Synthesis and X-ray Crystal Structure of 2 and 4-Trifluoromethyl Substituted Phenyl Semicarbazone and Thiosemicarbazone

Article abstract of DOI:10.1007/s10870-017-0677-z

Abstract: NMR and single crystal X-ray structure data for four structurally similar semicarbazones and thiosemicarbazones were compared. In solution, proton NMR showed considerable variation in their chemical shift values especially for the NH₂ protons. In the case of the semicarbazones this peak appeared as a broad singlet with an integration ratio of two while for the thiosemicarbazones the amino group showed two distinct singlets with marked chemical shift differences. This is attributed to the differences in the canonical forms of the thiosemicarbazone amino group and the semicarbazone analogue. Additionally, we provide evidence that the 2-trifluoromethyl phenyl substituted semicarbazone (2) formed an intermolecular hydrogen bond with one of the hydrogens of the NH₂ group while this was totally absent in the thiosemicarbazone. We explain this by the restricted rotation of the CN bond in the thiosemicarbazone due to its double bond character compared to the less restricted rotation in semicarbazone compound. Graphical Abstract: NMR and single crystal X-ray structure data for four structurally similar semicarbazones and thiosemicarbazones were compared for their hydrogen bonding characteristics.[Figure not available: see fulltext.]

Full text of DOI:10.1007/s10870-017-0677-z

J Chem Crystallogr
DOI 10.1007/s10870-017-0677-z
ORIGINAL PAPER
Synthesis and X-ray Crystal Structure of 2 and 4-Trifluoromethyl
Substituted Phenyl Semicarbazone and Thiosemicarbazone
T. K. Venkatachalam1 · Paul V. Bernhardt2 · Gregory K. Pierens1 · David C. Reutens1
Received: 28 January 2016 / Accepted: 11 March 2017
© Springer Science+Business Media New York 2017
Abstract NMR and single crystal X-ray structure data for
four structurally similar semicarbazones and thiosemicar-
bazones were compared. In solution, proton NMR showed
considerable variation in their chemical shift values espe-
cially for the NH2 protons. In the case of the semicarba-
zones this peak appeared as a broad singlet with an inte-
gration ratio of two while for the thiosemicarbazones the
amino group showed two distinct singlets with marked
chemical shift differences. This is attributed to the dif-
ferences in the canonical forms of the thiosemicarbazone
amino group and the semicarbazone analogue. Addition-
ally, we provide evidence that the 2-trifluoromethyl phenyl
substituted semicarbazone (2) formed an intermolecular
hydrogen bond with one of the hydrogens of the NH2 group
while this was totally absent in the thiosemicarbazone.
We explain this by the restricted rotation of the CN bond
Keywords Semicarbazones · NMR · X-ray crystal
in the thiosemicarbazone due to its double bond character
structure · Hydrogen bond
compared to the less restricted rotation in semicarbazone
compound.
Graphical Abstract NMR and single crystal X-ray struc-
ture data for four structurally similar semicarbazones and
thiosemicarbazones were compared for their hydrogen
bonding characteristics.
Introduction
Semicarbazones and thiosemicarbazones are compounds,
which can be easily obtained by the condensation of an
aldehyde with either semicarbazide or thiosemicarbazide
in a single step. These compounds were known from the
early part of the nineteenth century. Although the prepa-
ration of these simple compounds has been described
in the literature, the biological activity profiles of these
compounds were only studied in the latter part of the last
century. A variety of thiosemicarbazones/semicarbazones
show a wide range of biological activities including being
effective against tuberculosis [1] and cancer [2–5]. Apart
from being biologically active, these compounds have the
capacity to complex with various metal ions, and some
Electronic supplementary material The online version of this
article (doi:10.1007/s10870-017-0677-z) contains supplementary
material, which is available to authorized users.
