Synthesis, NMR structural characterization and molecular modeling of substituted thiosemicarbazones and semicarbazones using DFT calculations to prove the syn/anti isomer formation

Article abstract of DOI:10.1002/mrc.4041

Thiosemicarbazones possessing electron-donating and electron-withdrawing groups were prepared, and their spectral characteristics determined. In all cases, the spectra showed that one isomer was formed, allowing further functionalization to molecules of biological interest. We provide NMR data for some of the thiosemicarbazones and semicarbazones. We also provide evidence that for 2-pyridyl thiosemicarbazone, the syn isomer slowly converts into the anti isomer in dimethyl sulfoxide solvent with first-order kinetics. Molecular modeling and density functional theory calculations confirmed these observations. Copyright

Full text of DOI:10.1002/mrc.4041

Research article
Received: 6 November 2013
Revised: 17 December 2013
Accepted: 18 December 2013
Published online in Wiley Online Library: 17 January 2014
(wileyonlinelibrary.com) DOI 10.1002/mrc.4041
Synthesis, NMR structural characterization
and molecular modeling of substituted
thiosemicarbazones and semicarbazones
using DFT calculations to prove the syn/anti
isomer formation
T. K. Venkatachalam,* Gregory K. Pierens and David C. Reutens
Thiosemicarbazones possessing electron-donating and electron-withdrawing groups were prepared, and their spectral
characteristics determined. In all cases, the spectra showed that one isomer was formed, allowing further functionalization
to molecules of biological interest. We provide NMR data for some of the thiosemicarbazones and semicarbazones. We also
provide evidence that for 2-pyridyl thiosemicarbazone, the syn isomer slowly converts into the anti isomer in dimethyl
sulfoxide solvent with first-order kinetics. Molecular modeling and density functional theory calculations confirmed these
observations. Copyright © 2014 John Wiley & Sons, Ltd.
Keywords: thiosemicarbazones; semicarboazones; synthetic methods; structure elucidation; DFT calculations
were also able to form the syn isomer by photolysis and isolated
both isomers for several semicarbazones. In this paper, we de-
Introduction
Thiosemicarbazones are an important class of compounds
possessing remarkable biological properties making them of
interest to structural and medicinal chemists. A wide variety of
thiosemicarbazones containing an appropriate structural frame-
work were found to have antineoplastic, antibacterial and anti-
fungal properties.[1] Furthermore, their extraordinary complexing
capacity with metal ions such as iron, copper and zinc provides
additional versatility as potential candidates for the preparation
of coordinate complexes.[2,6–8] Thiosemicarbazones having anti-
cancer activity toward leukemic cells were reported as early as
the 1950s by Brockman et al.[3] The anticancer activity of these
thiosemicarbazones was attributed to their activity in inhibiting
ribonucleotide reductase.[4,5] Recently, copper thiophene 2-alde-
hyde thiosemicarbazone was reported by Jalilian et al.[9] as a
potential candidate for positron emission tomographic studies
This compound when labeled with the positron-emitting radioiso-
tope 61Cu was found to be distributed to various regions of the
mouse. Interestingly, these authors report the uptake of the tracer
by the lungs and kidneys. The potential medical applications of
thiosemicarbazones and their biological applications, and their
coordinating ability are reviewed by Yu et al.[10] and Casas
et al.,[11] respectively.
scribe the preparation and structural characterization of several
thiosemicarbazones and semicarbazones. Our group has devel-
oped an interest in thiosemicarbazone chemistry because of its
wide application and its ability to form chelates with metal ions,
specifically for its application toward Alzheimer’s disease. In this
regard, we evaluated their structural and conformational features
using high field NMR, critically evaluating the isomeric nature of
the final product.
Results and Discussion
The synthesis of thiosemicarbazones or semicarbazones was
achieved by condensation of the corresponding thiosemicar-
bazides or semicarbazides with appropriate aldehydes, as shown
in Scheme 1.
