The conformational analysis of 2-hydroxyaryl Schiff thiosemicarbazones

Article abstract of DOI:10.1039/b921402j

X-Ray measurements and quantum-mechanical (B3LYP and MP2) calculations of 2-hydroxyaryl Schiff thiosemicarbazones were performed to describe the tautomeric and conformational equilibrium. The structures of five N-alkyl- and N-aryl-thiosemicarbazone deriva

Full text of DOI:10.1039/b921402j

View Article Online / Journal Homepage / Table of Contents for this issue
PAPER
www.rsc.org/crystengcomm | CrystEngComm
The conformational analysis of 2-hydroxyaryl Schiff thiosemicarbazones†
*
M. Krasowska, A. Kochel and A. Filarowski
Received 13th October 2009, Accepted 26th January 2010
First published as an Advance Article on the web 16th February 2010
DOI: 10.1039/b921402j
X-Ray measurements and quantum-mechanical (B3LYP and MP2) calculations of 2-hydroxyaryl
Schiff thiosemicarbazones were performed to describe the tautomeric and conformational equilibrium.
The structures of five N-alkyl- and N-aryl-thiosemicarbazone derivatives were determined by single-
crystal X-ray diffraction at 100 K. The conformational schemes for determining the various states of
the compounds were calculated by the DFT (B3LYP/6-31+G(d,p)) method. The difference between the
phenolic and heterocyclic derivatives with respect to the OH $ HN tautomeric equilibrium is shown.
The influence of the environment’s polarity on C]S $ S]C conformational equilibrium was
determined by DFT calculations. The potential energy curves for rotating particular fragments of the
thiosemicarbazone moiety were calculated to estimate the rotational energetic barriers.
Introduction
The studied 2-hydroxyaryl Schiff thiosemicarbazone analogues
are a combination of 2-hydroxyaryl ketoimines and thio-
semicarbazones and the biological activities of these compounds
are worth further study. For a few decades compounds of this
type have been analyzed for their antiviral and anticancer
activity.1 According to the studies by Richardson and Ponka, the
therapeutic activity of 2-hydroxyaryl Schiff thiosemicarbazones
is conditioned by the balance of cellular iron.2 The important
possibility of antiproliferative effects against leukaemia and
neuroblastoma is being investigated.1,2 A thiosemicarbazone
derivative (Triapineꢀ) is considered a promising therapeutic
agent for the treatment of cancer. The action of this derivative is
conditioned by the inhibition of ribonucleotide reductase.1a This
compound is in the first phase of clinical trial.3 Both the thio-
semicarbazone and the ketoimine components are very inter-
esting due to their complex properties.4 Thiosemicarbazones
possess good bidentate and tridentate chelate properties, while
the 2-hydroxyaryl ketoimine moiety is also a valuable object for
the fundamental research of hydrogen bonding, namely reso-
nance-assisted hydrogen bond.5
Scheme 1
4-methoxyacetophenone N(4)-dimethylthiosemicarbazone and
salicylaldehyde N(4)-phenylthiosemicarbazone are presented in
the literature.6b,7c
The description of the thiocarbonyl bond direction is to serve
in determining the chelating properties of 2-hydroxyaryl Schiff
thiosemicarbazones and thus the possibilities of modelling their
pharmacological activities. To clarify the reason for the direction
of the C]S group, X-ray measurements and quantum-
mechanical calculations were performed.
X-Ray analysis of 2-hydroxyaryl Schiff thiosemicarbazones
shows the prevalence of conformer S]C, with the thiocarbonyl
group directed towards the intramolecular hydrogen bonding,
Scheme 1.6 However, conformer C]S, with the thiocarbonyl
group turned away from the intramolecular O–H/N hydrogen
bridge, Scheme1, is alsoobservedin thesolid state.7 Moreover, the
two or three independent molecules in the unit cells of 2-hydroxy-
Experimental
1-(2-Hydroxyphenyl)ethan-1-one thiosemicarbazone (T1), 1-(2-
hydroxyphenyl)ethan-1-one N-methylthiosemicarbazone (T2),
1-(2-hydroxyphenyl)ethan-1-one
(T3),
N-phenylthiosemicarbazone
N,N-dimethylth-
1-(2-hydroxyphenyl)ethan-1-one
iosemicarbazone (T4) and 1-(4-hydroxy-6-methyl-2-oxo-2H-
pyran-3-yl)ethan-1-one thiosemicarbazone (T5) were synthesized
from stoichiometric mixtures of the appropriate 2-hydroxyaryl-
ketone and N-aryl or N-alkyl- thiosemicarbazide in refluxing
alcohol (methanol for T1 and T5, ethanol for T2, T3, and T4)
according to ref. 8. In the case of T5, a few drops of dimethyl-
amine and conc. sulfuric acid were used as the catalyst.9,6b 2-
Hydroxyacetophenone, dehydroacetic acid, thiosemicarbazide,
4-methylthiosemicarbazide, 4-phenylthiosemicarbazide, and 4,4-
dimethyl-3-thiosemicarbazide were purchased from Aldrich.
