Organometallic cis-dichlorido ruthenium(II) ammine complexes

Article abstract of DOI:10.1002/ejic.201100250

Bifunctional neutral half-sandwich Ru^II complexes of the type [(I·⁶-arene)Ru(NH₃)Cl₂] where arene is p-cym (1) or bip (2) were synthesised by the reaction of N,N-dimethylbenzylamine (dmba), NH₄PF

Full text of DOI:10.1002/ejic.201100250

FULL PAPER
DOI: 10.1002/ejic.201100250
Organometallic cis-Dichlorido Ruthenium(II) Ammine Complexes
Soledad Betanzos-Lara,[a][‡] Abraha Habtemariam,[a] Guy J. Clarkson,[a] and
Peter J. Sadler*[a]
Keywords: Ruthenium / Sandwich complexes / Cytotoxicity / Antitumor agents / Arene ligands / N ligands
Bifunctional neutral half-sandwich RuII complexes of the
type [(η6-arene)Ru(NH3)Cl2] where arene is p-cym (1) or bip
(2) were synthesised by the reaction of N,N-dimethylbenz-
ylamine (dmba), NH4PF6 and the corresponding RuII arene
dimer, and were fully characterised. X-ray crystallographic
studies of [(η6-p-cym)Ru(NH3)Cl2]·{(dmba–H)(PF6)} (1a) and
[(η6-bip)Ru(NH3)Cl2] (2) show extensive H-bond interactions
in the solid state, mainly involving the NH3 and the Cl li-
gands, as well as weak aromatic stacking interactions. The
half-lives for the sequential hydrolysis of 1 and 2 determined
by UV/Vis spectroscopy at 310 K ranged from a few minutes
for the first aquation to ca. 45 min for the second aquation;
the diaqua adducts were the predominant species at equilib-
rium. Arene loss during the aquation of complex 2 was ob-
served. Upon hydrolysis, both complexes readily formed
mono- and di-9-ethylguanine (9-EtG) adducts in aqueous
solution at 310 K. The reaction reached equilibrium after ca.
1.8 h in the case of complex 1 and was slower but more com-
plete for complex 2 (before the onset of arene loss at ca. 2.7
h). Complexes 1 and 2 were not cytotoxic towards A2780 hu-
man ovarian cancer cells up to the maximum concentration
tested (100 μM).
first reported synthesis and structural characterisation of
an organometallic RuII complex with similarity to cisplatin,
bearing two ammonia ligands and one chlorido ligand, [(η6-
benzene)Ru(NH3)2Cl][PF6],[9,10] appeared thirty years ago
and was studied for its chemical properties. More recently,
the synthesis and properties of the p-cymene complex [(η6-
p-cym)Ru(NH3)2Cl]+ have been described.[11] This complex
is much less potent than cisplatin, displaying an IC50 value
(50% inhibitory concentration) 500 times larger than that
for the platinum drug under the same conditions. This lack
of activity has been attributed to its instability both in aque-
ous media and organic solutions. The synthesis of numer-
ous dichlorido RuII arene complexes bearing N-donor li-
gands[12] (mainly, but not restricted to, pyridine derivatives)
and mixed donor ligands (such as phosphanes)[13] has also
been reported. These dichlorido complexes not only display
interesting biological activities,[14] but have also found use
in other applications, such as catalysts for organic synthe-
sis.[15,16] The synthesis of bifunctional RuII arene complexes
has also included the use of bulkier N-monodentate ligands
such as paullone derivatives,[17] and pyr(id)ones,[18] or non-
N-based monodentate ligands such as 1,3,5-triaza-7-phos-
phatricyclo[3.3.1.1]decane (pta),[19] as well as biologically
active groups such as staurosporine[20] or tyrphostin[21] de-
rivatives. Moreover, based on several studies with platinum
anticancer compounds,[22,39] it seems that the presence of
an H-bond donor atom may be a desirable feature in the
design of bifunctional RuII arene complexes in order to, for
example, stabilise intrastrand cross-linking on DNA in a
similar fashion to cisplatin.[23] For this, monodentate NH2R
ligands have been used.[24,25] However, the evidence suggests
Introduction
Soon after the discovery of the cytotoxic properties of
cisplatin,[1–3] extensive studies of platinum am(m)ine halido
analogues led to a series of empirical rules governing the
chemotherapeutic potential of this class of derivatives.[4] It
was concluded that active compounds should: (i) be neutral,
presumably to facilitate passive diffusion into cells; (ii) have
two leaving groups in a cis-configuration; (iii) contain non-
leaving groups with poor trans-labilising ability, similar to
that of NH3 or organic amines; and (iv) have leaving groups
with a window of lability centred on the chlorido ligand.
