Versatile coordination behavior of N,N-di(alkyl/aryl)-N′- benzoylthiourea ligands: Synthesis, crystal structure and cytotoxicity of palladium(II) complexes

Article abstract of DOI:10.1016/j.ica.2011.06.031

The synthesis and characterization of Pd(II) complexes with the general formula cis-[Pd(L-O,S)₂] (HL = N,N-diethyl-N′-benzoylthiourea, N,N-diisobutyl-N′-benzoylthiourea or N,N-dibenzyl-N′- benzoylthiourea) and trans-[PdCl₂(HL-S)₂] (HL = N,N-diphenyl-N′-benzoylthiourea, N,N-di-n-butyl-N′-benzoylthiourea or N,N-diisopropyl-N′-benzoylthiourea) are reported. These complexes were formed from the reaction between PdCl₂ and N,N-di(alky/aryl)- N′-benzoylthiourea in acetonitrile with the formulation dependent on the nature of HL. The new Pd(II) complexes have been characterized by analytical and spectral (FT-IR, UV-Vis, ¹H NMR and ¹³C NMR, Mass) techniques. The molecular structures of two of the complexes (1 and 5) have been conformed by X-ray crystallography. Complex 1 shows cytotoxicity against human breast cancer cells.

Full text of DOI:10.1016/j.ica.2011.06.031

Inorganica Chimica Acta 376 (2011) 278–284
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Inorganica Chimica Acta
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Versatile coordination behavior of N,N-di(alkyl/aryl)-N0-benzoylthiourea
ligands: Synthesis, crystal structure and cytotoxicity of palladium(II) complexes
N. Selvakumaran a, Seik Weng Ng b, Edward R.T. Tiekink b, R. Karvembu a,
⇑
a Department of Chemistry, National Institute of Technology, Tiruchirappalli 620015, India
b Department of Chemistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 8 March 2011
Received in revised form 10 June 2011
Accepted 16 June 2011
Available online 23 June 2011
The synthesis and characterization of Pd(II) complexes with the general formula cis-[Pd(L-O,S)2] (HL = N,N-
diethyl-N0-benzoylthiourea, N,N-diisobutyl-N0-benzoylthiourea or N,N-dibenzyl-N0-benzoylthiourea) and
trans-[PdCl2(HL-S)2] (HL = N,N-diphenyl-N0-benzoylthiourea, N,N-di-n-butyl-N0-benzoylthiourea or N,N-
diisopropyl-N0-benzoylthiourea) are reported. These complexes were formed from the reaction between
PdCl2 and N,N-di(alky/aryl)-N0-benzoylthiourea in acetonitrile with the formulation dependent on the
nature of HL. The new Pd(II) complexes have been characterized by analytical and spectral (FT-IR,
UV–Vis, 1H NMR and 13C NMR, Mass) techniques. The molecular structures of two of the complexes (1
and 5) have been conformed by X-ray crystallography. Complex 1 shows cytotoxicity against human breast
cancer cells.
Keywords:
Palladium(II)
Thiourea
Synthesis
X-ray structures
Anti-cancer activity
Ó 2011 Elsevier B.V. All rights reserved.
1. Introduction
reaction was carried out between PdCl2 and N,N-di(alkyl/aryl)-N0-
benzoylthiourea ligand. N,N-di(ethyl/isobutyl/benzyl)-N0-ben-
We are currently interested in the coordination chemistry of N,N-
di(alkyl/aryl)-N0-benzoylthiourea ligands (Fig. 1) in view of their
interesting and versatile coordination behavior towards transition
metals [1,2]. Three different coordination modes have been found
so far for this type of ligand in their mononuclear transition metal
complexes. They are monobasic bidentate (O,S) [3], neutral mono-
dentate (S) [4] and neutral bidentate (O,N) [5]. Among these, mono-
basic bidentate (O,S) coordination is very common and leads to
stable Pd(II) [6,7], Cu(II) [8], Pt(II) [9,10], Co(III) [10], Rh(III) [11],
Ni(II) [10,12] and Co(II) [12] complexes. On the other hand, coordi-
nation through S only is rare and observed in few transition metal
complexes. When present, the monodentate coordination was ex-
plained on the basis of intramolecular hydrogen bond formation be-
tween the carbonyl O atom and the thiourea NH group (Fig. 2) [13].
