Crystal structure and conformation study of 3-Methyl-2, 6-bis (4-chlorophenyl) piperidin-4-one thiosemicarbazone derivative

Article abstract of DOI:10.1007/s10870-010-9802-y

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 the enzyme ribonucliotide diphosphate reductase (RDR) whic

Full text of DOI:10.1007/s10870-010-9802-y

J Chem Crystallogr (2010) 40:1099–1104
DOI 10.1007/s10870-010-9802-y
ORIGINAL PAPER
Crystal Structure and Conformation Study of 3-Methyl-2, 6-bis
(4-chlorophenyl) Piperidin-4-one Thiosemicarbazone Derivative
•
N. Sampath Rita Mathews M. N. Ponnuswamy
•
Received: 24 July 2009 / Accepted: 20 May 2010 / Published online: 11 June 2010
Ó 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 the enzyme ribonuclio-
tide diphosphate reductase (RDR) which is involved in the
synthesis of DNA precursors in the mammalian cells. One
of the important heterocyclic thiosemicarbazones, the title
compound (MBCPT) has been synthesized based on the
Mannich reaction and it was characterized by X-ray dif-
fraction methods. The crystallographic data of MBCPT
are: C19H20Cl2N4S; M.W = 407.35, Monoclinic, space
Introduction
The hydrazine group combines with aldehydes or ketones to
generate the thiosemicarbazone derivatives, which have a
wide range of biological activities such as antitumour [1],
antimalarial [2], antileukemic properties [3], antiviral activ-
ity [4], antibacterial [5] and antifertility property [6] because
of its reduction capability. The thiosemicarbazone moiety is
planar and adopts an extended (E) conformation. This planar
conformation is due to the extensive electron delocalization
throughout the moiety. In general, the N, S-donor ligands of
thiosemicarbazones and thiosemicarbazides are attributed to
their ability to form metal chelates [7], non-linear optical
properties [8] and their reductive capacities [9].
˚
group, P21/n, with cell parameters a = 12.053(8) A,
˚
˚
b = 11.431(10) A, c = 14.695(7) A, b = 95.82(4)8; V =
2014(2) A , Z = 4, Dcal = 1.343 Mg/m3, k (Cu Ka) =
˚
1.54184 A. The ring piperine adopts chair conformation.
3
˚
The total electron charges are smearing on the sulfur atom
due to electron delocalization which helps in complexation
with positively charged metal ions. Here, another electron
rich hydrazinic N atom is also involved in the complex for-
mation with metal ions. Both these S and N atoms chelate to
metal ion of the biological molecule and believed to possess
the pharmaceutical activity of this molecule. In addition to
the biological properties, the TSCs 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).
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 the tumor
inhibitors potentially act as N–N–S type ligands. The bio-
logical activities of heterocyclic thiosemicarbazones (TSCs)
depend on the parent aldehydes or ketones [13]. Pyridine-
2-carbaldehyde thiosemicarbazone was the first heterocy-
clic compound (HFoTsc), reported to have carcinostatic
The phenyl rings are oriented equatorially at 2 and 6th
positions of the piperidine ring. Molecular packing can be
viewed as a dimer held together by two N–H_S inter-
molecular hydrogen bonds. Molecules are tightly bound in
the unit cell by C–H_N, N–H_S and N–H_N types inter
and intra molecular hydrogen bonds.
Keywords Thiosemicarbazone Á Heterocyclic Á
Conformation, hydrogen bond Á Space group
N. Sampath (&) Á 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) 40:1099–1104
properties [14]. The mechanism of action of HFoTsc, is due
to its ability to inhibit the biosynthesis of DNA, possibly by
blocking the enzyme ribonucleotide reductase (RNR) or
blocking base replication; creation of lesions in DNA strands
by oxidative rupture [14, 15].
stereochemistry. The chemical diagram of the title com-
pound (MBCPT) is shown in Scheme 1.
Experimental
The skeletal ring of piperidine present in the molecules
has many synthetic and natural medicaments [16]. Piperi-
dine derivatives, namely, 4-piperidones are the synthetic
intermediates in various alkaloids and pharmaceutical
products [17]. This functionalized derivatives exhibit anti-
depressant [18], antiarrhythmic, tranquilizing and blood
cholesterol lowering activities [19].
Preparation of MBCPT
Step-1: Synthesis of Piperidin-4-one
Piperidin-4-one was prepared by Mannich condensation
reaction using respective aldehydes and ketones with
