Orthometallated versus coordination compounds for reactions of platinum(II) and palladium(II) with the ligand benzil bis(4-methyl-3-thiosemicarbazone)

Article abstract of DOI:10.1016/j.ica.2010.03.014

The ligand benzil bis(4-methyl-3-thiosemicarbazone) LH₂ reacts with K₂PtCl₄, both in the presence or in the absence of LiOH·H₂O, to yield simultaneously the cyclometallated mesocate [Pt₂(μ-L)₂] 1 and the coordination monomeric compound [PtL] 2, which can be easily separated by their different solubility. By contrast, reaction of Li₂PdCl₄ without base leads exclusively to the formation of the coordination compound [PdL] 3, while the use of LiOH·H₂O permits the selective synthesis of the cyclometallated mesocate [Pd₂(μ-L)₂] 4. All the complexes have been characterized by the usual techniques, including X-ray single crystal diffraction that show all the metals to be four-coordinate in a square-planar arrangement, but 2 and 3 with a N₂S₂ environment while in 1 and 4 it is CNS₂. The cytotoxic activity has been evaluated against the human lung carcinoma cell line NCI-H460, but the results show that the complexes are not active in this cell line.

Full text of DOI:10.1016/j.ica.2010.03.014

Inorganica Chimica Acta 363 (2010) 1735–1740
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Orthometallated versus coordination compounds for reactions of platinum(II)
and palladium(II) with the ligand benzil bis(4-methyl-3-thiosemicarbazone)
*
Elena López-Torres , M. Antonia Mendiola
Departamento de Química Inorgánica, C/Francisco Tomás y Valiente 7, Universidad Autónoma de Madrid, Cantoblanco, 28049 Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The ligand benzil bis(4-methyl-3-thiosemicarbazone) LH2 reacts with K2PtCl4, both in the presence or in
Received 6 November 2009
Received in revised form 1 March 2010
Accepted 4 March 2010
the absence of LiOHꢀH2O, to yield simultaneously the cyclometallated mesocate [Pt2(
l-L)2] 1 and the
coordination monomeric compound [PtL] 2, which can be easily separated by their different solubility.
By contrast, reaction of Li2PdCl4 without base leads exclusively to the formation of the coordination com-
pound [PdL] 3, while the use of LiOHꢀH2O permits the selective synthesis of the cyclometallated mesocate
Available online 9 March 2010
[Pd2(l-L)2] 4. All the complexes have been characterized by the usual techniques, including X-ray single
Keywords:
crystal diffraction that show all the metals to be four-coordinate in a square-planar arrangement, but 2
and 3 with a N2S2 environment while in 1 and 4 it is CNS2. The cytotoxic activity has been evaluated
against the human lung carcinoma cell line NCI-H460, but the results show that the complexes are not
active in this cell line.
Bis(thiosemicarbazone)
Orthometallation
Coordination compound
Crystal structure
Ó 2010 Elsevier B.V. All rights reserved.
1. Introduction
tential anticancer agents. Within this kind of ligands the bis(thio-
semicarbazones) are by far the less studied. A search in the
Since Rosenberg’s discovery of cisplatin cytotoxic activity in the
1960s the preparation of metallocomplexes with potential antitu-
mor activity has been one of the main challenges of transition me-
tal chemistry. As a consequence, thousands of cisplatin analogs
have been synthesized by varying the nature of the leaving groups
and the carrier ligands [1–4]. Nowadays, not only platinum-con-
taining complexes are extensively studied with the aim of broad-
ening the spectrum of transition metal-based complexes that
could be used in the treatment of cancer. Mainly due to the similar
structural properties, palladium(II) complexes were tested on var-
ious cancer cells among the first of the non-platinum metallocom-
plexes [5,6]. In addition, platinum and palladium complexes, in
particular organometallic derivatives, have applications in catalytic
and synthetic processes [7,8], as chiral auxiliaries [9] or as building
blocks for molecular architectures of higher complexity [10]. They
also show interesting mesogenic [11,12] and luminescent and elec-
tronic properties [13,14].