This is true in their Pt(II) [14], Pd(II) [13], Cu(I) [15] and Cd(II) [16]
complexes. There are very few reports in which N,N-di(alkyl/aryl)-
N0-benzoylthiourea ligands that is without the thiourea NH moiety,
where coordinated to the metal is through S only [17,18]. The reac-
tion between Pd(II) salts and N,N-di(alkyl/aryl)-N0-benzoylthiourea
ligands (HL) have so far yielded only complexes of the type cis-
[Pd(L-O,S)2] [6–8]. Interestingly, we were able to obtain Pd(II)
complexes of the type cis-[Pd(L-O,S)2] or trans-[Pd(HL-S)2] when
zoylthiourea ligands gave cis-[Pd(L-O,S)2] and N,N-di(phenyl/n-bu-
tyl/isopropyl)-N0-benzoylthiourea ligands formed trans-[PdCl2(HL-
S)2] on reaction with PdCl2 in acetonitrile. It was already realized
that N-substituents can influence the coordination mode of ligand;
for example, coordination of dimethyl substituted ferrocene car-
bonyl thiourea (HL0) to Cu(II) ion differed substantially from that
of the corresponding diethyl substituted analog (HL00). The former
yielded a bis-sulfur bridged Cu(II) dimer, [{CuL0(HL0)Cl}2] [17] while
the latter only coordinated in a bidentate manner to yield a single
mononuclear Cu(II) complex [CuL002] [19].
N,N-Di(alkyl/aryl)-N0-benzoylthiourea ligands were effectively
utilized for liquid–liquid extraction of the platinum group metals
from hydrochloric acid solutions [20–23]. The determination of
traces of the platinum group metals by means high performance
thin layer chromatography (HPTLC) after complexation with suit-
ably modified fluorescent N-aroylthiourea has also been of interest
[24–27]. Recently N,N-diethyl-N0-benzoylthiourea has been used
for the selective online preconcentration and highly selective trace
determination of Pd(II) by means of graphite furnace atomic
absorption spectroscopy [28].
Transition metal complexes with thiourea derivatives are also
known to exhibit a wide range of biological activities such as antivi-
ral, antibacterial, antifungal, anticancer, antitubercular, antithyroi-
dal, insecticidal, antimalarial, etc. [29–33]. N-Substituents not only
influenced the coordination behavior of ligands but also the chemi-
cal and physical properties of its complexes. Indeed cytotoxicity
⇑
Corresponding author. Tel.: +91 4312503636; fax: +91 431 2500133.
E-mail address: kar@nitt.edu (R. Karvembu).
0020-1693/$ - see front matter Ó 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2011.06.031

N. Selvakumaran et al. / Inorganica Chimica Acta 376 (2011) 278–284
279
O
N
mixture was stirred for 5 h. The red crystalline precipitate that
formed was filtered and washed with diethyl ether and then dried
in vacuum. Crystals of suitable quality for X-ray diffraction studies
were obtained by slow evaporation of its dichloromethane solu-
tion. Yield: 76%. m.p.: 134 °C. Anal. Calc. for C24H30N4O2PdS2: C,
49.96; H, 5.24; N, 9.71; S, 11.11. Found: C, 49.45; H, 4.97; N,
R
N
S
R
H
R
Abbreviation
HL1
9.45; S, 11.02%. IR (KBr)
UV–Vis (CH2Cl2) kmax (nm) (
240 (51 486). 1H (400 MHz, CDCl3)
m
/cmꢀ1: 1585 (
/dm3 molꢀ1 cmꢀ1): 274 (74 383),
(ppm): 1.28–1.32 (t,
mC'O), 1247 (mC'S).
e
C2H5
d
(CH3)2CHCH2
C6H5CH2
C6H5
HL2
J = 8.0 Hz, 12H, CH3), 3.83–3.87 (m, 8H, CH2), 7.39–8.30 (m, 10H,
aromatic). 13C NMR (400 MHz, CDCl3) d (ppm): 12.6, 13.1, 46.1,
47.2, 127.9, 129.6, 131.5, 137.1, 170.6, 171.0. MS (MALDI) m/z
616.95 [(1) K]+.
HL3
HL4
CH3(CH2)3
(CH3)2CH
HL5
2.3. Synthesis of cis-[Pd(L2-O,S)2] (2)
HL6
Complex 2 was prepared by a similar procedure as described for
1 from HL2 (0.351 g, 1.2 mmol) and PdCl2 (0.106 g, 0.6 mmol).
Yield: 87%. m.p.: 153 °C. Anal. Calc. for C32H46N4O2PdS2: C, 55.76;
H, 6.73; N, 8.13; S, 9.30. Found: C, 55.34; H, 6.48; N, 7.98; S,
Fig. 1. Structure of N,N-di(alkyl/aryl)-N0-benzoylthiourea ligands.
