Synthesis, X-ray diffraction structures, spectroscopic properties, and in vitro antitumor activity of isomeric (1H-1,2,4-triazole)Ru(III) complexes

Article abstract of DOI:10.1021/ic034605i

Three ruthenium(III) complexes containing 1H-1,2,4-triazole (Htrz), viz., (H₂trz)[cis-RuCl₄(Htrz)₂], 1, (H ₂trz)[trans-RuCl₄(Htrz)₂], 2, and (Ph ₃PCH₂Ph)[trans-RuCl₄(Htrz)₂], 3, have been synthesized by reaction between RuCl₃ and excess of the triazole in 2.38 M HCl (1 and 2), while 3 was obtained by metathesis of 2 and [Ph₃PCH₂Ph]Cl in water. The products were characterized by IR, UV-vis, electrospray mass spectrometry, cyclic voltammetry, and X-ray crystallography (1 and 3). X-ray diffraction study revealed cis and trans arrangements of the triazole ligands in 1 and 3, correspondingly, and unprecedented monodentate coordination of the triazole through N2 and stabilization of its 4H tautomeric form, which is the disfavored one for the free triazole. The cytotoxicity of 1 and 2 has been assayed in three human carcinoma cell lines SW480, HT29 (colon carcinoma), and SK-BR-3 (mammary carcinoma). Both compounds exhibit antiproliferative activity in vitro. Time-dependent response of all three lines to 1 and 2 and a structure-activity relationship, i.e., higher activity of the trans-isomer 2 than that of cis-species 1, have been observed.

Full text of DOI:10.1021/ic034605i

Inorg. Chem. 2003, 42, 6024−6031
Synthesis, X-ray Diffraction Structures, Spectroscopic Properties, and in
vitro Antitumor Activity of Isomeric (1H-1,2,4-Triazole)Ru(III) Complexes
,†
Vladimir B. Arion,* Erwin Reisner,†,‡ Madeleine Fremuth,† Michael A. Jakupec,†
,†
Bernhard K. Keppler,* Vadim Yu. Kukushkin,§ and Armando J. L. Pombeiro‡
Institute of Inorganic Chemistry of the UniVersity of Vienna, Wa¨hringerstr. 42,
A-1090 Vienna, Austria, Centro de Qu`ımica Estrutural, Complexo I, Instituto Superior Te´cnico,
AV. RoVisco Pais, 1049-001 Lisbon, Portugal, and Department of Chemistry,
St. Petersburg State UniVersity, 198504 Stary Petergof, Russian Federation
Received June 2, 2003
Three ruthenium(III) complexes containing 1H-1,2,4-triazole (Htrz), viz., (H trz)[cis-RuCl4(Htrz)2], 1, (H trz)[trans-
2
2
RuCl4(Htrz)2], 2, and (Ph3PCH Ph)[trans-RuCl4(Htrz)2], 3, have been synthesized by reaction between RuCl3 and
2
excess of the triazole in 2.38 M HCl (1 and 2), while 3 was obtained by metathesis of 2 and [Ph3PCH Ph]Cl in
2
water. The products were characterized by IR, UV−vis, electrospray mass spectrometry, cyclic voltammetry, and
X-ray crystallography (1 and 3). X-ray diffraction study revealed cis and trans arrangements of the triazole ligands
in 1 and 3, correspondingly, and unprecedented monodentate coordination of the triazole through N2 and stabilization
of its 4H tautomeric form, which is the disfavored one for the free triazole. The cytotoxicity of 1 and 2 has been
assayed in three human carcinoma cell lines SW480, HT29 (colon carcinoma), and SK-BR-3 (mammary carcinoma).
Both compounds exhibit antiproliferative activity in vitro. Time-dependent response of all three lines to 1 and 2 and
a structure−activity relationship, i.e., higher activity of the trans-isomer 2 than that of cis-species 1, have been
observed.
Introduction
metal-based drugs with improved clinical effectiveness,
reduced general toxicity, and a broader spectrum of activity.
Among the non-platinum compounds exhibiting anticancer
properties, those of ruthenium are very promising, showing
activity on even such tumors which developed resistance to
cisplatin or in which cisplatin is totally inactive. Moreover,
in contrast to cisplatin, the toxic side effects of these Ru
compounds are remarkably low.
The first ruthenium compound (Him)[trans-RuCl4(im)-
(Me2SO)] (NAMI-A; im ) imidazole) entered phase I clinical
trials in 1999 as an antimetastatic drug,16 whereas another
complex (Hind)[trans-RuCl4(ind)2] (KP1019; ind ) indazole,
Figure 1) has entered phase I clinical trials in 2003 as an
anticancer drug which is very active against colon carcinomas
and their metastases.17 Another (azole)Ru(III) complex,
(Him)[trans-RuCl4(im)2], also prepared in our laboratory,
The therapeutic potential of both nonphysiological and
physiological metal ion complexes against tumor cells, is
well documented.1-15 Current efforts are focused to develop
* To whom correspondence should be addressed. E-mail: arion@
ap.univie.ac.at (V.B.A.); keppler@ap.univie.ac.at (B.K.K.). Fax: + 43 1
427752680.
† University of Vienna.
‡ Instituto Superior Te´cnico.
§ St. Petersburg State University.
(1) Rosenberg, B.; Vancamp, L. Cancer Res. 1970, 30, 1799-1802.
(2) Graham, R. D.; Williams, D. R. J. Inorg. Nucl. Chem. 1979, 41, 1245-
1249.
(3) Myette, M. S.; Elford, M. L.; Chitambar, C. R. Cancer Lett. 1998,
129, 199-204.
(4) Lovejoy, D. B.; Richardson, D. R. Expert. Opin. InVest. Drugs 2000,
9, 1257-1270 and references therein.
(5) Erck, A.; Rainen, L.; Whileyman, J.; Chang, I.-M.; Kimball, A. P.;
Bear, J. Proc. Soc. Exp. Biol. Med. 1974, 145, 1278-1283.
(6) Saryan, L. A.; Ankel, E.; Krishnamurti, C.; Petering, D. H.; Elford,
H. J. Med. Chem. 1979, 22, 1218-1221.
(11) Guo, Z.; Sadler, P. J. Angew. Chem., Int. Ed. 1999, 38, 1512-1531.
(12) Pieper, T.; Borsky, K.; Keppler, B. K. Top. Biol. Inorg. Chem. 1999,
1, 171-199.
(13) Clarke, M. J. Coord. Chem. ReV. 2003, 236, 209-233.