The intensity data were collected at 100 K using a Kuma
KM4CCD diffractometer and graphite-monochromated Mo Ka
Faculty of Chemistry, University of Wrocław, 14 F. Joliot-Curie st., 50-383
Wrocław, Poland. E-mail: afil@wchuwr.pl; afil@ruc.dk; Fax: +48-71-
3282348; Tel: +48-71-3757283
† CCDC reference numbers 749539 for l-(2-hydroxyphenyl)ethan-l-one
thiosemicarbazone (T1), 749540 for l-(2-hydroxyphenyl)ethan-l-one
N-methylthiosemicarbazone (T2), 749541 for 1-(2-hydroxyphenyl)ethan-
1-one N-phenylthiosemicarbazone (T3), 749542 for 1-(2-hydroxyphenyl)-
ethan-1-one N,N-dimethylthiosemicarbazone (T4), and 749543 for
l-(4-hydroxy-6-mthyl-2-oxo-2H-pyran-3-yl)ethan-l-one thiosemicarbazone
(T5). For crystallographic data in CIF or other electronic format
see DOI: 10.1039/b921402j
This journal is ª The Royal Society of Chemistry 2010
CrystEngComm, 2010, 12, 1955–1962 | 1955

View Article Online
1956 | CrystEngComm, 2010, 12, 1955–1962
This journal is ª The Royal Society of Chemistry 2010

View Article Online
ꢁ
(0.71073 A) radiation generated from an X-ray tube operating at
50 kV and 35 mA. The images were indexed, integrated, and
scaled using the Oxford Diffraction data reduction package.10
The experimental details together with crystallographic data for
both compounds are given in Table 1. An absorption correction
was omitted. The structure was solved by direct methods using
SHELXS-9711 and refined by the full-matrix least-squares
method on all F2 data (SHELXL-97).12 Non-hydrogen atoms
were refined with anisotropic thermal parameters; hydrogen
atoms were included from Dr maps and refined isotropically.
The molecular structures with atom labelling are shown in
Fig. 1.
Scheme 2
short OH/N hydrogen bridge, Table 2. The short hydrogen
bridge in this compound is evoked by strong steric repulsion in the
O]C–C]C(CH3)–Nmoiety. Theimpactofthe stericeffectonthe
strength of intramolecular hydrogen bonding in 2-hydroxyaryl
Schiff bases is fairly well described in review papers.21
Computational
Quantum-mechanical calculations using the B3LYP functional
(DFT, the three-parameter exchange hybrid functional of Becke,
and gradient-corrected correlation functional of Lee, Yang, and
Parr)14 and MP2 (Møller–Plesset method)15 with the 6-
31+G(d,p) basis set were performed for full geometry optimi-
zations with the GAUSSIAN 03 program.16 The non-adiabatic
approach17 was used for the calculations of the dependencies
DE ¼ f(torsion angle) and DE ¼ f(d(OH)). All structural
parameters were optimized for each fixed torsional angle or OH
The DFT calculations of potential energy dependence on the
hydroxyl bond length, Fig. 2, support the prevalence of the OH
tautomeric form (the presence of only one minimum on the
ꢁ
potential energy curve in the region of d(OH) z 1 A) in T1–T4
and a possible presence of OH $ HN tautomeric equilibrium in
T5–T7. The observation of two almost equivalent minima on the
potential cure proves the presence of tautomeric equilibrium in
the experiment.21 One should note that an attempt to find a local
ꢂ
ꢁ
distance, changing gradually by 10 or 0.1 A, respectively. The
interaction with the dielectric continuum in the system was
modelled by the integral equation formalism (IEF-PCM),18 for
which the electric permittivity (3) was used to characterize the
surroundings.
ꢁ
ꢁ
minimum (at d(OH) z 1.6 A; d(HN) z 1 A) for T1–T4 by means
of B3LYP/6-31+G(d,p) calculations failed to give positive
results. Full optimization of the T1–T4 structures with the initial
location of the hydrogen under the nitrogen atom brings about
a skip of the hydrogen to the oxygen atom.
