Synthesis and characterization of dinuclear pyrazolato bridged platinum(IV) complexes

Article abstract of DOI:10.1016/j.poly.2007.11.020

Reactions of [PtMe₃(OCMe₂)₃](BF₄) and [(PtMe₃I)₄] with pyrazole (pzH) afforded mononuclear pyrazole platinum(IV) complexes [PtMe₃(pzH)₃](BF₄) (1) and [PtMe<

Full text of DOI:10.1016/j.poly.2007.11.020

Available online at www.sciencedirect.com
Polyhedron 27 (2008) 914–922
www.elsevier.com/locate/poly
Synthesis and characterization of dinuclear pyrazolato
bridged platinum(IV) complexes
a
Ronald Lindner , Goran N. Kaluderovic a,b, Reinhard Paschke c,
´
Christoph Wagner a, Dirk Steinborn a,*
a Institut fu¨r Chemie – Anorganische Chemie, Martin-Luther-Universita¨t, Kurt-Mothes-Straße 2, D-06120 Halle, Germany
b Department of Chemistry, Institute of Chemistry, Technology and Metallurgy, Studentski trg 14, 11000 Belgrade, Serbia
c Biozentrum, Martin-Luther-Universita¨t Halle-Wittenberg, Weinbergweg 22, D-06120 Halle, Germany
Received 11 October 2007; accepted 20 November 2007
Abstract
Reactions of [PtMe3(OCMe2)3](BF4) and [(PtMe3I)4] with pyrazole (pzH) afforded mononuclear pyrazole platinum(IV) complexes
[PtMe3(pzH)3](BF4) (1) and [PtMe3I(pzH)2] (2), respectively. The formation of dinuclear pyrazolato bridged platinum(IV) complexes
(PPN)[(PtMe3)2(l-pz)3] (3), (PPN)[(PtMe3)2(l-I)(l-pz)2] ꢀ 1/2Et2O (4) and [K(18C6)][(PtMe3)2(l-I)(l-pz)2] (5) was achieved by the reac-
tion of each 1 and 2 with [PtMe3(OCMe2)3](BF4) in the presence of KOAc followed by reaction with (PPN)Cl (PPN+ = bis(triphenylphos-
phine)iminium cation) and 18C6, respectively. The reaction of complex 4 with AgO2CCF3 followed by addition of RSR0 (R/R0 = Me/Me,
Me/Ph) resulted in the formation of complexes [(PtMe3)2(l-pz)2(l-RSR0)] (R/R0 = Me/Me, 6; Me/Ph, 7). All complexes were character-
ized unambiguously by microanalysis and NMR (1H, 13C) spectroscopic investigations. Additionally, crystal structures of complexes 3 and
4 as well as DFT calculation are presented. Furthermore, in vitro studies on the anti-proliferative activity of complexes 2 and 5 were carried
out.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Platinum complexes; Dinuclear complexes; Pyrazole ligands; Pyrazolato ligands; Crystal structures; DFT calculations; Antitumoral activity
1. Introduction
(pzH-jN) or can act after deprotonation as a bridging
pyrazolato ligand (l-pz-1jN:2jN0) [3–7].
The synthesis of oligonuclear metal complexes may pro-
ceed in a self organizing process when the formation of the
desired complex is thermodynamically favoured and the
bond formation occurs reversibly [1,2]. An alternative
way is a controlled synthesis in a stepwise reaction via
structurally preformed mononuclear precursor complexes.
In general, one of the coordination sites of the precursor
complexes has to be protected either by classical protecting
groups or by protons, inhibiting uncontrolled oligomeriza-
tion at the beginning of the reaction. Pyrazole (pzH) is a
ligand that can be monodentately coordinated to a metal
The synthesis of oligonuclear platinum(IV) complexes is
a challenging field in coordination chemistry. Their forma-
tion by ligand substitution reactions is often hampered due
to the kinetic inertness of the low-spin d6 electron configu-
ration of Pt(IV). The tris(acetone) complex [PtMe3-
(OCMe2)3](BF4) [8] was found to readily undergo ligand
substitution reactions as acetone is a weakly bound ligand
which has, additionally, a methyl ligand in the trans posi-
tion exerting a large trans effect.
Mononuclear complexes of neutral pyrazole ligands
(pzH-jN) [9,10] as well as dinuclear complexes containing
pyrazolato ligands (l-pz-1jN:2jN0) [9,10] are well known
in platinum(II) chemistry. In contrast to this no homonu-
clear complexes of Pt(IV) with bridging pyrazolato ligands
have been reported in the literature to date. Here we
*
Corresponding author. Tel.: +49 345 5525620; fax: +49 345 5527028.
E-mail address: dirk.steinborn@chemie.uni-halle.de (D. Steinborn).
0277-5387/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2007.11.020

R. Lindner et al. / Polyhedron 27 (2008) 914–922
915
describe the syntheses and characterization of dinuclear
platinum(IV) complexes with bridging pyrazolato ligands
starting from tris(acetone) complex [PtMe3(OCMe2)3]+
and the pyrazole complexes [PtMe3(pzH)3]+ and [PtMe3I-
(pzH)2], respectively, as precursor complexes. Due to
the advantages of platinum(IV) complexes can have over
platinum(II) complexes in chemotherapy, these com-
plexes were investigated with respect to their antitumoral
activity.
tane/CH2Cl2 (1/1, 3 ꢁ 2 ml) and dried under vacuum.
Yield 41 mg, 90%.
