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Synthesis, Characterization, and Biological Activity of Water-Soluble, Dual Anionic and Cationic Ruthenium-Arene Complexes Bearing Imidazol(in)ium-2-dithiocarboxylate Ligands.
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Article
Synthesis, Characterization, and Biological Activity of WaterSoluble, Dual Anionic and Cationic Ruthenium−Arene Complexes
Bearing Imidazol(in)ium-2-dithiocarboxylate Ligands
Mohammed Zain Aldin, Guillermo Zaragoza, William Deschamps, Jean-Claude Didelot Tomani,
Jacob Souopgui, and Lionel Delaude*
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Cite This: Inorg. Chem. 2021, 60, 16769−16781
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ABSTRACT: An efficient synthetic protocol was devised for the
preparation of five cationic ruthenium−arene complexes bearing
imidazol(in)ium-2-dithiocarboxylate ligands from the [RuCl2(pcymene)]2 dimer and 2 equiv of an NHC·CS2 zwitterion. The
reactions proceeded cleanly and swiftly in dichloromethane at room
temperature to afford the expected [RuCl(p-cymene)(S2C·NHC)]Cl
products in quantitative yields. When the [RuCl2(p-cymene)]2 dimer
was reacted with only 1 equiv of a dithiolate betaine under the same
experimental conditions, a set of five bimetallic compounds with the
generic formula [RuCl(p-cymene)(S2C·NHC)][RuCl3(p-cymene)]
was obtained in quantitative yields. These novel, dual anionic and
cationic ruthenium−arene complexes were fully characterized by
various analytical techniques. NMR titrations showed that the chelation of the dithiocarboxylate ligands to afford [RuCl(pcymene)(S2C·NHC)]+ cations was quantitative and irreversible. Conversely, the formation of the [RuCl3(p-cymene)]− anion was
limited by an equilibrium, and this species readily dissociated into Cl− anions and the [RuCl2(p-cymene)]2 dimer. The position of
the equilibrium was strongly influenced by the nature of the solvent and was rather insensitive to the temperature. Two
monometallic and two bimetallic complexes cocrystallized with water, and their molecular structures were solved by X-ray diffraction
analysis. Crystallography revealed the existence of strong interactions between the azolium ring protons of the cationic complexes
and neighboring donor groups from the anions or the solvent. The various compounds under investigation were highly soluble in
water. They were all strongly cytotoxic against K562 cancer cells. Furthermore, with a selectivity index of 32.1, the [RuCl(pcymene)(S2C·SIDip)]Cl complex remarkably targeted the erythroleukemic cells vs mouse splenocytes.
■
INTRODUCTION
N-Heterocyclic carbenes (NHCs) are powerful nucleophiles
that react instantaneously with carbon disulfide to afford stable
zwitterions conveniently designated as NHC·CS2 adducts.1,2
These inner salts are usually crystalline materials that form
strong M−S bonds with a wide range of metal centers.3 Borer
and co-workers first investigated their coordination chemistry
in the 1980s by synthesizing various complexes from 1,3dimethylimidazolium-2-dithiocarboxylate (IMe·CS2) and diverse late transition metal halides or nitrates.4 The products
obtained were characterized by IR and UV/visible spectroscopies. Cyclic voltammetry, electrical conductivity, and
magnetic susceptibility measurements were performed in
some instances; but no NMR or XRD data were provided,
and the molecular structures proposed remained hypothetical.
In 2009, while investigating the ability of NHC·CO2 and
NHC·CS2 zwitterions to generate in situ ruthenium−NHC
catalyst precursors for olefin metathesis and atom transfer
radical polymerization reactions, we synthesized and fully
characterized the first representatives of well-defined organo© 2021 American Chemical Society
metallic species featuring imidazolium or imidazolinium-2dithiocarboxylate ligands.5 Thus, five cationic ruthenium−
arene complexes featuring κ2-S,S′ chelates (1a−e) were
isolated in high yields upon reaction of the [RuCl2(pcymene)]2 dimer (p-cymene is 1-isopropyl-4-methylbenzene)
with 2 equiv of an NHC·CS2 zwitterion and potassium
hexafluorophosphate in ethanol at 60 °C for 1 h (Scheme 1).
Subsequent investigations carried out in collaboration with
the group of Wilton-Ely at Imperial College allowed the
extension of the coordination chemistry of the 1,1-dithiolate
betaines to other sources of ruthenium,6,7 as well as osmium,7
palladium,8 and gold.9 In 2016−2017, we described the
Received: August 26, 2021
Published: October 20, 2021
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Scheme 1. Synthesis of Cationic Ruthenium−Arene
Complexes Bearing Imidazol(in)ium-2-dithiocarboxylate
Ligands
Article
Chart 1. Imidazol(in)ium-2-dithiocarboxylate Ligands Used
in This Work
Preliminary experiments were carried out in NMR tubes
charged with the [RuCl2(p-cymene)]2 dimer (20 mg) and 2
equiv of an NHC·CS2 zwitterion. Upon the addition of CDCl3
(0.5 mL) and slowly mixing, a homogeneous solution was
obtained, whose color quickly changed from orange-red to
dark red-purple. After 10 min at room temperature, 1H NMR
analysis revealed the clean and quantitative conversion of the
starting dimer into monometallic [RuCl(p-cymene)(S2C·
NHC)]Cl complexes. These encouraging results prompted
us to perform the reactions on a larger preparative scale. Thus,
the ruthenium dimer (0.1 mmol) and 2 equiv of the ligands
(0.2 mmol) were weighed in a 10 mL glass vial containing a
magnetic stirring bar. A minimum amount of dichloromethane
(2−3 mL) was added, and the mixture was stirred for 10 min
at room temperature. The volatile solvent was easily removed
on a rotary evaporator, and the solid residue was broken down
into a fine powder by stirring it in the presence of petroleum
ether. The slurry was centrifuged, the supernatant liquid was
removed, and the remaining solid was dried under high
vacuum. Gratifyingly, almost quantitative yields (97−100%) of
pure products were obtained (Scheme 2). The 1H and 13C
NMR spectra of compounds 2a−e were compared with those
recorded previously for the analogous [RuCl(p-cymene)(S2C·
NHC)]PF6 salts (1a−e).5 They were quite similar, except for
the resonances of the imidazol(in)ium protons, which were
strongly influenced by the nature of the counterion (vide
infra). High-resolution mass spectrometry (ESI, + ve mode)
confirmed the correct formulation of the cationic part of these
complexes.