ammonium acetate in the ratio of [2:1:1], respectively, in
the medium of 95% ethanol, heated on a hot plate up to the
boiling range and kept overnight [20]. The product piper-
idin-4-one was separated after 3 days and it was recrys-
tallized by slow evaporation method in ethanol.
As part of the ongoing study on thiosemicarbazone
derivatives, the title compound 3-Methyl-2, 6-bis (4-chlo-
rophenyl) piperidin-4-one thiosemicarbazone (MBCPT)
was prepared and characterized by X-ray crystallogra-
phy methods to establish the molecular geometry and
O
O
H
R
R
O
CH3COONH4
95% Ethanol
N
H
+
+
CH
3
R
R
1
1
R
1
R= CH3; R1= Cl
H2N
N
S
Step-2: Synthesis of Piperidin-4-one Thiosemicarbazones
NH
The resulting product was treated with equimolar (1:1)
quantity of thiosemicarbazide in the presence of a small
amount of conc. HCl in pure ethanol in a water bath and
refluxed for 2 h. The product was separated out and dried.
Colorless crystals were grown by slow evaporation using
acetonitrile as solvent. Good quality crystal was chosen for
structural studies.
CH3
N
H
Cl
Cl
Scheme 1 Chemical diagram of molecule MBCPT
H N
2
S
R
NH
O
N
H N
NH
2
NH
R
2
S
Ethanol
N
H
N
H
R
1
R
R
R
1
1
1
R= CH3; R1= Cl
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J Chem Crystallogr (2010) 40:1099–1104
X-ray Data Collection and Reduction
1101
least squares procedure using SHELXL97 [23]. 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 R =
0.0824 and wR2 = 0.2249 for the observed reflections. The
maximum and minimum heights in the final difference
A prismatic crystal of MBCPT 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 dif-
fractometer [21]. Data were collected at 293(2) K using Cu
-3
˚
Fourier map were found to be 0.632 and -0.655 e A
,
respectively. Least-squares planes and asymmetry calcu-
lations were done using the program PARST97 [24]. The
thermal ellipsoid plot and packing were done using ORTEP
[25] and PLATON [26]. Non-bonded interaction graphics
were created using the program PLATON [26]. The crys-
tallographic data and methods of data collection, solution
and refinement are shown in Table 1. All other information
about MBCPT structure is included in the deposited
material (CCDC 740952), as a complete list of bond dis-
tances and angles.
˚
Ka radiation (k = 1.54184 A) and the data reduction was
carried out by XCAD4 [22] program. Out of 4045 reflec-
tions collected, 3856 reflections with I C 2r(I) were used
for structure solution and refinement. The intensity data
were corrected for Lorentz and polarization absorption
effects.
Structure Solution and Refinement
The structure was solved by direct-methods using the
program SHELXS97 [23], which revealed the position of all
non-hydrogen atoms, and refined on F2 by a full-matrix
Results and Discussion
The perspective view of the molecule MBCPT is shown
in Fig. 1. The bond lengths and bond angles for the non-
hydrogen atoms of MBCPT is shown in Fig. 2a, b,
respectively. The thiosemicarbazone (TSC) moiety is
planar and oriented to the best plane of piperidine ring at
an angle of 38.7(1)°. The S1 atom of MBCPT is trans to
N7 and shows an extended (E) configuration. These zig-
zag E configurations are supported extensively by N–
H_N intra molecular of hydrogen bonds [27]. The bond
lengths of TSC moiety show variations from their normal
values and this may be due to the partial double bond
Table 1 Crystal data and other relevant details for MBCPT
Parameters
MBCPT
CCDC
CCDC 740952
Empirical formula
Formula weight
Temperature
C19H20Cl2N4S
407.35
293(2) K
˚
1.54184 A (Cu Ka)
Wavelength
Crystal system, space group
Unit cell dimensions
Monoclinic, P21/n
˚
a = 12.053(8) A
˚
b = 11.431(10) A
˚
c = 14.695(7) A
b = 95.82(4)8
3
˚
2014(2) A
Volume
Z, Calculated density
F(000)
4, 1.343 Mg/m3
848
Theta range for data collection
Limiting indices
4.53 to 72.388
0 \= h \= 14
0 \= k \= 14
-18 \= l \= 18
Reflections collected/unique
Completeness to theta = 26.29
Refinement method
Data/restraints/parameters
Goodness-of-fit on F2
Final R-indices [I [ 2r(I)]
R-indices (all data)
Largest diff. peak and hole
4045/3856 [Rint = 0.0467]
97.00%
Full-matrix least-squares on F2
3856/0/236
1.075
R1 = 0.0824, wR2 = 0.2249
R1 = 0.0922, wR2 = 0.2386
-3
Fig. 1 ORTEP diagram of the molecule MBCPT showing the
thermal ellipsoids at 30% probability level. Hydrogen atoms were
removed for clarity
˚
0.632 and -0.655 e A
123

