Synthesis, catalytic properties and biological activity of new water soluble(ruthenium cyclopentadienyl PTA complexes [(C5R5)RuCl(PTA)2] (R = H, me; PTA = 1,3,5-triaza-7-phosphaadamantane)

Article abstract of DOI:10.1039/b210102e

The new water soluble ruthenium complexes ([(C₅R₅)RuCl(PTA)₂] (R = H, Me; PTA = 1,3,5-triaza-7-phosphaadamantane) were synthesised and characterised. Their evaluation as regioselective catalysts for hydrogenation of unsaturated ketones in aqueous biphasic conditions and as cytotoxic agents towards the TS/A adenocarcinoma cell line is briefly presented.

Full text of DOI:10.1039/b210102e

Synthesis, catalytic properties and biological activity of new water
soluble ruthenium cyclopentadienyl PTA complexes [(C R )RuCl(PTA) ]
5
5
2
(R = H, Me; PTA = 1,3,5-triaza-7-phosphaadamantane)†
a
a
a
a
a
Dina N. Akbayeva, Luca Gonsalvi, Werner Oberhauser, Maurizio Peruzzini,* Francesco Vizza,*
b
c
d
d
Peter Brüggeller, Antonio Romerosa, Gianni Sava and Alberta Bergamo
a
Istituto di Chimica dei Composti Organometallici, ICCOM-CNR, Via Jacopo Nardi 39, 50132 Firenze,
Italy. E-mail: peruz@fi.cnr.it, vizza@fi.cnr.it; Fax: +39 055 2478366; Tel: +39 055 245990
Institut für Allgemeine, Anorganische und Theoretische Chemie der Universität Innsbruck, Innsbruck,
Austria
Área de Quimica Inorganica, Universidad de Almería, 04071 Almería, Spain
Callerio Foundation Onlus, Via Fleming 22–31, 34127 Trieste, Italy
b
c
d
Received (in Cambridge, UK) 15th October 2002, Accepted 25th November 2002
First published as an Advance Article on the web 18th December 2002
The
(C
-phosphaadamantane) were synthesised and characterised.
Their evaluation as regioselective catalysts for hydro-
genation of unsaturated ketones in aqueous biphasic condi-
tions and as cytotoxic agents towards the TS/A adenocarci-
noma cell line is briefly presented.
new
water
soluble
ruthenium
complexes
indicates the metal coordination of chloride. The molecular
structure of 2·C Cl was determined by single-crystal X-ray
diffraction study and is shown in Fig. 1.‡ Two independent
molecules were found in the asymmetric unit showing no
significant differences in their metrical parameters. The overall
geometry of the complex is very similar to that observed for
[
7
5
R
5
)RuCl(PTA)
2
] (R = H, Me; PTA = 1,3,5-triaza-
2
H
4
2
three-legged piano-stool complexes of the type [(C
5
R
5
)MXL
2
]
9b
9a
1
such as [CpRuCl(PPh
3
)
2
], and [Cp*Fe(dppe)(h -P
4
4
)]BPh ,
In recent years, aqueous homogeneous catalysis has received
increased attention, due to greater environmental awareness and
with the Cp* ring essentially planar (dRuC(ave) = 1.86 Å). One
chlorine ligand (dRuCl = 2.46 Å) and two PTA molecules
(dRuP(ave) = 2.28 Å, in the range expected for Ru-PTA
complexes)5 complete the coordination polyhedron around
the metal, with P(1)–Ru–P(2) angle at 93.3°. Complexes 1 and
2 are air stable solids which easily dissolve in water (S25 °C = 40
1
cost effectiveness thanks to easier catalyst recycling. Some
a,8
water-soluble organometallic compounds have been used in
2
nuclear medicine, diagnostics and therapy. Water solubility
can be obtained using polar group-substituted phosphines or
3
23
23
cyclopentadienyls, or by using neutral water-soluble ligands
mg cm for 1 and 25 mg cm for 2) and chlorinated organic
solvents. Aqueous solutions of 1 and 2 are exceedingly stable
and the complexes were recovered unchanged after 16 h
such as 1,3,5-triaza-7-phosphaadamantane (PTA) whose late
transition metal coordination chemistry has been developed
4,5
mainly by Joó, Darensbourg and coworkers. PTA complexes
were used in catalytic processes including hydrogenation of
2
refluxing. Prolonged heating in D O did not cause deuterium
incorporation in either the cyclopentadienyl ring or PTA
ligands.