Discussion
The description of the C]S bond direction in the solid state is
not an easy task. Sufficiently, the comparison of the crystal
structures of 2-hydroxyaryl Schiff thiosemicarbazones in CSD.22
Both ketoimine6b, 7b, 7e, 7f and aldimine6a, 6c, 6d, 7a, 7c, 7d, 7g derivatives
To study the conformational and tautomeric states (Schemes 1
and 2), two subtypes of 2-hydroxyaryl Schiff thiosemicarbazone,
phenolic (T1–T4) and heterocyclic (T5–T7) derivatives, were
chosen, Scheme 3. The X-ray results revealed that the hydrogen
bonding in T1–T4 is medium-strong (cf. values in Table 2 with
data from ref. 20), with the OH form prevailing, Table 2 and
Fig. 1. The crystal structure of T5 shows the presence of a very
reveal the presence of C]S and S]C conformers. The addi-
2ꢀ
tional molecule (CH3OH in ref. 7d and T1, SO4
and
H2N(CH3)2+ in T5, H2O in ref. 7e and 7b, DMSO in ref. 6a, Clꢀ1
in ref. 6d) in the unit cell also does not definitely influence C]S
$ S]C equilibrium. This should underscore the fact that
2-hydroxyaryl Schiff thiosemicarbazones are effective co-
crystalling agents.
To define the crystallographic design of the thiocarbonyl
group, NH2, NHCH3, N(CH3)2, and NHC6H5 thio-
semicarbazone derivatives were synthesized to discover the
reasons for the formation of the C]S bond orientation. The
crystal structures of T1, T2, T4, and T5 reveal conformer S]C,
Fig. 1. The reason for the stabilization of the S]C conformer is
an additional OH/S hydrogen bonding leading to energy
benefits. This bond, together with the OH/N bond, forms
a bifurcated hydrogen bond. However, the structure of T3 is the
C]S conformer, Fig. 1, and the OH/S intramolecular
hydrogen bond is not observed in this compound. In line with
our crystallographic results, the C]S form is observed in the
NHC6H5 derivative (T3), whereas the S]C form is visible in the
NH2, NHCH3 and N(CH3)2 derivatives (T1, T2, T4, and T5).
This can be reasonably explained; the phenyl ring withdraws
a negative charge, thus making the basicity of the sulfur atom
weaker and, consequently, weakening the OH/S intramolecular
hydrogen bond. Such an effect facilitates its breaking.
Fig. 1 The molecular structure and atom labelling scheme of T1–T5.
The intramolecular hydrogen bond is shown as a broken line. Crystal
structures were visualized using the program Mercury CSD version 2.2.13
This journal is ª The Royal Society of Chemistry 2010
CrystEngComm, 2010, 12, 1955–1962 | 1957

View Article Online
Scheme 3 The optimized molecular structure of studied compounds. Grey, white, red, blue and yellow spheres represent C, H, O, N and S atoms.
Structures were visualized using the program ChemCraft version 1.6.19
This phenomenon should be defined by a loss of stabilizing
energy. However, the formation of the S/HN and S/HC
intermolecular hydrogen bonds in the solid state can compensate
the energy loss. These intermolecular hydrogen bonds are
competitive with respect to the bifurcated hydrogen bonding and
stabilize the C]S conformer.
obtained trends of the DEII–I energy changes are similar for
B3LYP and MP2 calculations.
One of the reasons for the prevalence of the C]S form in the
solid state can be the polarity of the environment. Therefore,
B3LYP calculations were carried out taking into account the
impact of the environment on C]S $ S]C equilibrium,
Table 3. These calculations show that the prevalence of the C]S
conformer in vacuum (DEII–I ¼ 5–7 kcal molꢀ1) steadily
decreases with increasing environmental polarity and is equal to
2.91–1.70 kcal molꢀ1 for water, Table 3. This difference in energy
is not so large and, when taking into account weak competitive
intermolecular interactions, the probability of detecting