Anal. Calc. for C9H17IN4Pt: C, 21.48; H, 3.40; N,
11.13. Found: C, 22.00; H, 3.49; N, 11.14%. 1H NMR
2
(500 MHz, (CD3)2CO): d 1.29 (s + d, JPt,H = 72.9 Hz,
2
6H, PtCH3 trans to pzH), 1.33 (s + d, JPt,H = 71.6 Hz,
3H, PtCH3 trans to I), 6.43 (m, 2H, H4), 7.74 (m, 2H,
H5), 7.88 (m, 2H, H3), 12.09 (br, 2H, NH); 13C NMR
1
(126 MHz, (CD3)2CO): d ꢂ10.5 (s + d, JPt,C = 682.3 Hz,
1
PtCH3 trans to pzH), 8.4 (s + d, JPt,C = 715.9 Hz, PtCH3
3
2. Experimental
trans to I), 106.4 (s + d, JPt,C = 8.6 Hz, C4), 131.1
2
3
(s + d, JPt,C = 5.3 Hz, C3), 138.5 (s + d, JPt,C = 11.5 Hz,
C5).
2.1. General considerations
Syntheses of complexes were carried out under argon
using standard Schlenk techniques whereas the work-up
procedures were performed on air. Methylene chloride,
acetone, n-pentane, benzene and diethyl ether were dried
(CH2Cl2 over CaH2, Me2CO over molecular sieve 3A, n-
pentane, benzene and Et2O over Na-benzophenone) and
distilled prior to use. [(PtMe3I)4] and [PtMe3(OCMe2)3]-
(BF4) were obtained according to the literature [11,8].
Microanalyses (C, H, N, S) were performed by the micro-
analytical laboratory of the University of Halle using
CHNS-932 (LECO) and Vario EL (elementar Analysensys-
2.1.3. Preparation of (PPN)[(PtMe3)2(l-pz)3] (3)
KOAc (118 mg, 1.20 mmol) was added to a solution of
[PtMe3(OCMe2)3](BF4) (100 mg, 0.200 mmol) in acetone
(10 ml). A solution of [PtMe3(pzH)3](BF4) (1) (106 mg,
0.200 mmol) in acetone (10 ml) was added dropwise to this
suspension. After 30 min the suspension was filtered and
the filtrate evaporated to dryness under vacuum. The solid
was extracted with CH2Cl2 (10 ml) and the extract was
added to a solution of (PPN)Cl (115 mg, 0.200 mmol) in
CH2Cl2 (10 ml). After evaporation to 10 ml the KCl was
filtered off and the product was precipitated within 12 h
by adding of Et2O (10 ml). The resulting solid was filtered
off, washed with n-pentane/CH2Cl2 (1/1, 3 ꢁ 2 ml) and
dried under vacuum. Yield 146 mg, 60%.
1
teme) elemental analyzers. H and 13C NMR spectra were
recorded on Varian Gemini 200, VXR 400 and Unity 500
NMR spectrometers. Solvent signals and residual protons
of solvent signals were used as internal standard.
Anal. Calc. for C51H57N7P2Pt2: C, 50.20; H, 4.71; N,
8.04. Found: C, 49.67; H, 5.01; N, 7.77%. 1H NMR
2
2.1.1. Preparation of [PtMe3(pzH)3](BF4) (1)
solution of [PtMe3(OCMe2)3](BF4) (100 mg,
(200 MHz, (CD3)2CO): d 0.85 (s + d, JPt,H = 66.2 Hz,
A
18H, PtCH3), 6.00 (m, 3H, H4), 7.31 (m, 6H, H3/H5),
0.200 mmol) in acetone (10 ml) was added to a solution
of pyrazole (40.9 mg, 0.600 mmol) in acetone (10 ml). The
solution was evaporated to dryness under vacuum and
the residue was extracted with CH2Cl2 (10 ml). The colour-
less product, which was precipitated within 12 h after add-
ing of n-pentane (10 ml), was washed with n-pentane/
CH2Cl2 (1:1, 3 ꢁ 2 ml) and dried under vacuum. Yield
96 mg, 90%.
7.50–7.77 (m, 30H, PPN+); 13C NMR (126 MHz,
1
(CD3)2CO): d ꢂ6.7 (s + d, JPt,C = 675.2 Hz, PtCH3),
3
103.9 (s + d + t, JPt,C = 15.4 Hz, C4), 127.9/130.2/132.7/
2/4
134.3 (PPN+), 134.8 (s + d + d + d ꢀ d,
J
= 25.9/
Pt,C
10.6 Hz, C3/C5).
2.1.4. Preparation of (PPN)[(PtMe3)2(l-I)(l-pz)2] ꢀ
1/2Et2O (4)
Anal. Calc. for C12H21BF4N6Pt: C, 27.13; H, 3.98; N,
15.82. Found: C, 27.07; H, 4.85; N, 15.77%. 1H NMR
(200 MHz, (CD3)2CO) d 1.12 (s + d, JPt,H = 70.1 Hz,
The reaction was carried out according to the above
procedure.
Instead
of
[PtMe3(pzH)3](BF4)
(1),
2
[PtMe3I(pzH)2] (2) (101 mg, 0.200 mmol) was used. Yield
163 mg, 60%.
9H, PtCH3), 6.56 (m, 3H, H4), 7.70 (m, 3H, H5), 8.00
(m, 3H, H3), 12.35 (br, 3H, NH). 13C NMR (50 MHz,
Anal. Calc. for C100H118I2N10OP4Pt4: C, 45.60; H, 4.52;
1
1
(CD3)2CO) d ꢂ7.7 (s + d,
JPt,C = 695.8 Hz, PtCH3),
N, 5.32. Found: C, 45.89; H, 4.59; N, 5.75%. H NMR
107.4 (s + d, 3JPt,C = 8.6 Hz, C4), 132.9 (s + d,
(500 MHz, (CD3)2CO): d 1.08 (s + d, JPt,H = 67.6 Hz,
2
2JPt,C = 5.3 Hz, C5), 140.4 (s + d, JPt,C = 8.4 Hz, C3).
