5-Mercapto-1,3,4-thiadiazole-2(3H)-thione: Synthesis and structure of alkylated derivatives

Article abstract of DOI:10.1002/jhet.1903

The observed structure of 1,3,4-thiadiazolidine-2,5-dithione (also known as 2,5-dimercapto-1,3,4-thiadiazole) has been previously reported in three different tautomeric forms including - dithiol and - dithione. This report examines the relative stability of each form and also reports synthesis and characterization of the structures of mono-alkylated and di-alkylated forms of 5-mercapto-1,3,4-thiadiazole-2(3H)-thione. The methods of X-ray crystallography, NMR spectroscopy, and ab initio electronic structure calculations were combined to understand the reactivity and structure of each compound.

Full text of DOI:10.1002/jhet.1903

May 2014
5-Mercapto-1,3,4-thiadiazole-2(3H)-thione: Synthesis and Structure of
Alkylated Derivatives
747
Jigar K. Mistry, Richard Dawes,* Amitava Choudhury, and Michael R. Van De Mark*
Department of Chemistry, Missouri S&T Coatings Institute, Missouri University of
Science and Technology, Rolla, Missouri 65409
*
E-mail: dawesr@mst.edu; mvandema@mst.edu
Received June 4, 2012
DOI 10.1002/jhet.1903
Published online 3 December 2013 in Wiley Online Library (wileyonlinelibrary.com).
The observed structure of 1,3,4-thiadiazolidine-2,5-dithione (also known as 2,5-dimercapto-1,3,4-thiadiazole)
has been previously reported in three different tautomeric forms including —dithiol and—dithione. This report
examines the relative stability of each form and also reports synthesis and characterization of the structures of
mono-alkylated and di-alkylated forms of 5-mercapto-1,3,4-thiadiazole-2(3H)-thione. The methods of X-ray
crystallography, NMR spectroscopy, and ab initio electronic structure calculations were combined to understand
the reactivity and structure of each compound.
J. Heterocyclic Chem., 51, 747 (2014).
INTRODUCTION
,3,4-Thiadiazolidine-2,5-dithione (CAS 1072-71-5) is
RESULTS AND DISCUSSION
1
MTT as well as the mono-alkylated structure can exist in
various tautomeric forms, and the di-alkylated structure
can exist in three structurally isomeric forms. The stability
of each tautomer was evaluated through ab initio electronic
structure calculations. These calculations are presented con-
sidering MTT first, followed by the alkylated derivatives.
also known as 2,5-dimercapto-1,3,4-thiadiazole, DMTD
or bismuththiol. Its derivatives find application as raw
material for various organic syntheses, analytical reagents,
fuel additives, lubricant additives, intermediates for other
pharmaceutical compounds, chelating compounds for
metals, and flash-rust and corrosion inhibitors in coatings.
In our previous work of evaluating, the corrosion inhibi-
tion performance of 2,5-bis(thioaceticacid)-1,3,4-thiadiazole
The structure of MMT.
Table 1 lists the results of
various levels of calculation for the three contending
tautomeric forms of MTT. Structure 2 is predicted to be
the lowest energy structural isomer by all of the
computational methods employed. The highest level
explicitly-correlated coupled-cluster (F12) calculations
(Table 1) with corrections for solvation in ethanol predict
structures 1 and 3 to lie about 4.7 and 5.9 kcal/mol higher
in energy, respectively. Finite temperature effects at
298 K were estimated and added to the energies by using
harmonic oscillator–rigid rotor approximate free energy
corrections obtained from force-field analyses at the
B3LYP/aug-cc-pVTZ and MP2/aug-cc-pVTZ levels.
Energies for the explicitly correlated F12 methods were
combined with thermal corrections from the MP2
(
H ADTZ) for its use as a potential flash-rust inhibitor
2
and a corrosion inhibitor in coatings [1], the compound 5-
mercapto-1,3,4-thiadiazole-2(3H)-thione (MTT) was used
as a starting material. The structure of MTT is often reported
in the literature in its tautomeric—dithiol form or in the—
dithione form. In fact, it has been shown to have three
tautomeric structures [2–4], with structure 1 being the most
commonly reported in the literature (Fig. 1).