Cambridge Structural Database showed that while there are 83
crystal structures of palladium(II) complexes with TSC ligands only
four of them are with a bis(thiosemicarbazone) [23–26]. The same
situation is found for platinum(II) complexes, where only three of
the 28 found contain a bis(thiosemicarbazone) [26–28].
When the TSC ligand contains an aromatic ring attached to the
imine carbon atom, the possibility of orthometallation versus
bidentate N,S coordination is always present. For bidentate mon-
otiosemicarbazones the cyclometallation is normally found, since
the CNS coordination induces the formation of two fused chelate
rings. By contrast, in the bis(thiosemicarbazone) ligands the forma-
tion of the C–M bond avoids the tetradentate chelate coordination
mode. Therefore, for this kind of ligands the factors involving the
synthesis of orthometallated over coordination compounds are still
unclear and, as far as we know, there is only one report of a
bis(TSC) that show the two coordination behaviours with the same
metal ion. Nevertheless, a selective synthesis procedure has not
been described, since both compounds are obtained under the
same reaction conditions [23,26].
Following our interest in the synthesis and the structural fea-
tures of metal complexes with bis(thiosemicarbazone) ligands
[29–32], here we report the preparation and characterisation of
four orthometallated and coordination compounds of platinum(II)
and palladium(II) with the potentially tetradentate ligand benzil
bis(4-methyl-3-thiosemicarbazone). The cytotoxic activity of the
new derivatives against the human lung cancer cell line NCI-
H460 has been also evaluated.
Thiosemicarbazone ligands (TSCs) possess antiviral, antimalar-
ial, antifungal, antimicrobial and antitumor activity and they are
among the most potent inhibitors of the ribonucleotide reductase
activity [15–22]. These activities are normally increased upon
coordination, so they are suitable ligands for the synthesis of po-
* Corresponding author. Tel.: +34 914972376; fax: +34 914974833.
E-mail addresses: elena.lopez@uam.es (E. López-Torres), antonia.mendio-
la@uam.es (M.A. Mendiola).
0020-1693/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.ica.2010.03.014

1736
E. López-Torres, M.A. Mendiola / Inorganica Chimica Acta 363 (2010) 1735–1740
[PdL] 3: To a solution of 100 mg (0.26 mmol) of LH2 in 15 mL of
2. Experimental
2.1. Measurements
ethanol were added 68 mg (0.26 mmol) of Li2PdCl4 synthesized
in situ by reaction of 46 mg (0.26 mmol) of PdCl2 with 44 mg
(1.03 mmol) of LiCl in 15 mL of the same solvent. The solution
was stirred at room temperature for 3 h and the green precipitate
formed was filtered off, washed with ethanol and diethyl ether and
dried in vacuum (119 mg, 94%). Calc. for C18H18N6S2Pd (488.52): C,
44.21; H, 3.71; N, 17.20; S, 13.09. Found: C, 44.02; H, 3.72; N,
17.04; S, 12.96%. 1H NMR (300 MHz, D6-DMSO, ppm): d = 8.00 (br
s, 2H, NHMe); 7.18–7.13 (m, 10H, Ph); 2.68 (s, 6H, Me). 13C NMR
(300 MHz, D6-DMSO, ppm): d = 179.0 (CS); 156.1 (CN), 131.4,
130.3, 129.6, 127.5 (Ph), 33.8 (Me). IR (KBr, cmꢁ1): 3368s, 3328s
Microanalyses were carried out using a LECO CHNS-932 Elemen-
tal Analyzer. IR spectra in the 4000–400 cmꢁ1 range were recorded
as KBr pellets on a Jasco FT/IR-410 spectrophotometer. Electrospray
mass spectrometry experiments were performed with an ion trap
instrument LCQ Deca XP plus (Thermo Instruments). An ESI source
was used in positive ionization mode. The instrumental parameters
were set as follows: mass range scanned from m/z 500–2000; source
voltage (kV): 4.5; sheath gas flow rate: 11; capillary temperature
(°C): 250; capillary voltage (V): 38 and tube lens voltage (V): 30.