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J Chem Crystallogr (2010) 40:1099–1104
[28]. The moiety adopts an extended conformation which
is evidenced by the torsion angles given below.
Conformation bonds
MBCPT Torsion angles (°)
C4–N7–N8–C9
N7–N8–C9–N10
N7–N8–C9–S1
-174.5(4)
-7.0(5)
174.1(3)
The extensive hetero p-electron delocalization is
responsible for stable extended conformation (Scheme 2).
In thiosemicarbazone, the negative charges on the terminal
free amino group N10 atom increases while that on N7
decreases, as it is commonly observed for thiosemicarba-
zone moieties [29, 30]. It is well known that N10 does not
take part either in metal complexation or in the reduction
process [30] in the biological systems. Either one or both
these processes are thought to be responsible for the bio-
logical activity of these groups [9]. Localization of electron
density on N10 atom cannot be expected to have any effect
on the biological activity of these compounds. It is believed
that the atoms N7 and S play key roles in metal chelation
and biological activities [30].
All the geometrical parameters and a least-squares plane
calculation [24] strongly confirm that the piperidine ring
adopts chair conformation. This conformation is supported
by the torsion angles (Fig. 3) and asymmetry parameters
also support the above fact. Based on the least-squares
plane computed for the piperidine ring of MBCPT, the
˚
Fig. 2 a Bond lengths (A) diagram of molecule MBCPT. b Bond
angles (°) diagram of molecule MBCPT. Hydrogen atoms are
removed for clarity
˚
atoms N1 and C4 deviate by 0.641(3) and -0.536(4) A on
either side of the ring.
The phenyl rings A (atoms C11 through C16) and B
(atoms C17 through C22) are substituted equatorially at
2nd and 6th positions of the piperidine ring in MBCPT and
it is confirmed with corresponding orientation angles of
character (Scheme 2), a common feature observed in TSC
˚
moieties [N7–N8 = 1.377(4) A; N8–C9 = 1.359(4) A;
˚
˚
C9–N10 = 1.307(5) A; C9–S1 = 1.676(4) A] for MBCPT
˚
NH+2
Scheme 2 Resonance structure
of thiosemicarbazone moiety
N
S-
N
H
R
NH2
NH2
N
N
S-
N
H
R
N
H
R
S
NH2
N
N+
H
S-
R
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J Chem Crystallogr (2010) 40:1099–1104
1103
Fig. 5 Dimerized structure between the symmetry related molecules
of MBCPT
Fig. 3 Selected torsion angle diagram of molecule MBCPT. Hydro-
gen atoms are removed for clarity
Table 2 Hydrogen bondings and possible non-bonded interactions
˚
for MBCPT (8, A)
D–H_A
d(D–H)
d(D_A)
d(H_A) \D–H_A
phenyl rings with respect to the piperidine ring by 67.7(1)
& 68.9(2)8, respectively. Both these phenyl rings are ori-
ented at an angle of 47.0(1)8 to each other. The methyl
group at 3rd position of the piperidine ring is in equatorial
orientation and the orientation angle of this group to the
piperidine ring is 70.0(3)°. This equatorial substitution is
also supported by the torsion angles [N1–C2–C3–C23=]
177.8(3) and [C23–C3–C4–C5=] 173.8(4)°.
C5–H5B_N8
0.970(4)
0.860(3)
0.970(4)
0.860(4)
0.930(4)
2.838(5)
2.613(5)
3.753(5)
3.427(4)
3.825(4)
2.458(3)
2.247(3)
2.889(2)
2.575(2)
2.927(2)
103.0(3)
105.6(3)
148.9(2)
171.0(2)
162.6(2)
N10–H10A_N7
C5–H5B_Cl2i
N10–H10B_S1ii
C19–H19_S1iii
Equivalent positions: (i) -x ? 1/2 ? 1, y ? 1/2, -z ? ‘, (ii)
-x ? 2, -y ? 1, -z, (iii) x, y - 1, z
Packing Features
in crystal packing. Here N–H_N intramolecular hydrogen
bond stabilizes the molecular conformation of the thio-
semicarbazone moiety. Similar intramolecular hydrogen
bonds have been observed in some of the thiosemicarba-
zones [27, 28]. The pair of intermolecular N–H_S
hydrogen bonds across the center of inversion results in the
formation of dimer (Fig. 5). Relevant details of all hydro-
gen bonds are given in Table 2.
The packing of the molecule MBCPT viewed down b-axis
is shown in Fig. 4. C–H_N, N–H_N and N–H_S types
of intra and intermolecular hydrogen bonds play vital roles
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. CCDC740952. 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).
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, S. Korea for its support.
Fig. 4 Packing of the molecules MBCPT viewed down the b- axis.
Dashed lines represent hydrogen bonds
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