An X-ray crystal structure of MTT was reported in 1976
consistent with structure 2 [5]. Several recent reports refer
to the structure of MTT as that of structure 3[6–8]. In order
to synthesize and evaluate the various mono-substituted
and di-substituted derivatives of MTT as potential anti-
flash-rust and anti-corrosives for coatings, it was important
to know and understand the substitution mechanism of this
compound and its various derivatives as well as to deter-
mine the structures and their stability. This report addresses
the structure and various substitution products of MTT by
combining results of ab initio electronic structure calcula-
tions, X-ray crystallography, and NMR spectroscopy to
validate and better understand the chemistry of MTT.
calculations.
A
correction for solvation modeled
[polarizable continuum model (PCM)] at the B3LYP/
aug-cc-pVTZ level (including geometric relaxation) was
added to both the DFT and F12 results. The X-ray crystal
structure determined in this study is shown in Fig. 2. Our
newly determined structure is in close agreement with
that previously reported by J. W. Bats [5].
Mono-alkylation of MTT. The mono-alkylation of MTT
can produce four possible structures (4–7). Structures 4 and 5
©
2013 HeteroCorporation

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J. K. Mistry, R. Dawes, A. Choudhury, and M. R. Van De Mark
Vol 51
5
-mercapto-1,3,4-thiadiazole-2(3H)-thione
Structure 1
Structure 2
Structure 3
Figure 1. Three tautomeric forms of MTT.
derive from S-alkylation, whereas structures 6 and 7 come
from N-alkylation (Fig. 3).
Table 1
Calculated relative energies (kcal/mol) for structures 1-3 including ther-
mal corrections at 298 K, and the effects of solvation in ethanol [where
designated by (s)].
The precursors to structures 4–7 are the anions that
could exist as either structure 8 or 9. The highest level ab
initio calculations for structures 8 and 9 predict that
structure 8 is more stable by 7.37 kcal/mol (Table 2), and
thus the proton is lost from the sulfur and not the nitrogen
during alkylation (Figs. 4 and 5).
SN2 reaction transition structures (TS) 10 and 11 were
located corresponding to methylation of 8 at the S or N
positions, respectively, with the use of chloromethane
Method
Structure 1 Structure 2 Structure 3
a
B3LYP/6-31G(d)
B3LYP/AVTZ
8.57
7.43
8.52
4.48
4.04
3.57
3.59
0.00
0.00
0.00
0.00
0.00
0.00
0.00
6.03
6.82
2.77
a
a
B3LYP/AVTZ (s)
b
MP2/AVDZ
MP2/AVTZ
9.51
b
10.08
10.50
9.92
b
MP2-F12/VDZ-F12
CCSD(T)-F12a/
(rather than iodomethane that was used in the experiment
b
to reduce the number of electrons in the calculations) as
the alkylating agent. Methylation at the S position is
strongly preferred with 10 predicted to be 6.21 kcal/mol
lower in free energy than 11 for the highest level calcula-
tions (including the preferential solvation of 11) (Table 3
and Fig. 6).
VDZ-F12
CCSD(T)-F12b/
VDZ-F12
3.57
4.68
0.00
0.00
9.99
5.87
b
CCSD(T)-F12a/
b
VDZ-F12 (s)
All F12 calculations used structures optimized at the MP2/AVTZ level
(
see text). (s) including implicit PCM solvation model for ethanol.
Thermal corrections computed at B3LYP/AVTZ level.
Thermal corrections computed at MP2/AVTZ level.
a
Methylation of 8 through TS 10 or 11 leads to product
structures 12 and 15, respectively, whereas methylation
of disfavored anion 9 at the two positions would lead to
structures 13 and 14. Table 4 compares the calculated
energies of all four possible products. Structure 12 is pre-
dicted to be the most stable of all four of the methylated
structures. Looking at the reaction scheme, structure 12 is
strongly favored both kinetically and thermodynamically.
The lower energy anion 8 reacts through the lower energy
TS 10 to form the most stable product 12. Not surprisingly,
the product of the first methylation step was confirmed by
b
Figure 2. Thermal ellipsoids for MTT as observed through X-ray crystal-
lography. [Color figure can be viewed in the online issue, which is avail-
able at wileyonlinelibrary.com.]
