Influence of the diketonato ligand on the cytotoxicities of [Ru(η6-p-cymene)-(R2acac)(PTA)]+ complexes (PTA = 1,3,5-triaza-7-phosphaadamantane)

Article abstract of DOI:10.1002/ejic.200701291

A series of compounds of general formula [Ru(η⁶-p-cymene) (R₂acac)(PTA)][X] (R₂acac = Me₂acac, tBu ₂acac, Ph₂acac, Me₂acac-Cl; PTA = 1,3,5-triaza-7-phosphaadamantane; X = BPh₄, BF₄), and the precursor to the Me₂acac-Cl derivative [Ru(η⁶-p- cymene)(Me₂acac-Cl)Cl], have been prepared and characterised spectroscopically. Five of the compounds have also been characterised in the solid state by X-ray crystallography. The tetrafluoroborate salts are water-soluble, quite resistant to hydrolysis, and have been evaluated for cytotoxicity against A549 lung carcinoma and A2780 human ovarian cancer cells. The compounds are cytotoxic towards the latter cell line, and relative activities are discussed in terms of hydrolysis (less important) and lipophilicity, which appears to exert the dominating influence. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejic.200701291

FULL PAPER
DOI: 10.1002/ejic.200701291
Influence of the Diketonato Ligand on the Cytotoxicities of [Ru(η6-p-cymene)-
(R2acac)(PTA)]+ Complexes (PTA = 1,3,5-triaza-7-phosphaadamantane)
Carsten A. Vock,*[a][‡] Anna K. Renfrew,[a] Rosario Scopelliti,[a]
Lucienne Juillerat-Jeanneret,[b] and Paul J. Dyson*[a]
Keywords: Bioorganometallics / Anticancer drugs / Metal-based drugs / Ruthenium / X-ray structure
A series of compounds of general formula [Ru(η6-p-cymene)
(R2acac)(PTA)][X] (R2acac = Me2acac, tBu2acac, Ph2acac,
Me2acac-Cl; PTA = 1,3,5-triaza-7-phosphaadamantane; X =
BPh4, BF4), and the precursor to the Me2acac-Cl derivative
[Ru(η6-p-cymene)(Me2acac-Cl)Cl], have been prepared and
characterised spectroscopically. Five of the compounds have
also been characterised in the solid state by X-ray crystal-
lography. The tetrafluoroborate salts are water-soluble, quite
resistant to hydrolysis, and have been evaluated for cytotoxi-
city against A549 lung carcinoma and A2780 human ovarian
cancer cells. The compounds are cytotoxic towards the latter
cell line, and relative activities are discussed in terms of hy-
drolysis (less important) and lipophilicity, which appears to
exert the dominating influence.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
Introduction
properties in such a way that DNA damage occurs in cells
with pH Ͻ 7 (like in the tumour mass of poorly oxygenated
cancer cells), while no effect is observed in normal cells with
pH Ͼ 7.[7] Indeed, this selectivity was observed in compara-
tive cell tests of several structurally diversified RAPTA de-
rivatives with TS/A adenocarcinoma cancer cells and non-
Since the discovery of cisplatin and its anticancer proper-
ties in 1965,[1,2] the use of metal complexes as potential
agents in anticancer and antibiotic therapy has become a
prospering field of research.[3] In particular, ruthenium
complexes have gained increasing attraction during the last
decade,[4] since ruthenium offers several interesting advan-
tages in comparison with platinum: a broad range of oxi-
dation states, i.e. RuII, RuIII and RuIV, are accessible under
physiological conditions, combined with a lower general
toxicity of ruthenium compounds in comparison with plati-
num complexes. Two (azole)RuIII complexes, NAMI-A (1)[5]
and KP1019 (2)[6] (Figure 1), have successfully completed
phase I clinical trials and will presumably enter phase II tri-
als in the near future.
Recently, there has been growing interest in the antican-
cer properties of (η6-arene)ruthenium(II) compounds with
various additional ligands. Compounds of general formula
[Ru(η6-arene)(pta)Cl2] (pta = 1,3,5-triaza-7-phosphaadam-
antane) have been developed in our group, the prototype
being [Ru(η6-p-cymene)(pta)Cl2] (3) (RAPTA-C) (Fig-
ure 1).[7,8] In vitro, 3 shows pH-dependent DNA-damaging
tumourigenic (healthy) HBL-100 mammary cells.[8a,8b]
A
series of (η6-arene)ruthenium(II) compounds of general for-
mula [Ru(η6-arene)(imidazole)nCl3–n][X]n–1 have been syn-
thesized and evaluated in the same comparative test sys-
tem,[9] the most promising compound in terms of selectivity
being the dicationic complex [Ru(η6-benzene)(mimid)3]-
[BF4]2 (4) (mimid = N-methylimidazole) (Figure 1) with
IC50 values of 249 µ (TS/A) vs. 740 µ (HBL-100), deter-
mined in MTT assays. The rather low cytotoxicities of com-
plexes like 4 with simple imidazole ligands could be con-
siderably improved by attaching structurally modified Pgp
inhibitors to an (η6-arene)ruthenium(II) centre through
imidazole linkers.[10] Using this strategy the most promising
derivative [Ru(η6-p-cymene)(anthraimid)Cl2] 5 {anthraimid
= N-(anthracen-9-yl)imidazole} (Figure 1) showed cyto-
toxicities from 22 to 37 µ in four different cancer cell
lines.[10] The cytotoxicities were significantly improved in
[a] Institut des Sciences et Ingénierie Chimiques, Ecole Polytech- comparison with the free ligand, and fluorescence micro-
nique Fédérale de Lausanne (EPFL),
scopy revealed the enrichment of fluorescent material in the
1015 Lausanne, Switzerland
cell nucleus, indicating DNA to be a possible target. Sadler
et al. have focussed extensively on monocharged complexes
with chelating ethylenediamine-type ligands.[11] The com-
plexes exhibit comparatively high cytotoxic properties, with
[Ru(η6-tetrahydroanthracene)(ethylenediamine)Cl][PF6] (6)
being of similar cytotoxicity as cisplatin in A2780 human
ovarian cancer cells.[11b]
Fax: +41-21-693 98 85
E-mail: c.vock@mx.uni-saarland.de
paul.dyson@epfl.ch
[b] University Institute of Pathology, Centre Hospitalier Uni-
versitaire Vaudois (CHUV),
1011 Lausanne, Switzerland
[‡] Current address: Laboratory of Pharmaceutical and Medicinal
Chemistry, Department of Pharmacy, Saarland University,
P. O. Box 151150, 66041 Saarbrücken, Germany
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C. A. Vock, A. K. Renfrew, R. Scopelliti, L. Juillerat-Jeanneret, P. J. Dyson
FULL PAPER
Figure 1. Structures of NAMI-A (1), KP1019 (2), RAPTA-C (3), [Ru(η6-benzene)(mimid)3][BF4]2 (4), [Ru(η6-p-cymene)(anthraimid)Cl2]
(5) and [Ru(η6-tetrahydroanthracene)(ethylenediamine)Cl][PF6] (6).
In previous studies we have shown that complexes of type
Results and Discussion
[Ru(η6-p-cymene)(O,OЈ-dicarboxylato)(PTA)] (dicarboxyl-
In contrast to previously published procedures,[13,14] the
ato = oxalato or 1,1-cyclobutanedicarboxylato), resist hy-
neutral complexes 7–10 were prepared in a one-pot reaction
by treating a solution of [Ru(η6-p-cymene)Cl2]2 and the ap-
propriate 1,3-diketone with an excess of Na2CO3 in acetone
at room temp. for 3–3.5 h. Removal of the solvent, and ex-
traction of the residue with CH2Cl2, followed by evapora-
tion of the solvent or crystallisation by addition of Et2O
and/or petroleum ether, afforded complexes 7–10 in moder-
ate to very good yields of 69–98%. Complexes 11·BF4–
14·BF4 were prepared by treatment of the corresponding
precursors 7–10 with PTA and an excess of NaBF4 in ace-
tone. For derivatives 11·BPh4–14·BPh4, an acetone/CH2Cl2
mixture was used as solvent, and only a slight excess of
NaBPh4 was applied. Occasional heating for both types of
products was useful to shorten reaction times; however,
continuous heating results in increased levels of by-product
impurities. Compounds 11–14 were obtained as yellow/yel-
low-orange solids in reasonable yields ranging from 51 to
76%.
drolysis in aqueous medium; however, the complexes essen-
tially showed no cytotoxic effect in several cancer cell
lines.[12] In contrast, Sadler et al. reported the synthesis, li-
gand-exchange reactions and biological evaluation of neu-
tral complexes [Ru(η6-p-cymene)(R2acac)Cl] (7–9) with dif-
ferent O,OЈ-chelating 1,3-diketone-based ligands R2acac
(Figure 2), thereby obtaining high cytotoxicities, compar-
able with the ethylenediamine-type complexes mentioned
above.[13] In order to combine both aspects, we have synthe-
sized a series of monocationic complexes [Ru(η6-p-cy-
mene)(R2acac)(PTA)][X] (11–13) (X = BPh4, BF4) (Fig-
ure 2). In addition, a new derivative 10 with the 3-chloro-
acetylacetonato ligand and its corresponding PTA deriva-
tive 14·BF4 were prepared and investigated. We present here
the spectroscopic and crystallographic aspects of the new
compounds in combination with biological in vitro cyto-
toxicity assays and hydrolysis studies.