Recent studies have focused on applying analogous struc-
ture-activity relationships to other metal complexes for an-
ticancer drug design.[5] Half-sandwich RuII arene complexes
of the general formula [(η6-arene)Ru(X)(Y)(Z)]n+ where X
and Y are two monodentate ligands or if linked a bidentate
chelating ligand, and Z is a leaving group, have recently
been shown to have potential as anticancer drugs.[6] In con-
trast, bifunctional neutral dichlorido RuII agents containing
tethered ligands of general formula [(η6:η1-arene:N)RuCl2],
Figure 1, as well as the more stable derivatives [(η6:η1-
arene:N)Ru(oxalate)],[7,8] have proved to be inactive. The
[a] Department of Chemistry, University of Warwick,
Coventry, CV4 7AL, UK
E-mail: P.J.Sadler@warwick.ac.uk
[‡] Current address: Departamento de Química Inorgánica, Facul-
tad de Química, Universidad Nacional Autónoma de México
(UNAM), Ciudad Universitaria, Coyoacán, México, D.F.
04510 México, Mexico
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejic.201100250.
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S. Betanzos-Lara, A. Habtemariam, G. J. Clarkson, P. J. Sadler
FULL PAPER
that the coordinated N-donor group can undergo facile li- purification steps to afford complex 1, the presence of the
gand-substitution reactions in solution and complexes such N,N-dimethylbenzylammonium ion (dmba–H)+ was de-
as [(η6-mesitylene)Ru(NHR2)Cl2] where R is ethyl or butyl, tected in solution by 1H NMR spectroscopy prior to
readily decompose in solution.[26] In the work reported recrystallisation of the reaction product. The signals were
here, the synthesis and structural characterisation of the assigned to the adduct [(η6-p-cym)Ru(NH3)Cl2]·{(dmba–
first examples of neutral water-soluble organometallic RuII H)(PF6)} (1a) [(CD3)2CO, 500 MHz δH: 3.01 (s, 6 H), 4.50
complexes which possess an ammonia ligand and two cis (s, 2 H), 7.50 (m, 3 H), 7.66 ppm (m, 2 H)], thus providing
chlorido ligands, are described. Their aqueous solution further evidence to support the proposed mechanism.
chemistry, ability to bind to model DNA nucleobases, and Furthermore, the nature of the solvent appears to play an
cytotoxicity towards human cancer cells were also investi- important role in the quality of the products; syntheses car-
gated.
ried out in CH3CN or CH2Cl2 also yielded complexes 1 and
2 but in lower yields (less than 40% in both cases). This
observation suggests that the reaction might proceed via a
nucleophilic substitution pathway. The intermediate species
generated upon the nucleophilic attack of NH3 on the RuII
centre might be considerably better stabilized by interac-
tions with a solvent of medium polarity-index such as meth-
anol (5.1), compared to either a more polar solvent as
CH3CN (5.8) or less polar solvent such as CH2Cl2 (3.1).[27]
Characterisation
Both complexes were fully characterised by 1D and 2D
1H NMR methods as well as elemental analysis, ESI-MS,
and X-ray crystallography. The 1H NMR resonances of
both arenes in complexes 1 and 2 are high-field-shifted by
about 1 ppm compared to the corresponding parent dimers.
The resonances for the NH protons in both complexes can
be readily assigned in a non-aqueous deuterated solvent
Figure 1. Top: General structure of amine-tethered dichlorido RuII
arene complexes. Bottom: Structures of the neutral RuII arene com-
plexes [(η6-p-cym)Ru(NH3)Cl2] (1), [(η6-p-cym)Ru(NH3)Cl2]·
{(dmba–H)(PF6)} (1a) and [(η6-bip)Ru(NH3)Cl2] (2) studied in this
work.