9.04%. IR (KBr)
(CH2Cl2) kmax (nm)
(42 575). 1H NMR (400 MHz, CDCl3)
m
/cmꢀ1: 1586 (
m
C'O), 1230 (
/dm3 molꢀ1 cmꢀ1): 276 (58 334), 241
(ppm): 0.91–0.99 (d,
mC'S). UV–Vis
(e
d
J = 8.0 Hz, 24H, CH3), 2.26–2.29 (m, 4H, CH), 3.64–3.68 (m, 8H,
CH2), 7.41–8.25 (m, 10H, aromatic). 13C NMR (400 MHz, CDCl3) d
(ppm): 20.3, 20.4, 27.4, 27.7, 60.3, 61.2, 127.9, 129.6, 131.4,
137.0, 170.3, 172.3. MS (MALDI) m/z 689.13 [M]+.
Fig. 2. Structure of N-benzoyl-N0-propylthiourea containing thiourea NH moiety
which forms an intramolecular hydrogen bond with the proximate carbonyl atom
(indicated by dashed line).
2.4. Synthesis of cis-[Pd(L3-O,S)2] (3)
Complex 3 was prepared by a similar procedure as described for
1 from HL4 (0.433 g, 1.2 mmol) and PdCl2 (0.106 g, 0.6 mmol).
Yield: 77%. m.p.:198 °C. Anal. Calc. for C44H38N4O2PdS2: C, 64.03;
H, 4.64; N, 6.79; S, 7.77. Found: C, 63.95; H, 4.36; N, 6.45; S,
studies using HeLa cancer cell lines have demonstrated that some of
the platinum acylthioureas showed cytotoxicity behavior with their
antiproliferative effects being dependent on the nature/type of the
substituent on the acyl thiourea ligand [9]. On the basis of the struc-
tural and thermodynamic analogy between Pt(II) and Pd(II) com-
plexes [34–38], there is also much interest in the design and
synthesis of Pd(II) derivatives capable of interacting with biomole-
cules producing a pharmacological action [39]. Furthermore, some
mixed ligand Pd(II) complexes have been shown to act as potential
anticancer agents [40–47]. In this context, we have also studied anti-
cancer activity of Pd(II) complexes containing N,N-di(alkyl/aryl)-N0-
benzoylthiourea ligand.
7.44%. IR (KBr)
(CH2Cl2) kmax (nm)
m
/cmꢀ1: 1541 (
/dm3 molꢀ1 cmꢀ1): 278 (69 199), 240
mC'O) 1251 (mC'S). UV–Vis
(e
(44 482). 1H NMR (400 MHz, CDCl3) d (ppm): 5.04 (s, 4H, CH2),
5.13 (s, 4H, CH2), 7.28–7.52 (m, 36, aromatic), 8.23 (d, J = 7.2 Hz,
4H, aromatic), 13C NMR (400 MHz, CDCl3) d (ppm): 52.4, 54.5,
127.7, 136.8, 172.1, 174.2. MS (MALDI) m/z 864.98 [M]+.
2.5. Synthesis of trans-[PdCl2(HL4-S)2] (4)
Complex 4 was prepared by a similar procedure as described for
1 from HL4 (0.399 g, 1.2 mmol) and PdCl2 (0.106 g, 0.6 mmol).
Yield: 78%. m.p.: 190 °C. Anal. Calc. for C40H32N4O2Cl2PdS2: C,
57.05; H, 3.83; N, 6.65; S, 7.60. Found: C, 56.89; H, 3.67; N, 6.45;
2. Experimental
2.1. Materials and physical measurements
S, 7.47%. IR (KBr)
UV–Vis (CH2Cl2) kmax (nm) (
m
/cmꢀ1: 3415 (
m
N–H), 1699 (
mC@O), 1243 (mC@S).
PdCl2 and ligand precursors were of reagent grade and used
without further purification. The N,N-di(alkyl/aryl)-N0-ben-
zoylthiourea derivatives were prepared according to previously
published method [1,2]. The solid state IR spectra were recorded
in the range 4000–400 cmꢀ1 on a PerkinElmer FT-IR spectropho-
tometer with KBr pellets. All the 1H and 13C NMR spectra were re-
corded, using CDCl3 as solvent and TMS as internal standard on a
Bruker 400 MHz NMR spectrometer. MALDI-TOF mass spectrome-
try experiments were performed on a 4800-Applied Bio System
mass spectrometer, using TiO2 as matrix. Electronic spectra of
the complexes were recorded on a T90 + PG instruments UV–Vis
spectrophotometer using dichloromethane as a solvent.