The 31P NMR spectra of 11–14 each consist of one single
peak in the region typical for (arene)(PTA)ruthenium(II)
complexes (from δ = –28.08 ppm for 13·BF4 to δ =
–30.60 ppm for 11·BPh4), indicating the presence of the
desired products when compared with the chemical shift of
δ = –30.16 for the related complex [Ru(η6-p-cymene)-
(O,OЈ-cyclobutanedicarboxylato)(PTA)].[12] 1H NMR spec-
troscopy in CDCl3 reveals differences for the resonances of
the aromatic protons at the cymene system between the cor-
responding BF4 and BPh4 derivatives. While for all BPh4
salts two distinct doublets are observed, the signals are
much less separated in the corresponding BF4 derivatives, in
the case of 11·BF4 and 14·BF4 merging to give one signal.
Furthermore, there is a strong shift of these signals to
higher frequencies, approaching to some extent the reso-
nance of free cymene, which is observed at δ = 7.13 ppm in
Figure 2. Structures of the neutral complexes 7–10 and the new
monocationic PTA derivatives 11–14.
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Cytotoxicities of [Ru(η6-p-cymene)(R2acac)(PTA)]+ Complexes
CDCl3, indicating that the cymene ring system might be Characterisation of 11·BF4, 11·BPh4, 12·BPh4, 13·BF4 and
less strongly coordinated in the BF4 salts than in the corre- 14·BF4 in the Solid State
sponding BPh4 compounds. In addition, the 31P NMR res-
onances are shifted to higher frequencies for BF4 salts in
Crystals suitable for X-ray analysis were obtained for
comparison with the corresponding BPh4 derivatives, the 11·BF4, 11·BPh4, 12·BPh4, 13·BF4 and 14·BF4. Crystallisa-
difference being most obvious for the couple 12·BF4/ tion conditions are described in the Experimental Section.
12·BPh4 with ∆δ = 1.62 ppm, indicating that the PTA li- Graphical representations for the cationic parts of com-
gand might compensate for the reduced bonding interaction plexes 11·BPh4, 12·BPh4, 13·BF4 and 14·BF4 are depicted
of the arene system.
in Figure 3. Selected bond lengths and angles are given in
The ESI mass spectra of 11–14 in CH3CN provide parent Table 1, and relevant crystallographic parameters are listed
peaks corresponding to the parent cations [Ru(η6-p-cy- in Table 5.
mene)(R2acac)(PTA)]+; no fragmentation peaks or ligand-
All four complexes adopt the expected three-legged
exchange products are observed. MS/MS analysis with 20– piano-stool geometry, with the corresponding β-diketonato
30% relative collision energy reveals the loss of the PTA ligand and the ruthenium centre forming a six-membered
ligand to be the first fragmentation reaction for all com- chelate. The O–Ru–O bond angles show little strain and
plexes.
are between 87.34(13)° and 88.63(7)°, comparable to those
Figure 3. ORTEP plots of 11·BPh4 (top, left), 12·BPh4 (top, right), 13·BF4 (bottom, left) and 14·BF4 (bottom, right) drawn with 50%
probability ellipsoids (BF4 and BPh4 anions omitted for clarity).
Eur. J. Inorg. Chem. 2008, 1661–1671
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FULL PAPER
Table 1. Selected bond lengths [Å] and angles [°] for 11·BF4, tween the BF4 fluorine atoms and the cymene hydrogen
11·BPh4, 12·BPh4, 13·BF4 and 14·BF4.
atoms H9 (aromatic system; H9–F3A 2.601 Å), H6 (isopro-
pyl group; H6–F4A 2.449 Å), H8C (isopropyl group; H8C–
F3A 2.595 Å) and H1B (methyl group; H1B–F4A 2.589 Å)
(Figure 4).
11·BF4 11·BPh4 12·BPh4 13·BF4 14·BF4
Ru1–P1
Ru1–C2
Ru1–C3
Ru1–C4
Ru1–C5
Ru1–C9
Ru1–C10
2.322(2) 2.3164(11) 2.3279(7) 2.347(2) 2.3208(13)
2.224(6) 2.187(4) 2.200(2) 2.202(7) 2.204(5)
2.264(5) 2.243(4) 2.250(2) 2.275(7) 2.246(5)
2.277(5) 2.256(4) 2.257(3) 2.269(7) 2.252(4)
2.235(5) 2.202(6) 2.194(2) 2.202(6) 2.205 (4)
2.200(5) 2.201(4) 2.202(2) 2.188(6) 2.206 (4)
2.199(6) 2.187(4) 2.196(2) 2.202(6) 2.195(4)
Hydrolysis Study for Complexes 11·BF4–14·BF4
To determine the stability of 11·BF4–14·BF4, a hydrolysis
study was carried out under pseudo-pharmacological con-
ditions. The hydrolytic decomposition of the compounds
was studied in 5 m NaCl solution (being a model for the
low intracellular NaCl concentration in cells) and in
100 m NaCl solution (approximating the higher NaCl
levels in blood plasma). Solutions of the complexes (c =
2.0 m) in aqueous NaCl (c = 5 m or 100 m in D2O
containing 1% of [D6]DMSO) were prepared and main-
tained at 37 °C for 7 d. The decomposition of the complexes
was monitored by 31P NMR spectroscopy (Figure 5). Dur-
ing the measurements in 100 m aqueous NaCl solution,
generally just one major product was observed, presumably
corresponding to [Ru(η6-p-cymene)(PTA)Cl2],[15] which al-
lowed the approximation of decomposition by integration
of the resonances of unchanged complex and hydrolysis
product in the 31P NMR spectra (Table 2). In 5 m aqueous
NaCl solution, the decomposition pattern for all complexes
with exception of 12·BF4 (which did not hydrolyze at all)
turned out to be more complicated; several hydrolysis
products were observed, probably including [Ru(η6-p-cy-
mene)(PTA)(H2O)Cl]+,[15] which prevented the extent of hy-
drolysis being quantified.
Ru1–Ar(centroid) 1.717
1.695
1.703
1.710
1.703
Ru1–O1
Ru1–O2
O1–Ru1–O2
2.077(4) 2.083(2) 2.071(2) 2.083(4) 2.073(3)
2.094(4) 2.091(3) 2.073(2) 2.086(4) 2.076(3)
88.2(2) 88.58(10) 88.63(7) 88.7(2) 87.34(13)
reported for similar complexes of type [Ru(η6-arene)-
(R2acac)Cl] [88.40(9)°].[14] Ruthenium–oxygen bond lengths
are in agreement with the literature and are not greatly af-
fected by variation of the R2acac substituent. Ru–arene
[1.695–1.717 Å] and Ru–P distances [2.3164(11)–
2.3279(7) Å] are close to those of [Ru(η6-p-cymene)(O,OЈ-
oxalato)(PTA)] [1.69 Å and 2.310(1) Å, respectively].[12]
Interestingly, replacement of the BPh4 counteranion by BF4
in 11 results in an increase of the Ru–arene distance by
2.2 pm, although this distance is within the esds (see
Table 2), but corroborates well with the 1H NMR study de-
scribed above. Indeed, several interactions are observed be-
Table 2. Decomposition of 11·BF4–14·BF4; the integral ratios com-
plex/hydrolysis product from 31P NMR spectroscopy are depicted.
Conditions: 2.0 m solution of complex in 100 m NaCl/D2O con-
taining 1% [D6]DMSO, T = 37 °C.