12H, PtCH3 trans to pz), 1.10 (t, JH,H = 7.0 Hz, 3H,
3
3
OCH2CH3), 1.31 (s + d, 2JPt,H = 75.7 Hz, 6H, PtCH3 trans
to I), 3.39 (q, 3JH,H = 7.0 Hz, 2H, OCH2CH3), 5.96 (m, 2H,
H4), 7.27 (m, 4H, H3/H5), 7.50–7.77 (m, 30H, PPN); 13C
2.1.2. Preparation of [PtMe3I(pzH)2] (2)
A solution of pyrazole (37.7 mg, 0.554 mmol) in acetone
(5 ml) was added to a suspension of [(PtMe3I)4] (100 mg,
69.2 lmol) in acetone (10 ml). After dissolving the solid
(4 h) the solution was evaporated to dryness under vacuum
and the solid was extracted with CH2Cl2 (10 ml). The prod-
uct was precipitated within 12 h on addition of n-pentane
(10 ml) and filtered off. The solid was washed with n-pen-
NMR (126 MHz, (CD3)2CO):
d
ꢂ11.1 (s + d,
1JPt,C = 646.3 Hz, PtCH3 trans to pz), 7.6 (s + d,
1JPt,C = 740.4 Hz, PtCH3 trans to I), 14.9 (s, OCH2CH3),
3
104.7 (s + d, JPt,C = 13.6 Hz, C4), 129.1/131.2/134.1/
135.4 (PPN+), 135.8 (s + d + d + d ꢀ d,
J
= 28.2/
Pt,C
2/4
11.8 Hz, C3/C5).

916
R. Lindner et al. / Polyhedron 27 (2008) 914–922
Table 1
2.1.5. Preparation of [K(18C6)][(PtMe3)2(l-I)(l-pz)2]
(5)
Crystal data and structure refinement data for 3 and 4
3
4
The reaction was carried out analogously to 4, but
instead of working with a solution of (PPN)Cl in CH2Cl2,
a solution of 18C6 (52.9 mg, 0.200 mmol) in CH2Cl2
(10 ml) was used. Yield 105 mg, 50%.
Empirical formula
Formula weight
Crystal system
Space group
C51H57N7P2Pt2 C50H54IN5O0.5P2Pt2
1220.16
monoclinic
P21/n
17.041(3)
11.555(2)
25.675(5)
90
105.92(2)
90
4862(2)
4
1312.00
triclinic
P1
ꢀ
Anal. Calc for C24H48IKN4O6Pt2: C, 27.59; H, 4.63; N,
5.36. Found: C, 27.74; H, 5.08; N, 5.34%. 1H NMR
˚
a (A)
9.830(2)
15.281(4)
17.948(4)
78.22(3)
74.32(3)
78.77(3)
2513(1)
2
1.734
6.277
1264
9068
˚
b (A)
2
˚
(500 MHz, (CD3)2CO): d 1.08 (s + d, JPt,H = 67.6 Hz,
c (A)
2
˚
a (A)
12H, PtCH3 trans to pz), 1.31 (s + d, JPt,H = 75.7 Hz,
˚
b (A)
6H, PtCH3 trans to I), 3.65 (s, 24H, CH2O), 5.96 (m, 2H,
H4), 7.27 (m, 4H, H3/H5).
˚
c (A)
3
˚
V (A )
Z
Dcalc (g/cm3)
1.667
5.856
2392
9482
2.1.6. Preparation of [(PtMe3)2(l-pz)2(l-Me2S)] (6)
AgO2CCF3 (15.5 mg, 70 lmol) was added to a solution
of (PPN)[(PtMe3)2(l-I)(l-pz)2] ꢀ 1/2Et2O (4) (92.2 mg,
70 lmol) in acetone (10 ml). After complete precipitation
of AgI (12 h) the reaction mixture was filtered. Me2S
(4.9 mg, 78 lmol) was added to the solution and the reac-
tion mixture was evaporated to dryness under vacuum.
The residue was extracted in benzene (10 ml) and washed
with H2O (10 ml). The combined organic phases were dried
(Na2SO4) and concentrated to 5 ml. Then the product was
precipitated by adding of n-pentane (10 ml), filtered of,
washed with n-pentane (3 ꢁ 2 ml) and dried under vacuum.
Yield 28.4 mg, 60%.
l (mmꢂ1
F(000)
)
Independent reflections
Number of observed reflections
[I > 2r(I)]
Data/restraints/parameters
Goodness-of-fit
6787
7690
9482/0/722
0.924
0.0364, 0.0621 0.0549, 0.0645
0.0723, 0.0790 0.1456, 0.1554
9068/0/554
1.056
R1 [I > 2r(I)], R1 (all data)
wR2 [I > 2r(I)], wR2 (all data)
2/4
130.4 (s, SPh), 136.7 (s + d + d + d ꢀ d,
2/4
J
= 10.5/
Pt,C
28.4 Hz, pz C3/C30/C5/C50), 136.7 (s + d + d + d ꢀ d,
J
= 9.8/24.1 Hz, pz C3/C30/C5/C50).