The compounds were further purified by recrystallization using
ethanol to furnish analytically pure compounds. In the present
study, we also prepared new thiosemicarbazones containing a
furan ring in their structures. The synthesized compounds were
further analyzed using UV, IR and high field NMR techniques. All
the protons and carbons in their structural frame were assigned
using standard NMR techniques.
Thiosemicarbazones are well known to exhibit both syn and
anti isomeric forms. The formation and stability of these two
forms depend on the particular thiosemicarbazone and its
structural features. Karabatsos et al.[12–16] reported NMR studies
on thiosemicarbazones on aromatic ring substituted phenyl
hydrazones, semicarbazones and thiosemicarbazones. In 1968,
Sternberg et al.[17] provided proton NMR evidence confirming
the presence of anti and syn isomers for semicarbazones. They
*
Correspondence to: T. K. Venkatachalam, Centre for Advanced Imaging, The Uni-
versity of Queensland, Brisbane, Australia 4072. E-mail: t.venkatachalam@uq.edu.au
Centre for Advanced Imaging, The University of Queensland, Brisbane,
Australia, 4072
Magn. Reson. Chem. 2014, 52, 98–105
Copyright © 2014 John Wiley & Sons, Ltd.

Synthesis and molecular modeling of thiosemicarbazones and semicarbazones
withdrawing substituents. The bromo-substituted compound (6)
showed only a small change of +0.05 ppm. The most significant
effect on chemical shift was observed in pyridyl
thiosemicarbazones especially with the nitrogen atom in the 11
position of the ring (+0.54 ppm). The rationale for changes ob-
served with the substituents is the resonance/inductive and po-
larization effects of individual groups attached to the phenyl
ring of the molecule.
Scheme 1. Synthetic scheme for preparation of substituted thiosemicar-
bazones and semicarbazones.
The UV spectra of thiosemicarbazones in chloroform solution
showed an intense peak between 309 and 388 nm with the
naphthyl-substituted thiosemicarbazone showing the highest
absorption maximum at 388 nm reflecting the extensive conju-
gation present in the structure. Among the phenyl-substituted
thiosemicarbazones, the dimethylamino-substituted thiosemicar-
bazone showed the highest shift at 371 nm. All the absorption
maxima are consistent with the structure of the individual
thiosemicarbazone.
The chemical shift observed for the NH protons (H3) with sub-
stituents showed an upfield shift of approximately À0.20 ppm
with electron-donating groups and a downfield to the same ex-
tent (+0.25 ppm) with electron-withdrawing groups. However,
compound 6, containing a meta-bromo substitution, showed
only a marginal change (+0.12 ppm). The highest change in the
chemical shift value was observed for compound 7, which con-
tains double substituents, namely fluorine and the
trifluoromethyl group in the phenyl moiety.
Examination of chemical shift of the CH protons (H5) of the
thiosemicarbazones revealed that except for compounds 4 and
7, all other derivatives showed only a marginal change in their
chemical shift valuesirrespective of the substituents. Most elec-
tron-withdrawing groups such as CF3 caused a strong downfield
shift for this proton. This is expected because electron-withdraw-
ing groups withdraw the electron density from the CH group
through resonance, causing this proton to shift downfield
(+0.38 ppm).
All compounds had an intense IR peak at 1700–1600 cmÀ1
indicative of the C S/C N stretching frequency. The NH/NH2 fre-
quency for these thiosemicarbazones was around 3450 cmÀ1
.
The hydroxyl-substituted phenyl thiosemicarbazone showed a
broad peak at 3432 cmÀ1 corresponding to the hydroxyl group’s
stretching frequency. However, this also relates to the presence
of NH and NH2 groups in the structure of the molecule. The
remaining IR spectral bands are assigned to the phenyl group
in the structure of the molecule.
