LCMS and single crystal XRD
techniques were used. Each technique provided unique information about the
molecular structure of chemical compounds.
3
.2.1. FTIR Analysis
The formation of thiazole ring was confirmed by the IR spectral data. In the newly
synthesized 4-(2,4-dichlorophenyl)-N-(2,6-dichlorophenyl)-1,3-thiazol-2-amine
scaffold, the absence of thioamide NH symmetric and asymmetric stretching
2
−1
−1
vibrations at 3140 cm and 3375 cm was indicated the cyclization of
carbothioamide into corresponding thiazole compound. Also supported by the

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-1
absence of absorption band in the region of 1700–1750 cm (>C=O group) and
−1
the disappearance of C-S stretching vibration at 1377 cm . The aromatic C-H
-
1
stretching frequency was observed at 3057cm for aromatic C–H as a weak band.
−1
The characteristic absorption bands for –NH group appeared at 3147cm . The C-
−1
Cl stretching frequency gave strong band at 774 and 726 cm .
Cl
Cl
Cl
N
NH
S
Cl
Figure 8: IR Spectrum of 4-(2,4-dichlorophenyl)-N-(2,6-dichlorophenyl)-1,3-thiazol-2-
amine.
3
.2.2. NMR Studies
1
H-NMR spectrum of target compound showed the sharp singlet at δ
8
.856 ppm integrating for -NH proton. The compound 4-(2,4-
dichlorophenyl)-N-(2,6-dichlorophenyl)-1,3-thiazol-2-amine has two aromatic
rings with four chloro groups. Hence, these protons resonated at
different chemical shifts. The protons of 2,4-dichlorohenyl group
resonated as four doublets, one at δ7.721 (J=8.4Hz) and other at
δ

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7
.046(J=10.8Hz) . Similarly one doublet appeared at δ 7.372(J=8Hz) and one
proton appeared as triplet at δ 7.160-7.120 ppm were due to aromatic protons
of 2,6 -dichlorophenyl moiety. The appearance of a singlet at δ 7.31
assigned for one proton of thiazole ring and one aromatic C-H of the
2
,4-dichloro phenyl moiety.
Cl
Cl
Cl
N
NH
S
Cl
1
Figure 9: H-NMR Spectrum of 4-(2,4-dichlorophenyl)-N-(2,6-dichlorophenyl)-1,3-thiazol-2-
amine
.

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3
.2.3. LCMS Study
The LC-mass spectra provided evidence to the molecular structure of 4-(2,4-
dichloro phenyl)-N-(2,6-dichlorophenyl)-1,3-thiazol-2-amine. LCMS spectrum
showed molecular ion peak m/z at 390.74(M+), 392.73[M+2], 394.73[M+4] with
1
00% purity, corresponded to the molecular weight of the compound
C H Cl N S. The accurate molecular mass of the synthesized compounds and
1
5
8
4
2
primary structure information was obtained from LCMS. The elemental analyses
data also supported the molecular frame work.
The UV-Visible spectrum shown in Fig 7 was recorded by using ethanol as a
solvent. Most of the absorption spectroscopy of organic compounds are based on
transitions of n or
00–700 nm. In this point of view, the max absorption peak observed at 241 nm
and 292nm. The transmittance of the heterocyclic compound is due to the π - π*
π electrons to the π*excited state, which takes place in the range
2
transition may be attributed to the excitation in the -C=C- aromatic ring. Chemical
composition of the synthesized compound Carbon (C), Hydrogen (H), and
Nitrogen (N) analysis was carried out. The experimental and calculated
percentages of C, H, and N were given in Table 2. The difference between
experimental and calculated percentages of C, H, and N within the 0.03 error. This
confirms the formation of the product in the stoichiometric proportion.
Table 2. Elemental Analysis for C H Cl N S
1
5
8
4
2
.
Element
Carbon
Nitrogen
Hydrogen
Experimental(%)
Calculated(%)
46.16
46.18
7.18
2.07
7.19
2.05

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Cl
Cl
Cl
N
NH
S
Cl
Figure 10: LC-Mass Spectrum of 4-(2,4-dichlorophenyl)-N-(2,6-dichlorophenyl)-1,3-thiazol-
-amine.
2

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The results of TG/DTA analysis is shown in fig 5 and fig 6. The DTA curve
o
o
implies that the compound undergoes an endothermic peak at 257 C and 496 C.
o
o
exothermic peak s at 294 C and 606 C. It is clear from the DTA curve that there
is no phase transition before melting. The sharpness of the peak indicates good
crystallinity and purity of the sample. The thermogram of composites show
maximum rate of decomposition at 257 °C corresponding to the maximum rate of
weight loss. The TGA curve shows weight losses when the film is heated between
2
57 °C and 510 °C. Thereafter, there was no further weight loss up to 900 °C.
Another important observation was that, there was no phase transition till the
material melts. The absence of water of crystallization in the molecular structure
was indicated by the absence of the weight loss around 100 °C.
Figure 5: TGA Curve
Figure 6: DTA Curve