* T. K. Venkatachalam
t.venkatachalam@uq.edu.au
1
Centre for Advanced Imaging, The University of Queensland,
Brisbane 4072, Australia
2
School of Chemistry and Molecular Biosciences, The
University of Queensland, Brisbane 4072, Australia
Vol.:(0123456789)
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J Chem Crystallogr
Scheme 1 General syn-
thetic scheme for synthesis of
semicarbazone and thiosemi-
carbazones and the structures of
semicarbazones and thiosemi-
carbazones used in the present
study
X
N
CHO
N
NH2
H
NH
2NHCXNH2
CH3COONa
EtOH
R
RT/24h
R
or
X=O
S
O
CF3
O
N
N
F
N
H
NH2
3C
N
H
NH2
(2)
(1)
S
CF3
S
N
N
F
N
H
NH2
3C
N
H
NH2
(4)
(3)
of the metal complexes also possess marked biological
activity. Iron complexes of thiosemicarbazone derivatives
have been found to be effective anti-cancer agents [6–13]
(see Kalinowski et al. [14] for a detailed review on the
use of thiosemicarbazones for cancer treatment). Lobana
et al. [15] have compiled a detailed review on the bond-
ing and structural characteristics of thiosemicarbazones
in particular and reported the development of strategies
for the preparation of newer derivatives and their poten-
tial applications. In recent years attachment of radiomet-
als to thiosemicarbazones has been undertaken to develop
cancer imaging agents [16–21]. Several single crystal
X-ray diffraction studies of both semicarbazones and
thiosemicarabzones have been published. The 4-pyridyl
semicarbazone and its zinc, cobalt and cadmium com-
plexes, [22] crystal structures of complexes of 2-pyridyl
semicarbazone [23–28] and the X-ray crystal structures
of both the ligand and the cadmium and indium chelates
of 4-nitrophenyl thiosemicarbazones [29, 30] have previ-
ously been described.
Experimental
All chemicals were obtained from Sigma-Aldrich and
used without further purification. NMR spectra were
recorded in deuterated dimethylsulfoxide and the chemi-
cal shifts were referenced by the DMSO protons at
2.54 ppm. The NMR data were acquired on a Bruker
700 MHz NMR spectrometer equipped with a cryoprobe.
The proton spectra where acquired with a sweep width
of 15 ppm centered at 7 ppm. The carbon spectra were
acquired with a sweep width of 220 ppm centered at
110 ppm. The COSY experiments were acquired with a
sweep width of 15 ppm using a 90° pulse of 9 µs with
256 increments. The 13C HSQC spectrum was acquired
with sweep widths of 18 and 160 ppm for proton and
carbon respectively and the carbon centered at 80 ppm.
Additionally, HMBC spectral data was also acquired to
establish the structures of the compounds (13C sweep
width of 220 ppm). The raw data were multiplied by an
exponential or shifted sine squared function before per-
forming the Fourier transform.
We studied the structural features of new thiosemicar-
bazone derivatives containing the trifluoromethyl group
in their structural framework.
Physical constants of compounds: 4-triflouromethyl phe-
nyl semicarbazone and thiosemicarbazone data have been
reported in our earlier publication [31] and the data for
1 3

J Chem Crystallogr
Fig. 1 1H NMR spectra of a 2-CF3 phenyl semicarbazone (2) and b 2-CF3 phenyl thiosemicarbazone (4) in d6-DMSO at room temperature
Fig. 2 13C NMR spectra of 2-CF3 phenyl semicarbazone (2) (a) and 2-CF3 phenyl thiosemicarbazone (4) (b) in d6-DMSO at room temperature
1 3

J Chem Crystallogr
and constrained to their parent N- or C-atom using a riding
model. The molecular structure diagrams were produced
with ORTEP3 [34]. The packing diagrams were drawn with
PLUTON [35]. The crystal data in CIF format have been
deposited at the Cambridge Crystallographic Data Centre
with deposition numbers 1440272–1440275.
Results and Discussion
The synthesis of semicarbazone and thiosemicarbazone
was achieved following Scheme 1, that is, 2- or 4-substi-
tuted trifluoromethyl benzaldehyde was condensed with
either semicarbazide hydrochloride or thiosemicarbazide
hydrochloride in the presence of sodium acetate in ethanol
to furnish the required compounds. The compounds were
further purified by recrystallization from methanol to yield
analytically pure products.
Fig. 3 Molecular structure of 4-CF3 phenyl semicarbazone (1) (30%
ellipsoid probability)
The trifluoromethyl substituted compounds were synthe-
sised because the CF3 group constitutes an important group
in medicinal chemistry due to its peculiar chemical proper-
ties centering on its hydrophobic nature, electron rich envi-
ronment and hydrogen bonding capacity. It can also confer
high in vivo stability to molecules [36–38]. The compounds
were further characterized using various NMR techniques
2-triflouromethyl phenyl semicarbazone and thiosemicar-
bazone are as follows:
2-CF3-Phenyl semicarbazone (2): 1H NMR (d6-DMSO):
δ ppm: 10.57 (s, 1H), 8.41–8.40 (d, 1H, J=7.0 Hz),
8.19 (s, 1H), 7.73–7.72 (d, 1H, J=7.0 Hz), 7.67–7.65 (t,
1H), 7.54–7.52 (t, 1H), 6.62 (bs, 2H, NH2); 13C NMR
(d6-DMSO): δ ppm: 156.5, 134.3, 132.7, 132.5, 128.9,
126.9, 125.9–123.7 (m, CF3), 125.6, 124.8.
