Synthesis, crystal structure, spectroscopic, electronic and nonlinear optical properties of potent thiazole based derivatives: Joint experimental and computational insight

Article abstract of DOI:10.1016/j.molstruc.2019.127354

Herein, two new thiazole derivatives: ethyl2-(2-benzylidenehydrazinyl)thiazole-4-carboxylate (3) and ethyl2-(2-(2-hydroxybenzylidene)hydrazinyl)thiazole-4-carboxylate (4) were synthesized by cyclization of 1-benzylidenethiosemicarbazide with ethyl bromopyruvate. The synthesis was validated by spectroscopic techniques like FTIR, ¹H- NMR, ¹³C-NMR and chemical structure of title compounds 3 and 4 has been determined using SC-XRD. Ancillary to experimental analysis, DFT calculations with B3LYP/6-311 + G (d,p) level were performed for comparative analysis of FT-IR spectroscopic data, optimized geometry, frontier molecular orbitals (FMOs), natural bond orbital (NBO) analysis and nonlinear optical (NLO) properties. Overall, experimental findings were supported by corresponding DFT computed results. TDDFT calculations were executed at M06/6-311 + G (d,p) level of theory to calculate the vertical electronic transition states. NBO analysis disclosed that intramolecular charge transfer and hyper-conjugative interactions among bonds provide stability to the investigated compounds 3 and 4. The global reactivity parameters calculated from energy of FMOs indicates that 3 and 4 enclose larger softness and fewer hardness values. NLO results of 3 and 4 were observed better than standard molecule recommended the NLO activity of said compounds. We hope that this joint experimental and computational insight may provide new ways for the utilization of title molecules as NLO material for optoelectronic applications.

Full text of DOI:10.1016/j.molstruc.2019.127354

Journal Pre-proof
Synthesis, crystal structure, spectroscopic, electronic and nonlinear optical properties
of potent thiazole based derivatives: Joint experimental and computational insight
Muhammad Haroon, Muhammad Khalid, Tashfeen Akhtar, Muhammad Nawaz Tahir,
Muhammad Usman Khan, Shabbir Muhammad, Abdullah G. Al-Sehemi, Shahid
Hameed
PII:
S0022-2860(19)31463-2
DOI:
https://doi.org/10.1016/j.molstruc.2019.127354
MOLSTR 127354
Reference:
To appear in: Journal of Molecular Structure
Received Date: 9 June 2019
Revised Date: 1 November 2019
Accepted Date: 1 November 2019
Please cite this article as: M. Haroon, M. Khalid, T. Akhtar, M.N. Tahir, M.U. Khan, S. Muhammad, A.G.
Al-Sehemi, S. Hameed, Synthesis, crystal structure, spectroscopic, electronic and nonlinear optical
properties of potent thiazole based derivatives: Joint experimental and computational insight, Journal of
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Synthesis, crystal structure, spectroscopic, electronic and nonlinear optical
properties of potent thiazole based derivatives: Joint experimental and
computational insight
Muhammad Haroon,1 Muhammad Khalid,*2 Tashfeen Akhtar,*1 Muhammad Nawaz Tahir,3
Muhammad Usman Khan,4 Shabbir Muhammad,5 Abdullah G. Al-Sehemi,6 Shahid Hameed,7
1Department of Chemistry, Faculty of Science, Mirpur University of Science and
Technology (MUST), Allama Iqbal Road, 10250 Mirpur, AJK, Pakistan
2Department of Chemistry, Khwaja Fareed University of Engineering & Information
Technology, Rahim Yar Khan-64200, Pakistan
3Department of Physics, University of Sargodha, Sargodha-40100, Pakistan
4Department of Applied Chemistry, Government College University, Faisalabad-38000,
Pakistan
5Department of Physics, College of Science, King Khalid University, Abha 61413, P.O.
Box 9004, Saudi Arabia.
6Department of Chemistry, College of Science, King Khalid University, Abha 61413, P.O.
Box 9004, Saudi Arabia
7Department of Chemistry, Quaid-i-Azam University, Islamabad-45320, Pakistan
*Corresponding authors E-mail addresses:
(Dr.Muhammad Khalid) khalid@iq.usp.br ; muhammad.khalid@kfueit.edu.pk
(Dr.Tashfeen Akhtar) tashfeenchem@must.edu.pk
Abstract:
Herein, two new thiazole derivatives: ethyl-2-(2-benzylidene-hydrazinyl)thiazole-4-
carboxylate (3) and ethyl-2-(2-(2-hydroxybenzylidene)hydrazinyl)thiazole-4-carboxylate (4)
were synthesized by cyclization of 1-benzylidene-thiosemicarbazide with ethyl bromopyruvate.
1
The synthesis was validated by spectroscopic techniques like FTIR, H-NMR, 13C-NMR and
chemical structure of title compounds 3 and 4 has been determined using SC-XRD. Ancillary to
experimental analysis, DFT calculations with B3LYP/6-311+G(d,p) level were performed for
comparative analysis of FT-IR spectroscopic data, optimized geometry, frontier molecular
orbitals (FMOs), natural bond orbital (NBO) analysis and nonlinear optical (NLO) properties.
Overall, experimental findings were supported by corresponding DFT computed results. TDDFT
calculations were executed at M06/6-311+G(d,p) level of theory to calculate the vertical

