1,3,4-Thiadiazole-Containing Azo Dyes: Synthesis, Spectroscopic Properties and Molecular Structure

Article abstract of DOI:10.3390/molecules25122822

Three series of azo dyes derived from 2-amino-5-aryl-1,3,4-thiadiazoles and aniline, N,N-dimethylaniline and phenol were synthesized in high yields by a conventional diazotization-coupling sequence. The chemical structures of the prepared compounds were confirmed by ¹H-NMR, ¹³C-NMR, IR, UV-Vis spectroscopy, mass spectrometry and elemental analysis. In addition, the X-ray single crystal structure of a representative azo dye was presented. For explicit determination of the influence of a substituent on radiation absorption in UV-Vis range, time-dependent density functional theory calculations were performed.

Full text of DOI:10.3390/molecules25122822

molecules
Article
1,3,4-Thiadiazole-Containing Azo Dyes: Synthesis,
Spectroscopic Properties and Molecular Structure
Agnieszka Kudelko 1,
* ,
, Monika Olesiejuk 1 , Marcin Luczynski 1, Marcin Swiatkowski 2
Tomasz Sieranski 2 and Rafal Kruszynski 2
1
Department of Chemical Organic Technology and Petrochemistry, The Silesian University of Technology,
Krzywoustego 4, PL-44100 Gliwice, Poland; monika.olesiejuk@polsl.pl (M.O.);
marcin.luczynski@polsl.pl (M.L.)
2
Department of X-ray Crystallography and Crystal Chemistry, Institute of General and Ecological Chemistry,
˙
Lodz University of Technology, Zeromskiego 116, PL-90924 Łódz´, Poland;
marcin.swiatkowski@p.lodz.pl (M.S.); tomasz.sieranski@p.lodz.pl (T.S.); rafal.kruszynski@p.lodz.pl (R.K.)
*
Correspondence: agnieszka.kudelko@polsl.pl; Tel.: +48-32-237-17-29
ꢀꢁꢂꢀꢃꢄꢅꢆꢇ
Academic Editors: Jorge Bañuelos Prieto and Ugo Caruso
Received: 10 June 2020; Accepted: 13 June 2020; Published: 18 June 2020
ꢀꢁꢂꢃꢄꢅꢆ
Abstract: Three series of azo dyes derived from 2-amino-5-aryl-1,3,4-thiadiazoles and
aniline, N,N-dimethylaniline and phenol were synthesized in high yields by a conventional
diazotization-coupling sequence. The chemical structures of the prepared compounds were
1
confirmed by H-NMR, 13C-NMR, IR, UV-Vis spectroscopy, mass spectrometry and elemental
analysis. In addition, the X-ray single crystal structure of a representative azo dye was presented.
For explicit determination of the influence of a substituent on radiation absorption in UV-Vis range,
time-dependent density functional theory calculations were performed.
Keywords: heterocycles; 2-arylazo-5-aryl-1,3,4-thiadiazoles; azo-coupling reactions; crystal structure
1. Introduction
Thiadiazoles are five-membered heterocyclic arrangements which are rarely found in nature.
Nitrogen, sulfur and carbon atoms can be arranged in several different ways in such a ring, which gives
rise to several isomers: 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole and 1,3,4-thiadiazole [1,2].
Of these four isomers, derivatives of 1,3,4-thiadiazole seem to be the most popular among scientists.
Many compounds containing such a scaffold exhibit a broad spectrum of biologic interactions and
have been shown to have antifungal [
activities [ ]. As well as other industrial applications, it is worth mentioning their use as viscosity
stabilizers in rubber processing [ ], additives for the production of lithium battery electrodes [ ],
3,4], antimicrobial [5], anti-inflammatory [6] and anticancer
7
8
9
dyes [10] and optoelectronic materials [11]. There are also reports of the applications of 1,3,4-thiadiazole
derivatives, in particular 2,5-dimercapto-1,3,4-thiadiazoles, as lubricants [12].
Azo dyes, characterized by the presence of azo moiety (N=N) in their structure, are the most
essential group of disperse dyes [13]. They have found a broad application mainly in dyestuff industry,
but also in food, cosmetics and pharmaceuticals production. Generally azo dyes exhibit excellent
coloring properties and offer vivid colors, starting from yellows, through oranges, reds and ending
up in blues. One of the subgroups of this family are conjugated 1,3,4-thiadiazoles containing an
azo group (N=N) in their structure. Such heterocyclic azo disperse dyes have received attention
from the scientific community due to their brightness, clarity and affinity to various fibers [14,15].
The most common methodology to introduce this type of group into a final azo compound is a
two-step transformation through appropriate diazonium salts [16]. The latter are usually produced
from the reaction of primary aromatic amines with nitrites in the presence of strong mineral acids at
Molecules 2020, 25, 2822; doi:10.3390/molecules25122822
www.mdpi.com/journal/molecules

Molecules 2020, 25, 2822
2 of 17
low temperatures. Due to the extreme instability of diazonium salts [17], they are used immediately
after their formation in coupling reactions with phenols or amines, substituted with electron-donating
groups. Other methods used to prepare azo dyes include the condensation of nitro compounds
with amines [18], reduction of nitro compounds [19
of nitroso compounds with amines [23]. In contrast to typical aromatic amines, diazotization and
subsequent coupling of 1,3,4-thiadiazole-2-amine derivatives is rarely described in the literature [24 26],
,20], oxidation of amines [21,22] or condensation
–
although thiadiazoles contain an important thiazole chromophoric core in their structure. This may be
due to the presence of an additional electronegative nitrogen atom, which decreases the basicity of the
external amino group and reduces its reactivity.
In continuation of our study on the synthesis and versatile applications of conjugated
1,3,4-thiadiazole derivatives [27–29], we attempted to synthesize and characterize the structural
features of a new series of 2-phenylazo-1,3,4-thiadiazoles, functionalized with aryl substituents directly
on the heterocyclic ring. Such systems combining the 1,3,4-thiadiazole ring with other aromatic
compounds through an azo linker may find potential industrial applications, not only as classical
synthetic dyes and pigments, laser dyes and monomers for the production of OLEDs, but also in
medicine and agriculture due to the presence of a toxophoric N–C–S moiety [30].
2. Results and Discussion
2.1. Synthesis
The starting reagents in the synthesis of 1,3,4-thiadiazole-containing azo dyes were commercially
available aromatic carboxylic acids substituted at position 4 with electron-donating or withdrawing
groups (1a
–
e, Scheme 1). They were heated with thionyl chloride SOCl2 and the resulting crude
acid chlorides were transformed into derivatives of 2-benzoylhydrazinecarbothioamide (2a
–
e
) in
a two-phase water–toluene solvent system in the presence of base (NaHCO3). The resulting
acyclic intermediates underwent cyclization in concentrated sulfuric acid to give the desired
2-amino-5-aryl-1,3,4-thiadiazoles (3a
the diazotization of 2-amino-1,3,4-thiadiazole derivatives (3a
of the diazonium salts formed from aniline, N,N-dimethylaniline and phenol (Scheme 1).
Diazotization involved the reaction of a primary heteroaromatic amine (3a ) with a nitrosating
–
e). The next stages in the few-step reaction sequence were
–
e) and the subsequent coupling
–
e
agent (nitrosyl cation) generated in situ from sodium nitrite and concentrated sulfuric acid at low
temperatures. Reactions were performed in a mixture of glacial acetic acid and propionic acid
in order to improve the solubility of the starting thiadiazoles. An excess of nitrous acid in the
post-reaction mixture was detected with potassium iodide–starch study and eliminated by adding urea.
The resulting colored diazonium salts were then used directly without purification in the coupling
sequence with aromatic amines: aniline (G=NH2) and N,N-dimethylaniline (G=NMe2) and with
phenol (G=OH). Due to the limited stability of diazonium salts, the transformations were carried
out at low temperatures (0–5 ◦C) and the final products were precipitated from solution by adding
base (Na2CO3) after reagents were combined. The reactions resulted in the formation of three series
of 2-arylazo-5-aryl-1,3,4-thiadiazole dyes in various yields (4a
yields were obtained from the transformations involving phenol (6a–e, 75–91%, Scheme 1), while the
reactions using N,N-dimethylaniline (5a , 56–69%, Scheme 1) and aniline (4a , 51–81%, Scheme 1)
–e, 5a–e, 6a–e, Scheme 1). The highest
–e
–e
produced lower yields. Such situation may be caused by partial deactivation of anilines in acidic
media. Generally, 1,3,4-thiadiazole-containing azo dyes are high-melting solids (melting point range
169–293 ◦C) and are insoluble in both water and hydrocarbons (hexane, toluene). They are highly
soluble in DMSO, acetone and methanol. It is worth noting that among the synthesized derivatives,
12 are new compounds not yet described in the literature.