13
X-ray crystallography (Fig. 7) and C NMR spectroscopy
to be structure 12.
Structure 4
Structure 5
Structure 6
Structure 7
R = Alkyl]
[
Figure 3. Four possible mono-substituted products of MTT.
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5-Mercapto-1,3,4-thiadiazole-2(3H)-thione: Synthesis and Structure of Alkylated
Derivatives
749
Table 2
Calculated relative energies (kcal/mol) for anion structures 8 and 9 in-
cluding thermal corrections at 298 K, and the effect of solvation in ethanol
[
where designated by (s)].
Method
Structure 8
Structure 9
a
B3LYP/6-31G(d)
B3LYP/AVTZ
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
15.50
13.68
10.62
11.22
10.74
10.25
10.44
10.44
7.37
a
Structure 10
Structure 11
a
B3LYP/AVTZ (s)
b
Figure 5. The S 2 transition structures for two possible alkylation sites—at
N
MP2/AVDZ
MP2/AVTZ
b
the sulfur (structure 10) or at the nitrogen (structure 11). [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
b
MP2-F12/VDZ-F12
CCSD(T)-F12a/VDZ-F12
CCSD(T)-F12b/VDZ-F12
b
b
b
CCSD(T)-F12a/VDZ-F12 (s)
Table 3
Calculated relative energies (kcal/mol) for S
N
2 transition structures 10 and
All F12 calculations used structures optimized at the MP2/AVTZ level
11 including thermal corrections at 298 K, and the effect of solvation in
(
see text). (s) including implicit PCM solvation model for ethanol.
Thermal corrections computed at B3LYP/AVTZ level.
a
ethanol [where designated by (s)].
b
Thermal corrections computed at MP2/AVTZ level.
TS
TS
Method
(Structure 10)
(Structure 11)
a
B3LYP/AVTZ
0.00
7.44
5.77
7.21
7.54
7.89
7.89
6.21
a
B3LYP/AVTZ (s)
0.00
0.00
0.00
0.00
0.00
0.00
b
MP2/AVTZ
b
MP2-F12/VDZ-F12
CCSD(T)-F12a/VDZ-F12
CCSD(T)-F12b/VDZ-F12
CCSD(T)-F12a/VDZ-F12 (s)
b
b
Structure 8
Structure 9
b
Figure 4. Two possible anionic forms of MTT. [Color figure can be
viewed in the online issue, which is available at wileyonlinelibrary.com.]
All F12 calculations used structures optimized at the MP2/AVTZ level
(see text). (s) including implicit PCM solvation model for ethanol.
a
Thermal corrections computed at B3LYP/AVTZ level.
b
Thermal corrections computed at MP2/AVTZ level.
The T -diagnostic is around 0.02 for all calculated
1
structures supporting the reliability of single-reference
whereas MP2 calculations actually favor 17. Preferential
solvation of 16 contributes the most to the net difference of
1.62kcal/mol at the CCSD(T)-F12a (s) level. Given the
smaller differences in barrier heights (than for the first
methylation step) and the discrepancy with the MP2 results,
additional DFT calculations were performed with the use of
iodomethane and the Quadruple Zeta Valence Polarization
(QZVP) basis set. Including solvation by ethanol and ther-
mal corrections at 298 K, the difference in barrier heights
increases to 2.91kcal/mol, making methylation at the S posi-
tion more strongly kinetically favored. Table 6 compares the
energies of di-methylation structures 18–20. Assuming a
concerted 6-membered transition state involving the sodium
salt and the alkyl halide, the relative energy was 31.4 kcal/
mol higher than TS 16 (Fig. 9).
13
methods to describe these systems. Calculated C NMR
shifts (relative to TMS) were obtained for structures 12
and 13 by using the GIAO method [9] with B3LYP and
the 6-31 G* basis set. Calculated shifts for the ring carbons
are 159.6 and 186.0 ppm (structure 12) and 158.6 and
1
67.1 ppm (structure 13). The calculated values for struc-
ture 12 agree closely with experimentally recorded values
of 159.4 and 187.6 ppm.