(14) Espo´sito, B. P.; Najjar, R. Coord. Chem. ReV. 2002, 232, 137-149.
(15) Sava, G.; Bergamo, A. Int. J. Oncol. 2000, 17, 353-365.
(16) Sava, G.; Gagliardi, R.; Bergamo, A.; Alessio, E.; Mestroni, G.
Anticancer Res. 1999, 19, 969-972.
(7) Booth, B.; Sartorelli, A. Nature 1966, 210, 104-105.
(8) Booth, B.; Donelly, T.; Zettner, A.; Sartorelli, A. Biochem. Pharmacol.
1971, 20, 3109-3118.
(9) Keppler, B. K.; Lipponer, K.-G.; Stenzel, B.; Kratz, F. In Metal
Complexes in Cancer Chemotherapy; Keppler, B. K., Ed.; VCH:
Weinheim, 1993; pp 187-220.
(10) Allardyce, C. S.; Dyson, P. J. Platinum Met ReV. 2001, 45, 62-69.
6024 Inorganic Chemistry, Vol. 42, No. 19, 2003
10.1021/ic034605i CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/26/2003

Isomeric (1H-1,2,4-Triazole)Ru(III) Complexes
Herein we report on the synthesis, structure, unusual
binding mode of the heterocyclic ligand, and spectroscopic
properties of (triazole)Ru(III) complexes containing isomeric
[cis-RuCl4(Htrz)2]- and [trans-RuCl4(Htrz)2]- anionic spe-
cies. The cytotoxic activity of the two complexes (H2trz)-
[cis-RuCl4(Htrz)2]‚H2O (1) and (H2trz)[trans-RuCl4(Htrz)2]
(2) with isomeric structures assayed in vitro in three human
cell lines HT29 (colon carcinoma), SK-BR-3 (breast carci-
noma), and SW480 (colon carcinoma) showed (i) a clear
indication for structure-activity relationship, where the trans
complex is more active than the cis one, and (ii) that the
activity against SW480 cell line is higher than that of (Him)-
[trans-RuCl4(im)2].
Figure 1. (Azole)Ru(III) complexes.
exhibits strong antiproliferative activity in autochtonous
colorectal carcinoma in rats.18 Remarkably, this complex
showed high antitumor activity in human colon carcinoma
cell lines (SW707 and SW948) in vitro comparable to that
of (Hind)[trans-RuCl4(ind)2] (KP1019).19 On the contrary,
a related derivative, (Hpz)[trans-RuCl4(pz)2] (pz ) pyrazole),
showed only marginal activity against those cell lines, giving,
however, an explicit indication on the effect of the nature
of the heterocycle on biological activity.
Experimental Section
Hydrated RuCl3 was purchased from Degussa and 1H-1,2,4-
triazole from Aldrich and used as received.
Synthesis of Complexes. A starting solution of “RuCl3” was
prepared following the procedure described by Kralik et al.22
Hydrated RuCl3 (5.00 g; 17.7 mmol) was dissolved in a mixture
of ethanol (96%)/1M HCl (250 mL, 1:1, v/v) and filtered off from
an insoluble material, and the filter paper was washed with
additional 5-mL portions of ethanol. The solution was refluxed on
stirring for 1.5 h, allowed to cool to room temperature, then
evaporated at 50 °C under reduced pressure to 38 mL, and diluted
with 1 M HCl to obtain 63 mL of the dark-red “ruthenium(III)
chloride” solution.
Searching for other potent antineoplastic agents structurally
related to (Hind)[trans-RuCl4(ind)2] and its imidazole deriva-
tive, we suggested the use of 1H-1,2,4-triazole (Htrz) as a
heterocyclic ligand. The 2-position of the triazole is of the
“pyrazole” type, while the 4-position is of the “imidazole”
type (Figure 1). Looking for structure-activity relationships
to be elucidated in this class of (azole)Ru(III) complexes of
the type [RuCl4L2]-, where L ) azole heterocycle, we
intended to study the effect of aza substitution on the
imidazole or pyrazole ring, on the tumor-inhibiting activity
in vitro, which could further help to create other Ru-based
effective metal-based drugs. We also (i) anticipated the
isolation of the cis/trans isomeric pair of [RuCl4(Htrz)2]-
and the study of antitumor activity of both isomers (previ-
ously [cis-RuCl4L2]-, L ) ind, im, pz, were neither isolated
nor, consequently, tested for their biological activity), and
(ii) expected that increased hydrophilicity of the triazole
might result in better aqueous solubility of the final
complexes in comparison with rather poorly soluble (Hind)-
[trans-RuCl4(ind)2], and that the increased solubility might
facilitate the galenic formulation for eventual clinical studies.
In addition, as will be discussed, the 1H-1,2,4-triazole exists
in different tautomeric forms, and it might adopt in metal
complexes both various ligating modes and those tautomeric
forms which are disfavored for the free heterocycle.20 The
latter makes the coordination chemistry of this ligand toward
ruthenium intriguing from the viewpoint of ligand reactiv-
ity.21
(H2trz)[cis-RuCl4(N2-Htrz)2]‚H2O (1) and (H2trz)[trans-RuCl4-
(N2-Htrz)2] (2). The dark-red solution of RuCl3 (10.0 mL, 2.8
mmol) was added to 1H-1,2,4-triazole (2.00 g, 29.0 mmol). After
0.7 h, orange needles of (H2trz)[trans-RuCl4(Htrz)2] (2) started to
form, and they were filtered off after 2.5 h. For the preparation of
1, the reaction system was left for 7 days, whereupon the
precipitated mixture of large red-brown crystals of the cis product
(1), orange needles of the trans product (2), and impurities were
separated by filtration. The red-brown crystals of 1 were separated
roughly by mechanical methods and purified by washing with five
3-mL portions of ethanol (96%) under ultrasound treatment (ca.
30 s), where all impurities and the trans product were dissolved.
Compounds 1 and 2 were washed with two 3-mL portions of ethanol
(96%) followed by two 3-mL portions of diethyl ether and dried at
room temperature in air. In the case of 1, the initial dark-red solution
of RuCl3 was seeded with (H2trz)[cis-RuCl4(N2-Htrz)2]‚H2O, which
was prepared with a very low yield (∼4%) by the same procedure.