Time [h]
Complex
11·BF4
12·BF4
13·BF4
14·BF4
Increased rates of reaction were observed in 100 m
aqueous NaCl solution for all compounds, with the stability
of the complexes increasing in the order 14·BF4 ϽϽ 11·BF4
Ͻ 13·BF4 Ͻ 12·BF4. The most stable complex, 12·BF4, be-
ars the sterically demanding tBu2acac β-diketonato ligand.
In 5 m NaCl solution, no changes were observed even af-
ter 7 d, and in 100 m NaCl solution 125 h were required
before any changes were observed. 13·BF4 is slightly less
stable, with small amounts of hydrolysis product in 5 m
aqueous NaCl detected after 7 d and approximately 20%
decomposition in 100 m NaCl solution after the same
time. 11·BF4 reacted comparatively rapidly in 100 m aque-
ous NaCl; however, approximately 65% of the complex re-
mained unchanged in solution after 7 d. In comparison,
14·BF4 with an electron-withdrawing chloro substituent at
the acetylacetonato ligand, is much less stable. In 100 m
aqueous NaCl solution, approximately 50% of the complex
had transformed after 53 h, and only 11% of unchanged
complex remained after 7 d. In 5 m NaCl solution, the
reaction was slightly slower, but a much more complicated
pattern of decomposition products was observed, indicated
0
25
53
77
99
125
168
100:0
100:0
100:0
100:0
100:0
100:0
95.3:4.7
89.5:10.5
100:0
100:0
96.4:3.6
95.5:4.5
90.8:9.2
87.4:12.6
80.3:19.7
100:0
97.8:2.2
93.5:6.5
90.5:9.5
83.4:16.6
77.2:22.8
65.0:35.0
73.8:26.2
49.8:50.2
37.0:63.0
25.1:74.9
19.1:80.9
10.8:89.2
1
by ca. six peaks in the 31P NMR spectrum after 7 d. H
NMR spectra measured in parallel show the presence of
detectable amounts of free p-cymene, indicating the loss of
the η6-coordinated aromatic ligand being involved in the
hydrolysis process.
Figure 4. Interactions between the cymene moiety and BF4 coun-
terions in complex 11·BF4.
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Cytotoxicities of [Ru(η6-p-cymene)(R2acac)(PTA)]+ Complexes
Figure 5. Kinetic hydrolysis experiment at 37 °C: 2.0 m solution of complex 11·BF4–14·BF4 in (top) 5.0 m NaCl/D2O (1% [D6]DMSO)
and (bottom) 100 m NaCl/D2O (1% [D6]DMSO).
In vitro Evaluation
Table 3. Results of the MTT-assays: IC50 values for compounds 10,
11a–13a and 14 in comparison with the literature values for 7–9.
Complexes 10 and 11·BF4–14·BF4 were evaluated in a
comparative in vitro MTT cell viability assay[16] with two
cancer cell lines, viz. A549 lung carcinoma and A2780 hu-
man ovarian cancer cells. The IC50 values for compounds
10 and 11·BF4–14·BF4 are listed in Table 3. The IC50 values
for complexes 7–9 in A2780 cells have been previously re-
ported and found to be 19 µ (7), 14 µ (8) and 11 µ (9),
respectively.[13]
IC50 [µ]
Compound
A549
A2780
10
51
Ͼ 2000
97
57
50
30
15
13
7
11·BF4
12·BF4
13·BF4
14·BF4
14
The PTA complexes 11·BF4–14·BF4 exhibited strong
cytotoxicities in A2780 cells, each of them being even toxicity was observed, with 10 being more cytotoxic than
slightly more cytotoxic than the corresponding parent 11·BF4–13·BF4 and of similar cytotoxicity to the PTA de-
chloro complexes 7–10. In comparison, the cytotoxicity of rivative 14·BF4.
the complexes towards the A549 lung cancer cell line was
To evaluate the influence of lipophilicity of the com-
significantly lower, with 11·BF4 being completely inactive. plexes on cytotoxicity, the logP values (P = partition coeffi-
The new neutral complex 10 exhibited slightly lower cyto- cient between n-octanol and H2O) of the free R2acac li-
toxic properties in A2780 cells than derivatives 7–9 (see gands were calculated. Since the experimental and theoreti-
above). However, in A549 cells a comparatively high cyto- cal determination of logP values for metal complexes is
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C. A. Vock, A. K. Renfrew, R. Scopelliti, L. Juillerat-Jeanneret, P. J. Dyson
FULL PAPER
rather difficult, especially here where various reactions oc- hydrophilic and show fast and complicated hydrolysis be-
cur in aqueous solution, we assumed that for the homo- haviour, and in general their observed cytotoxicities are low.
logous series of complexes [Ru(η6-p-cymene)(R2acac)- In comparison, the new derivatives presented here show
(PTA)][BF4], the change in lipophilicity should correlate to high cytotoxicities with no or only minor hydrolysis likely
the different R2acac ligands. Therefore, the different lipo- during the MTT assay time scale (with exception of com-
philicities of the complexes may be estimated by calculating pound 14·BF4). Therefore, it can be assumed that hydroly-
the corresponding values for the free ligands. The logP val- sis, in order to generate more labile species that can bind
ues for the free β-diketones (R2acac) in non-enolized form to DNA or proteins, may not be necessary to obtain high
are listed in Table 4.
cytotoxicities, although it is likely that nucleophiles in the
cell would accelerate hydrolysis (as was observed herein
with higher concentrations of chloride). It is possible that
the complexes may induce their effects by targeting recep-
tors inside the cell. Alternatively, the ability of (arene)ruthe-
nium(II) compounds to undergo substitution reactions by a
“ring-slippage” mechanism[19] could result in direct reaction
with potential biomolecular targets without necessitating
the need for prior activation by hydrolysis. In other words,
Table 4. Calculated logP values for the free β-diketones; values
were determined for the non-enolized β-diketone form.[17]
Free ligand
logP (calculated)
Me2acacH
tBu2acacH
Ph2acacH
0.339Ϯ0.369
2.796Ϯ0.396
3.043Ϯ0.303
1.637Ϯ0.468
Me2acac-ClH
For both the A2780 and the A549 cell line, the observed loss of the dicarboxylate ligand could occur after reaction
cytotoxicity data correlate well with the lipophilicity param- with the target inside the cell.[20]
eters. As an exception, complex 14·BF4 exhibited a much
higher cytotoxicity in A549 cells than expected from the
Conclusions
corresponding logP value of the free ligand Me2acac-ClH.
The similarity of the IC50 values obtained in A2780 cells
indicates that lipophilicity might not be of significant im-
portance for the mechanism of action in this cell line. In
contrast, the differences in the less sensitive A549 lung can-
cer cell line are more pronounced, with 14·BF4 being more
than 40 times more cytotoxic than 11·BF4.
We have synthesized and characterised a series of new
complexes [Ru(η6-p-cymene)(R2acac)(PTA)][X] (11–14) (X
= BPh4, BF4). The water-soluble BF4 salts have been evalu-
ated in MTT assays and found to be highly cytotoxic in
A2780 human ovarian cancer cells and to have pronounced
cytotoxicities also in A549 human lung cancer cells, which
are known to be insensitive against many applied chemo-
therapeutical agents. The hydrolysis behaviour was studied
under conditions similar to the physiological environment
in blood plasma and cells. The compounds were found to
exhibit reasonably to very good stability against hydrolysis
for days, the most reactive complex being [Ru(η6-p-cymene)-
(Me2acac-Cl)(PTA)][BF4] (14·BF4), and the least reactive
being [Ru(η6-p-cymene)(tBu2acac-Cl)(PTA)][X] (12·BF4).
Due to the high cytotoxicities in combination with stability
against hydrolysis and with respect to the cytotoxic behav-
iour of certain metal-free β-diketone derivatives, we assume
the mechanism of action to be different from “classical”
DNA or protein targeting known for organometallic drugs.
A receptor-based mechanism of action is considered to be
possible, at least in the first instance, as a direct reaction
without proceeding via a hydrolysis intermediate, although
hydrolysis cannot be ruled out within a cancer cell.
In general, hydrolysis of metal-based drugs is frequently
assumed to be necessary for their cytotoxic action in order
to generate reactive intermediates for binding to DNA, pro-
teins or other biomolecules. However, there is no clear cor-
relation between the hydrolysis behaviour and the cytotoxic
properties for the complexes 11·BF4–14·BF4. Compound
14·BF4 is the least stable derivative against hydrolysis, and
indeed it is the most cytotoxic derivative in A549 cells.