1
such as acetone. Figure S1 shows the H NMR spectrum
Results and Discussion
of complex [(η6-p-cym)Ru(NH3)Cl2] (1) in [D6]acetone as
an example. Suitable crystals of [(η6-p-cym)Ru(NH3)Cl2]·
{(dmba–H)(PF6)} (1a) were grown using the crude product
Synthesis
Two new RuII arene complexes [(η6-arene)Ru(NH3)Cl2] isolated from the synthesis (and prior to recrystallisation)
where arene is p-cym (1) or bip (2), showing constitutional in a saturated dichloromethane solution at ambient tem-
similarity to cisplatin were synthesised in good yields (68% perature, whereas crystals of the biphenyl complex [(η6-
and 66%, respectively), Figure 1. The first report of the syn- bip)Ru(NH3)Cl2] (2) were obtained from a saturated aceto-
thesis of organometallic complexes containing ammonia nitrile solution at ambient temperature. Selected bond
and chlorido ligands was thirty years ago[10] and resulted in lengths and angles are given in Table 1. The structures and
the monochlorido bisammine complexes [(η6-benzene)- atom labelling are shown in Figure 2 and the crystallo-
M(NH3)2Cl][PF6] (where M = Ru or Os). The synthetic graphic data are listed in Table S1. The two neutral RuII
routes were rather complicated and often gave mixtures of arene complexes adopt the familiar pseudo-octahedral
products. They involved reacting [(η6-benzene)M(Cl)2]2 di- three-legged piano stool geometry common to other half-
mers in concentrated aqueous ammonia and methanol, fol- sandwich RuII arene structures.[6,28] The Ru atom is η6-
lowed by the addition of a saturated aqueous NH4PF6 solu- bonded to p-cym in 1a and bip in 2, coordinated to an
tion to precipitate the complexes as the corresponding PF6 ammonia nitrogen, and to two chloride ions which consti-
salts. In the present work, the reaction of [(η6-arene)- tute the three legs of the piano stool. The unit cell of the
RuCl2]2 where the arene is p-cym or bip, with 2 mol equiv. RuII arene complex 1a also contains the N,N-dimethylbenz-
of N,N-dimethylbenzylamine (dmba) and 2 mol equivalents ylammonium hexafluorophosphate ionic pair (dmba–
of NH4PF6 in dry MeOH under a N2 atmosphere at ambi- H)(PF6). The Ru–Cl bonds in complexes 1a [2.421(2)/
ent temperature proved to be convenient. The first step in 2.427(2) Å] and 2 [2.4246(9)/2.4284(8) Å] as well as the cor-
the synthesis is believed to involve a fast reaction between responding Ru–N bonds [2.116(8) for 1a and 2.135(3) Å for
+
the base N,N-dimethylbenzylamine (dmba) and NH4 to 2] do not vary with a change in arene. The Ru–Cl bond
form NH3 in situ which then reacts with the RuII arene lengths are within the range found for other Ru–N(sp3) ar-
dimer to afford complexes 1 and 2. A similar reaction ene complexes[29] such as [(η6:η1-C6H5(CH2)3NH2)RuCl2][7]
mechanism has also been suggested for the synthesis of the and longer than those found in related structures where the
cationic complex [(η6-p-cym)Ru(NH3)2Cl]+.[11] During the N atom belongs to an aromatic pyridine ring.[30,13] The Ru–
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Organometallic cis-Dichlorido Ru(II) Ammine Complexes
N distances are not significantly affected by a change of
arene from p-cym (1a) to bip (2) and are within the range
found in similar complexes such as [(η6-p-cym)Ru(NH3)2-
Cl]+ [2.1504(15) and 2.1425(15) Å].[11] They are again on
average, slightly longer than those of analogous complexes
where the nitrogen donor atom belongs to an aromatic sys-
tem such as a pyridine derivative.[11] The Ru···p-cym(centroid)
distance (as measured from Mercury version 2.2.) in com-
plex 1a (1.657 Å) is slightly shorter than that for the bip
analogue 2 (1.670 Å). These two distances differ from those
observed when the N atom belongs to a (tethered) ethyl-
enediamine[7,8,32] (ca. 1.65 Å) but are slightly shorter (ca.
0.02–0.05 Å) than those found in related complexes where
the RuII centre is bound to an aromatic XY-chelating ligand
(XY are N, O, or S).[31] The X-ray crystal structures of com-
pounds 1a and 2 also show intra and/or intermolecular π-
π stacking interactions, a common feature in related RuII
complexes containing extended aromatic rings[32] as well as
H-bond interactions, Figure 3 and Figure 4. Tables S2 and
S3 list the hydrogen bond lengths [Å] and angles [°] in the
X-ray crystal structures of [(η6-p-cym)Ru(NH3)Cl2]·
{(dmba–H)(PF6)} (1a) and [(η6-bip)Ru(NH3)Cl2] (2),
respectively. The ionic pair in the crystal structure of 1a
also shows π-π stacking interactions, Figure S2. Complex
[(η6-bip)Ru(NH3)Cl2] (2) pairs with an adjacent molecule
also via intermolecular π-π stacking interaction. The mean
planes involving the uncoordinated phenyl (ph) rings in the
bip arene are parallel, Figure 5. A space-filling model of
complex 2 (inset in Figure 5) shows the presence of aro-
matic stacking with the shortest atomic contact C(8)···C(10)
being 3.587 Å and a ph(centroid)–ph(centroid) distance of
3.687 Å, typical of such weak interactions.[33] The uncoor-
dinated phenyl ring is tilted by 41.06° relative to the main
Figure 3. Intermolecular H-bond interactions present in the X-ray
crystal structure of [(η6-p-cym)Ru(NH3)Cl2]·{(dmba–H)(PF6)}
(1a). Atoms not involved in the specified interactions are omitted
for clarity.
plane defined by the coordinated ph(bound)
.
Table 1. Selected bond lengths [Å] and angles (°) for [(η6-p-cym)-
Ru(NH3)Cl2]·{(dmba–H)(PF6)} (1a) and [(η6-bip)Ru(NH3)Cl2] (2).