(H2trz)[cis-RuCl4(N2-Htrz)2]‚H2O (1). Yield: 0.28 g, 21%. The
complex is well soluble in water (10 mg/mL at 298 K), DMF, and
DMSO, slightly soluble in methanol and ethanol, and insoluble in
diethyl ether. Mp ) 135-140 °C (dec). Anal. Calcd for C6H12N9-
Cl4RuO (Mr ) 469.10 g/mol), %: C, 15.36; H, 2.58; N, 26.87; Cl,
30.23. Found, %: C, 15.47; H, 2.56; N, 26.60; Cl, 29.88. ESI-MS
(-ve), m/z: 380, [RuCl4(Htrz)2]-; 242, [RuCl4]-. IR spectrum in
KBr, selected bands, cm-1: 3450 s,br; ν(OH); 3149 s; ν(CH), 626
vs; (ring torsion vibration). UV-vis (H2O), λmax, nm (ꢀ, M-1 cm-1):
405 (shoulder, 780), 358 (2420).
(17) Galanski, M.; Arion, V. B.; Jakupec, M. A.; Keppler, B. K. Curr.
Pharm. Des., submitted.
(18) Berger, M. R.; Garzon, F. T.; Keppler, B. K. Anticancer Res. 1989,
9, 761-766.
(19) Galeano, A.; Berger, M. R.; Keppler, B. K. Arzneim-Forsch. 1992, 6,
821-824.
(20) Haasnoot, J. G. Coord. Chem. ReV. 2000, 200-202, 131-185.
(21) Pombeiro, A. J. L.; Kukushkin, V. Yu. Reactions of Coordinated
Ligands: General Considerations In, ComprehensiVe Coordination
Chemistry, 2nd ed.; Lever, A. B. P., Ed.; Elsevier: New York; Vol.
1, in press.
(H2trz)[trans-RuCl4(N2-Htrz)2] (2). Yield: 0.29 g, 23%. The
product is soluble in water (3 mg/mL at 298 K), DMF, and DMSO,
slightly soluble in methanol and ethanol, and insoluble in diethyl
ether. Mp ) 140 °C (dec). Anal. Calcd for C6H10N9Cl4Ru (Mr )
451.09 g/mol), %: C, 15.97; H, 2.23; N, 27.94; Cl, 31.44. Found,
(22) Kralik, F.; Vrestal, J. Collect. Czech. Chem. Commun. 1961, 26, 1298-
1304.
Inorganic Chemistry, Vol. 42, No. 19, 2003 6025

Arion et al.
Table 1. Crystal Data and Details of Data Collection for 1 and 3
%: C, 15.87; H, 2.43; N, 27.66; Cl, 30.89. ESI-MS (-ve): m/z
380, [RuCl4(Htrz)2]-; 242 [RuCl4]-. IR spectrum in KBr, selected
bands, cm-1: 3131 s; ν(CH), 626 vs; (ring torsion vibration). UV-
vis (H2O), λmax, nm (ꢀ, Μ-1 cm-1): 420 (370), 365 (2745), 240
(9420).
1
3
empirical formula
C6H12N9Cl4ORu
469.12
C29H30N6Cl4OPRu
752.43
fw
space group
a, Å
b, Å
c, Å
P21/c
P21/c
9.474(2)
8.794(2)
18.343(4)
94.40(3)
1523.7(6)
4
11.605(2)
17.149(3)
16.023(3)
97.81(3)
3159.2(10)
4
(Ph3PCH2Ph)[trans-RuCl4(N2-Htrz)2]‚H2O (3). A solution of
(Ph3PCH2Ph)Cl (0.066 g, 0.17 mmol) in ethanol (3 mL) was added
to a solution of (H2trz)[trans-RuCl4(Htrz)2] (0.075 g, 0.17 mmol)
in water (25 mL). The light-orange microcrystals which immediately
formed were filtered off, washed with ethanol and diethyl ether,
and dried at room temperature in air. Yield: 0.09 g, 77%. The com-
plex is soluble in DMSO, sparingly soluble in DMF and methanol,
and insoluble in water and diethyl ether. Mp ) 195 °C (dec). Anal.
Calcd for C29H30N6RuCl4OP (Mr ) 752.44 g/mol), %: C, 46.29;
H, 4.02; N, 11.17; Cl, 18.85. Found, %: C, 46.17; H, 4.03; N,
11.10; Cl, 18.65. ESI-MS (-ve), m/z: 380, [RuCl4(Htrz)2]-; 242,
[RuCl4]-; ESI-MS(+ve), m/z: 353, [Ph3PCH2Ph]+. IR spectrum
in KBr, selected bands, cm-1: 3470 s,br; ν(OH), 3145 m; ν(CH),
625 m; (ring torsion vibration). UV-vis (MeOH), λmax, nm (ꢀ, Μ-1
cm-1): 435 (380), 375 (3400).
â, deg
V, Å3
Z
λ, Å
0.71073
2.045
0.71073
1.582
F
calcd, g cm-3
cryst size, mm3
T, K
0.14 × 0.26 × 0.31
0.015 × 0.22 × 0.35
120
120
µ, cm-1
R1a
17.42
9.20
0.0225
0.0268
wR2b
0.0568
0-0621
GOFc
1.027
1.029
2 2
a R1 ) ∑||Fo| - |Fc||/∑|Fo|. b wR2 ) {∑[w(Fo2 - Fc2)2]/∑[w(Fo ) ]}1/2
.
c GOF ) {∑[w(Fo2 - Fc2)2]/(n - p)}1/2, where n is the number of reflections
and p is the total number of parameters refined.
SHELXL-97,25 molecular diagrams, ORTEP,26 computer, Pentium
II; scattering factors.27
Physical Measurements. Elemental analyses were carried out
by the Microanalytical Service of the Instituto Superior Te´cnico in
Lisbon or on a Carlo Erba microanalyzer at the Institute of Physical
Chemistry of the University of Vienna. Infrared spectra were
recorded on a Perkin-Elmer FTIR 2000 IR spectrometer in KBr
pellets (4000-400 cm-1). UV-vis spectra were recorded on a
Perkin-Elmer Lambda 20 UV-vis spectrometer using samples
dissolved in water or methanol. Electrospray ionization mass
spectrometry was carried out with a Bruker Esquire 3000 instrument
(Bruker Daltonic, Bremen, Germany). The given m/z values,
originating from the most intense isotopes, were obtained by the
mass linearization procedure. Expected and experimental isotope
distributions were compared. Melting points were measured on a
Kofler-table (Leica Galen III). Cyclic voltammograms were mea-
sured in a two-compartment three-electrode cell using a 0.5-mm-
diameter platinum-disk working electrode or alternatively with an
glassy carbon electrode (Ø)1.0 mm), probed by a Luggin capillary
connected to a silver wire pseudo-reference-electrode and a platinum
auxiliary electrode. Measurements were performed at room tem-
perature using an EG&G PARC 273A potentiostat/galvanostat.