However, it does not show superior properties in A2780
cells compared to 11·BF4–13·BF4. The most stable deriva-
tive 12·BF4 shows weaker cytotoxicities in both cell lines,
although it is still more (and towards A549 cells much
more) cytotoxic than the comparatively reactive species
11·BF4. The most cytotoxic compound in A2780 cells,
13·BF4, shows similar hydrolytic stability to 12·BF4 and is
probably not hydrolyzed during the timeframe of the MTT
experiments. Based on these observations, it can be as-
sumed that hydrolysis does not play a significant role in the
mechanism of action for compounds 11·BF4–14·BF4, and
that differences in cytotoxicity are more likely explained
from their lipophilicities. However, it has to be mentioned
that strong cytotoxicities have been also observed for free
ligands of type R2acacH, some of which have shown selec-
tive effects towards certain cancer cell lines.[18] The cyto-
toxicity of the (dissociated) ligand has to be taken into con-
sideration especially for the rapidly hydrolyzing derivatives
11·BF4 and 14·BF4, although the coordinated ligands may
also interact with the same intracellular targets.
Experimental Section
Synthesis and Chemical Characterization: [RuCl2(η6-p-cymene)]2
was synthesized according to a literature protocol.[21] All other rea-
gents and solvents were obtained from commercial sources and
used without further purification. H and 13C NMR spectra were
1
recorded with a Bruker 400 MHz spectrometer at room tempera-
ture in CDCl3. NMR spectra were referenced to internal solvents
as follows: δ(CHCl3, 1H) = 7.26 and δ(CDCl3, 13C) = 77.00.[22]
Electrospray ionization mass spectra (ESI-MS) and MS/MS frag-
mentation data were recorded with a Thermofinigan LCQ Deca
The family of RAPTA complexes [Ru(η6-arene)-
Cl2(PTA)] previously synthesized in our group[8] tend to be XP Plus quadrupole ion trap instrument in positive mode in
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2008, 1661–1671

Cytotoxicities of [Ru(η6-p-cymene)(R2acac)(PTA)]+ Complexes
CH3CN according to a literature procedure.[23] Elemental analyses
were provided by the analytical service of the EPFL.
[Ru(η6-p-cymene)(Ph2acac)Cl] (9): To a suspension of Na2CO3
(600 mg, 5.66 mmol, 4.96 equiv.) in acetone (50 mL), [Ru(η6-p-cy-
mene)Cl2]2 (700 mg, 1.14 mmol) and dibenzoylmethane (513 mg,
2.29 mmol, 2.01 equiv.) were added, and the resulting mixture was
stirred at room temperature for 3 h, followed by evaporation of the
solvent in vacuo. The residue was taken up in CH2Cl2 (20 mL), and
the mixture was filtered through a short pad of Celite. The residue
was washed with CH2Cl2 (4ϫ 10 mL). Concentration of the com-
bined filtrates in vacuo yielded an orange-red powder (1.10 g,
2.23 mmol, 98%). 1H NMR (400 MHz, CDCl3): δ = 1.41 [d, J =
6.9 Hz, 6 H, 1-CH(CH3)2], 2.34 (s, 3 H, 4-CH3), 3.03 [sept, J =
6.9 Hz, 1 H, 1-CH(CH3)2], 5.32 (d, J = 5.9 Hz, 2 H, 2-H, 6-H),
5.59 (d, J = 5.9 Hz, 2 H, 3-H, 5-H), 6.45 [s, 1 H, COCHCO
(Ph2acac)], 7.39 [t, J = 7.3 Hz, 4 H, 4ϫ meta-H (Ph2acac)], 7.45 [t,
J = 7.3 Hz, 2 H, 2ϫ para-H (Ph2acac)], 7.91 [d, J = 7.3 Hz, 4 H,
4ϫ ortho-H (Ph2acac)] ppm. 13C NMR (101 MHz, CDCl3): δ =
18.01 (4-CH3), 22.40 [1-CH(CH3)2], 30.82 [1-CH(CH3)2], 79.34 (C-
2, C-6), 83.12 (C-3, C-5), 93.33 [COCHCO (Ph2acac)], 97.39 (C-
4), 99.73 (C-1), 127.3 [4ϫ ortho-C (Ph2acac)], 128.1 [4ϫ meta-C
(Ph2acac)], 130.9 [2ϫ para-C (Ph2acac)], 139.0 [2ϫ ipso-C
(Ph2acac)], 181.5 [2ϫ CO (Ph2acac)] ppm.
[Ru(η6-p-cymene)(Me2acac)Cl] (7): To a suspension of Na2CO3
(864 mg, 8.15 mmol, 5.00 equiv.) in acetone (50 mL), acetylacetone
(0.840 mL, 817 mg, 8.16 mmol, 5.01 equiv.) and [Ru(η6-p-cymene)-
Cl2]2 (1.00 g, 1.63 mmol) were added, and the resulting mixture was
stirred at room temperature for 3 h and then filtered. The residue
was washed with CH2Cl2 (4ϫ 10 mL), and the combined filtrates
were concentrated in vacuo. The residue was dissolved in CH2Cl2
(20 mL), and the solution was filtered again. After washing the
filter with CH2Cl2 (4ϫ 10 mL), the combined filtrates were reduced
in vacuo to a volume of ca. 10 mL. Et2O (5 mL) and an excess of
petroleum ether (ca. 100 mL) were added, and the mixture was
stored at –25 °C for 30 min to accomplish precipitation. The pre-
cipitate was filtered, washed with petroleum ether (2ϫ 10 mL) and
dried in vacuo, affording the title compound as orange needles
(837 mg, 2.26 mmol, 69%). 1H NMR (400 MHz, CDCl3): δ = 1.30
[d, J = 6.9 Hz, 6 H, 1-CH(CH3)2], 1.98 [s, 6 H, 2ϫ CH3 (Me2acac)],
2.26 (s, 3 H, 4-CH3), 2.86 [sept, J = 6.9 Hz, 1 H, 1-CH(CH3)2],
5.14 [s, 1 H, COCHCO (Me2acac)], 5.19 (d, J = 5.9 Hz, 2 H, 2-H,
6-H), 5.44 (d, J = 5.9 Hz, 2 H, 3-H, 5-H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 18.07 (4-CH3), 22.25 [1-CH(CH3)2], 27.25
[2ϫ CH3 (Me2acac)], 30.70 [1-CH(CH3)2], 78.80 (C-2, C-6), 82.41
(C-3, C-5), 97.55 (C-4), 98.74 [COCHCO (Me2acac)], 99.53 (C-1),
186.4 [2ϫ CO (Me2acac)] ppm.
[Ru(η6-p-cymene)(Me2acac-Cl)Cl] (10): To a suspension of Na2CO3
(605 mg, 5.71 mmol, 5.01 equiv.) in acetone (35 mL), 3-chloro-
acetylacetone (680 µL, 5.66 mmol, 4.96 equiv.) and [Ru(η6-p-cy-
mene)Cl2]2 (700 mg, 1.14 mmol) were added, and the resulting mix-
ture was stirred at room temperature for 3 h, then the solvent was
removed in vacuo. The residue was extracted with CH2Cl2 (6ϫ
10 mL). The extracts were filtered and reduced in vacuo to a vol-
ume of ca. 10 mL. Petroleum ether (80 mL) was added, and the
mixture was stored at –25 °C for 20 min. The formed precipitate
was filtered, washed with petroleum ether (3ϫ 10 mL) and dried
in vacuo, affording a dark yellow to yellow-brown solid (733 mg,
1.81 mmol, 80%). 1H NMR (400 MHz, CDCl3): δ = 1.33 [d, J =
6.9 Hz, 6 H, 1-CH(CH3)2], 2.24 (s, 3 H, 4-CH3), 2.25 [s, 6 H, 2ϫ
CH3 (Me2acac-Cl)], 2.88 [sept, J = 6.9 Hz, 1 H, 1-CH(CH3)2], 5.21
(d, J = 5.9 Hz, 2 H, 2-H, 6-H), 5.47 (d, J = 5.9 Hz, 2 H, 3-H, 5-
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 17.94 (4-CH3), 22.26
[1-CH(CH3)2], 28.09 [2ϫ CH3 (Me2acac-Cl)], 30.77 [1-CH(CH3)2],
79.13 (C-2, C-6), 82.43 (C-3, C-5), 97.31 (C-4), 99.87 (C-1), 106.4
[COCClCO (Me2acac-Cl)], 184.7 [2ϫ CO (Me2acac-Cl)] ppm.