electronic transition states. NBO analysis disclosed that intramolecular charge transfer and
hyper- conjugative interactions among bonds provide stability to the investigated compounds 3
and 4. The global reactivity parameters calculated from energy of FMOs indicates that 3 and 4
enclose larger softness and fewer hardness values. NLO results of 3 and 4 were observed better
than standard molecule recommended the NLO activity of said compounds. We hope that this
joint experimental and computational insight may provide new ways for the utilization of title
molecules as NLO material for optoelectronic applications.
Keywords: Thiazole; Crystal structure; Spectroscopic data; DFT; NLO.
Introduction
The quest of medicinal and synthetic chemists to design novel, less toxic, more potent and cost
effective therapeutic agents including anticancer, antiviral and anti-inflammatory disorders is a
major challenge throughout the world. Heterocyclic bunches have been a major source for
designing new leads and hence meeting the drug discovery challenges. Thiazole scaffold has
topped the drug designing targets because of a variety of biological activities including
antibacterial [1], antifungal [2], antiviral [3, 4], antioxidant [5, 6], anti-inflammatory [7, 8], anti-
hypertensive [9], anti-schizophrenia [10], analgesic [11], anti-allergic [12] and anticancer [13]
associated with it. The thiazole motif is an important building block and is well established in
nature e.g. bleomycin is used for the treatment of cancer [14, 15]. The drugs like fanetizole,
meloxicam [16, 17], ritonavir [18-20], sulfathiazole [21] have thiazole nucleus as an active
pharmacophore. Hydrazinyl thiazole is an important derivative of thiazole which shows
significant biological properties including antibacterial [22], antioxidant [23, 24], antimalarial
[25], antifungal [26] and antitumor [27]. The present study is an attempt to synthesize simple
molecule from cheap, easily available starting materials to assist effective anticancer drug
discovery.
Apart from the importance of thiazole motifs in biological applications, it is also widely explored
by nonlinear optics (NLO) related theoretical and experimental scientists owing to their ultrafast
broadband-electronic responses and low dielectric constants that are useful in advanced
optoelectronic technologies [28-30]. Due to large importance of thiazole based heterocycles for
biological as well as NLO applications, it is the need of hour to synthesize and investigated these

compounds for better perspective of the society. Therefore, we utilized our expertise of both
experimental and theoretical chemistry [31-40] and outline the synthesis of two potent thiazole
based derivatives namely, ethyl 2-(2-benzylidenehydrazinyl)thiazole-4-carboxylate (3) and ethyl
2-(2-(2-hydroxybenzylidene)hydrazinyl)thiazole-4-carboxylate (4) by the cyclization of 1-
benzylidenethiosemicarbazide with ethyl bromopyruvate (as shown in scheme 1). To the best of
our knowledge, no study related to synthesis, single crystal X-ray diffraction (SC-XRD),
spectroscopic and computational investigation of compounds (3) and (4) are available in the
literature and these compounds are studied for the first time experimentally as well as
computationally. The proposed structures are validated by FTIR, 1H-,13C-NMR spectroscopy and
finally confirmed by using SC-XRD study. Currently, computational modeling studies are
widely employed to compare the structural and spectroscopic properties of the compounds with
their experimental and theoretical results. Therefore, density functional theory (DFT) studies
were executed to get insight about spectroscopic UV-Vis and FT-IR analysis. Geometry of 3 and
4 along with the electronic properties including frontier molecular orbitals (FMO), natural bond
orbitals (NBO) and NLO properties were explored. The primary theme of this study includes the
detailed spectroscopic and structural explanation of 3 and 4 utilizing theoretical and experimental
techniques.
Experimental
Instruments and materials
The reagents and solvent used in the synthesis are of high purity/analytical grade and used
without further purification. The completion of reaction was monitored by thin layer
chromatography (TLC), using Silica gel 60 HF254 pre-coated Aluminium sheets (Merck). The
melting point of title compounds were determined on Gallenkemp melting apparatus and are
uncorrected. FTIR spectra were recorded using IR Affinity-1 MIRacle 10, FT-IR
spectrophotometer, SHIMADZU (Japan), with ATR facility. Bruker Avance 300 MHz
spectrometer was used to record1H- and 13C-NMR spectra. Bruker Kappa APEX II CCD
Diffractometer was used to record X-ray diffractions.

Synthesis and chemistry
Synthesis of 1-benzylidenethiosemicarbazide (2)
The synthesis of intermediate (2) as shown in scheme 1 was carried out by the condensation
reaction of thiosemicarbazide with benzaldehyde and 2-hydroxybenzaldehyde, under reflux
using water and methanol [41]. Respective thiosemicarbazone (2) was subjected to cyclization
reaction with ethyl bromopyruvate in the presence of ethanol [42].
The synthesis of the compounds was indicated by the IR spectroscopy. The IR spectrum of the
compounds exhibited characteristic absorptions for C=O, C=C, C-N and C-S bonds, in their
typical regions and may be seen in the spectra clearly (supplementary material). The 1H- and 13C-
NMR spectra of the product were in accordance with their expected number of proton and
carbon signals. Aromatic protons were observed at 7.41-7.65 ppm with different mutliplicities
according to environment of the protons. Aliphatic protons of ester moiety appeared as triplet
and quartet at 1.28 and 4.24 ppm, respectively, for both compounds. In addition, thiazole ring
CH and CH=N- protons seen as singlets at 7.77, 8.0 ppm and 7.74, 8.29, for 3 and 4,
respectively. The 13C-NMR spectra showed the aromatic carbons between 126.42-134.61 ppm,
except hydroxyl bearing carbon (compound 4) observed at 156.40 ppm. The carbons of ethoxy
group were observed at14.64 and 60.85 ppm, respectively. Thiazole ring carbons were observed
around 119.42, 143.29 and 168.60 ppm. The carbonyl carbon of the ester was observed at 161.47
and 161.45 ppm for 3 and 4, respectively.
S
H2N
N
HN
NH2
S
N
NH2
H
O
H
Abs. Ethanol
N
O
O
N
N
Water, Methanol
S
R
R
R
3: R= -H
4: R = 2-OH
1
2
Scheme 1. Schematic representation for the synthesis of ethyl 2-[(2E)-2-substitutedbenzyl-
idenehydrazinyl]-1,3-thiazole-4-carboxylate.