aldehydes,5 olefins and allyl alcohols, in aqueous biphasic
a,b
5c
6
conditions. Hydrogenation of aqueous carbonate to formate has
Both complexes are active in regioselective hydrogenation of
benzylidene acetone (3) to 4-phenylbutan-2-one (4) in H O–n-
2
octane. By-products 4-phenylbutan-2-ol (5) and 4-phenylbut-
3-en-2-ol (6) were formed in small amount or traces, as
summarised in Table 1. Catalytic tests with 1 at 80 °C, 450 psi
7
also been investigated. The pH-dependent cytotoxicity of
6
(PTA)] has been shown by Dyson et al.8
[
Ru(h -p-cymene)Cl
2
5 5
Remarkably, water-soluble PTA complexes incorporating C R
coligands have never been described in spite of their obvious
potentialities in both aqueous catalysis and biological activity.
We present here preliminary results describing the novel
2
of H , showed very high selectivity to 4 (90%) at low
conversion (26%) after 13 h. At 130 °C 1 gave higher activity
(78% at 13 h), with a decrease in selectivity towards 4 (76%),
likely due to over-hydrogenation in a two-step reaction fashion.
The presence of an excess of PTA (Table 1, entry 6) caused a
decrease in conversion as expected for a dissociative mecha-
nism. Comparable selectivity to 4 (94%) at moderate conver-
sion (40%) was observed at 80 °C using 2. The activity of 2 does
not depend dramatically on the temperature, as a maximum
conversion of 38.7% was observed at 130 °C. However, higher
temperature caused a drop in selectivity (84%). The catalyst is
confined to the water phase and 1 could be recycled at least
three times showing moderate loss of activity and a slight
increase of selectivity for 4 (Table 2). Formation of metal
water-soluble complexes [(C
5 5 2
R )RuCl(PTA) ] [R = H (1), Me
(
2)] and providing a first assessment of their catalytic and
biological activity. The complexes were synthesised according
to Scheme 1 and obtained in moderate to good yield.†
NMR data† confirm that two PTA ligands are P-bonded to
the (C
5
R
5
)Ru moiety, while the low conductivity in water
Scheme 1
†
Electronic supplementary information (ESI) available: synthesis,
P{ H}, H, C NMR characterisation and elemental analysis of 1 and 2.
3
1
1
1
13
2
Fig. 1 X-Ray crystal structure of Cp*Ru(PTA) Cl, 2. Hydrogen atoms and
See http://www.rsc.org/suppdata/cc/b2/b210102e/
solvent omitted for clarity.
2
64
CHEM. COMMUN., 2003, 264–265
This journal is © The Royal Society of Chemistry 2003

aggregates was ruled out by comparison with results obtained
using Ru/SiO under the same conditions (Table 2, entry 14).
Detailed HP-NMR experiments were carried out at variable
temperature to obtain a better insight into the formation of
organometallic species nearing the catalytic conditions. In a
only at higher temperature is converted into the corresponding
monohydrido species 9.10 Under HP-NMR tube conditions, we
observed that hydride loss from 8 to 9 is easier in the presence
of solvents with Lewis base properties such as THF. The
2
2
different behaviour of 1 and 2 towards H activation may be
typical experiment, a solution of 1 and 3 (1+20 ratio) in H
2
O–
explained by the higher nucleophilicity of Ru in 2 compared to
1 due to Cp* which should favour oxidative addition against
heterolytic splitting. Formation of PTA oxide could be related to
faster deactivation of 2 in catalysis. Work is in progress to
elucidate the influence of anions and different Cp substituents
on the activity and selectivity in catalytic hydrogenation.
The biological activity of compounds 1 and 2 was prelimi-
narily tested on the proliferation of TS/A murine adenocarci-
noma tumor cells. While 1 is devoid of antiproliferative effects
at any tested concentration and at any time of tumor cell
exposure, 2 inhibits tumor cell proliferation. This activity starts
at 10 mM concentration and is maximal (262.6% vs. controls)
after 48 h treatment. A longer time of tumor cell exposure of 72
h did not increase such antiproliferative effects.