[Ru(η6-p-cymene)(tBu2acac)Cl] (8): To a suspension of Na2CO3
(605 mg, 5.71 mmol, 5.01 equiv.) in acetone (35 mL), 2,2,6,6-tetra-
methylheptane-3,5-dione (1.15 mL, 1.03 g, 5.59 mmol, 4.99 equiv.)
and [Ru(η6-p-cymene)Cl2]2 (700 mg, 1.14 mmol) were added, and
the resulting mixture was stirred at room temperature for 3.5 h.
The solvent was evaporated in vacuo. The residue was extracted
with CH2Cl2 (4ϫ 20 mL). The extracts were filtered and the sol-
vents evaporated in vacuo to a volume of ca. 10 mL. Et2O (20 mL)
and petroleum ether (ca. 100 mL) were added. The turbid solution
was concentrated in vacuo to a volume of ca. 40 mL, and ad-
ditional petroleum ether (ca. 100 mL) was added. Reduction of the
solvent volume in vacuo to ca. 20 mL and storing at –25 °C for 1 h
led to the precipitation of an orange-red crystalline solid, which
was filtered, washed with petroleum ether (3ϫ 10 mL) and dried
in vacuo (822 mg, 1.81 mmol, 79%). 1H NMR (400 MHz, CDCl3):
δ = 1.12 [s, 18 H, 2ϫ C(CH3)3 (tBu2acac)], 1.35 [d, J = 6.9 Hz,
6 H, 1-CH(CH3)2], 2.23 (s, 3 H, 4-CH3), 2.89 [sept, J = 6.9 Hz, 1
H, 1-CH(CH3)2], 5.13 (d, J = 5.8 Hz, 2 H, 2-H, 6-H), 5.39 [s, 1 H,
COCHCO (tBu2acac)], 5.40 (d, J = 5.8 Hz, 2 H, 3-H, 5-H) ppm.
13C NMR (101 MHz, CDCl3): δ = 17.74 (4-CH3), 22.37 [1-
CH(CH3)2], 28.47 [2ϫ C(CH3)3 (tBu2acac)], 30.73 [1-CH(CH3)2],
40.72 [2ϫ C(CH3)3 (tBu2acac)], 78.95 (C-2, C-6), 83.11 (C-3, C-5),
88.96 [COCHCO (tBu2acac)], 91.26 (C-4), 99.03 (C-1), 196.0 [2ϫ
CO (tBu2acac)] ppm.
[Ru(η6-p-cymene)(Me2acac)(PTA)][BF4] (11·BF4): To a solution of
7 (100 mg, 0.270 mmol) in acetone (10 mL) and CH2Cl2 (10 mL),
PTA (45.0 mg, 0.286 mmol, 1.06 equiv.) and NaBF4 (60.0 mg,
0.546 mmol, 2.02 equiv.) were added at room temperature. The
mixture was heated to reflux temperature with a heating gun and
then stirred at room temperature for 15 min. The heating/ambient
temperature cycle was repeated three more times (total reaction
Eur. J. Inorg. Chem. 2008, 1661–1671
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C. A. Vock, A. K. Renfrew, R. Scopelliti, L. Juillerat-Jeanneret, P. J. Dyson
FULL PAPER
time: 1 h). The solvent was removed in vacuo. The residue was ex-
tracted with CH2Cl2 (4ϫ 10 mL). The extracts were filtered and
the solvents evaporated in vacuo. The residue was taken up in
CH2Cl2 (5 mL) and ethyl acetate (40 mL). The resulting solution
was concentrated in vacuo to ca. 10 mL, and an orange-yellow pre-
cipitate began to form. Precipitation was accomplished by storing
the mixture at –25 °C for 1 h. Petroleum ether (50 mL) was added,
and the solid was filtered, washed with petroleum ether (2ϫ
10 mL) and dried in vacuo, affording a dark yellow crystalline solid
ppm. 13C NMR (101 MHz, CDCl3): δ = 16.94 (4-CH3), 21.90 [1-
CH(CH3)2], 27.03 [2ϫ CH3 (Me2acac)], 30.60 [1-CH(CH3)2], 51.40
[d, JCP = 13.2 Hz, 3ϫ PCH2N (PTA)], 72.95 [d, JCP = 7.2 Hz, 3ϫ
NCH2N (PTA)], 87.55 (d, JCP = 4.0 Hz, C-2, C-6), 88.09 (d, JCP
=
4.3 Hz, C-3, C-5), 98.17 (C-4), 101.5 [COCHCO (Me2acac)], 104.5
(C-1), 121.9 [4ϫ para-C (BPh4)], 125.7 [q, JCB = 2.8 Hz, 8ϫ meta-
C (BPh4)], 136.3 [q, JCB = 1.4 Hz, 8ϫ ortho-C (BPh4)], 164.1 [q,
JCB = 49.4 Hz, 4ϫ ipso-C (BPh4)], 189.3 [2ϫ CO (Me2acac)] ppm.
31P{1H} NMR (126 MHz, CDCl3): δ = –30.60 ppm. ESI-MS
(79.6 mg, 0.138 mmol, 51%). Crystals suitable for X-ray analysis (CH3CN): m/z (%) = 491.9 (100) [Ru(cymene)(Me2acac)(PTA)]+.
were obtained by layering a CHCl3 solution of 11·BF4 with Et2O
ESI-MS (CH3CN, MS/MS, 20% relative collision energy): m/z (%)
and storing at room temperature for several days. 1H NMR
= 491.9 (29) [Ru(cymene)(Me2acac)(PTA)]+, 335.0 (100) [Ru(cy-
(400 MHz, CDCl3): δ = 1.22 [d, J = 6.9 Hz, 6 H, 1-CH(CH3)2], mene)(Me2acac)]+. C45H53BN3O2PRu·1.5H2O (837.8): calcd. C
1.94 (s, 3 H, 4-CH3), 1.97 [s, 6 H, 2ϫ CH3 (Me2acac)], 2.50 [sept,
J = 6.9 Hz, 1 H, 1-CH(CH3)2], 4.17 [s, 6 H, 3ϫ PCH2N (PTA)],
4.50 [br. d, JAB = 13.3 Hz, 3 H, 3ϫ NCHAHBN (PTA)], 4.60 [br.
d, JAB = 13.3 Hz, 3 H, 3ϫ NCHAHBN (PTA)], 5.39 [s, 1 H,
COCHCO (Me2acac)], 5.83 (d, J = 1.1 Hz, 4 H, 2-H, 3-H, 5-H, 6-
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 16.78 (4-CH3), 21.99
[1-CH(CH3)2], 27.05 [2ϫ CH3 (Me2acac)], 30.64 [1-CH(CH3)2],
50.95 [d, JCP = 13.3 Hz, 3ϫ PCH2N (PTA)], 72.90 [d, JCP = 7.4 Hz,
3ϫ NCH2N (PTA)], 87.86 (d, JCP = 4.0 Hz, C-2, C-6), 88.73 (d,
JCP = 4.3 Hz, C-3, C-5), 97.98 (C-4), 101.5 [COCHCO (Me2acac)],
104.2 (C-1), 189.4 [2ϫ CO (Me2acac)] ppm. 31P{1H} NMR
(126 MHz, CDCl3): δ = –29.26 ppm. ESI-MS (CH3CN): m/z (%) =
492.1 (100) [Ru(cymene)(Me2acac)(PTA)]+. ESI-MS (CH3CN, MS/
MS, 30% relative collision energy): m/z (%) = 492.1 (8) [Ru(cy-
mene)(Me2acac)(PTA)]+, 335.0 (100) [Ru(cymene)(Me2acac)]+.
C21H33BF4N3O2PRu·0.5H2O (587.4): calcd. C 42.94, H 5.83, N
7.15; found C 42.78, H 5.66, N 7.32.
64.51, H 6.74, N 5.02; found C 64.54, H 6.36, N 4.91.