1
including COSY, HMBC and HSQC. The H NMR data
of the compounds are shown in Fig. 1a, b for the respec-
1
tive compounds. The H NMR of 2-trifluoromethyl phenyl
2-CF3-Phenyl-thiosemicarbazone
(4):
1H
NMR
semicarbazone (2) showed a singlet at 10.5 ppm for the iso-
lated NH proton followed by doublets for the protons in the
phenyl ring and an additional singlet for the CH protons. A
broad peak at 6.62 ppm was assigned to NH2 protons with
an integration value of 2. The 13C NMR spectrum of the
compound (Fig. 2a) showed nine carbons as expected. The
C=O carbon appeared at 156.5 ppm followed by other car-
bons in the structure. It is interesting to note that the CF3
carbon showed multiple couplings, and the peak was cen-
tred at 126.2 ppm. Figure 1b represents the 1H NMR spec-
trum of the 2-trifluoromethyl phenyl substituted thiosemi-
carbazone (4) in dimethyl sulfoxide solvent. In accordance
with the structure of the molecule, the NH proton appeared
at 11.7 ppm followed by the aromatic proton signals further
upfield. The spectrum also showed a singlet for each of the
NH2 protons respectively. Figure 2b shows the 13C spec-
trum for the same compound in d6-DMSO solvent. Once
again we observed the C=O peak at 178.4 ppm similar to
that obtained for the 2-trifluoromethyl substituted phenyl
semicarbazone, except it was shifted downfield as expected
for thio compounds. We also observed the CF3 carbon peak
as a quartet centered at 126.8 ppm confirming the presence
of this group in the structure of the molecule. This carbon
is shifted upfield relative to the 4-substituted trifluorome-
thyl group of the semicarbazone [31].
(d6-DMSO): δ ppm: 11.69 (s, 1H), 8.51–8.50 (d, 1H,
J=7.0 Hz), 8.44 (s, 1H), 8.36 (s, 1H), 8.16 (s, 1H),
7.75–7.74 (d, 1HJ=7.0 Hz), 7.69–7.67 (t, 1H), 7.58–7.57
(t, 1H); 13C NMR (d6-DMSO): δ ppm 178.4, 137.4, 132.5,
132.1, 129.7, 127.4, 126.8, 125.7, 124.2.
X-ray Crystallography
X-ray quality single crystals were obtained by slow diffu-
sion of methylene chloride into methanol solutions. Crys-
tallographic data were acquired at 190 K on an Oxford
Diffraction Gemini CCD diffractometer employing graph-
ite-monochromated Mo Kα radiation (0.71073 Å) and oper-
ating within the range 2<2θ<50°. Temperature control
was achieved with an Oxford Cryosystems Desktop Cooler.
Data reduction and empirical absorption corrections (semi-
empirical from equivalents) were performed with Oxford
Diffraction CrysAlisPro software [32]. The structure was
solved by direct methods with SHELXS and refined by
full-matrix least-squares analysis with SHELXL-97 [33]
within the WinGX graphical user interface [34]. All non-H
atoms were refined with anisotropic thermal parameters.
All hydrogen bonds were included at calculated positions
1 3

J Chem Crystallogr
Table 1 Crystal parameters for all the compounds
Compounds #
(1)
(2)
(3)
(4)
Empirical formula
Formula weight
Temperature
Wavelength
Crystal system
Space group
C9H8F3N3O
231.18
190 (2) K
0.71073 Å
Monoclinic
P21/c
C9H8F3N3O
231.18
190 (2) K
0.71073 Å
Monoclinic
P21/c
C9H8F3N3S
247.24
190 (2) K
0.71073 Å
Monoclinic
P21/c
C9H8F3N3S
247.24
190 (2) K
0.71073 Å
Monoclinic
P21/n
Unit cell dimen-
a=14.706 (3) Å
a=7.4630 (7 Å
a=15.8160 (13) Å
a=6.8489 (17) Å
b=8.555 (3) Å, β=94.716 (18)°
sions
b=5.1088 (10) Å,
b=6.4315 (6) Å,
b=8.4856 (5) Å,
β=102.976 (19)°
β=90.803 (8)°
β=104.826 (8)°
c=13.204 (2) Å
966.7 (3) Å3
4
c=20.892 (2) Å
1002.71 (17) Å3
4
c=8.4410 (7) Å
1095.14 (14) Å3
4
c=18.048 (4) Å
1053.9 (5) Å3
4
Volume
Z
Density (calculated) 1.588 Mg/m3
1.531 Mg/m3
0.141 mm−1
1.500 Mg/m3
0.312 mm−1
1.558 Mg/m3
0.324 mm−1
Absorption coef-
0.147 mm−1
ficient
F(000)
Crystal size
472
472
504
504
0.4×0.3×0.06 mm3
0.4×0.15×0.15 mm3
3.33°–24.99°
0.6×0.3×0.1 mm3
3.46°–25.00°
0.4×0.1×0.1 mm3
3.28°–24.99°
Theta range for data 3.75°–24.99°
collection
Index ranges
−17≤h≤17, −3≤k≤6, −4≤h≤8, −4≤k≤7,
−14≤l≤15 −24≤l≤24
−18≤h≤18,
−10≤k≤10,
−9≤l≤10
−6≤h≤8, −10≤k≤10, −21≤l≤21
Reflections col-
lected
3002
3634
8470
2452
Independent reflec- 1692 [R(int)=0.0516]
1763 [R(int)=0.0329]
99.3%
1923 [R(int)=0.0405]
99.8%
2452 [R(int)=0.0000]
99.8%
tions
Completeness to
theta=24.99°
99.8%
Absorption cor-
Semi-empirical from equivalents
1 and 0.30435
Semi-empirical from
equivalents
1 and 0.98219
Semi-empirical from equivalents
1 and 0.88951
Semi-empirical from
equivalents
1 and 0.38827
rection
Max. and min.