Ethyl 2-(2-(2-substitutedbenzylidene)hydrazinyl)thiazole-4-carboxylate
Respective thiosemicarbazone (2) (2.79 mM) was dissolved in absolute ethanol (20mL), ethyl
bromopyruvate (1.0 equivalent) added slowly to this mixture and set to reflux. The progress of
reaction was monitored by TLC (n-hexane:acetone; 2:1). After completion, the reaction mixture
was poured into ice cold water and precipitated solid was filtered, washed with excess of water
and dried. The compounds were recrystallized from THF.
Ethyl 2-(2-benzylidenehydrazinyl)thiazole-4-carboxylate (3)
Yield: 87%; Melting point: 264–266°C; IR (ATR, cm-1):λmax2981 (C-H stretching, aliphatic),
1755 (C=O stretching), 1604 (C=N stretching), 1570 (C=C Ar ring stretching), 1440 (C-H
1
bending, aliphatic), 1366 (C-N), 1263 (C-S). H-NMR (300MHz, DMSO-d6): δ 1.28 (3H, t, -
CH3, J= 7.20 Hz), 4.24 (2H, q, -CH2CH3, J= 7.20 Hz), 7.41 (3H, m, Ar), 7.65 (2H, m,Ar), 7.77
(1H, s, thiazole C-5), 8.00 (1H, s, -CH=N), 12.26 (1H, s, N-NH-C).13C-NMR (75 MHz, DMSO-
d6): δ 14.64 (-CH3), 60.85 (-OCH2-), 119.42 (thiazole C-5), 126.42, 129.31, 129.93, 134.61 (Ar),
142.35 (-CH=N), 143.29 (thiazole C-4), 161.47 (C=O, ester), 168.60 (thiazole C-2).
Ethyl 2-(2-(2-hydroxybenzylidene)hydrazinyl)thiazole-4-carboxylate (4)
Yield:89%,Melting point: Above 300oC, IR (ATR, cm-1): 3001 (C-H stretching, aliphatic), 1722
(C=O stretching), 1625 (C=N stretching), 1581 (C=C Arring stretching), 1440 (C-H bending,
aliphatic), 1336 (C-N), 1207 (C-S), 1097 (C-O stretching, ester). 1H-NMR (300MHz, CDCl3): δ
1.28 (3H, t, - CH3, J= 7.20 Hz), 4.24 (2H, q, -CH2-CH3, J= 7.20 Hz), 6.87 (2H, m, Ar), 7.22 (1H,
m, Ar), 7.64 (1H, m, Ar), 7.74 (1H, s, thiazole C-5), 8.29 (1H, s, -CH=N), 10.07 (1H, s, -OH),
12.24 (1H, s, N-NH-C). 13C-NMR (75 MHz, CDCl3): δ 14.64 (-CH3), 60.86 (-OCH2-), 119.08
(thiazole C-5), 116.59, 119.96, 120.54, 126.46, 131.19, 156.40 (Ar), 140.12 (-CH=N), 143.24
(thiazole C-4), 161.45 (C=O, ester), 168.38 (thiazole C-2).
Computational procedure
All DFT [43-45] based quantum chemical calculations for 3 and 4 were performed using
Gaussian 09 program package [46]. The starting geometries of 3 and 4 were obtained from SC-
XRD crystal structures. The optimization of the ground state structure of 3 and 4 was performed
in gas phase without symmetry restrictions at B3LYP level of DFT in conjunction with 6-
311+G(d,p) basis set. Frequency analysis of optimized geometries were performed at B3LYP/6-

311+G(d,p) level of theory to check their stability. There were no imaginary frequencies found
as result of FT-IR analysis which represents the success and completion of geometry
optimization. NBO 3.1 program package embedded in Gaussian 09 was used to perform NBO
analysis using same B3LYP/6-311+G(d,p) functional. FMO analysis and NLO properties of 3
and 4 are performed in gas phase at B3LYP level and 6-311+G(d,p) basis set combination.
However, the UV-vis spectra were computed by using time-dependent density functional theory
(TDDFT) M06/6-311+G(d,p) level of theory. All input files were made using GaussView 5.0
[47], while output results were interpreted and visualized using GaussView 05 [47], Avogadro
[48] and Chemcraft [49] programs.
Results and discussion
Structral Insight by XRD stduy
Results and discussion
Structure determination and refinement by SC-XRD
X-ray diffraction experiment was carried out at room temperature by a Bruker Kappa APEXII
CCD single crystal diffractometer, equipped with a charge-coupled device (CCD detector), using
monochromatized MoKα radiation (λ=0.71073 Å). The automatic data collection was performed
by APEX2 [50], the cell determination by SAINT V7.68A [50], and the data reduction by SAINT
V7.68A. Absorption effects were corrected by SADABS-2008/1, via a multi-scan method. The
structure was solved by SHELXS [51] and refined by a full matrix least-squares technique on F2
using SHELX2014/6 [52], with anisotropic thermal parameters for the non-H atoms. The H-
atoms were positioned geometrically at C-H = 0.93-0.97 Å, N-H = 0.86 Å and O-H = 0.82 Å,
respectively and included in the refinement as riding with Uiso(H) = xUeq(C, N, O), where x =
1.5 for methyl and hydroxyl H-atoms and x = 1.2 for all other H-atoms. The software used to
prepare material for publication is WinGX [53] and PLATON [54]. The molecular structure
graphics of the compounds were done using ORTEP-3 for Windows [53] and PLATON [54].
The crystal data, data collection parameters and refinement results of 3 and 4 are summarized in
Table 1.