Deaeration of solutions was accomplished by passing a stream of
high-purity nitrogen through the solution for 10 min prior to the
measurements and then maintaining a blanket atmosphere of
nitrogen over the solution during the measurements. The potentials
were measured in 0.2 M [n-Bu4N][BF4]/DMF, at a scan rate of
200 mV/s, and are quoted relative to the [Fe(η5-C5H5)2]0/+ redox
Cell Lines and Culture Conditions. Three human cell lines
were used for cytotoxicity experiments as described: HT29 and
SW480 (adenocarcinoma of the colon) were kindly provided by
Brigitte Marian (Institute of Cancer Research, University of Vienna,
Austria), and SK-BR-3 (adenocarcinoma of the breast) was a gift
from Evelyn Dittrich (General Hospital, University of Vienna,
Austria). Cells were grown as adherent monolayer cultures in min-
imum essential medium (MEM) containing 10% heat-inactivated
fetal bovine serum, 2 mM L-glutamine, 1 mM sodium pyruvate,
50 µg/mL streptomycin, and 50 U/mL penicillin (all purchased from
Gibco). Cultures were maintained at 37 °C in a humidified
atmosphere containing 5% CO2.
Drug Cytotoxicity. Monolayer cell cultures were trypsinized,
and single-cell suspensions were obtained by repeated pipetting.
A final cell density of 3 × 104, 1.5 × 104 and 3 × 104 cells/mL
for HT29, SW480 and SK-BR-3, correspondingly, was prepared
in complete culture medium, and 200 µL cell suspension was added
to each well of a 96-well microculture plate. On the day following
plating, medium was removed, and compounds were added at the
respective concentrations dissolved in complete culture medium.
Each concentration was given to eight microcultures in parallel.
The MTT assay was performed after the cells had been incubated
for 24 and 96 h. Cells treated for 24 h were incubated in drug-free
culture medium for a further 72 h before the MTT dye was added
whereas the MTT reaction was performed immediately after drug
exposure in the case of the 96 h treatment. 3-(4,5-Dimethylthiazol-
2-yl)-2,5-diphenyltetrazoliumbromide (MTT) was dissolved in aqua
tridest at 5 mg/mL, and 20 µL was added to each well already
filled with a fresh 150 µL portion of complete culture medium and
incubated for 4 h at 37 °C. Afterward, the precipitated dye was
dissolved in 150 µL DMSO, and optical densities were measured
at a wavelength of 550 nm by means of a microplate reader (Tecan
Spectra Classic). Each experiment was performed in triplicate, and
evaluation is based on means.
ïx
couple (E1/2 ) 0.72 V vs NHE),23 which was used as internal
standard, employing a platinum disk working electrode.
Crystallographic Structure Determination. X-ray diffraction
measurements were performed on a Nonius Kappa CCD diffrac-
tometer at 120 K. Single crystals were positioned at 35 and 30
mm from the detector, and 676 and 341 frames were measured,
each for 10 and 120 s over a 1.5° and 2° scan for 1 and 3
correspondingly. The data were processed using Denzo-SMN
software. Crystal data, data collection parameters, and structure
refinement details for 1 and 3 are given in Table 1. The structures
were solved by direct methods and refined by full-matrix least-
squares techniques. Non-hydrogen atoms were refined with aniso-
tropic displacement parameters. H atoms were located on difference
Fourier maps and isotropically refined. The following computer
programs were used: structure solution, SHELXS-97,24 refinement,
(24) Sheldrick, G. M. SHELXS-97, Program for Crystal Structure Solution;
University Go¨ttingen: Go¨ttingen, Germany, 1997.
(25) Sheldrick, G. M. SHELXL-97, Program for Crystal Structure Refine-
ment; University Go¨ttingen: Go¨ttingen, Germany, 1997.
(26) Johnson, C. K. Report ORNL-5138; Oak Ridge National Laboratory:
Oak Ridge, TN, 1976.
(27) International Tables for X-ray Crystallography; Kluwer Academic
Press: Dordrecht, The Netherlands, 1992; Vol. C, Tables 4.2.6.8 and
6.1.1.4.
(23) Barrette, W. C., Jr.; Johnson, H. W., Jr.; Sawyer, D. T. Anal. Chem.
1984, 56, 1893-1898.
6026 Inorganic Chemistry, Vol. 42, No. 19, 2003

Isomeric (1H-1,2,4-Triazole)Ru(III) Complexes
Scheme 1
Figure 2. Part of the crystal structure of 1 showing the formation of a
stack pair by π-π interaction between two adjacent triazole ligands. Atoms
marked with i, ii, and iii are at the symmetry positions (-x + 1, -y + 1,
-z + 1), (x - 1, y, z), and (-x + 2, -y + 1, -z + 1), respectively.
Table 2. Bond Lengths (Å) and Angles (deg) in the Coordination
Polyhedron and in the Coordinated Triazole Ligands of 1 and 3
atom1-atom2
1
3A
3B
Ru1-N2
2.0627(10)
2.0733(10)
2.0668(13)
Ru1-N7
Ru2-N7
2.0575(14)
Ru1-Cl1
2.3663(6)
2.3628(6)
2.3870(5)
2.3478(5)
2.3493(6)
2.3591(6)
Ru1-Cl2
Results and Discussion
Ru1-Cl3
Ru1-Cl4
Synthesis and Characterization of Complexes. Ruthe-
nium(III) chloride reacts with an excess of 1H-1,2,4-triazole
in 2.38 M HCl solution (where the heterocycle exists as the
triazolium salt; pKa ) 2.5528) to give two products isolated
as the solid (H2trz)[cis-RuIIICl4(Htrz)2]‚H2O (1) as large red-
brown blocks and (H2trz)[trans-RuIIICl4(Htrz)2] (2) as orange
needles (Scheme 1). While the crystals of 1 proved to be
suitable for an X-ray structure determination, our attempts
to prepare single crystals of 2 for an X-ray data set collection
resulted in crystals of rather poor quality, which however
permitted us to establish the trans arrangement of the two
triazole ligands in the complex anion. In addition, a metath-
esis reaction between 2 and triphenylbenzylphosphonium
chloride has been carried out to obtain 3 (Scheme 1), which
was studied by X-ray crystallography (see following descrip-
tion). Complexes 1 and 2 show, as expected, better water
solubility than the indazole derivative (Hind)[trans-RuCl4-
(ind)2]. Aqueous solubility is often the major problem
precluding the clinical use of potent metal-based drugs. Note
also that the solubility of 1 is significantly higher than that
of 2 (see Experimental Section). The negative ion ESI mass
spectra of 1-3 showed a 100% intense peak at m/z 380 due
to [RuIIICl4(Htrz)2]- ions. Their isotopic patterns in the mass
spectra agree well with the calculated isotopic distribution.
