Novel 2-amino-1,3,4-thiadiazoles and their acyl derivatives: Synthesis, structural characterization, molecular docking studies and comparison of experimental and computational results

Article abstract of DOI:10.1016/j.molstruc.2016.01.045

This study aims to synthesize and characterize compounds containing 2-amino-1,3,4-thiadiazole and compare experimental results to theoretical results. For this purpose, firstly mono, di and tetra 2-amino-1,3,4-thiadiazole compounds (2a-c, 14, 20 and 25) w

Full text of DOI:10.1016/j.molstruc.2016.01.045

Journal of Molecular Structure 1110 (2016) 102e113
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Novel 2-amino-1,3,4-thiadiazoles and their acyl derivatives: Synthesis,
structural characterization, molecular docking studies and comparison
of experimental and computational results
,
Mustafa Er a *, Gamze Isildak b, Hakan Tahtaci c, Tuncay Karakurt d
a Department of Chemical Engineering, Faculty of Engineering, Karabuk University, 78050 Karabuk, Turkey
b Department of Chemistry, Faculty of Science, Karabuk University, 78050 Karabuk, Turkey
c Department of Polymer Engineering, Faculty of Technology, Karabuk University, 78050 Karabuk, Turkey
d Department of Chemical Engineering, Faculty of Engineering and Architecture, Ahi Evran University, 40100, Kırs¸ehir, Turkey
a r t i c l e i n f o
a b s t r a c t
Article history:
This study aims to synthesize and characterize compounds containing 2-amino-1,3,4-thiadiazole and
compare experimental results to theoretical results. For this purpose, firstly mono, di and tetra 2-amino-
1,3,4-thiadiazole compounds (2aec, 14, 20 and 25) were synthesized in relatively high yields (74e87%).
The target compounds (3e11, 15e17, 21e23 and 26e28) were then synthesized in moderate to high
yields (65e85%) from the reactions of 2-amino-1,3,4-thiadiazole compounds with various acyl chloride
derivatives.
Received 1 September 2015
Received in revised form
17 January 2016
Accepted 18 January 2016
Available online 20 January 2016
The structures of all synthesized compounds were elucidated by IR, 1H NMR, 13C NMR, elemental
analyses and mass spectroscopy techniques. The structures of 2b (C9H8N4O2S) and 2c (C11H13N3O2S)
were also elucidated by X-ray diffraction analysis.
Keywords:
2-amino-1,3,4-thiadiazole
Crystal structure
NMR
Lastly, IR spectrum, 1H NMR and 13C NMR chemical shift values, frontier molecular orbital (FMO)
values of these molecules containing heteroatoms were examined using the Becke-3- Lee-Yang-Parr
(B3LYP) method with the 6-31G(d) basis set. Two different molecular structures containing 2-amino-
1,3,4-thiadiazole (2b, 2c) were used in our study to examine these properties. Also, compounds 2b and 2c
form a stable complex with beta-Lactamase as can be understood from the binding affinity values and
the results show that the compound might inhibit the beta-Lactamase enzyme. It was found that
theoretical and experimental results obtained in the experiment were compatible with each other and
with the values found in the literature.
B3LYP
© 2016 Elsevier B.V. All rights reserved.
1. Introduction
and its derivatives have become the focus of attention in drug,
agriculture and material chemistry due to their high activity in 20
In recent years, despite significant increases in their discovery,
the uses of compounds with biological activities were quite limited
due to the development of resistance against these compounds and
the presence of various side effects. For these reasons, chemists
have been striving to develop compounds with biological activities
for use in pharmaceutical chemistry.
and 50 positions against nucleophilic substitution reactions [1e8].
The eN]CeS group in the structure allows for great structural
stability and is known to be the component responsible for bio-
logical activity [9,10]. 1,3,4-thiadiazole and its heterocyclic de-
rivatives have been synthesized on a large scale for many years due
to a variety of biological activities, including antifungal, antibacte-
rial, antimicrobial, anti-inflammatory, anticonvulsant, anti-HIV,
antituberculosis, and antiproliferative activities [11e27]. The syn-
thesis of these compounds is particularly important due to the high
anticancer activities of 2-amino-1,3,4-thiadiazole and derivatives,
[28e31]. In addition, it has been reported in various studies con-
ducted with 1,3,4-thiadiazole and its derivatives that these com-
pounds were used in various areas such as polymer, dye, herbicide
Thiadiazole is a five-membered heterocyclic aromatic com-
pound with the molecular formula of C2H2N2S. 1,3,4-Thiadiazole
* Corresponding author. Tel.: þ90 370 4332021; fax: þ90 370 4333290.
E-mail addresses: mustafaer@karabuk.edu.tr (M. Er), isildak.g@hotmail.com
(G. Isildak), hakantahtaci@karabuk.edu.tr (H. Tahtaci), tuncaykarakurt@gmail.com
(T. Karakurt).
http://dx.doi.org/10.1016/j.molstruc.2016.01.045
0022-2860/© 2016 Elsevier B.V. All rights reserved.

M. Er et al. / Journal of Molecular Structure 1110 (2016) 102e113
103
and insecticide production [32e35].
using standard Schlenk techniques. The 1H NMR and 13C NMR
spectra of the compounds were recorded in DMSO-d6 using an
Agilent NMR VNMRS spectrometer at 400 MHz and 100 MHz,
respectively. TMS was used as an internal standard. The IR spectra
were measured in ATR using a Perkin Elmer FT-IR Spectrometer
Frontier. The mass spectra were measured with a Thermo TSQ
Quantum Access Max LC-MS/MS spectrometer. Elemental analyses
were performed on a LECO 932 CHNS (Leco-932, St. Joseph, MI,
USA) instrument and the results were within 0.4% of the theo-
retical values. Melting points were recorded on a Thermo Scientific
IA9000 series apparatus and were uncorrected. All of the chemicals
were obtained from Merck Chemicals.
Today, beta-lactam antibiotics are the most widely used anti-
biotic derivatives. The most important source of resistance against
beta-lactam antibiotic derivatives for members of Enter-
obacteriaceae are beta-lactamase enzymes secreted by bacteria.