Table 1: X-ray crystallographic data of 3 and 4
Crystal parameters
Compound (3)
Compound (4)
CCDC
1814894
1886923
Chemical formula
Mr
C13H13N3O2S
275.32
C13H13N3O3S
291.32
Crystal system, space group
Temperature (K)
a, b, c (Å)
Orthorhombic, P212121
296
5.0751 (5), 10.7359 (12), 24.500 15.637 (2), 4.8486 (7), 17.924 (2)
Monoclinic, P21/n
296
(4)
93.005 (5)
1357.1 (3)
4
β (°)
V (Å3)
1334.9 (3)
4
Z
Radiation type
µ (mm−1)
Mo K
0.24
α
Mo Kα
0.25
Crystal size (mm)
Data collection
Diffractometer
Absorption correction
0.34 × 0.28 × 0.18
0.32 × 0.20 × 0.16
Bruker Kappa APEXII CCD
Multi-scan
Bruker Kappa APEXII CCD
Multi-scan
(SADABS; Bruker, 2005)
0.915, 0.948
(SADABS; Bruker, 2005)
0.907, 0.970
Tmin, Tmax
No. of measured, independent and 5218, 2795, 1613
9587, 2512, 1283
observed [I> 2σ'(I)] reflections
Rint
0.050
0.658
0.079
0.606
(sin
Refinement
R[F2> 2 (F2)], wR(F2), S
θ
/λ)max (Å-1)
0.056, 0.123, 0.95
0.066, 0.176, 0.98
σ
'
No. of reflections
No. of parameters
H-atom treatment
2795
173
2512
183
H-atom parameters constrained
0.25, -0.19
H-atom parameters constrained
0.30, −0.33
∆
ρmax, ∆ρmin (e Å-3)
Absolute structure
Flack x determined using 411
quotients [(I+)-(I-)]/[(I+)+(I-)]
(Parsons, Flack and Wagner, Acta
Cryst. B69 (2013) 249-259).
-0.04 (12)
Absolute structure parameter
Table 2: Hydrogen-bond geometry (Å, º) for compound (3)
D—H···A
D—H
0.86
0.93
H···A
2.21
2.53
D···A
3.068 (5)
3.387 (7)
D—H···A
177
153
N2—H2A···N3i
C5—H5···O1ii
Symmetry codes: (i) x+1/2, −y+1/2, −z; (ii) x+3/2, −y+1/2, −z.

Table 3: Hydrogen-bond geometry (Å, º) of compound (4)
D—H···A
D—H
0.93
0.86
0.86
0.82
0.82
H···A
2.50
2.21
2.65
2.00
2.95
D···A
D—H···A
138
C9—H9···O1i
N2—H2A···N3ii
N2—H2A···O2ii
O1—H1···N1
O1—H1···S1
3.248 (5)
3.072 (4)
3.084 (5)
2.637 (4)
3.626 (3)
178
112
134
141
Symmetry codes: (i) −x+1, −y+2, −z; (ii) −x+3/2, y−1/2, −z+1/2
Compound (3)
Suitable crystals of the title compound 3 shown in Figure 1a, ethyl 2-[(2E)-2-
benzylidenehydrazinyl]-1,3-thiazole-4-carboxylate, were obtained from tetrahydrofuran, by slow
evaporation at room temperature. The crystal refinement and experimental details are presented
in the Table 1. In the title compound the benzylidenehydrazine moiety A (C1-C7/N1/N2), the
thiazole ring B (C8/N3/C10/C9/S1) and the ethyl-carboxylate group C (C11-C13/O1/O2) are
planar with r. m. s. deviations of 0.0312, 0.0019 and 0.0369 Å, respectively. The dihedral angle
between A/B, A/C and B/C is 8.5 (2)°, 7.4 (3)° and 5.2 (4)°, respectively. There is no
intramolecular H-interaction, but strong intermolecular H-bonding of C-H…O and N-H…N
types (Figure 1b, Table 2). Due to these interactions, each molecule is connected to three
different molecules (Figure 1b) and form infinite one-dimensional chains along the
crystallographic a-axis. There exist π-π interactions at a distance of 3.389(2) Å with parallel
offset of 3.778 Å between Cg1…Cg1i [i = 1 + x, y, z] and at a distance of 3.202(2) parallel offset
of 3.937 Å between Cg2…Cg2i [i = 1 + x, y, z] occurs. These rings also have π-π interactions at
a distance of 3.514(2) Å [Cg2…Cg1ii = 1 + x, y, z] without any slippage. Here Cg1 and Cg2 are
the centroids of thiazole ring (C8/N3/C9/C10/S1) and the benzene ring (C1-C6), respectively.
These H-interactions and π-π interactions play vital role in stabilizing the molecules (Figure 2a,
2b)
(a) The ORTEP diagram

(b) Molecular packing diagram.
Figure 1. Compound 3: (a) ORTEP diagram with thermal ellipsoids drawn at 50 % probability level. The
H-atoms are drawn as small circles of arbitrary radii. (b) The molecules are dimmerized and dimmers are
connected to adjacent molecules.
a)

b)
Figure 2: Compound 3: The partial packing showing the parallel off set stacking between neighboring
molecules and H-interaction a) and b).
Compound (4)
In the compound 4 (Figure 3a) ethyl 2-[(2E)-2-(2-hydroxybenzylidene)hydrazinyl]-1,3-
thiazole-4-carboxylate, the 2-hydroxybenzylidenehydrazine moiety A (C1-C7/N1/N2/O1), the
thiazole ring B (C8/N3/C10/C9/S1) and the ethyl-carboxylate group C (C11-C13/O2/O3) are
planar with r. m. s. deviations of 0.0069, 0.0012 and 0.0426 Å, respectively. The dihedral
angle between A/B, A/C and B/C is 2.5 (2)°, 1.6 (2)° and 2.9 (2)°, respectively. There is an
intramolecular H-interaction of O-H…N type to complete S(6) loop. The molecules are
dimmerized due to C-H…O bonding, where CH is of thiazole ring and O is of hydroxyl group.
Strong intermolecular H-bonding of C-H…O and N-H…N types are also present from
adjacent molecules on both sides of the dimmer (Figure 3b, 3c, Table 3). The molecules are
stabilized in the form of infinite one-dimensional chains along the base vector [0 1 0]. There
exist π-π interactions at a distance of 3.3710(16) Å with parallel offset of 3.485Å between
Cg1…Cg1i[i = x, 1 + y, z] and at a distance of 3.5135(19)Å with parallel offset of 3.341Å
between Cg2…Cg2i[i = x, 1 + y, z] occurs. These rings also have π-π interactions at a distance

of 3.5328(19)Å [Cg1…Cg2i] as parallel face-centred. Here Cg1 and Cg2 are the centroids of
thiazole ring (C8/N3/C9/C10/S1) and the benzene ring (C1-C6), respectively. These H-
interactions and π-π interactions play vital role in stabilizing the molecules. There is no parallel
offset or phase to phase π-π interactions, it is observed as parallel off centered π-π interactions
in compounds 3 and 4 as discussed by Martinez et.al (Figures 2a, 2b, 3d) [55]. Analysis of
short ring-interactions with Cg-Cg distances for both compounds 3 and 4 are provided in
supplementary material.
(a) The ORTEP diagram
(b) Molecular packing diagram.

