Crystal structure and conformation study of 4-chlorobenzaldehyde thiosemicarbazone derivative

Article abstract of DOI:10.1007/s10870-010-9804-9

Thiosemicarbazones (TSCs) are very versatile tridentate ligands having the ability to bind transition metal ions by bonding through sulfur and hydrazinic terminal nitrogen atoms. TSC also inhibits ribonucleotide diphosphate reductase (RDR), the enzyme inv

Full text of DOI:10.1007/s10870-010-9804-9

J Chem Crystallogr (2010) 40:1110–1114
DOI 10.1007/s10870-010-9804-9
ORIGINAL PAPER
Crystal Structure and Conformation Study
of 4-Chlorobenzaldehyde Thiosemicarbazone Derivative
•
N. Sampath Rita Mathews M. N. Ponnuswamy
•
Received: 22 September 2009 / Accepted: 20 May 2010 / Published online: 11 June 2010
ꢀ Springer Science+Business Media, LLC 2010
Abstract Thiosemicarbazones (TSCs) are very versatile
tridentate ligands having the ability to bind transition metal
ions by bonding through sulfur and hydrazinic terminal
nitrogen atoms. TSC also inhibits ribonucleotide diphos-
phate reductase (RDR), the enzyme involved in the syn-
thesis of DNA precursors in the mammalian cells. One of
the important phenyl thiosemicarbazones, the title com-
pound (p-CBT) has been synthesized and it was charac-
terized by X-ray diffraction methods. The crystallographic
data of p-CBT are: C8H8ClN3S; M.W. = 213.68, Triclinic,
Introduction
Thiosemicarbazide is a tridentate ligand, which combines
with aldehydes or ketones to generate the thiosemicarba-
zone (TSC) derivatives. These derivatives have a wide
range of biological activities such as antitumour [1], anti-
malarial [2], antileukemic properties [3], antiviral activity
[4], antibacterial [5] and antifertility property [6] because
of their reduction capability. TSC moiety is planar and
adopts an extended (E) conformation due to the extensive
p-electron delocalization throughout the moiety. In gen-
eral, the N, S—donor ligands of thiosemicarbazones are
attributed to their ability to form metal chelates [7], non-
linear optical properties [8] and reductive capacities [9].
The entire electron charges are smearing on the sulfur
and hydrazinic N atoms due to electron delocalization
which helps in complexation with positively charged metal
ions. Both S and N atoms chelate the metal ions of the
biological molecule and believed to be responsible for the
pharmaceutical activity. In addition, TSCs also possess
second-order nonlinear optical (NLO) properties which
have broad applications in opto-electronics, such as optical
frequency conversion [10, 11] and optical parameter
oscillator (OPO).
˚
space group, P¯ı, with cell parameters a = 7.934(2) A,
˚
˚
b = 11.242(3) A, c = 11.615(2) A, a = 74.775(3), b =
3
˚
75.389(2), c = 83.448(2); V = 966.0(4) A , Z = 4, Dcal
= 1.469 Mg/m3,
k
(Cu Ka) = 1.54184 A. Molecular
˚
packing can be viewed as a dimer held together by two
N–H…S type intermolecular hydrogen bonds. In addition,
C–H…Cl and N–H…N types of inter and intra molecular
hydrogen bonds also help the molecules in crystal packing.