Synthesis of Bimetallic [RuCl(p-cymene)(S2C·NHC)][RuCl3(p-cymene)] Complexes. During our exploratory
runs, we recorded the 1H NMR spectrum of a 1:1 mixture
of [RuCl2(p-cymene)]2 and IMes·CS2 in CDCl3. It revealed
the existence of three distinct ruthenium−arene species in
solution. Indeed, triplicate resonances with noninteger
integrals were detected for all the aromatic and aliphatic
protons of the p-cymene ligand. This unusual pattern was most
visible for the methine protons of the isopropyl groups, which
led to three well-separated septets in the ratios 1:0.44:0.56
(Figure 1). The most shielded resonance centered at 2.51 ppm
was easily assigned to the [RuCl(p-cymene)(S2C·IMes)]+
formation of mono- and bimetallic metal−carbonyl compounds based on manganese10 and rhenium11 that featured
chelating or bridging NHC·CS2 ligands.12 More recently, we
disclosed the synthesis of superbulky imidazolium-2-dithiocarboxylate ligands and their complexation to rhenium and
ruthenium,13 while other researchers relied on NHC·CS2
betaines to prepare copper-based coordination polymers14
and clusters15 or gold nanoparticles9 and self-assembled
monolayers.16 A few reports on the formation of dinuclear
iron−carbonyl17 and tetranuclear ruthenium−carbonyl clusters,18 in which the dithiocarboxylate unit underwent chemical
transformations, also appeared in the literature.
In light of our sustained interest in ruthenium−arene
catalyst precursors19 and azolium-2-dithiocarboxylate betaines,3 we decided to reassess our 2009 study5 and to delve
further into the reactivity of the [RuCl2(p-cymene)]2 dimer
with NHC·CS2 zwitterions. Herein, we disclose a new efficient
synthetic protocol for the preparation of monometallic
[RuCl(p-cymene)(S2C·NHC)]Cl complexes. We also investigate the influence of the Ru/dithiolate ligand ratio on the
outcome of the reaction, and we show that a 1:1 mixture of the
metal dimer and five different NHC·CS2 zwitterions cleanly
and transiently affords dual anionic and cationic [RuCl(pcymene)(S2C·NHC)][RuCl3(p-cymene)] complexes, which
are remarkably water-soluble and biologically active against
tumorous cells.
■
RESULTS AND DISCUSSION
Synthesis of Monometallic [RuCl(p-cymene)(S2C·
NHC)]Cl Complexes. The five representative NHC·CS2
zwitterions that we selected in 2009 were employed again in
the present work.5 They include three unsaturated imidazolium-dithiocarboxylate inner salts bearing aliphatic or aromatic
substituents of increasing bulkiness on their nitrogen atoms,
namely, the cyclohexyl (Cy), mesityl (Mes), and 2,6diisopropylphenyl (Dip) groups, together with two imidazolinium derivatives nicknamed SIMes·CS2 and SIDip·CS2
(Chart 1).
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Scheme 2. Synthesis of Monometallic Ruthenium−Arene
Complexes 2a−e
Article
[RuCl3(p‐cymene)]− ⇆ [RuCl 2(p‐cymene)] + Cl−
(2)
2[RuCl 2(p‐cymene)] → [RuCl 2(p‐cymene)]2
(3)
+
Kd =
−
(2[Ru 2])([Ru ] − [Ru ])
[Ru][Cl−]
=
[Ru−]
[Ru−]
(4)
In order to understand how the Ru:NHC·CS2 ratio
influenced the outcome of the complexation, we loaded an
NMR tube with the [RuCl2(p-cymene)]2 homobimetallic
dimer (16.1 mg) dissolved in CDCl3 (0.5 mL). Two molar
equiv of the IMes·CS2 ligand (20 mg) were divided into 20
portions of ca. 1 mg and added stepwise to this solution. A
reaction took place instantaneously at room temperature, and
the color of the mixture changed progressively from orange-red
to dark and darker shades of red-purple. 1H NMR spectra were
recorded after each addition of the ligand (Figure 2). The
Figure 2. Stacked 1H NMR spectra obtained upon stepwise addition
of IMes·CS2 (2 equiv) to [RuCl2(p-cymene)]2 in CDCl3 at 298 K
showing the methine protons of the p-cymene ligand.
three septets arising from the p-cymene methine protons
located between 2.4 and 3.2 ppm were integrated using the
peak of residual CHCl3 at 7.26 ppm as an internal standard.