To ascertain the prevalence of one particular conformer,
conformational analysis was performed for the isolated molecule
in vacuum by means of B3LYP calculations. The calculations for
the compounds showed the C]S conformer prevailing (Fig. 3,
DEII–I ¼ 6.87, 7.43, 7.50, 4.06, 4.92, 5.32, and 5.42 kcal molꢀ1
(B3LYP calculations) and 5.54, 6.64, 6.41, 5.87, 3.74, 4.60, and
4.56 kcal molꢀ1 (MP2 calculations) for T1–T7, respectively). The
a
particular conformer is highly equivalent. These weak
ꢂ
ꢁ
Table 2 The selected experimental and calculated (B3LYP/6-31+G(d,p)) bond lengths (A) and angles ( ) of hydrogen bonds (esds in parentheses) for
T1–T7
Compound
Method
B3LYP
Conformer
d(OH)
d(H/N)
d(O/N)
a(OHN)
d(C–O)
d(C]N)
d(C]S)
d(O/S)
T1
S]C
C]S
S]C
S]C
C]S
S]C
S]C
C]S
C]S
S]C
C]S
S]C
S]C
C]S
S]C
S]C
C]S
S]C
C]S
0.988
0.985
0.90(1)
0.989
0.985
0.81(2)
0.988
0.982
0.92(2)
0.990
0.993
0.85(2)
1.008
1.002
0.89(2)
1.007
1.002
1.006
0.998
1.761
1.749
1.74(1)
1.755
1.748
1.87(3)
1.763
1.777
1.81(2)
1.755
1.690
1.81(2)
1.650
1.662
1.63(2)
1.658
1.665
1.670
1.690
2.602
2.621
2.53(1)
2.599
2.622
2.568(2)
2.604
2.643
2.625(2)
2.597
2.576
2.556(2)
2.524
2.560
2.481(2)
2.531
2.564
140.7
145.6
146(2)
140.9
145.9
145(2)
140.8
145.1
146(2)
140.6
146.5
146(2)
142.5
146.9
158(2)
142.3
147.1
142.1
146.5
1.344
1.352
1.369(2)
1.344
1.353
1.359(2)
1.344
1.353
1.358(2)
1.343
1.349
1.355(2)
1.321
1.329
1.308(2)
1.321
1.330
1.300
1.306
1.304(2)
1.299
1.306
1.292(2)
1.300
1.306
1.296(2)
1.300
1.303
1.293(2)
1.304
1.309
1.309(1)
1.303
1.309
1.663
1.677
1.693(2)
1.666
1.680
1.692(2)
1.660
1.678
1.685(2)
1.675
1.682
1.688(1)
1.666
1.676
1.681(1)
1.670
1.679
3.789
X-Ray
B3LYP
3.571(1)
3.759
T2
T3
T4
T5
X-Ray
B3LYP
3.499(2)
3.759
X-Ray
B3LYP
3.714
X-Ray
B3LYP
3.547(1)
3.705
X-Ray
B3LYP
3.571(1)
3.685
T6
T7
B3LYP
2.540
2.582
1.322
1.331
1.304
1.310
1.664
1.677
3.679
1958 | CrystEngComm, 2010, 12, 1955–1962
This journal is ª The Royal Society of Chemistry 2010

View Article Online
ꢁ
S/HC (d(S/C) ¼ 3.445(2) A) intermolecular hydrogen bonds
make the C]S conformer more stable than the S]C conformer.
For a more deliberate study of C]S $ S]C equilibrium,
calculations of the stepwise rotation of particular fragments of
the thiosemicarbazone group were performed. The calculations
of the energy under rotation around the N–C bond for the OH
tautomeric form (the torsion angle 4(NNCN), Fig. 4 A) show
a relatively high energy barrier (10–15 and 8–12 kcal molꢀ1
obtained by the B3LYP and MP2 calculations, respectively,
Table 4). Supposedly, the height of the barrier decreases with
increasing of the environmental polarity, which speaks in favour
of detecting two conformers in the experiment. The visible
decrease in energy under rotation around the N–C bond between
120–150ꢂ (Fig. 4A) caused by re-orientation of molecular struc-
ture, namely the change in the C]N–N–C angle by 15–16ꢂ
proves the flattening of structure.
It should be notice that C]S $ S]C conformational equi-
librium is reflected in the character of the bonds. The reduction
of the C]S, C–O, O/N, N–N and C]N bonds is observed for
Fig. 2 The calculated (B3LYP/6-31+G(d,p)) proton transfer energy
potential for T1 (-), T2 (,), T3 (B), T5 (C), T6 (:) and T7 (O).
ꢁ
ꢁ
conformer S]C (d(C]S) ¼ 1.663 A, d(C–O) ¼ 1.344 A,
ꢁ
ꢁ
ꢁ
d(ON) ¼ 2.602 A, d(C]N) ¼ 1.300 A, d(N–N) ¼ 1.358 A;
ꢁ
for T1) with respect to conformer C]S (d(C]S) ¼ 1.677 A, d(C–
intermolecular hydrogen bonds play an important role in crystal
packing.23,24 The compound T3 is an example in which weak S/
ꢁ
ꢁ
ꢁ
O) ¼ 1.352 A, d(ON) ¼ 2.621 A, d(C]N) ¼ 1.306 A, d(N–N) ¼
ꢁ
1.364 A; for T1). This applies to both phenolic and heterocyclic
ꢁ
ꢁ
HN (d(S/N) ¼ 3.846(2) A, S/HC (d(S/C)) ¼ 3.881(2) A) and
derivatives (Table 2).