1H and 13C NMR spectra were recorded on a spectrometer Bruker
AMX-300 using D6-DMSO as solvent and TMS as internal reference.
m
(NH), 1600w m(CN), 1552s (thioamide II), 810w m
(CS). MS (ESI+):
m/z = 488.0 [M+H]+. Single crystals suitable for X-ray analysis were
obtained by slow evaporation of a solution in ethanol/acetonitrile
1:1.
[Pd2(l-L)2] 4: the complex was synthesised following the same
2.2. Materials
procedure described for 3 but adding 22 mg (0.52 mmol) of
LiOHꢀH2O and stirring for 12 h. The orange solid formed was fil-
tered off, washed with ethanol and diethyl ether and dried in vac-
uum (112 mg, 85%). Calc. for C36H36N12S4Pd2 (977.05): C, 44.21; H,
3.71; N, 17.20; S, 13.09. Found: C, 44.46; H, 3.73; N, 17.12; S, 12.27.
1H NMR (300 MHz, D6-DMSO, ppm): d = 10.39 (s, 2H, NH); 9.30 (q,
2H, NHMe); 9.22 (q, 2H, NHMe); 7.84 (t, 4H, Ph); 7.42–7.41 (m, 6H,
Ph); 7.17 (d, 2H, Ph); 6.68 (t, 2H, Ph); 6.35 (t, 2H, Ph); 6.29 (d, 2H,
Ph); 3.18 (d, 6H, Me); 3.15 (d, 6H, Me). 13C NMR (300 MHz, D6-
DMSO, ppm): d = 172.4, 172.1 (CS), 147.7, 146.9 (CN); 134.5,
133.0, 130.8, 130.6, 130.3, 129.1, 128.0, 127.9, 127.5, 124.4 (Ph);
1,2-Diphenylethanedione (benzil), 4-methyl-3-thiosemicarba-
zide, potassium tetrachloroplatinate(II), palladium(II) chloride,
lithium hydroxide monohydrate and lithium chloride were pur-
chased from Aldrich and used as received.
2.3. Synthesis of the compounds
Benzil bis(4-methyl-3-thiosemicarbazone) LH2 was synthesized
following the previously reported procedure [33]. Selected spectro-
scopic data: 1H NMR (300 MHz, D6-DMSO, ppm): d = 9.85 (s, 2H,
NH); 8.89 (q, 2H, NHMe); 7.72 (m, 4H, Ph); 7.38 (m, 6H, Ph); 3.01
(d, 6H, Me). 13C NMR (300 MHz, D6-DMSO, ppm): d = 178.6 (CS);
140.4 (CN); 133.2, 130.3, 129.0, 126.8 (Ph); 31.5 (Me). IR (KBr):
33.7, 32.3 (Me). IR (KBr, cmꢁ1): 3373s, 3204s
m(NH), 1568s (thio-
amide II), 869w, 846w
m
(CS). MS (ESI+): m/z = 979.00 [M+H]+,
489.0 [PdL+H]+. Single crystals suitable for X-ray diffraction were
obtained by slow evaporation of a solution in DMF.
3435s and 3335s
845w (CS).
[Pt2( -L)2] 1 and [PtL] 2: a solution of 81 mg (0.195 mmol) of
m(NH), 1601w m(CN), 1546s (thioamide II),
m
2.4. Crystallography
l
K2PtCl4 in 4 mL of distilled water was added to a solution of
75 mg (0.19 mmol) of LH2 and 16 mg (0.38 mmol) of LiOHꢀH2O dis-
solved in 14 mL of ethanol and the reaction mixture was refluxed
for 24 h. The red solid formed was filtered off, washed with dis-
tilled water, ethanol and diethyl ether and dried in vacuum to yield
Data for complexes 1–4 were acquired using a Bruker AXS Kap-
pa Apex-II diffractometer equipped with an Apex-II CCD area
detector using a graphite monochromator (Mo K
a radiation,
k = 0.71073 Å). The substantial redundancy in data allows empiri-
cal absorption corrections (SADABS) [34] to be applied using multiple
measurements of symmetry-equivalent reflections. The raw inten-
sity data frames were integrated with the SAINT program, which also
applied corrections for Lorentz and polarization effects [35].