The proton and carbon NMR spectra contained only one set of
peaks consistent with either an anti isomer or a syn isomer. An al-
ternative possibility is that there was an equilibrium between the
syn and anti isomers, which was fast on the NMR time scale
resulting in an average chemical shift being observed. Table 1
shows the proton chemical shift values observed for
thiosemicarbazones containing electron-withdrawing and elec-
tron-donating groups on the aromatic ring as well as few
semicarbazones. The trifluoromethyl group was chosen specifi-
cally to investigate the influence on proton chemical shifts be-
cause of its electron-withdrawing nature. Benzaldehyde
thiosemicarbazone (compound 1) was chosen as a standard for
analyzing the variation in the chemical shift values between
substituted and unsubstituted thiosemicarbazones. The values
in Table 1 provide evidence of an upfield shift of the protons re-
lating to electron-donating groups such as OH and NMe2. Elec-
tron-withdrawing groups displayed the opposite trend in
keeping with the dependence between chemical shifts and the
Hammett sigma values of the corresponding substituent groups.
The NH2 protons of the thiosemicarbazones, which are far
removed from the substituents on the phenyl ring, are slightly
affected because of the extended conjugation in the molecule.[18,19]
This group appeared as two singlets demonstrating that the
protons were magnetically different because of restricted rotation
about the N–C bond. These thiosemicarbazones can be alkylated
to exclusively obtain only the S-alkylated product, providing
additional evidence regarding the charge associated with the sulfur
atom compared to the amino group.[20–25] This NH2 group in the
semicarbazones normally shows as a broad singlet with the protons
being indistinguishable.
The effect of electron-donating groups was only marginal in
the range of +0.10 ppm. The ortho protons (H7) in the phenyl
ring showed a change in the chemical shift value of À0.20 ppm
for the electron-donating groups, while the value was between
À0.02 and +0.39 ppm for electron-withdrawing groups. The meta
proton (H8) was considerably affected by both electron-with-
drawing and electron-donating groups. Compound 8, which con-
tains a pyridyl moiety, showed an enormous change in the
chemical shift of +1.19 ppm, which is attributed to the presence
of a nitrogen instead of a carbon atom in the structure of the
thiosemicarbazone. This is also seen in compound 9 with a nitro-
gen atom in position 11 instead of a carbon atom. Table 1 also
shows the proton chemical shifts of newer thiosemicarbazones
containing a furan ring as well as napthyl ring in their structure.
The NH2 proton chemical shift was almost similar to that ob-
served for other thiosemicarbazones. Compounds 10 and 11
showed a considerable change in their proton chemical shift as
a result of the change in sulfur atom to oxygen atom in the struc-
ture. In general, the chemical shift values were consistent with
other similar thiosemicarbazones reported in the literature.
The carbon chemical shifts of the thiosemicarbazones,
semicarbazones and furon-substituted thiosemicabazone are
shown in Table 2. The chemical shift of the C S group was almost
constant for all compounds (approximately 177–179 ppm). Values
for the CH carbon (C5) were in the range of 133–143 ppm.
Compound 7 containing both a fluoromethyl group and a
trifluoromethyl group in the phenyl moiety showed an upfield
shift of nearly 10 ppm compared to other compounds. This is
understandable due to the electron-withdrawing power of these
groups. The trifluoromethyl group on the ortho position of the
aromatic group showed a chemical shift value of 137.4ppm.
Electron-donating groups showed a chemical shift of 142 ppm,
demonstrating that there was no definite trend in the chemical
shift values obtained for the CH group (C5). Turning our
attention toward the chemical shift for the aromatic carbons of
the phenyl group, for C6, the chemical shifts were in the range
Considering the change in the chemical shift with different
substituents, in compounds containing electron-donating
groups, the two NH2 protons showed a value of roughly À0.20
ppm upfield from the unsubstituted benzaldehyde
thiosemicarbazone. The same protons were shifted downfield
by approximately +0.15 ppm in compounds with electron-
Magn. Reson. Chem. 2014, 52, 98–105
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T. K. Venkatachalam, G. K. Pierens and D. C. Reutens
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Copyright © 2014 John Wiley & Sons, Ltd.