transmission
Refinement method Full-matrix least-squares on F2
Full-matrix least-
squares on F2
1763/0/145
Full-matrix least-squares on F2
1923/0/173
Full-matrix least-
squares on F2
2452/0/147
Data/restraints/
parameters
1692/0/145
Goodness-of-fit
0.997
1.092
1.169
0.975
on F2
Final R indices
[I>2sigma(I)]
R indices (all data) R1=0.1115, wR2=0.1468
R1=0.0593, wR2=0.1179
R1=0.0435,
wR2=0.0911
R1=0.0516, wR2=0.1109
R1=0.0627, wR2=0.1154
R1=0.0707,
wR2=0.1720
R1=0.1134,
wR2=0.1880,
0.010 (3)
R1=0.0641,
wR2=0.1034
Largest diff. peak
and hole
0.226 and −0.297 e Å−3
0.187 and −0.216 e Å−3 0.283 and −0.245 e Å−3
0.327 and −0.339
e Å−3
Single Crystal X-ray Studies of 2-
N2–H proton is intact and therefore this compound exists
as a keto tautomer instead of the enol configuration,
which is not observed for this semicarbazone, although it
is known that these semicarbazones can exhibit keto-enol
tautomerism. Furthermore we find that the compound
exists as an anti-conformer. The N1–N2 bond length
in the structure is 1.374 (4) Å, which is consistent with
the reported value for the phenyl semicarbazone (1.355
(4) Å). The C8–O1 bond is 1.237 (4) Å, which is consist-
ent with the expected value for a C=O compound (1.227
(3) Å) [39].
and 4-Trifluoromethyl Substituted Phenyl
Semicarbazone and Thiosemicarbazones
Figure 3 shows the molecular structure of 4-trifluorome-
thyl phenyl semicarbazone (1). The crystal data along
with the collection parameters are shown in Table 1.
Table 2 shows selected bond lengths. The bond lengths
and angles were as expected. It appears from the crystal
structure that the CF3 group is in the same plane as that
of the semicarbazone moiety. It is also evident that the
1 3

J Chem Crystallogr
Angles
Table 2 Selected bond lengths and angles of semicarbazones/thiosemicarbazones
Compound (1)
Compound (2)
Bonds
Lengths
Bonds
Angles
Bonds
Lengths
Bonds
C(1)–C(6)
C(1)–C(2)
C(1)–C(7)
C(2)–C(3)
C(3)–C(4)
C(4)–C(5)
C(4)–C(9)
C(5)–C(6)
C(7)–N(1)
C(8)–O(1)
C(8)–N(3)
C(8)–N(2)
C(9)–F(3)
C(9)–F(1)
C(9)–F(2)
N(1)–N(2)
1.395 (5)
1.396 (4)
1.447 (5)
1.388 (5)
1.374 (5)
1.397 (4)
1.489 (5)
1.376 (5)
1.291 (4)
1.237 (4)
1.319 (4)
1.373 (4)
1.339 (4)
1.344 (4)
1.351 (4)
1.374 (4)
C(6)–C(1)–C(2)
C(6)–C(1)–C(7)
C(2)–C(1)–C(7)
C(3)–C(2)–C(1)
C(4)–C(3)–C(2)
C(3)–C(4)–C(5)
C(3)–C(4)–C(9)
C(5)–C(4)–C(9)
C(6)–C(5)–C(4)
C(5)–C(6–C(1)
N(1)–C(7)–C(1)
O(1)–C(8)–N(3)
O(1)–C(8)–N(2)
N(3)–C(8)–N(2)
F(3)–C(9)–F(1)
F(3)–C(9)–F(2)
118.0 (3)
122.8 (3)
119.1 (3)
120.3 (3)
121.0 (3)
119.3 (3)
120.0 (3)
120.6 (3)
119.9 (3)
121.5 (3)
121.8 (3)
124.8 (3)
118.5 (3)
116.7 (3)
106.6 (3)
106.1 (3)
C(1)–C(6)
C(1)–C(2)
C(1)–C(7)
C(2)–C(3)
C(2)–C(9)