(c) b projection
d) pi-pi interaction
Figure 3: Compound 4: (a) ORTEP diagram with thermal ellipsoids drawn at 50 % probability level. The
H-atoms are drawn as small circles of arbitrary radii. (b) The molecules are dimmerized and dimmers are
connected to adjacent molecules (c) b projection (d) pi-pi interaction.

Computational studies
Geometric structures
The optimized geometric parameters (bond lengths and bond angles) of 3 and 4 have been
determined by using B3LYP/6-311+g(d,p) functional. The comparative study is done between
DFT calculated parameters and experimentally determined parameters obtained through XRD.
Atom numbering scheme of 3 and 4 as shown in supplementary information, Figures S2 and S3
was used to calculate the DFT and XRD structural parameters and results are collected in Tables
S1 and S2 (Supplementary Information) respectively. Overall, maximum deviation in bond
angles is observed in the ambient of 0.055 ± 0.012Å and 0.059 ± 0.011Å in 3 and 4, respectively.
In case of bond angles, 5.1° ± 2.5° and 4.5° ± 2.4° are the divergence ranges noticed in 3 and 4,
respectively. In 3,the maximum deviation in bond length 0.055Å and bond angle 5.1° is noticed
for C(18)-C(19) and N(4)-N(5)-C(14) respectively. Similarly in 4, C(12)-C(13) and C(8)-N(15)-
N(14) are the bond length and bond angles that displayed maximum divergence of 0.059Å and
4.5° respectively. The comparative analysis reveals that the experimentally determined bond
lengths and bond angles are slightly greater than the calculated parameters as can be seen in
Tables S1 and S2. The aforesaid difference between DFT and experimental findings is because
of the medium effect. Except of these few divergences, all computed and experimental measured
structural parameters are found in very good agreement as indicated in Tables S1-S2,
respectively.
Uv-Visible study
Ultraviolet-Visible (UV–Vis) spectroscopy is recognized as an important tool to describe the
probability of charge transfer, contributing configurations to the transition and electronic
transition nature within the investigated molecules. In order to explain the vertical electronic
transitions, UV–Visible spectrum of 3 and 4 was calculated in solvent phase, while TDDFT was
executed at the level of M06/6-311+G(d,p) in gas phase for both crystals (monomers). The
vertical excitation energies (EDFT), absorption peak λmax, dominant molecular orbital
contributions and oscillator strength (f) of 3 and 4 reported in Table 4.

Table 4: Wavelength, excitation energy and oscillator strength for 3 and 4 calculated at M06/6-
311+G(d,p) level of theory.
ꢄꢅꢆꢇ
(eV)
f’
Expt.
Cal.
ꢁꢂꢃ(nm)
MO contributions
Comps.
ꢀ
ꢁꢂꢃ(nm)
ꢀ
336a,, 336b, 336c
338.84
285.95
282.67
274.28
264.39
261.08
342.07
299.63
288.10
283.69
262.63
257.16
3.6589 0.6007
4.3356 0.0001
4.3858 0.0799
4.5200 0.0147
4.6892 0.0002
H
H
H
H
H
H
H
→
→
→
→
→
→
→
L (99%)
L+2 (82%)
L+1 (94%)
L+5 (50%), H-2
L+4 (71%), H
L+2 (14%), H
L (97%)
3
→
L (39%)
→
→
L+3 (19%)
L+3 (60%), H→L+4 (18%)
4.7486
0
339b , 333c
325a,
3.6244 0.5624
4.1376 0.0801 H-1
→L (88%)
4.3032
0
H
H
H
→
→
→
L+2 (93%)
L+1(95%)
L+3 (79%)
4
4.3701 0.0793
4.7205 0.0007
4.8209 0.041
H-2
→L (30%), H→L+5 (54%)
EDFT = Excitation energy (eV); ꢈ=wavelength (nm); f = oscillator strength; MO = molecular orbitals; H = HOMO;
L = LUMO; Expt. = Experimental; Cal. = DFT Calculated; comps.= Compounds; a= acetone, b=DMF, c= THF
The electronic transition range can be defined by f which is not a vector quantity
(dimensionless). The very low or zero magnitude of f shows that transition is forbidden. Vertical
transitions with an absorption maximum at 261.08 nm in 3 and 288.10 nm in 4 are forbidden
with zero f value. Due to minute structural difference between 3 and 4, calculated absorption
maxima (λmax) values are found very close to each other at 338.84 nm and 342.07 nm in 3 and 4
respectively. Only first vertical transition in 3 and 4 respectively are noticed showing greater
intensity of absorption than others. The main vertical transition in 3 with highest f value (0.6007)
and least EDFT value is originated from HOMO→LUMO (99 %). Similarly in 4, transition
occurred from HOMO→LUMO (97%) is the main transition among all vertical transitions that
occurred with least EDFT (3.6244) and highest f value (0.5624). Overall, experimental measured
absorption maximum value 336 nm (acetone, DMF and THF) showed good agreement with DFT
computed absorption maximum value found at 338.84 nm respectively. Similarly in 4, calculated
wavelengths 342.07 nm matched nicely with the experimental values 333 nm (THF) and 339 nm
(DMF) respectively. Since experimental calculations of 3 and 4 were performed in acetone,
DMF and THF solvents while calculated values are obtained from gas phase calculations,
therefore, minute difference between experimental and calculated value is due to the solvent
effect. Furthermore, the wavelength values in DMF are obtained greater than THF and acetone
due to high polarity effect which leads to the red shift in UV-Vis absorption band. MO
contribution indicates that maximum intramolecular charge in 3 and 4 are transferred from