Molecules 2020, 25, 2822
3 of 17
Scheme 1.
Preparation of 2-amino-1,3,4-thiadiazole precursors (3a
–e) and synthesis of
2-arylazo-5-aryl-1,3,4-thiadiazole dyes (4a
–
e,
5a 6a ). Reaction conditions: (i) toluene, reflux,
–
e
,
–e
5–15 h; (ii) toluene, NaHCO3, H2O, rt, 24 h; (iii) conc. H2SO4, 24 h and then aqueous NH3; (iv) NaNO2,
conc. H2SO4, AcOH/EtCOOH, 0–5 ◦C; (v) H2O, 0–5 ◦C and then Na2CO3.
2.2. Spectral Characterization
The structures of the final diazotization products of 2-amino-5-aryl-1,3,4-thiadiazole and their
subsequent coupling with aniline, N,N-dimethylaniline and phenol were confirmed by typical
1
spectroscopic methods (1H-NMR, 13C-NMR, UV-Vis, FT-IR and HRMS). In the H-NMR spectra
of 2-arylazo-5-aryl-1,3,4-thiadiazoles (4a–e, 5a–e, 6a–e), the characteristic signals become from protons
located in the benzene rings associated with the 1,3,4-thiadiazole core and appeared in the range
between 6.74–8.40 ppm. Signals of the characteristic amino group (7.06–7.18 ppm), N,N-dimethylamino
group (~3.18 ppm), t-butyl (~1.33 ppm) and methoxy (~3.86 ppm) were also observed. In the 13C-NMR
spectra the characteristic peaks from 1,3,4-thiadiazole carbon atoms C-2 and C-5 were observed at
164–166 ppm and 178–181 ppm, respectively. Signals due to methoxy group (~55.5 ppm), t-butyl group
(30.8–34.8 ppm) and N,N-dimethylamino group (40.0–40.2 ppm) were observed upfield in the spectra.
The formation of azo dyes 4a–e, 5a–e, 6a–e was further shown by HRMS and elemental analyses.
The IR spectra of all prepared dyes were recorded from 4000 and 650 cm−1. For the dyes 4a
two bands, respectively at 3400–3310 cm−1 and 3201–3190 cm−1, were visible, which were attributed
–e,
to the presence of a free amino group. Such bands were not observed in the case of derivatives 5a
–
e
,
,
representing a group of tertiary amines. In series 6a–e
, a broad band appeared from 3500–3100 cm−1
which confirms the presence of a hydroxyl group. All dyes showed a weak band at 1505–1525 cm−1 for
an azo group (N=N).
The UV-Vis spectra of three series of 2-arylazo-5-aryl-1,3,4-thiadiazole dyes (4a–e, 5a–e, 6a–e)
measured in MeOH exhibit several (four in most cases) absorption maxima (Figure 1, Table 1).
The same is observed for calculated spectra (Figure 1, Table 1) which are in good comparison with
those measured. All maxima result from multiple different transitions and include both n→π* and
π→π* transitions. For series
5 and 6 with compounds possessing a t-butyl group, additionally the
σ→π* transitions are observed. Due to complexity of electronic transition creating each absorption
maximum, there is no one evident dependence between the substituents and absorption maximum
position/absorption coefficient (Figure S1). Nevertheless, some dependences exist within groups with
one kind of R or G substituent. The change of the G substituent causes the red shift of the most
intense absorption maximum (appearing in the visible regions of 490–507 nm for 4a
–e, 515–530 nm
for 5a and 405–415 nm for 6a ) in order of G substituents: OH, NH2, NMe2. This sequence is in
–
e
–e

Molecules 2020, 25, 2822
4 of 17
agreement with electron donating properties of the studied substituents. These red shifts are well
reproduced in calculated spectra (Table 1). For the compounds with amino substituents (G=NH2,
NMe2) this maximum is the most red-shifting for a compound possessing a nitro group (Table 1).
For the compounds with hydroxy group (G=OH) the red shift forced by the presence of a nitro group
(6c) is between some other red shifted compounds, and it is smaller than that shift observed for the
compound 6b. This effect is also reflected in the calculated spectra (Table 1). The simultaneous presence
of a hydroxy group (G=OH) and methoxy one (R=MeO) in 6b is an explanation of this phenomenon.
For each series, the methoxy moiety induces red-shift effect (toward most of the compounds), but for
amino substituents G=NH2, NMe2 it was smaller than for their hydroxy counterpart G=OH (influence
of this group could only be noticed for calculated spectra). Increase of the red shift for stronger
electron donating EDG substituents (G=NMe2 and NH2) is larger than caused by methoxy moiety
and overrule strong electron withdrawing properties of nitro substituent. In case of the weaker EDG
substituent (G=OH) with electron donating properties close to the methoxy substituent, the electron
withdrawing properties of nitro substituent dominate at some point, and cause above described
difference in red shifts. For each compound, the most intense (global) maximum is attributed to
HOMO–LUMO (H
possessing the nitro substituent these experimentally observed absorption maxima result also from
other than H L transitions, possessing relatively large oscillator strengths (Table 1, Figures S2–S4).
→L) transitions (Table 1, Supplementary Materials, Figures S2–S4). For compounds
→
In all cases, these transitions do not engage the antibonding orbitals of the nitro group (Table 1).
For the second most intense absorption maximum (experimentally observed at lower wavelengths),
the changes of its shift between the corresponding compounds (e.g., 4a vs. 5a vs. 6a) are not as high
as those observed for the most intense maxima. Those maxima appear in the ultraviolet regions of
237–267 nm for 4a–e, 243–256 nm for 5a–e and 243–260 nm for 6a–e and they results from multiple
π→ π* and n→ π* transitions involving antibonding orbitals of all substituents (i.e., NH2, NMe2, OH,
MeO, NO2 and Br, Table 1). The experimental and calculated spectra show some minor differences.
For compounds with amino groups (G=NH2, NMe2), the calculated spectra do not contain absorption
maxima observed experimentally in the range of 284–299 nm. This may result from the interaction
of compound molecules with the solvent (i.e., formation of specific hydrogen bonds) defectively
reproduced in continuous model of solvation.
Figure 1. UV-Vis absorption spectra of the studied azo dyes in MeOH at a concentration
of 4.0
×
10−5-mol/L at room temperature:
(
Series 4) Absorption spectra of azo dyes 4a
containing
containing
–e
containing 4-aminophenylazo group; (Series 5) absorption spectra of azo dyes 5a
4-(N,N-dimethylamino)phenylazo group; (Series 6) absorption spectra of azo dyes 6a–e
–
e
4-hydroxyphenylazo group. Respective calculated spectra are shown as well.

Molecules 2020, 25, 2822
5 of 17
Table 1. Most important electronic transitions. H letter indicates Highest Occupied Molecular Orbital HOMO, L indicates Lowest Unoccupied Molecular Orbital
LUMO and +/ (number) represent subsequent orbitals above HOMO and LUMO, respectively. The logarithm of molar absorption coefficients log and oscillator
stand for the particular compound in a
−
ε
strengths are given in parenthesis under the wavelengths, respectively for experimental and calculated maxima. The letters a–e
given series (4, 5 or 6).
The Most Important
Orbitals Involved in
Electronic Transitions
λ
(nm)
Character of Transition
max
Experimental
c
Calculated
4 (G=NH2)
c
a
b
d
e
a
b
d
e
(a, e)H-2→L+1
(b)H→L+2
(a, e)n(NH2)/π→π*
261.44
(0.0909)
276.70
(0.1045)
237.50
(0.0536)
256.39
(0.0432)
270.17
(0.2800)
(b)n(NH2)/n(MeO)/π→π*(C6-rings)
(c)n(NH2)/n(NO2)/π→π*
(c)H-2→L+2
(d)H-8→L
(d)n(Br)/π(S-ring)→π*
(a)H-6→L
(a)n(NH2)/π→π*
(b)H-1→L+1
(c)H-6→L+1
(d)H-2→L+1
(e) H→L+2
(b)n(NH2)/n(MeO)/π→π*
(c)π→π*
237
(3.95)
256
(4.05)
267
(4.07)
249
(3.90)
248
(4.02)
262.74
(0.0776)
280.67
(0.2599)
253.28
(0.0806)
274.45
(0.3976)
273.29
(0.1360)
(d)n(Br)/n(NH2)/π→π*
(e)n(NH2)/π→π*(C6-rings)
266.87
(0.1051)
268.23
(0.0893)
(a)H→L+3
(a, c)n(NH2)/π→π*(C6-rings)
(c)H→L+4
272.57
(0.1083)
(a)H→L+2
(a)n(NH2)/π→π*(C6-rings)
285
(3.72)
286
(3.88)
286
(3.63)
284
(3.79)
(a, c, e)n(NH2)/π→π*
(b)n(NH2)/n(MeO)/π→π*
(d)n(Br)/n(NH2)/π→π*
325.66
(0.0203)
322.13
(0.0500)
312.40
(0.0522)
333.77
(0.0204)
324.73
(0.0294)
(a, b, d, e)H→L+1
(c)H-2→L+1
316
(3.56)
319
(3.78)
321
(4.03)
318
(3.56)
319
(3.68)
344.08
(0.1372)
(c)H-2→L
(c)n(NH2)/π→π*
383.91
(0.1281)
428.57
(0.7203)
(b)H-1→L
(c)H→L+1
(b)n(NH2)/n(MeO)/π→π*
(c)n(NH2)/π→π*
491
(4.52)
491
(4.46)
507
(4.35)
496
(4.41)
492
(4.47)
(a, c, e)n(NH2)/π→π*
(b) n(NH2)/n(MeO)/π→π*
(d)n(Br)/n(NH2)/π→π*
459.54
(1.4831)
478.70
(1.3233)
529.34
(0.8884)
464.44
(1.4918)
464.82
(1.4522)
H→L