Beta-lactamase enzymes are mostly synthesized by Gram negative
bacteria and cause resistance against antibiotics that carry beta-
lactam ring [36]. Beta-lactam antibiotics inhibit transpeptidase
and carboxypeptidase enzymes, which are responsible for pepti-
doglycan synthesis, and inhibit cell wall synthesis [37]. The most
significant pathogen that synthesizes beta-lactamase among Gram-
positive bacteria is Staphylococcus aureus.
In the light of the important data gathered through research of
the literature, the primary purpose of this study was to synthesize a
variety of substituted groups containing 1,3,4-thiadiazole ring with
potential biological activity, acylate these compounds with various
acyl groups, and to characterize them. The synthetic routes of all
synthesized compounds are given in Schemes 1e4.
The secondary purpose of the study was to theoretically
examine the following properties of the synthesized compounds to
support experimental studies: IR, NMR spectra and frontier mo-
lecular orbital (FMO).
Also, structures of 2b and 2c compounds were compared with
the ligands of prominent antibacterial targets in terms of similarity.
Trial docking studies made for this enzyme showed that the crystal
structure 1BLH of beta-Lactamase from S. aureus was the most
appropriate target of the 2b and 2c compounds.
2.2. Synthesis
2.2.1. General method for the synthesis of mono 2-amino-1,3,4-
thiadiazole derivatives (2aec)
In a round-bottomed flask, compounds (1aec) (0.002 mol) and
thiosemicarbazide (0.003 mol) in trifluoroacetic acid (5 mL) at
60 ꢀC were stirred for 3e5 h. The progress of the reaction was
monitored by TLC at appropriate time intervals. After completion of
the reaction, the mixture was poured into 200 mL of ice-cold water
and neutralized with ammonia. The solution was filtered and the
solid matter was obtained. It was washed with deionized water,
ethanol and diethyl ether, respectively. The solid was recrystallized
from the appropriate solvent. The physical properties and spectral
data derived from the obtained products are listed below.
2. Experimental
2.2.1.1. 5-(thiophen-2-ylmethyl)-1,3,4-thiadiazol-2-amine
(2a).
Yield: (74%); White solid, mp 183e184 ꢀC (from DMF-EtOH, 1:3). IR
(ATR, cmꢁ1): 3260e3100 (eNH2), 3045 (Ar-CH), 2973 (Aliph. CH),
1517e1503 (C]N), 1159 (NeN), 622e578 (CeS). 1H NMR (400 MHz,
2.1. Materials and methods
The reactions were carried out under a nitrogen atmosphere
DMSO-d6) d (ppm): 4.36 (s, 2H, eCH2), Thiophene-H [6.93 (d,
Scheme 1. General synthesis of mono 2-amino-1,3,4-thiadiazole derivatives (2aec), and their acyl derivatives (3e11).

104
M. Er et al. / Journal of Molecular Structure 1110 (2016) 102e113
Scheme 2. General synthesis of di 2-amino-1,3,4-thiadiazole derivative (14), and its acyl derivatives (15e17).
J ¼ 5.2 Hz, 1H), 6.96 (d, J ¼ 5.2 Hz, 1H), 7.38 (dd, J ¼ 5.2, 2.8 Hz, 1H)],
7.10 (s, 2H, NH2). 13C NMR (100 MHz, DMSO-d6,
ppm): 30.54
(eCH2), Thiophene-C [126.12 (CH), 127.01 (CH), 127.80 (CH), 140.71
(C)], Thiadiazole-C [157.71 (C), 169.71 (C)]. Analysis (% calculated/
found) for C7H7S2N3 (Mw 197.28) C: 42.62/42.69; H: 3.58/3.67;
N:21.30/21.33. MS (ESI-m/z): 198.02 (M þ 1, 100).
2.2.1.3. 5-(3,4-dimethoxybenzyl)-1,3,4-thiadiazol-2-amine
(2c).
d
Yield: (87%); White crystals, mp 205e207 ꢀC (from DMF-EtOH,1:3).
IR (ATR, cmꢁ1): 3267e3083 (eNH2), 3028 (Ar-CH), 2959 (Aliph.
CH), 1589e1511 (C]N), 1135 (NeN), 633e577 (CeS). 1H NMR
(400 MHz, DMSO-d6)
d (ppm): 3.71 (s, 6H, OCH3), 4.04 (s, 2H,
eCH2), Phenyl-H [6.75 (d, J ¼ 7.2 Hz, 1H), 6.85 (s, 1H), 6.87 (d,
J ¼ 7.2 Hz, 1H)], 7.02 (s, 2H, NH2). 13C NMR (100 MHz, DMSO-d6,
d
ppm): 35.83 (eCH2), 56.08 (eOCH3), Phenyl-C [112.53 (CH),112.95
2.2.1.2. 5-(4-nitrobenzyl)-1,3,4-thiadiazol-2-amine
(2b). Yield:
(75%); White crystals, mp 181e182 ꢀC (from DMF-EtOH, 1:3). IR
(ATR, cmꢁ1): 3271e3112 (eNH2), 3067 (Ar-CH), 2954 (Aliph. CH),
1531e1506 (C]N),1155 (NeN), 622e603 (CeS). 1H NMR (400 MHz,
(CH), 121.27 (CH), 131.06 (C), 148.34 (C), 149.37 (C)], Thiadiazole-C
[159.03 (C), 169.46 (C)]. Analysis (% calculated/found) for
C11H13N3O2S (Mw 251.30) C: 52.57/52.59; H: 5.21/5.25; N:16.72/
16.78. MS (ESI-m/z): 274.08 (M þ Na, 100).
DMSO-d6)
d
(ppm): 4.32 (s, 2H, eCH2), Phenyl-H [7.54 (d, J ¼ 8.0 Hz,
2H), (8.16 (d, J ¼ 8.0 Hz, 2H)], 7.14 (s, 2H, NH2). 13C NMR (100 MHz,
DMSO-d6,
d
ppm): 35.59 (eCH2), Phenyl-C [124.42 (CH), 130.67
2.2.2. General acylation reactions of mono 2-amino-1,3,4-
thiadiazole derivatives (3e11)
In a two-necked flask, compounds (2aec) (0.003 mol) were
suspended in dry benzene (40 mL) and pyridine (1 mL). Acyl
chloride derivatives (0.003 mol) were added drop-wise to this
(CH), 146.54 (C), 147.08 (C)], Thiadiazole-C [156.39 (C), 169.78 (C)].