Keywords Thiosemicarbazone ꢀ Heterocyclic ꢀ
Conformation ꢀ Hydrogen bond ꢀ Space group
The relationship between the metal ions and cancer are
intriguing and controversial. French and Freedlander [12]
suggested that some antitumour agents also possess the
ability to function as chelating agents. French and Blanz
[1] prepared many TSC derivatives and found that all
tumor inhibitors potentially act as N–N–S type ligands. The
biological activities of TSCs depend on the parent alde-
hydes or ketones [13]. Pyridine-2-carbaldehyde thiosemi-
carbazone was the first heterocyclic compound (HFoTsc)
reported to have carcinostatic properties [14]. The mech-
anism of action of HFoTsc is due to its ability to inhibit the
N. Sampath (&) ꢀ R. Mathews
Department of Advanced Technology Fusion, Konkuk
University, 1 Hwayang dong, Gwangjin-gu,
Seoul 143-701, Korea
e-mail: sampath@konkuk.ac.kr; sams76@gmail.com
M. N. Ponnuswamy (&)
Department of Crystallography and Biophysics, University
of Madras, Guindy Campus, Chennai, 600 025, India
e-mail: mnpsy@hotmail.com
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J Chem Crystallogr (2010) 40:1110–1114
1111
diffractometer [16]. Data were collected at 293(2) K using
˚
H2N
CuKa radiation (k = 1.54184 A) and the data reduction
S
was carried out by XCAD4 [17] program. Out of 3932
reflections collected, 3611 reflections with I C 2r(I) were
used for structure solution and refinement. The intensity
data were corrected for Lorentz and polarization absorp-
tion effects.
N
NH
Cl
H
Scheme 1 Chemical diagram of p-CBT
Structure Solution and Refinement
biosynthesis of DNA, possibly by blocking the enzyme
ribonucleotide reductase (RNR) or blocking the base rep-
lication; creation of lesions in DNA strands by oxidative
rupture [14, 15].
The structure was solved by direct-methods using the
program SHELXS97 [18], which revealed the position of all
non-hydrogen atoms, and refined on F2 by a full-matrix
least squares procedure using SHELXL97 [18]. The non-
hydrogen atoms were refined anisotropically and the
hydrogen atoms were allowed to ride over their parent
atoms. The final cycle of refinement converged to
R1 = 0.0721 and wR2 = 0.2098 for the observed reflec-
tions. The maximum and minimum heights in the final
difference Fourier map were found to be 0.986 and -
As part of the ongoing study on thiosemicarbazone
derivatives, different para substituted phenyl thiosemicar-
bazone derivatives have been synthesized and their anti-
microbial activity against 10 different bacterial species and
2 Candida fungi (unpublished result) were tested. One of
the molecules, 4-chlorobenzaldehyde thiosemicarbazone
(p-CBT) is found to have better activity against these
bacteria and fungi compared to other compounds. So the
title compound p-CBT was synthesized and its structural
study has been done by X-ray crystallography method to
establish the molecular geometry and stereochemistry. The
chemical diagram of compound is shown in Scheme 1.
-3
˚
0.577 e A
, respectively. Least-squares planes and
asymmetry calculations were done using the program
PARST97 [19]. The thermal ellipsoid plot and packing
were done, respectively, using ORTEP [20] and PLATON
[21]. Non-bonded interaction graphics were created using
the program PLATON [21]. The crystallographic data and
methods of data collection, solution and refinement are
shown in Table 1. All other information about p-CBT
structure is included in the deposited material (CCDC
743746) as a complete list of bond distances and angles.
Experimental
Synthesis of Phenyl Thiosemicarbazones
The respective benzaldehydes (0.1 M) were taken in the
medium of 100% pure ethanol with little more amounts
(0.12 M) of thiosemicarbazide in presence of conc. HCl.
This reaction mixture was allowed to react in a water bath
for 4 h and the respective thiosemicarbazone derivative
was separated out as colorless solids and dried. The dried
sample was crystallized using acetonitrile as solvent.
Result and Discussion
The synthesized 4-chlorobenzaldehyde thiosemicarbazone
(p-CBT) crystallized in space group P¯ı, and it showed
crystallographically two independent molecules in the
H2N
S
S
H2N
O
N
H
NH
NH NH2
Cl
Cl
Ethanol/ Conc. HCl
H
X-Ray Data Collection and Reduction
asymmetric unit A and B. The perspective view of p-CBT
ORTEP diagram is shown in Fig. 1. The bond lengths,
bond angles and selected torsion angles of non-hydrogen
atoms, respectively, are shown in Fig. 2a, b and c.