Pt,C
Anal. Calc. for C14H30N4Pt2S: C, 24.85; H, 4.47; N,
8.28; S, 4.74. Found: C, 25.37; H, 4.76; N, 8.38; S,
4.40%. 1H NMR (200 MHz, (CD3)2CO): d 0.76 (s + d,
2JPt,H = 66.8 Hz, 12H, PtCH3 trans to pz), 1.40 (s + d,
2JPt,H = 73.0 Hz, 6H, PtCH3 trans to S), 2.38 (s + d + t,
3JPt,H = 8.7 Hz, 6H, S(CH3)2), 6.18 (m, 2H, H4), 7.39 (m,
4H, H3/H5); 13C NMR (126 MHz, (CD3)2CO): d ꢂ9.8
2.2. X-ray crystallography
Single-crystal X-ray diffraction analyses of suitable crys-
tals of complexes 3 and 4 were performed at 220(2) K on a
STOE-IPDS diffractometer using Mo Ka radiation
˚
(k = 0.71073 A, graphite monochromator). A summary of
1
the crystallographic data, the data collection parameters
and the refinement parameters is given in Table 1. Absorp-
tion correction for 3 was applied numerically (Tmin
(s + d, JPt,C = 642.1 Hz, PtCH3 trans to pz), 5.2 (s + d,
1J Pt,C = 694.9 Hz, PtCH3 trans to S), 15.2 (s, SCH3, pz),
3JPt,C = 14.9 Hz,
C4)
= 27.7/10.3 Hz, C3/C5).
136.3
/
105.5
(s + d + d + d ꢀ d,
(s + d + t,
2/4
Tmax = 0.49/0.60). The structures were solved by direct
methods with SHELXS-97 [12]. The structure refinements
were carried out by full-matrix least-square procedures
against F2 (SHELXL-97 [12]) for all reflections. All non-
hydrogen atoms were refined with anisotropic displacement
parameters. Hydrogen atoms were refined isotropically. In
complex 3 all H atoms except those of the methyl ligands
were found in the difference Fourier map. The H atoms
of the methyl ligands and those of complex 4 were added
to the models in their calculated positions using the ‘‘riding
model”. The thermal ellipsoids of the C atoms of the ether
molecule in 4 point to a disorder, but refinement in split
positions did not succeed.
J
Pt,C
2.1.7. Preparation of [(PtMe3)2(l-pz)2(l-MeSPh)] (7)
The reaction was carried out according to the above
procedure. Instead of Me2S, MeSPh (9.7 mg, 78 lmol)
was used. Yield 31.0 mg, 60%.
Anal. Calc. for C19H32N4Pt2S: C, 30.89; H, 4.37; N,
7.58; S, 4.34. Found: C, 31.42; H, 4.56; N, 7.65; S,
4.31%. 1H NMR (400 MHz, (CD3)2CO): d 0.43 (s + d,
2JPt,H = 66.0, 6H, PtCH3 trans to pz), 0.74 (s + d,
2JPt,H = 66.0 Hz, 6H, PtCH03 trans to pz), 1.50 (s + d,
2JPt,H = 74.7 Hz, 6H, PtCH3 trans to S), 2.69 (s + d + t,
3JPt,H = 7.9 Hz, 3H, SCH3), 6.26 (m, 1H, pz H40), 6.32
(m, 1H, pz H4), 6.66 (m, 2H, Ph o-H), 7.40 (m, 3H, m/p-
H), 7.47 (m, 2H, pz H30/H50), 7.51 (m, 2H, pz H3/H5).
2.3. Computational details
13C NMR (126 MHz, (CD3)2CO):
d
ꢂ9.0 (s + d,
DFT calculations of compounds 3c,1 4c, 8c, 8c0, pzꢂ and
Iꢂ were carried out by the GAUSSIAN 03 program package [13]
using the modified Perdew–Wang 1991 exchange functional
1JPt,C = 643.9 Hz, PtCH03 trans to pz), ꢂ7.1 (s + d,
1JPt,C = 642.0 Hz, PtCH3 trans to pz), 5.3 (s + d,
1JPt,C = 704.4 Hz, PtCH3 trans to S), 13.0 (s, SCH3),
105.9 (s + d + t, 3JPt,C = 14.9 Hz, pz C40), 106.3
3
1
(s + d + t, JPt,C = 14.9 Hz, pz C4), 122.5/128.4/130.0/
The index ‘‘c” denotes calculated equilibrium structures.

R. Lindner et al. / Polyhedron 27 (2008) 914–922
917
by Adamo and Barone [14] plus the Perdew–Wang 1991 cor-
relation functional [15] (MPWPW91). The 6-311G(d,p) [16]
basis set as implemented in GAUSSIAN 03 was employed for C,
H and N atoms, while the relativistic pseudopotentials of the
Ahlrichs group and related basis functions of TZVPP qual-
ity [17] were employed for Pt and I atoms. All systems were
fully optimized without any symmetry restrictions. The
resulting geometries were characterized as equilibrium
structures by the analysis of the force constants of normal
vibrations. The interaction energies were corrected for basis
set superposition errors (BSSE), that were estimated with
counterpoise type calculations [18].
found to react rapidly in acetone with three equivalents
of pyrazole yielding the cationic tris(pyrazole) complex 1
(Scheme 1). Furthermore, the tetranuclear platinum com-
plex [(PtMe3I)4] was also found to react with pyrazole
yielding the neutral bis(pyrazole) complex 2, but this reac-
tion took one day at room temperature (Scheme 1). Both
mononuclear complexes were isolated as airstable colour-
less (1) and pale yellow (2) crystals in high yields (ca.