THF-d (1+1) was pressurised with 450 psi of H in a 10 mm
8
2
NMR sapphire tube. At 25 °C only the singlet at 223.6 ppm due
to 1 was observed in the 31P{ H} spectrum. By heating to 50 °C,
a sharp singlet at 212.0 ppm appeared, becoming the major
species (ca. 2+1 ratio to 1) after 150 min at 80 °C. We attribute
1
this signal to the new hydride [CpRuH(PTA)
2
] (7), based on the
2
singlet to doublet splitting ( J(HP) 36 Hz) in the proton coupled
31
P NMR spectrum and on an independent synthesis of the
complex.§ At the end of the NMR experiment, the room
temperature solution contained only 1 and 7 in ca. 1+2 ratio.
Depressurisation under nitrogen did not change this ratio
suggesting a very high stability of 7 in solution. In a separate
HP-NMR experiment, 7 was formed in the absence of the
substrate under the conditions described above, suggesting
In summary, we have synthesised precursors of a new series
of [(C R )RuX(PTA) ] water soluble complexes which could
5 5 2
heterolytic activation of H
2
by 1.10 The presence of 7 in
catalysis was confirmed by 31P NMR analysis of the reaction
mixture taken from an autoclave run. In contrast with what was
expected, in all experiments no sign of PTA dissociation was
observed.
be applied to regioselective CNC catalytic hydrogenation and
are potential starting materials for stable water soluble organo-
metallic hydrides. Furthermore, 2 showed significant activity as
an inhibitor of specific tumor cell proliferation.
We acknowledge CNR/Agenzia 2000, CNR/CONACYT,
MCYT (Spain) INTAS (00179), NATO and EC through COST
and RTN (HPRN-CT-2002-00176) for promoting this scientific
activity.
Proton coupled 31P HP-NMR experiments performed in
H
2
O–THF-d
conditions described above evidenced fast conversion at 50 °C
to the dihydride [Cp*Ru(H) (PTA) ]Cl (8) (221.4 ppm, t,
J(HP) 33 Hz; H NMR 210.08 ppm, t), which slowly gave the
8
with 2 (d 234.4, s, 25 °C) and 3 under the
2
2
2
1
2
monohydride [Cp*Ru(H)(PTA)
2
] (9) (221.7 ppm, d, J(HP) 36
Hz; H NMR 214.58 ppm, t) after leaving the tube at 80 °C for
0 min. After 150 min at 80 °C, the solution contained 9, 8, 2
1
Notes and references
3
‡
2 4 2
Crystals of 2·C H Cl were grown at 218 °C from a diluted pentane–
and PTA oxide (10).¶ After depressurisation and venting with
nitrogen, the signals due to 8 and 9 disappeared leaving, after 16
h at room temperature, a 1+1 mixture of 2 and 10, similar to that
observed after a catalytic experiment in an autoclave under
comparable conditions (100 °C, 450 psi).
The combination of catalytic tests and NMR experiments
suggest that 1 and 2 behave differently under hydrogen pressure
at high temperature. Whilst 1 forms the monohydrido complex
dichloroethane solution. A Nonius Kappa CCD diffractometer was used
with combined o–w-scans. Cell refinement, data reduction, and the
empirical absorption correction were done by Denzo and Scalepack
programs. Empirical formula C24
.71073 Å; crystal system, triclinic; space group, P1; unit cell dimensions
a = 12.5986(2), b = 16.2139(3), c = 16.3454(3) Å, a = 64.0661(8), b =
3 6 2
H43Cl N P Ru; M 685.01; T 213(2) K; l
¯
0
3
23
8
0
2.934(1), g = 80.159(1)°; V 2954.1(1) Å ; Z = 4; r 1.541 Mg m ; m
21
.751 mm Reflections collected/unique 25086/13313 [Rint = 0.0180].
CCDC 195496. See http://www.rsc.org/suppdata/cc/b2/b210102e/ for crys-
tallographic data in CIF or other electronic format.
7
at 50 °C, complex 2 converts at first into the dihydride 8 which
§
Complex 7 was synthesised by refluxing 1 in benzene under nitrogen with
a 5-fold excess of NaOMe for 3 h. Extraction with CH Cl and usual
Cl , 81.01 MHz)
Table 1 Aqueous biphasic hydrogenation of 3 using complexes 1 and 2a
2
2
31
1
workup gave a 5+1 mixture of 7 and 1. P{ H} NMR (CD
2
2
1
2
Catalyst % conv. (h)b
4b (%)
5b (%)
6b (%)
d 212.96 (s). H NMR (CD
2
Cl
2
, 200.13 MHz) d 214.46 (t, J(HP) 36.0 Hz,
Entry
1
H, RuH).