The software package SHELXTL version 6.10 was used for space
group determination, structure solution and refinement. The struc-
tures were solved by direct methods (SHELXS-97) [36], completed
with difference Fourier syntheses, and refined with full-matrix
87 mg (77%) of [Pt2(l-L)2] 1. Calc. for C36H36N12S4Pt2 (1154.37): C,
37.42; H, 3.14; N, 14.56; S, 11.08. Found: C, 37.21; H, 3.24; N,
14.87; S, 11.21%. 1H NMR (300 MHz, D6-DMSO, ppm): d = 10.50
(s, 2H, NH); 9.32 (q, 2H, NHMe); 9.27 (q, 2H, NHMe); 7.86–7.60
(m, 4H, Ph); 7.43–7.41 (m, 6H, Ph); 7.20 (d, 2H, Ph); 6.75 (t, 2H,
Ph); 6.62 (t, 2H, Ph); 6.20 (d, 2H, Ph); 3.20 (d, 6H, Me); 3.16 (d,
6H, Me). 13C NMR (300 MHz, D6-DMSO, ppm): d = 170.5, 169.8
(CS), 146.4, 145.9 (CN); 133.9, 132.4, 130.2, 130.0, 128.9, 128.8,
127.8, 127.5, 127.3, 126.6 (Ph); 33.2, 31.9 (Me). IR (KBr, cmꢁ1):
least squares using SHELXL-97 minimizing
x
(F2o ꢁ F2c ). Weighted R
factors (Rw) and all goodness of fit S are based on F2; conventional
R factors (R) are based on F [37]. All non-hydrogen atoms were re-
fined with anisotropic displacement parameters and the hydrogen
atoms were positioned geometrically. All scattering factors and
anomalous dispersions factors are contained in the SHELXTL 6.10 pro-
gram library. Main crystallographic data and refinement are sum-
marised in Table 1.
3367s, 3334s m(NH), 1570s (thioamide II), 862w, 849w m(CS). MS
(ESI+): m/z = 1155.0 [M+H]+, 578.0 [PtL+H]+. Single crystals suitable
for X-ray diffraction were obtained by slow evaporation of a solu-
tion in DMF.
The mother liquor was allowed to evaporate slowly until red
crystals suitable for X-ray analysis of [PtL] 2 were formed, which
were filtered off, washed with diethyl ether and vacuum dried
(20 mg, 18%). Calc. for C18H18N6S2Pt (577.18): C, 37.42; H, 3.14;
N, 14.56; S, 11.08. Found: C, 37.53; H, 3.30; N, 14.58; S, 11.25%.
1H NMR (300 MHz, D6-DMSO, ppm): d = 8.10 (br s, 2H, NHMe);
7.25–7.01 (m, 10H, Ph); 2.82 (s, 6H, Me). 13C NMR (300 MHz,
D6-DMSO, ppm): d = 180.7 (CS); 157.3 (CN), 131.6, 130.2, 129.3,
2.5. In vitro cytotoxic activity
The human lung carcinoma cell lines NCI-H460 used in this
study were grown in RPMI 1640 medium supplemented with
10% fetal bovine serum (FBS) and 2 mM L-glutamine in an atmo-
127.7 (Ph), 33.6 (Me). IR (KBr, cmꢁ1): 3349s
m
(NH), 1591w
m
(CN),
sphere containing 5% of CO2 at 37 °C.
1550s (thioamide II), 811w
m
(CS). MS (ESI+): m/z = 599.05
Cell proliferation was evaluated by the sulforhodamine B assay.
[M+Na]+, 577.1 [M+H]+.
NCI-H460 cells were seeded in 96-well sterile microplates with a
When the reaction was made without lithium hydroxide both
complexes were also formed but the reaction was not completed.
density of 1.5 ꢀ 104 cells per well with 100
lL of medium and were
incubated for 24 h. The cells were incubated for 96 h at 37 °C with

E. López-Torres, M.A. Mendiola / Inorganica Chimica Acta 363 (2010) 1735–1740
1737
Table 1
Crystallographic data for complexes 1ꢀ2DMF, 2, 3 and 4ꢀ2DMF.