Molecules 2020, 25, 2822
6 of 17
Table 1. Cont.
The Most Important
Orbitals Involved in
Electronic Transitions
λ
(nm)
Character of Transition
max
Experimental
c
Calculated
5 (G=NMe2)
a
b
d
e
a
b
c
d
e
(a)π→π*
(a)H-2→L+1
(b, e) H-1→L+1
(c)H-2→L+2
(d)H-8→L
(b) n(MeO)/n(NMe2)/π→π*
(c)n(NO2)/π→π*
264.95
(0.1359)
278.83
(0.0592)
241.40
(0.0442)
256.30
(0.0430)
270.21
(0.0655)
(d)n(Br)/π→π*
(e)σ(t-Bu)/n(Me2)/π→π*
(a)H-6→L
(a, c)π→π*
(b)H→L+2
(c)H-6→L+1
(d)H-2→L+1
(e)H-1→L+1
243
(3.96)
256
(3.83)
249
(3.73)
251
(3.80)
245
(4.06)
275.87
(0.1374)
283.75
(0.1408)
261.09
(0.0967)
274.64
(0.1508)
270.38
(0.0853)
(
b
)n(MeO)/n(NMe2)/π→π*(C6-ring near MeO)
(d)n(Br)/n(NMe2)/π→π*
(e)σ(t-Bu)/n(Me2)/π→π*
(a)n(NMe2)/π→π*
(a)H→L+3
(b, d)H-5→L
(c)H→L+4
(e)H-6→L
(b)n(MeO)/π→π*
281.40
(0.0925)
287.77
(0.2354)
277.34
(0.1087)
282.30
(0.2530)
279.49
(0.2116)
(c)n(NMe2)/π→π*(C6-ring near NMe2)
(d)n(Br)/π→π*
(e)σ(t-Bu)/π→π*
281.87
(0.0869)
(e)H→L+2
(e)n(NMe2)/π→π*(C6-rings)
293
(3.79)
293
(3.73)
299
(3.85)
290
(3.61)
295
(3.92)
(a, d, e)n(NMe2)/π→π*
(b)n(MeO)/n(NMe2)/π→π*
(c)n(NO2)/π→π*
320
(3.68)
334
(3.46)
325
(3.49)
323
(3.80)
337.91
(0.0197)
333.19
(0.0329)
353.80
(0.1689)
346.81
(0.0206)
336.73
(0.0263)
(a, b, d, e)H→L+1
(c)H-2→L
393.91
(0.0395)
453.15
(0.8353)
(b)H-1→L
(c)H→L+1
(b)n(MeO)/n(NMe2)/π→π*
(c)n(NMe2)/π→π*
(a, c, d, e)n(NMe2)/π→π*
(b)n(MeO)/n(NMe2)/π→π*
515
(4.50)
515
(4.25)
530
(3.95)
520
(4.30)
515
(4.41)
483.86
(1.4831)
497.00
(1.1993)
568.89
(0.8657)
488.69
(1.5864)
487.35
(1.5439)
H→L

Molecules 2020, 25, 2822
7 of 17
Table 1. Cont.
The Most Important
Orbitals Involved in
Electronic Transitions
λ
(nm)
Character of Transition
max
Experimental
c
Calculated
6 (G=OH)
a
b
d
e
a
b
c
d
e
220.52
(0.0983)
(b)H-4→L+1
(b)π(C6-ring near OH)→π*
236
(4.00)
231
(3.68)
234.73
(0.0439)
232.01
(0.0382)
(a)H→L+3
(a)n(OH)/π→π*(C6-ring near S-ring)
(c)H-2→L+2
(c)n(NO2)/(OH)/π→π*
(a)n(OH)/π→π*(C6-ring near OH)
(b)π(C6-ring near MeO)→π*
(c)n(NO2)/(OH)/π→π*
(a, e)H→L+2
(b)H-3→L+1
(c)H-8→L
251.23
(0.0758)
234.51
(0.0525)
249.20
(0.0821)
238.98
(0.0306)
234.61
(0.0464)
(d)π(C6-rings)→π*
(d)H-4→L+1
(e)σ(t-Bu)/n(OH)/π→π*(C6-ring near t-Bu)
(a, c)n(OH)/π→π*
(a)H-2→L+1
(b, c, e)H-6→L
(d)H→L+3
256
(3.90)
254
(4.04)
260
(3.72)
245
(4.04)
243
(4.10)
254.98
(0.1078)
271.99
(0.1002)
264.75
(0.0369)
251.23
(0.0556)
265.07
(0.2413)
(b)n(MeO)/n(OH)/π→π*
(d)n(Br)/n(OH)/π→π*(C6-ring near OH)
(e)σ(t-Bu)/n(OH)/π→π*
262.06
(0.1766)
266.81
(0.1192)
(a)H-6→L+1
(d)H-2→L+1
(a)n(OH)/π→π*
(d)n(Br)/n(OH)/π→π*
270.78
(0.1692)
(d)n(Br)/n(OH)/π→π*
(d)H-6→L
(a)n(OH)/π→π*
298
(3.54)
291
(3.74)
290
(3.76)
290
(3.64)
297.41
(0.0427)
302.67
(0.1542)
304.17
(0.0596)
298.30
(0.0985)
(b)n(MeO)/n(OH)/π→π*
(d)n(Br)/n(OH)/π→π*
(e)σ(t-Bu)/n(OH)/π→π*
(a, b, c, e)H→L+1
325.44
(0.0438)
(a)H-4→L
(a)π(C6-ring near OH)→π*
310
(3.74)
305.19
(0.1361)
(c)H-2→L+1
(c)n(NO2)/(OH)/π→π*

Molecules 2020, 25, 2822
8 of 17
Table 1. Cont.
The Most Important
Orbitals Involved in
Electronic Transitions
λ
(nm)
Character of Transition
max
Experimental
Calculated
341.08
(0.0630)
(c)H-3→L
(c)π(C6-ring near OH)→π*
(a, c)n(OH)/π→π*
(a, d, e)H-2→L
(b)H-1→L
345.44
(0.0461)
370.43
(0.3618)
385.35
(0.2630)
355.56
(0.0770)
355.42
(0.1288)
(b)n(MeO)/n(OH)/π→π*
(d)n(Br)/n(OH)/π→π*
(e)σ(t-Bu)/n(OH)/π→π*
405
(4.46)
415
(4.35)
410
(4.13)
409
(4.28)
409
(3.96)
(c)H-1→L+1
(a, c)n(OH)/π→π*
432.77
(1.1904)
471.46
(0.9677)
458.02
(1.1983)
439.27
(1.2728)
444.00
(1.1983)
(b)n(MeO)/n(OH)/π→π*
(d)n(Br)/n(OH)/π→π*
(e)σ(t-Bu)/n(OH)/π→π*
H→L
Used abbreviations: n—non-bonding orbital; S-ring—thiadiazole ring; C6-ring—benzene ring; *—antibonding orbital.

Molecules 2020, 25, 2822
9 of 17
2.3. Molecular Structure
The structure of one of the obtained azo dyes was confirmed by X-ray crystal structure analysis
(CCDC1946289). All atoms of the studied 2-[4-(N,N-dimethylamino)phenylazo]-5-(4-methoxyphenyl)
-1,3,4-thiadiazole (5b) occupied general positions (Figure 2).
Figure 2. Molecular structure of compound 5b plotted with 50% probability of displacement ellipsoids.
Hydrogen atoms are drawn as spheres with arbitrary radii.
The five- and six- membered rings were practically planar (the largest deviating atom C2, C7, C14
stuck out 0.0060(8), 0.0079(9), 0.0073(9) Å from the weighted least squares plane containing the respective
atom), but the whole molecule is considerably bent. The benzene rings containing C3 and C11 atoms
were inclined at 10.11(7) and 24.90(6)◦ to the central 1,3,4-thiadiazole ring, respectively and mutually at
26.85(6)◦. The N,N-dimethylamino group was inclined at 11.53(14)◦ to the neighboring benzene ring,
which is a larger value than is typically observed for similar systems (4.6%–5.8◦) [30]. However, it still
falls within the range of 2.3%–18.8◦ (the angle values of median population). The C–S bonds (Table 2)
were shorter than typical single C–S bonds (i.e., a mean value of 1.819 Å for a bond between an sp3
carbon atom and a divalent sulfur) and similar to the values observed for slightly delocalized systems
containing sp2 carbon atoms (i.e., a mean value of 1.741 Å) [31]. A similar effect exists for an N–N
bond (a formal bond length of 1.454 Å) and opposite effects were observed for slightly longer C=N
bonds (Table 2) and double C=N bonds (i.e., a mean value of 1.279 Å [32]). Combined, these effects
demonstrate small, but observable delocalization of electron density within the 1,3,4-thiadiazole ring.
The azo N=N bond (Table 2) shows a transitional character between a well-localized and a completely
delocalized system (mean values of 1.245 and 1.304 Å) [33]. This, along with the shortening of the
neighboring C–N bonds, also demonstrates the considerable degree of delocalization of electron density
within the C–N=N–C moiety. Due to the absence of classical hydrogen bond donors, the studied
compounds are connected only by weak C–H•••A non-classic hydrogen bonds (where A denotes the
following acceptors: N, O, S and
π
electrons) [34] and π•••π stacking interactions (Table 3, Table 4) [35].
Table 2. Selected structural data of studied compound 5b.
αijk [◦]
αijk [◦]
i—j
i—j—k
i—j—k
dij [Å]
S1—C1
S1—C2
1.7462(14)
1.7366(14)
1.3092(18)
1.3124(18)
1.3757(17)
1.3821(18)
1.2907(16)
1.3851(18)
1.4651(19)
1.3520(18)
1.4635(18)
1.4606(18)
1.3610(17)
1.4346(17)
C1—S1—C2
S1—C2—N2
C2—N2—N1
N2—N1—C1
N1—C1—S1
N1—C1—N3
S1—C1—N3
C1—N3—N4
N3—N4—C3
N4—C3—C4
N4—C3—C8
S1—C2—C11
N2—C2—C11
C2—C11—C12
86.22(7)
C2—C11—C16
C5—C6—N5
C7—C6—N5
C6—N5—C9
C6—N5—C10
C9—N5—C10
C13—C14—O1
C15—C14—O1
C14—O1—C17
122.25(13)
121.16(12)
121.27(12)
120.76(12)
120.34(12)
118.16(12)
115.86(12)
124.38(13)
117.14(11)
114.29(11)
112.80(12)
112.25(12)
114.42(11)
120.62(13)
124.91(10)
111.67(11)
115.29(11)
125.47(12)
116.30(12)
122.98(10)
122.55(13)
118.81(13)
C1—N1
C2—N2
N1—N2
C1—N3
N3—N4
N4—C3
C2—C11
N5—C6
N5—C9
N5—C10
O1—C14
O1—C17