Figure 4. X-ray crystal structure of [(η6-bip)Ru(NH3)Cl2] (2) show-
ing N–H···Cl contacts.
Bond length/angle
1a
2
[a]
Ru(1)–arene(centroid)
Ru(1)–Cl(1)
Ru(1)–Cl(2)
1.657
1.670
2.427(2)
2.421(2)
2.116(8)
83.80(2)
84.30(2)
85.11(8)
2.4284(8)
2.4246(9)
2.135(3)
84.29(8)
84.73(8)
85.26(3)
Ru(1)–N(1)
N(1)–Ru(1)–Cl(1)
N(1)–Ru(1)–Cl(2)
Cl(2)–Ru(1)–Cl(1)
[a] Calculated with Mercury, version 2.2.
Figure 2. X-ray crystal structures of [(η6-p-cym)Ru(NH3)Cl2]·
{(dmba–H)(PF6)} (1a) and [(η6-bip)Ru(NH3)Cl2] (2). Thermal el-
lipsoids show 50% probability. The hydrogen atoms have been
omitted for clarity. The ion pair in 1a is not shown.
Figure 5. X-ray crystal structure of [(η6-bip)Ru(NH3)Cl2] (2) show-
ing a π-π stacking interaction between two uncoordinated bip rings
in neighbouring molecules. Inset: space-filling model.
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S. Betanzos-Lara, A. Habtemariam, G. J. Clarkson, P. J. Sadler
FULL PAPER
Figure 6. Time evolution of the hydrolysis reaction for 100 μm (5% MeOH/95% H2O) solutions of complexes 1 and 2 at 310 K followed
by UV/Vis spectroscopy.
Kinetics of Hydrolysis
The hydrolysis rate constants and half-lives are listed in
Table 2. It can be seen that the first step is fast for both
complexes (half-lives ca. 1 min). The aquation rates for the
second step are also similar for both complexes. The loss of
the first chlorido ligand might be expected to be faster than
the substitution of the second because of the increase in
positive charge on the molecule. This is the case for both
complexes 1 and 2; the first hydrolysis rate (k1) of complex
1 is not only ca. 48 times faster than the second (k2) but
also ca. 1.5 times faster than k1 for the bip complex 2.
Dissolution of compounds 1 and 2 in 5% MeOH/95%
H2O (100 μm) at 310 K gave rise to ligand-substitution reac-
tions at the RuII centre as indicated by rapid changes in
UV/Vis absorption bands. The time evolution spectra for
the two RuII arene complexes at 310 K are shown in Fig-
ure 6. The initial electronic absorption spectrum of aqueous
[(η6-p-cym)Ru(NH3)Cl2] (1) at 310 K exhibits peaks with
maxima at ca. 255, 320, and 410 nm. The highest energy
absorption band increases in intensity while the lower en-
ergy band decreases. The band centred at ca. 320 nm disap-
pears upon hydrolysis. In the case of [(η6-bip)Ru(NH3)Cl2]
(2) in aqueous solution, the initial electronic absorption
spectrum at 310 K exhibits peaks with maxima at ca. 255
and 274 nm which increased in intensity only slightly over
a period of ca. 6 h. Related mononuclear RuII arene com-
plexes of the type [(η6-arene)Ru(X)(Y)Cl]n+ where XY is
a bidentate chelating ligand[34–36] are known to undergo a
monoexponential decrease in absorbance due to the loss of
one chloride and substitution by water.[37] The presence of
two chlorido ligands that can be substituted by water in
complexes 1 and 2 and the absence of a clear isosbestic
point in their UV/Vis absorption spectra correlates with a
bi-exponential kinetics as shown by the fit to the data, Fig-
ure S3. The rate constants for hydrolysis of complex 2 were
determined over a 160 min period.
Hydrolysis Equilibria
1
Upon dissolution of complexes 1 or 2 in D2O, the H
NMR spectrum shows the presence of a number of species.
In order to characterise the products of hydrolysis and de-
termine the extent of the reactions, freshly-made 100 μm
solutions of complexes 1 and 2 (in 5% [D4]MeOD/95%
D2O) were allowed to equilibrate for 24 h at 310 K and were
1
then studied at the same temperature using H NMR spec-
1
troscopy. Figure S4 shows the time dependence of the H
NMR CH3(isopropyl) peaks of the p-cym ring of complex 1 at
310 K. The 1H NMR spectra of complexes 1 and 2 initially
contained one major set of peaks (dichlorido species) and
then a second and third set of peaks, which increased in
intensity over time. The new sets of peaks were assigned to
the mono- and di-aqua adducts, [(η6-arene)Ru(NH3)-
(OH2)Cl]+ and [(η6-arene)Ru(NH3)(OH2)2]2+, respectively.