Magn. Reson. Chem. 2014, 52, 98–105

Synthesis and molecular modeling of thiosemicarbazones and semicarbazones
Table 2. 13C NMR chemical shifts for thiosemicarbazones in DMSO-d6 at 25 °C (in ppm)
Compound
2
5
6
7
8
9
10
11
12
13
14
1[29]
178.0
177.5
177.0
178.4
178.4
178.2
182.0
178.5
178.6
178.4
156.5
156.2
177.7
173.3
142.3
142.9
143.4
137.4
140.4
140.5
144.0
133.1
139.5
142.5
136.6
139.8
131.6
143.1
134.2
125.0
121.4
132.1
138.3
136.7
136.0
126.1
141.6
153.3
142.0
153.8
149.8
109.7
2
129.1
128.6
126.8
127.9
128.9
131.0
160.3 (F)
121.2
120.2
120.6
119.6
115.2
156.7
115.7
159.6
151.4
129.8
129.4
132.3
134.2
121.4
—
115.7
111.7
132.5
125.5
130.7
133.0
128.0
150.1
149.3
149.9
149.1
130.2
128.0
129.1
128.6
127.4
127.9
127.0
128.4
113.6
121.2
—
—
—
—
39.8 (NMe2)
—
3
111.7
—
124.2 (CF3)
—
—
—
—
—
4
125.7
5
125.5
124.1 (CF3)
—
6
122.4 (Br)
123.1 (Br)
131.0
—
Lit. [33]a
7
—
—
123.3 (CF3)
—
—
—
8
150.1
9
136.5
124.1
—
—
—
—
10
11
12
13
149.9
120.6
—
—
—
—
136.4
123.4
152.6
132.5
—
—
—
110.1
120.3
128.7
125.0
123.5
124.5
127.9
127.6
122.9
118.4
Compound 12: 130.0 (15) and 124.1 (16).
Compound 13: 131.4 (15).
aNot assigned, acetone-d6; positions 12, 13 and 14 are hydrogen, unless specified.
of 121–138 ppm. For compounds with a nitrogen atom in their
ring, the chemical shift for C6 was shifted downfield as expected.
The other chemical shifts were consistent with the structure of
the compounds.
We also examined the nitrogen chemical shifts for several
thiosemicarbazones, and the data are presented in Table 3. The
C N chemical shifts varied from 309.5 to 344 ppm for the
compounds. Interestingly, the pyridyl- and trifluoromethyl-
substituted compounds showed a higher chemical shift value as
compared to other derivatives. On the other hand, the electron-
donating group attached thiosemicarbazones (compounds 2
and 3) showed a lower chemical shift values. This trend was con-
sistent with the chemical shift observed for the NH and NH2 nitro-
gens. For example, the NH group’s chemical shift varied from
Table 3. Proton chemical shifts values of syn and anti isomers of compound 9 in DMSO-d6 (in ppm)
Compound
1a
1b
3
5
7
8
9
10
(E) anti
(Z) syn
(E) antia
(Z) syna
(E) antib
(Z) synb
8.33
8.56
8.30
8.62
8.34
8.58
8.16
8.21
8.15
8.29
8.17
8.24
11.65
14.00
11.60
14.15
11.63
14.04
8.08
7.41
8.13
7.49
8.08
7.43
8.26
7.77
8.28
7.85
8.27
7.79
7.81
8.06
7.74
8.20
7.82
8.09
7.35
7.54
7.40
7.66
7.37
7.57
8.55
8.79
8.60
8.80
8.56
8.79
aFrom Ref. [26].
bFrom Ref. [27].