C(3)–C(4)
C(4)–C(5)
C(5)–C(6)
C(7)–N(1)
C(8)–O(1)
C(8)–N(3)
C(8)–N(2)
C(9)–F(1)
C(9)–F(3)
C(9)–F(2)
N(1)–N(2)
1.395 (3)
1.402 (3)
1.47(3)
C(6)–C(1)–C(2)
C(6)–C(1)–C(7)
C(2)–C(1)–C(7)
C(3)–C(2)–C(1)
C(3)–C(2)–C(9)
C(1)–C(2)–C(9)
C(4)–C(3)–C(2)
C(5)–C(4)–C(3)
C(4)–C(5)–C(6)
C(5)–C(6)–C(1)
N(1)–C(7)–C(1)
O(1)–C(8)–N(3)
O(1)–C(8)–N(2)
N(3)–C(8)–N(2)
F(1)–C(9)–F(3)
F(1)–C(9)–F(2)
118.02 (19)
119.37 (19)
122.61 (19)
120.2 (2)
118.7 (2)
121.05 (19)
120.4 (2)
120.0 (2)
120.3 (2)
121.0 (2)
119.43 (19)
123.78 (19)
119.70 (19)
116.51 (19)
105.60 (18)
105.49 (19)
1.391 (3)
1.488 (3)
1.375 (3)
1.374 (3)
1.380 (3)
1.275 (3)
1.239 (2)
1.334 (3)
1.364 (3)
1.339 (3)
1.340 (2)
1.347 (3)
1.369 (2)
Compound (3)
Compound (4)
Bonds
Lengths
Bonds
Angles
Bonds
Lengths
Bonds
Angles
C(1)–C(2)
C(1)–C(6)
C(1)–C(7)
C(2)–C(3)
C(3)–C(4)
C(4)–C(5)
C(4)–C(9)
C(5)–C(6)
C(7)–N(1)
C(8)–N(3)
C(8)–N(2)
C(8)–S(1)
C(9)–F(2′)
C(9)–F(1′)
C(9)–F(3)
C(9)–F(2)
1.380 (4)
1.387 (4)
1.461(4)
1.385 (4)
1.373 (5)
1.385 (5)
1.494 (5)
1.375 (4)
1.275 (4)
1.319 (4)
1.347(3)
1.687 (3)
1.220 (11)
1.259 (13)
1.298 (9)
1.316 (9)
C(2)–C(1)–C(6)
C(2)–C(1)–C(7)
C(6)–C(1)–C(7)
C(1)–C(2)–C(3)
C(4)–C(3)–C(2)
C(3)–C(4)–C(5)
C(3)–C(4)–C(9)
C(5)–C(4)–C(9)
C(6)–C(5)–C(4)
C(5)–C(6)–C(1)
N(1)–C(7)–C(1)
N(3)–C(8)–N(2)
N(3)–C(8)–S(1)
N(2)–C(8)–S(1)
F(2′)–C(9)–F(1′)
F(3)–C(9)–F(2)
118.8 (3)
119.6 (3)
121.5 (3)
121.0 (3)
119.5 (3)
120.2 (3)
120.5 (3)
119.3 (3)
119.9 (3)
120.6 (3)
120.5 (3)
117.3 (2)
123.3 (2)
119.5 (2)
117.9 (13)
108.6 (8)
C(1)–C(6)
C(1)–C(2)
C(1)–C(7)
C(2)–C(3)
C(2)–C(9)
C(3)–C(4)
C(4)–C(5)
C(5)–C(6)
C(7)–N(1)
C(8)–N(3)
C(8)–N(2)
C(8)–S(1)
C(9)–F(2)
C(9)–F(1)
C(9)–F(3)
N(1)–N(2)
1.374 (6)
1.396 (6)
1.464 (7)
1.392 (6)
1.495 (6)
1.373 (7)
1.365 (8)
1.379 (6)
1.269 (6)
1.299 (6)
1.343 (6)
1.699 (4)
1.330 (6)
1.330 (6)
1.332 (5)
1.364 (5)
C(6)–C(1)–C(2)
C(6)–C(1)–C(7)
C(2)–C(1)–C(7)
C(3)–C(2)–C(1)
C(3)–C(2)–C(9)
C(1)–C(2)–C(9)
C(4)–C(3)–C(2)
C(5)–C(4)–C(3)
C(4)–C(5)–C(6)
C(1)–C(6)–C(5)
N(1)–C(7)–C(1)
N(3)–C(8)–N(2)
N(3)–C(8)–S(1)
N(2)–C(8)–S(1)
F(2)–C(9)–F(1)
F(2)–C(9)–F(3)
F(1)–C(9)–F(3)
118.3 (4)
119.3 (4)
122.3 (4)
120.3 (5)
118.4 (4)
121.3 (4)
119.7 (5)
120.2 (4)
120.3 (5)
121.1 (5)
120.5 (4)
118.2 (4)
123.1 (4)
118.6 (4)
104.7 (4)
107.2 (5)
106.6 (4)
Table 3 shows the hydrogen bonds observed for 1. The
N–H protons are all involved in H-bonding. Examination
of the crystal packing diagram of this compound revealed
(Fig. 4) one intramolecular and three intermolecular hydro-
gen bonds (Table 3) two hydrogen bonds. Interestingly,
the CF3 group at the 4-position of the molecule was not
involved in an intermolecular hydrogen bond similar to that
observed for 2 described below.
