Ultrasound-assisted improved synthesis of 5-(benzylthio)-1,3,4-thiadiazol-2-amine derivatives: an experimental and computational study

Article abstract of DOI:10.1007/s13738-018-1567-9

The main objects of this study are: (1) to propose alternative efficient methods for the synthesis of 5-amino-1,3,4-thiadiazole-2-thiol and 5-(benzylthio)-1,3,4-thiadiazol-2-amine derivatives, (2) to investigate the reactions and the chemical species which take place in the investigated reactions computationally via density functional theory (DFT) calculations, (3) to make a comparison between experimental and computationally obtained data, and (4) to make a comparison between the computational methods to find out the best computational technique to simulate the investigated molecules and reactions. The study consists of two parts. In the first part, synthesis of 5-amino-1,3,4-thiadiazole-2-thiol and 5-(benzylthio)-1,3,4-thiadiazol-2-amine derivatives have been carried out. For both syntheses, it has been proposed that the reactions can be carried out effectively with the use of ultrasound. To the best of our knowledge, this is the first use of ultrasound for both reactions. The results showed that ultrasound can increase the efficiency of the investigated reactions and can be a good alternative to conventional methods. In the second part of the study, some DFT calculations have been performed on the chemical species which take place in the investigated reactions. In computational studies, seven different basis sets have been used. In this second part, comparisons have been made (1) between experimental and computationally obtained data, and (2) between the computational techniques to reveal the best method for the investigated molecules.

Full text of DOI:10.1007/s13738-018-1567-9

Journal of the Iranian Chemical Society (2019) 16:899–912
https://doi.org/10.1007/s13738-018-1567-9
ORIGINAL PAPER
Ultrasound-assisted improved synthesis of 5-(benzylthio)-1,3,4-
thiadiazol-2-amine derivatives: an experimental and computational
study
Taner Erdogan1
Received: 24 August 2018 / Accepted: 30 November 2018 / Published online: 3 December 2018
©
Iranian Chemical Society 2018
Abstract
The main objects of this study are: (1) to propose alternative efficient methods for the synthesis of 5-amino-1,3,4-thiadiazole-
2
-thiol and 5-(benzylthio)-1,3,4-thiadiazol-2-amine derivatives, (2) to investigate the reactions and the chemical species
which take place in the investigated reactions computationally via density functional theory (DFT) calculations, (3) to make
a comparison between experimental and computationally obtained data, and (4) to make a comparison between the compu-
tational methods to find out the best computational technique to simulate the investigated molecules and reactions. The study
consists of two parts. In the first part, synthesis of 5-amino-1,3,4-thiadiazole-2-thiol and 5-(benzylthio)-1,3,4-thiadiazol-
2
-amine derivatives have been carried out. For both syntheses, it has been proposed that the reactions can be carried out
effectively with the use of ultrasound. To the best of our knowledge, this is the first use of ultrasound for both reactions.
The results showed that ultrasound can increase the efficiency of the investigated reactions and can be a good alternative to
conventional methods. In the second part of the study, some DFT calculations have been performed on the chemical species
which take place in the investigated reactions. In computational studies, seven different basis sets have been used. In this
second part, comparisons have been made (1) between experimental and computationally obtained data, and (2) between
the computational techniques to reveal the best method for the investigated molecules.
Keywords Thiadiazole · Ultrasound · Sonochemistry · Computational chemistry · DFT
Introduction
widely applied in optics and electrochemistry [6]. In recent
years, there has been an intense investigation of different
classes of thiadiazole compounds [7].
Thiadiazole compounds are important molecules in organic
and pharmaceutical chemistry. Derivatives of these het-
erocycles display a broad spectrum of biological activities
comprising antimicrobial, antituberculosis, anti-inflamma-
tory and anticancer. They can act as antihypertensive and
anticonvulsant agents [1–3], α-glucosidase inhibitors [4] and
cyclooxygenase-2 inhibitors [5]. On the other hand, they
exhibit high potential as pesticides in agrochemistry, and are
In this study, (1) the synthesis of 5-amino-1,3,4-thiadi-
azole-2-thiol from thiosemicarbazide and carbon disulfide,
and (2) the synthesis of 5-(benzylthio)-1,3,4-thiadiazol-
2-amine derivatives from 5-amino-1,3,4-thiadiazole-2-thiol
and corresponding aryl halides have been investigated. Reac-
tion pathway is given in Fig. 1.
In literature, there are several methods for the synthesis
of 5-amino-1,3,4-thiadiazole-2-thiol from thiosemicarbazide
and carbon disulfide [8–12]. Generally, in these methods
NaOH, KOH, Na CO , K CO , NaHCO and HCl have been
Electronic supplementary material The online version of this
article (https://doi.org/10.1007/s13738-018-1567-9) contains
supplementary material, which is available to authorized users.
2
3
2
3
3
used as catalysts. Ethanol and water are the most common
solvents for this reaction and the others are DMF, pyridine
and piperidine. These methods generally require minimum
*
Taner Erdogan
erdogantaner@outlook.com.tr
4
h of refluxing and 5 h of total reaction time.