e
/dm3 molꢀ1 cmꢀ1): 284 (52 184), 228
(52 923). 1H NMR (400 MHz, CDCl3) d (ppm): 7.30–7.34 (m, 20H,
aromatic), 7.37–7.77 (m, 10H, aromatic), 11.95 (s, 2H, NH). 13C
NMR (400 MHz, CDCl3) d (ppm): 128.9, 129.6, 134.5, 137.1, 164.2,
170.3. MS (MALDI) m/z 808.93 [M]+.
2.6. Synthesis of [trans-[PdCl2(HL5-S)2] (5)
Complex 5 was prepared by a similar procedure as described for
1 from HL5 (0.351 g, 1.2 mmol) and PdCl2 (0.106 g, 0.6 mmol).
Yield: 72%. m.p.:148 °C. Anal. Calc. for C32H48Cl2N4O2PdS2: C,
50.43; H, 6.35; N, 7.35; S, 8.41. Found: C, 50.10; H, 6.09; N, 7.01;
2.2. Synthesis of cis-[Pd(L1-O,S)2] (1)
S, 8.28%. IR (KBr)
UV–Vis (CH2Cl2) kmax (nm) (
(48 098). 1H NMR (400 MHz, CDCl3)
m
/cmꢀ1: 3120 (
m
N–H), 1694 (
/dm3 molꢀ1 cmꢀ1): 275 (65 926), 240
(ppm): 0.99–1.18 (t,
mC@O), 1251 (mC@S),
e
Ligand (HL1) (0.284 g, 1.2 mmol) dissolved in acetonitrile
(20 ml) was added drop wise to an acetonitrile solution (20 ml)
of PdCl2 (0.106 g, 0.6 mmol) at room temperature and the resulting
d
J = 7.2 Hz, 12H, CH3), 1.19–1.46 (m, 8H, CH2), 1.59–1.82 (m, 8H,
CH2), 3.43–3.87 (m, 8H, CH2), 7.41–8.12 (m, 10H, C6H5), 11.4 (s,

280
N. Selvakumaran et al. / Inorganica Chimica Acta 376 (2011) 278–284
2H, NH). 13C NMR (400 MHz, CDCl3) d (ppm): 13.1, 13.8, 20.1, 20.3,
2.8. X-ray crystallography
28.6, 29.7, 55.2, 53.4, 128.9, 129.1, 131.4, 133.5, 163.4, 178.2.
Crystals of 1 and 5 suitable for X-ray diffraction were grown
from their respective dichloromethane solutions. X-ray diffraction
measurements of 1 and 5 were performed on a Bruker SMART
APEX-II CCD diffractometer and Agilent Supernova dual diffrac-
tometer with Atlas (Mo) detector, respectively, using graphite
2.7. Synthesis of trans-[PdCl2(HL6-S)2] (6)
Complex 6 was prepared by a similar procedure as described for
1 from HL6 (0.317 g, 1.2 mmol) and PdCl2 (0.106 g, 0.6 mmol).
Yield: 82%. m.p.: 126 °C. Anal. Calc. for C28H40N4O2Cl2PdS2: C,
47.63; H, 5.71; N, 7.94; S, 9.08. Found: C, 47.38; H, 5.45; N, 7.58;
monochromatized Mo Ka radiation so that hmax was 27.5°. Crystal
data are given in Table 1. The structures were solved by direct-
methods (SHELXS-86 [48]) and refined (anisotropic displacement
parameters, H atoms in the riding model approximation and a
S, 8.87%. IR (KBr)
UV–Vis (CH2Cl2) kmax (nm) (
m
/cmꢀ1: 3164 (
m
N–H), 1677 (
mC@O), 1266 (mC@S).
e
/dm3 molꢀ1 cmꢀ1): 278 (61 323), 244
weighting scheme of the form w = 1/[r
2(Fo2) + aP2 + bP] where
(44 268). 1H NMR (400 MHz, CDCl3) d (ppm): 1.28–1.72 (m, 24H,
CH3), 4.39–4.40 (m, 4H, CH), 7.30–8.03 (m, 10H, C6H5), 11.3 (s,
2H, NH). 13C NMR (400 MHz, CDCl3) d (ppm): 20.2, 21.1, 54.3,
54.8, 128.1, 128.9, 129.20, 130.1, 164.4, 170.4.