bond lengths for this compound are listed in Table 2.
We observe a similar trend regarding the bond lengths
as observed for 1. In compound 2, we observed the keto
form. Furthermore it also showed an anti-conformer con-
figuration similar to 1. Examination of the intra and inter-
molecular hydrogen bonding characteristics for the com-
pound revealed interesting results (Table 3). As observed
for the previous compound, the N–H groups are involved
in H-bonding. Additionally, intermolecular hydrogen
bonding observed between the fluorine atom and the H3
Figure 5 shows the molecular structure of 2-trifluo-
methyl phenyl substituted semicarbazone (2). Selected
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J Chem Crystallogr
Table 3 Hydrogen bonds for
compounds (1)–(4)
Compound #
D-H...A
d(D-H)
d(H...A)
d(D...A)
<(DHA)
1
N(2)–H(2A)...O(1)#1
N(3)–H(3A)...O(1)#2
N(2)–H(2)...O(1)#1
N(3)–H(3A)...O(1)#2
N(3)–H(3B)...F(2)#3
N(2)–H(2A)...S(1)#1
N(3)–H(3B)...S(1)#2
N(3)–H(3B)...S(1)#1
N(2)–H(2)...S(1)#2
0.88
0.88
0.88
0.88
0.88
0.88
0.88
0.88
0.88
2.05
2.02
2.03
2.06
2.34
2.52
2.61
2.51
2.53
2.865 (4)
2.876 (4)
2.894 (2)
2.937 (2)
3.118 (2)
3.386 (2)
3.443 (2)
3.386 (4)
3.393 (4)
153.3
164.2
166.7
174.2
146.8
169.9
158.7
171.1
166.5
2
3
4
Symmetry transformations used to generate equivalent atoms (1): #1 −x+1, −y+2, −z+2 #2 −x+1,
y−1/2, −z+5/2
(2): #1 −x+1, −y+2, −z+1 #2 −x+2, −y+2, −z+1 #3 x+1, y, z;(3): #1 −x+1, y+1/2, −z+1/2 #2
−x+1, y−1/2, −z+1/2
(4) #1 −x+1/2, y−1/2, −z+5/2 #2 −x+1/2, y+1/2, −z+5/2
atom of the molecule with a donor–acceptor distance of
3.118 (2) Å (Fig. 6). It is intriguing that the 4-CF3 group
substituted phenyl semicarbazone analogue did not show
the presence of such an intermolecular hydrogen bond.
We believe that perhaps the proximity of the CF3 group
at position 2 might have influenced the formation of the
intermolecular hydrogen bond. If this rationale is correct
then we should anticipate a similar outcome in the case
of 2-CF3 substituted phenyl thiosemicarbazone’s X-ray
crystal structure.
keto form with anti-conformer similar to the afore-dis-
cussed compounds. Table 2 shows selected bond lengths
for 3; they are within expected ranges. We observe the
classical hydrogen bonds N2–H2…S1 and N3–H3B…S1
[3.386 (2) and 3.443 (2)] (see Table 3). In 3 (Fig. 8). A
weak interaction with quite unfavourable donor-H-accep-
tor angle in N3–H…N1 (104°) is also apparent. This type
of weak intramolecular between the imine N atom and
the adjacent NH group was also reported for N4-substi-
tuted thiosemicarbazones [40].