A single crystal of p-CBT was mounted on a glass fiber
and used for data collection. Cell parameters and an
orientation matrix for data collection were obtained by
least-squares refinement of the diffraction data from 25
reflections in an ENRAF–NONIUS CAD4 automatic
The S and hydrazinic N8 atoms are in trans position
with respect to C10–N9 bond. Similar type of trans con-
figuration is noted in many structures of thiosemicarbazide
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J Chem Crystallogr (2010) 40:1110–1114
Table 1 Crystal data and other relevant details for p-CBT
Parameters
p-CBT
CCDC
CCDC 743746
C8H8ClN3S
213.68
Empirical formula
Formula weight
Temperature
293(2) K
˚
1.54184A (CuKa)
Wavelength
Crystal system, space group
Unit cell dimensions
Triclinic, P¯ı
˚
a = 7.934(2) A
˚
b = 11.242(3) A
˚
c = 11.615(2) A
a = 74.775(3)ꢁ
b = 75.389(2)ꢁ
c = 83.448(2)ꢁ
966.0(4)
3
˚
Volume A
Z, Calculated density
F(000)
4, 1.469 Mg/m3
440
Theta range for data collection
Limiting indices
4.06ꢁ to 72.23ꢁ
-6 B h B 9
-13 B k B 13
-13 B l B 14
Reflections collected/unique
Refinement method
3932/3611 [Rint = 0.078]
Full-matrix least-squares on F2
3611/0/236
Data/restraints/parameters
Goodness-of-fit on F2
Final R-indices [I [ 2r(I)]
R-indices (all data)
1.015
R1 = 0.0721, wR2 = 0.2098
R1 = 0.0918, wR2 = 0.2461
-3
˚
0.986 and B 0.577 e A
Largest diff. peak and hole
˚
Fig. 2 a Bond lengths (A) diagram of molecule p-CBT. b Bond
angles (ꢁ) diagram of molecule p-CBT. c Selected torsion angles (ꢁ)
of p-CBT. Hydrogen atoms are removed for clarity
Fig. 1 ORTEP diagram of the molecule p-CBT (A and B) showing
the thermal ellipsoids at 30% probability level. Hydrogen atoms were
removed for clarity
Scheme 2 Resonance structures of thiosemicarbazone moiety
thiosemicarbazone moiety adopts an extended conforma-
tion and almost lie in the same plane of the benzene ring
(Scheme 2). The corresponding torsion angles are as
follows:
[22, 23], N-methyl-2,6-diphenyl-3-isopropyl piperidin-4-
one thiosemicarbazone [24] and 3,4,5-trimethoxy benzal-
dehyde thiosemicarbazone monohydrate [25]. The torsion
angles and mean plane calculations confirm that the whole
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J Chem Crystallogr (2010) 40:1110–1114
1113
Conformational bonds
p-CBT angle (ꢁ)
Mol. A
Mol. B
C7–N8–N9–C10
N8–N9–C10–N11
N8–N9–C10–S1
177.9(3)
-6.7(4)
174.2(2)
177.8(3)
-6.9(4)
174.5(2)
The bond length variations in C4–C7 of molecules A and
˚
B of p-CBT [1.465(4) and 1.468(4) A] indicate the influ-
ence of conjugation between the phenyl ring and C7–N8
˚
[1.279(4) and 1.262(4) A for A and B of p-CBT] imine
double bonds (Fig. 2a). Similar effect is also noted in some
other structures 2,3-Dihydroxybenzaldehyde thiosemicar-
bazone [26] and Salicylaldehyde-4,40-(hexane-1,6-diyl)
thiosemicarbazone [27]. In molecule p-CBT, C3–C4 bond
Fig. 3 Packing of the molecules p-CBT viewed down a-axis. Dashed
lines represent hydrogen bonds
˚
˚
lengths [1.382(5) A for A and 1.409(5) A for B] are not
similar and this may be due to the influence of the chlorine
atom substituted at the para position of phenyl ring. The
˚
˚
bond lengths C1–Cl [1.751(3) A for A and 1.736(3) A for
B] are also significantly different; this is due to the electron
releasing capability of the chlorine to the benzene ring.