90%). The constitution of both complexes was determined
unambiguously by microanalysis and NMR spectroscopy
(1H, 13C).
Deprotonation of the coordinated pyrazole ligand in 1
and 2 afforded l-pyrazolato complexes. Thus, complexes
1 and 2 reacted with [PtMe3(OCMe2)3](BF4) in the pres-
ence of KOAc yielding dinuclear tris(l-pyrazolato) and
(l-iodo)bis(l-pyrazolato) complexes, respectively (Scheme
2). To yield crystalline complexes, the primarily obtained
potassium salts were converted in a methatetical reaction
to the PPN salts 3 and 4, respectively. Addition of the
crown ether 18C6 to the potassium salt of the (l-iodo)-
bis(l-pyrazolato) complex resulted in the formation of
the [K(18C6)] salt 5. The colourless, airstable complexes
(3, 4, 5) were obtained in moderate yields (ca. 50–60%)
and characterized by microanalysis, NMR spectroscopy
(1H, 13C) and single-crystal X-ray diffraction analyses.
Substitution of the l-iodo ligand in complex 4 could be
achieved by reaction with silver trifluoroacetate followed
by addition of thioethers (Scheme 2). Thus, the thioether
bridged complexes 6 and 7 were obtained as colourless, air-
stable crystals in moderate yields (ca. 60%). Their identities
have been confirmed by microanalysis and NMR spectros-
copy (1H, 13C).
2.4. In vitro studies
Stock solutions of investigated platinum complexes and
reference compound cisplatin were made in dimethyl sulf-
oxide (DMSO) at a concentration of 20 mM and diluted
by nutrient medium to various working concentrations.
Nutrient medium was RPMI-1640 (PAA Laboratories)
supplemented with 10% fetal bovine serum (Biochrom
AG) and penicillin/streptomycin (PAA Laboratories).
2.4.1. Cell cultures
The human tumor cell lines anaplastic thyroid cancer
8505C, head and neck tumors A253 and FaDu, cervical can-
cer A431, lung carcinoma A549, ovarian cancer A2780,
colon carcinoma DLD-1, HCT-8 and HT-29 were culti-
vated in the Biocentrum, Martin Luther University Halle-
Wittenberg. All cells were maintained as monolayers in
nutrient medium in a humidified atmosphere with 5% CO2.
2.4.2. Cytotoxicity assay
The cytotoxic activity of the platinum compounds was
measured by the sulforhodamine-B (SRB) assay [19]. In
brief, exponentially growing cells were seeded into 96-well
plates and 24 h later, after the cell adherence, nine different
concentrations of investigated compounds were added to
the wells. The final concentrations were in the range from
0.1 to 100 lM. All experiments were done in triplicate.
Nutrient medium with corresponding concentrations of
compounds, but void of cells was used as blank. Five days
after seeding the cells were fixed with 10% trichloroacetic
acid and processed according to the published SRB assay
protocol. Absorbance was measured at 570 nm using a
96-well plate reader (SpectraFluor Plus Tecan, Germany)
and the percentages of surviving cells relative to untreated
controls were determined. The concentration IC50, was
defined as the concentration of a drug that inhibited cell
survival by 50%, compared with vehicle-treated control.
3.2. Spectral properties
1H and 13C NMR spectra gave proof that complexes 1
and 2 exhibit (mean) C3v and Cs symmetry, respectively.
Thus, in complex 1 all three pyrazole and methyl ligands
are chemically equivalent. In complex 2 the two pyrazole
Me
+ Ag(BF4), −AgI
Me
Me
[(PtMe I) ]
1/4
(BF4)
3
4
Pt
Me2CO
Me2CO
OCMe2
OCMe2
N
N
H
H
N
N
+ 2
+ 3
Me
Me
Me
H
Me
Me
Me
I
(BF4)
Pt
H
Pt
N
N
N
N
N
N
3. Results and discussion
H
5
N
N
HN
HN
5
3.1. Syntheses
3
4
4
3
(1)
(2)
The complex [PtMe3(OCMe2)3](BF4), obtained by the
reaction of [(PtMe3I)4] with Ag(BF4) in acetone [8], was
Scheme 1.

918
R. Lindner et al. / Polyhedron 27 (2008) 914–922
Me
Me
N
N
N
N
Me
Me
1) + 1 / KOAc
Pt
Pt
(PPN)
2) + (PPN)Cl
Me
Me
3
5
2
Me
Pt
4
Me
Me
(3)
(BF4)
Me2CO
OCMe2
OCMe2
I
Me
Me
1) + 2 / KOAc
Me
Me
Me
Me
2a) Y = (PPN) (4)
Pt
Pt
Y
2a) + (PPN)Cl
2b) + 18C6
N
N
3
5
2
4
2b) Y = [K(18C6)] (5)
1) + AgO2CCF3, −AgI
2) + RSR'
R
R'
S
Me
Me
Me
R/R´ = Me/Me (6),
Me/Ph (7)
Me
Pt
Pt
N
N
Me
Me
3
5
2
4
Scheme 2.
ligands were found to be equivalent, whereas two different
Table 2
1
methyl signals were observed. H and 13C NMR spectro-
Selected coupling constants (in Hz) of complexes (PPN)[(PtMe3)2(l-
pz)2(l-X)] (3, 4) and [(PtMe3)2(l-pz)2(l-L)] (6, 7)
scopic measurements established the identities of com-
plexes 3–7. In all these complexes the chemical
equivalence d(C3) = d(C5) and d(H3) = d(H5)2 indicated a
mirror plane perpendicular to the pyrazolato ligands. Fur-
thermore, in accordance with a (mean) D3h symmetry, the
anion in 3 showed six and three chemically equivalent
methyl and pyrazolato ligands, respectively. In accordance
with a (mean) C2v symmetry, in complexes 4, 5 and 6 two
equivalent pyrazolato ligands and two groups of chemi-
cally inequivalent methyl ligands (trans to pzꢂ and trans
to Iꢂ/Me2S) were observed. On the other hand, in complex
7 (mean Cs symmetry) two inequivalent pyrazolato ligands
and three inequivalent methyl ligands were found.