Magn. Reson. Chem. 2014, 52, 98–105
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T. K. Venkatachalam, G. K. Pierens and D. C. Reutens
Scheme 2. Anti and syn isomer structure of thiosemicarbazones.
169.1 to 173.9 ppm for the pyridyl-substituted compounds, while
the electron-donating group attached thiosemicarbazones
showed a chemical shift values of 169 ppm. Similarly, the NH2
group nitrogen chemical shift followed a uniform trend as de-
scribed earlier. The observed nitrogen chemical shifts for several
of the thiosemicarbazones were consistent with those reported
in the literature for thiosemicarbazones of similar structure.[26]
Figure 2. 1H NMR spectra of various isomers of compound 9 in DMSO-
d6: (a) syn isomer, (b) mixture of syn/anti isomers and (c) anti isomer (note:
only the aromatic region is illustrated).
Syn and anti isomerism
Semicarbazones, thiosemicarbazones, phenyl hydrazones and
oximes have the unique capability of forming syn and anti
isomers. Generally, a mixture of isomers is synthesized. An
example of syn and anti isomers of a thiosemicarbazone is
shown in Scheme 2.
It is evident from the aforementioned illustration that in the (E)
or anti isomer, the chemical environment of the NH proton (H3) is
different to that for the (Z) or syn isomer. This is due to the proton
of the NH group being in closer proximity to the aromatic
protons for the syn isomer compared to the anti isomer.[27] The
NMR spectra for all the compounds reported in our study showed
only one set of peaks, demonstrating the preferential formation
of one isomer over the other or a fast exchange between the
two isomers. Based on the chemical shift values, we propose that
all the compounds in Tables 1 and 2 exist in an anti isomer
configuration.
To examine whether it is viable to synthesize any of the com-
pounds in the present study as the syn isomer, the anti isomers
were refluxed in methanol using silica gel as a catalyst.[27] Thin
layer chromatography revealed that only compound 9 formed
the syn isomer. A fresh sample of the syn isomer of compound
9 was prepared and dissolved in deuterated dimethyl sulfoxide
(DMSO-d6) and the proton NMR acquired. The NMR spectrum
showed a peak at 14 ppm, consistent with previous observa-
tions.[26,27] The chemical shift for the NH protons and the aro-
matic moiety differs between isomers. The downfield shift of
the NH protons for the syn thiosemicarbazone is consistent with
hydrogen bonding between the NH groups and the aromatic ni-
trogen. The 1H spectrum was acquired at different times over an
Figure 3. HSQC spectrum of syn/anti isomer (compound 9) during the
conversion in DMSO-d6 at room temperature.
18-h period. The peak at 14 ppm (H3, syn) decreased in intensity
with a corresponding increase in the peak at 11.6 ppm (H3, anti).
A plot of the formation of the anti isomer in Fig. 1 follows a first-
order rate equation with a rate constant of 2.4 × 10À3/min.
Figure 2 compares the starting 1H NMR spectrum, the correspond-
ing spectra approximately half way through the conversion and
the final spectrum of the anti compound; Fig. 3 shows a 13C HSQC
at approximately 50% conversion showing the two isomers.[28]
Tables 3 and 4 show the proton and carbon chemical shifts of
anti and syn isomers and, for protons, the comparison with
values reported in the literature for compound 9.
Molecular modeling was performed for compounds 8, 9 and
11 because compounds 8 and 9 were thiosemicarboazones,
which differed in the position of the aromatic nitrogen, and
compounds 9 and 11 had the same aromatic nitrogen but were
a thiosemicarbazone and a semicarbazone, respectively (Fig. 4).
The compounds were initially investigated by a Monte Carlo
conformational search (MacroModel, Schrodinger[30]), and the
conformations with 3 kcal/mol were then further optimized using
density functional theory (DFT) calculations (Gaussian 09[31]) with
the inclusion of the integral equation formalism for the polariz-
able continuum model (IEF-PCM) and solvent model for DMSO.