Di-alkylation of MTT. The di-alkylation of MTT was
analogously investigated. From structure 12 (mono-
alkylated MTT), a second alkylation can occur at two
possible alkylation sites—either at the sulfur (forming
structure 16) or at the nitrogen (forming structure 17)
(Fig. 8).
Considering the second methylation step starting from 12
and again with the use of chloromethane as the alkylating
agent (to simplify the calculations), TS structures 16 and
7 were located connecting 12 with product structures 19
and 20, respectively. Table 5 compares calculated energies
for TSs 16 and 17. Methylation at the S position appears to
be kinetically favored as 16 is predicted to be lower in
estimated free energy at 298 K than 17 for the B3LYP and
CCSD(T)-F12 calculations. The differences in this case are
only 1.0 and 0.6 kcal/mol (B3LYP and CCSD(T)-F12),
TSs 16 and 17 connect 12 with 19 and 20, respectively,
whereas 18 is included for comparison. Structure 19 is pre-
dicted to be significantly less stable (2.9–3.8 kcal/mol) than
20 yet has been confirmed through X-ray crystallography
as the only detectable product structure. The highest level
calculations reported here are expected to be quite reliable
especially for estimating the relative energies of
product structures. The best calculations with the use of
chloromethane do predict 19 as the kinetically favored
product and DFT calculations for iodomethane favor it
1
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J. K. Mistry, R. Dawes, A. Choudhury, and M. R. Van De Mark
Vol 51
Figure 6. Four potential mono-alkylation structures 12–15. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]
Table 4
Calculated relative energies (kcal/mol) for structures 12–15 including thermal corrections at 298 K, and the effect of solvation in ethanol [where
designated by (s)].
Method
Structure 12
Structure 13
Structure 14
Structure 15
a
B3LYP/6-31G(d)
B3LYP/AVTZ
0.00
0.00
0.00
1.56
0.02
0.00
0.00
0.00
0.00
8.33
7.21
8.58
5.77
3.83
3.38
3.35
3.34
4.72
1.06
1.92
2.72
0.00
0.00
0.61
1.03
1.01
1.83
6.31
7.72
4.39
9.23
9.60
10.55
10.25
10.30
6.93
a
a
B3LYP/AVTZ (s)
b
MP2/AVDZ
MP2/AVTZ
b
b
MP2-F12/VDZ-F12
CCSD(T)-F12a/VDZ-F12
CCSD(T)-F12b/VDZ-F12
b
b
b
CCSD(T)-F12a/VDZ-F12 (s)
All F12 calculations used structures optimized at the MP2/AVTZ level (see text). (s) including implicit PCM solvation model for ethanol.
a
Thermal corrections computed at B3LYP/AVTZ level.
Thermal corrections computed at MP2/AVTZ level.
b
Table 5
N
Calculated relative energies (kcal/mol) for S 2 transition structures 16 and
17 including thermal corrections at 298 K, and the effect of solvation in
ethanol [where designated by (s)].
TS
TS
Figure 7. Thermal ellipsoids for Me–MTT as observed through X-ray
crystallography. [Color figure can be viewed in the online issue, which
is available at wileyonlinelibrary.com.]
Method
(Structure 16)
(Structure 17)
a
B3LYP/AVTZ
B3LYP/AVTZ (s)
MP2/AVTZ
MP2-F12/VDZ-F12
CCSD(T)-F12a/VDZ-F12
CCSD(T)-F12b/VDZ-F12
CCSD(T)-F12a/VDZ-F12 (s)
B3LYP/QZVP (s) iodo
0.00
1.04
2.02
0.00
0.00
0.64
0.61
1.62
2.91
a
0.00
0.79
0.40
0.00
0.00
0.00
0.00
b
b
b
b
b
c
All F12 calculations used structures optimized at the MP2/AVTZ level
(
see text). (s) including implicit PCM solvation model for ethanol.
Thermal corrections computed at B3LYP/AVTZ level.
Thermal corrections computed at MP2/AVTZ level.