HOMO to LUMO electronic transition which is the characteristic of soft molecules, hence, may
have potential of utilization in biological and NLO applications.
Natural bond orbitals (NBO) analysis
NBO analysis is helpful for the detection of hydrogen bonding, originates from hyper-
conjugative interactions in the investigated molecules [56, 57]. It is widely deployed recently to
examine the bonds interaction and migration of charge densities from Lewis-type NBOs (filled
or donor) to non-Lewis NBOs (vacant or acceptor) orbitals. NBO analysis utilizes the chemical
bonding concepts to explain the transformation of canonical delocalized molecular orbital’s into
localized molecular orbitals. This process includes chronological transformation of non-
orthogonal atomic orbitals to the sets of NBOs, natural hybrid orbitals (NHOs) and natural
atomic orbitals (NAOs).NBO analysis of 3 and 4 was performed at B3LYP/6–311+G(d,p) level
of theory and results are presented in Tables S3 and S4, respectively. To explore the interactions,
second-order Fock matrix was carried out using following equation [58].
(F )2
i, j
E(2) = q
(1)
i ε j
−εi
In above equation, E(2) represents the stabilization energy, qi describe the donor-orbital
occupancy, Fi,j point out the off diagonal NBO Fock matrix elements and ꢀi and ꢀj represents the
diagonal elements.
Results indicate that most credible transitions noticed in 3 and 4 are π(C12–C14)→π*(C16–C18)
and π(C8–C10)→π*(C11–N25) which offer highest stabilization energy value of 20.52 and
26.36 kJ/mol to the structures of 3 and 4 respectively. A bit larger value for stabilization energy
of 4 as compared to 3 is because of the presence of one activating OH group in the architecture
of 4 which facilitates the intramolecular charge transfer and hyper conjugative interactions. Due
to feeble interactions between σ (donor) and σ* (acceptor), smallest stabilization energy values
5.03 kJ/mol and 5.24 kJ/mol are observed in 3 and 4 as a result of σ(N5-H6)→σ*(S1-C21) and
σ(C14-S33)→σ*(C16-C17) transitions, respectively. The existence of conjugation in 3 is
confirmed from π→π* interactions π(N7–C21)→π*(C22–C24), π(C8–C10)→π*(C12–C14),
π(C8–C10)→π*(C16–C18), π(C12–C14)→π*(C8–C10), π(C16–C18)→π*(N4–C19), π(C16–
C18)→π*(C8–C10) and π(C16–C18)→π*(C12–C14)with substantial stabilization energy values
19.25, 20.36, 19.74, 18.89, 20.35, 18.53 and 19.81 kJ/mol, respectively (Table S3). In 4,

transitions such as π(C1–C2)→π*(C4–C6), π(C1–C2)→π*(C8–C10), π(C4–C6)→π*(C1–
C2),π(C4–C6)→π*(C8–C10), π(C8–C10)→π*(C1–C2), π(C8–C10)→π*(C4–C6) and π(C13–
N28)→π*(C14–C16) confirmed the existence of conjugation by providing the stabilization
energy value of 24.79, 17.26, 18.03, 24.93, 22.11, 17.21 and 19.37 kJ/mol to these bonds (Table
S4). Furthermore, in case of resonance, LP(O3)→π*(O2-C25) and LP(N26)→π*(C13-N28)
interactions are the most credible transitions observed in 3 and 4 which provide strongest
stabilization energy values 44.06 and 46.33 kJ/mol to 3 and 4, respectively. This larger energy
provides stabilization to the molecular structure and strengthens the intramolecular O2-C25…O3
and C13-N28…N26 bonds. The lone pairs of O3 and N26 donate their electrons to the π-type
anti-bonding orbital of O2-C25 and C13-N28 present in 3 and 4, respectively. Some transitions
such as LP(N7)→π*(C22-C24) and LP(N28)→π*(C14-C16) lead to substantial stabilization
energy value 5.63 kJ/mol in both 3 and 4 respectively. In a nutshell, it can be concluded that
extended conjugation is present in both compounds. Successful intramolecular charge transfer
and hyperconjugative interactions among bonds provide stability to the investigated compounds
3 and 4.
Frontier molecular orbital (FMO) analysis
Different characteristics including molecular interactions, reactivity, charge transfer, optical
properties and electronic features of molecules under investigation are studied using FMOs
namely highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital
(LUMO) [59-61]. HOMO is the electron rich molecular orbital with higher energy and electron
donating capability. Contrary, LUMO is the electron deficient molecular orbital with lower
energy and having electron accepting capability. To describe the photophysical perspective,
energy of HOMO (EHOMO), LUMO (ELUMO) and their gap (∆E = ELUMO-EHOMO), FMO analysis
was executed using B3LYP/6-311+G(d,p) functional and results are collected in Table 5. The
EHOMO, ELUMO, their two low level orbitals (LUMO+1, LUMO+2) and two above level orbitals
(HOMO-1, HOMO-2) of 3 and 4 are found to be negative which indicates that 3 and 4 are stable
[62]. Due to almost same architectures of 3 and 4, ∆E values of both compounds are comparable.
However, presence of one activating OH group in 4 slightly reduced the energy gap as compared
to 3. Therefore, bit smaller energy gap is found to be in 4 with ∆E value of 0.14363 a.u.