For compound 9, the syn and anti isomers had two different
conformations with the lowest energy syn isomer (planar
0
-0.5
-1
-1.5
-2
-2.5
-3
0
200
400
600
800
1000
1200
Figure 1. Rate of formation of anti isomer from syn isomer (compound
9) with various time intervals at 25 °C in DMSO-d6.
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Synthesis and molecular modeling of thiosemicarbazones and semicarbazones
Table 4. Carbon chemical shifts values for syn and anti isomers of compound 9 in DMSO-d6 (in ppm)
Compound
2
5
6
7
8
9
10
(E) anti
(Z) syn
178.4
178.9
142.5
133.7
153.3
151.9
120.2
126.6
136.5
138.3
124.1
124.1
149.3
148.4
Scheme 3. Proposed mechanism for the slow conversion of the syn iso-
mer to the anti isomer of compound 9.
report of Hauser et al.[34] suggests that acid-catalyzed reaction of
oximes follows the formation of carbo cation and rotation of the
single bond, which results in isomerization.
In summary, we have synthesized several thiosemicarbazones
containing electron-donating and electron-withdrawing groups
and have fully analyzed their structure using NMR. We have
demonstrated that all compounds in the present study exist as anti
isomers. The anti isomer of 2-pyridyl thiosemicarbazone (compound
9) can be converted to the syn isomer with prolonged heating with
silica gel in methanol. However, the syn isomer was not stable in
protoic solvents and slowly converted back to the anti isomer.
Figure 4. Lowest energy structures for the syn [a (lowest energy) and b]
and anti [c (lowest energy) and d] isomers of compound 9.
conformation) being 0.2 kcal/mol lower energy compared to the
lowest anti isomer (planar conformation). The alternate confor-
mation was much higher in energy. Compound 8 only had one
conformation for each isomer because of the symmetry of the
molecule. Both isomers were examined by DFT, which showed
that the anti isomer was about 5.3 kcal/mol lower energy than
the syn isomer explaining why only the anti isomer was formed.
The syn isomer was not planar because of steric interactions from
the protons H7 and H11. Like compound 9, each isomer of com-
pound 11 had two different conformations. In changing from a
thiosemicarbazone to a semicarbazone, the energy difference be-
tween isomers was reduced, but the anti isomer had the lower
energy by 0.08 kcal/mol, in contrast to compound 9. Both isomers
were of planar conformation in their lowest energy structures.
The molecular modeling results are in keeping with our experimen-
tal observations of the conversion of the syn isomer of compound 9
back to the anti isomer over time. We propose the following mech-
anisms for the conversion of the syn isomer to the anti isomer of
compound 9 (Scheme 3). In the first mechanism, initially, there is
a proton transfer from N3 to N11, which is immediately followed
Experimental
All the chemicals were obtained from Sigma-Aldrich and were
used without further purification. NMR spectra were recorded in
DMSO, and the chemical shifts for protons are reported relative
to DMSO at 2.5 ppm. The NMR data were acquired on a Bruker
900 MHz NMR spectrometer equipped with a cryoprobe. The
proton spectra were acquired with a sweep width of 18 ppm
centered at 7 ppm. The carbon spectra were acquired with a
sweep width of 220 ppm centered at 110 ppm. The COSY exper-
iment were acquired with a sweep width of 18 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. Ad-
ditionally HMBC spectral data were also acquired to establish the
Table 5. 15N chemical shifts for selected compounds in DMSO-d6 (in ppm)
Compound
N=C
NH
NH2
Pyridyl nitrogen
by
a bond rotation around N4–C5. This is followed by
2
3
4
5
6
7
8
9
309.5
305.5
327.1
325.8
321.5
344.1
344.1
341.5
169.1
169.2
172.6
171.3
171.3
173.9
173.2
171.9
106.9
106.4
109.9
109.9
109.5
110.9
110.9
110.2
—
—
rearrangement of the proton from N4 back to N3. The anti isomer
is trapped, explaining why we observe all the syn isomer
converting to the anti isomer. We have measured the 15N NMR
chemical shifts of the compounds (Table 5). The 15N chemical shifts
do not show the presence of any intermediate in the proton trans-
fer mechanism, probably due to fast conversion. Although this
mechanism is feasible based on the H3 chemical shift observed in
the spectra, an alternative mechanism based on the literature
—
—
—
—
332.6
329.1
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T. K. Venkatachalam, G. K. Pierens and D. C. Reutens
structures of the compounds (13C sweep width of 220 ppm). The
raw data were usually multiplied by an exponential or shifted
sine squared function before performing the Fourier transform.