Compound
X/
1JPt,C
1JPt,C
(trans
X/L)
2JPt,H
2JPt,H
(trans
X/L)
L = ligand
(transN)
(transN)
3
4
6
7
X = pzꢂ
X = Iꢂ
L = Me2S
L = MeSPh
675.2
646.3
642.1
643.9/642.0
66.2
67.6
66.8
66.0/66.0
740.4
694.9
704.4
75.7
73.0
74.7
1
but, as known [21], these are not so sensitive as the JPt,C
coupling constants are.
In the neutral mononuclear complex [PtMe3I(pzH)2] (2)
the magnitude of the JPt,C coupling constant trans to N
(682.3 Hz) demonstrated that, in comparison with the req-
uisite coupling constants in 3–7 (642.0–675.2 Hz), pyrazole
has a smaller trans influence than that of the l-pyrazolato
ligand. Furthermore, the comparison to the 1JPt,C coupling
constants in complexes 2 and 4 trans to the iodo ligand
1
1
In fac-trimethylplatinum(IV) complexes the JPt,C and
2JPt,H coupling constants are indicative of the trans influ-
ence of ligands trans to the methyl ligands [20]. The values
for dinuclear complexes 3, 4, 6 and 7 are given in Table 2.
1
On the basis of the JPt,C coupling constants the expected
sequence of the trans influence was found: 642.0–
675.2 Hz (pzꢂ in 3–7) >694.9 Hz (Me2S in 6) ꢃ 704.4 Hz
(MeSPh in 7) >740.4 Hz (Iꢂ in 4). The unusually low trans
influence of the pyrazolato ligand in complex 3 compared
with that in complexes 4–7 (675.2 Hz versus 642.0–
646.3 Hz) might be reasoned to be due to a different angle
strain in the tris- and bis(l-pyrazolato) complexes as well
as a different cis influence of the pzꢂ ligand compared to
Iꢂ/MeSR ligands. Principally, the same order of the trans
influence can be derived from the 2JPt,H coupling constants
(715.9 versus 740.4 Hz) showed a trans influence Iterminal >
Ibridging as expected.
3.3. Structures
Crystals of complexes 3 and 4 suitable for X-ray diffrac-
tion analyses were obtained by recrystallization from
CH2Cl2/Et2O. The complexes crystallized as isolated cat-
ions and anions without unusual intermolecular interac-
tions. The shortest distances of non-hydrogen atoms
˚
between cations and anions are 3.52 A (C13ꢀ ꢀ ꢀC12, 3)
˚
˚
and 3.43 A (C1ꢀ ꢀ ꢀC18, 4). At distances <3.8 A from the
anion, in complex 3 seven PPN cations are found whereas
Numbering scheme of pzH/pzꢂ ligands see Schemes 1 and 2.
2

R. Lindner et al. / Polyhedron 27 (2008) 914–922
919
Table 3
˚
Selected interatomic distances (in A) and angles (in °) of complexes
(PPN)[(PtMe3)2(l-pz)3] (3) and (PPN)[(PtMe3)2(l-I)(l-pz)2] ꢀ 1/2Et2O (4)
3
4
Pt–C
2.045(8)–2.085(7) Pt–Ctrans N
Pt–Ctrans I
2.138(5)–2.157(5) Pt–N
1.328(8)–1.352(8) N–N
Pt–I
2.05(2)–2.08(1)
2.06(2)/2.07(1)
2.123(8)–2.15(1)
1.35(1)/1.37(1)
2.826(1)/2.833(1)
3.706(1)
Pt–N
N–N
Ptꢀ ꢀ ꢀPt
3.7827(8)
88.1(3)–89.5(3)
Ptꢀ ꢀ ꢀPt
C–Pt–C
C
C
C
C
trans N-Pt–Ctrans N 87.3(6)/89.0(5)
trans N-Pt–Ctrans I
trans I–Pt–Ncis
trans N–Pt–Ncis
87.3(5)–89.9(6)
88.6(6)–91.4(4)
89.7(4)–91.3(6)
C–Pt–Ncis
89.3(3)–91.8(3)
C–Pt–Ntrans 176.8(2)–179.3(2) Ctrans N –Pt–Ntrans 177.4(4)–178.4(4)
C
trans I–Pt–I
175.9(4)/179.1(4)
90.5(3)/91.0(3)
81.83(4)
N–Pt–N
90.1(2)–91.7(2)
N–Pt–N
Pt–I–Pt
Fig. 1. Molecular structure of [(PtMe3)2(l-pz)3]ꢂ in crystals of 3 (H atoms
are omitted for clarity, 30% probability ellipsoids).