DFT calculation using iodomethane (see text).
a
b
c
Figure 8. The transition structures for di-alkylation of MTT. [Color
figure can be viewed in the online issue, which is available at wileyonline-
library.com.]
product of MTT, namely H ADTZ was obtained to recon-
2
firm the aforementioned results that both of the substitu-
1
13
tions occur on sulfur. Both H and C NMR spectra of
dimethylated MTT and H ADTZ are consistent with the
X-ray determined structure 19. 2,5-bis(methylthio)-1,3,4-
even more. The barrier for methyl transfer converting 19
into 20 was computed (at the B3LYP/AVTZ level) to be
2
13
5
5.5 kcal/mol, which supports the idea that once 19 is
thidiazole-2-thiol (dimethylated MTT) showed
C
formed, it will not easily convert to the more stable 20.
Because 2,5-bis(methylthio)-1,3,4-thidiazole-2-thiol is a
liquid compound, a crystal structure for the di-alkylation
peaks in d-DMSO at 165.56 ppm (–N═C–S–Me), and
15.60 (–CH3) and GC–MS parent peak at 177 (isotopic
abundance peaks because of sulfur at 178 and 179), and
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5-Mercapto-1,3,4-thiadiazole-2(3H)-thione: Synthesis and Structure of Alkylated
Derivatives
751
Table 6
Calculated relative energies (kcal/mol) for structures 18, 19, and 20 in-
cluding thermal corrections at 298 K, and the effect of solvation in ethanol
[
where designated by (s)].
Method
Structure 18
Structure 19
Structure 20
a
B3LYP/6-31G(d)
B3LYP/AVTZ
8.89
10.34
7.09
7.89
5.89
6.76
6.43
4.45
3.40
2.93
0.00
0.00
0.00
0.00
0.00
0.00
0.00
a
a
B3LYP/AVTZ (s)
b
MP2/AVDZ
MP2/AVTZ
9.42
b
11.23
12.16
11.75
b
MP2-F12/VDZ-F12
CCSD(T)-F12a/
Figure 10. Thermal ellipsoid for 2,5-bis(thioaceticacid)-1,3,4-thiadiazole
(H ADTZ) as observed through X-ray crystallography. [Color figure can
2
b
VDZ-F12
CCSD(T)-F12b/
VDZ-F12
11.82
8.50
2.93
3.81
0.00
0.00
be viewed in the online issue, which is available at wileyonlinelibrary.
com.]
b
CCSD(T)-F12a/
b
VDZ-F12 (s)
EXPERIMENTAL
All F12 calculations used structures optimized at the MP2/AVTZ level
(
see text). (s) including implicit PCM solvation model for ethanol.
Thermal corrections computed at B3LYP/AVTZ level.
Thermal corrections computed at MP2/AVTZ level.
a
Materials. The starting material MTT was obtained from R.
T. Vanderbilt who lists the chemical as DMTD (Structure 1) and
was re-crystallized from benzene before use. All the solvents
were dried and distilled before use unless otherwise specified.
All other chemicals were procured from Fisher or Aldrich and
used as received.
b
significant m/z peaks at 146 and 147 (because of the loss of
two methyl groups), which confirmed the identity of
the compound as 2,5-bis(methylthio)-1,3,4-thiadiazole.
X-ray crystallography.
compounds were collected on
Intensity data sets for all the
Bruker Smart Apex
a
1
3
H ADTZ showed C peaks in d-DMSO at 165.56 ppm
2
diffractometer using SMART software [10]. Suitable crystals
were selected and mounted on a glass fiber using epoxy-based
glue. The data were collected at room temperature employing a
(
–N═C–S–), 169.11 ppm (–COOH), and 35.74 ppm (–CH –)
2
(Fig. 10).
ꢀ
scan of 0.3 in o with an exposure time of 20 s/frame. The cell
refinement and data reduction were carried out with SAINT [11],
the program SADABS was used for the absorption correction
[11]. The structure was solved by direct methods using SHELXS-
CONCLUSION
A combined study by means of X-ray crystallography, C
NMR spectroscopy and ab initio electronic structure calcula-
tions was performed, determining the structure of MTT and
its substituted derivatives conclusively and explaining the
chemistry of its reaction mechanisms (Fig. 11).