1ꢀ2DMF
2
3
4ꢀ2DMF
Formula
Mw
C48H64N16O4Pt2S4
1447.57
C18H18N6PtS2
577.59
C18H18N6PdS2
488.90
C48H64N16O4Pd2S4
1270.19
Crystal system
Space group
a (Å)
b (Å)
c (Å)
triclinic
P1
orthorhombic
P212121
9.9036(6)
10.0039(6)
19.5031(11)
90
90
90
1932.3(2)
4
1.985
7.494
19 968
5850 [Rint = 0.0494]
0.0394/0.0892
1.099
orthorhombic
P212121
9.9500(6)
10.0000(6)
19.8560(12)
90
90
90
1975.7(2)
4
1.644
1.166
19 367
4033 [Rint = 0.0512]
0.0299/0.0619
1.050
triclinic
P1
ꢀ
ꢀ
10.9309(9)
11.5788(10)
11.6509(10)
93.768(5)
98.693(5)
111.642(5)
1343.0(2)
1
1.790
5.418
23 372
5893 [Rint = 0.0483]
0.0383/0.0940
1.184
11.0508(5)
11.6967(5)
11.8934(6)
94.086(2)
97.680(2)
112.202(2)
1398.09(11)
1
1.509
0.850
53 620
6417 [Rint = 0.0492]
0.0383/0.0982
1.120
a
(°)
b (°)
c
(°)
U (Å3)
Z
Dcalc (g cmꢁ3
)
Absorption coefficient (mmꢁ1
Reflections collected
Independent reflections
Final R1/wR2
)
Goodness of fit
Flack parameter
0.003(10)
0.00(3)
different concentrations of the compounds dissolved in DMSO
(1 mg/mL) and diluted to the same DMSO final concentration of
1%, which was found to be non toxic for the cells tested. The cells
[Pt2(l-L)2] 1 and the coordination compound [PtL] 2, which can
be easily isolated due to their different solubility in ethanol. Reac-
tion without basic medium yields compounds 1 and 2 but the reac-
tion is not complete and the complexes are impure for unreacted
ligand. By contrast, the analogue palladium derivatives can be
selectively synthesised choosing the adequate reaction conditions.
Thus, complex [PdL] 3 can be obtained from Li2PdCl4 generated
were fixed by adding 50 lL of 30% trichloroacetic acid (TCA) per
well. The plates were incubated at 4 °C for 1 h and then washed
five times with distilled water. The cellular material fixed with
TCA was stained with 0.4% sulforhodamine B dissolved in 1% acetic
acid for 10 min. Unbound dye was removed by rinsing with 0.1%
acetic acid. The protein-bound dye was extracted with 10 mM
unbuffered Tris base for determination of optical density (at
515 nm) in a Tecan Ultra Evolution spectrophotometer.
in situ by PdCl2 and LiCl in ethanol, while complex [Pd2(l-L)2] 4
is synthesised in the same conditions but in the presence of
LiOHꢀH2O, and to difference with platinum reactions, do not need
refluxing of the solvent (Scheme 1).
The effects of the complexes were expressed as corrected per-
centage inhibition values according to the following equation:
The analytical data confirm the ligand to metal ratio as well as
the absence of Cl ligands. The mass spectra of all the complexes ex-
hibit the peak [ML+H]+, which corresponds to the molecular ion in
complexes 2 and 3. In complexes 1 and 4 also the peak [M2L2+H]+
can be observed, suggesting the formation of dimeric species. For
all the peaks the found and calculated isotopic patterns are
identical.
% inhibition ¼ ½1 ꢁ ðT=CÞꢂ ꢃ 100
where T is the mean absorbance of the treated cells and C the mean
absorbance in the controls.
For comparison purposes, the cytotoxicity of cisplatin was eval-
uated under the same experimental conditions. All the compounds
were tested in two independent studies with triplicate points. The
in vitro studies were performed at the Screening Unit of the Insti-
tute for Industrial Pharmacy of the Universidad de Santiago de
Compostela (Spain).