UV/Vis spectra were obtained from a Lambda UV spectrometer
using chloroform as solvent. Infrared spectra were taken on a
KBr disc on a Lambda FTIR spectrometer.
(4) 2-Trifluoromethyl phenyl thiosemicarbazone:, UV (CHCl3):
324 nm; IR (KBr): 3441, 3258, 3162, 1650, 1603, 1597, 1536, 1453,
1385, 1313, 1279, 1216, 1177, 1101, 1031, 948, 874, 760 cmÀ1
(5) 4-Trifluoromethyl phenyl thiosemicarbazone:, UV (CHCl3): 348
(sh), 324 nm; IR (KBr): 3439, 3271, 3156, 3021, 1599, 1535, 1513,
1455, 1415, 1365, 1325, 1302, 1292, 1161, 1139, 1098, 1064,
1017, 933, 839 cmÀ1
General procedure for synthesis of compounds
The appropriate aldehyde (0.05 mol) thiosemicarbazone (0.025 mol),
anhydrous sodium acetate (2.0 g), ethanol (20 ml) and water (20 ml)
were stirred for 10 min. After this period, concentrated hydrochloric
acid (0.5 ml) was added, and the mixture was stirred when a clear
solution resulted and was allowed to stir over night. The precipitate
was filtered and washed with ethanol and dried under vacuum.
Further purification was achieved by crystallization from methanol.
(6) 3-Bromophenyl thiosemicarbazone:, UV (CHCl3): 322 nm; IR
(KBr): 3378, 3258, 1668, 1603, 1589, 1528, 1468, 1423, 1356,
1306, 1083, 940 cmÀ1
(7) 2-Fluoro-4-4-trifluorophenyl thiosemicarbazone:, UV (CHCl3):
330 nm; IR (KBr): 3432, 3268, 3155, 1652, 1596, 1594, 1538, 1532,
1472, 1423, 1368, 1335, 1307, 1222, 1206, 1163, 1145, 1094,
1064, 1036, 924,890, 743 cmÀ1
Conversion of (E) isomers to (Z) isomers
(8) 4-Pyridylthiosemicarbazone:, UV (CHCl3): 326 nm; IR (KBr):
3441, 3258, 3162, 2919, 1650, 1597, 1536, 1415, 1385, 1278,
1177, 1101, 1031, 990, 926, 873, 820, 759 cmÀ1
The respective thiosemicarbazones (0.5 g) and silica gel (2.5 g,
60 μm; Merck) were added to methanol (30 ml). The contents
were allowed to reflux for 6 h, and the solution was cooled and
the mixture filtered. The solvent was removed to obtain a solid,
which was extracted with a hot mixture of ethyl acetate and
methanol. Subsequently, the ethyl acetate/methanol solvent
mixture was evaporated, and the resultant solid was subjected
to column chromatography using ethyl acetate to furnish both
(E) and (Z) isomers. The fast-moving fractions containing (Z)
isomer were pooled together after a thin layer chromatography
analysis, and the solvent was evaporated to yield pure (Z) isomer
(~20% yield). All compounds other than compound 9 did not
produce any syn isomer on prolonged heating.