Figure 7 shows the molecular structure of 4-CF3 sub-
stitued phenyl thiosemicarbazone (3). This molecule also
showed that the trifluoromethyl group is in the same plane
as the thiosemicarbazone moiety. Again, we observe the
In order to complete the series and compare the crystal
structure characteristics, we prepared the 2-trifluorome-
thyl substituted phenyl thiosemicarbazone (4) to under-
stand whether this compound forms a similar type of
intermolecular hydrogen bond with the fluorine and the
Fig. 5 Molecular structure of 2-CF3 phenyl semicarbazone (2) (30%
ellipsoid probability)
Fig. 4 Crystal packing diagram for 4-CF3 phenyl semicarbazone (1)
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J Chem Crystallogr
Fig. 6 Crystal packing diagram for 2-CF3 phenyl semicarbazone (2)
(see the new intermolecular hydrogen bonding between F and N3–H)
Fig. 8 Crystal packing diagram for 4-CF3 phenyl thiosemicarbazone
(3)
N–H(3) group as seen in (2). Figure 9 shows the molec-
ular structure of 4. Selected bond lengths are shown in
Table 2. The bond length of C(8)–S(1) is 1.699(4) Å
confirms the C=S (thioketo) character of the compound.
However, and in contrast to 2, in 4 no intermolecular
hydrogen bond between the fluorine atoms of the trifluro-
methyl group and the NH group was observed (Fig. 10).
This puzzling observation may be rationalized by the
electronegativity differences between oxygen and sul-
phur. More importantly, we propose the existence of an
equilibrium between a neutral and a zwitterionic struc-
ture for the thiosemicarbazone, and a lower tendency
to form such a species for the oxygen analogue. Further
proof of this comes from the 1H NMR spectra of both the
compounds (see the NMR spectra). At least in solution
(DMSO solvent) we see that the NH2 protons appear as
a broad singlet in the case of the semicarbazones while
the same functional group exhibits distinct singlets in the
thiosemicarbazone analogue, demonstrating that the pro-
tons are in different environments on the NMR timescale.
Thus a close look at the hydrogen bond formation
between the trifluoromethyl group attached in 2-posi-
tion of the phenyl ring of these semicarbazone and thio-
semicarbazone revealed the importance of the canonical
Fig. 7 Molecular structure of 4-CF3 phenyl thiosemicarbazone (3)
Fig. 9 X-ray crystal structure of 2-trifluoromethyl phenyl thiosemi-
carbazone (4) (30% ellipsoid probability)
(30% ellipsoid probability)
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J Chem Crystallogr
Acknowledgements This research work is partially supported by
a Linkage Grant (LP130100703 for DCR) from Australian Research
Council Australia.
References
1. Klayman DL, Scovill JP, Bartosevich JF, Mason CJ (1979) J
Med Chem 22:1367–1373
2. Easmon J, Heinisch G, Holzer W, Rosenwirth B (1992) J Med
Chem 35:3288–3296
3. Kalinowski DS, Yu Y, Sharpe PC, Islam M, Liao Y-T, Lovejoy
DB, Kumar N, Bernhardt PV, Richardson DR (2007) J Med
Chem 50:3716–3729
4. Richardson DR, Sharpe PC, Lovejoy DB, Senaratne D,
Kalinowski DS, Islam M, Bernhardt PV (2006) J Med Chem
49:6510–6521
5. Shipman C Jr, Smith SH, Drach JC, Klayman DL (1981) Antimi-
crob Agents Chemother 19:682
6. Aouad F, Florence A, Zhang Y, Collins F, Henry C, Ward RJ,
Crichton RR (2002) Inorg Chim Acta 339:470–480
7. Chaston TB, Lovejoy DB, Watts RN, Richardson DR (2003)
Clin Cancer Res 9:402–414
8. Chaston TB, Watts RN, Yuan J, Richardson DR (2004) Clin
Cancer Res 10:7365–7374
Fig. 10 Crystal packing diagram of 2-trifluoromethyl phenyl thio-
semicarbazone (4) (note: there is no intermolecular hydrogen bond
with fluorine atoms in this molecule)
9. Le NT, Richardson DR (2004) Blood 104:2967–2975
10. Nurtjahja-Tjendraputra E, Fu D, Phang JM, Richardson DR
(2007) Blood 109:4045–4054
11. Richardson DR (2005) Curr Med Chem 12:2711–2729
12. Suvarapu LN, Somala AR, Koduru JR, Baek SO, Ammireddy
VR (2012) Asian J Chem 24:1889
structure associated with the latter than the former. Fur-
ther work is in progress to synthesize additional new
flouro substituted semi and thiosemicarbazones and to
establish their hydrogen bonding characteristics along
with optimizing strategies to radio label with positron
emitting isotopes for imaging purposes.