3.2. Crystal structures
The crystal structures of complexes 2 and 3 reveal that both
complexes are isomorphous and crystallise in the chiral space
group P212121. To avoid duplicity only the molecular diagram of
complex 3 is depicted in Fig. 1 and both complexes will be dis-
cussed together. The compounds consist of discrete units of [ML]
formed by a doubly deprotonated ligand coordinated to the metal
center as a N2S2 chelate, leading to the formation of three five-
membered chelate rings. The metal is in a distorted square planar
geometry with a value of the s4 parameter of 0.21 and 0.20 for
3. Results and discussion
3.1. Synthesis
Reaction of the ligand benzil bis(4-methyl-3-thiosemicarba-
zone) with K2PtCl4 in ethanol under reflux and in the presence of
LiOHꢀH2O yielded two complexes, the orthoplatinated mesocate
complexes 2 and 3, respectively (s4 = 0 for SP and s4 = 1 for Td)
[38]. Both thiosemicarbazone limbs are deprotonated, which in-
µ
[Pt2( -L)2] 1
[PdL] 3
RT 3 h
(94%)
(precipitate, 77%)
Li2PdCl4
K2PtCl4
HN
N
N
NH
S
S
LiOH.H2O
reflux 24 h
LiOH.H2O
RT 12 h
NHMe
MeHN
µ
[Pd2( -L)2] 4
LH2
[PtL] 2
(85%)
(filtrate, 18%)
Scheme 1.

1738
E. López-Torres, M.A. Mendiola / Inorganica Chimica Acta 363 (2010) 1735–1740
the methyl groups is different, while C(5) is positioned toward
N(2), C(6) is close to S(2), what was not observed in the platinum
and palladium derivatives with benzil bis(4-ethyl-3-thiosemicar-
bazone), in which the alkyl groups were pointing to the sulfurs
[23,26]. This different orientation of the methyl groups leads to
the formation of a 2D network in the ab plane through hydrogen
bonds involving the sulfur atoms and the NHMe groups.
Complexes 1 and 4 are also isomorphous and crystallise with
two molecules of DMF, so in Fig. 2 only complex 1 is shown. Their
crystal structures unambiguously show they are centrosymmetric
mesocates formed by two deprotonated thiosemicarbazone ligands
bridging two metal centres. Each thiosemicarbazone limb is
bonded to two different metal ions and presents a different coordi-
nation mode and different deprotonation state. One of the arms is
orthometallated, the NH group is deprotonated and is bonded to
the metal through the aryl carbon C(22), the imine nitrogen N(3)
and the sulfur atom S(1), while the other arm is in its neutral form
and is only bonded through S(2). Thus, the metals are in a CNS2
environment in a distorted square planar geometry with s4 values
of 0.15 for both complexes. This coordination mode affords four
five-membered chelate rings as well as the formation of a rectan-
gular 16-membered central cage that is around 4.8 ꢃ 6.5 Å and in
which the metal centres are at a distance of more than 4.5 Å, dis-
carding any interaction between them. The two arms belonging
to the same ligand form angles of 55.80° for complex 1 and
53.33° for complex 4. In the orthometallated limbs the thiosemi-
carbazone moiety and the aromatic ring are virtually coplanar
while in the monodentate ones form angles of 21.33° and 24.54°
in complexes 1 and 4, respectively. This structure is analogous to
the one found in the palladium complex with the ligand benzil
bis(4-ethyl-3-thiosemicarbazone) [26], but complex 1 represents
the first orthoplatinated complex with a bis(thiosemicarbazone) li-
gand. In the crystal packing each mesocate is bonded to four DMF
molecules though hydrogen bonds involving N(1) and N(6).