The dependence of the potential energy on the rotation of the
Car–Cim bond (the torsion angle f(CCCN)), Fig. 4 B, for the OH
tautomeric form reveals a local minimum at about 150ꢂ for the
phenolic derivatives, whereas such a minimum is not observed
for the heterocyclic. The lack of a stable structure (conformers V
and VI, Fig. 3 B) is also typical of fully optimized heterocyclic
derivatives. Such a phenomenon is conditioned by the steric
repulsion between the imine nitrogen and the carbonylic oxygen,
evoking a growth in energy upon rotation of the Car–Cim bond
(f z 110–150ꢂ, Fig. 4B). The situation changes drastically in the
HN form of the heterocyclic compounds because one observes
the minimum at 180ꢂ angle, Fig. 5 A, which is due to the
formation of the C5]O3/HN1 intramolecular hydrogen bond
(numbering according T5, Fig. 1). The calculated dependence of
the potential energy on the torsion angle f(CCCN) presents
a small energy difference between conformers I and VI (DEIV–I
y
2.17 kcal molꢀ1, Fig. 5 A, and 2–3 kcal molꢀ1, Fig. 6). However,
the rotational barrier is very high (25 kcal molꢀ1), which puts in
question the observation of conformers VI and VII, Fig. 6, in the
solid state. One should note that the HN tautomeric form and the
VI conformer for 2-hydroxyaryl Schiff thiosemicarbazones have
not been presented in CSD.22
The calculated dependence DE ¼ f(Q(CNNC)) for the OH
tautomeric form, Fig. 4 C, indicates only a small possibility for
the existence of a rotamer with a perpendicular location of the
NH–C(]S)NR2 moiety with respect to the phenolic plane.
Nevertheless, such geometry prevails for the HN tautomeric
form of T5–T7. This is supported by the calculation of the energy
on rotation around the N–N bond, which shows only one
minimum at the torsion Q angle equal to 60ꢂ, Fig. 5 B. Thus,
a discussion about the direction of the thiocarbonyl bond in T5–
T7 for the HN tautomer appears pointless.
Fig. 3 A scheme of the conformer energy for the T1–T3 phenolic (A)
and T5–T7 heterocyclic (B) derivatives (black: R ¼ H, white: R ¼ CH3,
grey: R ¼ C6H5) obtained by B3LYP/6-31+G(d,p) for the OH tautomeric
form. (A and B) The structures of conformers III and IV (R ¼ H) are
equivalent to conformers I and II, respectively. (B) n.o. ¼ not observed;
conformers V, VI, and X are not obtained during full optimization.
According to the close packing rule the flattest molecules
should be observed in the unit cell. This is well reflected in the
This journal is ª The Royal Society of Chemistry 2010
CrystEngComm, 2010, 12, 1955–1962 | 1959

View Article Online
Table 3 The calculated (B3LYP/6-31+G(d,p), IEF-PCM) relative energy DEII–I, kcal molꢀ1, (DEII–I ¼ EII ꢀ EI, where the EI and EII energies of the
C]S and S]C conformers are calculated for the same medium) depending on electric permittivity (3)
Solvent/Compound
T1
T2
T3
T4
T5
T6
T7
Vacuum (3 ¼ 1.00)
CCl4 (3 ¼ 2.228)
6.87
5.89
4.82
4.03
3.19
3.22
2.98
3.21
2.91
7.43
6.19
4.82
3.97
3.15
3.15
2.99
2.90
2.82
7.50
5.80
4.07
3.17
2.17
1.98
2.00
1.71
1.89
4.06
2.99
2.04
1.54
1.05
1.11
0.95
0.84
1.63
4.92
4.38
3.76
3.32
2.93
2.98
2.86
2.92
2.82
5.32
4.37
3.49
2.95
2.50
2.47
2.40
2.28
2.27
5.42
4.16
2.94
2.49
1.81
1.68
1.70
1.50
1.70
CHCl3 (3 ¼ 4.90)
CH2Cl2 (3 ¼ 8.93)
C2H5OH (3 ¼ 24.55)
CH3OH (3 ¼ 32.63)
CH3CN (3 ¼ 36.64)
DMSO (3 ¼ 46.64)
H2O (3 ¼ 78.39)
crystal packing of T3. As mentioned above, the calculated struc-
ture of the HN form shows rotation of the thiosemicarbazone
fragment, which minimized the presence of the HN tautomer in
the solid state because it contradicts the close packing rule.
In terms of the dependence DE ¼ f(c(NCNR)), Fig. 4 D, the
height of the rotational barrier is quite larger and partially
caused by the double character of the C9–N3 bond. The stepwise
rotation of the amine group to c(NCNR) y 120ꢂ causes
a lengthening of the C9–N3 bond to 1.420 A and brings about
a significant energy expenditure (DE y 20 kcal molꢀ1, Table 4).
Subsequent rotation leads to a shortening of the C9–N3 bond to
ꢁ
1.38 A and, accordingly, a decrease in energy.
ꢁ
The obtained trend of DEII–I energy changes for maximum and
local minimum of the particular compound are similar in the
Fig. 4 The calculated (B3LYP/6-31+G(d,p)) potential energy curves for the particular fragments of the rotation of the thiosemicarbazone group
(A: 4(NNCN), B: f(CCCN), C: Q(CNNC) and D: c(NCNC) torsion angles; T1: -, T2: ,, T3: B, T5: C, T6: : and T7: O).