Analysis (% calculated/found) for C9H8N4O2S (Mw 236.25) C: 45.75/
45.59; H: 3.41/3.45; N:23.72/23.78. MS (ESI-m/z): 237.06 (M þ 1,
100).
Scheme 3. General synthesis of tetra 2-amino-1,3,4-thiadiazole derivative (20), and its acyl derivatives (21e23).

M. Er et al. / Journal of Molecular Structure 1110 (2016) 102e113
105
Scheme 4. General synthesis of tetra oxy 2-amino-1,3,4-thiazdiazole derivative (25), and its acyl derivatives (26e28).
solution at room temperature with the assistance of a dropping
the Supplementary Material Section.
funnel. The mixture was then refluxed and stirred for 4e6 h. The
progress of the reaction was monitored by TLC at appropriate time
intervals. After completion of the reaction, the solution was filtered
and the solid matter was obtained. It was washed with deionized
water, ethanol and diethyl ether, respectively. The solid matter was
recrystallized from the appropriate solvent. All physical properties
and spectral data derived from the obtained products are given in
the Supplementary Material Section.
2.2.5. General acylation reactions of tetra oxy 2-amino-1,3,4-
thiadiazole derivatives (26e28)
In a two-necked flask, compound (25) (0.003 mol) was sus-
pended in dry benzene (40 mL) and pyridine (1 mL). Acyl chloride
derivatives (0.012 mol) were added drop-wise to this solution at
room temperature with the assistance of a dropping funnel. The
mixture was then refluxed and stirred for 4e6 h. The progress of
the reaction was monitored by TLC at appropriate time intervals.
After completion of the reaction, the solution was filtered and the
solid matter was obtained. It was washed with deionized water,
ethanol and diethyl ether, respectively. The solid matter was
recrystallized from the appropriate solvent. All physical properties
and spectral data derived from the obtained products are given in
the Supplementary Material Section.
2.2.3. General acylation reactions of di 2-amino-1,3,4-thiadiazole
derivatives (15e17)
In a two-necked flask, compound (14) (0.003 mol) was sus-
pended in dry benzene (40 mL) and pyridine (1 mL). Acyl chloride
derivatives (0.006 mol) were added drop-wise to this solution at
room temperature with the assistance of a dropping funnel. The
mixture was then refluxed and stirred for 4e6 h. The progress of
the reaction was monitored by TLC at appropriate time intervals.
After completion of the reaction, the solution was filtered and the
solid matter was obtained. It was washed with deionized water,
ethanol and diethyl ether, respectively. The solid matter was
recrystallized from the appropriate solvent. All physical properties
and spectral data derived from the obtained products are given in
the Supplementary Material Section.
3. X-ray crystal structure determination and theoretical
calculations
X-ray diffraction data of the crystals was collected with a Bruker
AXS APEX CCD [38] diffractometer and a MoKa beam. The structure
solution of the crystals was performed with the SHELXT-2014 [39]
program using direct methods. In order to determine the positions
of atoms other than hydrogen in the solution phase, the refinement
process was performed with the SHELXL-2014 [39] program which
depends on the full-matrix least-squares method. Isotropic
refinement was used in the first phase in order to increase the
sensitivity of the atom positions and determine the missing atoms.
No missing atoms were discovered other than hydrogen. This data
was seen as a result of the refinement process and anisotropic
refinement was then performed. Hydrogen atoms were determined
in the following phase of the refinement. The positions of hydrogen
atoms were obtained geometrically using the overlapping method.
When placing hydrogen atoms geometrically, aromatic bond
lengths were fixed at the following positions: 0.93 Å, methylene
(eCH2) bond lengths at 0.97 Å; methyl (eCH3) bond lengths at
0.96 Å; and NeH bond lengths at 0.86 Å. After the structure solution
2.2.4. General acylation reactions of tetra 2-amino-1,3,4-
thiadiazole derivatives (21e23)
In a two-necked flask, compound (20) (0.003 mol) was sus-
pended in dry benzene (40 mL) and pyridine (1 mL). Acyl chloride
derivatives (0.012 mol) were added drop-wise to this solution at
room temperature with the assistance of a dropping funnel. The
mixture was then refluxed and stirred for 4e6 h. The progress of
the reaction was monitored by TLC at appropriate time intervals.
After completion of the reaction, the solution was filtered and the
solid matter was obtained. It was washed with deionized water,
ethanol and diethyl ether, respectively. The solid matter was
recrystallized from the appropriate solvent. All physical properties
and spectral data derived from the obtained products are given in

106
M. Er et al. / Journal of Molecular Structure 1110 (2016) 102e113
and refinement processes, the ORTEP-3 [40] program was used for
molecular drawings and PLATON [41], WinGX [40], and MERCURY
[42] programs were used for calculations. Theoretical calculations
related to the compounds were performed with the 6-31G(d) basis
set [43], the DFT(B3LYP) [44] theory, the Gaussian09 program [45],
and the Gausview 5 program [46] which was used to examine
Gaussian outputs graphically.
C-2 carbon signals of the 2-amino-1,3,4-thiadiazole ring in these
compounds were recorded in the range of 159.03e148.35 ppm and
C-5 carbon signals were recorded in the range of
170.19e169.46 ppm. In addition, sp3 hybridized methylene group
(eS-CH2) carbons appeared in compounds 14 and 20 at 35.77 ppm
and 35.52 ppm, respectively. Methylene group (eOCH2) carbons in
the compound 25 appeared at 65.16 ppm due to the electronega-
tivity of the oxygen atom. sp3 hybridized methylene group (eCH2)
carbon signals in the 2aec compounds were recorded in the range
of 35.83e30.57 ppm. While sp3 hybridized vinyl group (eCH]CH)
carbons in compound 14 were observed at 128.96 ppm, C]C car-
bon peaks in compounds 20 and 25 were observed at 133.39 and
135.13 ppm, respectively. The data belonging to the 2-amino-1,3,4-
thiadiazole ring is highly compatible with the data found in the
literature [50]. Other spectral data belonging to the carbon skeleton
of the molecule fully supports the suggested structures. In the mass
spectra belonging to these compounds, it was observed that mo-
lecular ion peaks appeared to be compatible with the suggested
structures and they supported the structures.