Molecules 2020, 25, 2822
10 of 17
Table 3. Non-classic hydrogen bonds and the first level graph motifs in the studied compound. Cg(C3)
indicates centroid of ring containing C3 atom.
D-H•••A
<(DHA) [◦]
Gda(n)
d(D-H) [Å]
d(H•••A) [Å]
d(D•••A) [Å]
C9—H9A•••N1 i
C10—H10B•••O1 ii
C16—H16•••S1
R22(22)
C(17)
S(5)
0.98
0.98
0.95
0.95
2.58
2.54
2.86
2.97
3.5351(1)
3.5031(1)
3.2088(1)
3.8190(1)
165.4
166.3
102.7
148.8
C7—H7•••Cg(C3) iii
Symmetry transformations used to generate equivalent atoms: (i)
(iii) x, −y + 1.5, z − 0.5.
C(2)
−
x + 1,
−
y + 1,
−
z
−
2; (ii) x + 1, y, z;
2
The unitary graph set is composed of R2 (22)C(17)S(5)C(2) motifs of the lowest degree. The ring
motif assembles the molecules into supramolecular dimers (Figure 3), and the C(17) chain motif
extends these dimers to a supramolecular ribbon extending along the crystallographic axis (Figure 4).
2
4
This ribbon is constructed from alternating R2 (22)R4 (26) ring motifs of a binary graph set of the
lowest degree. The neighboring ribbons are interconnected by C–H•••π and π•••π interactions
(Table 3, Table 4) and form a three-dimensional network assembled by non-covalent interactions.
Figure 3. Supramolecular dimers forming a R22(22) motif of a unitary graph set. Symmetry codes as in
Table 3. Non-classic hydrogen bonds are indicated by dotted lines.
Table 4. Interactions in the studied compound. Each ring is indicated by one atom, which belongs
solely to this ring.
α is a dihedral angle between planes I and J, β is an angle between Cg(I)-Cg(J) vector
and normal to plane I and dp is the perpendicular distance of Cg(I) on ring J plane.
R(I)•••R(J)
α [◦]
β [◦]
d(Cg•••Cg) [Å]
3.6217(1)
3.5355(1)
dp [Å]
C3•••C3 iv
0
0
15.5
22.3
3.4908
3.2703
C11•••C11 v
Symmetry transformations used to generate equivalent atoms: (iv)
−
x+1, y+1,
−
−z+1;(v) −x, −y+1, −z+1.

Molecules 2020, 25, 2822
11 of 17
Figure 4. Part of molecular packing showing a supramolecular ribbon extending along the
crystallographic axis. Hydrogen bonds indicated by dotted lines.
3. Experimental
3.1. General Information
All reagents were purchased from commercial sources and used without further purification.
Melting points were measured on a Stuart SMP3 melting point apparatus. The 1H-NMR and 13C-NMR
spectra were recorded on an Agilent 400-NMR spectrometer in DMSO-d6 solution using TMS as the
internal standard. FT-IR spectra were recorded between 4000 and 650 cm−1 using a FT-IR Nicolet
6700 apparatus with a Smart iTR accessory. UV-Vis spectra were recorded at room temperature
in MeOH solutions (c = 4.0
mass spectra were recorded on a Waters ACQUITY UPLC/Xevo G2QT instrument. Thin-layer
chromatography was performed on silica gel 60 F254 (Merck) TLC plates using CHCl3/EtOAc (5:1 v/v
×
10−5 mol/L) on a Jasco V-660 spectrophotometer. High-resolution
)
as the mobile phase. Elemental analyses were performed with a VarioEL analyzer. The excited
states of the obtained compounds were calculated using TD–DFT method. All calculations (including
geometry optimization) were performed utilizing Gaussian09 rev. D.01 [36] with B3LYP functional and
employing 6.31 g++(2d, 2p) basis set. The geometry of all compounds was optimized and during this
calculation D3 version of Grimme’s dispersion with Becke–Johnson damping [37] was used. In both,
the optimization process and TD–DFT calculations, the polarizable continuum model [38] was used to
include overall solvation effects (with methanol selected as a solvent). The assignment of the calculated
excited states to the observed experimental maxima was based on the comparison of excitation energies
and the oscillator strengths/intensities of the corresponding maxima. The analysis of the character of
respective orbital excitations was based on orbital contour plots.
3.2. Synthesis and Characterization
3.2.1. General Procedure for the Synthesis of 2-Benzoylhydrazinecarbothioamide Derivatives (2a–e)
A carboxylic acid (1a–e, 0.10 mol) and thionyl chloride SOCl2 (22 mL, 0.30 mol) were refluxed in
dry toluene (10 mL) until the acid was fully consumed (TLC; 5–15 h). After cooling, the mixture was
concentrated on a rotary evaporator, washed with additional dry toluene (10 mL) and concentrated
again. The crude acid chloride was then dissolved in 50 mL of dry toluene and added dropwise to a
mixture of thiosemicarbazide (9.11 g, 0.10 mol), NaHCO3 (8.40 g, 0.10 mol) and H2O (150 mL). The whole
solution was agitated at room temperature overnight. The precipitated solid was filtered off, dried in
air and recrystallized from a mixture of EtOH–H2O to obtain pure 2-benzoylhydrazinecarbothioamide
derivatives (2a–e).
2-Benzoylhydrazinecarbothioamide (2a). The product was obtained as a white solid (8.60 g, 44%);
mp 197–198 ◦C (196–198 ◦C [39]).
2-(4-Methoxybenzoylhydrazinecarbothioamide (2b). The product was obtained as a white solid
(15.32 g, 68%); mp 225–227 ◦C (226 ◦C [40]).