1960 | CrystEngComm, 2010, 12, 1955–1962
This journal is ª The Royal Society of Chemistry 2010

View Article Online
Table 4 The calculated relative energies for critical points of the dependencies by the MP2/6-31+G(d,p) and B3LYP/6-31+G(d,p) methods. DEmax-I,
DEloc.min-I, and DETS are the relative energies in the maximum, local minimum, and transition state on the potential curves (Fig. 4A–4D), respectively
DEmax-I
DEloc.min-I
DETS
B3LYP
Compound
Dependency, figure
MP2
B3LYP
MP2
B3LYP
T1
DE ¼ f(4(NNCN)), 4A
DE ¼ f(f(CCCN)), 4B
DE ¼ f(c(NCNR)), 4D
DE ¼ f(4(NNCN)), 4A
DE ¼ f(f(CCCN)), 4B
DE ¼ f(Q(CNNC)), 4C
DE ¼ f(c(NCNR)), 4D
DE ¼ f(4(NNCN)), 4A
DE ¼ f(f(CCCN)), 4B
DE ¼ f(Q(CNNC)), 4C
DE ¼ f(c(NCNR)), 4D
DE ¼ f(4(NNCN)), 4A
DE ¼ f(c(NCNR)), 4D
DE ¼ f(4(NNCN)), 4A
DE ¼ f(Q(CNNC)), 4C
DE ¼ f(c(NCNR)), 4D
DE ¼ f(4(NNCN)), 4A
DE ¼ f(Q(CNNC)), 4C
DE ¼ f(c(NCNR)), 4D
11.62
4.81
16.66
9.85
4.86
14.61
7.01
17.79
12.47
6.88
5.54
4.55
0.02
6.64
4.46
3.44
3.71
6.41
3.89
2.74
n. o.a
3.74
0.00
4.60
3.14
3.34
4.56
2.54
n. o.a
6.85
6.13
0
7.46
6.05
4.92
5.2
14.67
7.08
n. o.a
12.53
6.92
T2
T3
5.23
5.76
n. o.a
n. o.a
12.26
6.43
17.37
10.61
3.89
5.15
9.99
10.92
16.59
8.67
19.67
12.2
6.4
7.5
5.49
4.86
3.29
4.89
0
5.36
3.75
4.90
5.41
4.08
2.45
5.58
n. o.a
n. o.a
13.66
n. o.a
11.31
n. o.a
n. o.a
11.01
n. o.a
n. o.a
14.17
13.63
17.56
11.33
3.97
19.42
10.95
4.55
T5
T6
4.21
17.18
n. o.a
4.86
T7
9.50
13.47
a
n. o. ¼ not observed.
MP2 and B3LYP calculations (Table 4). However, all the data
obtained by the MP2 method are 2 kcal molꢀ1 less than those
obtained by B3LYP. This shows some superiority the MP2
method in describing the conformational task because it shows
the possibility of observing the particular conformer in the
experiment.
second case the withdrawal of hydrogen from the N–NH–C
fragment and its location on the sulfur atom provokes an energy
increase of 13.84 kcal molꢀ1. The great difference in energy
between the S]C and HS–C tautomers does not support the
observation of a thiol form in the solid state.
One more possible phenomenon in 2-hydroxyaryl Schiff thi-
osemicarbazones is thiol–thione equilibrium. We have completed
the calculations for the protonated sulfur atom (the C–S–H
form) of: (1) the transfer of the OHN bridge proton to the sulfur
atom and (2) the transfer of the N–NH–C proton to the sulfur
atom. In the first case, withdrawal of the proton from the OH/
N bridge and its localization on the sulfur atom gives a way to the
withdrawal of the hydrogen from the C–NHR group and its
transfer to an oxygen atom under full optimization. The energy
of such a tautomer is quite great, DE ¼ 20.65 kcal molꢀ1. In the
Summary
We performed the synthesis and X-ray measurements of 2-
hydroxyaryl Schiff thiosemicarbazones, which show different
orientations of the thiocarbonyl group. The prevalence of the
C]S form of the phenylthiosemicarbazone derivative is shown.
This form is stabilized by intermolecular hydrogen bonds,
whereas the S]C form observed in N-alkyl derivatives is stabi-
lized by a bifurcate intramolecular hydrogen bond. The B3LYP
and MP2 calculations completed for gas phase showed
Fig. 5 The calculated (B3LYP/6-31+G(d,p)) potential energy curves for the particular fragments (A: f(CCCN) and B: Q(CNNC) torsion angles) of the
rotation of the thiosemicarbazone group for T6. The calculated stereoviews of compound T6 were generated using ChemCraft version 1.6.19
This journal is ª The Royal Society of Chemistry 2010
CrystEngComm, 2010, 12, 1955–1962 | 1961