¶
9 + 8 (48%, superimposed signals), 2 (47%), 10 (5%). PTA oxide 10, 31
P
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
2
2
2
2
39.1 (3)
52.7 (6)
78.5 (13)
99.7 (21)
22.9 (13)
26.3 (13)
24.3 (3)
32.1 (6)
38.7 (13)
40.0(13)
34.7
43.6
60.0
74.8
15.4
23.7
19.7
26.3
32.5
37.4
23
2.0
3.8
13.6
21.9
1.2
1.6
1.2
1.2
1.4
2.4
5.3
4.9
3.0
6.3
1.0
3.4
4.6
4.8
0.9
2
2 8
NMR: (H O–THF-d , 166.98 MHz) d 24.57, septet, J(PH) 10 Hz.
1
Aqueous Phase Organometallic Catalysis, ed. B. Cornils and W. A.
c
Herrmann, Wiley-VCH, Weinheim, Germany, 1998.
2 Z. Guo and P. J. Sadler, Angew. Chem., Int. Ed., 1999, 38, 1512.
d
3
See for example A. Bényei and F. Joó, J. Mol.. Catal., 1990, 58, 151; D.
M. Schutt, T. J. R. Weakley and D. R. Tyler, New. J. Chem., 1996, 20,
1
13.
d
4 D. J. Darensbourg, J. B. Robertson, D. L. Larkins and J. H. Reibenspies,
Inorg. Chem., 1999, 38, 2473 and references therein.
10
1.7
a
mmol; n-octane, 30 cm3;
Conditions: 3, 1.8 mmol; catalyst, 9 3 10
H O, 15 cm ; 130 °C; H , 450 psi; 1200 rpm. GC values based on pure
2 2
samples. PTA, 18 3 10 mmol added. 80 °C.
5
(a) D. J. Darensbourg, F. Joó, M. Kannisto, A. Katho, J. H. Reibenspies
and D. J. Daigle, Inorg. Chem., 1994, 33, 200; (b) D. J. Darensbourg, N.
W. Stafford, F. Joó and J. H. Reibenspies, J. Organomet. Chem., 1995,
3
b
c
23
d
4
88, 99; (c) J. Kovács, T. D. Todd, J. H. Reibenspies, F. Joó and D. J.
Darensbourg, Organometallics, 2000, 19, 3963.
6 F. Joó, L. Nádasdi, A. C. Bényei and D. J. Darensbourg, J. Organomet.
Chem., 1996, 512, 45.
Table 2 Recycling of 1 in aqueous biphasic hydrogenation of 3a
Entry
Cycle
% conv.b
4b (%)
5b (%)
6b (%)
7 G. Laurenczy, F. Joó and L. Nadasdi, Inorg. Chem., 2000, 39, 5083.
8
C. S. Allardyce, P. J. Dyson, D. J. Ellis and S. L. Heath, Chem.
Commun., 2001, 1396; P. Dyson, WO 02/40494 A1.
1
1
1
1
a
1
2
3
4
1
2
3
32.5
24.4
20.5
99.9
27.9
21.9
19.2
35.0
1.7
1.1
0.8
2.9
1.4
0.5
0.4
9 (a) M. I. Bruce, F. S. Wong, B. W. Skelton and A. H. White, J. Chem.
Soc., Dalton. Trans., 1981, 1398; (b) I. de los Rios, J.-R. Hamon, P.
Hamon, C. Lapinte, L. Toupet, A. Romerosa and M. Peruzzini, Angew.
Chem., Int. Ed., 2001, 40, 3910.
10 E. T. Papish, M. P. Magree and J. R. Norton, in Recent Advances in
Hydride Chemistry, ed. M. Peruzzini and R. Poli, Elsevier, Amsterdam,
The Netherlands, 2001, ch. 2.
c
Ru/SiO
2
64.5
23
mmol; n-octane, 30 cm3;
Conditions: 3, 1.8 mmol; catalyst, 9 3 10
2
3
b
H
O, 15 cm ; 130 °C; H
2
, 450 psi; 1200 rpm, 3 h. GC values based on pure
c
samples. Ru load 1.7% w/w.
CHEM. COMMUN., 2003, 264–265
265