13
9
7 [12,13] and difference Fourier syntheses. Full-matrix least-
2
squares refinement against |F | was carried out by using the
SHELXTL-PLUS [12,13] suite of programs. All non-hydrogen
atoms were refined anisotropically. Hydrogen atoms were
placed geometrically and held in the riding mode during the
Structure 18
Structure 19
Structure 20
[
R, R' = Alkyl]
Figure 9. Three possible structures of the di-substituted product of MTT. [Color figure can be viewed in the online issue, which is available at wileyon-
linelibrary.com.]
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J. K. Mistry, R. Dawes, A. Choudhury, and M. R. Van De Mark
Vol 51
Figure 11. The results of X-ray crystallography, NMR spectroscopy, and ab initio electronic structure calculations indicate the preferred structures of
MTT, mono-alkylated MTT, and di-alkylated MTT.
final refinement. However, hydrogen atoms on N and S in case of
MTT and on N in the case of 5-(methylthio)-1,3,4-thidiazole-2-
thiol were well located from the difference Fourier map and
refined subsequently.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the Cambridge
Crystallographic Data Centre as supplementary publication
nos. CCDC 883750 [5-mercapto-1,3,4-thiadiazole-2(3H)-thione],
CCDC 883751 [5-(methylthio)-1,3,4-thidiazole-2(3H)-thione], and
CCDC 883752 [2,5-(S-acetic acid)dimercapto-1,3,4-thiadiazole].
Copies of the data can be obtained, free of charge, on application
to CCDC: 12 Union Road, Cambridge CB2 1EZ, UK, (fax: +44-
N
formed by deprotonation as well as S 2 TSs leading to possible
product structures. The GAUSSIAN09 [15] and MOLPRO2010 [16]
software packages were used for all the calculations reported
here. Geometry optimizations and harmonic vibrational frequency
calculations were used to locate and confirm minimum energy
configurations for each structure. Structures were optimized by
using the B3LYP [17] hybrid DFT method with the 6-31 G* and
aug-cc-pVTZ basis sets as implemented in the GAUSSIAN
program. Additional optimizations were performed with the use
of Møller–Plesset second-order perturbation theory (MP2) [18]
with Dunning’s double and triple-zeta augmented correlation-
consistent basis sets (aug-cc-pVDZ and aug-cc-pVTZ) [19].
Some high-level explicitly correlated F12 [20] single-point energy
calculations were performed by using the structures previously
determined at the MP2/aug-cc-pVTZ level. Peterson’s specialized
double-zeta F12 basis set VDZ-F12[9] was used to compute
energies with the MP2-F12 and CCSD(T)-F12 methods. The
MOLPRO program was used for all explicitly correlated F12
calculations. For all structures, the effect of solvation was
estimated (allowing structural relaxation) at the B3LYP/aug-cc-
pVTZ level by using the implicit PCM solvation model as
parameterized for ethanol in the GAUSSIAN09 program [21]. The
(0)1223-336033 or e-mail: deposit@ccdc.cam.ac.uk).
NMR spectroscopy. The instrument used for recording the
H NMR and C NMR data for liquid state NMR was 400 MHz
1
13
Varian FT/NMR spectrometer. The reference peak used was d for
TMS at 0.0 ppm.
NMR of MTT. The Bruker DRX300 spectrometer with CP-
MAS and 7 mm diameter solid rotor was used for the solid state
NMR. Measurements were made at 5 kHz spinning and the
reference peak used was d for glycine C═O carbon at
1
3
1
76.03ppm. MTT showed C peaks at 159.60ppm (–N═C–SH)
and 189.07 ppm (–N–C═S). The 400 MHz Varian FT/NMR
T1-diagnostic was recorded to confirm the applicability of the
1
3
single-reference methods used in this study.
spectrometer was used for the C NMR liquid state NMR with
13
the use of ethanol-D6 as solvent, and the spectra showed
C
Synthesis of mono-methylated MTT [6] (Structure 12).
To a stirred aqueous solution of potassium hydroxide (0.1 mol,
5.61 g) in absolute ethanol (2.17 mol, 99.97 g), MTT (0.1 mol,
15.02 g) was added. The reaction mixture was stirred for half an
hour before methyl iodide (0.11 mol, 15.61 g) was added to the
mixture and refluxed for 6 h, and then it was cooled and filtered.