The data obtained were plotted on a graph where the x axis
represented the percentage of IMes·CS2 added to the reaction
mixture (100% corresponds to 2 equiv of ligand per ruthenium
dimer), and the y axis corresponded to the percentage of each
ruthenium−arene complex with respect to the sum of all three
cationic, neutral, and anionic species (Figure 3).
The linear correlation observed in Figure 3 for the formation
of the [RuCl(p-cymene)(S2C·IMes)]+ cation with respect to
the amount of zwitterion added to the reaction medium nicely
confirmed that the chelation of the dithiocarboxylate ligand
occurred quickly and irreversibly with no induction period, as
described in eq 1. Conversely, the nonlinear consumption of
the [RuCl2(p-cymene)]2 dimer and the transient formation of
the [RuCl3(p-cymene)]− anion corroborated the existence of
an equilibrium between these two species, as described in eqs 2
and 3. Such a dissociation equilibrium was already evidenced
by Vock and Dyson when they prepared the Ph4P[RuCl3(pcymene)] complex21 and by Robertson and Stephenson when
they synthesized the related Cs[RuCl3(benzene)] salt.22 We
have determined the dissociation constant (Kd) of the
[RuCl3(p-cymene)]− anion from the relative concentrations
of the three ruthenium−arene species obtained by integrating
1
Figure 1. H NMR spectrum of a 1:1 stoichiometric mixture of
[RuCl2(p-cymene)]2 and IMes·CS2 in CDCl3 at 298 K showing the
methine protons of the p-cymene ligand.
cation by comparison with the spectra recorded for complex 2a
and its hexafluorophosphate analogue 1a,5 while the septet
located around 2.92 ppm is characteristic of the [RuCl2(pcymene)]2 dimer dissolved in CDCl3.20 The third, unexpected
signal observed at 3.11 ppm was attributed to the [RuCl3(pcymene)]− anion to balance the reaction of 1 equiv of dimer
with 1 equiv of ligand (eq 1). The nonstoichiometric
proportions of the three ruthenium−arene species indicated,
however, that the trichlorido(p-cymene)ruthenate anion was
not formed quantitatively and was therefore in equilibrium
with a formal 16-electron species that quickly dimerized into
the saturated di-μ-chlorido bridged dimer (eqs 2 and 3). These
puzzling observations spurred us to investigate in more detail
the course of the reaction between the [RuCl2(p-cymene)]2
dimer and NHC·CS2 zwitterions.
[RuCl 2(p‐cymene)]2 + NHC· CS2 → [RuCl(p‐cymene)(S2 C· NHC)]+
+ [RuCl3(p‐cymene)]−
(1)
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Figure 5. 1H NMR spectra of a 1:1 stoichiometric mixture of
[RuCl2(p-cymene)]2 and IMes·CS2 in DMSO-d6 (top) and D2O
(bottom) at 298 K showing the methine protons of the p-cymene
ligand.
Figure 3. Evolution of the relative proportions of cationic [RuCl(pcymene)(S2C·IMes)]+ (“[Ru+]”), neutral [Ru2Cl2(p-cymene)]2
(“[Ru2]”), and anionic [RuCl3(p-cymene)]− (“[Ru−]”) complexes
as a function of the Ru:IMes·CS2 ratio (100% corresponds to 2 equiv
of ligand per ruthenium dimer).
involving the labile Ru−Cl bonds of the anionic, neutral, or
cationic ruthenium−arene species. Indeed, the behavior of the
[RuCl2(arene)]2 dimers in the presence of water has been
cross-examined since the 1970s. 23 Eventually, the
[RuCl2(C6H6)]2 complex was shown to afford three aquation
products in D2O, viz., [RuCl2(C6H6)(D2O)], [RuCl(C6H6)(D2O)2]+, and [Ru(C6H6)(D2O)3]2+.24 The reactivity of
numerous monometallic [RuCl2(arene)L] complexes toward
DMSO25 and water26 has also been extensively investigated,
because it critically affects the biological activity of these
metallodrugs.
In order to isolate and to characterize the bimetallic
[RuCl(p-cymene)(S2C·NHC)][RuCl3(p-cymene)] complexes,
we performed reactions on a preparative scale starting from an
equimolar mixture of the [RuCl2(p-cymene)]2 dimer and an
NHC·CS2 zwitterion (0.1 mmol each). The two reagents were
weighed in a 10 mL glass vial containing a magnetic stirring
bar, and dichloromethane (3 mL) was added. The mixture was
stirred for 10 min at room temperature. The solvent was
removed on a rotary evaporator, and the solid residue was
broken down into a fine powder by stirring it in the presence of
petroleum ether. The slurry was decanted, the supernatant
liquid was removed, and the remaining solid was dried under
high vacuum. This straightforward procedure that did not
involve any filtration or transfer into another container allowed
us to prepare a set of five dual anionic and cationic complexes
(3a−e) in almost quantitative yields (95−100%) (Scheme 3).