In the four compounds bond distances and angles (Table 3) are
in agreement with other square planar platinum(II) and palla-
dium(II) complexes with thiosemicarbazone ligands found in the
literature [26,39,40]. It can be pointed out that in the coordination
compounds 2 and 3 both M-S bonds are almost identical, while in
the orthometallated complexes 1 and 4 the bond with S(2), the one
Fig. 1. Molecular structure of complex [PdL] 3. Thermal ellipsoids at 50% proba-
bility level.
duces more electronic delocalization through the ligand skeleton
(Table 2). The ligand, excluding the phenyl groups, can be consid-
ered planar, with S(2) slightly out of the plane. The disposition of
Table 2
33
Selected bond distances of the ligand skeleton in LH2 and its complexes.
LH2
1ꢀ2DMF
2
3
4ꢀ2DMF
N(1)–C(1)
C(1)–N(2)
C(1)–S(1)
N(2)–N(3)
N(3)–C(2)
C(2)–C(3)
C(3)–N(4)
N(4)–N(5)
N(5)–C(4)
C(4)–S(2)
C(4)–N(6)
1.320(5)
1.378(4)
1.681(4)
1.370(4)
1.302(4)
1.505(5)
1.287(5)
1.354(4)
1.352(5)
1.675(4)
1.348(5)
1.347(9)
1.322(8)
1.739(7)
1.366(8)
1.311(8)
1.499(8)
1.294(8)
1.365(7)
1.350(8)
1.709(7)
1.313(8)
1.328(9)
1.336(9)
1.775(7)
1.350(8)
1.320(8)
1.476(10)
1.307(8)
1.350(8)
1.349(9)
1.760(7)
1.330(9)
1.333(5)
1.324(5)
1.765(4)
1.367(4)
1.306(4)
1.479(5)
1.310(4)
1.362(4)
1.319(4)
1.761(4)
1.331(5)
1.326(5)
1.326(4)
1.738(3)
1.348(4)
1.321(4)
1.486(4)
1.284(4)
1.361(4)
1.348(4)
1.714(3)
1.308(4)
Fig. 2. Molecular structure of complex [Pt2(l-L)2] 1. Thermal ellipsoids at 50% probability level. Hydrogen atoms of the phenyl and methyl groups have been omitted for
clarity.

E. López-Torres, M.A. Mendiola / Inorganica Chimica Acta 363 (2010) 1735–1740
1739
Table 3
groups, ten for the aromatic rings and two for the methyl groups,
which correlates with the structures found in the crystal struc-
tures, in which each arm of LH2 has a different coordination mode.
In these complexes the signals corresponding to the CS and CN
groups are clearly shifted with respect to LH2, indicating their
bonding.
Selected bond distances and angles in the complexes.
1ꢀ2DMF
1.993(5)
1.997(6)
2
3
4ꢀ2DMF
2.008(2)
2.008(3)
M(1)–N(3)
M(1)–C(22)
M(1)–N(4)
M(1)–S(1)
1.975(6)
1.969(3)
1.996(6)
2.2684(16)
2.2669(18)
1.981(3)
2.2762(10)
2.2790(10)
2.3509(17)
2.2906(15)
81.8(2)
2.3661(10)
2.3043(8)
82.68(12)
M(1)–S(2)
3.4. Cytotoxic activity
N(3)–M(1)–C(22)
N(3)–M(1)–N(4)
N(3)–M(1)–S(1)
N(3)–M(1)–S(2)
C(22)–M(1)–S(1)
N(4)–M(1)–S(1)
C(22)–M(1)–S(2)
N(4)–M(1)–S(2)
S(1)–M(1)–S(2)
80.1(2)
85.10(17)
165.11(17)
81.53(12)
84.77(9)
165.79(9)
82.98(16)
174.41(16)
164.81(18)
82.16(8)
174.72(7)
164.84(10)
The cytotoxicity of the four compounds was tested against the
human lung carcinoma cell line NCI-H460 and for comparison cis-
platin was also evaluated under the same experimental conditions.
Table 4 shows the new complexes do not show high cytotoxic
activity in this cell line and that the cell growth inhibition is not af-
fected by the metal centre and the nuclearity. This result was not
expected, since related compounds have shown to be active
against the human ovarian carcinoma cell lines A2780 and
A2780cisR [26].