The filtered product 5-(methylthio)-1,3,4-thidiazole-2(3H)-thione
(mol. wt. 164.27) was crystallized from benzene to yield a
yellowish needle-shaped precipitates that were dried under
vacuum. The yield was 74% (12.15 g). The melting point of the
peaks at 148.50 ppm (–N═C–SH) and 190.20 ppm (–N–C═S)
confirming the structure to be in the thiol–thione form (one H on
sulfur and another on nitrogen). MTT was observed to form
disulfides in DMSO, and thus DMSO was not considered a
suitable solvent for recording the NMR spectra even though some
1
13
researchers have reported the H NMR and C NMR spectra of
MTT in DMSO-d6 [14].
Ab initio electronic structure calculations.
A variety of
abinitio electronic structure calculations were performed to study
candidate starting material structures 1–3. From the starting
material, two consecutive methylation reactions were studied
comparing at each stage the relative energies of possible anions
ꢀ
compound was found to be 137–138 C. 5-(methylthio)-1,3,4-
13
thidiazole-2(3H)-thione showed C peaks in d-DMSO at 159.39
(–N═C–S–Me), 187.51 (–N–C═S), and 14.67 ppm (–CH3);
Scheme 1. Synthesis of mono-methylated MTT.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2014
5-Mercapto-1,3,4-thiadiazole-2(3H)-thione: Synthesis and Structure of Alkylated
Derivatives
753
1
H peaks in d-DMSO at 2.52 (S–CH ) and 14.30ppm (N–H);
sodium hydroxide (0.3 mol, 12 g) in 1,4-dioxane (0.12 mol,
100 mL), MTT (0.1 mol, 15.02 g) was added. The reaction
mixture was stirred for 30 min before methyl iodide (0.21 mol,
29.80 g) was added to the mixture and refluxed for 6 h, after
which the reaction product was cooled, poured into water, and
3
–1
IR bands at 3050, 1480, 1365, and 1100 cm ; MS peaks at 164,
9
1, 88, 73 and 59m/z (Scheme 1).
Synthesis of di-methylated MTT [22] (Structure 19). To
a stirred aqueous solution of 100 mL DI/distilled water with
Scheme 2. Synthesis of di-methylated MTT.
2
Scheme 3. Synthesis of 2,5-bis(thioaceticacid)-1,3,4-thiadiazole (H ADTZ).
Scheme 4. Proposed mechanism for reactions of MTT.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

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54
J. K. Mistry, R. Dawes, A. Choudhury, and M. R. Van De Mark
Vol 51
extracted twice with diethyl ether, dried over anhydrous sodium
sulfate, filtered, and rotavaped to give a yellowish liquid
product 2,5-bis(methylthio)-1,3,4-thiadiazole (mol. wt. 178.30).
The yield was 79% (14.08 g). The boiling point of the
[5] Bats, J. W. Acta Crystallogr, Sect B: Struct Crystallogr Cryst
Chem 1976, 32, 2866.
[6] Katritzky, A. R.; Wang, Z.; Offerman, R. J. J Heterocycl Chem
1
990, 27(2), 139.
[7] Kuodis, Z.; Rutavichyus, A; Valiulene, S. Chem Heterocycl
ꢀ
compound was found to be 311–313 C. 2,5-Bis(methylthio)-
Compd 2000, 36(5), 598.
13
1
,3,4-thidiazole was a yellowish liquid that showed C peaks
[8] Durust, Y. Phosphorus Sulfur Silicone (ISSN: 1024-6507)
in d-DMSO at 165.56 (–N═C–S–Me) and 15.60 ppm(–CH );
2009, 184, 2923.
3
1
H peaks in d-DMSO at 2.55 ppm (–CH
3
), and GC–MS parent
[9] Peterson, K. A.; Adler, T. B.; Werner, H. J. J Chem Phys 2008,
28, 084102.
10] Bruker. SMART; Bruker AXS Inc.: Madison, Wisconsin,
USA, 2002.
1
peak at 177 (isotopic abundance peaks because of Sulfur at 178
and 179) and significant m/z peaks at 146 and 147 (because of
the loss of 2 methyl groups), which confirmed the identity of
the compound as 2,5-bis(methylthio)-1,3,4-thiadiazole.