The mass-to-charge ratios of peaks in ESI-MS spectra of
the solutions after 24 h were consistent with the formation
of the di-aqua complexes; Table S4 (observed as the base
peak in the spectra). For complex [(η6-bip)Ru(NH3)Cl2] (2)
Table 2. Hydrolysis data for complexes 1 and 2 (100 μm in 5%
MeOH/95% H2O) at 310 K determined by UV/Vis spectroscopy.
1
2
1
First aquation
k1 ϫ10–3 [min–1][a,b]
t1/2 [min]
an additional set of H NMR peaks [δ = 7.88 (d), 7.70 (t),
7.42 (t)] assignable to free bip was also observed after
160 min.
720.0Ϯ21.8
1.0
555.0Ϯ27.2
1.2
Table 3 summarizes the percentage of species detected at
equilibrium and after 24 h of reaction as determined by H
NMR peak integration. These data suggest that the p-cym
complex 1 undergoes mono- and di-hydrolysis reactions to
a larger extent (ca. 2 to 7 times) than complex 2 (before
biphenyl loss). Changing the arene from p-cym (1) to bip
Second aquation
k2 ϫ10–3 [min–1][a,b]
t1/2 [min]
1
15.2Ϯ0.7
45.7
15.9Ϯ5.8
43.6
[a] The errors quoted are fitting errors. [b] The rate constants for
complex 2 were determined over the period of time before the onset
of arene loss (at ca. 160 min detected by H NMR).
1
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Organometallic cis-Dichlorido Ru(II) Ammine Complexes
(2) greatly reduces the stability of the complex in aqueous 2, at equilibrium (before the onset of arene loss, ca.
solution at 310 K since no loss of the arene p-cym was ob- 160 min), ca. 5% of the corresponding mono 9-EtG adduct
served for complex 1.
[(η6-bip)Ru(NH3)(9-EtG-N7)Cl]+ (2-EtG) and 32% of the
diguanine adduct [(η6-bip)Ru(NH3)(9-EtG-N7)2]2+ (2-
EtG2) had been formed. The reactions of complex 2 with
9-EtG take longer to reach equilibrium compared to those
of complex 1, and are less thermodynamically favoured.
The mass-to-charge ratios obtained from ESI-MS data were
used to characterise some of the guanine adducts (see Table
S5).
Table 3. Percentage of species present at equilibrium in 100 μm
solutions of complexes 1 and 2 (5% [D4]MeOD/95% D2O) after
24 h at 310 K determined by H NMR spectroscopy.
1
% Species
Ru–Cl2 Ru–OH2 Ru–(OH2)2 Arene loss
[(η6-p-cym)Ru(NH3)Cl2] (1) 3.1
[(η6-bip)Ru(NH3)Cl2] (2) 24[a]
20.8
2[a]
76.1
18[a]
0.0
56[a]
Table 4. Extent of formation of 9-EtG-N7 adducts on reactions of
complexes 1 and 2 with 2 mol equiv. of 9-EtG in 5% [D4]MeOD/
95% D2O at 310 K as determined by integration of 1H NMR
peaks.
[a] Approximate values due to peak overlap.
Compound
Time
[min]
% Mono-
(9-EtG-N7)
adduct
% Di-
Interactions with Nucleobases
(9-EtG-N7)
adduct
DNA is one of the potential targets for transition metal
anticancer complexes.[38] For this reason, reactions of com-
plexes 1 and 2 with 9-ethylguanine (9-EtG) as a model nu-
cleobase were investigated. The interactions were studied by
[(η6-p-cym)Ru(NH3)Cl2] (1)
[(η6-bip)Ru(NH3)Cl2] (2)
106[a]
1440
160[b]
20.4
20.4
5[b]
53.0
53.0
32[b]
1
multidimensional H NMR spectroscopy and the nature of
[a] Time to reach equilibrium. [b] Time before the onset of arene
loss; approximate value due to peak overlap.
the products verified by ESI-MS. 9-EtG (2 mol-equiv.) was
added to an NMR tube containing a 100 μm solution of 1
or 2 in 5% [D4]MeOD/95% D2O at 310 K and the reaction
was then followed for ca. 6 h. The interactions occur via the
initial in situ formation of the corresponding reactive
mono- and di-aqua adducts for each complex. After ca.