13. Yuan J, Lovejoy DB, Richardson DR (2004) Blood
104:1450–1458
14. Kalinowski DS, Quach P, Richardson DR (2009) Future Med
Chem 1:1143–1151
15. Lobana TS, Sharma R, Bawa G, Khanna S (2009) Coord Chem
Rev 253:977–1055
16. Dearling JL, Blower PJ (1998) Chem Commun 2531–2532
17. Donnelly PS (2011) J Chem Soc Dalton Trans 40:999–1010
18. Fujibayashi Y, Taniuchi H, Yonekura Y, Ohtani H (1997) J Nucl
Med 38:1155
Conclusion
19. Green MA, Mathias CJ, Willis LR, Handa RK, Lacy JL, Miller
MA, Hutchins GD (2007) Nucl Med Biol 34:247–255
20. Oh M, Tanaka T, Kobayashi M, Furukawa T, Mori T, Kudo T,
Fujieda S, Fujibayashi Y (2009) Nucl Med Biol 36:419–426
21. Vāvere AL, Lewis JS (2008) Nucl Med Biol 35:273–279
22. Zhou J, Liu X, Chen Z-F, Liang H (2006) Chin J Synth Chem
14:471–475
In summary we have determined the single crystal X-ray
crystal structure of four structurally similar semi and thi-
osemicarbazones. The 1H NMR in dimethyl sulfoxide
showed considerable differences between the semi and thi-
osemicarbazones NH2 group and the 13C spectral data was
23. Chumakov YM, Tsapkov V, Antosyak BY, Bairac N, Simonov
1
YA, Bocelli G, Pahontu E, Gulea
54:455–463
A (2009) Cryst Rep
consistent with the H NMR data. The NH2 group in the
semicarbazone appeared as a broad singlet with an integra-
tion ratio of 2 while in thiosemicarbazone the protons of
the NH2 group appeared well separated as a broad singlet
with an integration ratio of 1. In terms of hydrogen bonding
characteristics, there was not much change in the 4-trifluo-
romethyl substituted semi and thiosemicarbazones. How-
ever, we observe that in the case of 2-trifluoromethyl sub-
stituted semicarbazone that the fluorine atom of this group
formed an intermolecular hydrogen bond with one of the
protons of the NH group while this feature was absent in
the case of thiosemicarbazone with similar structure.
24. Garbelini ER, Maria da Graça M, Back DF, Evans DJ, Müller-
Santos M, Ribeiro RR, Lang ES, Nunes FS (2012) J Mol Struct
1008:35–41
25. Garbelini ER, Ribeiro RR, Hörner M, Locatelli A, Nunes FS
(2011) Spectrochim Acta Pt A 78:1337–1341
26. Gulya A, Tsapkov V, Chumakov YM, Roshu T (2006) Russ J
Gen Chem 76:1100–1105
27. Qing Y, Xiaoge B, Ligang Z, Hedong B, Hong L (2006) Chem J
Inter 8:49
28. Shaabani B, Khandar AA, Dusek M, Pojarova M, Mahmoudi F,
Feher A, Kajňaková M (2013) J Coord Chem 66:748–762
29. Basu S, Acharyya R, Basuli F, Peng S-M, Lee G-H, Mostafa G,
Bhattacharya S (2010) Inorg Chim Acta 363:2848–2856
1 3

J Chem Crystallogr
30. Tian Y-P, Wu J-Y, Xie F-X, Shanmuga Sundara Raj S, Yang P,
Fun H-K (1999) Acta Crystallogr Sect C 55:1641–1644
31. Venkatachalam T, Pierens GK, Reutens DC (2014) Magn Reson
Chem 52:98–105
37. Müller K, Faeh C, Diederich F (2007) Science 317:1881–1886
38. Ojima I (2009) Fluorine in medicinal chemistry and chemical
biology. Wiley, Chichester
39. Attia MI, Ghabbour HA, El-Azzouny AA, Al-Deeb OA,
Almutairi MS, Fun H-K (2013) J Chem 2013
32. Rigaku Oxford Diffraction, Version 171.38.43
33. Sheldrick GM (2008) Acta Crystallogr Sect A 64:112–122
34. Farrugia LJ (2012) J Appl Crystallogr 45:849–854
35. Spek A (2009) Acta Cryst D 65:148–155
40. Bernhardt PV, Caldwell LM, Lovejoy DB, Richardson DR
(2003) Acta Crystallogr Sect C 59:o629–o633
36. Banks RE, Smart BE, Tatlow J (2013) Organofluorine chemistry:
principles and commercial applications. Springer, Berlin
1 3