Table 5: Computed energies (E) for 3 and 4.
3
4
MO(s)
HOMO
LUMO
HOMO-1
LUMO+1
HOMO-2
LUMO+2
E
∆
E
E
∆E
-0.21628
-0.0724
-0.26549
-0.04539
-0.27137
-0.02712
-0.21922
-0.07559
-0.24558
-0.04957
-0.27206
-0.02062
0.14388
0.22010
0.24425
0.14363
0.19601
0.25144
E= energy, ∆E = ELUMO-EHOMO, units in Hartree (a.u); HOMO, highest occupied molecular orbital; LUMO, lowest
unoccupied molecular orbital, MO, molecular orbital
The FMOs of 3 and 4 are represented pictographically in Figure 4. Blue color indicates the
negative phase while red color represents positive phase of molecular orbitals respectively.
Compound 3
Compound 4
Figure 4. Frontier molecular orbitals of 3 and 4, units in Hartree (a.u.)
Global reactivity parameters [63-66] are helpful to interpret the stability, chemical reactivity and
internal charge transfer of investigated compounds. Therefore, EHOMO, ELUMO and ∆E values are

utilized further to calculate the chemical potential (
ELUMO), ionization potential (IP=-EHOMO), global softness (
(EHOMO-ELUMO)/2), electrophilicity index
=ꢀ2/2η) and electro negativity (X=-
(EHOMO+ELUMO)/2) values of 3 and 4 and results are collected in Table 6.
ꢀ=EHOMO+ELUMO/2), electron affinity (EA=-
ꢉ
=1/2η), global hardness (η =-
(
ꢊ
Table 6: Ionization potential (I), electron affinity (A), electronegativity (
χ), global hardness (η),
chemical potential (
ꢀ), global electrophilicity (
ω
)and global softness (σ)
I
A
χ
η
ꢀ
ω
σ
3
4
0.21628
0.21922
0.07240
0.07559
0.14434
0.14740
0.07194
0.07181
-0.14434
-0.14741
0.14480
0.15127
6.95023
6.96233
The ∆E value has direct relation with the chemical hardness, strength or kinetic stability and
inverse relation with chemical softness and reactivity of the molecules under investigation. Thus,
molecules displaying small ∆E value are taken as soft molecule with less kinetic stability, high
reactivity and easy tunable character. On the other hand, molecules with large ∆E value are
considered as hard molecules with greater kinetic stability, less reactivity and resistance to
change in electronic configurations. In 3 and 4, global softness (σ) values 6.95023 and 6.96233
Eh are found 96.61 and 96.95 times greater than their global hardness (η) values 0.07194 and
0.07181 Eh, respectively. Overall, compound (3) holds larger hardness and smaller softness value
than compound (4). This implies that 4 is soft, more reactive and kinetically unstable as
compared to 3. The ionization potential (I), electron affinity (A), electronegativity (χ) and global
electrophilicity (ω) values of 4 are also found greater than 3. The larger softness value of 4 over
3 is due to small ∆E value of 4 (0.14363) than 3 (0.14388). The preceding results validate that
investigated molecules 3 and 4 enclose larger softness and lower hardness values, hence, may
have potential for utilization in NLO and biological related applications.
FT-IR analysis
Experimental and theoretical scientists utilized FT-IR analysis to explore the molecular
vibrations present in the investigated compounds. In our studied molecules 3 and 4, nature of
vibrational modes present was studied by performing experimental and theoretical infrared
calculations. B3LYP level of theory in conjunction with 6-311+G(d,p) basis set was used to
study the theoretical vibrational spectra and results are displayed in supplementary information,
Figure S1. All vibrational frequencies in 3 and 4 were found positive as indicated in Figure S1.

Lack of imaginary frequencies indicates that both molecules are at local energy minima at
potential energy surfaces.
Nonlinear optical (NLO) properties
Development of materials with promising NLO properties are receiving striking considerations
in electro-optic claims owing to their ultrafast responses and small dielectric constants.
Furthermore, utilization of NLO response properties in biological applications is also an area of
hot research [67, 68]. Non-centrosymmetric architecture and nature of the compounds possess
NLO character due to intramolecular charge transfer (ICT) and delocalization of electrons. Non-
centrosymmetric architecture can be attained by suitable substitution of electron donor and
acceptor units on basis backbone of the molecules which leads to the designing of efficient NLO
materials [69-74]. To explore the NLO potential of investigated compounds 3 and 4 in biological
applications, NLO response properties of compounds 3 and 4 are measured at B3LYP/
6311+G(d,p) level of DFT. Average polarizability (α), first hyperpolarizability (βtot) and second
〈 〉
ꢋ values of 3 and 4 are calculated using following equations.
hyperpolarizability
(2)
(3)
<
α
>=1/ 3
(
α xx
+
α yy
+α zz )
βtot =[(βxxx
+
βxyy
+
βxzz )2 +(βyyy
+
βxxy
+
βyzz )2 +(βzzz βyyz )2]1/2
+βxxz +
1
(4)
< γ >= (γꢌꢌꢌꢌ + γꢍꢍꢍꢍ + γꢎꢎꢎꢎ + 2ꢏγꢌꢌꢍꢍ + γꢍꢍꢎꢎ + γꢌꢌꢎꢎꢐ)
5
The calculated results for dipole moment, linear polarizabilities (α), first hyperpolarizability (βtot)
and second hyperpolarizability (γ) of 3 and 4 are collected in Tables 7-9 respectively.
Table 7: The dipole moment (µ) and computed dipole polarizabilities for 3 and 4
µx
-2.1636
1.1389
µy
1.6876
-0.3937
µz
-0.0006
0.0101
µ
αxx
396.81
406.35
αyy
199.60
204.30
αzz
112.17
113.60
αtotal (a.u)
236.20
241.42
2.7439
1.2051
3
4
Table 8: The computed first hyperpolarizability/second order NLO (a.u.) for 3 and 4
βxxx
βxxy
βxyy
βyyy
βxxz
βyyz
βxzz
βyzz
βzzz
βtot (a.u)
1878.55
1428.03
3
4
95.0862 121.271 40.4586 0.36645 -0.08352 -0.06867 -73.5337 67.9151
-1915.24
-1453.03 137.270 114.702 -7.28998 -5.32773 0.19271 -0.06566 -86.6512 -36.8273