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Figure 7: UV-Visible spectrum
The X-ray molecular structure analysis of the compound (6) indicated that the
compound crystallizes in monoclinic system under the space group P2 /c, with cell
1
parameters a =13.166(2) Å, b=9.8986(11) Å, c=13.788(2)Å,
β =116.297(5)º and
Z=4. The bond lengths and bond angles agree with the standard values and are
comparable to related structure [17-19]. The mean plane of the thiazole ring is
bridged via amine group with 2,4-dichlorophenyl ring plane and makes a dihedral
angle of 71.84(17)º. Chlorine atoms (Cl13, Cl14, Cl21 and Cl22) are slightly
deviated by 0.026(1), 0.104(1), 0.086(1) and -0.012(1) Å, respectively, from the
mean position of the 2,4-dichlorophenyl and 2,6-dichlorophenyl rings,
respectively. Also, central thiazole ring plane makes a dihedral angle of 62.01 (16)º
with 2,6-dichlorophenyl ring plane. The crystal structure ( 6) is stabilized by N-
H…N intermolecular hydrogen bonds type (see Table 2), and further the
molecules are linked into dimers with an
(8) ring motif forming a zig-zag
ladder-type arrangement when extended along the c-axis. Also included with offset

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interactions involving the phenyl rings of the molecules [intercentroid
distances vary from 3.929(2) to 3.996(1)] within the ladders. Neighboring ladders
are linked via offset
interactions involving the phenyl rings of the molecules
and these interactions in turn lead to the formation of layers parallel to the ab
plane.
Table 3: Hydrogen-bonding geometry (Å, ° )
D–H...A
D–H
H–A
D–A
D–H...A
N6–H6...N3
0.860
2.160
2.995(3) 164
Hirshfeld surface analysis of the crystal
Although with the observation of X-ray crystallographic study, the solid state
structure determinations have further enabled to elucidate the unique
intermolecular interactions present in the solid-state structure complexes by
determining the Hirshfeld surfaces and analyzing with the visual output forms.
Hirshfeld surface is the region around the molecule in the crystal space, which is
the boundary separating two regions—the interior (the reference molecule) and the
exterior (neighboring molecules).The partitioning of space with Hirshfeld surfaces
enables the analysis of fingerprint molecular interactions in crystalline
environments. Fingerprint plots were shown by evaluating the pairs of
and
distances from the surface to the nearest atom interior/ exterior to the surface,
respectively [20]. The total Hirshfeld surfaces for the above crystal have been
generated by using CrystalExplorer 3.1 program [21]. The Hirshfeld surface of the
crystal is represented in Figure-3. The
values are mapped onto the

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Hirshfeld surface by using a red-blue-white color scheme: where red regions
correspond to closer contacts with negative
correspond to longer contacts with positive
value, the blue regions
value and the white regions
correspond to
value of zero. If
<
, the molecule acts as donor and if
>
then the molecule acts as acceptor [22-23]. In Figure-3, the red region
indicates the hydrogen bond donor of N-H…N (N6-H6…N3) with H6…N3 length
of 2.015Å and the angle of N6-H6….N3 is 163.055º , respectively, which are
comparable with the X-ray results.
Figure 3:
mapped on Hirshfeld surface for the visualization of the inter
contacts of the molecule 6.
(a)All to All

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(b)H….H
(c)C….H/H….C
(d)Cl….H/H….Cl

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(e)N…H/H….N
Figure 4: The fingerprint plots (a-e) show the percentage contributions to the
total Hirshfeld surface area.
In Figures 4(a - e), for thiazole crystal, the maximum contribution to the
Hirshfeld surface is from the H….Cl interactions is about 34.2% and other contacts
like N…H, C….H and H….H contributions are 5.9%,10.5% and 15.8%
respectively to the total Hirshfeld surface. Table 3 gives the percentage
contribution of various intermolecular contacts to the Hirshfeld surface.
Table-4: Percentage of various intermolecular contacts contributing to
Hirshfeld surface in thiazole crystal.
Percentage
Percentage
Intercontacts
Intercontacts
contribution(%)
contribution(%)
Cl…H/H….Cl
C….H/H….C
N….H/H….N
34.2
10.5
5.9
H…H
Cl…C/C….Cl
C….C
15.8
12.1
4.9

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4
. Conclusions:
A novel 4-(2,4-dichlorophenyl)-N-(2,6-dichlorophenyl)-1,3-thiazol-2-amine(6)
bearing chloro substituent were synthesized in appreciable yields and their
1
structures were characterized by H-NMR, LC-Mass, FT-IR, UV-visible and
TG/DTA analysis. The molecular structure of this compound was determined by
single crystal XRD method and intermolecular interactions were analyzed by
visualizing Hirschfield surface.
Acknowledgements:
Authors are thankful to the director, SAIF-STIC, Cochin University of Science and
Technology for providing NMR data. The authors thank the National facility,
Department of Studies in Physics, University of Mysore, Mysuru-570 006, India,
and Dr. N. K. Lokanath for providing the X-ray intensity data.
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The syntheses of novel 4-(2,4-dichlorophenyl)-N-(2,6-dichlorophenyl)-1,3-thiazol-2-
1
amine (6) was confirmed by FT-IR, H-NMR, Mass spectrum and elemental analyses.
The x-ray diffraction studies revealed that compound (6) crystallized in monoclinic
crystal system with P2 /n Space group with Z=4.
1
The percentage of intermolecular contacts contributing to Hirshfeld surface in
thiazole crystal was resolved by Hirshfeld surface analyses with 2D finger print plots