P = (Fo2 + 2Fc2)/3) with SHELXL-97 on F2 [48]. The molecular struc-
tures are shown in Figs. 3 and 4 which were drawn with displace-
ment ellipsoids at the 70% probability level [49]. The crystal
packing diagrams were drawn with DIAMOND [50] using arbitrary
spheres.
Table 1
Crystal data for 1 and 5.
2.9. Cell culture
Crystal data
1
5
MCF 7 (human breast cancer cell line, NCCS Pune) and L929
(mouse fibroblast cell line, NCCS Pune) were maintained in mini-
mum essential medium (MEM) supplemented with 10% fetal bo-
vine serum (FBS). The cells were incubated in CO2 incubator with
5% CO2. After attaining confluency, the cells were detached from
the flask with Trypsin-EDTA. The cell suspension was centrifuged
at 3000 rpm for 3 min and then re-suspended in the growth med-
ium for further studies.
Empirical formula
Formula weight
Crystal color
Crystal dimensions (mm)
Crystal system
Lattice type
Space group
a (Å)
C
24H30N4O2PdS2
C32H48Cl2N4O2PdS2
762.16
red
577.04
red
0.20 ꢁ 0.30 ꢁ 0.40
monoclinic
primitive
P21/n
10.2394(5)
18.4336(9)
13.2898(7)
105.138(1)
2421.4(2)
4
1.583
1184
0.968
100(2)
22 469
0.023
5562
5133
0.20 ꢁ 0.25 ꢁ 0.30
monoclinic
primitive
P21/c
11.0344(3)
17.3072(5)
9.4781(3)
93.878(3)
1805.93(9)
2
1.402
792
0.968
295(2)
9254
0.027
4026
3059
b (Å)
c (Å)
b (°)
V (Å3)
2.10. Cytotoxicity experiments
Z
Dx (g cmꢀ3
F(0 0 0)
)
For cytotoxicity experiments, L929 and MCF7 were seeded on a
96 well plate with a density of 10 000 cells/cm2. MTT [3-(4,5-
dimethylthiazole-2-yl)-2,5-diphenyltetrazolium] assay was used
to evaluate cytotoxicity of the HL1 and 1. This is a colorimetric test
based on the selective ability of viable cells to reduce the tetrazo-
lium component of MTT into purple colored formazan crystals.
Three different concentrations of the samples (1, 5 and 10 mg/
ml) were prepared by dilution with the media. After attaining
90% confluency, the cells were washed with phosphate buffer sal-
l
(Mo K
a
) (mmꢀ1
)
Temperature (K)
Reflections collected
Rint
Unique reflections
Obs. reflections [I > 2
R (Obs. reflections)
r(I)]
0.022
0.029, 2.089
0.058
0.039
0.047, 0.764
0.106
a, b, in weighting scheme
wR (all data)
ine (PBS) and the compounds of different concentrations (100 ll)
Fig. 3. Molecular structure of 1 showing atomic labeling scheme.

N. Selvakumaran et al. / Inorganica Chimica Acta 376 (2011) 278–284
281
Fig. 4. Molecular structure of 5 showing atomic labeling scheme. The primed atoms are related by the symmetry operation 1 ꢀ x, 1 ꢀ y, 1 ꢀ z.
were added and incubated. Cells in media alone devoid of com-
pound acted as negative control and wells treated with Triton X-
100 as positive control for a period of 24 h. 5 mg of MTT (Sigma)
complexes are air stable and soluble in common organic solvents
such as CHCl3, CH2Cl2, DMSO and DMF.
was dissolved in 1 ml of PBS and filter sterilized. 10
MTT solution was further diluted to 100 l with 90 l of serum
and phenol red free medium. The cells were incubated with
100 l of the above solution for 4 h to form formazan crystals by
mitochondrial dehydrogenases. 100 l of the solubilization solu-
tion (10% Triton X-100, 0.1 N HCl and isopropanol) was added in
each well and incubated at room temperature for 1 h to dissolve
the formazan crystals. The optical density of the solution was mea-
sured at a wavelength of 570 nm using a Beckmann Coulter Elisa
plate reader (BioTek Power Wave XS). Triplicate samples were ana-
lyzed for each experiment.
ll of the
3.1. IR spectra
l
l
The bands at 1652, 1687 and 1689 cmꢀ1 in the IR spectra of HL1,
HL2 and HL3, respectively can be assigned to the C@O stretching
mode of the carbonyl group, which shifted to the lower wave num-
ber (1541–1586 cmꢀ1) upon complexation in 1, 2 and 3. A thionyl
(C@S) vibration band which appeared in the IR spectra of ligands
(1311–1263 cmꢀ1) similarly underwent a shift into lower fre-
quency (1251–1225 cmꢀ1) in their Pd(II) complexes. The NH
stretching vibration in the range 3328–3260 cmꢀ1 for HL1, HL2
and HL3 disappeared in their Pd(II) complexes. The IR data indi-
cates that each ligand underwent enolization followed by deproto-
nation prior to coordination to Pd(II) ion through O and S atoms.