10 min of reaction, a second and third set of low-field-
shifted peaks appeared and increased in intensity. These
peaks are tentatively assigned to the corresponding mono-
and dinucleobase adducts with coordination of the RuII
centre to N7 of 9-EtG. This coordination mode has been
previously observed for similar RuII arene guanine and ade-
nine adducts[39,40,36a] and is confirmed by the changes in
chemical shift of the H8 peak for bound 9-EtG-N7 in the
monoguanine RuII arene adducts of both complexes [(η6-p-
cym)Ru(NH3)(9-EtG-N7)Cl]+ (1-EtG) or [(η6-bip)Ru-
(NH3)(9-EtG-N7)Cl]+ (2-EtG). These have chemical shifts
of ca. 8.20 ppm, cf. 8.08 ppm for free 9-EtG under the same
conditions. Metallation at the N7 site of purine bases usu-
ally produces a low field shift of the H8 resonance by about
0.3–1.0 ppm,[41,42] The second singlet was assigned to the
corresponding diguanine adducts [(η6-p-cym)Ru(NH3)(9-
Cancer Cell Growth Inhibition
Neither complex 1 nor 2 was cytotoxic towards the
A2780 human ovarian cancer cell line up to the maximum
concentration tested (100 μm), Table S6. It is known that
metal coordination complexes can undergo ligand-substitu-
tion reactions with components of the media in which they
are dissolved.[47] In the case of complexes 1 and 2, the di-
minished anticancer activity could be due to inactivation by
reaction with components of the cell culture media even
before reaching the cell or by other biomolecules once
within the cell. This same hypothesis of inactivation has
been previously suggested for complexes of the type [(η6-p-
cym)Ru(X)(Y)Z] where X, Y or Z are monodentate ligands
such as halides, acetonitrile or isonicotinamide.[6]
Conclusions
We have shown that neutral RuII half-sandwich com-
EtG-N7)2]2+ (1-EtG2) or [(η6-bip)Ru(NH3)(9-EtG-N7)2]2+ plexes containing two cis chlorido ligands and an ammine
(2-EtG2) and has a chemical shift in the range of 8.30– ligand can be synthesised by the reaction of N,N-dimethyl-
8.40 ppm, Figure S5. A similar profile of bifunctional reac- benzylamine and NH4PF6, first forming NH3 in situ which
tivity is well-known for cisplatin, which can form intra- and/ then reacts with the appropriate RuII arene dimer to afford
or inter-strand crosslinks.[43–45] Furthermore, coordination complexes [(η6-arene)Ru(NH3)Cl2] 1 (p-cym) and 2 (bip). A
to two guanine bases has been demonstrated for the frag- notable feature of these species in the solid state is the ex-
ment {(η6-benzene)Ru}2+ [46]
Both complexes reacted rela- tensive network of H-bond interactions through the NH3
.
tively rapidly with 9-EtG (less than 2 h to reach equilib- and the Cl ligands as well as π-π stacking aromatic interac-
rium); Table 4 lists the percentage of species detected after tions, particularly in the case of complex 2. Hydrolysis of
24 h of reaction as determined from integration of 1H the complexes was relatively rapid and occurred in two
NMR signals. As it can be seen, at equilibrium complex 1 steps with half-lives of ca. 1 min and 46 min. Hydrolysis of
had reacted with 9-EtG to form ca. 21% of the correspond- the bip complex 2 appeared to be followed by arene loss
ing monoguanine adduct [(η6-p-cym)Ru(NH3)(9-EtG-N7)- with time. The possibility that DNA could be a target for
Cl]+ (1-EtG) and 53% of the diguanine adduct [(η6-p-cym) these complexes in cancer cells was investigated by explor-
Ru(NH3)(9-EtG-N7)2]2+ (1-EtG2). In the case of complex ing their reactions with the model DNA nucleobase 9-ethyl-
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S. Betanzos-Lara, A. Habtemariam, G. J. Clarkson, P. J. Sadler
FULL PAPER
4.19, N 3.88; found C 39.83, H 4.32, N 4.43. ESI-MS calcd. for
C12H14Cl2NRu {[M] + [H+]}+ m/z 344.2; found m/z 343.9. 1H
NMR [(CD3)2CO, 500 MHz]: δ = 3.39 (m, 3 H), 5.77 (t, J =
5.63 Hz, 1 H), 5.93 (t, J = 5.63 Hz, 2 H), 6.03 (t, J = 5.63 Hz, 2
H), 6.12 (d, J = 6.25 Hz, 2 H), 6.24 (d, J = 6.25 Hz, 1 H) ppm.
guanine (9-EtG) in aqueous solution. Both complexes read-
ily formed mono- and diguanine adducts upon hydrolysis.
The reaction of complex 1 with 9-EtG was faster, and to a
greater extent than that of 2. Hydrolysis is known to be a
mechanism for activation of cytotoxic chlorido metal com-
plexes.[6] However, none of the neutral complexes were cyto-
toxic against the A2780 human ovarian cancer cell line up
to the maximum concentration tested (100 μm), perhaps be-
cause they are too reactive towards components of the cell
culture medium, and in the case of 2 due to arene loss.