[Ru(η6-p-cymene)(tBu2acac)(PTA)][BF4] (12·BF4): To a solution of
8
(100 mg, 0.220 mmol) in acetone (15 mL), PTA (36.0 mg,
0.229 mmol, 1.04 equiv.) and NaBF4 (120 mg, 1.09 mmol,
4.97 equiv.) were added at room temperature. The mixture was
stirred at room temperature for 2 h, and the solvent was removed
in vacuo. The residue was extracted with CH2Cl2 (5ϫ 10 mL). The
extracts were filtered through a pad of Celite and reduced in vacuo
to a volume of ca. 10 mL. Addition of Et2O (80 mL) and pentane
(60 mL) and subsequent cooling to –25 °C for 20 min led to the
formation of a precipitate, which was filtered, washed with Et2O
(2ϫ 10 mL) and dried in vacuo, affording a yellow solid (111 mg,
0.168 mmol, 76%). 1H NMR (400 MHz, CDCl3): δ = 1.16 [s, 18
H, 2ϫ C(CH3)3 (tBu2acac)], 1.23 [d, J = 6.9 Hz, 6 H, 1-CH-
(CH3)2], 1.96 (s, 3 H, 4-CH3), 2.48 [sept, J = 6.9 Hz, 1 H, 1-
CH(CH3)2], 4.16 [s, 6 H, 3ϫ PCH2N (PTA)], 4.49 [d, JAB
=
13.3 Hz, 3 H, 3ϫ NCHAHBN (PTA)], 4.58 [d, JAB = 13.3 Hz, 3 H,
3ϫ NCHAHBN (PTA)], 5.72 [s, 1 H, COCHCO (tBu2acac)], 5.80
(d, J = 5.8 Hz, 2 H, 2-H, 6-H), 5.89 (d, J = 5.8 Hz, 2 H, 3-H, 5-
H) ppm. 13C NMR (101 MHz, CDCl3): δ = 16.96 (4-CH3), 21.94
[1-CH(CH3)2], 28.47 [2ϫ C(CH3)3 (tBu2acac)], 30.55 [1-CH-
(CH3)2], 41.79 [2ϫ C(CH3)3 (tBu2acac)], 50.80 [d, JCP = 13.4 Hz,
3ϫ PCH2N (PTA)], 72.95 [d, JCP = 7.4 Hz, 3ϫ NCH2N (PTA)],
88.10 (d, JCP = 3.4 Hz, C-2, C-6), 89.71 (d, JCP = 3.7 Hz, C-3, C-
5), 92.43 [COCHCO (tBu2acac)], 96.38 (C-4), 103.8 (C-1), 199.1
[2ϫ CO (tBu2acac)] ppm. 31P{1H} NMR (126 MHz, CDCl3): δ =
–29.91 ppm. ESI-MS (CH3CN): m/z (%) = 576.1 (100) [Ru(cymene)
(tBu2acac)(PTA)]+. ESI-MS (CH3CN, MS/MS, 30% relative colli-
sion energy): m/z (%) = 419.0 (100) [Ru(cymene)(tBu2acac)]+.
C27H45BF4N3O2PRu (662.52): calcd. C 48.95, H 6.85, N 6.34;
found C 48.57, H 6.76, N 6.34.
[Ru(η6-p-cymene)(Me2acac)(PTA)][BPh4] (11·BPh4): To a solution
of 7 (100 mg, 0.270 mmol) in acetone (10 mL) and CH2Cl2
(10 mL), PTA (45.0 mg, 0.286 mmol, 1.06 equiv.) and NaBPh4
(97.0 mg, 0.283 mmol, 1.05 equiv.) were added, and the mixture
was heated to reflux temperature with a heating gun and then
stirred at room temperature for 15 min. The heating/ambient tem-
perature cycle was repeated two more times (total reaction time:
45 min). The solvent was removed in vacuo, and the residue was
extracted with CH2Cl2 (4ϫ 10 mL). The extracts were filtered and
reduced in vacuo to a volume of ca. 10 mL. Addition of Et2O
(50 mL) and stirring at room temperature for several minutes led
to the formation of a precipitate, which was filtered off, washed
with Et2O (2ϫ 10 mL) and dried in vacuo, affording a light yellow
powder (164 mg, 0.202 mmol, 75%). Crystals suitable for X-ray
analysis were obtained by layering a CHCl3 solution of 11·BPh4
with Et2O and storing at 4 °C for 36 h. 1H NMR (400 MHz,
CDCl3): δ = 1.12 [d, J = 6.9 Hz, 6 H, 1-CH(CH3)2], 1.61 (s, 3 H,
4-CH3), 1.93 [s, 6 H, 2ϫ CH3 (Me2acac)], 2.27 [sept, J = 6.9 Hz, 1
H, 1-CH(CH3)2], 3.77 [s, 6 H, 3ϫ PCH2N (PTA)], 4.33 [d, JAB
=
13.3 Hz, 3 H, 3ϫ NCHAHBN (PTA)], 4.47 [d, JAB = 13.3 Hz, 3 H,
3ϫ NCHAHBN (PTA)], 4.87 (d, J = 5.9 Hz, 2 H, 2-H, 6-H), 5.06
(d, J = 5.9 Hz, 2 H, 3-H, 5-H), 5.34 [s, 1 H, COCHCO (Me2acac)],
6.93 [t, J = 7.2 Hz, 4 H, 4ϫ para-H (BPh4)], 7.07 [t, J = 7.2 Hz, 8
H, 8ϫ meta-H (BPh4)], 7.45 [br. mc, 8 H, 8ϫ ortho-H (BPh4)]
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Cytotoxicities of [Ru(η6-p-cymene)(R2acac)(PTA)]+ Complexes
[Ru(η6-p-cymene)(tBu2acac)(PTA)][BPh4] (12·BPh4): To a solution
of 8 (100 mg, 0.220 mmol) in acetone (10 mL) and CH2Cl2
(10 mL), PTA (36.0 mg, 0.229 mmol, 1.04 equiv.) and NaBPh4
(79.0 mg, 0.231 mmol, 1.05 equiv.) were added at room tempera-
ture. The mixture was heated to reflux temperature with a heating
gun and then stirred at room temperature for 15 min. The heating/
of petroleum ether (60 mL) and accomplished by storing the mix-
ture at room temperature for 20 min. The solid was filtered off,
washed with petroleum ether (3ϫ 10 mL) and dried in vacuo, af-
fording a dark yellow crystalline solid (81.0 mg, 0.115 mmol, 63%).