Another peak observed in all three cases was detected at
m/z 242 and corresponds to the [RuIIICl4]- ion. The positive
ion mass spectrum of 3 displayed a peak at m/z 353 arising
from the Ph3PCH2Ph+ cation.
Ru2-Cl3
2.3557(7)
2.3671(9)
Ru2-Cl4
N1-N2
1.3775(13)
1.3205(15)
1.3483(15)
1.3554(15)
1.3127(15)
1.3868(14)
1.3127(15)
1.3461(15)
1.3516(17)
1.3164(16)
1
1.3734(18)
1.3146(19)
1.340(2)
1.341(2)
1.312(2)
N2-C3
C3-N4
N4-C5
C5-N1
N6-N7
1.3783(18)
1.313(2)
1.341(2)
1.343(2)
1.316(2)
3B
N7-C8
C8-N9
N9-C10
C10-N6
atom1-atom2-atom3
N1-N2-C3
N2-C3-N4
C3-N4-C5
N4-C5-N1
C5-N1-N2
N6-N7-C8
N7-C8-N9
C8-N9-C10
N9-C10-N6
C10-N6-N7
3A
108.21(9)
107.48(12)
109.70(14)
105.90(13)
110.46(14)
106.46(13)
109.14(10)
105.85(10)
110.57(10)
106.24(9)
108.63(9)
109.23(10)
105.85(10)
111.05(11)
105.23(10)
107.81(13)
109.95(14)
105.43(14)
111.11(15)
105.69(13)
and differs, as expected, from that of 2, in which three bands
at 240 nm (ꢀ ) 9425 M-1cm-1), 365 nm (ꢀ ) 2745
M-1cm-1), and 420 nm (ꢀ ) 370 M-1 cm-1) are observed.
The latter two bands are red-shifted in methanol solution of
3 to 375 nm (ꢀ ) 3400 M-1 cm-1) and 435 nm (ꢀ ) 380
M-1 cm-1), which can presumably be assigned to chloride
pπ f Ru dπ LMCT transitions.29
Crystal Structures. The asymmetric unit of 1 contains
an essentially octahedral anion [RuCl4(Htrz)2]-, the triazo-
lium cation, and a water molecule. A part of the crystal
structure of 1 is shown in Figure 2. Selected bond distances
and angles are quoted in Table 2.
The electronic absorption spectrum of 1 in water shows
one band with an absorption maximum at 358 nm (ꢀ ) 2420
M-1 cm-1) and a shoulder at ∼405 nm (ꢀ ) 780 M-1 cm-1)
(28) Potts, K. T. Chem. ReV. 1961, 61, 87-127.
(29) Rack, J. J.; Gray, H. B. Inorg. Chem. 1999, 38, 2-3.
Inorganic Chemistry, Vol. 42, No. 19, 2003 6027

Arion et al.
Figure 3. View of two independent complex anions of 3 (A and B),
showing the atom-labeling scheme. Displacement ellipsoids are drawn at
the 50% probability level.
The ruthenium(III) atom is bound to two, cis arranged to
each other, monodentate triazole ligands and four chloride
anions. The Ru-N2 and Ru-N7 bond distances at 2.0627-
(10) and 2.0733(10) Å, respectively, are comparable with
those in (Ph4P)[trans-RuCl4(ind)2] at 2.0517(21) and 2.0711-
(22) Å.30 The triazole ligands coordinated via N2 and N7
are tilted relative to the mean plane through RuN2N7Cl3Cl4,
the corresponding angles being at 42.5° and 138.7°. The Ru-
Cl bond distances (Table 2) are normal for ruthenium(III)
complexes.31-33 The most striking feature, however, is the
stabilization of the 4H tautomeric form of the 1,2,4-triazole
in this species through binding of the ligand via N2 to
ruthenium(III) ion. To the best of our knowledge, no such
behavior has been observed for any other metal ions so far,
and this gives a novel example for predominant stabilization
by complexation of a tautomer which is the minor one in
the metal-free ligands.21
Figure 4. Part of the crystal structure of 3 showing the formation of a
(100) sheet built from complex anions and water molecules. Atoms marked
i and ii are at the symmetry positions (x, y, z + 1) and (-x, 0.5 + y, 0.5
- z), respectively.
Table 3. Bond Lengths (Å) and Angles (deg) in the Triazolium Cation
in 1
atom1-atom2
1
N11-N12
1.3644(16)
1.3070(18)
1.3556(18)
1.3295(17)
1.3116(16)
1
103.69(11)
111.44(12)
106.37(11)
107.24(12)
111.25(11)
N12-C13
C13-N14
N14-C15
C15-N11
atom1-atom2-atom3
N11-N12-C13
N12-C13-N14
C13-N14-C15
N14-C15-N11
C15-N11-N12
It is worth mentioning the formation of stacked pairs of
[RuCl4(Htrz)2]- through π-π intermolecular interaction
between triazole planes as shown in Figure 2. For the triazole
rings of adjacent anions, the minimum distance between the
ring centroids of the interacting species is ca. 3.38 Å, with
the planes separated by 3.10 Å. In addition, the built dimeric
species is stabilized by strong H-bonding interactions. All
nitrogen atoms of the coordinated triazole ligands are
involved in hydrogen bonding. The hydrogen atoms of the
water molecule appear to take part in two bifurcated
hydrogen bonds, involving Cl2 and Cl3. Other intermolecular
contacts involving the triazolium cation and water molecule
are shown in Figure 2.