The IR spectra of 4, 5 and 6 showed the following significant
changes when compared with the spectra of corresponding ligands
(HL4, HL5 and HL6). The C@S stretching frequency observed in the
region 1355–1282 cmꢀ1 in the IR spectra of free ligands shifted to
lower frequency (1267–1205 cmꢀ1) in their complexes. For free li-
gands, the stretching frequency in the region 1691–1650 cmꢀ1, as-
signed to the carbonyl moiety, was unaltered in their complexes
indicating non participation of carbonyl oxygen in coordination. Fi-
nally, the NH stretching in the ligands (3383–3174 cmꢀ1) is also
present in the same region in the corresponding Pd(II) complexes
indicating that enolization and deprotonation did not occur. The
IR data revealed that in 4, 5 and 6, the thiourea derivatives are
coordinated through the S atom only.
l
l
3. Results and discussion
The present work deals with the synthesis and characterization
of two different kinds of Pd(II) complexes. Reactions of PdCl2 with
HL1, HL2 or HL3 in acetonitrile gave square planar complexes of
the type cis-[Pd(L-O,S)2] while similar reactions with HL4, HL5 or
HL6 resulted in square planar complexes of the type trans-
[PdCl2(HL-S)2] (Scheme 1). The molar ratio of PdCl2 and ligand
was 1:2 in each case. The complexation reaction was highly selec-
tive in the sense that only one product was formed in each reac-
tion. The structures of the complexes were confirmed by
analytical, spectral and X-ray diffraction studies. The Pd(II) com-
plexes were also subjected to anticancer activity studies. All the
Scheme 1. Synthesis of palladium(II) complexes.

282
N. Selvakumaran et al. / Inorganica Chimica Acta 376 (2011) 278–284
3.2. Electronic spectra
All the complexes are diamagnetic (
leff = 0) indicating +2 oxida-
tion state of metal ion. The electronic spectra of all Pd(II) com-
plexes were recorded in dichloromethane solution. Two bands
were observed in the electronic spectra of 1–6 in the region 228–
284 nm. These bands have been assigned to charge transfer transi-
tions based on their very high molar extinction coefficient values
(42 575–74 383 dm3 molꢀ1 cmꢀ1). This is in accord with other
square planar Pd(II) complexes [51].
3.3. NMR spectra
In the 1H NMR spectra of 1, 2 and 3, the characteristic signal at
11.25–11.95 ppm for N–H observed in the spectra of free ligands,
disappeared, indicating deprotonation prior to coordination
through enolization. By contrast, the resonance due to N–H was
present around 11.30–11.95 ppm in the NMR spectra of 4, 5 and
6, indicating no enolization of ligands HL4, HL5 and HL6 and that
they function as neutral ligand in 4, 5 and 6. Otherwise, the 1H
NMR spectra exhibited the expected resonances, multiplicity and
integration consistent with the respective formulation. In the 13C
NMR spectra of all the complexes, carbonyl and thiocarbonyl car-
bon resonances were observed in the 170.3–178.2 and 163.4–
172.1 ppm range respectively [6].
Fig. 5. Crystal packing diagram for 1 shown in projection down the a axis.
3.4. Crystal structures
polymorphs of the uncoordinated HL1 ligand available in the liter-
ature [52,53] for comparison. Using the data of the most recent
determination [53], it is salient to compare the formally C@S and
C@O double bond distances of 1.67667(13) and 1.2188(14) Å,
respectively, in HL1 with those given in Table 2. Evidently, there
is significant elongation of these bonds in the complex. Further,
the N–C bond distances of the chelate rings [N2–C1 1.345(2) and
N2–C6 1.327(2) Å; N4–C13 1.345(2) and N4–C18 1.326(2) Å] have
considerably shortened compared to the equivalent distances in
HL1 of 1.4184(15) and 1.3868(15) Å, respectively. These results
are consistent with deprotonation of HL1 during the reaction and
The Pd atom in cis-[Pd(L1-O,S)2] (1), is coordinated by two N,N-
diethyl-N0-benzoylthiourea anions via the S and O atoms (Fig. 3).