164.81(18)
165.99(9)
93.81(18)
101.37(6)
93.60(10)
101.53(3)
85.14(18)
109.78(6)
84.42(9)
109.36(4)
Table 4
Cytotoxicity for complexes 1–4 and cisplatin against the lung carcinoma cell line NHI-
460 expressed as percentage of inhibition at 100 M.
4. Conclusions
l
[Pt2( -L)2] 1
[PtL] 2
[PdL] 3
l
1
6
7
9
87
1
2
2
3
1
The reactivity of K2PtCl4 and Li2PdCl4 with the ligand benzil
bis(4-methyl-3-thiosemicarbazone) LH2 was investigated. The
dinuclear mesocates [Pt2(l-L)2] 1 and [Pd2(l-L)2] 4 and the coordi-
nation compounds [PtL] 2 and [PdL] 3 were synthesised, and their
structures were unambiguously determined by X-ray diffraction.
The synthetic route described in this paper for the selective synthe-
sis of the palladium derivatives could be extended to the isolation
of analogous complexes with related ligands which, as far as we
know, has not been achieved to date.
[Pd2(l-L)2] 4
Cisplatin
in trans to the aryl carbon, is significantly longer, which correlates
well with the shorter C(4)–S(2) bonds found (Table 2).
The orthometallated Pt(II) complex represent the first example
of cyclometallation in a bis(thiosemicarbazone) with platinum that
has been characterised by single crystal X-ray diffraction. The anal-
ogous palladium complex is the second example whose structure
has been determined by diffraction techniques.
The antitumor activity was evaluated against the lung carci-
noma cell line NCI-H460 and the results show that the complexes
are not active in this cell line.
3.3. NMR spectroscopy
The 1H NMR spectra of complexes 2 and 3 show the signal cor-
responding to the hydrazinic hydrogen atoms at 9.85 ppm has dis-
appeared, indicating the double deprotonation of the ligand. The
resonance attributable to the NHMe hydrogen is upfield shifted
upon coordination in both complexes, as well as the signals corre-
sponding to the phenyl and methyl groups. In the spectra of the
orthometallated compounds a singlet corresponding to the hydra-
zinic hydrogen of the not deprotonated arm can be observed at
10.50 and 10.39 ppm for complexes 1 and 4, respectively, which
are downfield shifted with respect to LH2. The resonance of the
NHMe groups are also downfield shifted and in both complexes
consists of two signals, as expected due to the different state of
deprotonation and coordination mode of the limbs. The not coordi-
nated phenyl group signals are also downfield shifted, as well as
the methyl ones that are also split into two as a result of the asym-
metry. The coordination of one of the phenyl rings and the loss of
one aromatic hydrogen, with the corresponding loss of symmetry
of the ring, can be clearly observed by the appearance of two trip-
lets and two doublets at lower ppm. The upfield shift is due to the
flow of charge from the electron-rich metal centre into the aro-
matic ring. This metal-to ligand back bonding probably induces
the downfield shift of the rest of the protons in the molecule.
13C NMR spectra of complexes 2 and 3 show one signal corre-
sponding to the CS groups, one to the CN, four to the aromatic rings
and one to the methyl groups, indicating the symmetric behaviour
of the two limbs, as was found in the solid state. The signal corre-
sponding to the CN bonds are strongly downfield shifted, indicat-
ing coordination of these groups to the metals. By contrast, the
CS signals display a very small shift, although the X-ray structure
determination confirms they are bonded to the metals. This can
be explained by the extensive charge delocalization induced after
the ligand deprotonation. The spectra of complexes 1 and 4 show
two signals for the thioamide carbon atoms, two for the imine
Acknowledgments
The authors want to thank César J. Pastor for the crystal struc-
ture measurements and to the Comunidad Autónoma de Madrid
and the Universidad Autónoma de Madrid for financial support
(Project CCG08-UAM/SAL-4000).
Appendix A. Supplementary material
CCDC 746400, 746401, 746402 and 746403 contain the supple-
mentary crystallographic data for 1, 2, 3 and 4. 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.2010.03.014.
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