The asymmetric unit of 3 contains two crystallographically
distinct RuCl2(Htrz) moieties, each of them being a half of
the trans-[RuCl4(Htrz)2]-, with Ru1 and Ru2 situated on
crystallographic inversion points, a Ph3PCH2Ph+ cation and
a water molecule. Both Ru1 and Ru2 are coordinated by a
pair of symmetry related trans-triazole ligands and four
symmetry related chloride ions in an octahedral manner. The
structures of the complex anions 3A and 3B are shown in
Figure 3. Selected bond distances and angles are given in
Tables 2 and 3. The Ru1-N2 and Ru2-N7 at 2.0668(13)
and 2.0575(14) Å compare well with those in cis species
1. The trans-arranged triazole ligands are almost parallel to
each other and bisect the angles Cl1-Ru1-Cl2 and Cl3-
Ru2-Cl4 in 3A and 3B, correspondingly. The torsion angles
N1-N2‚‚‚N2A-C3A and N6-N7‚‚‚N7A-C8A are at
3.3° and -0.8° in 3A and 3B, respectively. Like in 1, the
triazole ligands adopt the 4H tautomeric form, being
coordinated through N2 in the nomenclature used for 1H-
or 4H-1,2,4-triazole. The Ru-Cl bond distances vary from
2.3493(6) to 2.36.71(9) Å and do not present unexpected
features.
The packing diagram reveals a layered structure composed
of alternating sheets of hydrogen bonded anionic [RuCl4-
(Htrz)2]- species, water molecules (Figure 4), and Ph3PCH2-
Ph+ cations. Between sheets there are weak interactions of
the C-H‚‚‚Cl type.
Although the structures of both isomeric species have been
unequivocally established by X-ray crystallography, the mode
of coordination of 1,2,4-triazole in them deserves some
additional comments which are given in the following
paragraphs.
Coordination Mode of Triazole. The coordination chem-
istry of 1,2,4-triazole shows interesting features,20 mainly
because of the diverse modes of binding to metal ions and
tautomerism. There are known two NH-tautomeric forms 1H
and 4H for 1,2,4-triazole, which differ from each other in
electron distribution and in the position of a relatively acidic
NH group.
(30) Peti, W.; Pieper, T.; Sommer, M.; Keppler, B. K.; Giester, G. Eur. J.
Inorg. Chem. 1999, 1551-1555.
(31) Alessio, E.; Balducci, G.; Lutman, A.; Mestroni, G.; Calligaris, G.;
Attia, W. M. Inorg. Chim. Acta 1993, 203, 205-217.
(32) Jasval, J. S.; Rettig, S. J.; James, B. R. Can. J. Chem. 1990, 68, 1808-
1817.
(33) Alessio, E.; Balducci, G.; Calligaris, M.; Costa, G.; Attia, W. M.;
Mestroni, J. Inorg. Chem. 1991, 30, 609-618.
6028 Inorganic Chemistry, Vol. 42, No. 19, 2003

Isomeric (1H-1,2,4-Triazole)Ru(III) Complexes
(NO3)3 (mecyt ) 1-methylcytosinato)50 and in a helical
polymer complex [AgI(trz)(PPh3)2]n.51 The 4H tautomer
stabilization occurs probably when the N1, N2 endo-bridging
mode is adopted, as in [CuCl2(Htrz)],52 [CuBr2(Htrz)],53 [Ni3-
(Htrz)6(H2O)6](NO3)6,54,55 [MoO3(Htrz)0.5]n,56 [RhI3(µ-Htrz)-
(η3-C3H5)6],57 or [Ag(NO3)(Htrz)]2.58 The triply bridging
triazolato group has been documented for ZnCl(trz),59 [{Cu3-
(trz)2}V4O12]n,60 and two rhodium(I) complexes [Rh3(µ3-trz)-
(µ-Cl)Cl(η4-tfbb)(CO)4]‚0.5CH2Cl2 (tfbb ) tetrafluoroben-
zobarrelene)61 and [Rh3(µ-Cl)Cl(µ3-trz)(η3-C3H5)2(CO)4]‚
0.5C2H4Cl2.57
In both isomers, the coordination of 1,2,4-triazole to
ruthenium via N2 has been found. These are the first known
complexes in which triazole acts as a monodentate ligand
being bound via N2 to a metal ion. The N2 atom in triazole
is less basic than N4;62 therefore, such a behavior is rather
unexpected. The reason is probably the acidic reaction
medium, which is needed to avoid the deprotonation of the
1H-1,2,4-triazole upon coordination. Moreover, we suggest
that N4 is easily protonated under these conditions and N2
possessing a lone pair is probably imposed to coordinate to
ruthenium with subsequent rearrangement of the azole ring
double bonds and deprotonation at N1, due to the polarization
effect of Ru3+, which is more close to the positively charged
metal center than N4.
Figure 5. Tautomeric forms of 1,2,4-triazole.
The species 1H(A) and 1H(B) are statistically distinct, but
energetically equal (Figure 5).34 Therefore, it implies that
the 1H tautomer is twice as probable as 4H. Dipole moment
measurements of 1,2,4-triazole in dioxane indicated the
presence of some amount of 4H-tautomer in solution.35
Analogously, 15N NMR studies showed the presence of about
40% of 4H-tautomer in concentrated solutions of Htrz in
methanol.36 In the solid, Htrz crystallizes exclusively as a
1H-tautomer.37-39 However, the 4H-tautomer can be stabi-
lized upon ligation to metal centers. In addition, 1,2,4-triazole
can act in metal complexes as a neutral ligand or as a
triazolate anion (trz)-. Moreover, the 1H-1,2,4-triazole can
easily be derivatized. More than 200 X-ray diffraction
structures are well documented,20 of them only 10% concern
the metal complexes of the unsubstituted 1,2,4-triazole. This
behaves as monodentate ligand coordinating to the first row
or second row transition metal ion through N4 ([MnII(SO4)-
(Htrz)(H2O)4],40 [Cd(NCS)2(Htrz)2],41 [FeCl3(bpy)(Htrz)],42
or Zn(II) in human carbonic anhydrase43) when neutral or
via N1 ([Au(trz)(PPh3)]2,44 [PhC(CH3)2CH2]3Sn(trz)45) when
deprotonated. exo-Didentate linking of metal ions through
two nonadjacent nitrogens is a feature of both triazole and
triazolate ligands. The exo-didentate N2, N4 binding mode
was found in a number of compounds with general formulas
[MII(NCS)2(Htrz)2], where M ) Fe,46 Co,47,48 Mn,49 Zn, and
Cu.47 exo-Didentate N1, N4 linking of triazolate anion has
been discovered in trans-{[(NH2Me)2PtII(mecyt)2PdII]2(trz)}-
Cyclic Voltammetric Studies. The cyclic voltammograms
of 1 [Figure 6 (top)], 2, and 3 [Figure 6 (bottom)] in DMF,
at a platinum disk working electrode, at the scan rate 200
mV/s, display one single-electron oxidation wave (Iox) that
meets the usual reversibility and diffusion controlled electron-
ox
transfer criteria, at E1/2 ) 0.33, 0.46, and 0.45 V versus
FcH/FcH+, respectively, assigned to the Ru(III) to Ru(IV)
oxidation, and one irreversible reduction wave (Ired) at Ep
red
) -1.23, -1.24, and -1.26 V, correspondingly, due to the
Ru(III) to Ru(II) reduction. Another irreversible reduction
red
wave is observed at Ep ) -0.92 V in 1 and 2, but it
(34) Claramunt, R. M.; Lo´pez, C.; Garcia, M. A.; Otero, M. D.; Torres,
M. R.; Pinilla, E.; Alarco´n, S. H.; Alkorta, I.; Elguero, J. New J. Chem.
2001, 25, 1061-1068.
disappears in 3, or when a glassy carbon working electrode
is used in 1 or 2, and is associated to the reduction of the
ox
protic counterion H2trz+. Irreversible oxidation waves at Ep
(35) Mazheika, I. B.; Chipen, G. I.; Hiller, S. A. Khim. Geterotsikl. Soedin.
1966, 776-781.
) -0.82, -0.63, and 0.66 V in 1, -0.88, -0.64, and 0.67
(36) Witanowski, M.; Stefaniak, L.; Januszewski, H.; Grabowski, Z.; Webb,
G. A. Tetrahedron 1972, 28, 637-653.
(37) Goldstein, P.; Ladell, J.; Abowitz, G. Acta Crystallogr. 1969, B25,
135-143.
(50) Pichierri, F.; Chiarparin, E.; Zangrando, E.; Randaccio, L.; Holthenrich,
D.; Lippert, B. Inorg. Chim. Acta 1997, 264, 109-116.
(51) Nomiya, K.; Tsuda, K.; Kasuga, N. C. J. Chem. Soc., Dalton Trans.
1998, 1653-1659.
(52) Jarvis, J. A. J. Acta Crystallogr. 1962, 15, 964-966.
(53) Asaji, T.; Sakai, H.; Nakamura, D. Inorg. Chem. 1983, 22, 202-206.
(54) Reimann, C. W.; Zocci, M. J. Chem. Soc., Chem. Commun. 1968,
272.
(38) Jeffrey, G. A.; Ruble, J. R.; Yates, J. H. Acta Crystallogr. 1983, B39,
388-394.
(39) Fuhrmann, P.; Koritsanszky, T.; Luger, P. Z. Kristallogr. 1997, 212,
213-220.
(40) Schomburg, D.; Link, M.; Linoh, H.; Tacke, R. J. Organomet. Chem.
1988, 339, 69-80.
(41) Corter, S.; Engelfriet, D. W. Acta Crystallogr. 1981, B37, 1214-1218.
(42) Haasnoot, J. G.; De Keyzer, G. C. M.; Verschoor, G. C. Acta
Crystallogr. 1983, C39, 1207-1209.
(55) Reimann, C. W.; Zocci, M. Acta Crystallogr. 1971, B27, 682-691.
(56) Hagrman, P. J.; LaDuca, R. L., Jr.; Koo, H.-J.; Rarig, R., Jr.;
Haushalter, R. C.; Whangbo, M.-H.; Zubieta, J. Inorg. Chem. 2000,
39, 4311-4317.
(43) Driessen, W. L.; De Graaf, R. A. G.; Vos, J. G. Acta Crystallogr.
1983, C39, 1635-1637.
(57) Oro, L. A.; Pinillos, M. T.; Tejel, C.; Foces-Foces, C.; Cano, F. H. J.
Chem. Soc., Dalton Trans. 1986, 2193-2200.
(44) Mangani, S.; Liljas, A. J. Mol. Biol. 1993, 232, 9-14.
(45) Nomiya, K.; Noguchi, R.; Ohsawa, K.; Tsuda, K. J. Chem. Soc., Dalton
Trans. 1998, 4101-4108.
(58) Schmidbaur, M.; Mair, A.; Mu¨ller, G.; Lachmann, J.; Gamper, S. Z.
Naturforsch. 1991, 46b, 912-918.
(46) Engelfriet, D. W.; Verschoor, G. C. Acta Crystallogr. 1981, B37, 237-
240.
(59) Kro¨ber, J.; Bkouche-Waksman, I.; Pascard, C.; Thomann, M.; Kahn,
O. Inorg. Chim. Acta 1995, 230, 159-163.
(47) Engelfriet, D. W.; Den Brinker, W.; Verschoor, G. C.; Gorter, S. Acta
Crystallogr. 1979, B35, 2922-2927.
(48) Engelfriet, D. W.; Groeneveld, W. L.; Groenendijk, H. A.; Smit, J.
J.; Nap, G. M. Z. Naturforsch. 1980, 35a, 115-128.
(49) Engelfriet, D. W.; Groeneveld, W. L.; Nap, G. M. Z. Naturforsch.
1980, 35a, 1387-1389.
(60) Hagrman, P. J.; Bridges, C.; Greedan, J. E.; Zubieta, J. J. Chem. Soc.,
Dalton Trans. 1999, 2901-2903.
(61) Oro, L. A.; Pinillos, M. T.; Tejel, C.; Foces-Foces, C.; Cano, F. H. J.
Chem. Soc., Dalton Trans. 1986, 1087-1094.
(62) Meot-Ner, M.; Liebman, J. F.; Del Bene, J. E. J. Org. Chem. 1986,
51, 1105-1110.
Inorganic Chemistry, Vol. 42, No. 19, 2003 6029

Arion et al.
Figure 6. Cyclic voltammogram of 1 in DMF at scan rate 200 mV/s with
a platinum working electrode (top) and of 3 in DMF at scan rate 200 mV/s
with a glassy carbon working electrode (bottom). Asterisk indicates reduction
wave of the H2trz+ counterion.
V in 2, and -0.86, -0.66, and 0.64 V in 3 are detected upon
scan reversal following the cathodic scan.
The current function (ipV-1/2c-1, where ip is the peak
current, V is the scan rate, and c is the concentration) of the
oxidation wave at -0.82 in 1, -0.88 in 2, or -0.86 V in 3,
which is maximum at higher scan rates, decreases with the
decrease of the scan rate with concomitant increase of the
current function of the oxidation wave at - 0.63 in 1, -
0.64 in 2, or -0.66 V in 3. This indicates the cathodic
formation of an intermediate (oxidized at the former wave)
that is further converted into the thermodynamic product
oxidized at the latter wave, which is better seen at lower
scan rates (Figures S1-S4).