Pt–N–N
P–N–P
123.9(4)–125.5(4) Pt–N–N
123.2(5)–123.4(6)
139.6(6)
133.7(4)
P–N–P
Pt–N–N–Pt 2.7(7)–5.9(7)
C–C–N–N –0.3(8)–1.3(8)
Pt–N–N–Pt
N–N–C–C
–1(1)/1(1)
0(1)–1(1)
plexes 3 and 4, quantum chemical calculations were
performed on the DFT level. The calculated equilibrium
structures of the dinuclear anions [(PtMe3)2(l-pz)3]ꢂ (3c)
and [(PtMe3)2(l-I)(l-pz)2]ꢂ (4c) contained in complexes 3
and 4/5 are illustrated in Fig. 3. Two different diastereoiso-
mers of fragments [(PtMe3)2(l-pz)2] (8c/8c0, Fig. 3), with
similar energies, were observed in these calculations. Only
fragment 8c is discussed here, because it exhibits a structure
close to complexes 3c and 4c. Thus, 8c is expected to be an
intermediate in the substitution processes of complex 4.
Selected structural parameters of the equilibrium structures
of 3c, 4c and 8c are listed in Table 4. The calculated struc-
tures 3c and 4c show a good agreement with the experimen-
tally found values. Interestingly, both in the calculated and
experimental structures the Ptꢀ ꢀ ꢀPt distance of the (l-iodo)-
bis(l-pyrazolato) complex (4c/4) was found to be shorter
than in the tris(l-pyrazolato) complex (3c/3). An even
shorter Ptꢀ ꢀ ꢀPt distance was found in the complex fragment
8c. Thus, addition of the l-pyrazolato (8c?3c) and l-iodo
ligand (8c?4c) results in a lengthening of the Ptꢀ ꢀ ꢀPt dis-
tance, indicating that the ‘‘coordination pocket” of this
fragment is too small for both the l-iodo and the l-pyrazo-
lato ligand.
Fig. 2. Molecular structure of [(PtMe3)2(l-I)(l-pz)2]ꢂ in crystals 4 (H
atoms are omitted for clarity, 30% probability ellipsoids).
in complex 4 six PPN cations and another anion are found.
The molecular structures of the anions are shown in Figs. 1
and 2, selected geometrical parameters are given in Table 3.
The structure of the tris(l-pyrazolato) bridged dinuclear
anion in crystals of 3 is approximately of D3h symmetry
(Fig. 1). The platinum atoms exhibit an octahedral coordi-
nation (angles between neighbouring ligands: 88.1(3)–
˚
91.8(3)°). The Ptꢀ ꢀ ꢀPt distance amounts to 3.7827(8) A
excluding any direct interaction. The structure of the (l-
iodo)bis(l-pyrazolato)
bridged
dinuclear
anion
[(PtMe3)2(l-I)(l-pz)2]ꢂ in crystals of 4 is very nearly of
C2v symmetry (Fig. 2). The platinum atoms are octahe-
drally coordinated exhibiting a PtC3N2I coordination
(angles between neighbouring ligands: 87.3(6)–91.4(4)°).
The Pt–C bond lengths did not prove to be dependent on
the ligand in the trans position (Pt–C (trans to N):
On the basis of an energetic approach the strength of
metal–ligand interactions can be expressed either as the dis-
sociation energy Ediss of the complex into the free frag-
ments in their equilibrium structures or as the interaction
energy Eint of the ‘‘prepared” fragments (isolated frag-
ments having the same geometry as in the complex). For
an explanation of these fundamental steps, see Ref. [22].
Thus, the equation
˚
˚
2.05(2)–2.08(1) A; Pt–C (trans to I): 2.06(2)/2.07(1) A).
The Ptꢀ ꢀ ꢀPt distance in 4 is significantly shorter than in 3
˚
(3.706(1) versus 3.7827(8) A).
ꢂEdiss ¼ Eint þ Eprep
3.4. DFT calculations
holds whereas the preparation energy Eprep of a bond for-
mation A + B?AB is the energy which is necessary to pro-
mote fragments A and B from their equilibrium geometries
To gain further insight into the strength of the plati-
num–l-ligand bonds in the dinuclear platinum(IV) com-

920
R. Lindner et al. / Polyhedron 27 (2008) 914–922
Fig. 3. Calculated equilibrium structures of [(PtMe3)2(l-pz)3]ꢂ (3c), [(PtMe3)2(l-I)(l-pz)2]ꢂ (4c) and [(PtMe3)2(l-pz)2] (8c/8c0).
Table 4
stants. The preparation energy of the platinum fragment
˚
Selected interatomic distances (in A) and angles (in °) of calculated
equilibrium structures [(PtMe3)2(l-X)(l-pz)2]ꢂ (l-X = pzꢂ, 3c; Iꢂ, 4c) and
[(PtMe3)2(l-pz)2] (8c)
in 3c was found to be larger than that in 4c (6.3 versus
4.6 kcal/mol) as expected by inspection of the Ptꢀ ꢀ ꢀPt dis-
˚
˚
˚
tances (3.636 A (8c) <3.780 A (4c) <3.830 A (3c)).
3c
4c
8c
Pt–Ctrans L
Pt–Ctrans N
Pt–N
2.071
2.071
2.174
1.358–1.359
3.780
86.8–89.7
89.9–92.5
178.9–179.8
2.043a
2.054
2.161
1.363
3.5. Antitumoral activities
2.068–2.070
2.168–2.172
1.357–1.358
3.830
88.4–96.2
88.9–91.3
178.1–179.3
Since the discovery of cisplatin (cis-[PtCl2(NH3)2]) by
Rosenberg [23] the anticancer activity of platinum com-
plexes is well known. In contrast to the large number of
platinum(II) complexes, substantially fewer platinum(IV)
complexes have been investigated with respect to their can-
cerostatic properties [24,25]. However, a number of plati-
num(IV) complexes have been tested in clinical trials.