Molecules 2020, 25, 2822
12 of 17
2-(4-Nitrobenzoylhydrazinecarbothioamide (2c). The product was obtained as a yellow solid (18.02 g,
75%); mp 212–214 ◦C (214 ◦C [41]).
2-(4-Bromobenzoylhydrazinecarbothioamide (2d). The product was obtained as a white solid
(16.72 g, 75%); mp 216–218 ◦C. 1H-NMR (400 MHz, DMSO-d6): δ 7.68–7.72 (m, 3H, Ar: H-3, H-5, NH),
7.82–7.88 (m, 3H, Ar: H-2, H-6, NH), 9.34 (s, 1H, NH), 10.45 (s, 1H, NH); 13C-NMR (100 MHz,
DMSO-d6):
δ 125.5, 129.5, 129.9, 131.1, 131.7, 164.9 (C=O), 182.0 (C=S); Anal. Calcd for C8H8BrN3OS:
C, 35.05; H, 2.94; N, 15.33. Found: C, 34.95; H, 2.89; N, 15.40.
2-(4-t-Butylbenzoylhydrazinecarbothioamide (2e). The product was obtained as a beige solid (12.06 g,
48%); mp 210–211 ◦C. 1H-NMR (400 MHz, DMSO-d6):
δ
1.33 (s, 9H, C(CH3)3), 7.48 (d, 2H, J = 8.4 Hz
Ar: H-3, H-5), 7.52–7.60 (m, 2H, NH2), 7.84 (d, 2H, J = 8.4 Hz, Ar: H-2, H-6), 9.31 (s, 1H, NH),
10.39 (s, 1H, NH) 30.8, 34.8, 124.9, 126.1, 128.3, 154.6, 165.6 (C=O),
13C-NMR (100 MHz, DMSO-d6):
,
;
δ
182.0 (C=S); Anal. Calcd for C12H17N3OS: C, 57.34; H, 6.82; N, 16.72. Found: C, 57.21; H, 6.88; N, 16.63.
3.2.2. General Procedure for the Synthesis of 2-Amino-1,3,4-thiadiazole Derivatives (3a–e)
Derivatives of 2-benzoylhydrazinecarbothioamide 2a–e (0.05 mol) were dissolved in 50 mL of
concentrated H2SO4 and agitated at room temperature overnight. Then, the mixture was alkalized
with 25% ammonia and the precipitated product was filtered off, dried in air and recrystallized from a
mixture of EtOH–H2O to yield the corresponding 2-amino-1,3,4-thiadiazoles 3a–e.
2-Amino-5-phenyl-1,3,4-thiadiazole (3a). The product was obtained as a white solid (3.89 g, 45%);
mp 232–233 ◦C (230 ◦C [42]).
2-Amino-5-(4-methoxyphenyl)-1,3,4-thiadiazole (3b). The product was obtained as a white solid
(3.42 g, 33%); mp 184–185 ◦C (185–187 ◦C [43]).
2-Amino-5-(4-nitrophenyl)-1,3,4-thiadiazole (3c). The product was obtained as a yellow solid (8.33 g,
75%); mp 254–256 ◦C (250–252 ◦C [44]).
2-Amino-5-(4-bromophenyl)-1,3,4-thiadiazole (3d). The product was obtained as a white solid (8.96 g,
70%); mp 226 ◦C (222–224 ◦C [41]).
2-Amino-5-(4-t-butylphenyl)-1,3,4-thiadiazole (3e). The product was obtained as a white solid
(
4.78 g, 41%); mp 251–253 ◦C. 1H-NMR (400 MHz, DMSO-d6):
δ
1.29 (s, 9H, C(CH3)3), 7.35 (s, 2H,
NH2), 7.48 (d, 2H, J = 8.4 Hz, Ar: H-3, H-5), 7.67 (d, 2H, J = 8.4 Hz, Ar: H-2, H-6); 13C-NMR (100 MHz,
DMSO-d6): 30.8, 34.5, 125.8, 126.0, 128.3, 152.2, 156.3, 168.1; Anal. Calcd for C12H15N3S: C, 61.77; H,
δ
6.48; N, 18.01. Found: C, 61.70; H, 6.40; N, 18.12.
3.2.3. General Procedure for the Synthesis of 2-(4-Aminophenylazo)-5-phenyl-1,3,4-thiadiazole
Derivatives (4a–e)
Sodium nitrite (1.31 g, 0.019 mol) was introduced portion wise into concentrated sulfuric
◦
acid (20 mL). The solution was heated to 5◦0 C in a water bath until complete dissolution and
then rapidly cooled in an ice/salt bath to 0 C. In the meantime, the solution of the appropriate
2-amino-5-aryl-1,3,4-thiadiazole 3a–e (0.015 mol) in glacial acetic acid (30 mL) and propionic acid
(15 mL) was prepared and added dropwise to an agitated solution of sodium nitrite in concentrated
sulfuric acid at 0–5 ◦C. Then, the mixture was stirred for 24 h, and excess nitrous acid was decomposed
by the addition of urea. The resulting diazonium salt solution was slowly introduced into the mixture
of aniline (1.37 mL, 1.39 g, 0.015 mol) in 15 mL of water at 0–5 ◦C. The colored mixture was stirred at
room temperature for the next 24 h and finally neutralized with saturated sodium carbonate solution
(75 mL). The solid was filtered off, washed twice with hot water (2
×
25 mL) and dried in air. The crude
product (4a–e) was purified by column chromatography on silica gel (CHCl3/EtOAc, 5:1 v/v).
2-(4-Aminophenylazo)-5-phenyl-1,3,4-thiadiazole (4a). The product was obtained as a brown reddish
solid (2.11 g, 51%); mp 236–238 ◦C; Rf (CHCl3/EtOAc, 5:1 v/v) 0.18. H-NMR (400 MHz, DMSO-d6):
1
δ
6.75 (d, 2H, J = 8.8 Hz, 2-Ar: H-3, H-5), 7.13 (s, 2H, NH2), 7.57–7.59 (m, 3H, 5-Ar: H-30, H-40, H-50),
7.77 (d, 2H, J = 8.8 Hz, 2-Ar: H-2, H-6), 8.04 (d, 2H, J = 8.4 Hz, 5-Ar: H-20, H-60); 13C-NMR (100 MHz,
DMSO-d6): 114.1, 127.5, 127.8, 129.4, 130.1, 131.5, 142.3, 156.6, 165.7, 180.2. IR (ATR) : 3311, 1636,
δ
ν

Molecules 2020, 25, 2822
13 of 17
1507 cm−1; HRMS calcd for (C14H11N5S + H+): 282.0813; found: 282.0818; Anal. Calcd for C14H11N5S:
C, 59.77; H, 3.94; N, 24.89. Found: C, 59.83; H, 3.97; N, 24.93.
2-(4-Aminophenylazo)-5-(4-methoxyphenyl)-1,3,4-thiadiazole (4b). The product was obtained as a
1
brown reddish solid (2.47 g, 53%); mp 269–270 ◦C; Rf (CHCl3/EtOAc, 5:1 v/v) 0.16. H-NMR (400 MHz,
DMSO-d6):
J = 8.8 Hz, 5-Ar: H-30, H-50), 7.75 (d, 2H, J = 8.8 Hz, 2-Ar: H-2, H-6), 7.98 (d, 2H, J = 8.8 Hz, 5-Ar: H-20,
H-60); 13C-NMR (100 MHz, DMSO-d6):
55.5, 114.1, 114.8, 122.6, 127.6, 129.2, 142.3, 156.3, 161.8, 165.6,
179.5. IR (ATR)
: 3422, 3333, 1651, 1508 cm−1; HRMS calcd for (C15H13N5SO + H+): 312.0919; found:
δ 3.86 (s, 3H, OCH3), 6.74 (d, 2H, J = 8.8 Hz, 2-Ar: H-3, H-5), 7.06 (s, 2H, NH2), 7.11 (d, 2H,
δ
ν
312.0912; Anal. Calcd for C15H13N5SO: C, 57.86; H, 4.21; N, 22.49. Found: C, 57.73; H, 4.24; N, 22.43.
2-(4-Aminophenylazo)-5-(4-nitrophenyl)-1,3,4-thiadiazole (4c). The product was obtained as a dark
brown solid (3.42 g, 70%); mp 176–178 ◦C (178–179 ◦C [24]); Rf (CHCl3/EtOAc, 5:1 v/v) 0.23. IR (ATR)
ν:
3403, 1637, 1513 cm−1; Anal. Calcd for C14H10N6O2S: C, 51.53; H, 3.09; N, 25.75. Found: C, 51.47; H,
3.05; N, 25.77.
2-(4-Aminophenylazo)-5-(4-bromophenyl)-1,3,4-thiadiazole (4d). The product was obtained as a dark
1
violet solid (3.67 g, 68%); mp 261–263 ◦C; Rf (CHCl3/EtOAc, 3:1 v/v) 0.23. H-NMR (400 MHz DMSO-d6):
δ
6.75 (d, 2H, J = 9.2 Hz, 2-Ar: H-3, H-5), 7.18 (s, 2H, NH2), 7.75–7.78 (m, 4H, 2-Ar, 5-Ar: H-2, H-6,
H-30, H-50), 7.97 (d, 2H, J = 8.8 Hz, 5-Ar: H-20, H-60); 13C-NMR (100 MHz, DMSO-d6):
114.2, 124.9,
: 3321, 1636, 1507 cm−1; HRMS calcd for
δ
129.2, 129.3, 130.4, 132.4, 142.3, 156.7, 164.6, 180.5. IR (ATR)
(C14H10N5SBr+H+): 359.9919; found: 359.9914; Anal. Calcd for C14H10N5SBr: C, 46.68; H, 2.80; N,
ν
19.44. Found: C, 46.81; H, 2.79; N, 19.49.
2-(4-Aminophenylazo)-5-(4-t-butylphenyl)-1,3,4-thiadiazole (4e). The product was obtained as a brown
1
solid (2.43 g, 81%); mp 171–173 ◦C; Rf (CHCl3/EtOAc, 5:1 v/v) 0.27. H-NMR (400 MHz, DMSO-d6):
δ
1.33 (s, 9H, C(CH3)3), 6.74 (d, 2H, J = 8.4 Hz, 2-Ar: H-3, H-5), 7.10 (s, 2H, NH2), 7.58 (d, 2H, J = 8.8 Hz
5-Ar: H-30, H-50), 7.76 (d, 2H, J = 8.4 Hz, 2-Ar: H-2, H-6), 7.96 (d, 2H, J = 8.8 Hz, 5-Ar: H-20, H-60);
13C-NMR (100 MHz, DMSO-d6):
30.8, 34.8, 114.1, 126.2, 127.3, 127.4, 130.2, 142.3, 154.5, 156.5, 165.7,
179.9. IR (ATR)
: 3325, 1621, 1507 cm−1; HRMS calcd for (C18H19N5S+H+): 338.1440; found: 338.1438;
,
δ
ν
Anal. Calcd for C18H19N5S: C, 64.07; H, 5.68; N, 20.75. Found: C, 64.21; H, 5.70; N, 20.71.
3.2.4. General procedure for the synthesis of
2-[4-(N,N-dimethylamino)phenylazo]-5-phenyl-1,3,4-thiadiazole derivatives (5a–e)
Sodium nitrite (1.31 g, 0.019 mol) was introduced portion wise into concentrated sulfuric
◦
acid (20 mL). The solution was heated to 50◦ C in a water bath until complete dissolution and
then rapidly cooled in an ice/salt bath to 0 C. In the meantime, a solution of the appropriate
2-amino-5-aryl-1,3,4-thiadiazole 3a–e (0.015 mol) in glacial acetic acid (30 mL) and propionic acid
(15 mL) was prepared and added dropwise to an agitated solution of sodium nitrite in concentrated
sulfuric acid at 0–5 ◦C. Then, the mixture was stirred for 24 h and excess nitrous acid was decomposed
by the addition of urea. The resulting diazonium salt solution was slowly introduced into the mixture of
N,N-dimethylaniline (1.90 mL, 1.82 g, 0.015 mol) in 15 mL of water at 0–5 ◦C. The colored mixture was
stirred at room temperature for the next 24 h and finally neutralized with saturated sodium carbonate
solution (75 mL). The solid was filtered off, washed twice with hot water (2
The crude product (5a ) was purified by column chromatography on silica gel (CHCl3/EtOAc, 5:1 v/v).
2-[4-(N,N-Dimethylamino)phenylazo]-5-phenyl-1,3,4-thiadiazole (5a). The product was obtained as a
×
25 mL) and dried in air.
–
e
brown solid (3.20 g, 69%); mp 194–195 ◦C (191 ◦C [26]); Rf (CHCl3/EtOAc, 5:1 v/v) 0.32. IR (ATR)
ν: 1603,
1525 cm−1; Anal. Calcd for C16H15N5S: C, 62.11; H, 4.89; N, 22.64. Found: C, 62.08; H, 4.86; N, 22.67.
2-[4-(N,N-Dimethylamino)phenylazo]-5-(4-methoxyphenyl)-1,3,4-thiadiazole (5b). The product was
1
obtained as a dark red solid (3.00 g, 59%); mp 219–221 ◦C; Rf (CHCl3/EtOAc, 5:1 v/v) 0.27. H-NMR
(400 MHz, DMSO-d6):
H-5), 7.12 (d, 2H, J = 8.8 Hz, 5-Ar: H-30, H-50), 7.85 (d, 2H, J = 9.2 Hz, 2-Ar: H-2, H-6), 7.99 (d, 2H,
J = 8.8 Hz, 5-Ar: H-20, H-60); 13C-NMR (100 MHz, DMSO-d6):
40.2, 55.5, 112.2, 114.8, 122.5, 126.0,
129.2, 129.4, 142.0, 154.6, 164.8, 179.4. IR (ATR)
: 1603, 1516 cm−1; HRMS calcd for (C17H17N5SO+H+):
δ 3.17 (s, 6H, N(CH3)2), 3.86 (s, 3H, OCH3), 6.92 (d, 2H, J = 9.2 Hz, 2-Ar: H-3,
δ
ν