(9) 2-Pyridyl thiosemicarbazone:, UV (CHCl3): 325 nm: IR (KBr):
3419, 3233, 3156, 1612, 1528, 1469, 1433, 1364, 1293, 1173,
1108, 999, 932, 876, 822, 774, 618 cmÀ1
(10) 4-Pyridylsemicarbazone:, UV (CHCl3): 309 nm; IR (KBr): 3417,
2961, 1638, 1589, 1412, 1319, 1137, 1076, 1053, 994, 940, 818,
750 cmÀ1; HSQC (N): 158.0 (NH), 76.7: NH2; HMBC: 133.0 (CH N),
116.2 ( pyridyl N).
(11) 2-Pyridylsemicarbazone:, UV (CHCl3): 330 nm; IR (KBr: 3379,
3104, 2827, 1685, 1668, 1589, 1561, 1423, 1359, 1177, 1083,
745 cmÀ1; N (HSQC) NH: 156.2, NH2: 76.3; 15N HMBC: CH N:
130.1, pyridyl N: 112.7.
Molecular modeling
Monte Carlo conformational searching was performed using
Macromodel v10.0 (Schrodinger, New York)[30] for syn and anti
isomers. Torsional sampling Monte Carlo Multiple Minimum
(MCMM) was performed with 1000 steps per rotatable bond. Each
step was minimized with the OPLS-2005 force field using the
Truncated Newton Conjugate Gradient (TNCG) method with max-
imum iterations of 50 000 and energy convergence threshold of
0.02. All other parameters were left as the default values. The low-
est energy conformations (<3 kcal/mol from global minimum)
were further optimized using DFT calculations in Gaussian[31]
(B3LYP/6311+G(d,p), with DMSO solvent).
(12) 2-(5-(3-Triflouromethyl)phenyl)-furanyl thiosemicarbazone:,
UV (CHCl3): 385 (sh), 361, 295 (sh) nm; IR (KBr): 3416, 3235,
3154, 1678, 1601, 1538, 1513, 1503, 1475, 1452, 1365, 1338,
1302, 1292, 1227, 1161, 1141, 1112, 1100, 1074, 1023, 979, 938,
921, 898, 841, 804, 791 cmÀ1
(13) 2-Hydroxy-1-naphthylthiosemicarbazone:, UV (CHCl3): 388,
374, 335 nm; 1H NMR (900 MHz, DMSO-d6): 11.40 (s, 1H), 10.41
(s, 1H), 9.05(s, 1H), 8.51 (bs, 1H), 8.21 (s, 1H), 7.87 (d, 1H), 7.85
(d, 1H) 7.82 (s, 1H), 7.56 (t, 1H), 7.36 (t, 1H), 7.20 (d, 1H); 13C
NMR (225 MHz, DMSO-d6): 173.3, 156.7, 143.1, 132.5, 131.4,
128.7, 128.1, 127.9, 123.5, 122.9, 118.4, 109.7
Physical constants of compounds
(1) Benzaldehyde thiosemicarbazone[29]:, 1H NMR (300 MHz,
DMSO-d6): 11.42 (s, 1H), 8.19 (s, 1H), 8.05 (s, 1H), 7.98 (s, 1H),
7.78 (d, 2H, J = 6.8 Hz), 7.40 (t, 1H, J = 7.2 Hz), 7.39 (t, 2H,
J = 7.2 Hz); 13C NMR (75 MHz, DMSO-d6): 178.0, 142.3, 134.2,
129.8, 127.3, 128.7
Acknowledgement
This research was funded by a Program Grant from the National
Health and Medical Research Council of Australia.
References
(2) 4-Hydroxy phenyl thiosemicarbazone:, UV (CHCl3): 327 nm; IR
(KBr): 3432, (br), 1601, 1575, 1548, 1510, 1461, 1437, 1374, 1286,
1260, 1234, 1164, 1056, 948, 924, 819 cmÀ1
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