These include iproplatin (cis, trans, cis-[PtCl2(OH)2-
(NH2iPr)2]) [24] tetraplatin ([PtCl4(D,L-dach)]; dach =
1,2-diaminocyclohexane) [24] and satraplatin (cis, trans-
[PtCl2(OAc)2(NH3)(NH2cy)]) [24,26]. As reported in the lit-
erature [27], dinuclear platinum(II) complexes should be
able to coordination to DNA in a fashion differing from
that observed for mononuclear complexes and thus might
show activity against tumor cell lines resistant to cisplatin.
N–N
Ptꢀ ꢀ ꢀPt
C–Pt–C
C–Pt–Ncis
C–Pt–Ntrans
a
3.636
88.7–91.5
90.6–92.6
175.8–179.8
trans to the free coordination site.
to the geometries which they acquire in the complex AB.
As shown in Fig. 4, for both processes the l-pyrazolato li-
gand in 3c is more strongly bound (Eint = ꢂ80.5 kcal/mol,
ꢂEdiss = ꢂ73.7 kcal/mol) than the l-iodo ligand in 4c
(Eint = ꢂ50.8 kcal/mol, ꢂEdiss = ꢂ46.2 kcal/mol), which
is in accord with the differences in the trans influence of
1
the bridging ligands measured by the JPt,C coupling con-

R. Lindner et al. / Polyhedron 27 (2008) 914–922
921
Fig. 4. Energy decomposition analyses of bond formation between fragment 8c and pzꢂ and Iꢂ, respectively. Interaction energies include BSSE
corrections. (a) 8cprep denotes the fragment 8c having the geometry as in complex 3c and 4c, respectively.
Table 5
In contrast to the investigation of the anticancer activities
IC50 values of complexes 2 and 5 against different human tumor cell lines
of dinuclear platinum(II) complexes, investigations with
Cell line
IC50 [lM]
dinuclear platinum(IV) complexes are lacking. To study
the activity of the synthesized trimethylplatinum(IV) com-
plexes two different compounds were chosen (2, 5), exhibit-
ing mono- and dinuclear arrangement, but containing
similar (iodo, pyrazole/pyrazolato) ligands.
Complex 2a
Complex 5a
Cisplatinb
8505C
A253
A431
A549
A2780
DLD-1
FaDu
HCT-8
HT-29
a
35.03 0.86
20.95 0.94
19.29 0.35
36.22 0.75
4.82 0.31
37.04 0.56
36.42 0.85
44.97 3.20
35.03 1.19
1.96 0.15
1.13 0.03
0.95 0.01
2.30 0.03
1.49 0.07
2.51 0.14
2.32 0.06
3.76 0.13
2.18 0.08
5
0.8
0.65
1.5
0.55
5
1.2
1.5
0.6
To investigate the activities of complexes 2 and 5 against
various human tumor cell lines, in vitro experiments were
carried out. The antitumoral activities of compounds 2
and 5 in comparison to the respective activity of cisplatin
are presented in Table 5. The anti-proliferative activity of
complex 2 was found to be about one order of magnitude
lower than that of cisplatin (IC50(2)/IC50(cisplatin) = 7.0–
58.4). In contrast, the activity of complex 5 proved to be
in the same order than the corresponding activity of cis-
platin (IC50(5)/IC50(cisplatin) = 0.4–2.7). Two cell lines
(8505C, DLD-1), which exhibit low sensitivities against cis-
platin, were included in these investigations. On these par-
ticular cell lines, complex 5 was found to be more active
than cisplatin (IC50(5)/IC50(cisplatin) = 0.4–0.5). However,
taking into consideration that 5 is a dinuclear complex,
roughly the same anti-proliferative activity per Pt atom
was observed. The reason for the significantly higher
anti-proliferative activity of the dinuclear complex 5 in
comparison with the mononuclear complex 2 is not yet
clear. It can be speculated that the dinuclear fragment
[(PtMe3)2(l-pz)2] allows a bridging coordination of the
nucleobases.
Mean value SD from experiments.
Mean value without SD.
b
To summarize, the investigations showed that dinuclear
pyrazolato bridged platinum(IV) complexes can be built up
by the synthesis of mononuclear pyrazole precursor com-
plexes followed by controlled deprotonation of the pyra-
zole ligands. Due to the highly stable fac-PtMe3 moiety,
threefold bridged dinuclear platinum(IV) complexes were
obtained. The substitution lability of the l-iodo ligand in
complex 4/5 opened up a way to synthesize and to charac-
terize further complexes having a relatively rigid Me3Pt(l-
pz)2PtMe3 fragment in which to metal centers in high oxi-
dation state are in the vicinity of one another. Furthermore
it could be demonstrated that the investigated dinuclear
complex 5 exhibited a quite high proliferative activities
against a series of human tumor cell lines.

922
R. Lindner et al. / Polyhedron 27 (2008) 914–922
Cammi, C. Pomelli, J.W. Ochterski, P.Y. Ayala, K. Morokuma, G.A.
Acknowledgements
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The authors gratefully acknowledge financial support by
the state of Sachsen-Anhalt (Germany). We also thank
Merck (Darmstadt, Germany) for gift of chemicals.
Appendix A. Supplementary material
CCDC 663385 and 663386 contain the supplementary
crystallographic data for 3 and 4. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/
conts/retrieving.html, or from the Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: (+44) 1223-336-033; or e-mail: depos-
it@ccdc.cam.ac.uk. Energies and Cartesian coordinates of
atom positions of the calculated structures 3c, 4c, 8c, 8c0,
pzꢂeq and Iꢂ are available from the authors. Supplementary
data associated with this article can be found, in the online
version, at doi:10.1016/j.poly.2007.11.020.
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