Crystals suitable for X-ray analysis were obtained by layering a
CHCl3 solution of 13·BF4 with ethyl acetate and storing at 4 °C
ambient temperature cycle was repeated three more times (total for 4 d. 1H NMR (400 MHz, CDCl3): δ = 1.32 [d, J = 6.9 Hz, 6 H,
reaction time: 1 h). The solvent was removed in vacuo, and the
residue was extracted with CH2Cl2 (4ϫ 10 mL). The extracts were
filtered and reduced in vacuo to a volume of ca. 10 mL. Formation
of a yellow crystalline precipitate was induced by addition of Et2O
(50 mL), followed by concentration to ca. 20 mL, addition of petro-
leum ether (50 mL), followed by concentration to ca. 20 mL and
addition of petroleum ether (50 mL). The solid was filtered, washed
with petroleum ether (2ϫ 10 mL) and dried in vacuo, affording a
yellow-orange crystalline solid (144 mg, 0.161 mmol, 73%). Crys-
tals suitable for X-ray analysis were obtained by layering a CHCl3
solution of 12·BPh4 with Et2O and storing at 4 °C for 5 d. 1H
NMR (400 MHz, CDCl3): δ = 1.12 [s, 18 H, 2ϫ C(CH3)3 (tBu2-
1-CH(CH3)2], 2.10 (s, 3 H, 4-CH3), 2.65 [sept, J = 6.9 Hz, 1 H, 1-
CH(CH3)2], 4.26 [s, 6 H, 3ϫ PCH2N (PTA)], 4.45 [d, JAB
=
13.3 Hz, 3 H, 3ϫ NCHAHBN (PTA)], 4.56 [d, JAB = 13.3 Hz, 3 H,
3ϫ NCHAHBN (PTA)], 5.94 (d, J = 5.9 Hz, 2 H, 2-H, 6-H), 6.01
(d, J = 5.9 Hz, 2 H, 3-H, 5-H), 6.77 [s, 1 H, COCHCO (Ph2acac)],
7.49 [t, J = 7.5 Hz, 4 H, 4ϫ meta-H (Ph2acac)], 7.58 [t, J = 7.5 Hz,
2 H, 2ϫ para-H (Ph2acac)], 7.84 [d, J = 7.5 Hz, 4 H, 4ϫ ortho-H
(Ph2acac)] ppm. 13C NMR (101 MHz, CDCl3): δ = 17.12 (4-CH3),
22.16 [1-CH(CH3)2], 30.67 [1-CH(CH3)2], 51.16 [d, JCP = 13.1 Hz,
3ϫ PCH2N (PTA)], 72.80 [d, JCP = 7.4 Hz, 3ϫ NCH2N (PTA)],
88.43 (d, JCP = 3.9 Hz, C-2, C-6), 89.41 (d, JCP = 4.4 Hz, C-3, C-
5), 95.13 [COCHCO (Ph2acac)], 98.31 (C-4), 104.0 (C-1), 126.9 [4ϫ
acac)], 1.13 [d, J = 7.1 Hz, 6 H, 1-CH(CH3)2], 1.60 (s, 3 H, 4-CH3), ortho-C (Ph2acac)], 128.9 [4ϫ meta-C (Ph2acac)], 132.3 [2ϫ para-
2.29 [sept, J = 7.1 Hz, 1 H, 1-CH(CH3)2], 3.74 [s, 6 H, 3ϫ PCH2N (Ph2acac)], 137.0 [2ϫ ipso-C (Ph2acac)], 183.3 [2ϫ CO
(PTA)], 4.30 [d, JAB = 13.3 Hz, 3 H, 3ϫ NCHAHBN (PTA)], 4.47 (Ph2acac)] ppm. 31P{1H} NMR (162 MHz, CDCl3):
C
δ
=
[d, JAB = 13.3 Hz, 3 H, 3ϫ NCHAHBN (PTA)], 4.89 (d, J = 6.9 Hz,
2 H, 2-H, 6-H), 5.03 (d, J = 6.9 Hz, 2 H, 3-H, 5-H), 5.68 [s, 1 H,
COCHCO (tBu2acac)], 6.95 [t, J = 7.2 Hz, 4 H, 4ϫ para-H (BPh4)],
7.08 [t, J = 7.2 Hz, 8 H, 8ϫ meta-H (BPh4)], 7.45 [br. mc, 8 H, 8ϫ
–28.08 ppm. ESI-MS (CH3CN): m/z (%) = 616.1 (100) [Ru(cymene)-
(Ph2acac)(PTA)]+. ESI-MS (CH3CN, MS/MS, 30% relative colli-
sion energy): m/z (%) = 616.1 (100) [Ru(cymene)(Ph2acac)(PTA)]+,
459.0 (27) [Ru(cymene)(Ph2acac)]+. C31H37BF4N3O2PRu·H2O
ortho-H (BPh4)] ppm. 13C NMR (101 MHz, CDCl3): δ = 17.07 (4- (720.5): calcd. C 51.68, H 5.46, N 5.83; found C 51.56, H 5.18, N
CH3), 21.91 [1-CH(CH3)2], 28.46 [2ϫ C(CH3)3 (tBu2acac)], 30.45
[1-CH(CH3)2], 41.80 [2ϫ C(CH3)3 (tBu2acac)], 51.24 [d, JCP
6.15.
=
13.0 Hz, 3ϫ PCH2N (PTA)], 72.97 [d, JCP = 6.9 Hz, 3ϫ NCH2N
(PTA)], 87.88 (d, JCP = 3.4 Hz, C-2, C-6), 89.01 (d, JCP = 4.0 Hz,
C-3, C-5), 92.43 [COCHCO (tBu2acac)], 96.90 (C-4), 103.7 (C-1),
122.0 [4ϫ para-C (BPh4)], 125.7 [8ϫ meta-C (BPh4)], 136.3 [8ϫ
ortho-C (BPh4)], 164.1 [q, JCB = 49.3 Hz, 4ϫ ipso-C (BPh4)], 199.0
[2ϫ CO (tBu2acac)] ppm. 31P{1H} NMR (126 MHz, CDCl3): δ =
–29.84 ppm. ESI-MS (CH3CN): m/z (%) = 575.9 (100) [Ru(cy-
mene)(tBu2acac)(PTA)]+. ESI-MS (CH3CN, MS/MS, 20% relative
collision energy): m/z (%) = 576.0 (65) [Ru(cymene)(tBu2acac)
(PTA)]+, 419.2 (100) [Ru(cymene)(tBu2acac)]+. C51H65BN3O2PRu
(894.95): calcd. C 68.45, H 7.32, N 4.70; found C 68.47, H 7.32, N
4.73.
[Ru(η6-p-cymene)(Ph2acac)(PTA)][BPh4] (13·BPh4): To a solution
of 9 (100 mg, 0.202 mmol) in acetone (10 mL) and CH2Cl2
(10 mL), PTA (34.0 mg, 0.216 mmol, 1.07 equiv.) and NaBPh4
(70.0 mg, 0.205 mmol, 1.01 equiv.) were added at room tempera-
ture. The mixture was heated to reflux temperature and then stirred
at room temperature for 15 min. The heating/ambient temperature
cycle was repeated three more times, and afterwards the mixture
was stirred at room temperature for additional 75 min (total reac-
tion time: 2.25 h). The solvent was removed in vacuo, and the resi-
due was extracted with CH2Cl2 (4ϫ 10 mL). The extracts were fil-
tered, petroleum ether (40 mL) was added, and precipitation was
induced by gradually decreasing the CH2Cl2 content in several cy-
cles of partial solvent evaporation and re-addition of petroleum
ether. Precipitation was accomplished by storing the mixture at
[Ru(η6-p-cymene)(Ph2acac)(PTA)][BF4] (13·BF4): To a solution of 9
(90.5 mg, 0.183 mmol) in acetone (15 mL), PTA (30.8 mg,
0.196 mmol, 1.07 equiv.) and NaBF4 (200 mg, 1.82 mmol, –25 °C for 15 min. The solid was filtered, washed with petroleum
9.95 equiv.) were added at room temperature. The mixture was
heated to reflux temperature with a heating gun, then stirred at
room temperature for 30 min, heated to reflux temperature again
and stirred afterwards at room temperature for 3 h (total reaction
time: 3.5 h). The solvent was removed in vacuo, and the residue
was extracted with CH2Cl2 (5ϫ 10 mL). The extracts were filtered.
Petroleum ether (50 mL) was added to the filtrate, and the solvent
was evaporated in vacuo to afford an oily residue, which was taken
up in CH2Cl2 (5 mL). Precipitation was induced by slow addition
ether (3ϫ 15 mL) and dried in vacuo, affording a yellow powder
(139 mg, 0.149 mmol, 74%). 1H NMR (400 MHz, CDCl3): δ = 1.22
[d, J = 6.9 Hz, 6 H, 1-CH(CH3)2], 1.73 (s, 3 H, 4-CH3), 2.42 [sept,
J = 6.9 Hz, 1 H, 1-CH(CH3)2], 3.82 [s, 6 H, 3ϫ PCH2N (PTA)],
4.28 [d, JAB = 13.3 Hz, 3 H, 3ϫ NCHAHBN (PTA)], 4.42 [d, JAB
= 13.3 Hz, 3 H, 3ϫ NCHAHBN (PTA)], 5.01 (d, J = 5.8 Hz, 2 H,
2-H, 6-H), 5.18 (d, J = 5.8 Hz, 2 H, 3-H, 5-H), 6.72 [s, 1 H,
COCHCO (Ph2acac)], 6.93 [t, J = 7.2 Hz, 4 H, 4ϫ para-H (BPh4)],
7.08 [t, J = 7.2 Hz, 8 H, 8ϫ meta-H (BPh4)], 7.43–7.52 [m, 12 H,
Eur. J. Inorg. Chem. 2008, 1661–1671
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
1669