Molecules 2020, 25, 2822
14 of 17
340.1232; found: 340.1233; Anal. Calcd for C17H17N5SO: C, 60.16; H, 5.05; N, 20.63. Found: C, 60.27; H,
5.03; N, 20.61.
2-[4-(N,N-Dimethylamino)phenylazo]-5-(4-nitrophenyl)-1,3,4-thiadiazole (5c). The product was
obtained as a brown solid (3.19 g, 60%); mp 169–171 ◦C; Rf (CHCl3/EtOAc, 5:1 v/v) 0.38. 1H-NMR
(400 MHz, DMSO-d6):
δ 3.18 (s, 6H, N(CH3)2), 7.04 (d, 2H, J = 8.8 Hz, 2-Ar: H-3, H-5), 7.96 (d, 2H,
J = 9.2 Hz, 5-Ar: H-30, H-50), 8.37–8.40 (m, 4H, 2-Ar, 5-Ar: H-2, H-6, H-20, H-60); 13C-NMR (100 MHz,
DMSO-d6):
δ 40.0, 112.3, 124.4, 124.5, 126.9, 129.1, 130.1, 142.1, 155.5, 164.8, 179.8. IR (ATR) ν:
1597, 1516 cm−1; HRMS calcd for (C16H14N6SO2 + H+): 355.0977; found: 355.0979; Anal. Calcd for
C16H14N6SO2: C, 54.23; H, 3.98; N, 23.71. Found: C, 54.40; H, 3.99; N, 23.76.
5-(4-Bromophenyl)-2-[4-(N,N-dimethylamino)phenylazo]-1,3,4-thiadiazole (5d). The product was
1
obtained as a dark violet solid (3.49 g, 60%); mp 201–203 ◦C; Rf (CHCl3/EtOAc, 5:1 v/v) 0.40. H-NMR
(400 MHz, DMSO-d6):
J = 8.4 Hz, 5-Ar: H-30, H-50), 7.84 (d, 2H, J = 9.2 Hz, 2-Ar: H-2, H-6), 7.97 (d, 2H, J = 8.4 Hz, 5-Ar: H-20,
H-60); 13C-NMR (100 MHz, DMSO-d6):
40.0, 112.3, 124.9, 128.8, 129.2, 129.3, 132.4, 142.1, 154.8, 164.7,
180.5. IR (ATR)
: 1597, 1522 cm−1; HRMS calcd for (C16H14N5SBr+H+): 388.0232; found: 388.0238;
δ 3.18 (s, 6H, N(CH3)2), 6.91 (d, 2H, J = 9.2 Hz, 2-Ar: H-3, H-5), 7.77 (d, 2H,
δ
ν
Anal. Calcd for C16H14N5SBr: C, 49.49; H, 3.63; N, 18.04. Found: C, 49.37; H, 3.66; N, 18.09.
5-(4-t-Butylphenyl)-2-[4-(N,N-dimethylamino)phenylazo]-1,3,4-thiadiazole (5e). The product was
1
obtained as a dark violet solid (3.07 g, 56%); mp 225–227 ◦C; Rf (CHCl3/EtOAc, 5:1 v/v) 0.39. H-NMR
(400 MHz, DMSO-d6):
H-5), 7.59 (d, 2H, J = 8.4 Hz, 5-Ar: H-30, H-50), 7.86 (d, 2H, J = 9.2 Hz, 2-Ar: H-2, H-6), 7.97 (d, 2H,
J = 8.4 Hz, 5-Ar: H-20, H-60); 13C-NMR (100 MHz, DMSO-d6):
30.8, 34.8, 40.1, 112.3, 126.2, 127.4,
δ 1.33 (s, 9H, C(CH3)3), 3.18 (s, 6H, N(CH3)2), 6.93 (d, 2H, J = 9.2 Hz, 2-Ar: H-3,
δ
127.6, 142.1, 153.4, 154.5, 154.7, 165.8, 179.8. IR (ATR) ν
: 1604, 1524 cm−1; Anal. Calcd for C20H23N5S:
HRMS calcd for (C20H23N5S+H+): 366.1752; found: 366.1754; Anal. Calcd for C20H23N5S: C, 65.72; H,
6.34; N, 19.16. Found: C, 65.80; H, 6.33; N, 19.18.
3.2.5. General Procedure for the Synthesis of 2-(4-Hydroxyphenylazo)-5-phenyl-1,3,4-thiadiazole
Derivatives (6a–e)
Sodium nitrite (1.31 g, 0.019 mol) was introduced portion wise into concentrated sulfuric
◦
acid (20 mL). The solution was heated to 50◦ C in a water bath until complete dissolution and
then rapidly cooled in an ice/salt bath to 0 C. In the meantime, a solution of the appropriate
2-amino-5-aryl-1,3,4-thiadiazole 3a–e (0.015 mol) in glacial acetic acid (30 mL) and propionic acid
(15 mL) was prepared and added dropwise to an agitated solution of sodium nitrite in concentrated
sulfuric acid at 0–5 ◦C. Then, the mixture was stirred for 24 h and excess nitrous acid was decomposed
by the addition of urea. The resulting diazonium salt solution was slowly introduced into the mixture
of phenol (1.41 g, 0.015 mol) in 15 mL of water at 0–5 ◦C. The colored mixture was stirred at room
temperature for 24 h and finally neutralized with saturated sodium carbonate solution (75 mL).
The solid was filtered off, washed twice with hot water (2
(6a–e) was purified by column chromatography on silica gel (CHCl3/EtOAc, 5:1 v/v).
×
25 mL) and dried in air. The crude product
2-(4-Hydroxyphenylazo)-5-phenyl-1,3,4-thiadiazole (6a). The product was obtained as a red solid
(3.47 g, 82%); mp 200–202 ◦C (196–198 ◦C [25]); Rf (CHCl3/EtOAc, 5:1 v/v) 0.25. IR (ATR)
ν: 3060, 1608,
1512 cm−1; Anal. Calcd for C14H10N4OS: C, 59.56; H, 3.57; N, 19.85. Found: C, 59.50; H, 3.52; N, 19.87.
2-(4-Hydroxyphenylazo)-5-(4-methoxyphenyl)-1,3,4-thiadiazole (6b). The product was obtained as
1
an orange solid (4.26 g, 91%); mp 271–273 ◦C; Rf (CHCl3/EtOAc, 5:1 v/v) 0.23. H-NMR (400 MHz,
DMSO-d6):
5-Ar: H-30, H-50), 7.92 (d, 2H, J = 9.2 Hz, 2-Ar: H-2, H-6), 8.03 (d, 2H, J = 8.8 Hz, 5-Ar: H-20, H-60);
13C-NMR (100 MHz, DMSO-d6):
55.5, 114.9, 116.7, 122.1, 126.8, 129.6, 144.7, 162.2, 164.1, 167.3, 178.4.
IR (ATR)
: 3099, 1601, 1518 cm−1; HRMS calcd for (C15H12N4SO2+H+): 313.0759; found: 313.0755;
δ 3.86 (s, 3H, OCH3), 7.02 (d, 2H, J = 9.2 Hz, 2-Ar: H-3, H-5), 7.13 (d, 2H, J = 8.8 Hz,
δ
ν
Anal. Calcd for C15H12N4SO2: C, 57.68; H, 3.87; N, 17.94. Found: C, 57.59; H, 3.85; N, 17.99.
2-(4-Hydroxyphenylazo)-5-(4-nitrophenyl)-1,3,4-thiadiazole (6c). The product was obtained as a dark
◦
brown solid (3.92 g, 80%); mp 258–260 C; Rf (CHCl3/EtOAc, 5:1 v/v) 0.35. 1H-NMR (400 MHz,

Molecules 2020, 25, 2822
15 of 17
DMSO-d6):
δ
6.97 (d, 2H, J = 8.8 Hz, 2-Ar: H-3, H-5), 7.92 (d, 2H, J = 8.8 Hz, 5-Ar: H-30, H-50),
117.4, 124.4,
: 3080, 1598, 1515 cm−1; HRMS calcd for
8.28–8.40 (m, 4H, 2-Ar, 5-Ar: H-2, H-6, H-20, H-60); 13C-NMR (100 MHz, DMSO-d6):
δ
124.6, 127.5, 129.0, 144.7, 157.3, 164.1, 167.4, 179.1. IR (ATR)
(C14H9N5SO3 + H+): 328.0504; found: 328.0502; Anal. Calcd for C14H9N5SO3: C, 51.37; H, 2.77; N,
ν
21.40. Found: C, 51.50; H, 2.78; N, 21.47.
5-(4-Bromophenyl)-2-(4-hydroxyphenylazo)-1,3,4-thiadiazole (6d). The product was obtained as a
brown solid (4.06 g, 75%); mp 263–265 C; Rf (CHCl3/EtOAc, 5:1 v/v) 0.33. 1H-NMR (400 MHz,
◦
DMSO-d6):
δ
7.03 (d, 2H, J= 9.2 Hz, 2-Ar: H-3, H-5), 7.80 (d, 2H, J = 8.8 Hz, 5-Ar: H-30, H-50),
7.94 (d, 2H, J = 9.2 Hz, 2-Ar: H-2, H-6), 8.03 (d, 2H, J = 8.8 Hz, 5-Ar: H-20, H-60); 13C-NMR (100 MHz,
DMSO-d6):
δ 116.8, 125.5, 127.1, 129.6, 131.7, 132.5, 144.7, 164.4, 166.4, 179.4. IR (ATR) ν: 3047,
1587, 1507 cm−1; HRMS calcd for (C14H9N4SOBr + H+): 360.9759; found: 360.9757; Anal. Calcd for
C14H9N4SOBr: C, 46.55; H, 2.51; N, 15.51. Found: C, 46.61; H, 2.50; N, 15.59.
5-(4-t-Butylphenyl)-2-(4-hydroxypheny◦lazo)-1,3,4-thiadiazole (6e). The product was obtained as an
orange solid (4.06 g, 80%); mp 291–293 C; Rf (CHCl3/EtOAc, 5:1 v/v) 0.37. 1H-NMR (400 MHz,
DMSO-d6):
H-30, H-50), 7.94 (d, 2H, J = 9.2 Hz, 2-Ar: H-2, H-6), 8.01 (d, 2H, J = 8.8 Hz, 5-Ar: H-20, H-60); 13C-NMR
(100 MHz, DMSO-d6): 30.8, 34.8, 116.7, 126.3, 126.9, 127.6, 129.6, 144.8, 155.1, 164.1, 167.5, 178.8.
IR (ATR)
: 3100, 1582, 1507 cm−1; HRMS calcd for (C18H18N4SO + H+): 339.1280; found: 339.1281;
δ 1.33 (s, 9H, C(CH3)3), 7.03 (d, 2H, J = 9.2 Hz, 2-Ar: H-3; H-5), 7.60 (d, 2H, J = 8.8 Hz, 5-Ar:
δ
ν
Anal. Calcd for C18H18N4SO: C, 63.88; H, 5.36; N, 16.56. Found: C, 63.76; H, 5.39; N, 16.51.
4. Conclusions
An efficient synthetic strategy for the preparation of new azo dyes using weak heteroaromatic
amines containing a 1,3,4-thiadiazole scaffold as the diazo component and aniline, N,N-dimethylaniline
and phenol as simultaneous coupling precursors, was presented. Three series of azo dyes,
the derivatives of 2-phenylazo-5-phenyl-1,3,4-thiadiazole, were obtained in good to excellent yields.
The new dyes obtained—demonstrating a broad color spectrum and good solubility in some polar
solvents—may serve as potential candidates for the dye industry and will be tested in the near future.
Supplementary Materials: Copies of the 1H-NMR, 13C-NMR, UV-Vis and IR spectra of the compounds as well
as figures showing the calculated spectra and the contour plots of the most important molecular orbitals are
available in the online Supplementary Materials.
Author Contributions: A.K., M.O. and M.L. conceived and designed the experiments, performed the experiments
and analyzed the data. M.S., T.S. and R.K. performed emission measurements, X-ray structural analysis and
time-dependent density functional theory calculations. A.K. wrote the manuscript with the help of M.O. and R.K.
All authors read and approved the final manuscript.
Funding: The synthetic part of the project was financially supported by the EU under the project RPO WL
RPLU.01.02.00-06-1116/16. The crystallographic part was financed by funds allocated by the Ministry of Science
and Higher Education to the Institute of General and Ecological Chemistry, Lodz University of Technology
in Poland.
Conflicts of Interest: The authors declare no conflicts of interest.
References
1.
Koutentis, P.A.; Constantinides, C.P. 1,3,4-Thiadiazoles. In Comprehensive Heterocyclic Chemistry III;
Katritzky, A., Ramsden, C.A., Scriven, E.F.V., Taylor, R.J.K., Eds.; Elsevier Science Ltd.: Oxford, UK,
2008; Volume 5, pp. 567–605.
2.
3.
4.
Hu, Y.; Li, C.; Wang, X.; Yang, Y.; Zhu, H. 1,3,4-Thiadiazole: Synthesis, reactions, and applications in
medicinal, agricultural, and materials chemistry. Chem. Rev. 2014, 114, 5572–5610. [CrossRef] [PubMed]
Li, Y.; Geng, J.; Liu, Y.; Yu, S.; Zhao, G. Thiadiazole—A promising structure in medicinal chemistry.
Chem. Med. Chem. 2013, 8, 27–41. [CrossRef] [PubMed]
Karaburun, A.; Acar Cevik, U.; Osmaniye, D.; Saglik, B.; Kaya Cavusoglu, B.; Levent, S.; Ozkay, Y.;
Koparal, A.; Behcet, M.; Kaplancikli, Z.A. Synthesis and evaluation of new 1,3,4-thiadiazole derivatives as
potent antifungal agents. Molecules 2018, 23, 3129. [CrossRef] [PubMed]