In the second part of the study, compounds 3e11, 15e17, 21e23,
and 26e28 were synthesized in moderate to high yields (65e85%)
from the reactions of acyl chloride derivatives with 2-amino-1,3,4-
thiadiazole derivatives (2aec, 14, 20, and 25) in the presence of dry
benzene.
In the IR spectra of these compounds, eNH2 group symmetric
and asymmetric absorption bands disappeared that were found in
the initial compounds and observed in the 3296e3112 cmꢁ1 range.
The most significant evidence that these compounds were acylated
is the fact that eNH absorption bands observed in the range of
3176e3117 cmꢁ1 formed in compounds 3e11, 15e17, 21e23, and
26e28. Other important evidence is the emergence of carbonyl
group (C]O) absorption bands seen in the range of
1699e1657 cmꢁ1 as a result of the acylation of 2-amino-1,3,4-
thiadiazole.
eNH2 group proton signals observed in the range of
7.37e7.02 ppm disappeared in 2-amino-1,3,4-thiadiazole de-
rivatives (2aec, 14, 20, 25) which were the initial compounds of
these compounds in the 1H NMR spectra. Instead of these signals, a
singlet corresponding to one proton in the 13.36e12.41 ppm range
was observed in compounds 3e11. A singlet corresponding to two
protons in the 13.42e12.52 ppm range was also observed in com-
pounds 15e17. A singlet corresponding to four protons in the
13.38e12.30 ppm range was observed in compounds 21e23 and
26e28, and this data is the most important evidence that these
compounds were acylated.
In addition, peaks observed in the 7.37e7.02 ppm range of the-
NH2 group in 2-amino-1,3,4-thiadiazole derivatives (2aec, 14, 20,
25) shifted to high ppm values after the acylation due to the elec-
tron withdrawing property of the carbonyl group. This data is
considered as more important evidence regarding these structures
and it is consistent with findings in the literature [51]. eNH proton
signals (eNHeC]O) of resulting compounds 3e11, 15e17, 21e23
and 26e28 observed at 13.38e12.30 ppm disappeared after the
exchange treatment with D2O.
These compounds' C]O group signals belonging to the acyl
group in 13C NMR spectra appeared in the range of
169.57e160.36 ppm. The fact that these peaks were found in 13C
NMR spectrum is also considered important evidence that the
amino group at the 2-position of the thiadiazole ring was acylated.
Other 13C NMR spectra results of these compounds are given in
detail in the Supplementary Material Section.
On the other hand, mass spectra of all synthesized compounds
were observed as expected and supported by molecular ion peaks.
Spectra (IR, 1H NMR, 13C NMR, and mass) of all synthesized com-
pounds are given in the Supplementary Material Section.
4. Results and discussion
In the first part of the study, 2-amino-1,3,4-thiadiazole de-
rivatives (2aec, 14, 20, and 25) were synthesized in high yields
(74e87%) from the reaction of nitrile compounds (1aec, 13, 19, and
24) with thiosemicarbazide in trifluoroacetic acid (TFA) at 60 ꢀC.
Nitrile derivatives used as initial compounds (1aec) were obtained
by purchase, while nitrile compounds (13, 19, and 24) were ob-
tained as specified in the literature [47,48].
Compelling data from the experiment includes the fact that
sharp absorption bands belonging to the eC^N group observed in
the range of 2220e2269 cmꢁ1 in nitrile derivatives in IR spectrum
disappeared, and symmetric and asymmetric absorption bands
corresponding to the eNH2 group in 2-amino-1,3,4-thiadiazole
derivatives emerged as two separate bands in the range of
3296e3112 cmꢁ1. This data provides the most important evidence
for cyclization.
The structures of 2-amino-1,3,4-thiadiazole derivatives (2aec,
14, 20, and 25) were also confirmed by the assistance of 1H NMR
spectroscopy.
The eNH2 group proton signals of compounds 2aec bonded to
1,3,4-thiadiazole ring from C-2 position in 1H NMR spectra were
recorded as a singlet corresponding to two protons in the range of
7.14e7.02 ppm. Proton peaks belonging to the eNH2 group dis-
appeared as a result of the protonedeuterium exchange performed
with D2O. The methylene (eCH2) protons bonding thiophene and
phenyl groups to the thiadiazole ring from the 5-position were
observed as a singlet corresponding to two protons in the range of
4.36e4.04 ppm. Proton peaks belonging to the thiophene ring were
determined as a doublet corresponding to one proton at 6.93 and
6.96 ppm and as a doublet of a doublet corresponding to one proton
at 7.38 ppm.
In compound 14, the eNH2 proton signal at the 2-position of the
thiadiazole ring was observed as a singlet corresponding to four
protons at 7.31 ppm. In compounds 20 and 25, tetra analogs of
compound 14, the proton signal was observed as a singlet corre-
sponding to eight protons at 7.37 ppm and 7.14 ppm, respectively. In
compound 14, methylene protons (eS-CH2) were observed as a
singlet corresponding to four protons at 3.69 ppm, while in com-
pound 20, these peaks were determined to be a singlet corre-
sponding to eight protons at 3.88 ppm. In compound 25, the
methylene protons (eO-CH2) bonded to the aromatic ring were
observed as a singlet corresponding to eight protons at 5.21 ppm in
the low field due to electronegativity of the oxygen atom. Vinylic
(eCH]CH) protons in the compound 14 were observed as a broad
singlet at 5.76 ppm. Singlet peaks observed at 7.14 ppm, 7.31 ppm,
and 7.37 ppm disappeared almost entirely and supported the sug-
gested structures, especially in exchange treatments of the eNH2
groups bonded to the 2-position of thiadiazole in these compounds
with D2O. Other 1H NMR spectra results of these structures are
given in detail in the Supplementary Material Section.