X-ray Crystallography: Diffraction data were collected either on an
Oxford Diffraction Gemini four-circle system with a Ruby CCD
area detector or on a Siemens SMART three-circle system with
CCD area detector equipped with an Oxford Cryosystem Cryos-
tream Cooler. All structures were refined by full-matrix least-
squares against F2 using SHELXL 97[49] and were solved by direct
methods using SHELXS[50] (TREF) with additional light atoms
found by Fourier methods. Hydrogen atoms were added at calcu-
lated positions and refined using a riding model, except the hydro-
gens on the NH nitrogens which were located in a difference map.
Their positions were allowed to refine but with a distance restraint.
Anisotropic displacement parameters were used for all non-H
atoms; H-atoms were given an isotropic displacement parameter
equal to 1.2 (or 1.5 for methyl and NH H-atoms) times the equiva-
lent isotropic displacement parameter of the atom to which they
are attached.
Experimental Section
Materials: RuCl3·3H2O was purchased from Precious Metals On-
line (PMO Pty Ltd.) and used as received. N,N-dimethylbenzyl-
amine (dmba) and NH4PF6 were obtained from Aldrich. The RuII
arene precursor dimers [(η6-p-cym)RuCl2]2 and [(η6-bip)RuCl2]2
where arene is p-cymene (p-cym) or biphenyl (bip), were prepared
following literature methods.[48] The solvents used for UV/Vis ab-
sorption spectroscopy, dry methanol (reagent grade), and for NMR
spectroscopy, [D6]acetone, [D]chloroform, [D4]methanol and D2O,
were purchased from Aldrich.
Synthesis of Ruthenium Complexes: The neutral complexes [(η6-ar-
ene)Ru(NH3)Cl2] where arene is p-cym or bip were synthesised
using a similar procedure. A suspension of the appropriate RuII
arene dimer [(η6-arene)RuCl2]2, N,N-dimethylbenzylamine (dmba)
and NH4PF6 in 10 mL of dry MeOH was stirred at ambient tem-
perature under N2 atmosphere for 18 h. After evaporation of the
clear orange solution that formed, the resulting solid was recrystal-
lised by redissolution in the minimum amount of MeOH, CH2Cl2
or CH3CN and leaving to stand at 298 K for 5 h. The precipitate
that formed was filtered off and washed with portions of Et2O/
CCDC-809024 (for 1a) and -809025 (for 2) contain the supplemen-
tary crystallographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
NMR Spectroscopy: 1H and 13C NMR spectra were acquired in
5 mm NMR tubes at 298 K (unless otherwise stated) on a Bruker
DRX-500 NMR spectrometer. All data processing was carried out
using XWIN NMR version 3.6 (Bruker U. K. Ltd.). 1H NMR
chemical shifts were internally referenced to TMS via 1,4-dioxane
in D2O (δ = 3.71 ppm) or residual CHCl3 (δ = 7.27 ppm),
CD2HOD (δ = 3.31 ppm) or DMSO (δ = 2.50 ppm). 1D spectra
were recorded using standard pulse sequences. Typically, data were
MeOH and dried overnight in vacuo resulting in a microcrystalline acquired with 128 transients into 16 k data points over a spectral
product. Details of the amounts of reactants, colour changes, and
nature of the products for the individual reactions are described
below, as well as any variations in the synthetic procedure.
width of 14 ppm. 2D spectra were recorded using standard pulse-
pulse sequences. COSY was used to identify pairs of nuclei which
are J-coupled to one another. Typically, data were acquired with
72 transients into 1024 k data points over a spectral width of
14 ppm (unless otherwise stated) using a relaxation delay of 1.5 s
and a mixing time of 0.06 s.
[(η6-p-cym)Ru(NH3)Cl2] (1) and [(η6-p-cym)Ru(NH3)Cl2]·{(dmba–
H)(PF6)} (1a):
A
solution of [(η6-p-cym)RuCl2]2 (0.10 g,
0.16 mmol), N,N-dimethylbenzylamine (0.05 mL, 0.32 mmol) and
NH4PF6 (0.05 g, 0.32 mmol) in dry MeOH turned from brick red
to orange; an orange solid of [(η6-p-cym)Ru(NH3)Cl2] (1) was ob-
tained by recrystallization from methanol, whereas bright orange
Elemental Analysis: Elemental analyses were performed by the
Warwick Analytical Service which is the analytical division of Exe-
ter Analytical (U. K. Ltd.) using an Exeter Analytical Elemental
crystals suitable for X-ray diffraction of [(η6-p-cym)Ru(NH3)Cl2]· Analyzer (CE440).
[(dmba–H)(PF6)] (1a) were grown from a saturated dichlorometh-
Electrospray Ionization Mass Spectrometry (ESI -MS): Positive-ion
ane solution of the crude product at ambient temperature; yield
(for recrystallised 1) 68% (0.04 g, 0.12 mmol).