The Pd atom lies 0.0422(5) Å out of the least-square plane through
the O2S2 donor atoms (rms deviation = 0.012 Å) which define an
approximate square plane; each S atom is trans to an O atom. Each
of the six-membered chelate ring is essentially planar with the rms
for the six atoms defining S1-containing ring being only 0.065 Å
(max. deviation = 0.069(1) Å for the O1 atom) compared to a rms
of 0.134 Å for the second (max. deviation = 0.145(1) Å for the S2
atom) indicating a small distortion towards an envelope conforma-
tion; the dihedral angle formed between the two chelate rings is
1.80(5) Å. Each phenyl ring is effectively co-planar to the chelate
ring to which it is connected as seen in the values of the O1–C6–
C7–C8 and O2–C18–C19–C20 torsion angles of ꢀ179.25(16) and
5.8(2)°, respectively. Indeed, the only significant deviations from
overall planarity in the molecule is found in the orientation of
the N-bound ethyl groups with those connected to the N1 atom ly-
ing to the opposite side of the molecule compared to those bound
to the N2 atom. Taken as a whole, the molecule of 1 approximates
non-crystallographic twofold symmetry. There are two
significant delocalization of p-electron density over the six atoms
comprising the respective chelate rings in the complex. The low
temperature structure determination reported herein resolves lit-
erature ambiguities arising from disorder [6,7] and incorrect com-
position [52]. Molecules of cis-[Pd(L-O,S)2] are consolidated in the
crystal packing by C–H. . .
p
interactions1 involving ethyl-H atoms
interacting with the phenyl rings (Fig. 5) Globally, molecules form
layers in the ac-plane and stack along the b axis being connected
along that axis by C–H. . .
p interactions involving the methylene-
H2a atom and C19–C24 phenyl ring; the remaining interactions1
contribute to the stability of the layers.
The Pd atom in trans-[PdCl2(HL-S)2] (5) is located on a center of
inversion so that the trans-Cl2S2 donor set is planar (Fig. 4). Allow-
ing for differences in the composition of the HL1 and HL5 ligands,
the Pd-S bond distance in 5 is significantly longer than in 1 consis-
tent with the S atom having more thione character in the former.
This is also reflected in the significant shortening of the S1–C8
bond in 5 compared to the equivalent bonds in 1. In the same
way, the carbonyl bond is significantly shorter in 5, consistent with
its non-coordination. The molecular structure described herein for
5 resembles closely that reported for trans-[PdI2(HL-S)2] [54]. The
Table 2
Selected bond lengths (Å) and bond angles (°) for 1 and 5.
1
5
Pd–S1
Pd–S2
Pd–O1
Pd–O2
S1–C1
S2–C13
C6–O1
2.2311(4)
2.2357(4)
2.0135(13)
2.0217(12)
1.7376(18)
1.7392(17)
1.267(2)
Pd–Cl1
Pd–S1
S1–C8
O1–C7
2.3070(9)
2.3178(8)
1.710(3)
1.214(4)
C18–O2
S1–Pd–S2
S1–Pd–O1
S1–Pd–O2
S2–Pd–O1
S2–Pd–O2
O1–Pd–O2
1.264(2)
86.785(16)
93.25(4)
178.34(4)
177.05(4)
93.59(4)
Cl1–Pd–S1
85.52(3)
1
Intermolecular C–H...p interactions operating in the crystal structure of cis-[Pd(L-
O,S)2]. Interactions between supramolecular layers: C2–H2a...Cg(C19-C24)i = 2.86 Å,
C2...Cg(C19-C24)i = 3.738(2) Å, and angle at H2a = 149° for symmetry operation i: 3/2-
x, -1/2 + y, 3/2-z. Interactions within supramolecular layers: C3–H3c...Cg(C19-C24)ii
2.84 Å, 3.556(2) Å, 131° for ii: 1-x, 1-y, 1-z. C4–H4a...Cg(C7-C12)iii 2.95 Å, 3.5135(19)
Å, 117° for iii: 1-x, 1-y, 2-z. C14–H14a...Cg(C7-C12)ii 3.00 Å, 3.6091(18) Å, 121°.
86.30(5)

N. Selvakumaran et al. / Inorganica Chimica Acta 376 (2011) 278–284
283
Fig. 6. Crystal packing diagram for 5 (a) supramolecular chain sustained by p. . .p interactions (shown as purple dashed lines) and (b) view of the stacking of layers along the
c-axis. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
120
24 h on L929
100
80
24 h on MCF7
60
48 h on L929
40
20
48 h on MCF7
0
Fig. 8. Effect of HL1 on the viability of breast cancer cells (all determinations are
expressed as a percentage of the control).