[
[11] Bruker. SAINT and SADABS; Bruker AXS Inc.: Madison,
Wisconsin, USA, 2008.
Di-alkylation of MTT can also be achieved by sequential alkyl-
ation of mono-alkylated MTT, but one-pot dimethylation proce-
dure is convenient and therefore preferred. Di-methylated MTT
has been synthesized in similar yields by taking mono-methylated
MTT in absolute ethanol with potassium hydroxide as the
base and iodomethane as the alkylating agent (as per the mono-
methylation described earlier) (Scheme 2).
[12] Sheldrick, G. M. SHELXS-97 and SHELXTL-97; University
of Göttingen, Göttingen, 1997.
[13] Sheldrick, G. M. Acta Cryst 2008, A64, 112.
[14] Salimon, J.; Salih, N.; Hameed, A.; Ibraheem, H.; Yousif, E. J
Appl Sci Res 2010, 6(7), 866.
[15] Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima,
T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.;
Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin,
K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.;
Millam, N. J.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo,
C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin,
A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Martin, R. L.; Morokuma,
K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.;
Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.;
Cioslowski, J.; Fox, D. J. Gaussian 09, Revision B.01; Gaussian, Inc.:
Wallingford, CT, 2010.
2
Synthesis of H ADTZ [1] (Fig. 10). To a stirred aqueous
solution of chloroacetic acid (94.5 g, 1 mol) and sodium
carbonate (53 g, 0.5 mol), MTT (75 g, 0.5 mol) was added. The
reaction mixture was stirred and refluxed for 3 h, then it was
cooled and filtered. Ethanol was added to the reaction mixture,
yielding a white precipitate. The product 2,5-(S-acetic acid)-
2
dimercapto-1,3,4-thiadiazole (H ADTZ) (mol. wt. 266.32) was
then washed with ethanol and dried under vacuum to give a
white solid (H ADTZ). The yield was 83% (110.51 g). The
2
ꢀ
melting point of the compound was found to be 164–165 C.
1
3
2
H ADTZ showed C peaks in d-DMSO at 164.56 (–N═C–S–),
1
1
2
69.11 (–COOH), and 35.74 ppm (–CH –); H peaks in d-
[16] MOLPRO, a package of ab initio programs designed by H.-J.
DMSO at 4.11 (–CH ) and 11.46 ppm (–OH); IR bands at 3410,
2
Werner and P. J. Knowles, Version 2010.1, R. Lindh, F. R. Manby, M.
Schütz et al.
À1
2
920, 2830, 1750, and 1600 cm (Schemes 3 and 4).
[
[
17] Becke, A. D. J Chem Phys 1993, 98, 5648.
18] Head-Gordon, M.; Head-Gordon, T. Chem Phys Lett 1994,
2
20, 122.
19] Kendall, R. A.; Dunning T. H., Jr.; Harrison, R. J. J Chem
Phys 1992, 96, 6796.
20] Adler, T. B.; Knizia, G.; Werner, H. J. J Chem Phys 2007, 127,
21106.
21] (a) Ditchfield, R. Mol Phys 1974, 27, 789; (b) Wolinski, K.;
Hilton, J. F.; Pulay, P. J Am Chem Soc 1990, 112, 8251.
22] Tashbaev, G. A.; Nasyrov, I. M.; Zakharov, K. S.; Zegel’-
man, L. A. Izvestiya Akademii Nauk Tadzhikskoi SSR, Otdelenie
Fiziko-Matematicheskikh, Khimicheskikh Geologicheskikh Nauk
991, 1, 88.
REFERENCES AND NOTES
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[
1] Sianawati, E.; Mistry, J. K.; Van De Mark, M. R. Eur Coat J
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2
2
008, 12, 35.
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[2] Yakubovich, A. Y.; Ginsburg, V. A. Zh Obshch Khim 1958,
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8, 1031.
[
3] Sidky, M. M.; Mahran, M. R.; Zayed, M. F.; Abdou W. M.;
Hafez, T. S. Org Prep Proced Int 1982, 14(4), 225.
4] Masten, S. A. Review of Toxicology Studies: 2,5-Dimercapto-
,3,4-Thiadiazole for National Toxicology Program, Jan. 2005.
[
[
i
1
1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet