Molecular and supramolecular properties of nitroaromatic thiosemicarbazones: Synthesis, spectroscopy, X-ray structure elucidation and DFT calculations

Article abstract of DOI:10.1016/j.molstruc.2016.11.039

The reactions of 6-nitropiperonal with H₂N[sbnd]NH[sbnd]C(S)[sbnd]NHR, R?=?Me, Et, Ph or H, afforded four nitroaromatic thiosemicarbazones 1–4, respectively. 1–4 were characterized by elemental analysis (CHN), FTIR, and ¹H and ¹³C{¹H} NMR spectroscopy. In addition, the crystal structures of 2 and 3 were determined by single-crystal X-ray diffraction. Our X-ray structural results have shown that the nitropiperonal and thiosemicarbazone moieties exhibit an almost coplanar arrangement for both 2 and 3. Moreover, they establish 2-D networks along the [111] base vector by means of classical and nonclassical hydrogen bonds. Electronic and spectroscopic properties of 1–4 were investigated at the DFT B3LYP/6-311G** level of calculation. The C[dbnd]S group of 1–4 constitutes a nucleophilic region, whereas the NO₂ group defines an electrophilic centre, as expected. Furthermore, a DFT vibrational analysis of 4 allowed a reliable assignment of the thiosemicarbazone-based vibrations. Also, a good agreement between theoretical and experimental ¹³C chemical shift values was obtained for 1–4.

Full text of DOI:10.1016/j.molstruc.2016.11.039

Journal of Molecular Structure 1131 (2017) 79e86
Contents lists available at ScienceDirect
Journal of Molecular Structure
journal homepage: http://www.elsevier.com/locate/molstruc
Molecular and supramolecular properties of nitroaromatic
thiosemicarbazones: Synthesis, spectroscopy, X-ray structure
elucidation and DFT calculations
a
a
,
**
b
c
c, *
L.C. Dias , G.M. de Lima
, C.B. Pinheiro , M.A.C. Nascimento , R.S. Bitzer
a
Departamento de Química, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil
Departamento de Física, Universidade Federal de Minas Gerais, Belo Horizonte, MG, 31270-901, Brazil
Instituto de Química, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, 21941-909, Brazil
b
c
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 August 2016
Received in revised form
The reactions of 6-nitropiperonal with H NeNHeC(S)eNHR, R ¼ Me, Et, Ph or H, afforded four nitro-
2
aromatic thiosemicarbazones 1e4, respectively. 1e4 were characterized by elemental analysis (CHN),
FTIR, and 1H and C{ H} NMR spectroscopy. In addition, the crystal structures of 2 and 3 were deter-
mined by single-crystal X-ray diffraction. Our X-ray structural results have shown that the nitropiperonal
and thiosemicarbazone moieties exhibit an almost coplanar arrangement for both 2 and 3. Moreover,
they establish 2-D networks along the [111] base vector by means of classical and nonclassical hydrogen
bonds. Electronic and spectroscopic properties of 1e4 were investigated at the DFT B3LYP/6-311G** level
13
1
1
November 2016
Accepted 13 November 2016
Available online 14 November 2016
Keywords:
2
of calculation. The C]S group of 1e4 constitutes a nucleophilic region, whereas the NO group defines
Nitroaromatic compounds
Thiosemicarbazones
X-ray structure analysis
Hirshfeld surface analysis
DFT calculations
an electrophilic centre, as expected. Furthermore, a DFT vibrational analysis of 4 allowed a reliable
assignment of the thiosemicarbazone-based vibrations. Also, a good agreement between theoretical and
experimental 13C chemical shift values was obtained for 1e4.
© 2016 Elsevier B.V. All rights reserved.
®
1. Introduction
a
-N-Heterocyclic TSCs, such as Triapine , stand out amongst the
most effective RR inhibitors, inasmuch as they are strong iron
chelators and establish redox-active iron complexes [4]. Moreover,
pieces of evidence have connected the redox ability of thio-
semicarbazone Cu(II) complexes to their antitumour activity inso-
far as these compounds can generate reactive oxygen species (ROS)
[5]. Structure-activity relationship studies of pyridyl-containing
TSCs have revealed that (i) replacement of the thiocarbonyl C]S
group by C]O precludes the biological activity of the corre-
sponding semicarbazones, whereas replacement by C]Se does not
generally lead to reduced biological activity; (ii) the attachment
point of the thiosemicarbazone chain to the pyridine ring should be
Thiosemicarbazones (TSCs) and their metal complexes are
widely known for their analytical applications and biological ac-
tivities, which range from antitumoural through antiviral, anti-
bacterial and antifungal to antimalarial [1]. Two chemical
compounds, namely p-acetamidobenzaldehyde thiosemicarbazone
(
CAS number: 104-06-3) and 3-aminopyridine-2-carboxaldehyde
thiosemicarbazone (CAS number: 143621-35-6), are important
examples of TSCs [2,3]. The former chemical, commercially known
as thioacetazone, has been employed in many countries of sub-
Saharan Africa in the treatment of tuberculosis [2]. In its turn, the
®
latter thiosemicarbazone, known as Triapine , behaves as a small
at the 2-position, viz. a-pyridyl, otherwise activity is drastically
molecule ribonucleotide reductase (RR) inhibitor and has under-
gone phases I and II clinical trials as a potent antitumour single
agent [3].
reduced; and (iii) replacement of 2-pyridyl by phenyl also results in
loss of biological activity [6]. 2-Pyridyl-containing TSCs demon-
strated remarkable antimalarial activity when the thio-
semicarbazone N4 atom was attached to bulky substituents [7]. All
of these results should be taken into account in the design of new
TSCs and their metal complexes in view of the development of
more effective antiproliferative and antimicrobial agents [8].
In general, the pharmacological effectiveness of nitro-
containing compounds is associated with the electrochemical
*
Corresponding author.
** Corresponding author.
E-mail addresses: gmlima@ufmg.br (G.M. de Lima), rodrigobitzer@gmail.com
(
R.S. Bitzer).
http://dx.doi.org/10.1016/j.molstruc.2016.11.039
022-2860/© 2016 Elsevier B.V. All rights reserved.
0

80
L.C. Dias et al. / Journal of Molecular Structure 1131 (2017) 79e86
reduction of the nitro group [9]. Accordingly, the biological action
MeOH (20 mL) was added dropwise a MeOH solution of 6-
nitropiperonal (0.96 g, 4.9 mmol). After the addition of two drops
of nitro compounds results either from the production of the su-
peroxide radical anion biocatalysed by NO.
-
or from the direct ac-
of H
cooling at room temperature, the yellow precipitate was isolated by
filtration, washed with EtOH and Et O, and air dried. Attempts to
2
2 4
SO 95e98%, the resulting mixture was refluxed for 4 h. After
tion of their reduced metabolites [9]. In effect, the presence of
nitroaromatic groups in the chemical structure of TSCs is likely to
enhance their biological activity against tumour cell lines and mi-
croorganisms [10]. As part of our ongoing interest in the synthesis
of bioactive compounds [11e18], we decided to prepare new
potentially bioactive nitro-containing TSCs. In this article, we report
the synthesis, spectroscopy, and X-ray structure and Hirshfeld
surface analyses of four nitroaromatic TSCs (Fig. 1). In addition,
electronic and spectroscopic properties of these nitro compounds
have been investigated using density functional theory (DFT). A
purpose of this article is to provide molecular and supramolecular
properties of 1e4, which can be further exploited in structure-ac-
tivity relationship studies. Biological studies of these nitroaromatic
TSCs are underway.
2
grow single crystals of 1 for X-ray diffraction studies were unsuc-
ꢁ
cessful. Yield: 68%. M.p.: 246 C (d). Anal. Calc. for C10
10
H N
4
O
4
S
(MW 282.3): C, 42.54; H, 3.57; N, 19.85%. Found: C, 43.22; H, 3.69;
ꢀ
1
N, 20.5%. IR (KBr pellet,
(CN)imine, 1538vs as(NO
(dmso-d , 400 MHz,
8.47 (s, 1H, H8), 7.98 (s, 1H, H2), 7.59 (s, 1H, H6), 6.26 (s, 2H, H4),
n
max/cm ): 3342s
n
(NH)NHMe, 1612vs
1
n
n
2
), 1328 m (NO
n
s
2
), 822 m
n(CS). H NMR
6
d/ppm): 11.7 (s, 1H, H10), 8.67 (m, 1H, H12),
13
1
3.00 (d, J ¼ 4.0 Hz, 3H, H13). C{ H} NMR (dmso-d
6
, 100 MHz, d/
ppm): 177.6 (C11),151.5 (C5),148.2 (C3),142.8 (C1),136.6 (C8),125.5
(C7), 105.4 (C2), 104.5 (C4), 103.3 (C6), 30.6 (C13).
2.3. Synthesis of (E)eN-ethyl-2-{(6-nitrobenzo[d][1,3]dioxol-5-yl)
methylene}thiosemicarbazone (2)
2
. Computational and experimental details
Similarly prepared from ethylthiosemicarbazide (0.61 g,
5.1 mmol) and 6-nitropiperonal (0.96 g, 4.9 mmol). X-ray quality
2.1. Materials and spectroscopic measurements
single crystals were obtained from a mixture of dmf/EtOH (3:1).
ꢁ
Starting materials and solvents were purchased from Aldrich,
Yield: 88%. M.p.: 257e259 C. Anal. Calc. for C11
12
H N
4
O
4
S (MW
Alfa-Aesar, Merck, Synth or Vetec and used as received. Solution
NMR spectra were recorded at room temperature using a Bruker
DPX400 spectrometer equipped with an 89 mm wide-bore magnet
296.3): C, 44.59; H, 4.08; N, 18.91%. Found: C, 43.43; H, 4.14; N,
ꢀ1
19.28%. IR (KBr pellet,
mine, 1532vs as(NO ), 1324 m
, 400 MHz,
H8), 7.98 (s, 1H, H2), 7.59 (s, 1H, H6), 6.26 (s, 2H, H4), 3.59 (m,
n
max/cm ): 3344s
n
(NH)NHEt, 1612vs
n
(CN)i-
1
n
2
n
s
(NO
2
), 815 m
n(CS). H NMR (dmso-
1
13
1
operating at 400 ( H) or 100 MHz ( C{ H}). Chemical shift values
d
6
d/ppm): 11.6 (s, 1H, H10), 8.71 (m, 1H, H12), 8.47 (s, 1H,
(
d
/ppm) were determined relative to SiMe
4
(
d
TMS 0.00) with in-
dmso 2.50 ( H) and
1
13
1
ternal reference to the solvent residual signals [
3
d
J ¼ 8.0 Hz, 2H, H13), 1.15 (t, J ¼ 8.0 Hz, 3H, H14). C{ H} NMR
1
3
1
1
9.52 ( C)]. Vicinal He H coupling constants (J) are given in Hz.
(dmso-d , 100 MHz, /ppm): 177.3 (C11), 152.2 (C5), 149.0 (C3),
6
d
Atom numbering schemes for NMR assignments are shown in Fig.1.
143.6 (C1), 137.4 (C8), 126.2 (C7), 106.2 (C2), 105.3 (C4), 104.1 (C6),
38.8 (C13), 15.0 (C14).
1
13
1
The H and C{ H} NMR spectra of 1e4 are shown in Fig. S1
Appendix A). Infrared (IR) spectra were recorded from solid sam-
(
ꢀ
1
ples (KBr pellets) over the range 4000-400 cm using a Perki-
nElmer GX FTIR spectrometer. Melting points were determined
using a Mettler Toledo FP90 equipment. C, H and N elemental mi-
croanalyses were performed on a PerkinElmer PE-2400 CHN
analyzer.
2.4. Synthesis of (E)eN-phenyl-2-{(6-nitrobenzo[d][1,3]dioxol-5-
yl)methylene}thiosemicarbazone (3)
Similarly prepared from phenylthiosemicarbazide (0.84 g,
5.0 mmol) and 6-nitropiperonal (0.96 g, 4.9 mmol). X-ray quality
single crystals were obtained from a mixture of dmf/EtOH (3:1).
ꢁ
2.2. Synthesis of (E)eN-methyl-2-{(6-nitrobenzo[d][1,3]dioxol-5-
Yield: 82%. M.p.: 250e251 C. Anal. Calc. for C15
H
12
N
4
O
4
S (MW
yl)methylene}thiosemicarbazone (1)
344.4): C, 52.31; H, 3.51; N, 16.27%. Found: C, 53.50; H, 3.53; N,
ꢀ1
16.28%. IR (KBr pellet,
n
max/cm ): 3282 m, br
n
(NH)NH
N
e , 1612vs
1
To a solution of methylthiosemicarbazide (0.54 g, 5.1 mmol) in
n
(CN)imine, 1536vs as(NO
n
2
), 1326 m (NO ), 816 m n
n
s
2
(CS). H NMR
Fig. 1. Structural formulas for 1e4 and atom numbering schemes for NMR chemical shift assignments.

L.C. Dias et al. / Journal of Molecular Structure 1131 (2017) 79e86
81
Table 1
Table 2
Selected 1H and 13C{ H} NMR data (
1
d/ppm) for 1e4.
Crystal data and structure refinement parameters for 2 and 3.
1H (dmso-d
13
1
2
3
C
Assignment
6
)
6
C{ H} (dmso-d )
Formula
C
11
H
12
4
N O
4
S
15
H
12
N
4
O
4
S
1
2
3
4
1
2
3
4
Formula weight
Temperature/K
Wavelength/Å
Crystal system
Space group
a/Å
296.31
293(2)
0.71073 (Mo-K
Triclinic
P-1 (No. 2)
7.7761(6)
13.2187(12)
13.4839(12)
106.413(8)
94.187(7)
99.245(7)
1301.96(19)
4
344.35
293(2)
S¼C-NHR
CH¼N
8.67
8.71
10.2
8.28
177.6
177.3
176.4
178.8
8.22
a
)
0.71073 (Mo-K
Triclinic
P-1 (No. 2)
9.2531(5)
9.7479(6)
10.2172(6)
64.979(6)
66.390(5)
84.234(5)
762.54(8)
2
1.500
0.241
356
0.24 ꢂ 0.18 ꢂ 0.10
2.31 to 26.37
ꢀ11 ꢃ h ꢃ 11
ꢀ12 ꢃ k ꢃ 12
ꢀ12 ꢃ l ꢃ 12
11455
a)
8.47
e
8.47
e
8.59
e
8.46
e
136.5
142.8
104.5
e
137.4
143.6
105.3
e
138.1
143.4
104.8
e
137.9
143.6
105.2
e
CeNO
2
OeCH
NHeN
2
eO
6.26
11.7
6.26
11.6
6.27
12.0
6.25
11.6
b/Å
c/Å
ꢁ
ꢁ
a
/
b
/
1H NMR (dmso-d
H8), 8.28 (s, 1H, H12), 8.22 (s, 1H, H12), 8.00 (s, 1H, H2), 7.57 (s, 1H,
H6), 6.25 (s, 2H, H4). C{ H} NMR (dmso-d
178.8 (C11), 152.2 (C5), 149.0 (C3), 143.6 (C1), 137.9 (C8), 126.1 (C7),
06.3 (C2), 105.2 (C4), 104.1 (C6).
6
, 400 MHz, d/ppm): 11.6 (s, 1H, H10), 8.46 (s, 1H,
ꢁ
g
/
3
Volume/Å
Z
1
3
1
6
, 100 MHz, d/ppm):
ꢀ
3
Calculated density/Mg m
Absorption coefficient/mm
F(000)
1.512
0.269
616
ꢀ
1
1
3
Crystal size/mm
0.34 ꢂ 0.06 ꢂ 0.05
ꢁ
q
range/
1.91 to 26.37
2
.6. Single-crystal X-ray diffraction
Limiting indices
ꢀ9 ꢃ h ꢃ 9
ꢀ
16 ꢃ k ꢃ 13
11 ꢃ l ꢃ 16
Intensity data for 2 and 3 were collected at 293(2) K on a Xca-
libur, Atlas, Gemini Ultra diffractomer using graphite-
monochromated Mo-K radiation (
reduction and cell refinement were performed using the CrysAlis
RED program [19]. The structures were solved using SUPERFLIP [20]
ꢀ
Reflections collected
Independent reflections
9000
5321
3120
l
¼ 0.71073 Å). Data collection,
a
(
R
int ¼ 0.0393)
(Rint ¼ 0.0354)
3120/0/226
100.0%
Data/restraints/parameters
Completeness to
Goodness-of-fit on F
5321/8/385
99.9%
q
2
2
and refined by full-matrix least squares on F using SHELXL-97 [21].
1.013
0.925
Final R indices [I > 2
s
(I)]
R
1
¼ 0.0596
wR
¼ 0.1219
¼ 0.1109
wR
¼ 0.1463
0.788 and ꢀ0.368
R
1
¼ 0.0441
wR
¼ 0.1085
¼ 0.0662
wR
¼ 0.1273
0.433 and ꢀ0.588
Further crystallographic details are given in Table 1. All non-
hydrogen atoms were anisotropically refined. Molecular graphics
were generated by Mercury 3.8 [22]. The crystal structure of 2
shows discrete positional disorder at nitro O8 atom, which was
suitably treated during the refinement procedure.
2
2
R indices (all data)
R
1
R
1
2
2
Drmax and Drmin/e Åꢀ3
(
dmso-d
6
, 400 MHz,
d
/ppm): 12.0 (s, 1H, H10),10.2 (s, 1H, H12), 8.59
2.7. DFT calculations
(
s, 1H, H8), 8.19 (s, 1H, H2), 7.62 (s, 1H, H6), 7.51 (m, 2H, H14 and
H18), 7.39 (m, 2H, H15 and H17), 7.23 (m, 1H, H16), 6.27 (s, 2H, H4).
All DFT calculations were carried out using JAGUAR 7.9 [23] with
an energy convergence criterion of 1.00 ꢂ 10 hartree. Gas-phase
13
1
ꢀ8
C{ H} NMR (dmso-d
48.7 (C3), 143.4 (C1), 139.0 (C13), 138.1 (C8), 128.1 (C15 and C17),
26.4 (C7), 125.6 (C16), 125.5 (C14 and C18), 106.2 (C2), 104.8 (C4),
03.7 (C6).
6
, 100 MHz,
d/ppm): 176.4 (C11), 151.8 (C5),
1
1
1
geometry optimizations were performed using the B3LYP [24]
hybrid functional along with the triple-zeta 6-311G** basis set.
The molecular structures of 2 and 3 in the crystalline state were
used as starting geometries. The optimized Cartesian coordinates
are listed in Table S1 (Appendix A). Partial atomic charges were
derived by integration of the electrostatic potentials (ESPs). The
harmonic vibrational frequencies of each optimized geometry were
computed from analytic second derivatives at the same level of
calculation and verified to be real. No scaling factor was used to
correct the calculated frequencies. NMR shielding constants were
computed at the B3LYP/6-311G** level of calculation using a
pseudospectral gauge-including atomic orbitals (GIAO) algorithm
2.5. Synthesis of (E)-2-{(6-nitrobenzo[d][1,3]dioxol-5-yl)
methylene}thiosemicarbazone (4)
Similarly prepared from thiosemicarbazide (0.46 g, 5.0 mmol)
and 6-nitropiperonal (0.96 g, 4.9 mmol). Attempts to grow single
crystals of 4 for X-ray diffraction studies were unsuccessful. Yield:
ꢁ
9
3%. M.p.: 230 C (d). Anal. Calc. for C
9
8
H N
4
O
4
S (MW 268.2): C,
4
0.30; H, 3.01; N, 20.89%. Found: C, 41.43; H, 3.40; N, 21.01%. IR (KBr
ꢀ
1
1
13
pellet,
n
max/cm ): 3416s
n
s
(NH
2
), 3234 m, br
), 1326vs
n
(NH)NH
e
N
, 1602vs
(CS).
[25]. Theoretical H and C chemical shift values were evaluated
relative to TMS.
n
(CN)imine
þ
d
(NH ), 1538vs
2
n
as(NO
2
n
s
(NO ), 836 m n
2
Scheme 1. Preparation of 1e4.

82
L.C. Dias et al. / Journal of Molecular Structure 1131 (2017) 79e86
3. Results and discussion
3.1. Synthesis and preliminary characterization
The nitroaromatic TSCs 1e4 were prepared according to Scheme
1. They were isolated as air-stable analytically pure yellow solids in
moderate to high yields. In the FTIR spectra of 1e3, the
n
(CN)imine
ꢀ
1
band occurs at 1612 cm . For 4, this mode is coupled with the
ꢀ
1
d
(NH
2
) scissoring vibration at 1602 cm . As expected, two bands
group. For 1e4, the symmetric (NO
bands lie near 1325 cm while the asymmetric as(NO ) vibrations
were detected in the range 1532e1538 cm . The band assigned to
were observed for the NO
2
n
s
2
)
ꢀ
1
n
2
ꢀ1
ꢀ1
the n(CS) mode was shifted from about 987 cm in the starting
thiosemicarbazides to lower wavenumbers in 1e4. A detailed
vibrational analysis of 4, including DFT results, is discussed in
Section 3.3.
Products 1e4 were characterized by 1H and 13C{ H} NMR
1
Table 4
a,b
Noncovalent interactions for 2 and 3.
Type
Geometric parameters
Motifc,d
Ga
(r)
ꢁ
DeH/A
DeH/Å
H/A/Å D/A/Å
DeH/A/
d
2
Intramolecular
C8eH8A/O4
C19eH19/O8A
C10eH10D/S1
N4eH4N/N2
N8eH8N/N6
Intermolecular
C1eH1B/O8A
C7eH7/O6a
0.93
0.93
0.97
0.84
0.86
2.20
2.18
2.70
2.256
2.27
2.768
2.707
3.134
2.627
2.652
119
115
108
107
107
S(6)
S(6)
S(5)
S(5)
S(5)
0.97
0.93
0.93
0.93
2.51
2.45
2.60
2.53
2.63
2.92
2.93
2.65
2.976
3.309
3.485
3.352
3.491
3.778
3.761
3.392(3) 144
3.333(4) 150
3.417(3) 166(3)
3.555(3) 133(3)
3.506(3) 132
109
153
160
147
148
155
149
D
C(13)
C15eH15/O3b
C18eH18/O5c
C(14)
2
R
2
(8)
C21eH21B/O4b 0.97
C(11)
C4eH4/S2
0.93
0.93
0.86
0.86
0.87(3)
0.84(4)
0.86
D
2
C8eH8A/S1d
N7eH7N/O1
N8eH8N/O3b
N3eH3N/S1d
N4eH4N/S2
N7eH7N/S2e
R
2
(12)
D
Fig. 2. Molecular structures of 2 (a) and 3 (b). Ellipsoids are drawn at the 50% prob-
ability level. Hydrogen atoms are drawn as fixed-size spheres of radius 0.15 Å.
2.56
C(10)
2
2.56(3)
2.93(4)
2.87
R
2
(8)
D
2
R
2
(8)
pe
p
stacking
Cg···Cg/Å
Intermolecular
Cg(1)/Cg(2)f
Intramolecular
C8eH8/O4
3.72
e
3
0.93
0.93
0.83
2.24
2.61
2.10
2.817
3.253
2.585
120
126
117
S(6)
S(6)
S(5)
C2eH2/S1
Table 3
N1eH1N/N3
Intermolecular
C15eH15B/N2i
C4eH4/O2ii
C8eH8/O4iii
C13eH13/O1iv
C15eH15B/O4v 0.97
C3eH3/S1vi
N2eH2N/O3iii
ꢁ
Selected bond lengths (Å) and angles ( ) for 2 and 3.
0.97
0.93
0.93
0.93
2.80
2.58
2.66
2.47
2.63
3.00
2.34
3.394
3.475
3.375
3.307
3.317
3.893
3.189
120
161
134
149
128
162
164
R2
2
2
2
2
(18)
(28)
(12)
(8)
2
C(8)eN(2)
C(9)eN(3)
C(9)eN(4)
C(9)eS(1)
C(19)eN(6)
N(1)eO(3)
N(1)eO(4)
1.277(4)
1.357(5)
1.320(5)
1.676(3)
1.267(5)
1.202(4)
1.232(5)
N(6)eN(7)
C(20)eN(7)
C(20)eN(8)
C(20)eS(2)
N(2)eN(3)
N(5)eO(7)
N(5)eO(8A)
1.366(3)
1.350(4)
1.321(4)
1.678(3)
1.365(4)
1.189(5)
1.27(1)
2
R
2
R
2
R
C(8)
2
0.93
0.87
R
R
2
(14)
(16)
2
2
pe
p
stacking
Cg···Cg/Å
Intermolecular
Cg(1)/Cg(1)i
N(2)eC(8)eC(5)
N(3)eC(9)eN(4)
N(3)eC(9)eS(1)
N(4)eC(9)eS(1)
O(3)eN(1)eO(4)
120.1(3)
116.0(3)
119.5(2)
124.5(3)
121.3(3)
N(6)eC(19)eC(16)
N(7)eC(20)eN(8)
N(7)eC(20)eS(2)
N(8)eC(20)eS(2)
O(7)eN(5)eO(8A)
120.1(3)
116.6(2)
118.6(2)
124.8(2)
115.6(8)
4.17
e
a
Symmetry codes. For 2: (a) x,y,1 þ z; (b) x,y, e1þz; (c) 2ex, ey, e1ez; (d)
1ex,2ey,1ez; (e) 1ex,1ey, ez; (f) 2ex,1ey, ez. For 3: (i) 1ex, ey,1ez; (ii) 2ex,1ey,
ez; (iii) ex, ey,1ez; (iv) 1ex, e1ey,1ez; (v) 1 þ x,y,z; (vi) 1ex,2ey, ez.
b
Cg(J) stands for centroid (centre-of-gravity) of the jth ring. For 2: J ¼ 1, C2eC7;
J ¼ 2, C13eC18. For 3: J ¼ 1, C9eC14.
3
C(7)eS(1)
C(7)eN(2)
C(7)eN(1)
N(4)eO(3)
1.659(2)
1.363(3)
1.337(3)
1.217(2)
N(2)eN(3)
C(8)eN(3)
N(4)eO(4)
1.365(2)
1.275(3)
1.221(3)
c
A motif is defined by only one type of classical or nonclassical hydrogen-bond
a
pattern and can be encoded by Etter's graph-set assignment G
graph-set assignment of chain motifs (repeating moiety) of 2, noncovalent in-
teractions between the two independent units were included along the shortest
d
(r) [31]. In the
pathway.
N(1)eC(7)eN(2)
N(1)eC(7)eS(1)
N(2)eC(7)eS(1)
113.3(2)
128.4(2)
118.2(2)
C(9)eC(8)eN(3)
O(3)eN(4)eO(4)
118.7(2)
122.2(2)
d
In the graph-set assignment of CeH/p interactions, the r value (pattern degree)
corresponds to the number of atoms in the repeating unit from hydrogen to the first
carbon atom of the acceptor ring Cg(J), regarding the shortest pathway.

L.C. Dias et al. / Journal of Molecular Structure 1131 (2017) 79e86
83
ꢁ
spectroscopy (Fig. S1). Our NMR results agree with the literature
eNHC(S)NHN]CHe backbone (dihedral angle ¼ 11.3 ). Moreover,
the eNHC(S)NHN]CHe and 6-nitrobenzo[d] [1,3]dioxol-5-yl
moieties display an almost coplanar arrangement for both prod-
1
13
[26e28]. The more relevant H and C resonances are those related
to the following functional groups: S]C-NHR, CH]N, OeCH
2
eO
H
1
ꢁ
ꢁ
and NHeN (Table 2). According to Table 2, the position of the
resonances ascribed to the CH]N, OeCH
ucts, with dihedral angles ranging from 3.2 and 7.6 in 2 to 10.7 in
3. Similar conformation was observed in thiophene-
thiosemicarbazone derivatives [30].
2
eO and NHeN groups
does not significantly change on varying the R group (R ¼ Me, Et, Ph
1
or H). On the other hand, the H NMR signal assigned to the S]C-
The supramolecular arrangements of 2 and 3 primarily result
from classical and nonclassical hydrogen bonds (Table 4). These
contacts were recognized by Mercury 3.8 (sum of van der Waals
radii plus 0.1 Å) [22] and confirmed by Hirshfeld surface analysis
[32e36]. Fig. S2 (Appendix A) illustrates the Hirshfeld surfaces for 2
and 3 mapped with dnorm. These maps were generated by Crysta-
lExplorer 3.1 [37]. Red spots on dnorm maps suggest relevant non-
covalent close contacts (Fig. S2). Based on our unbiased analysis
and on more relaxed geometric criteria [38e41], we propose that
the DeH$$$A interactions listed in Table 4 are attractive and
directional rather than mere van der Waals isotropic contacts. The
noncovalent interactions described for 2 involve both independent
molecules, namely 2-I and 2-II.
NHR moiety of 3 lies at a higher frequency (d 10.2) compared to the
respective signals for 1, 2 and 4. This result can be accounted for by
1
deshielding effects provided by the Ph group. For 4, two H signals
were identified for H12, namely
d 8.22 and 8.28. The intramolecular
N12eH12/N9 hydrogen bond is likely to be responsible for the
1
3
more deshielded resonance (
to the C]S groups of 1e4 appear near
d 8.28). The C NMR signals assigned
13
d
178. In turn, the CH ¼ N
13
signals lie about 40 ppm upfield for all products. The S ¼ C-NHR
signals are slightly affected by stereoelectronic effects provided by
the R groups: R ¼ Ph (
78.8). The phenyl ring offers an electronic conjugation system,
whereas the methyl and ethyl groups display inductive effects.
d 176.4) < Et (d 177.3) < Me (d 177.6) < H (d
1
According to Table 4, compound 2 exhibits intramolecular
NeH/N, CeH/O and CeH/S hydrogen-bonding interactions.
Moreover, two independent molecules in its unit cell are non-
covalently connected by the C1eH1B/O8A, C4eH4/S2,
N7eH7N/O1, and N4eH4N/S2 contacts. These dimeric motifs
contribute to a 2-D supramolecular arrangement along the [111]
base vector (Fig. 3). In addition to the classical N3eH3N/S1d and
nonclassical C8eH8A$$$S1d and C18eH18/O5c ring-like motifs,
this 2-D architecture also includes a 1-D network along the c-axis
formed by the C7eH7/O6a, C15eH15/O3b, N8eH8N/O3b, and
C21eH21B/O4b chain motifs (Fig. 3). Parallel 2-D sheets are
interconnected by the N7eH7N/S2e hydrogen bond as well as by
3
.2. X-ray structure and Hirshfeld surface analyses
Both 2 and 3 crystallize in the triclinic P-1 space group (Table 1).
Their molecular structures in the crystalline state are depicted in
Fig. 2. Selected bond lengths and angles for both products are listed
in Table 3. All bond lengths display typical values [29]. Two crys-
tallographically independent molecules were recognized for 2
(Fig. 2a), whereas the asymmetric unit of 3 comprises only one
molecule (Fig. 2b). According to Table 3, the imine C]N distances
exhibit similar values for both TSCs, namely 1.277(4) and 1.267(5) Å
for 2 and 1.275(3) Å for 3. In addition, the C]S bond of 3 [C(7)eS(1),
the Cg(1)$$$Cg(2)f (Cg$$$Cg, 3.72 Å) pep stacking interaction. In 2,
1
.659(2) Å] is slightly shorter than the respective bond of 2 [C(9)
both S1 and S2 are involved in trifurcated acceptor schemes, while
O3, O4 and O8A are bifurcated.
eS(1), 1.676(3) Å and C(20)eS(2), 1.678(3) Å]. In 3, the phenyl group
attached to N(1) is almost coplanar with the thiosemicarbazone
Fig. 3. Packing diagram of 2 showing the 2-D supramolecular structure along the [111] base vector. Symmetry codes: (a) x,y,1 þ z; (b) x,y, e1þz; (c) 2ex, ey, e1ez; (d) 1ex,2ey,1ez.

84
L.C. Dias et al. / Journal of Molecular Structure 1131 (2017) 79e86
Fig. 4. Packing diagram of 3 showing the 2-D supramolecular arrangement along the [111] base vector. Symmetry codes: (ii) 2ex,1ey, ez; (iii) ex, ey,1ez; (iv) 1ex, e1ey,1ez; (vi)
1ex,2ey, ez.
Similar to 2, product 3 also displays intramolecular NeH/N,
CeH/O and CeH/S hydrogen bonds (Table 4). Furthermore, the
results, both the Nimine and S atoms are negatively charged,
whereas the nitro N atoms display large net positive charges.
Moreover, the C]S group of 1e4 constitutes a nucleophilic region,
crystal packing of 3 reveals a 2-D supramolecular structure along
2
the [111] base vector (Fig. 4). In addition to the large R
2
(28)
2
whilst the NO group defines an electrophilic centre (Fig. 6 and S3).
C4eH4/O2ii ring motif, this 2-D arrangement comprises a 1-D
network along the a-axis formed by the C8eH8/O4iii and
N2eH2N/O3iii interactions and a 1-D chain along the b-axis
formed by the C3eH3/S1vi and C13eH13/O1iv contacts (Fig. 4).
In this structure, parallel 2-D sheets are interconnected by the
nonclassical C15eH15B/O4v and C15eH15B/N2i hydrogen bonds
This result indicates that the electrochemical reduction of these
nitroaromatic TSCs is feasible and may be exploited in their
bioactivities.
A DFT vibrational analysis of 4 has been performed in order to
provide a reliable assignment of the normal modes associated with
the thiosemicarbazone eNHC(S)NHN]CHe moiety. Experimental
(FTIR) and calculated bands for 4 are summarized in Table S2
as well as by the Cg(1)$$$Cg(1)i (Cg$$$Cg, 4.17 Å)
pep stacking
interaction. Our supramolecular analysis shows that in 3 atom O4 is
trifurcated while S1 is involved in a bifurcated hydrogen-bonding
acceptor scheme.
According to our Hirshfeld surface analyses, the H/O/O/H
close contacts largely contribute to the Hirshfeld surface areas for
the two crystallographically independent molecules of 2, 2-I and 2-
II, and 3, followed by the isotropic H/H van der Waals contacts
(Appendix A). In the FTIR spectrum of 4, the
(CH)imine, and (NH ) modes occur at 3416, 3234,
3028, and 1602 cm , respectively, in excellent agreement with the
literature [44]. The coupled (HNNCH)
(NH (HNC), and (CH ) þ (NN) modes appear at 1432, 1266,
) þ
and 1098 cm , respectively. Furthermore, the (NCN) and (CS)
s 2 N
n (NH ), n(NH)NHe ,
n
n
(CN)imine
þ
d
2
ꢀ
1
r
r
þ
n(CN)CNH2,
r
r
2
d
r
r
2
n
ꢀ1
n
s
n
(Fig. 5). Moreover, the H/C/C/H contacts, referred to as CeH$$$p
interactions, significantly contribute to the Hirshfeld surface area
for 3. For 2, the H/S/S/H contributions are larger than those
observed for the H/C/C/H close contacts (Fig. 5).
3.3. DFT calculations
Electronic and spectroscopic properties of 1e4 have been
investigated at the DFT level of theory. All calculations were carried
out at the B3LYP/6-311G** level. This level of calculation has pro-
vided accurate results for TSCs and their metal complexes
[28,42e45]. The geometries optimized for 1e4 are illustrated in
Fig. 6, which also shows ESP atomic charges. The ESPs of 1e4
ꢀ3
mapped onto the 0.001 electrons bohr isodensity surfaces are
depicted in Fig. S3 (Appendix A). The geometric parameters
calculated for 2 and 3 resemble those obtained by X-ray diffraction
data (Table 3). In addition, Fig. 6 reveals that the bond lengths and
angles calculated for 1e4 are quite similar. According to our ESP
Fig. 5. Percentage contributions of atom-type/atom-type close contacts to the Hirsh-
feld surface areas for 2, 2-I and 2-II, and 3.

L.C. Dias et al. / Journal of Molecular Structure 1131 (2017) 79e86
85
ꢁ
Fig. 6. Molecular structures optimized for 1e4 at the B3LYP/6-311G** level of calculation. Selected bond distances (Å), bond angles ( ), and partial atomic charges (a.u.) are also
shown.
stretching modes lie at 1075 and 836 cmꢀ1, respectively. As sug-
gested by the literature [44], a number of thiosemicarbazone-based
vibrations, including d(NNC) (524 cm ) and d(NCS) (398 cm ),
nitropiperonal and thiosemicarbazone moieties exhibit an almost
coplanar arrangement for both 2 and 3. Moreover, these thio-
semicarbazones form 2-D networks along the [111] base vector by
means of classical and nonclassical hydrogen bonds. Electronic and
spectroscopic properties of 1e4 were studied at the B3LYP/6-
311G** level of calculation. Our computational ESP results showed
that each product displays a nucleophilic C]S region and an
electrophilic site at the nitro group. This electronic feature can be
further exploited in biological studies of 1e4 since their nitro
groups are feasible to undergo electrochemical reduction.
Furthermore, a DFT vibrational analysis of 4 allowed a reliable
assignment of the thiosemicarbazone-based vibrations. Also, a
ꢀ1 ꢀ1
were also identified in the low-frequency spectrum of 4.
Density-functional (GIAO) calculations were used in support of
our 1H and C NMR signal assignments in Section 3.1. The 1
13
H
chemical shift values calculated for H10 and H12 (see Fig.1 for atom
numbering scheme) differ considerably from the experimental
1
values. In general, the calculated H chemical shift values lie at
frequencies lower than the experimental ones. In these cases, the
mean percent deviations amount to 26.9 (1), 25.6 (2), 22.1 (3), and
2
9.7% (4). For the remaining protons, the calculated chemical shift
1
13
values agree very well with the experimental ones. As can be seen
in Fig. S4 (Appendix A), a good agreement between theoretical and
experimental 13C chemical shift values was obtained for 1e4.
good agreement between calculated and experimental H and
C
chemical shift values was obtained for 1e4.
Acknowledgements
4
. Conclusions
The authors are grateful to the Brazilian funding agencies CAPES,
CNPq, FAPERJ and FAPEMIG for sponsorship.
Four nitroaromatic thiosemicarbazones were prepared from 6-
nitropiperonal and H
2
NeNHeC(S)eNHR [R ¼ Me (1), Et (2), Ph
(
3) or H (4)] in moderate to high yields. Products 1e4 were char-
Appendix A. Supplementary data
1
13
1
acterized by FTIR, H and C{ H} NMR spectroscopy. In addition,
the crystal structures of 2 and 3 were determined by single-crystal
X-ray diffraction. According to our X-ray structural results, the
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.molstruc.2016.11.039.

8
6
L.C. Dias et al. / Journal of Molecular Structure 1131 (2017) 79e86
E.B. Paniago, J.L. Wardell, S.M.S.V. Wardell, K. Krambrock, I.C. Mendes,
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