The structures of 2-amino-1,3,4-thiadiazole derivatives (2aec,
14, 20, and 25) were also confirmed by the assistance of 13C NMR
spectroscopy. In 13C NMR spectra, it was observed that resonance
values of carbons at C-2 and C-5 positions of the 2-amino-1,3,4-
thiadiazole ring were highly compatible with these types of com-
pounds in the literature [49].

M. Er et al. / Journal of Molecular Structure 1110 (2016) 102e113
107
Table 1
Crystallographic data for compounds 2b and 2c.
Empirical formula
Formula weight
Temperature
Wavelength (Å)
Crystal system
Space group
A
C9H8N4O2S (2b)
236.25 (a.k.b)
296 K
MoKa, 0,71073 Å
Monoclinic
P2(1)/c
C11H13N3O2S (2c)
251.30 (a.k.b)
296 K
MoKa, 0,71073 Å
Monoclinic
P2(1)/c
37.1645(34)
6.0621(5)
10.8956(10)
5.9071(5) Å
5.3662(5) Å
32.3060(3) Å
90ꢀ
B
C
a
b
g
(ꢀ)
(ꢀ)
(ꢀ)
90ꢀ
ꢀ
ꢀ
94.703(3)
92.482(3)
90ꢀ
90ꢀ
Volume
1020.61(16) Å3
2452.42(5) Å3
8
Z (molecule/cell)
Calculated density
m
4
1.54 gr cmꢁ3
1.36 gr cmꢁ3
0.258 mmꢁ1
1056
0.307 mmꢁ1
F(000)
488
Crystal size(mm)
0.14 ꢂ 0.14 ꢂ 0.20
0.12 ꢂ 0.16 ꢂ 0.22
q
range
3.28ꢀe28.32ꢀ
3.29ꢀe27.56ꢀ
Index ranges
ꢁ7 ꢃh ꢃ 7, ꢁ7 ꢃk ꢃ 7, ꢁ42 ꢃ l ꢃ 42
ꢁ47 ꢃ h ꢃ 49, ꢁ8 ꢃk ꢃ 8, ꢁ14 ꢃ l ꢃ 14
Reflections collected
Reflections observed [I ꢄ 2
Independent reflections
Tmin,Tmax
29614
55145
s(I)]
2383
2521
0.5863, 0.7457
0.0487
4551
6064
0.6079, 0.7457
0.0656
R
int
S
1.212
1.148
R, wR
Extinction correction
CCDC
0.0540, 0.111
SHELXL-2014
1416511
0.072, 0.173
SHELXL-2014
1416512
4.1. X-ray structure analysis of the crystals (compounds 2b and 2c)
Crystal parameters belonging to C9H8N4O2S (2b) and
asymmetric unit. The dihedral angle between phenyl-thiadiazole
rings was 83.11ꢀ for the 2b molecule and 87.16ꢀ for the 2c mole-
cule. CeS, NeN and CeN bond lengths of both molecules seem to be
shorter than corresponding single bond lengths. This data indicates
a multiple bond order and it restores aromaticity to the ring. Also,
the CeS bond found in the thiadiazole rings contains the carbon
atom with sp2 hybridization. These results are compatible with data
found in the literature [52e56]. Experimental and calculated bond
lengths and bond angles are shown in Table 2.
C
11H13N3O2S (2c) molecules, details of data collection and the
refinement processes are given in Table 1. ORTEP diagrams of the
molecules drawn with 40% probability ellipsoids and diagrams of
input molecules used in the Gaussian program are given in Fig. 1.
The compounds have non-planar thiadiazole and phenyl rings.
Compound 2c was formed as two identical molecules in the
Fig. 1. (a) ORTEP-3 and calculated form of C9H8N4O2S (2b) crystal. (b) ORTEP-3 and calculated form of C11H13N3O2S (2c) crystal.

108
M. Er et al. / Journal of Molecular Structure 1110 (2016) 102e113
Table 2
Experimental and theoretical parameters belonging to compounds 2b and 2c.
Compound 2b (C9H8N4O2S) Compound 2c (C11H13N3O2S)
Bond length(Å)
Exp.
Cal.
1.764
1.774
1.373
1.370
1.306
1.296
1.503
Bond length(A)
Exp.
Cal.
1.770
1.774
1.371
1.322
1.347
1.295
1.503
Bond length(A)
Exp.
Cal.
1.775
1.775
1.369
1.321
1.342
1.295
1.502
S1eC1
S1eC2
N1eC1
N2eN3
N2eC1
N3eC2
C2eC3
1.732(2)
1.734(2)
1.345(3)
1.391(3)
1.308(3)
1.283(3)
1.507(4)
S1AeC1A
S1AeC2A
N2AeN3A
N2AeC1A
N1AAeC1A
N3AAeC2A
C2AAeC3A
1.735(3)
1.742(3)
1.371(4)
1.310(4)
1.283(4)
1.339(4)
1.493(5)
S1BeC1B
S1BeC2B
N2BeN3B
N2BeC1B
N1BeC1B
N3BeC2B
C2BeC3B
1.739(3)
1.739(3)
1.385(4)
1.301(4)
1.336(4)
1.284(4)
1.493(4)
Bond angles(ꢀ)
C1eS1eC2
S1eC2eN3
S1eC1eN2
N3eN2eC1
S1eC2eC3
Bond angles(ꢀ)
C1AAeS1AAeC2A
SA1eC2AeN3A
S1A-C1A-N2A
N3AeN2AeC1A
S1AeC2AeC3A
Bond angles(ꢀ)
C1BeS1BeC2B
S1BeC2BeN3B
S1BeC1BeN2B
N3BeN2BeC1B
S1BeC2BeC3B
87.0(1)
114.1(2)
113.8(2)
111.9(2)
121.4(2)
84.0
87.6(3)
112.6(3)
113.2(5)
112.4(5)
122.3(4)
86.3
87.3(3)
113.1(5)
113.5(5)
111.3(5)
122.6(6)
86.5
112.9
114.3
113.1
120.5
113.4
112.9
113.3
123.0
113.1
112.5
113.4
123.3
Fig. 2. Representation of intermolecular NeH/N interactions of (a) 2b, (b) 2c crystals.