Concentration (mg/ml)
Fig. 7. Effect of 1 on the viability of breast cancer cells (all determinations are
expressed as a percentage of the control).
cancer cells. Cytotoxicity of 1 was compared with that of cispaltin.
At higher concentrations (5 and 10 mg/ml) cisplatin showed higher
toxicity compared to 1 whereas cytotoxicity of 1 was comparable
with that of cisplatin at a concentration of 1 mg/ml [56].
observed molecular conformation in 5 is stabilized by an intramo-
lecular N–H. . .Cl interaction.2 As each of the S1, O1 and N1 atoms
also forms a close intramolecular contact with a C–H atom,2 the
most important intermolecular interactions operating in the crystal
4. Conclusion
structure are of the type p . The latter lead to the formation of
. . .p 2
Pd(II) complexes of N,N-di(alkyl/aryl)-N0-benzoylthiourea have
been synthesized and characterized spectroscopically with two
representative examples examined by X-ray crystallography. N,N-
Di(alkyl/aryl)-N0-benzoylthiourea exhibited two different coordi-
nation modes with Pd(II). Eventhough the present ligands do not
contain thiourea NH moiety, they are able to exhibit neutral mono-
dentate coordination through the S atom in three complexes (4, 5,
and 6). In remaining three complexes (1, 2 and 3), N,N-di(alkyl/
aryl)-N0-benzoylthiourea exhibited normal monobasic O,S biden-
tate coordination. One of the complexes (1) is cytotoxic to MCF cell
lines.
a supramolecular chain along the a-axis (Fig. 6a). Chains are ar-
ranged into layers in the ab-plane and stack along the c-axis (Fig. 6b).
3.5. Cytotoxicity studies
MTT assay was performed to evaluate the anticancer potential
of complexes 1–6. Only complex 1 showed significant activity
against MCF7 cells and cytotoxicity of 1 was compared with that
of ligand HL1. It is very evident that complex 1 at higher concentra-
tion (10 mg/ml) can inhibit the growth of MCF7 cells than at the
lower concentrations of 1 and 5 mg/ml, whereas it did not affect
the normal L929 cells even at higher concentration after 48 h
(Fig. 7). HL1 was less toxic on MCF7 after 24 h (Fig. 8) but was en-
hanced after 48 h exposure. Compared to HL1, complex 1 was
shown to be more toxic on MCF7 at a concentration of 5 and
10 mg/ml after 24 and 48 h. Higher cytotoxicity of complex 1 com-
pared to HL1 suggests that the dual function approach that com-
bines two biological mechanisms via single molecule significantly
improves the biological activity of metal-based drugs [55]. Inter-
estingly, complex 1 showed more than 80% cell viability after
48 h on L929 cells, indicating the possibility of specific toxicity to
Acknowledgements
N.S. acknowledges NITT for fellowship. The authors thank Dr. R.
Jayakumar, Amrita Institute of Medical Sciences, Kochi, India for
useful discussion on cytotoxicity studies. The authors also thank
the University of Malaya for support of the crystallographic facility.
Appendix A. Supplementary material
2
CCDC 809545 and 809546 contain the supplementary crystallo-
graphic data for complexes 5 and 1, respectively. These data can be
obtained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif. Supplementary
data associated with this article can be found, in the online version,
at doi:10.1016/j.ica.2011.06.031.
Intra- and inter-molecular interactions in the crystal structure of trans-[PdCl2(HL-
S)2]. Intramolecular: N1–H1...Cl1i = 2.43 Å, N1–H1...Cl1i = 3.114(3) Å and angle at
H1 = 135° for symmetry operation i: 1-x, 1-y, 1-z; C9–H9a...N1 = 2.39 Å, C9–
H9a...N1 = 2.811(4)
Å and angle at H9a = 105°, C9–H9b...O1 = 2.52 Å, C9–
H9b...O1 = 2.851(4) Å and angle at H9b = 100°; and C14–H14b...S1 = 2.79 Å, C14–
H14b...S1 = 3.315(4) Å and angle at H14b = 115°. Intermolecular: ring centroid(C1-
C6)...ring centroid(C1-C6)ii = 3.847(3) Å for ii: 2-x, 1-y, 1-z.

284
N. Selvakumaran et al. / Inorganica Chimica Acta 376 (2011) 278–284
[32] M. Eweis, S. Elkholy, S. Elsabee, M. Z. Int. J. Biol. Macromol. 38 (2006) 1.
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