Molecules 2020, 25, 2822
16 of 17
5.
6.
7.
Gur, M.; Sener, N.; Kastas, C.A.; Ozkan, O.E.; Muglu, H.; Elmaswaria, M.A.M. Synthesis and characterization
of some new heteroaromatic compounds having chirality adjacent to a 1,3,4-thiadiazole moiety and their
antimicrobial activities. J. Heterocycl. Chem. 2017, 54, 3578–3590. [CrossRef]
Hafez, H.N.; Hegab, M.I.; Ahmed-Farag, I.S.; El-Gazzar, A.B.A. A facile regioselective synthesis of
novel spiro-thioxanthene and spiro-xanthene-90,2-[1,3,4]thiadiazole derivatives as potential analgesic and
anti-inflammatory agents. Bioorg. Med. Chem. 2008, 18, 4538–4543. [CrossRef]
Altintop, M.D.; Sever, B.; Ozdemir, A.; Iglin, S.; Alti, O.; Turan-Zitouni, G.; Kaplancikli, Z.A. Synthesis
and evaluation of a series of 1,3,4-thiadiazole derivatives as potential anticancer agents. Anticancer Agents
Med. Chem. 2019, 18, 1606–1616. [CrossRef]
8.
9.
Richwine, J.R. 2,5-Dimercapto-1,3,4-thiadiazole as a Cross-Linker for Saturated Halogen-Containing Polymers.
Inventor: Hercules Incorporated Wilmington, Assignee. U.S. Patent 4288576, 8 September 1981.
Jin, L.; Wang, G.; Li, X. Poly(2,5-dimercapto-1,3,4-thiadiazole)/sulfonated graphene composite as cathode
material for rechargeable lithium batteries. J. Appl. Electrochem. 2011, 41, 377–382. [CrossRef]
10. Maradiya, H.R. Monoazo disperse dyes based on 2-amino-1,3,4-thiadiazole derivatives. J. Serb. Chem. Soc.
2002, 67, 709–718. [CrossRef]
11. Yan, H.; Su, H.; Tian, D.; Miao, F.; Li, H. Synthesis of triazolo-thiadiazole fluorescent organic nanoparticles as
primary sensor toward Ag+ and the complex of Ag+ as secondary sensor toward cysteine. Sens. Actuators
B Chem. 2011, 160, 656–661. [CrossRef]
12. Hipler, F.; Fischer, R.A.; Muller, J. Matrix-isolation pyrolysis investigation of mercapto-functionalized
1,3,4-thiadiazoles: Thermal stability of thiadiazole lubricant additives. Phys. Chem. Chem. Phys. 2005
7, 731–737. [CrossRef]
,
13. Dawson, J.F. Developments in disperse dyes. Color. Technol. 1978, 9, 25–35. [CrossRef]
14. Arcoria, A.; De Giorgi, M.R.; Fatuzzo, F.; Longo, M.L. Dyeing properties of basic azo-dyes from 2-amino
thiadiazole. Dyes Pigment. 1993, 21, 67–74. [CrossRef]
15. De Giorgi, M.R.; Carpignano, R.; Cerniani, A. Structure optimization in a series of thiadiazole disperse dyes
using a chemometric approach. Dyes Pigment. 1998, 37, 187–196. [CrossRef]
16. Zollinger, H. Azo dyes and Pigments. In Color Chemistry: Syntheses, Properties, and Applications of Organic
Dyes and Pigments, 3rd ed.; Viley-VCH: Zurich, Switzerland, 2003; pp. 165–254.
17. Ullrich, R.; Grewer, T. Decomposition of aromatic diazonium compounds. Thermochim. Acta 1993, 225, 201–211.
[CrossRef]
18. Zhao, R.; Tan, C.; Xie, Y.; Gao, C.; Liu, H.; Jiang, Y. One step synthesis of azo compounds from nitroaromatics
and anilines. Tetrahedron Lett. 2011, 52, 3805–3809. [CrossRef]
19. Chung, T.F.; Wu, Y.M.; Cheng, C.H. Reduction of aromatic nitro compounds by ethylenediamine. A new
selective reagent for the synthesis of symmetric azo compounds. J. Org. Chem. 1984, 49, 1215–1217. [CrossRef]
20. Srinivasa, G.R.; Abiraj, K.; Channe Gowda, D. Lead-catalyzed synthesis of azo compounds by ammonium
acetate reduction of aromatic nitro compounds. Synth. Commun. 2003, 33, 4221–4227. [CrossRef]
21. Noureldin, N.A.; Bellegarde, J.W. A novel method. The synthesis of ketones and azobenzenes using
supported permanganate. Synthesis 1999, 6, 939–942. [CrossRef]
22. Bhatnagar, I.; George, M.V. Oxidation with metal oxides. III. Oxidation of diamines and hydrazines with
manganese dioxide. J. Org. Chem. 1968, 33, 2407–2411. [CrossRef]
23. Faustino, H.; El-Shisthawy, R.M.; Reis, L.V.; Santos, P.F.; Almeida, P. 2-Nitrosobenzothiazoles: Useful
synthons for new azobenzothiazole dyes. Tetrahedron Lett. 2008, 49, 6907–6909. [CrossRef]
24. Tambe, S.M.; Tasaganva, R.G.; Inamdar, S.R.; Kariduraganavar, M.Y. Synthesis and characterization of
nonlinear optical side-chain polyimides containing the thiadiazole chromophores. J. Appl. Pol. Sci. 2012
125, 1049–1058. [CrossRef]
,
25. Tomi, I.H.R.; Al-Daraji, A.H.R.; Al-Qaysi, R.R.T.; Hasson, M.M.; Al-Dulaimy, K.H.D. Synthesis,
characterization and biological activities of some azo derivatives of aminothiadiazole derived from nicotinic
and isonicotinic acids. Arab. J. Chem. 2014, 7, 687–694. [CrossRef]
26. Kumar, C.T.K.; Keshavayya, J.; Rajesk, T.N.; Peethambar, S.K.; Ali, A.R.S. Synthesis, characterization, and
biological activity of 5-phenyl-1,3,4-thiadiazole-2-amine incorporated azo dye derivatives. Org. Chem. Int.
2013, 370626. [CrossRef]

Molecules 2020, 25, 2822
17 of 17
27. Kedzia, A.; Kudelko, A.; Swiatkowski, M.; Kruszynski, R. Microwave-promoted synthesis of highly
luminescent s-tetrazine-1,3,4-oxadiazole and s-tetrazine-1,3,4-thiadiazole hybrids. Dyes Pigment. 2020
172, 107865. [CrossRef]
,
28. Wróblowska, M.; Kudelko, A.; Kuz´nik, N.; Łaba, K.; Łapkowski, M. Synthesis of Extended 1,3,4-Oxadiazole
and 1,3,4-Thiadiazole Derivatives in the Suzuki Cross-Coupling Reactions. J. Heterocycl. Chem. 2017
54, 1550–1557. [CrossRef]
,
29. Wróblowska, M.; Kudelko, A.; Łapkowski, M. Efficient Synthesis of Conjugated 1,3,4-Thiadiazole Hybrids
through Palladium-Catalyzed Cross Coupling of 2,5-Bis(4-bromophenyl)-1,3,4-thiadiazole with Boronic
Acids. Synlett 2015, 26, 2127–2130. [CrossRef]
30. Mavrova, A.T.; Wesselinova, D.; Tsenov, Y.A.; Denkova, P. Synthesis, cytotoxity and effects of some
1,2,4-triazole and 1,3,4-thiadiazole derivatives on immunocompetent cells. Eur. J. Med. Chem. 2009, 44, 63–69.
[CrossRef]
31. Groom, C.R.; Bruno, I.J.; Lightfoot, M.P.; Ward, S.C. The Cambridge Structural Database. Acta Crystallogr. B
2016, 72, 171–179. [CrossRef]
32. Cowley, J.M. Scattering factors for the diffraction of electrons by crystalline solids. In International Tables for
Crystallography, Volume C: Mathematical, Physical and Chemical Tables, 3rd ed.; Prince, E., Ed.; Kluwer Academic
Publishers: Dordrecht, The Netherlands, 2004; pp. 259–262.
33. Sheldrick, G.M. Crystal structure refinement with SHELXL. Acta Crystallogr. 2015, C71, 3–8.
34. Desiraju, G.R.; Steiner, T. The Weak Hydrogen Bond in Structural Chemistry and Biology; Oxford University Press:
Oxford, UK, 1999; pp. 293–342.
35. Kruszynski, R.; Sieranski, T. Can stacking interactions exist beyond the commonly accepted limits?
Cryst. Growth Des. 2016, 16, 587–595. [CrossRef]
36. 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.; et al. Gaussian 09, Revision, D.01; Gaussian, Inc.: Wallingford, CT, USA, 2009.
37. Grimme, S.; Ehrlich, S.; Goerigk, L. Effect of the damping function in dispersion corrected density functional
theory. J. Comp. Chem. 2011, 32, 1456–1465. [CrossRef] [PubMed]
38. Tomasi, J.; Mennucci, B.; Cammi, R. Quantum mechanical continuum solvation models. Chem. Rev. 2005
105, 2999–3093. [CrossRef]
,
39. Campaigne, E.; Selby, T.P. Thiazoles and thiadiazines. The condensation of ethyl 4-chloroacetoacetate with
thiosemicarbazide. J. Heterocycl. Chem. 1978, 15, 401–411. [CrossRef]
40. Plumitallo, A.; Cardia, M.C.; Distinto, S.; DeLogu, A.; Maccioni, E. Synthesis and anti-microbial activity
evaluation of some new 1-benzoyl-isothiosemicarbazides. Farmaco 2004, 59, 945–952. [CrossRef] [PubMed]
41. Malbec, F.; Milcent, R.; Barbier, G. D
é
rivés de la dihydro-2,4 triazole-1,2,4 thione-3 et de l’amino-2
thiadiazole-1,3,4
[CrossRef]
à partir de nouvelles thiosemicarbazones d’esters. J. Heterocycl. Chem. 1984, 21, 1689–1698.
42. Giri, S.; Nizamuddin Srivastava, U.C. Synthesis of some N-(5-aryl/aryloxymethyl-1,3,4-thiadiazol-2-yl)
glyoxylamide thiosemicarbazones as potential antiviral and antifungal agents. Agric. Biol. Chem. 1983
47, 103–105. [CrossRef]
,
43. Jatav, V.; Mishra, P.; Kashaw, S.; Stables, J.P. Synthesis and CNS depressant activity of some novel
3-[5-substituted 1,3,4-thiadiazole-2-yl]-2-styryl quinazoline-4(3H)-ones. Eur. J. Med. Chem. 2008, 43, 135–141.
[CrossRef] [PubMed]
44. Carvalho, A.S.; Gibaldi, D.; Pinto, A.C.; Bozza, M.; Boechat, N. Synthesis and trypanocidal evaluation of
news 5-[N-(3-(5-substituted)-1,3,4-thiadiazolyl)]amino-1-methyl-4-nitroimidazoles. Lett. Drug Des. Discov.
2006, 3, 98–101. [CrossRef]
Sample Availability: Samples of the compounds 4a–e, 5a–e, 6a–e are available from the authors.
©
2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
(CC BY) license (http://creativecommons.org/licenses/by/4.0/).