View Article Online
(c) L. Latheef, E. Manoj and M. R. P. Kurup, Acta Crystallogr.,
Sect. C: Cryst. Struct. Commun., 2005, 62, o16; (d) U. Abram,
K. Ortner, R. Gust and K. Sommer, J. Chem. Soc., Dalton Trans.,
2000, 735; (e) D. S. Kalinowski, P. C. Sharpe, P. V. Bernhardt and
D. R. Richardson, J. Med. Chem., 2007, 50, 6212.
7 (a) D. Chattopadhyay, S. K. Mazumdar, T. Banerjee, S. Grosh and
T. C. W. Mak, Acta Crystallogr., Sect. C: Cryst. Struct. Commun.,
1988, 44, 1025; (b) S. W. Ng, V. G. K. Das, B. W. Skelton and
A. H. White, J. Organomet. Chem., 1989, 377, 211; (c) E. B. Seena,
M. D. P. Kurup and E. Suresh, J. Chem. Crystallogr., 2008, 38, 93;
(d) M. Soriano-Garcia, J. Valdes-Martinez, R. A. Toscano,
J. Gomez-Lara and M. Villalobos-Penaloza, Acta Crystallogr., Sect.
C: Cryst. Struct. Commun., 1986, 42, 623; (e) J. Valdes-Martinez,
M. Rubio, R. C. Rosado, J. Salcedo-Loaiza, R. A. Toscano,
J. Espinosa-Perez, S. Hernandez-Ortega and K. Ebert, J. Chem.
Crystallogr., 1994, 27, 627; (f) M. Soriano-Garcia, J. Valdes-
Martinez and R. A. Toscano, Acta Crystallogr., Sect. C: Cryst.
Struct. Commun., 1988, 44, 1247; (g) I. Dilovic, M. Rubcic,
V. Vrdoljak, S. K. Pavelic, M. Kralj, I. Piantanida and M. Cindric,
Bioorg. Med. Chem., 2008, 16, 5189.
Fig. 6 A scheme of the conformer energy obtained by B3LYP/6-
31+G(d,p) for T5–T7 (black: R ¼ H, white: R ¼ CH3, grey: R ¼ C6H5).
The structures of conformers IV and V (R ¼ H) are equivalent to
conformers II and III (R ¼ H), respectively.
8 B. S. Furnuss, A. J. Hannaford, P. W. G. Smith and A. Tatchell,
Vogel’s Textbook of practical Organic Chemistry, Longmans: New
York, 1989, pp. 997–999.
9 (a) S. Garrat, J. Org. Chem., 1963, 28, 1886; (b) J. P. Scovill,
Phosphorus, Sulfur Silicon Relat. Elem., 1991, 60, 15;
(c) S. Manivannan and S. Dhanuskodi, J. Cryst. Growth, 2004, 262,
473; (d) S. Dhanuskodi and S. Manivannan, J. Cryst. Growth, 2004,
262, 395.
10 Oxford Diffraction Poland Sp., Crysl Alis CCD, Crysl Alis RED
version 1.171.13 beta (release 14.11.2003) Copyright 1995–2003.
11 G. M. Sheldrick, SHELXS97 Program for Solution of Crystal
Structure, University of Goettingen, Germany, 1997.
a prevailing C]S conformer. However, calculations taking into
consideration the growth in polarity showed the presence of both
conformers. This theoretical investigation is in agreement with
experiment. The presented stereochemistry study based on
B3LYP and MP2 calculations should account for crystal
packing.
12 G. M. Sheldrick, SHELXl97 Program for Refinement of Crystal
Structure, University of Goettingen, Germany, 1997.
13 C. F. Macrae, I. J. Bruno, J. A. Chisholm, P. R. Edgington,
P. McCabe, E. Pidcock, L. Rodriguez-Monge, R. Taylor, J. van de
Streek and P. A. Wood, J. Appl. Crystallogr., 2008, 41, 466.
14 (a) A. D. Becke, J. Chem. Phys., 1993, 98, 5648; (b) C. Lee, W. Yang
and R. G. Parr, Phys. Rev. B: Condens. Matter, 1988, 37, 785.
Acknowledgements
The authors gratefully acknowledge the financial support from
Wroclaw University (grant 2223/W/WCH/09) and the Wroclaw
Centre for Networking and Supercomputing (WCSS) for
computational facilities.
€
15 C. Moller and M. S. Plesset, Phys. Rev., 1934, 46, 618.
16 Gaussian 03, Revision E.01, M. J. Frisch, G. W. Trucks,
H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman,
J. A. MontgomeryJr., T. Vreven, K. N. Kudin, J. C. Burant,
J. M. Millam, S. S. Iyengar, J. Tomasi, V. Barone, B. Mennucci,
M. Cossi, G. Scalmani, N. Rega, G. A. Petersson, H. Nakatsuji,
M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa,
M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, M. Klene,
X. Li, J. E. Knox, H. P. Hratchian, J. B. Cross, V. Bakken,
C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala,
K. Morokuma, G. A. Voth, P. Salvador, J. J. Dannenberg,
V. G. Zakrzewski, S. Dapprich, A. D. Daniels, M. C. Strain,
O. Farkas, D. K. Malick, A. D. Rabuck, K. Raghavachari,
J. B. Foresman, J. V. Ortiz, Q. Cui, A. G. Baboul, S. Clifford,
J. Cioslowski, B. B. Stefanov, G. Liu, A. Liashenko, P. Piskorz,
I. Komaromi, R. L. Martin, D. J. Fox, T. Keith, M. A. Al-Laham,
C. Y. Peng, A. Nanayakkara, M. Challacombe, P. M. W. Gill,
B. Johnson, W. Chen, M. W. Wong, C. Gonzalez and J. A. Pople,
Gaussian, Inc., Wallingford CT, 2004.
References
1 (a) Y. Yu, D. S. Kalinowski, Z. Kovacevic, A. R. Siafakas,
P. J. Jansson, C. Stefani, D. B. Levejoy, P. C. Sharpe,
P. V. Bernhardt and D. R. Richardson, J. Med. Chem., 2009, 52,
5271; (b) D. C. Greenbaum, Z. Mackey, E. Hansell, P. Doyle,
J. Gut, C. R. Caffrey, J. Lehrman, P. J. Rosenthal,
J. H. McKerrow and K. Chibale, J. Med. Chem., 2004, 47, 3212;
(c) P. Ponka, J. Borova, J. Neuwirt and O. Fuchs, FEBS Lett.,
1979, 97, 317; (d) A. C. Sartorelli, K. C. Agrawal, A. S. Tisftsoglon
and A. C. Moore, Adv. Enzyme Regul., 1977, 15, 117.
2 (a) D. R. Richardson and P. Ponka, J. Lab. Clin. Med., 1998, 132,
351; (b) D. R. Richardson, E. H. Tran and P. Ponka, Blood, 1995,
86, 4295; (c) I. Napier, P. Ponka and D. R. Richardson, Blood,
2005, 105, 1867.
3 R. A. Finch, M.-C. Liu, S. P. Grill, W. C. Rose, R. Loomis,
K. M. Vasquez, Y.-C. Cheng and A. C. Sartorelli, Biochem.
Pharmacol., 2000, 59, 983.
17 A. Filarowski, A. Koll, A. Hansen and M. Kluba, J. Phys. Chem. A,
2008, 112, 3478.
4 (a) H.-C. Fang, X.-Y. Yi, Z.-G. Gu, G. Zhao, Q.-Y. Wen, J.-Q. Zhu,
A.-W. Xu and Y.-P. Cai, Cryst. Growth Des., 2009, 9, 3776;
(b) J. Jezierska, Asian J. Chem., 1992, 4, 189.
5 (a) G. Gilli, F. Bellucci, V. Ferretti and V. Bertolasi, J. Am. Chem.
Soc., 1989, 111, 1023; (b) P. Gilli, V. Ferretti, V. Bertolasi and
G. Gilli, in Advances in Molecular Structure Research, ed.
M. Hargittai and I. Hargittai, JAI Press: Greenwich, CT, 1996, Vol.
2, p. 67; (c) L. Sobczyk, S. Grabowski and T. M. Krygowski, Chem.
Rev., 2005, 105, 3513.
18 J. Tomasi, B. Mennucci and E. Cances, THEOCHEM, 1999, 464,
211.
19 G. A. Zhurko, CHEMCRAFT, http://www.chemcraftprog.com.
20 T. Steiner, Angew. Chem., Int. Ed., 2002, 41, 48.
21 (a) A. Filarowski, J. Phys. Org. Chem., 2005, 18, 686;
(b) A. Filarowski, A. Koll and L. Sobczyk, Curr. Org. Chem., 2009,
13, 172.
22 F. H. Allen, Acta Crystallogr., Sect. B: Struct. Sci., 2002, 58, 380.
23 T. Steiner and G. S. Desiraju, in The Weak Hydrogen Bond in
Structural Chemistry and Biology, Oxford University Press, New
York, 1999.
6 (a) P. V. Bernhardt, L. M. Caldwell, D. B. Lovejoy and
D. R. Richardson, Acta Crystallogr., Sect. C: Cryst. Struct.
€
24 (a) C. B. Aakeroy, J. Desper and J. F. Urbina, Chem. Commun., 2005,
Commun.,
2003,
59,
o629;
(b)
D.
Kovala-Demertzi,
N. Kourkoumelis, M. A. Demertzis, J. R. Miller, C. S. Frampton,
€
2820; (b) C. B. Aakeroy, J. Desper and M. E. Fasulo, CrystEngComm,
2006, 8, 586.
J. K. Swearingen and D. X. West, Eur. J. Inorg. Chem., 2000, 727;
1962 | CrystEngComm, 2010, 12, 1955–1962
This journal is ª The Royal Society of Chemistry 2010