The oxidation wave at 0.66 in 1, 0.63 in 2, or 0.64 V in
3 can be assigned to the oxidation of chloride, liberated upon
cathodic reduction of the complexes as known63 to occur on
chemical reduction of Ru(III)-chloro complexes. This is also
consistent with reported observations64 for this type of
complexes and is further supported by the fact that addition
of [Ph3PCH2Ph]Cl to the solution revealed chloride oxidation
at ca. 0.65 V. Comparison of the oxidation potentials of the
various complexes indicates that the cis isomer (in 1) is easier
to oxidize than the trans one (in 2 and 3), indicating a more
stabilized HOMO in the latter isomer.
Figure 7. Dose-response curves of the complexes 1 (9 96 h, 0 24 h),
and 2 (b 96 h; O 24 h) in colon carcinoma cells SW480 (top) and HT29
(middle) and in mammary carcinoma cells SK-BR-3 (bottom) after 24 h
and 96 h of exposure under standard conditions (pH 7.4). Each data point
is the mean of three independent determinations.
Lever’s redox potential parametrization approach65 for
octahedral complexes of reversible RuIII/RuII couples assum-
ing ligand additivity allows us to estimate the redox potentials
red
for our complexes. The thus calculated potential, E1/2
)
-1.26 V (estimated by considering the EL value of 0.18 V
versus NHE for the 1,2,4-triazole ligand, in complexes
studies in organic solvents), is in very good agreement with
the measured reduction potentials (see preceding details),
although the latter correspond to irreversible waves and to
the unusual N2-coordination mode of 1,2,4-triazole. How-
ever, one should mention that this agreement in organic
solvents cannot be extrapolated to aqueous medium, where
the RuIII/RuII redox potentials shift anodically and are pH
dependent as already demonstrated for (Him)[trans-RuCl4-
(im)2].66 Further investigation of our systems in aqueous
media is under way.
(63) Ford, P. C. Coord. Chem. ReV. 1970, 5, 75-99.
(64) Serli, B.; Zangrando, E.; Iengo, E.; Mestroni, G.; Yellowlees, L.;
Alessio, E. Inorg. Chem. 2002, 41, 4033-4043.
(65) Lever, A. B. P. Inorg. Chem. 1990, 29, 1271-1285.
(66) Ni Dhubhghaill, O. M.; Hagen, W. R.; Keppler, B. K.; Lipponer, K.
G.; Sadler, P. J. J. Chem. Soc., Dalton Trans. 1994, 3305-3310.
6030 Inorganic Chemistry, Vol. 42, No. 19, 2003

Isomeric (1H-1,2,4-Triazole)Ru(III) Complexes
Cytotoxicity in Human Carcinoma Cell Lines. Re-
sponses of SW480, HT29 (colon carcinoma), and SK-BR-3
(mammary carcinoma) cells to continuous exposure to
various concentrations of 1 and 2 for 24 and 96 h are
presented in Figure 7. Two remarkable features become
evident: (i) Time-dependent response of all three cell lines
to 1 and 2 has been observed. No marked antiproliferative
effect is seen after 24 h of drug-exposure time in concentra-
tions up to 2000 µM; in neither case was the IC50 reached.
In contrast, the effect is evident after 96 h. This can be due
to slow activating reactions of the complexes in the medium
or slow incorporation mode into the cell. Which of these
mechanisms is responsible for this observation has to be
determined by further experiments. The fact that the marked
time dependence of the cell damage is observed despite
extended postincubation after the 24-h treatment indicates
that intracellular activation of the compounds cannot explain
this effect. (ii) The structure-activity relationship is worth
mentioning. The trans isomer, 2, shows higher antiprolif-
erative activity in all three human carcinoma cell lines, as
compared to cis compound 1, the difference being more
pronounced on colon carcinoma cells than on the mammary
cell line.
The trans complex, 2, shows even higher antiproliferative
activity after the 96 h treatment on SW480 than (Him)[trans-
RuCl4(im)2] (IC50 ) 840 µM for imidazole complex;67 113
( 8 µM for 2), leading to further interest in comparing trans
and cis complexes to figure out whether the ligand or the
configuration of the complex is more important for evolving
activity.
Final Remarks. For the first time, both trans and cis
isomers of (azole)Ru(III) complexes of the type [RuCl4L2]-,
where L ) azole heterocycle, have been prepared, in which
unprecedented monodentate coordination of triazole via N2
and stabilization of the 4H tautomeric form have been
observed. This work demonstrates the availability of both
isomers for complexes of the type [RuCl4L2]- and makes
the search for cis isomers with species other than triazole
heterocycles relevant. The performed preparative studies gave
a unique opportunity to carry out structure-activity relation-
ships for such type of complexes. Compounds 1 and 2 show
considerable in vitro antitumor activity in three human cell
lines: SW480, HT29, and SK-BR-3, the activity against
SW480 being higher than for (Him)[trans-RuCl4(im)2]. It is
worth mentioning that in contrast to PtCl2(NH3)2, where the
trans-species exhibits only marginal tumor-inhibiting activity,
the activity of trans product 2 was superior to that of cis
complex 1, suggesting another mechanism of action than that
for cisplatin. As expected, both isomeric species are signifi-
cantly more water-soluble than the indazole derivative
(Hind)[trans-RuCl4(ind)2], which suggest them as compounds
of great potential for development as anticancer drugs.
Studies on their anticancer activity in vivo, hydrolytic
stability, interaction with biologically relevant targets, and
cell uptake of Ru species are under way in our group.
Acknowledgment. The authors are indebted to FWF,
COST, the Foundation for Science and Technology and the
POCTI-programme (Portugal) for financial support. We also
thank Dr. G. Giester for X-ray data collection, Dr. Fa´tima
Guedes da Silva, and Lic. Nate´rcia Martins for assistance in
the electrochemical study. E.R. was supported by FWF
(Austrian Science Fund) and University of Vienna (Faculty
of Sciences and Mathematics, International Relations Office).
Supporting Information Available: X-ray crystallographic files
in CIF format for 1 and 3. Additional figures. This material is
available free of charge via the Internet at http://pubs.acs.org.
(67) Jakupec, M. A. Unpublished results.
IC034605I
Inorganic Chemistry, Vol. 42, No. 19, 2003 6031