The bond lengths in the thiosemicarbazone moieties in
both the molecular fragments show delocalization effect
and this is extended even up to the imine nitrogen group.
TSC moieties are oriented at angles 21.1(1)ꢁ and 21.3(1)ꢁ
(A and B, respectively) to the phenyl rings of the molecule
p-CBT. The bond angles C2–C1–C6 in the molecules A
and B of p-CBT are 121.3(3)ꢁ and 121.9(3)ꢁ, respectively.
This widening of bond angles in the p-CBT molecule is
comparable with reported structures (p-substituted/unsub-
stituted thiosemicarbazones) have ranges of 119ꢁ to 121ꢁ
[26, 27], but in N,N-dimethylaminebenzaldehyde thio-
semicarbazone (DABT), the angle C2–C1–C6 [117.0(2)ꢁ]
is shortened due to the H…H short contacts [28].
Table 2 Hydrogen bondings and the possible non-bonded interac-
˚
tions for p-CBT (ꢁ, A)
D–H…A
d(D–H) d(D…A) d(H…A) \D–H…A
N11A–H11A…N8A
N11B–H11C…N8B
N9A–H9A…S1Bi
N9B–H9B…S1Ai
C6B–H6B…Cl1Bii
C6A–H6A…Cl1Aiii
860(3) 2.642(3) 2.288(2) 104.9(2)
0.860(3) 2.664(3) 2.319(2) 104.2(2)
0.860(2) 3.461(3) 2.773(1) 138.1(2)
0.860(2) 3.445(3) 2.755(1) 138.2(2)
0.930(3) 3.827(3) 2.980(1) 152.1(2)
0.930(3) 3.847(3) 2.993(1) 153.3(2)
N11B–H11D…S1Biv 0.860(2) 3.509(3) 2.657(1) 171.2(2)
Equivalent positions
i. -x ? 1, -y-1, -z ? 2
ii. -x ? 1, -y, -z
iii. -x ? 1, -y, -z ? 1
iv. -x, -y-1, -z ? 2
Packing Features
observed in other similar structures [29, 30] and it is found
to be a common feature of these moieties. These dimer
interactions extend along the c-axis of unit cell packing.
The packing of molecules viewed down a-axis is shown in
Fig. 3. The p-CBT molecules are stabilized by N–H…N,
N–H…S and C–H…N types of intra and intermolecular
hydrogen bonds (Table 2). The N–H…N type intra
molecular hydrogen bond forms a five-membered ring and
this interaction is helping to the TSC extended conforma-
tion [29, 30]. The molecule p-CBT also has a weak p…p
interaction [31] between the molecules A and B of benzene
rings Cg1 [C1A through C6A] and Cg2 [C1B through C6B]
Supplementary Material
Crystallographic data (excluding structure factors) for the
structure reported in this paper has been deposited with the
Cambridge Crystallographic Database Centre as supple-
mentary publication no. CCDC743746. Copies of available
material can be obtained, free of charge at http://www.
ccdc.cam.ac.uk/conts/retrieving.html (or from the CCDC,
12 Union Road, Cambridge CB2 1EZ, UK; fax: ?44
1223336033; e-mail: deposit@ccdc.cam.ac.uk).
˚
forming a centroid–centroid distance of 3.75 A. Pair of
N11–H11…S hydrogen bonds across the centres of inver-
sion results a dimer between the symmetry related mole-
cules of p-CBT (Fig. 3). Such dimerization has also been
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J Chem Crystallogr (2010) 40:1110–1114
Acknowledgement The author NS is grateful to the Council of
Scientific and Industrial Research (CSIR), India in the form of Senior
Research Fellow (SRF).The author is also grateful to Konkuk Uni-
versity, Seoul, South Korea for its support.
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