There are several methods in the extant literature for
1
Department of Chemistry and Chemical Processing
Technologies, Kocaeli Vocational School, Kocaeli
University, Kocaeli, Turkey
the synthesis of 5-(benzylthio)-1,3,4-thiadiazol-2-amine
derivatives from 5-amino-1,3,4-thiadiazole-2-thiol and
Vol.:(0
1
123456789)
3

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Journal of the Iranian Chemical Society (2019) 16:899–912
Synthesis of 5‑(benzylthio)‑1,3,4‑thiadiazol‑2‑amine
derivatives (5a–f)
General procedure
5
-Amino-1,3,4-thiadiazole-2-thiol (3) (1 eq.) was dis-
solved in 6–7 mL anhydrous THF and potassium-tert-
butylate (1 eq.) was added. After 2–3 min of sonication,
aryl halide (4a–f) (1 eq.) was added and the mixture was
sonicated for 20 min at room temperature. The progress
of the reaction was monitored by TLC. After completion
of the reaction, 1–2 mL of methanol was added, solvent
was removed under reduced pressure and water was added.
The mixture was extracted with dichloromethane and the
organic phase was dried with sodium sulfate. After fil-
tration of the sodium sulfate, solvent was removed under
reduced pressure. After recrystallization from ethanol,
the product was purified with preparative thin-layer
chromatography.
Fig. 1 Reaction pathway
5
8
-(Benzylthio)-1,3,4-thiadiazol-2-amine (5a) White solid,
5% yield, m.p.: 160–162 °C, (Lit [7]. m.p.: 158–160 °C),
+
, 1
m/z (ESI): 224 [M–H] H NMR (400 MHz, DMSO-d ) δ
6
7
.23–7.35 (7H, m), 4.28 (2H, s).
5
-((2-Chlorobenzyl)thio)-1,3,4-thiadiazol-2-amine
(
5b) Light yellow solid, 82% yield, m.p.: 150–152 °C,
+
, 1
(
Lit [16]. m.p.: 151–152 °C), m/z (ESI): 258 [M–H]
H
NMR (400 MHz, DMSO-d ) δ 7.47–7.40 (2H, m), 7.33–
6
corresponding aryl halides [7, 13–15]. All these methods are
base catalyzed, and NaOH and KOH are the most common
bases. The reactions are generally carried out at room tem-
perature but reaction times can be up to 24 h.
7.26 (4H, m), 4.35 (2H, s).
5-((4-Chlorobenzyl)thio)-1,3,4-thiadiazol-2-amine
(5c) Light yellow solid, 80% yield, m.p.: 160–162 °C, (Lit
+
, 1
[
16]. m.p.: 161–162 °C), m/z (ESI): 258 [M–H] H NMR
Experimental
(400 MHz, DMSO-d ) δ 7.48–7.25 (6H, m), 4.28 (2H, s).
6
Ultrasound-assisted reactions were carried out using Bandelin
Sonorex ultrasonic bath. LC–MS and NMR spectra were taken
on Waters 2695 Alliance Micromass ZQ and Varian Mercury
AS400. Melting points were determined using Barnstead Elec-
trothermal 9100 melting point apparatus.
5-((4-Bromobenzyl)thio)-1,3,4-thiadiazol-2-amine
(5d) Light yellow solid, 85% yield, m.p.: 172–174 °C,
+
, 1
m/z (ESI): 302 [M–H] H NMR (400 MHz, DMSO-d ) δ
6
7.50 (2H, d, J = 8.8 Hz), 7.30–7.28 (4H, m), 4.26 (2H, s).
5
-((2,4-Dichlorobenzyl)thio)-1,3,4-thiadiazol-2-amine
Synthesis of 5‑amino‑1,3,4‑thiadiazole‑2‑thiol (3)
(5e) Light yellow solid, 82% yield, m.p.: 132–134 °C,
+
, 1
(
Lit [16]. m.p.: 133–134 °C), m/z (ESI): 292 [M–H]
H
To a solution of thiosemicarbazide (1) (2.5 g, 0.0274 mol) and
carbon disulfide (2) (2.09 g, 0.0274 mol) in ethanol, saturated
aqueous solution of disodium carbonate (1.45 g, 0.0137 mol)
was added and the mixture was sonicated for 30 min at 50 °C.
The progress of the reaction was monitored by TLC. After
completion of the reaction, the mixture was cooled to room
temperature and water was added. Reaction mixture was neu-
tralized with HCl solution, and the precipitates were collected
and recrystallized from ethanol.
NMR (400 MHz, DMSO-d ) δ 7.63 (1H, s), 7.43–7.34
6
(4H, m), 4.33 (2H, s).
5-((2,6-Dichlorobenzyl)thio)-1,3,4-thiadiazol-2-amine
(5f) White solid, 80% yield, m.p.: 168–170 °C, m/z (ESI):
+
, 1
292 [M–H] H NMR (400 MHz, DMSO-d ) δ 7.49–7.33
6
(5H, m), 4.44 (2H, s).
1
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Journal of the Iranian Chemical Society (2019) 16:899–912
901
Computational studies
Single point energies for optimized structures
In the second part of the study, some DFT calculations
on the reactants and synthesized molecules have been
performed, and a comparison between experimental and
computationally obtained data has also been made. In this
part, a comparison between computational methods has
also been made to reveal the best method for the inves-
tigated molecules. Geometry optimizations, frequency
analysis, NMR calculations and condensed Fukui func-
tion calculations have been carried out at DFT B3LYP
Single point energy (SPE) is the sum of nuclear repulsion
energy and the electronic energy of the molecule at the
specified nuclear configuration. A single point energy cal-
culation is a prediction of the energy and related properties
for a molecule with a specified geometric structure [20].
SPEs have been determined for the optimized structures at
DFT B3LYP level of theory using 6-31G(d), 6-31 +G(d),
6-31G(d,p), 6-31+G(d,p), 6-311G(d,p), 6-311+G(d,p) and
6-311+G(2d,p) basis sets. Energies for the compounds 3,
4a–f and 5a–f are given in Table 1. All values in Table 1
have been given in eV unit. As can be seen from Table 1,
generally larger basis sets estimate lower energies for all
compounds. In general, basis set sequence is as follows in
terms of calculated energies: 6-31G(d) > 6-31G(d,p) > 6
-31 + G(d) > 6-31 + G(d,p) > 6-311G(d,p) > 6-311 + G(d,p
)>6-311+G(2d,p).
(
Becke three-parameter hybrid functional combined with
Lee–Yang–Parr correlation functional) level of theory
and various basis sets, including 6-31G(d), 6-31 + G(d),
6
-31G(d,p), 6-31 + G(d,p), 6-311G(d,p), 6-311 + G(d,p)
and 6-311 + G(2d,p) basis sets, have been used. In NMR
calculations, both GIAO (gauge-independent atomic
orbital) and CSGT (continuous set of gauge transforma-
tions) methods have been used. All computations have
been performed using Gaussian 09 Rev. D.01 Program
Package [17], and Avogadro 1.1.1 software [18] has
been used for conformational search. GaussView5 [19]
has been used for the visualization of the computational
results. HP Z620 workstation equipped with dual Xeon E5
family processors was used for the computational studies.
Optimized structure analysis
Geometric parameters have been determined computa-
tionally at DFT B3LYP level of theory using 6-31G(d),
6-31G(d,p), 6-311G(d,p), 6-31 + G(d), 6-31 + G(d,p),
6-311 + G(d,p) and 6-311 + G(2d,p) basis sets. Optimized
structures of compounds 5a–f, calculated at B3LYP/6-
3
11 + G(2d,p) level of theory, are given in Fig. 2. For
Table 1 Single point energies for compounds 3, 4a–f and 5a–f
Compounds
3
opt1a
−28261.98
opt2b
opt3c
−28265.23
opt4d
opt5e
−28262.68
opt6f
−28265.55
opt7g
−28262.25
−77353.32
−32402.32
−32402.37
−147316.61
−44908.48
−44908.41
−35619.61
−48125.76
−48125.81
−105582.91
−60631.92
−60631.84
−28262.37
−77353.88
−32402.39
−32402.44
−147317.86
−44908.58
−44908.52
−35619.77
−48125.96
−48126.01
−105583.78
−60632.16
−60632.08
−28265.90
−77421.48
−32405.85
−32405.90
−147451.05
−44912.84
−44912.78
−35624.96
−48131.94
−48131.99
−105654.54
−60638.94
−60638.87
4
4
4
4
4
4
5
5
5
5
5
5
a
b
c
d
e
f
a
b
c
d
e
f
−77353.02
−32402.08
−32402.13
−147316.36
−44908.27
−44908.21
−35619.14
−48125.32
−48125.38
−105582.48
−60631.53
−60631.45
−77421.32
−32405.41
−32405.46
−147450.98
−44912.31
−44912.25
−35624.07
−48130.96
−48131.02
−105653.74
−60637.87
−60637.79
−77354.17
−32402.63
−32402.68
−147318.11
−44908.78
−44908.72
−35620.25
−48126.39
−48126.44
−105584.21
−60632.55
−60632.47
−77421.40
−32405.54
−32405.59
−147451.07
−44912.48
−44912.41
−35624.43
−48131.35
−48131.40
−105654.11
−60638.29
−60638.21
a
6
6
6
6
-31G(d)
b
c
d
e
f
-31G(d,p)
-311G(d,p)
-31+G(d)
6
-31+G(d,p)
6
-311+G(d,p)
6
g
-311+G(2d,p)
1
3

902
Journal of the Iranian Chemical Society (2019) 16:899–912
Fig. 2 Calculated molecular structures of compounds 5a–f
compound 5a, selected experimental and computational
data are given in Table 2. The computational data in
Table 2 have been obtained at B3LYP/6-311 + G(2d,p)
level of theory. In Table 2, experimental and computa-
tionally obtained data have also been compared and the
results are given in percentage error. The experimental
values are obtained from the literature [21]. Geometry
optimizations have been performed with seven different
basis sets but it was observed that there are no consider-
able differences between basis sets for the estimation of
the geometric parameters.
Frequency analysis
Frequency analysis was also carried out at DFT B3LYP
level of theory using 6-31G(d), 6-31G(d,p), 6-311G(d,p),
6-31 + G(d), 6-31 + G(d,p), 6-311 + G(d,p) and
6-311+G(2d,p) basis sets. Thus, vibrational spectra of the
investigated molecules have been obtained and it has been
validated that the optimized structures are real global min-
ima. For instance, calculated IR spectra of the compounds 3
and 5a at B3LYP/6-311+G(2d,p) level of theory are given
in Fig. 3. In IR spectra, antisymmetric –NH stretching
2
Table 2 Calculated and
Bond lengths (Å)
Bond angles (°)
experimental geometric
parameters for compound 5a
Atoms
Exp [21]
Calc.
Error (%)
Atoms
Exp [21]
Calc.
Error (%)
1C–2N
1C–5S
1C–6S
2N–3N
3N–4C
1.384
1.736
1.742
1.311
1.324
1.291
1.769
1.757
1.377
1.294
6.7
1.9
0.9
5.0
2.3
2N–1C–5S
2N–1C–6S
5S–1C–6S
2N–3N–4C
3N–4C–7N
113.8
121.9
123.9
112.1
124.0
86.9
113.7
126.2
120.1
113.0
123.8
85.6
0.1
3.5
3.1
0.8
0.2
1.5
1
C–5S–4C
1
3

Journal of the Iranian Chemical Society (2019) 16:899–912
903
Fig. 3 Calculated IR spectra of
compounds 3 and 5a
−
1
peaks have been observed at 3648 cm for compound 3
NMR spectral analysis
−
1
and 3646 cm for compound 5a. Symmetric –NH stretch-
2
−
1
ing peaks have been observed at 3545 cm for compound 3
Nuclear magnetic shield tensors have been computationally
determined at DFT B3LYP level of theory using 6-31G(d),
6-31G(d,p), 6-311G(d,p), 6-31 + G(d), 6-31 + G(d,p),
6-311 + G(d,p) and 6-311 + G(2d,p) basis sets with both
GIAO and CSGT methods. Calculated and experimental
−
1
and 3544 cm for compound 5a. For compound 5a, peaks
−
1
at 3189–3158 cm belong to aromatic –CH stretching. Both
for compounds 3 and 5a, peaks for –NH bending have been
2
−
1
observed at 1640 cm . 1C–2N stretching peaks of the thia-
−
1
1
diazole ring have been observed at 1463 cm for compound
H NMR data of the compound 5a are given in Tables 3
−
1
3
and 1452 cm for compound 5a. For compound 3, peak
and 4. To emphasize the agreement between computational
and experimental data, a color scale from green to red has
−
1
at 2663 cm belongs to 6S–8H stretching.
1
Table 3 Calculated and experimental H NMR chemical shifts for compound 5a (CSGT)
a
b
c
d
e
f
g
Exp.
csgt1
1.27
1.27
2.26
2.26
4.64
4.67
4.65
4.67
4.64
csgt2
2.02
2.02
2.71
2.71
5.17
5.21
5.18
5.21
5.17
csgt3
2.80
2.80
2.92
2.92
6.34
6.30
6.25
6.30
6.34
csgt4
1.60
1.60
2.70
2.70
5.08
5.05
4.99
5.05
5.08
csgt5
2.50
2.50
3.15
3.15
5.66
5.65
5.58
5.65
5.66
csgt6
3.26
3.26
3.58
3.58
6.61
6.50
6.42
6.50
6.61
csgt7
3.73
3.73
4.38
4.38
7.41
7.30
7.25
7.30
7.41
15-H
16-H
17-H
18-H
19-H
20-H
21-H
22-H
23-H
7.23-7.35
7.23-7.35
4.28
4.28
7.23-7.35
7.23-7.35
7.23-7.35
7.23-7.35
7.23-7.35
Green color corresponds to the best agreement between computational and experimental data while red color corresponds to the worst
a
6
6
6
6
-31G(d)
b
c
d
e
f
-31G(d,p)
-311G(d,p)
-31+G(d)
6
-31+G(d,p)
6
-311+G(d,p)
6
g
-311+G(2d,p)
1
3

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Journal of the Iranian Chemical Society (2019) 16:899–912
1
Table 4 Calculated and experimental H NMR chemical shifts for compound 5a (GIAO)
a
b
c
d
e
f
g
Exp.
giao1
3.35
3.35
4.37
4.37
7.32
7.22
7.18
7.22
7.32
giao2
3.70
3.70
4.42
4.42
7.52
7.40
7.35
7.40
7.52
giao3
3.73
3.73
4.42
4.42
7.66
7.52
7.47
7.52
7.66
giao4
3.64
3.64
4.38
4.38
7.44
7.39
7.22
7.39
7.44
giao5
4.09
4.09
4.45
4.45
7.65
7.57
7.40
7.57
7.65
giao6
4.01
4.01
4.54
4.54
7.74
7.57
7.45
7.57
7.74
giao7
3.89
3.89
4.58
4.58
7.74
7.57
7.50
7.57
7.74
15-H
16-H
17-H
18-H
19-H
20-H
21-H
22-H
23-H
7.23-7.35
7.23-7.35
4.28
4.28
7.23-7.35
7.23-7.35
7.23-7.35
7.23-7.35
7.23-7.35
Green color corresponds to the best agreement between computational and experimental data while red color corresponds to the worst
a
6
6
6
6
-31G(d)
b
c
d
e
f
-31G(d,p)
-311G(d,p)
-31+G(d)
6
-31+G(d,p)
6
-311+G(d,p)
6
g
-311+G(2d,p)
been applied in Tables 3 and 4. Green color represents
the more successful results while red color represents the
worse results. As can be seen from Tables 3 and 4, GIAO
method is more successful than CSGT method. Addition-
ally, it can be said that CSGT method is becoming more
successful with the use of larger basis sets. As can be seen
from Table 3, for CSGT method, acceptable results can only
be obtained at B3LYP/6-311+G(2d,p) level of theory. On
the other hand, GIAO method generally overestimates the
chemical shifts with the use of larger basis sets and it can
be said that relatively small basis sets for GIAO method are
1
more successful. It was observed that in H NMR calcula-
tions, almost all basis sets are unsuccessful for the estimation
of chemical shifts of –NH group protons. The agreement
2
between experimental and computational data is also been
represented in Figs. 4 and 5.
Fig. 4 Calculated and experi-
1
mental H NMR chemical shifts
for compound 5a (CSGT)
1
3

Journal of the Iranian Chemical Society (2019) 16:899–912
905
Fig. 5 Calculated and experi-
1
mental H NMR chemical shifts
for compound 5a (GIAO)
Molecular electrostatic potential maps
atom or molecule in the gaseous state. Additionally, elec-
tronegativity, chemical hardness, chemical softness, elec-
tronic chemical potential and electrophilicity index can be
calculated using the following equations [23–29]:
Molecular electrostatic potential (MEP) map gives informa-
tion about the electron-rich and electron-deficient parts of
the investigated molecules. MEP maps were calculated at
DFT B3LYP level of theory using 6-31G(d), 6-31G(d,p),
I = −EHOMO
,
(1)
(2)
(3)
(4)
(5)
(6)
(7)
6
-311G(d,p), 6-31+G(d), 6-31+G(d,p), 6-311+G(d,p) and
-311+G(2d,p) basis sets. Calculated MEP diagrams of the
A = −ELUMO
,
6
compounds 5a–f at B3LYP/6-311+G(2d,p) level of theory
are given in Fig. 6. For compounds 5a–f, it can be seen
that negative charge was dominantly located on the nitrogen
atoms of the thiadiazole ring and positive charge was located
ꢀ = (I + A)∕2,
= (I − A)∕2,
S = 1∕2ꢀ,
ꢀ
on the –NH group attached to thiadiazole ring.
2
ꢀ
= −(I + A)∕2,
Frontier molecular orbitals and global reactivity
descriptors
2
ꢀ = ꢁ ∕2ꢂ.
Chemical hardness is a measure of the resistance
of a compound to change in its electronic configura-
tion [30]. Chemical hardness values of compounds
5a–f showed a similar trend to the HOMO–LUMO gap
values. It can be seen that chemical hardness of com-
pound 5a is the biggest one and sequence is as follows:
5a > 5c > 5d > 5b > 5e > 5 f. Electrophilicity index is con-
sidered to be a measure of electrophilic power [23]. A good
electrophile is characterized by a high value of electrophi-
licity index; in opposite, lower values correspond to good
nucleophiles. It was found that the electrophilicity index
of compound 5a is the lowest one and the sequence is as
follows: 5e > 5f > 5d > 5c > 5b > 5a. HOMO–LUMO gaps
also can be used to predict the stability of the investigated
molecules, and larger HOMO–LUMO gaps correspond to
more stable molecules. Calculated HOMO–LUMO gaps
Lowest unoccupied molecular orbital (LUMO) and the high-
est occupied molecular orbital (HOMO) calculations were
carried out at DFT B3LYP level of theory using 6-31G(d),
6
6
-31G(d,p), 6-311G(d,p), 6-31 + G(d), 6-31 + G(d,p),
-311+G(d,p) and 6-311+G(2d,p) basis sets. HOMO and
LUMOs of the compounds 5a–f calculated at B3LYP/6-
3
11+G(2d,p) level of theory are given in Fig. 7.
Ionization potential (I), electron affinity (A), electron-
egativity (χ), chemical hardness (η), chemical softness (S),
electronic chemical potential (µ) and electrophilicity index
(
ω) values have been determined with various basis sets.
Ionization potential can be defined as the minimum energy
required to remove an electron from an atom or molecule
and can be calculated using Eq. (1), and electron affinity
can be calculated using Eq. (2) [22] and corresponds to
the energy released when an electron is added to a neutral
1
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Journal of the Iranian Chemical Society (2019) 16:899–912
Fig. 6 MEP maps for compounds 5a–f
for compounds 5a–f are given in Fig. 8. It can be seen
from Fig. 8 that HOMO–LUMO gap values are generally
increasing with the use of larger basis sets. The largest
HOMO–LUMO gap values are obtained with 6-31G(d)
and the smallest ones obtained with 6-311+ G(2d,p) basis
set for all compounds.
electronic chemical potential values have been obtained for
compound 5a, and the highest ionization potential, electron
affinity, electronegativity and electrophilicity index values
have been obtained for compound 5e.
Mulliken atomic charges
Global reactivity descriptors for compound 5a, calcu-
lated with various basis sets, are given in Table 5. It can
be seen from Table 5 that for a given molecule, generally,
HOMO–LUMO gap, chemical hardness, and electronic
chemical potential values are decreasing with the use of
larger basis sets, and ionization potential, electronegativity,
electrophilicity index and electron affinity values are increas-
ing with the use of larger basis sets. On the other hand, it
was observed that there is not a considerable difference in
chemical softness values calculated with various basis sets.
Global reactivity descriptors have been calculated at
B3LYP 6-311+G(2d,p) level of theory for compounds 5a–f
which are given in Table 6. It can be seen from Table 6 that
the highest HOMO–LUMO gap, chemical hardness, and
The Mulliken charge distribution over the atoms affects the
molecular polarizability, electronic structure, dipole moment,
etc. In the computational studies, the Mulliken charge dis-
tribution of the synthesized molecules were determined at
DFT B3LYP level of theory with the use various basis sets
including 6-31G(d), 6-31G(d,p), 6-311G(d,p), 6-31+G(d),
6-31 + G(d,p), 6-311 + G(d,p) and 6-311 + G(2d,p) basis
sets. The Mulliken atomic charges have been calculated at
B3LYP/6-311+G(2d,p) level of theory for compounds 5a–f,
and are given in Table 7 and Fig. 9. Atoms in the thiadia-
zole ring and the nitrogen atom of the –NH group which is
2
attached to thiadiazole ring possess almost the same Mulliken
atomic charges for all compounds. Considerable Mulliken
1
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Journal of the Iranian Chemical Society (2019) 16:899–912
907
Fig. 7 HOMO and LUMOs of compounds 5a–f
ꢀ
ꢁ
atomic charge differences between compounds 5a–f appears
on the 6S atom and especially on the 8C and phenyl ring car-
bons because of the effects of halogens on the phenyl ring.
In Fukui function calculations, for a given molecular sys-
tem, independent single point calculations and natural popu-
lation analysis have been performed for N, N+1 and N−1
electron systems. After determination of the ρ (N+1), ρ (N)
0
f = ꢀ (N + 1) − ꢀ (N − 1) ∕2.
k
(10)
k
k
Condensed Fukui functions for compounds 4a–f and
5
a–f are given in Tables 8 and 9. As expected, for aryl
halides (4a–f), 7C carbon atom is the reactive site for a
nucleophilic attack. It can be seen from Table 8, for all aryl
+
halides, the highest f values have been obtained for 7C
k
k
k
+
carbon atom. The order of the f values for aryl halides
k
and ρ (N−1) values for all k atoms, condensed Fukui func-
k
+
is as follows: 4a > 4d > 4e > 4b > 4f > 4c. As can be seen
tions have been calculated using Eqs. (8–10). As known, f
k
+
−
from Table 9, for compounds 5a–f, the highest fk values
corresponds to nucleophilic attack, f corresponds to electro-
k
−
0
have been obtained for 8C carbon atom and highest fk val-
philic attack and f corresponds to radical attack.
k
ues have been obtained for 1C carbon atom in all cases.
+
fk = ꢀ (N + 1) − ꢀ (N),
k
k
(8)
(9)
−
fk = ꢀ (N) − ꢀ (N − 1),
k
k
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Journal of the Iranian Chemical Society (2019) 16:899–912
Fig. 8 Calculated HOMO–
LUMO gaps for compounds
5
a–f
Table 5 Global reactivity
opt1a
opt2b
opt3c
opt4d
opt5e
opt6f
opt7g
descriptors for compound 5a
LUMO
HOMO
Gap
I
A
χ
η
S
µ
ω
−0.5135
−5.8292
5.3157
5.8292
0.5135
3.1714
2.6579
0.1881
−3.1714
1.8920
−0.5165
−5.8227
5.3062
5.8227
0.5165
3.1696
2.6531
0.1885
−3.1696
1.8933
−0.7970
−6.0126
5.2156
6.0126
0.7970
3.4048
2.6078
0.1917
−3.4048
2.2227
−0.9238
−6.0823
5.1585
6.0823
0.9238
3.5031
2.5792
0.1939
−3.5031
2.3789
−0.9293
−6.0717
5.1424
6.0717
0.9293
3.5005
2.5712
0.1945
−3.5005
2.3828
−0.9704
−6.1160
5.1457
6.1160
0.9704
3.5432
2.5728
0.1943
−3.5432
2.4398
−0.9559
−6.0850
5.1291
6.0850
0.9559
3.5205
2.5645
0.1950
−3.5205
2.4164
a
6
6
6
6
-31G(d)
b
c
d
e
f
-31G(d,p)
-311G(d,p)
-31+G(d)
6
-31+G(d,p)
6
-311+G(d,p)
6
g
-311+G(2d,p)
Results and discussion
the synthesis of 5-(benzylthio)-1,3,4-thiadiazol-2-amine
derivatives.
In this work, novel ultrasound-assisted methods have been
proposed for the synthesis of 5-amino-1,3,4-thiadiazole-
In the synthesis of 5-amino-1,3,4-thiadiazole-2-thiol, the
ultrasound-assisted reaction has been carried out at 50 °C. The
reaction has also been carried out at room temperature but in
this case lower reaction yields have been observed. The reac-
tion also carried out at various reaction times. It was observed
that increasing reaction time increases the reaction yield grad-
ually but over 30 min there is not a considerable increase in the
reaction yield. The results showed that the ultrasound-assisted
2
-thiol and for the synthesis of 5-(benzylthio)-1,3,4-
thiadiazol-2-amine derivatives. The proposed methods
allow investigated reactions in good yields. Yields for
the reactions are approximately 90% for the synthesis
of 5-amino-1,3,4-thiadiazole-2-thiol and 80–85% for
1
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Journal of the Iranian Chemical Society (2019) 16:899–912
909
Table 6 Global reactivity
5
a
5b
5c
5d
5e
5f
descriptors for compounds 5a–f
LUMO
HOMO
Gap
I
A
χ
η
S
µ
ω
−0.9559
−6.0850
5.1291
6.0850
0.9559
3.5205
2.5645
0.1950
−3.5205
2.4164
−1.2109
−6.1130
4.9021
6.1130
1.2109
3.6620
2.4511
0.2040
−3.6620
2.7356
−1.2090
−6.1952
4.9862
6.1952
1.2090
3.7021
2.4931
0.2006
−3.7021
2.7487
−1.2357
−6.2020
4.9664
6.2020
1.2357
3.7188
2.4832
0.2014
−3.7188
2.7847
−1.4452
−6.2121
4.7669
6.2121
1.4452
3.8286
2.3834
0.2098
−3.8286
3.0751
−1.4408
−6.1185
4.6776
6.1185
1.4408
3.7797
2.3388
0.2138
−3.7797
3.0541
Table 7 Mulliken atomic
5
a
5b
5c
5d
5e
5f
charges for compounds 5a–f
1
2
3
4
5
6
7
8
9
1
1
1
1
1
C
N
N
C
S
S
N
C
0.645
0.650
−0.127
−0.279
0.058
−0.256
−0.421
−0.403
−0.695
0.951
0.643
−0.127
−0.278
0.061
−0.245
−0.337
−0.402
−1.156
1.668
−0.423
−0.762
1.355
−0.751
−0.430
0.635
−0.126
−0.280
0.060
−0.246
−0.330
−0.402
−1.043
1.640
−0.347
−0.570
0.756
−0.562
−0.350
0.660
−0.128
−0.277
0.055
−0.253
−0.429
−0.401
−0.921
0.905
0.594
−1.053
1.296
−0.562
−0.645
0.653
−0.122
−0.284
0.061
−0.266
−0.549
−0.403
−0.305
0.331
−0.132
−0.277
0.059
−0.250
−0.337
−0.403
−0.891
1.550
−0.366
−0.212
−0.041
−0.206
−0.366
C
0C
1C
2C
3C
4C
0.729
0.417
−0.733
−0.082
−0.168
−0.416
−0.426
−0.228
−0.432
0.426
Fig. 9 Mulliken atomic charges
for compounds 5a–f
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Journal of the Iranian Chemical Society (2019) 16:899–912
Table 8 Condensed Fukui
fk−
fk+
fk0
fk−
fk+
fk0
function for compounds 4a–f
4a
4b
4c
C1
C2
C3
C4
C5
C6
C7
C1
C2
C3
C4
C5
C6
C7
C1
C2
C3
C4
C5
C6
C7
−0.023
−0.194
−0.023
−0.042
−0.151
−0.042
0.021
−0.016
−0.071
−0.193
0.036
−0.139
−0.082
0.042
−0.053
−0.085
−0.053
−0.018
−0.196
−0.018
0.041
−0.024
−0.040
−0.024
0.003
−0.060
0.003
−0.023
−0.117
−0.023
−0.019
−0.105
−0.019
0.093
−0.024
−0.050
−0.108
0.028
−0.101
−0.040
0.058
−0.039
−0.049
−0.043
−0.014
−0.127
0.001
4d
4e
4f
C1
C2
C3
C4
C5
C6
C7
C1
C2
C3
C4
C5
C6
C7
C1
C2
C3
C4
C5
C6
C7
−0.044
−0.053
−0.044
−0.018
−0.152
−0.018
0.030
−0.023
−0.035
−0.023
−0.004
−0.040
−0.004
0.112
−0.032
−0.011
−0.024
0.018
−0.063
0.001
0.078
−0.020
−0.066
−0.020
−0.006
−0.050
−0.006
0.071
−0.033
−0.044
−0.033
−0.011
−0.096
−0.011
0.071
−0.015
−0.036
−0.070
0.025
−0.130
−0.008
0.060
−0.102
−0.011
−0.102
−0.022
−0.028
−0.022
0.050
0.164
−0.032
−0.029
−0.023
0.020
−0.063
0.002
0.002
−0.061
−0.116
0.032
−0.197
−0.016
0.041
−0.184
0.043
−0.184
−0.038
−0.005
−0.038
0.029
0.074
−0.024
−0.012
−0.033
−0.010
−0.057
0.019
0.062
0.051
Table 9 Condensed Fukui
fk−
fk+
fk0
fk−
fk+
fk0
function for compounds 5a–f
5
a
1C
0.048
−0.101
−0.110
−0.021
−0.125
−0.270
−0.121
−0.020
0.041
−0.111
−0.120
−0.021
−0.127
−0.268
−0.129
−0.023
0.045
−0.092
−0.103
−0.019
−0.119
−0.255
−0.116
−0.015
0.032
−0.091
−0.042
−0.043
−0.118
−0.664
−0.025
0.215
0.040
−0.096
−0.076
−0.032
−0.121
−0.467
−0.073
0.097
5d
5e
5f
1C
2N
3N
4C
5S
6S
7N
8C
1C
2N
3N
4C
5S
6S
7N
8C
1C
2N
3N
4C
5S
6S
7N
8C
0.045
−0.088
−0.099
−0.019
−0.115
−0.247
−0.112
−0.012
0.045
−0.094
−0.110
−0.019
−0.123
−0.268
−0.122
−0.019
0.058
−0.149
−0.121
−0.027
−0.103
−0.335
−0.135
0.008
0.034
−0.096
−0.029
−0.044
−0.112
−0.671
−0.026
0.211
0.039
−0.092
−0.064
−0.032
−0.114
−0.459
−0.069
0.099
2
3
4
5
6
7
8
N
N
C
S
S
N
C
5
b
1C
0.032
0.037
0.033
0.039
2
3
4
5
6
7
8
N
N
C
S
S
N
C
−0.096
−0.030
−0.045
−0.113
−0.674
−0.026
0.219
−0.104
−0.075
−0.033
−0.120
−0.471
−0.077
0.098
−0.100
−0.030
−0.044
−0.110
−0.673
−0.025
0.222
−0.097
−0.070
−0.031
−0.116
−0.471
−0.074
0.102
5
c
1C
0.033
0.039
0.010
0.034
2
3
4
5
6
7
8
N
N
C
S
S
N
C
−0.100
−0.047
−0.040
−0.116
−0.661
−0.025
0.221
−0.096
−0.075
−0.030
−0.117
−0.458
−0.070
0.103
−0.058
−0.028
−0.043
−0.104
−0.576
−0.023
0.208
−0.104
−0.075
−0.035
−0.104
−0.455
−0.079
0.108
1
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Journal of the Iranian Chemical Society (2019) 16:899–912
911
method for the synthesis of 5-amino-1,3,4-thiadiazole-2-thiol
is a good alternative to conventional heating, because of the
dramatically decreased reaction times. The methods in which
conventional heating is used, it takes minimum 4 h of reflux
to complete the reaction.
Conclusion
In conclusion, in this study, for the synthesis of
5-amino-1,3,4-thiadiazole-2-thiol (3) and for the synthe-
sis of 5-(benzylthio)-1,3,4-thiadiazol-2-amine derivatives
(5a–f), ultrasound-assisted alternative methods to conven-
tional techniques have been proposed. Optimization stud-
ies on the investigated reaction also carried out for the
determination of the optimum reaction conditions. It has
been observed that proposed ultrasound-assisted methods
are rapid, efficient, time and energy saving, and also good
alternatives to conventional techniques. Some DFT cal-
culations have also been performed on the chemical spe-
cies which take place in the investigated reactions, and the
computationally obtained data have been compared with
the experimental results. To determine which computa-
tional techniques are more suitable to define the inves-
tigated reactions and chemical species, seven basis sets
In the synthesis of 5-(benzylthio)-1,3,4-thiadiazol-2-amine
derivatives, it takes 20 min to consume all the reactants at room
temperature. This reaction was also carried out with the use of
potassium hydroxide as a base. In this case, it was observed
that the reaction yields are identical but it takes a bit longer
time to complete the reaction. The results showed that ultra-
sound-assisted method is a good alternative to conventional
methods because of the decreased reaction times. In conven-
tional methods, it takes up to 24 h to convert 5-amino-1,3,4-
thiadiazole-2-thiols to their 5-(benzylthio)-1,3,4-thiadiazol-
2
-amine derivatives.
In the computational part, in NMR calculations, it has
been observed that in general, GIAO method is more suc-
cessful than CSGT method. It has also been observed that
the accuracy of the CSGT method increases with the use of
larger basis sets in opposite to GIAO method. In this study, for
CSGT method acceptable results have been obtained only with
1
and in some certain cases different methods (i.e. H NMR
calculations) have also been used and compared with each
other.
6
-311+G(2d,p) basis set which is the largest basis set used in
Funding This work was financially supported by Kocaeli University
Scientific Research Projects Unit. Project Numbers: 2011/062; 2017/38
HD.
this study. On the other hand, for GIAO method it has been
observed that relatively small basis sets are more successful.
For GIAO methods, it has been observed that 6-31G(d) and
6
-31+G(d) basis sets are the best ones which are the smallest
basis sets used in this study. Relatively larger basis sets with
References
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