Intermolecular NeH/N hydrogen bonds were observed in both
crystals, while CeH/ interaction was observed in the 2b mole-
cule. The 2b crystal is packed in three dimensional space with
intermolecular NeH/N hydrogen bonds and CeH/ interactions,
whereas the 2c crystal is packed with intermolecular NeH/N
hydrogen bonds. 2b molecule formed the R22ð8Þ ring motif in three
dimensional space with the intermolecular hydrogen bond, which
is formed by N2i (ꢁxþ3,ꢁy, z) atom and H1 atom bonded to N1
atom, whereas it formed the C(9) chain with the intermolecular
hydrogen bond, which is formed by N2ii (x, yþ1, z) atom and H2
atom bonded to N1 atom (Fig. 2(a)). There is also a strong inter-
result of the solution phase and drawings of molecules' packing in
unit cells, respectively. Information related to hydrogen bonds is
given in Table 3.
In theoretical calculations related to 2b and 2c molecules, co-
ordinates obtained from X-ray data were used as the initial ge-
ometry. Geometric optimizations of the system were obtained
using the DFT/B3LYP method and the 6-31G(d) basis set. Bond
p
p
molecular CeH/p interaction in the structure. Intermolecular
CeH/ interactions support the packing in three dimensional
p
space. An interaction occurred between the center of the Cg1 ring
identified with C1/S1/C2/N3/N2 and the H5 atom bonded to C5
atom [C5eH5/Cgiii; symmetry code; (iii) ꢁ1þx,y,z] (Fig. 3). 2c
molecule formed the R22ð8Þ ring motif in three dimensional space
with the intermolecular hydrogen bond, which is formed by N2Ai
(x,ꢁ1þy,z) atom of the H1B atom bonded to N1B atom and N2Bi
(x,1 þ y,z) atom of H1A atom bonded to N1A atom, whereas it
formed the C(9) chain with the intermolecular hydrogen bond,
which is formed by N3Ai (x,5/2-y,-1/2 þ z) atom of H2A atom
bonded to N1A atom and N3Bi (x,3/2ꢁy,1/2 þ z) atom of H2B atom
bonded to N1B atom (Figs. 2(b) and 4).
Molecules were bound to each other with these interactions. It
was observed that NeH/N hydrogen bonds formed the closed
rings according to the center of symmetry. Figs. 2e4 provide dia-
grams of the Mercury shape belonging to the structure found as a
Fig. 3. Packing of the 2b crystal with CeH/p interactions.

M. Er et al. / Journal of Molecular Structure 1110 (2016) 102e113
109
point group symmetry and an 84 base vibration frequency. In
addition, vibration frequencies were calculated with the
DFT(B3LYP/6-31G(d)) basis set for all monomer and tetramer
structures in this study. The calculated spectra are displayed in
Fig. 5. In order to approximate the calculation results compared to
the experimental results, each frequency value was multiplied with
the scale value of 0.9613 [57]. It was observed that the experimental
results were closer to vibration frequency values calculated for the
tetramer structure (Fig. 6) when compared to the monomer
structure.
The eNH2 group is found in the compounds 2b and 2c. We can
expect the eNH2 group to have a symmetric vibration and also an
asymmetric vibration. In the literature, theoretical eNH2 sym-
metric and asymmetric vibration frequencies have been given as
3230e3150 and 3450e3300 cmꢁ1, respectively. In addition, the
eNH2 bending vibration frequency range has been reported as
1640e1580 cmꢁ1 [58,59]. In the cases of NeH or OeH groups
regarding molecules forming an intermolecular or intramolecular
hydrogen bond, the stretching vibration frequency values of these
groups decrease while their bending vibration frequency values
increase [60].
Theoretically, the eNH2 asymmetric vibration frequency was
Fig. 4. Packing of the 2c crystal with NeH/N interactions.
lengths and bond angles found as a result of experimental and
theoretical studies are shown in Table 2 comparatively.
4.2. IR spectra (compounds 2b and 2c)
While the 2b molecule had C1 point group symmetry containing
24 atoms and a 66 base vibration frequency, the 2c molecule had C1
Table 3
Intermolecular interaction geometries for C9H8N4O2S (2b) and C11H13N3O2S (2c)
single crystals (Å, ꢀ).
D-H
H/A
D/A
D-H/A
C9H8N4O2S (2b)
N1e H1/N2i
Experimental
DFT
0.86(3)
1.03
2.18(3)
1.94
3.047(3)
2.97
176(3)
175
N1e H2/N2ii
Experimental
DFT
0.85(4)
1.02
2.53(4)
2.11
3.332(3)
3.00
159(3)
144
C5eH5/Cg1iii
Experimental
0.93(3)
2.63(3)
3.47(3)
154(3)
Symmetry codes:i ¼ ꢁxþ3,ꢁy, z, ii ¼ x, yþ1, z, iii ¼ ꢁ1þx,y,z
C
11H13N3O2S (2c)
N1BeH1B/N2Aiv
Experimental
DFT
0.86(4)
1.02
2.18(4)
1.94
3.019(4)
2.96
167(4)
170
N1BeH2B/N3Bv
Experimental
DFT
0.86(3)
1.02
2.10(3)
2.05
2.94(3)
3.04
167(3)
163
N1A-H1A/N2Bvi
Experimental
DFT
0.86(4)
1.03
2.11(4)
1.97
2.96(4)
3.00
171(4)
172
N1A-H2A/N3Avii
Experimental
DFT
0.86(3)
1.02
2.25(3)
2.03
3.03(3)
3.04
151(3)
167
Symmetry codes:iv ¼ x,ꢁ1þy,z, v ¼ x,3/2-y,1/2 þ z, vi ¼ x,1 þ y,z, vii ¼ x,5/2-y,-
1/2 þ z
Fig. 5. Theoretical IR spectra of (a) 2b, (b) 2c compounds.

110
M. Er et al. / Journal of Molecular Structure 1110 (2016) 102e113
Fig. 6. Optimized tetramer structures calculated for (a) 2b, (b) 2c compounds.
calculated as 3403 cmꢁ1 and 3345 cmꢁ1 for the tetramer structures
of 2b and 2c molecules, while it was calculated as 3627 cmꢁ1 and
3513 cmꢁ1 for the monomer structures of 2b and 2c molecules,
respectively. Similarly, the eNH2 symmetric vibration frequency
was calculated as 3141 cmꢁ1 and 3176 cmꢁ1 for tetramer structures
of 2b and 2c molecules, while it was calculated as 3349 cmꢁ1 and
3410 cmꢁ1 for monomer structures of 2b and 2c molecules,
respectively. Experimentally, eNH2 asymmetric vibration fre-
quency was observed to be 3271 cmꢁ1 and 3267 cmꢁ1 for 2b and 2c
compounds respectively, eNH2 symmetric vibration frequency was
observed to be 3112 cmꢁ1 and 3083 cmꢁ1 for 2b and 2c compounds,
respectively.
In addition, the angle bending vibration frequency was calcu-
lated as 1662 cmꢁ1 and 1675 cmꢁ1 for tetramer structures of 2b and
2c molecules, while it was calculated as 1622 cmꢁ1 and 1605 cmꢁ1
for monomer structures of 2b and 2c compounds, respectively.
Experimentally, this value was observed to be 1602 cmꢁ1 and
1629 cmꢁ1 for 2b and 2c compounds, respectively. In the light of
these results, it can be concluded that the eNH2 group can be used
for intermolecular bonds.
thiadiazole ring was calculated to be 1501/1490, 1137 and 639/
609 cmꢁ1, respectively for 2b compound, whereas it was calculated
to be 1503/1491, 1139 and 632/578 cmꢁ1, respectively for 2c com-
pound. These values were stated to be 1550/1490, 1141 and 726/
561 cmꢁ1 in the literature [61].
Experimentally, stretching vibration frequency of C]N group in
the thiadiazole ring was observed to be 1531/1506 cmꢁ1 and 1589/
1511 cmꢁ1 for 2b and 2c compounds, respectively. NeN stretching
vibration frequency was observed to be 1155/1135 cmꢁ1 for 2b and
2c compounds respectively, whereas CeS stretching vibration fre-
quency was observed to be 622/603 cmꢁ1 and 633/577 cmꢁ1 for 2b
and 2c compounds respectively. It was observed that the experi-
mental measurements and theoretical calculations were compat-
ible with the values found in the literature [62e66].
4.3. 1H and 13C NMR spectra (compounds 2b and 2c)
The GIAO (Gauge-Independent Atomic Orbital) method [67,68]
was used to determine NMR chemical shift values of the mole-
cules (2b and 2c) and TMS (tetramethylsilane) was taken as refer-
ence. Dimethyl sulfoxide (DMSO) solvent was used for TMS and 1H
NMR, and 13C NMR chemical shift values calculated for DFT/B3LYP/
Theoretically, stretching vibration frequency of monomer
structures belonging to C]N, NeN and CeS groups in the
Fig. 7. Frontier orbitals and energies of (a) 2b, (b) 2c compounds.

M. Er et al. / Journal of Molecular Structure 1110 (2016) 102e113
111
6-31G(d) were 32.1 and 189.4 ppm, respectively. 1H NMR and 13C
NMR chemical shift values for 2b and 2c compounds obtained
theoretically using experimental and optimized structures are
given in Table S1. (Table S1 is provided as Supplementary Material).
As can be seen in the 13C NMR spectrum of molecules (2b and 2c),
the peaks of C1 and C2 atoms constitute evidence that the com-
pounds have a thiadiazole ring. Chemical shift values of these
atoms were higher than other carbon atoms. Three electronegative
atoms (N1, N2, and S1) around the C1 atoms especially resonate in
the low field due to the high deshielding effect of these atoms, and
this causes the chemical shift values of 2b and 2c atoms to be
168.3 ppm and 166.6 ppm, respectively, which are higher when
compared to other carbon atoms.
the HOMO orbitals in the 2c molecule while the electron with-
drawing eNO2 group bonded to phenyl ring localized the LUMO
orbitals in the 2b molecule.
Molecular hardness parameters were obtained using the finite
difference formula suggested by Parr and Pearson [71,72], and they
were calculated using the operational definition of the hardness
parameter h:
h
¼ 1/2 (IE-EA)
Here, IE indicates the initial ionization energy and EA indicates
the electron affinity. The hardness value can provide the following
approach through the highest occupied molecular orbital energies
Experimentally, chemical shifting value of C1 atom was found to
be 169.8 ppm and 169.5 ppm for 2b and 2c compounds,
respectively.
Theoretically, C2 atoms found in 2b and 2c molecules (together
with two N3 and S1 atoms) had lower electronegativity when
compared to the N1 atom, and they therefore resonated in a higher
field due to the lower deshielding effect. This occurrence caused
chemical shift values to be 164.8 ppm for the 2b molecule and
161.6 ppm for the 2c molecule, which is comparatively lower.
Experimentally, chemical shifting value of C2 atom was found to
be 156.4 ppm and 159.0 ppm for 2b and 2c compounds, respec-
tively. It was observed that the experimental measurements and
theoretical calculations were compatible with the values found in
the literature [66e69].
In the 1H NMR spectra, the hydrogen peak belonging to the
eNH2 groups were observed at 7.1 ppm and 7.0 ppm corresponding
to two protons for compounds 2b and 2c, respectively. In theoret-
ical calculations, these peaks were found to be 4.4 ppm for the 2b
molecule and 3.7e4.0 ppm for the 2c molecule which is almost the
half the value of the experimental results. This result might be due
to the assumption in the theoretical calculation that the molecule
does not have the NeH … N hydrogen bond. Other theoretical and
experimental 13C NMR and 1H NMR peaks belonging to the com-
pounds 2b and 2c are given in Table S1. (Table S1 is provided as
Supplementary Material).
4.4. Frontier molecular orbital analysis and molecular hardness
parameters (compounds 2b and 2c)
After stable structures and structural parameters for these
molecules (2b and 2c) were obtained, the following parameters
were examined: induced dipole moment; polarizability; first
hyperpolarizability; HOMO and LUMO energy values. At the same
time, hardness was obtained from these energy values. In this study
we investigated how these properties changed with the effects of
different electron-providing groups.
The most important orbitals in molecules are frontier molecular
orbitals called HOMO and LUMO. The energy difference between
these orbitals is a measure of the chemical stability of the molecule.
Since it is also a measure of electron conductivity, it is a critical
parameter to determine the molecular electrical transport prop-
erty. Therefore, this energy difference is largely responsible for
chemical and spectroscopic properties of a molecule [70].
The calculations were made in the gas phase. For these mole-
cules, the HOMO energy value was found to be ꢁ6.61 and ꢁ5.82 eV,
while the LUMO energy value was found to be ꢁ2.75 and ꢁ0.49 eV,
respectively. The difference between these energy levels (DEHOMO-
LUMO) was 3.86 for 2b and 5.33 for 2c. In the examined molecules, it
was seen that electron withdrawing groups and electron donating
groups bonded to two phenyl rings and polarized the charge dis-
tribution. The dipole moment changed as a result.
Fig. 8. Representation of docking results of (a) 2b, (b) 2c compounds. H-bond,
pep,
and -alkyl interactions are represented with green, pink, and orange lines, respec-
p
tively. (For interpretation of the references to colour in this figure legend, the reader is
As shown in Fig. 7, the electron donating eOCH3 group localized
referred to the web version of this article.)

112
M. Er et al. / Journal of Molecular Structure 1110 (2016) 102e113
Table 4
Affinity and RMSD values of different confirmations of 2b and 2c molecules.
Compound 2b
Compound 2c
Mode
Mode
Affinity (kcal/mol)
Distance from best mode
Affinity (kcal/mol)
Distance from best mode
RMSD 1.b.
RMSD u.b.
RMSD 1.b.
RMSD u.b.
1
2
3
4
5
6
7
8
9
ꢁ6.7
ꢁ6.5
ꢁ6.4
ꢁ6.3
ꢁ6.2
ꢁ6.2
ꢁ5.9
ꢁ5.8
ꢁ5.5
0.000
4.516
3.847
2.719
4.397
1.483
1.771
3.826
2.448
0.000
6.831
4.880
3.500
5.972
1.812
1.864
4.983
3.136
1
2
3
4
5
6
7
8
9
ꢁ6.2
ꢁ6.0
ꢁ5.9
ꢁ5.9
ꢁ5.9
ꢁ5.9
ꢁ5.6
ꢁ5.6
ꢁ5.6
0.000
2.387
1.357
2.254
1.503
2.467
4.268
4.321
3.047
0.000
3.484
2.604
3.261
1.899
3.263
5.795
5.442
5.040
(EHOMO) and the lowest unoccupied molecular orbital energies
(ELUMO):
Lactamase enzyme. Thus, new antibiotic agents may be devel-
oped. However biological tests need to be done so as to validate the
computational predictions.
h
z 1/2(ELUMO- EHOMO)
5. Conclusions
In some studies found in the literature, the effects of the hard-
ness parameter on charge transfers were examined, and it was
reported in these studies that a small value indicated a stronger
h
In this study, compounds containing 2-amino-1,3,4-thiadiazoles
and their acyl derivatives were synthesized with high yields and
with easily applicable methods. The structures of all synthesized
compounds were elucidated with various spectroscopic methods.
Among the synthesized compounds, single-crystal versions of
compounds 2b and 2c were obtained. After the stable structures
and structural parameters of these compounds were calculated,
their HOMO, LUMO energies and hardness parameters of these
energies were found. The effects of electron donating groups
(eOCH3) and electron withdrawing groups (eNO2) in these mole-
cules (2b and 2c) were investigated. The fact that the hardness
value calculated for the 2b molecule was lower compared to the 2c
molecule demonstrates that the charge transfer is stronger in the
2b molecule. Finally, the docking simulation process was used to
obtain possible bonding models and confirmations for 2b and 2c
compounds. Docking study results show that the 2b and 2c com-
pounds might inhibit the Beta-Lactamase enzyme, thus new anti-
biotic agents may be developed.
h
charge transfer interaction [73e75]. The hardness value was
calculated to be 3.86 and 5.33 for 2b and 2c, respectively. The fact
that the hardness value calculated for the 2b molecule was lower
when compared to the 2c molecule shows that the charge transfer
will be stronger in the 2b molecule.
4.5. Molecular docking studies (compounds 2b and 2c)
The Beta-Lactamase crystal structure (pdb code: 1BLH) for
docking works was obtained from the Protein Data Bank (http://
www.rcsb.org/pdb). Before the docking process, water molecules
were removed from the Beta-Lactamase of S. aureus (PDB: 1BLH),
and hydrogen atoms and Gasteiger charges were added. Ligands of
2b and 2c molecules were then docked to target molecule binding
sites (Fig. 8). Autodock Vina [76] was used for docking works and
AutoDock Tools was used for creating docking data entry files.
Receptor-ligand interactions were demonstrated with Discover
Studio Visualizer 4.0 and Pymol softwares. The estimated bonding
energy as a result of molecular docking (docking score) and RMSD
values are given comparatively in Table 4.
The docking results were accepted as correct when the RMSD
value was lower than 2 Å [77]. The RMSD value is the root mean
square deviation from the determined confirmation of the ligand
structure. In other words, this value indicates the deviation of the
ligand from the active site with which it interacts, and it is the most
important criterion used for docking results. The criterion to be
considered after RMSD is the bonding energy. The reason behind
this priority order is that the structure may give low bonding en-
ergy outside the active site as well. Therefore, first the proximity to
the active site is considered and then the energy of the bonding in
the active site.
Acknowledgments
The financial support under the contract (KBÜ-BAP-14/1-YL-
012) from the Karabük University is gratefully acknowledged. In
addition, computing resources used in this work were provided by
the National Center for High Performance Computing of Turkey
(UHeM) under grant number 1002742013.
Appendix A. Supplementary data
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.molstruc.2016.01.045.
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