ESI(+) mass spectra were obtained either on a Bruker Esquire2000
Ion Trap Spectrometer or a Bruker MicroTOF Spectrometer. Sam-
ples were prepared in either 100% H2O or 95% MeOH/5% H2O
mixture and typically injected at 2 μLmin–1, nebulizer gas (N2)
25 psi, dry gas (N2) 9 Lmin–1, dry temp. 300 °C, capillary –4000 V
(+ mode), end plate offset –500 V, capillary exit 70–170 V, and Oct
RF 50–400 V pp, unless otherwise stated. Data were processed
using DataAnalysis version 3.3 (Bruker Daltonics).
1: C10H17Cl2NRu (323.23): calcd. 37.16, H 5.30, N 4.33; found C
37.70, H 5.04, N 4.31.
1a: C19H31Cl2F6N2PRu: calcd. C 37.76, H 5.17, N 4.63; found C
37.72, H 5.04, N 4.21. ESI-MS calcd. for C10H18Cl2NRu {[M] +
[H+]}+ m/z 324.2; found m/z 324.0. 1H NMR for (1) [(CD3)2CO,
500 MHz]: δ = 1.30 (d; J = 7.50 Hz, 6 H), 2. 20 (s, 3 H), 3.10 (m,
3 H), 5.36 (d, J = 6.25 Hz, 2 H), 5.58 (dd, J = 6.25 Hz, 2 H) ppm.
UV/Vis Absorption Spectroscopy: UV/Vis absorption spectra were
recorded on a Cary 50-Bio spectrophotometer using 1-cm path
length quartz cuvettes (600 μL) and a PTP1 Peltier temperature
controller. Spectra were recorded at 310 K in deionised water from
200 to 800 nm and were processed using UV-Winlab software for
Microsoft Windows 95®.
[(η6-bip)Ru(NH3)Cl2] (2): A solution of [(η6-bip)RuCl2]2 (0.10 g,
0.16 mmol),
N,N-dimethylbenzylamine
(dmba)
(0.049 mL,
0.32 mmol) and NH4PF6 (0.05 g, 0.32 mmol) in dry MeOH turned
from brick red to orange; a bright orange solid was obtained; yield
66% (0.04 g, 0.11 mmol). Crystals suitable for X-ray diffraction
were grown from an acetonitrile-saturated solution of recrystallised
2 at ambient temperature. C12H13Cl2NRu·H2O: calcd. C 39.90, H
Aqueous Solution Chemistry: Hydrolysis of the RuII arene com-
plexes was monitored by UV/Vis spectroscopy. The nature of the
3262
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© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Inorg. Chem. 2011, 3257–3264

Organometallic cis-Dichlorido Ru(II) Ammine Complexes
hydrolysis products as well as the extent of the reactions were veri-
fied by 1H NMR spectroscopy or ESI-MS. For UV/Vis spec-
troscopy, the complexes were dissolved in methanol and diluted
with H2O to give 100 μm solutions (5% MeOH/95% H2O). The
absorbance was recorded at several time intervals at the selected
wavelength (at which the maximum changes in absorbance were
registered) over ca. 4 h at 310 K. The data were then subjected to
kinetic analysis for the first and second aquation steps. Plots of
the change in absorbance with time were computer-fitted to the
appropriate biexponential kinetic equation using Origin version 8.0
(Microcal Software Ltd.) to give the half-lives (t1/2, min) and rate
constants (kn, min–1). For 1H NMR spectroscopy, the complexes
were dissolved in [D4]MeOD and diluted with D2O to give 100 μm
solutions (5% [D4]MeOD/95% D2O). The spectra were acquired at
various time intervals on a Bruker DMX 700 spectrometer (1H =
700 MHz) using 5 mm diameter tubes. All data processing was car-
ried out using XWIN NMR version 2.0 (Bruker U. K. Ltd.). 1H
NMR signals were referenced to dioxane as an internal reference
(δ = 3.71). The relative amounts of RuII arene halido species or
aqua adducts were determined by integration of peaks in 1H NMR
spectra.
(ERC) for funding, Dr Ana María Pizarro for the assistance with
cell testing, Dr Ivan Prokes and Dr Lijiang Song and Mr Philip
Aston of the University of Warwick for their assistance with NMR
and MS instruments, respectively.
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Acknowledgments
S. B.-L. thanks Warwick Postgraduate Research Scholarships/Over-
seas Research Students Awards Scheme (WPRS/ORSAS), U.K.
and Consejo Nacional de Ciencia y Tecnología (CONACyT),
Mexico for funding her research scholarship. We also thank The
European Regional Development Fund/Advantage West Midlands
(ERDF/AWM), Science City and European Research Council
Eur. J. Inorg. Chem. 2011, 3257–3264
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Betanzos-Lara, A. Habtemariam, G. J. Clarkson, P. J. Sadler
FULL PAPER
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Received: March 13, 2011
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Eur. J. Inorg. Chem. 2011, 3257–3264