C. A. Vock, A. K. Renfrew, R. Scopelliti, L. Juillerat-Jeanneret, P. J. Dyson
FULL PAPER
4ϫ meta-H (Ph2acac), 8ϫ ortho-H (BPh4)], 7.59 [t, J = 7.2 Hz, 2
H, 2ϫ para-H (Ph2acac)], 7.78 [d, J = 7.7 Hz, 4 H, 4ϫ ortho-H
dition of Et2O (100 mL) and hexanes (30 mL) led to the formation
of a precipitate, which was filtered, washed with Et2O (3ϫ 10 mL)
(Ph2acac)] ppm. 13C NMR (101 MHz, CDCl3): δ = 17.30 (4-CH3), and dried in vacuo, affording
a
yellow powder (149 mg,
22.06 [1-CH(CH3)2], 30.57 [1-CH(CH3)2], 51.66 [d, JCP = 13.0 Hz, 0.243 mmol, 66%). Crystals suitable for X-ray analysis were ob-
3ϫ PCH2N (PTA)], 72.89 [d, JCP = 7.2 Hz, 3ϫ NCH2N (PTA)],
88.11 (d, JCP = 3.7 Hz, C-2, C-6), 88.78 (d, JCP = 4.4 Hz, C-3, C-
5), 95.14 [CH (Ph2acac)], 98.39 (C-4), 104.1 (C-1), 122.0 [4ϫ para-
C (BPh4)], 125.8 [q, JCB = 2.6 Hz, 8ϫ meta-C (BPh4)], 126.8 [4ϫ
ortho-C (Ph2acac)], 129.0 [4ϫ meta-C (Ph2acac)], 132.5 [2ϫ para-
C (Ph2acac)], 136.3 [q, JCB = 1.4 Hz, 8ϫ ortho-C (BPh4)], 136.9
[2ϫ ipso-C (Ph2acac)], 164.1 [q, JCB = 49.3 Hz, 4ϫ ipso-C (BPh4)],
183.2 [2ϫ CO (Ph2acac)] ppm. 31P{1H} NMR (162 MHz, CDCl3):
δ = –29.70 ppm. ESI-MS (CH3CN): m/z (%) = 615.9 (100) [Ru(cy-
mene)(Ph2acac)(PTA)]+. ESI-MS (CH3CN, MS/MS, 20% relative
collision energy): m/z (%) = 615.9 (75) [Ru(cymene)(Ph2acac)-
tained by layering a CH2Cl2 solution of 14·BF4 with Et2O and
storing at room temperature for 24 h. 1H NMR (400 MHz,
CDCl3): δ = 1.23 [d, J = 6.9 Hz, 6 H, 1-CH(CH3)2], 1.95 (s, 3 H,
4-CH3), 2.27 [s, 6 H, 2ϫ CH3 (Me2acac-Cl)], 2.50 [sept, J = 6.9 Hz,
1 H, 1-CH(CH3)2], 4.18 [s, 6 H, 3ϫ PCH2N (PTA)], 4.51 [d, JAB
= 13.3 Hz, 3 H, 3ϫ NCHAHBN (PTA)], 4.62 [d, JAB = 13.3 Hz, 3
H, 3ϫ NCHAHBN (PTA)], 5.88 (d, J = 1.1 Hz, 4 H, 2-H, 3-H, 5-
H, 6-H) ppm. 13C NMR (101 MHz, CDCl3): δ = 16.86 (4-CH3),
21.99 [1-CH(CH3)2], 28.08 [2ϫ CH3 (Me2acac-Cl)], 30.76 [1-
CH(CH3)2], 50.88 [d, JCP = 13.4 Hz, 3ϫ PCH2N (PTA)], 72.83 [d,
JCP = 7.5 Hz, 3ϫ NCH2N (PTA)], 88.10 (d, JCP = 3.8 Hz, C-2, C-
(PTA)]+, 458.9 (100) [Ru(cymene)(Ph2acac)]+. C55H57BN3O2PRu· 6), 89.00 (d, JCP = 4.4 Hz, C-3, C-5), 97.83 (C-4), 103.9 (C-1), 108.8
0.25CH2Cl2·1.5H2O (983.2): calcd. C 67.50, H 6.20, N 4.27; found
C 67.36, H 5.76, N 4.26.
[COCClCO (Me2acac-Cl)], 187.8 [2ϫ CO (Me2acac-Cl)] ppm.
31P{1H} NMR (126 MHz, CDCl3): δ = –30.05 ppm. ESI-MS
(CH3CN): m/z (%)
= 525.8 (100) [Ru(cymene)(Me2acac-Cl)-
(PTA)]+. ESI-MS (CH3CN, MS/MS, 20% relative collision energy):
m/z (%) = 525.9 (20) [Ru(cymene)(Me2acac-Cl)(PTA)]+, 368.9
(100) [Ru(cymene)(Me2acac-Cl)]+. C21H32BClF4N3O2PRu·0.5H2O
(621.8): calcd. C 40.56, H 5.35, N 6.76; found C 40.49, H 5.25, N
6.76.
[Ru(η6-p-cymene)(Me2acac-Cl)(PTA)][BF4] (14·BF4): To a solution
of 10 (150 mg, 0.371 mmol) in acetone (30 mL), PTA (59.0 mg,
0.375 mmol, 1.01 equiv.) and NaBF4 (205 mg, 1.87 mmol,
5.03 equiv.) were added, and the mixture was stirred at room tem-
perature for 3 h. The solvent was removed in vacuo, and the residue
was extracted with CH2Cl2 (5ϫ 10 mL). The extracts were filtered
through a pad of Celite and reduced in vacuo to ca. 15 mL. Ad-
Crystallography: Crystal structure determinations of 11·BF4, 11·
BPh4, 12·BPh4, 13·BF4 and 14·BF4 were performed with a KUMA
CCD area detector (graphite-monochromated Mo-Kα radiation) at
140 K (Table 5). Multiscan absorption corrections were applied
Table 5. Crystallographic parameters for 11·BF4, 11·BPh4, 12·BPh4, 13·BF4 and 14·BF4.
11·BF4
11·BPh4
12·BPh4
13·BF4
14·BF4
Empirical formula
Formula mass
Colour, habit
Crystal system
Space group
a [Å]
b [Å]
c [Å]
α [°]
β [°]
C21H33BF4N3O2PRu C45H53BN3O2PRu
C51H65BN3O2PRu
894.91
yellow, prismatic
monoclinic
P21/n
16.2440(11)
15.3450(11)
19.196(2)
90
103.181(6)
90
C31H37BF4N3O2PRu
702.50
C21H32BClF4N3O2PRu
612.80
578.35
810.75
yellow, prismatic
monoclininc
P21/n
yellow, prismatic
triclinic
P1
yellow, prismatic
monoclinic
P21/n
22.7719(10)
11.840(2)
23.606(8)
90
98.246(10)
90
6280(2)
8
yellow, prismatic
triclinic
¯
¯
P1
11.865(2)
14.783(3)
14.088(2)
90
103.63(2)
90
10.1560(4)
11.5070(8)
17.4540(12)
90.646(6)
92.492(5)
90.357(5)
2037.6(2)
2
8.519(3)
9.636(2)
15.307(3)
85.24(2)
84.16(2)
85.01(2)
1241.8(5)
4
γ [°]
V [Å3]
2401.4(7)
4
4658.8(6)
4
Z
Crystal size [mm]
dcalcd. [gcm–1]
µ [mm–1]
No. of reflections
R(int)
0.30ϫ0.28ϫ0.23
1.600
0.774
15178
0.0564
0.34ϫ0.22ϫ0.20
1.321
0.46
13888
0.0378
0.38ϫ0.30ϫ0.27
1.276
0.41
30143
0.0528
0.205ϫ0.084ϫ0.055
1.486
0.607
75297
0.1875
0.30ϫ0.20ϫ0.17
1.639
0.858
10371
0.0626
4205
No. of observed reflections 4327
5064
9927
9503
R1 (observed reflections)
wR2 (all)
Restraints
0.0596
0.1572
36
0.0409
0.1010
0
0.0401
0.1056
0
0.0642
0.1104
0
0.0502
0.1257
0
Parameters
339
1.106
484
1.078
541
0.966
781
1.081
312
1.013
Goodness-of-fit on F2
1670
www.eurjic.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2008, 1661–1671

Cytotoxicities of [Ru(η6-p-cymene)(R2acac)(PTA)]+ Complexes
using PLATON.[24] The structures were solved by direct methods
using SHELXS 97[25] and refined by least-squares methods on F2
using SHELXL 97. All non-hydrogen atoms were refined aniso-
tropically and hydrogen atoms placed in geometrically calculated
positions. In 11·BPh4, the C8 p-cymene methyl group is disordered
over two positions and the occupancy of the two sites refined to
0.54:0.46. The disordered BF4 counterion in 14·BF4 was refined to
two sites of occupancy 0.70:0.30. CCDC-668990 (11·BF4), -668988
(11·BPh4), -668989 (12·BPh4), -668992 (13·BF4), and -668991
(14·BF4) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cam-
bridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
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Acknowledgments
We thank the Swiss Cancer League, the EPFL and COST (Switzer-
land) for support. We also thank Hervé Pittet for practical syn-
thetic assistance. A postdoc stipend provided from the Swiss
National Science Foundation (SNF) for C. A. V. is gratefully ac-
knowledged.
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Received: November 30, 2007
Published Online: February 6, 2008
Eur. J. Inorg. Chem. 2008, 1661–1671
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjic.org
1671