Table 9: The second hyperpolarizability values for 3 and 4
γxxxx γyyyy γzzzz γxxyy
-932.510 -151.516 -2430.57
-1053.49 -155.107 -2576.54
γzzxx
-2450.74
-2508.92
γyyzz
〈 〉
ꢑ (a.u.)
-195.895 -14720.8
-213.785 -11332.4
-11605.9
-11947.7
3
4
Dipole moment indicates the charge distribution along x, y and z directions. Dipole moment
value of 3 (2.7439 D) is found to be 2.28 times greater than the dipole moment value of 4
(1.2051 D). Furthermore, dipole moment of 3 and 4 are also compared with the urea molecule
which is frequently studied as standard for comparison of first hyperpolarizability and dipole
moment value. Dipole moment of 3 is found greater while 4 is observed bit smaller than dipole
moment of urea molecule (1.3732 D) [75].
Linear polarizability (
and z direction tensors (αyy
a.u) is computed to be greater than the value of 3 (236.20 a.u). In case of first hyperpolarizability
βtot), the dominant contribution to βtot is made by x-axis direction transition with negative values
α
) results indicates that x-axis polarizability tensor (αxx
) is dominant than y
,
αzz and caused effectively in αtotal values. The αtotal value of 4 (241.42
)
(
in 3 (-1915.24 a.u) and 4 (-1453.03 a.u).Large contribution of x-axis transition in 3 as compared
to 4 leads to greater βtot value 1878.55 (a.u) in 3 than 4 found to be 1428.03 a.u. NLO findings
were further compared with standard urea molecule which indicated that βtot values of 3 and 4
are marked 43.68 and 33.21 times larger than βtot value of urea = 43 a.u [75]. Similar to linear
and first hyperpolarizability, dominant transition which contribute significantly in case of second
hyperpolarizability value is x-direction transitions, which is noticed to be greater than their
respective y and z-axis tensors. Second hyperpolarizability (γ) value of 3 and 4 are found to be -
14720.8 and -11332.4 a.u, respectively. Conclusively from preceding discussion and urea
molecule comparative analysis, both compounds have vital NLO character and can be used as
excellent NLO candidates in biology and technological related applications.
Conclusion
The present study reported the successful synthesis of novel thiazole-based crystals namely:
ethyl 2-(2-benzylidenehydrazinyl)thiazole-4-carboxylate (3) and ethyl 2-(2-(2-hydroxy-
benzylidene)hydrazinyl)thiazole-4-carboxylate (4). Both compounds were characterized through
1
FTIR, H-NMR and 13C-NMR spectra and single crystal X-ray diffraction studies. X-rays
analysis revealed that 3 is crystallized in the orthorhombic space group P212121, with cell
parameters a=5.0751 (5), b=10.7359 (12), c=24.500 (4) Å, while 4 is crystallized in monoclinic

space group P21/n, with cell parameters a = 15.637 (2), b=4.8486 (7), c=17.924 (2), β=93.005
(5). DFT based UV-Vis absorption was in excellent agreement with the experimental
spectroscopic data. NBO study showed that both compounds are involved in the intra molecular
charge transfer, hence greater molecular stability on account of hyper conjugation. FMO analysis
proved that global softness (σ) values 6.95023 and 6.96233 Eh of 3 and 4 are 96.61 and 96.95
times greater than their global hardness (η) values 0.07194 and 0.07181 Eh respectively.
Compound 4 is found to be soft, more reactive and kinetically instable as compared to compound
3. The ionization potential (I), electron affinity (A), electronegativity (χ) and global
electrophilicity (ω) values of 4 are also found greater than 3. NLO properties were observed
larger as compared to the urea molecule indicating the considerable NLO character. Larger
softness, lower hardness and urea molecule comparative results validate that 3 and 4 may have
significant contribution for technological and biological applications.
Conflict of interest
No conflicts declared.
Supplementary data
Crystallographic data for the structure reported in this paper have been deposited with the
Cambridge Crystallographic Center under CCDC No. 1814894 (3) and 1886923 (4). Copies of
the data can be obtained free of charge on application to CCDS, 12 Union Road, Cambridge CB2
1EZ, UK; E-mail: deposit@ccdc.cam.ac.uk].
Acknowledgments
Authors are thankful to Departamento de Química Fundamental, Instituto de Quimica,
Universidade de São Paulo, Av. Prof. LineuPrestes, 748, São Paulo, 05508-000, Brazil for
providing theoretical lab facilities for DFT study. Muhammad Khalid (grant#1314/2017) is
thankful to HEC Islamabad Pakistan for financial support. Moreover, the authors extend their
appreciation to Deanship of Scientific Research at King Khalid University for funding this work
through Research Groups Project under grant number (R.G.P2/17/40)

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Highlights
•
Two novel ethyl 2-(2-(2-substitutedbenzylidene)hydrazinyl)thiazole-4-carboxylate
crystals were synthesized.
•
•
•
•
XRD, 1H-NMR, 13C-NMR, FT-IR and UV-Vis were performed for the characterization.
Computational study was done at B3LYP/6-311+G(d,p) level for comparative analysis.
Comparative study reveals a good agreement between experimental and DFT results.
FMOs, NBO analysis and nonlinear optical (NLO) properties were calculated.

Dear Editor,
Journal of Molecular Structure
All the co-authors are aware of and approve of the submission.
Conflict of interest
No conflicts declared.
Warm Regards
Most sincerely,
Dr. Muhammad Khalid (Corresponding Author)
Assistant Professor,
Department of Chemistry, Khwaja Fareed University of Engineering & Information
Technology, Rahim Yar Khan-64200, Pakistan
Email: khalid@iq.usp.br ; muhammad.khalid@kfueit.edu.pk