Cabeza and co-workers first disclosed the synthesis and the
molecular structure of the trichlorido(p-cymene)ruthenate
anion associated with a dipyridinium cation in 2005.27 The
year after, Vock and Dyson prepared the phosphonium salt
Ph4P[RuCl3(p-cymene)] and solved its solid-state structure.21
Subsequently, several other research groups carried out the
synthesis of mixed organic/organometallic salts combining the
[RuCl3(p-cymene)]− anion with tetrahydropyrimidinium,28
imidazolium,29 ammonium,30 phenothiazinium,31 or guanidinium cations.32 To the best of our knowledge, prior to this
work, only five reports from the literature described salts in
which both the anion and the cation were ruthenium−(pcymene) complexes (Chart 2). In many cases, they were
obtained adventitiously instead of the targeted monometallic
products. Thus, in 2006, Dyson et al. fortuitously crystallized
the [RuCl(p-cymene)(bimid)2][RuCl3(p-cymene)] complex 4
(bimid is N-butylimidazole) in a failed attempt to obtain the
neutral [RuCl2(p-cymene)(bimid)] derivative.33 Then, in
2008, Marchetti, Pettinari, and co-workers prepared a set of
their methine protons for various Ru:IMes·CS2 ratios (eq 4,
see the Supporting Information for computational details). At
25 °C in CDCl3, Kd = 0.02 mol L−1. Lowering the temperature
to 0 °C or increasing it to 50 °C did not significantly alter this
value. Contrastingly, replacing CDCl3 with either a less polar
solvent (CD2Cl2) or a more polar, protic solvent (CD3OD)
significantly altered the equilibrium between the neutral and
the anionic species (Figure 4). Hence, the almost statistical
Figure 4. 1H NMR spectra of a 1:1 stoichiometric mixture of
[RuCl 2 (p-cymene)]2 and IMes·CS 2 in CD 2 Cl 2 (top), CDCl 3
(middle), and CD3OD (bottom) at 298 K showing the methine
protons of the p-cymene ligand.
distribution between the [RuCl3(p-cymene)]− and the Cl−
anions observed in chloroform at room temperature (a 56:44
ratio) was shifted toward the former ruthenate complex in
dichloromethane (74:26) or toward the later inorganic anion
in methanol (27:73). In DMSO-d6, only the cationic complex
2a and the neutral [RuCl2(p-cymene)(DMSO-d6)] solvate
were detected, which corresponded to a (0:100) distribution in
favor of the chloride counteranion (Figure 5). Spectra
recorded in D2O were more difficult to interpret. This is
most likely due to the occurrence of aquation reactions
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Article
above (cf. Figure 1), they displayed three sets of signals for the
various aliphatic and aromatic protons of p-cymene on 1H
NMR spectroscopy. These resonances were assigned,
respectively, to the [RuCl(p-cymene)(S2C·NHC)]+ cations
and to a mixture of [RuCl3(p-cymene)]− anions in equilibrium
with the [RuCl2(p-cymene)]2 dimer. 1H and 13C NMR
analyses also confirmed the successful incorporation of an
imidazol(in)ium-2-dithiocarboxylate ligand in the bimetallic
compounds under scrutiny. In particular, the strongly
deshielded resonance of the CS2− unit observed at 213−220
ppm clearly evidenced the chelation of an NHC·CS2 zwitterion
to a ruthenium center (Table 1). Indeed, this diagnostic signal
Scheme 3. Synthesis of Dual Anionic and Cationic
Ruthenium−Arene Complexes 3a−e
Table 1. 13C NMR Chemical Shifts (ppm) of the CS2− Unit
of NH·CS2 Zwitterions in Various Cationic Complexes of
the [RuCl(p-cymene)(S2C·NHC)]+ Type and in the Free
Ligandsa
three [RuCl(p-cymene)(N^N)][RuCl3(p-cymene)] complexes
5a−c with various bis(pyrazolyl)alkane (N^N) ligands.34 One
example of [RuCl(p-cymene)(semicarbazone)][RuCl3(p-cymene)] salt (6)35 and three related thiosemicarbazone
derivatives (7a−c)36 originated from the groups of Su and
Li, while an additional compound, [RuCl(p-cymene)(1FcMeIm)2][RuCl3(p-cymene)] (8), was unexpectedly formed
when Walsby et al. tried to crystallize the [RuCl2(pcymene)(1-FcMeIm)] complex (1-FcMeIm is 1-ferrocenyl(methyl)imidazole).37 Apart from p-cymene, benzene was the
only other arene succinctly investigated for the preparation of
ruthenate complexes, with an early report from Robertson and
Stephenson describing the synthesis of Cs[RuCl3(benzene)]22
and only two examples of dual anionic and cationic
ruthenium−benzene complexes, viz., a bis(pyrazolyl) derivative
analogous to products 5a−c described by Marchetti, Pettinari,
and co-workers in 2008,34 and the chiral compound 9
serendipitously crystallized by Tamm et al. in 2014.38
Structural Analysis. Various analytical techniques were
applied to fully characterize complexes 3a−e. As discussed
NHC
NHC·
CS2b
[Ru+](PF6−)
(1)c
[Ru+](Cl−)
(2)
[Ru+][Ru−]
(3)
IMes (a)
IDip (b)
ICy (c)
SIMes (d)
SIDip (e)
221.6d
219.7
226.0
222.7
219.8
212.4
211.8
218.1
213.1
211.8
212.2
211.8
218.8
213.9
211.7
214.2
213.2
220.2
215.8
213.3
a
Data recorded in CDCl3 at 298 K. bData from ref 2. cData from ref
5. dData recorded in DMSO-d6 at 298 K.
was detected at the same location in monometallic complexes
1a−e (212−218 ppm)5 and 2a−e (212−219 ppm). Besides,
there was always a small albeit significant upfield shift (ca. 6
ppm) between these values and those recorded for the free,
uncoordinated betaines (220−226 ppm).2 Most of the other
1
H and 13C resonances arising from the [RuCl(p-cymene)(S2C·NHC)]+ moiety were also rather similar, whether we
looked at the NMR spectra of compounds 1a−e, 2a−e, or 3a−
e. A change in the counterion nature, however, markedly
influenced the chemical shifts of the imidazol(in)ium ring
protons in the three types of cationic complexes under
investigation (Table 2). Thus, the chemical shifts of the
aromatic protons on the imidazolium rings of IMes·CS2, IDip·
CS2, or ICy·CS2 drifted from ca. 7 ppm in the free ligands to
more than 8 ppm in mono- and bimetallic complexes 2a−c and
Chart 2. Dual Anionic and Cationic Ruthenium−Arene Complexes Known Prior to This Work
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Table 2. 1H NMR Chemical Shifts (ppm) of the
Imidazol(in)ium Protons in the Free Ligands and in Various
Cationic Complexes of the [RuCl(p-cymene)(S2C·NHC)]+
Typea
NHC
NHC·
CS2b
[Ru+](PF6−)
(1)c
[Ru+](Cl−)
(2)
[Ru+][Ru−]
(3)
IMes (a)
IDip (b)
ICy (c)
SIMes (d)
SIDip (e)
7.84d
7.01
6.99
4.20
4.41
7.57
7.71
7.53
4.32
4.42
8.25
8.39
8.13
4.64
4.68
8.30
8.49
8.06
4.64
4.65
Article
the monometallic complexes 2a−e. They featured only a single
signal unambiguously assigned to an [RuCl(p-cymene)(S2C·
NHC)]+ molecular ion based on its isotopic profile (see the
Supporting Information for details). In the negative mode, a
peak at m/z = 340.92101 corresponding to the [RuCl3(pcymene)]− anion was always detected, but its intensity was
rather low; and other unidentified species were sometimes
observed. These results are in line with a facile dissociation of
the labile ruthenate complex and the formation of other
ruthenium species in the ionization chamber. We did not
characterize complexes 3a−e by elemental analysis, because of
their strong tendency to cocrystallize with various solvents in
an unpredictable manner.
X-ray Crystallography. Attempts to crystallize complexes
3a−e by slow diffusion of petroleum ether in a dichloromethane solution at 6 °C under the exclusion of air and
moisture were not successful. However, water turned out to be
a good solvent for these compounds (vide infra), and we
ventured to crystallize them from water/organic solvent
mixtures. Gratifyingly, a crystalline sample of [RuCl(pcymene)(S2C·IMes)][RuCl3(p-cymene)] (3a) was obtained
from acetone/water. X-ray diffraction analysis revealed that the
anionic and cationic ruthenium−arene fragments had
cocrystallized with one molecule of H2O (Figure 6). We
a
Data recorded in CDCl3 at 298 K. bData from ref 2. cData from ref
5. dData recorded in DMSO-d6 at 298 K.
3a−c, with intermediate values in compounds 1a−c. The
nonaromatic backbone of the imidazolinium-based ligands
SIMes·CS2 and SIDip·CS2 underwent a less dramatic downfield move, with chemical shifts varying from 4.20 and 4.41
ppm in the free ligands to 4.64 and 4.65 ppm in complexes
3d,e. These variations reveal the existence of strong
interactions between the azolium ring and the counteranion
of compounds 1−3 in solution. As expected, the trichlorido(pcymene)ruthenate complex or a single chloride anion were
more influential than a weakly coordinating hexafluorophosphate anion.39
The FT-IR spectra of bimetallic complexes 3a−e were
recorded in KBr pellets and compared with those reported
previously for monometallic complexes 1a−e5 and for the
parent uncoordinated NHC·CS2 zwitterions2 (Table 3).
Similar patterns were observed for the three types of
compounds. In addition to the various aliphatic and aromatic
C−H stretching vibration bands located around 3000 cm−1,
the most intense absorption originating from the [RuCl(pcymene)(S2C·NHC)]+ cations came from the asymmetric
stretching of the N2C+ groups, which gave rise to a strong band
located at ca. 1475 cm−1 for the aromatic imidazolium
derivatives and at ca. 1545 cm−1 for their imidazolinium
counterparts. Due to the poor electronic communication
between the azolium ring and the orthogonal dithiocarboxylate
unit of bulky NHC·CS2 zwitterions, these bands were not
significantly affected by the complexation process. Conversely,
a substantial shift of the CS2− asymmetric stretching vibration
bands to lower energies occurred upon chelation of the
dithiocarboxylate inner salts to ruthenium, together with a
notable decrease in their intensity. This attenuation did not
allow us to identify them with certainty in all cases. Hence, the
ν̅asym (CS2−) values listed in Table 3 should be treated with
circumspection and not overly interpreted.
Positive HR-ESI-MS spectra of complexes 3a−e recorded in
acetonitrile were very clean and similar to those recorded for
Figure 6. Molecular structure of [RuCl(p-cymene)(S2C·IMes)][RuCl3(p-cymene)] cocrystallized with water (3a·H2O) showing the
H-bonds of the imidazolium protons (hydrogen atoms were omitted
except those directly bound to the heterocyclic ring and oxygen).
were also able to grow monocrystals of the analogous SIMesbased complex 3d from a dichloromethane solution saturated
with water. In this case, the bimetallic complex cocrystallized
with H2O in a 2:3 stoichiometric ratio (Figure 7).
Table 3. Wavenumbers of IR Stretching Vibration Bands (cm−1) in the Free Ligands and in Various Cationic Complexes of the
[RuCl(p-cymene)(S2C·NHC)]+ Typea
NHC
νa̅ sym (N2C+) in
NHC·CS2b
νa̅ sym (N2C+) in [Ru+]
(PF6−) (1)c
νa̅ sym (N2C+) in [Ru+]
[Ru−] (3)
νa̅ sym (CS2−) in
NHC·CS2b
νa̅ sym (CS2−) in [Ru+]
(PF6−) (1)c
ν̅asym (CS2−) in [Ru+]
[Ru−] (3)
IMes (a)
IDip (b)
ICy (c)
SIMes (d)
SIDip (e)
1488
1469
1474
1531
1524
1485
1470
1474
1559
1549
1484
1468
1469
1553
1541
1052
1058
1058
1064
1080
1025
1010
1029
1032
1058
1009
1001
1026
1031
1055
a
Data recorded in KBR pellets. bData from ref 2. cData from ref 5.
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Figure 7. Molecular structure of [RuCl(p-cymene)(S2C·SIMes)][RuCl3(p-cymene)] cocrystallized with water (2(3d)·3(H2O))
showing the H-bonds of the imidazolinium protons (hydrogen
atoms were omitted except those directly bound to the heterocyclic
ring and oxygen).
Article
Figure 9. Molecular structure of [RuCl(p-cymene)(S2C·ICy)]Cl
cocrystallized with water (2(2c)·9.75(H2O)) showing the H-bonds of
the imidazolium protons (hydrogen atoms were omitted except those
directly bound to the heterocyclic ring and oxygen).
A close examination of the solid materials obtained from the
crystallization of 3a in acetone/water showed that they
contained a small amount of green crystals that turned out
to be the hydrated complex 2a, as evidenced by XRD analysis
(Figure 8). Moreover, the slow evaporation of a dichloro-
details). Last but not least, only the [RuCl2(p-cymene)]2 dimer
was detected by XRD analysis in a sample of complex 3b
subjected to crystallization. All these results are in line with a
reversible dissociation of the [RuCl3(p-cymene)]− anion into
Cl− and [RuCl2(p-cymene)]2 during the crystallization
process. When crystals of pure bimetallic complexes 3a·H2O
and 2(3d)·3(H2O) containing the trichlorido(p-cymene)ruthenate counteranion were dissolved in CD2Cl2 or CDCl3,
NMR analyses confirmed that an equilibration had taken place,
and the three cationic, neutral, and anionic ruthenium−arene
species were present in solution (cf. Figure 1).
The cationic parts of complexes 2a, 3a, 2c, and 3d displayed
the typical three-legged piano stool geometry already
evidenced in complex 1a and in many other ruthenium−
arene species.40 In these four compounds, the S1−C1−S2 bite
angle of the dithiocarboxylate unit averaged 112° (Table 4 and
Figure 10). The C1−S1 and C1−S2 distances were very
similar, and their lengths (1.68 Å) were much closer to the
distance commonly observed for CS double bonds (1.67 Å)
than for C−S single bonds (1.75 Å),41 in line with the uniform
delocalization of a negative charge between the two sulfur
atoms. Likewise, the N1 and N2 nitrogen atoms were almost
equally spaced from the central C2 carbon atom, thereby
indicating similar contributions of the N1−C2N2+ and
+
N1C2−N2 resonance forms to the amidinium functionality. As expected, the replacement of IMes·CS2 or ICy·CS2
with the imidazolinium-2-dithiocarboxylate zwitterion SIMes·
CS2 in complex 3d significantly impacted the C3−C4 distance
and the N1−C2−N2 angle, due to the saturation of its
heterocyclic backbone. Other geometric parameters remained
roughly unchanged.
The bond lengths and angles recorded for the [RuCl(pcymene)(S2C·IMes)]+ cation in the molecular structures of 1a,
2a·H2O, and 3a·H2O were not significantly altered by a change
in the nature of the counterion or the cocrystallized solvent.
Yet, variations in the relative orientations of the carbene and
arene ligands and of the dithiocarboxylate and mesityl groups
with respect to the central imidazolium ring of the NHC ligand
were evidenced when comparing the relevant torsion angles
(Table 4 and Figure 10). These discrepancies are a likely
Figure 8. Molecular structure of [RuCl(p-cymene)(S2C·IMes)]Cl
cocrystallized with water (2a·H2O) showing the H-bonds of the
imidazolium protons (hydrogen atoms were omitted except those
directly bound to the heterocyclic ring and oxygen).
methane solution of [RuCl(p-cymene)(S2C·ICy)][RuCl3(pcymene)] (3c) in the presence of moisture led to the isolation
of orange crystals whose molecular structure determined by
XRD analysis corresponded to a hydrated chloride salt with the
formula 2(2c)·9.75(H2O) (Figure 9). A powder diffractogram
of the bulk solid mass out of which these crystals where
handpicked revealed the presence of another compound not
suitable for single-crystal analysis that was probably the
bimetallic complex 3c (see the Supporting Information for
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Article
Table 4. Selected Bond Lengths (Å) and Angles (deg) for the [RuCl(p-cymene)(S2C·NHC)]+ Cations Derived from the
Crystal Structures of [RuCl(p-cymene)(S2C·IMes)]PF6 (1a), [RuCl(p-cymene)(S2C·IMes)]Cl (2a), [RuCl(p-cymene)(S2C·
IMes)][RuCl3(p-cymene)] (3a), RuCl(p-cymene)(S2C·ICy)]Cl (2c), and [RuCl(p-cymene)(S2C·SIMes)][RuCl3(p-cymene)]
(3d)a
complex
1ab
2a·H2O
3a·H2O
2(2c)·9.75(H2O)
2(3d)·3(H2O)
complex
1ab
2a·H2O
3a·H2O
2(2c)·9.75(H2O)
2(3d)·3H2O
C1−S1
C1−S2
C1−C2
C2−N1
1.680(3)
1.673(2)
1.464(3)
1.351(3)
1.679(2)
1.681(2)
1.455(3)
1.358(3)
1.688(5)
1.683(6)
1.435(8)
1.355(7)
1.675(3)
1.681(3)
1.474(5)
1.344(4)
1.674(6)
1.678(6)
1.481(9)
1.321(8)
S1−C1−S2
N1−C2−N2
S1−C1−C2−N1
112.3(1)
112.3(1)
110.3(3)
111.9(2)
112.4(4)
107.3(2)
106.9(2)
106.3(5)
108.2(3)
113.8(6)
C2−N2
C3−C4
Ru1−Cl1
Ru1−cym
1.342(3)
1.324(4)
2.4128(9)
1.351(3)
1.348(3)
2.3977(5)
1.349(7)
1.352(8)
2.3887(16)
1.333(5)
1.345(5)
2.4140(9)
1.311(8)
1.519(8)
2.390(2)
C2−N1−C5−C6
C2−N2−C14−C15
45.0(4)
30.5(3)
16.2(8)
−87.4(4)
36.9(8)
−102.6(3)
73.7(3)
77.9(7)
77.8(3)
−117.8(2)
−90.1(7)
74.0(8)
−111.4(7)
Cl1−Ru1−C23−C29
1.710
1.689(9)
1.705(3)
1.697(2)
1.705(3)
S1−Ru1−S2
−6.3(2)
79.0(2)
−11.7(5)
−23.0(3)
−13.0(5)
S1−Ru1−Cl1
71.69(2)
71.79(2)
72.07(5)
71.90(3)
72.10(6)
86.24(2)
87.75(2)
84.08(6)
85.98(3)
84.73(6)
a
See Figure 10 for atom labeling. bData from ref 5.
ring of the p-cymene ligand formally occupying three
coordination sites and the three chlorido ligands occupying
the remaining three facial positions. Hence, a typical piano
stool geometry was again evidenced for this assembly. The
Ru−Cl bond lengths averaged 2.43 Å, and the Cl−Ru−Cl
angles were close to 90° (Table 5). At 1.64 Å, the distance
between the metal center and the centroid of the arene ring
was slightly shorter than in the cationic moiety, where it
reached 1.70 Å (cf. Table 4). The deviation of planarity
between the methyl group of p-cymene and the nearest
chlorido ligand equaled 20° in the [RuCl3(p-cymene)]− anion,
irrespective of the accompanying cation and number of
cocrystallized water molecules, thereby leading to a staggered
conformation (Figure 11).
Figure 10. Conformations of the [RuCl(p-cymene)(S2C·IMes)]+
cation in the molecular structures of complexes 1a (pink), 2a·H2O
(green), and 3a·H2O (blue).
consequence of the conformational changes needed to
accommodate neighboring counteranions of different sizes
and solvent molecules in the crystal structure. The rotational
freedom of the arene ligand was particularly striking. Indeed,
the bulky isopropyl substituent of p-cymene was approximately
anti to the chlorido ligand in complexes 1a, 3a, 2c, and 3d,
whereas it adopted a gauche conformation in the solid-state
structure of 2a.
Metrics determined for the [RuCl3(p-cymene)]− anion from
the molecular structures of complexes 3a and 3d were in good
agreement with those reported previously for mixed organic/
organometallic salts21,27−32 and dual anionic and cationic
complexes33,35−37 featuring this moiety. The ruthenium atom
exhibited a distorted octahedral geometry with the aromatic
Figure 11. View of the [RuCl3(p-cymene)]− anion in the molecular
structure of complex 3d showing its staggered conformation.
An examination of the close contacts between the cation, the
anion, and the solvent in the various molecular structures
under scrutiny revealed the existence of strong interactions
between the azolium ring protons and neighboring n- or πdonors (Table 6). At least one of the hydrogens of the
positively charged heterocycle was always directly bonded to
an heteroatom from the counteranion, whether it was a
fluorine atom from PF6− in 1a, the Cl− anion in 2a and 2c
(Figures 8 and 9), or a chlorido ligand from [RuCl3(p-
Table 5. Selected Bond Lengths (Å) and Angles (deg) for the [RuCl3(p-cymene)]− Anion Derived from the Crystal Structures
of RuCl(p-cymene)(S2C·IMes)][RuCl3(p-cymene)] (3a) and [RuCl(p-cymene)(S2C·SIMes)][RuCl3(p-cymene)] (3d)a
complex
Ru2−Cl2
Ru2−Cl3
Ru2−Cl4
Ru2−cym
Cl2−Ru2−Cl3
Cl2−Ru2−Cl4
Cl3−Ru2−C33−C39
3a·H2O
2(3d)·3H2O
2.4337(16)
2.4186(17)
2.4300(14)
2.4397(17)
2.4176(16)
2.4416(18)
1.641(3)
1.648(3)
89.27(5)
88.00(6)
88.10(6)
87.40(6)
−20.2(5)
20.3(6)
a
See Figure 11 for atom labeling.
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Table 6. Selected Bond Lengths (Å) and Angles (deg) for
the Hydrogen Bonds between the Azolium Ring Protons
and the Counteranions or Solvent Molecules Derived from
the Crystal Structures of [RuCl(p-cymene)(S2C·IMes)]PF6
(1a), [RuCl(p-cymene)(S2C·IMes)]Cl (2a), [RuCl(pcymene)(S2C·IMes)][RuCl3(p-cymene)] (3a), [RuCl(pcymene)(S2C·ICy)]Cl (2c), and [RuCl(p-cymene)(S2C·
SIMes)][RuCl3(p-cymene)] (3d)
complex
1aa
2a·H2O
3a·H2O
2(2c)·
9.75(H2O)
2(3d)·3H2O
Donor−H···
Acceptor
D−H
H···A
D···A
D−H···A
C4−H4···F45
C3−H3···Mes
C4−H4···Cl2
C3−H3···O1
C3−H3···Cl4
C4−H4···Cl2
C3−H3···Cl2
0.93
0.93
0.95
0.95
0.95
0.95
0.95
2.54
2.98
2.57
2.58
2.66
2.55
2.56
3.356(4)
3.878
3.451(2)
3.131(3)
3.453(6)
3.414(6)
3.476(4)
147
162
154
117.5
141.1
151.8
161.4
C4−H4···O2W
C3−H3B···Cl4b
C4−H4A···Cl2b
C4−H4B···Cl1c
0.95
0.99
0.99
0.99
2.49
2.60
2.83
2.72
3.403(6)
3.554(7)
3.398(6)
3.553(7)
162.1
162.7
117.4
141.5
Article
Table 7. Solubility (mM) of the [RuCl(p-cymene)(S2C·
NHC)]Cl Complexes (2a−e) and the [RuCl(pcymene)(S2C·NHC)][RuCl3(p-cymene)] Complexes (3a−
e) in Distilled Water at Room Temperature
NHC
[Ru+](Cl−) (2)
[Ru+][Ru−] (3)
IMes (a)
IDip (b)
ICy (c)
SIMes (d)
SIDip (e)
5.6
4.6
3.1
2.6
5.0
10
5.6
5.0
2.8
3.3
metallic compounds 2a−d. These results demonstrate that the
[RuCl3(p-cymene)]− counterion is a valuable alternative to the
chloride anion for ensuring a high solubility of cationic
ruthenium−arene complexes in water. Among the ten
compounds screened, complex 3a that featured the IMes·CS2
ligand displayed the highest solubility, leading to a 0.01 M
saturated solution in water. This corresponds to a 0.02 M
concentration in metal species. Although these values are not
exceptional, they compare favorably with solubilities in the
0.1−5 mM range previously reported for various other
ruthenium−arene complexes.43 Besides, they are more than
sufficient to enable biological studies in aqueous media and to
circumvent hypothetical drug delivery problems.
Biological Activity. Although the cytotoxic effects of
ruthenium complexes have been known since the early
1950s,44 metallopharmaceuticals based on this element have
long been overshadowed by their platinum counterparts, most
notably cisplatin and its derivatives,45 as anticancer therapeutic
agents.46 This was due in part to their poor solubility and
stability in water. Since the mid-1990s, however, ruthenium−
arene species have emerged as robust, highly active, and
selective antitumoral and antimetastatic drugs toward various
lines of cancerous cells, both in vitro and in vivo.47 Accordingly,
tremendous research efforts have been devoted to the synthesis
and biological evaluation of neutral [RuCl2(p-cymene)(L)] or
cationic [RuCl(p-cymene)(L−L′)]X complexes bearing carefully designed mono- (L) or bidentate ligands (L−L′) to
ensure a good water compatibility and a high activity.48
Moreover, the critical influence of the counteranion was also
highlighted in several reports.49
To the best of our knowledge, the biological activity of
ruthenium−arene complexes bearing imidazol(in)ium-2-dithiocarboxylate ligands had never been investigated so far.
Hence, we decided to probe the antitumoral activity and the
cytotoxicity of [RuCl(p-cymene)(S2C·NHC)]Cl complexes
2a−e toward K562 human erythroleukemic cells and mouse
splenocytes, respectively. We reasoned that the monometallic
complexes would be more suitable for this exploratory work
than the bimetallic salts 3a−e because they have a well-defined
structure with a single type of ruthenium centers. Besides,
NMR spectroscopy showed that the [RuCl3(p-cymene)]−
anion was not observed in DMSO and water (vide supra),
the two solvents used for the cell viability tests. Very
gratifyingly, all five monometallic compounds were biologically
active already at micromolar concentrations (Table 8). With a
half maximal inhibitory concentration (IC50) for K562
erythroleukemic cells of 0.05 μM and a cytotoxic concentration
(CC50) for mouse splenocytes of 0.07 μM, the [RuCl(pcymene)(S2C·IMes)]Cl complex 2a displayed the highest in
vitro toxicity toward both the cancerous and healthy cells. It
was also slightly selective toward the former ones. Contrast-
a
Data from ref 5. bSymmetry code: −1/2 + x, y, 3/2 − z. cSymmetry
code: 3/2 − x, 1/2 + y, z.
cymene)]− in 3a and 3d (Figures 6 and 7). Additional
hydrogen bonding from the imidazolium or imidazolinium
protons occurred with water molecules in 2a and 2c, with
other chlorido ligands from [RuCl3(p-cymene)]− in 3a and 3d,
and through π-stacking with the mesityl ring of a neighboring
cation in 1a. Although these supramolecular associations were
observed in the solid state, they should be preserved to some
extent in solution to justify the large differences of chemical
shifts evidenced by 1H NMR spectroscopy when monitoring
the resonances of the azolium backbone protons (cf. Table 2).
Advanced NMR and DFT techniques were successfully applied
to quantify the ion pairing in other cationic ruthenium−(pcymene) complexes,42 but we did not further investigate this
issue. For the sake of completeness, it should be mentioned
that H-bonds were also detected between the cocrystallized
water molecules and the counteranions of complexes 2a, 3a,
2c, and 3d (see the Supporting Information for details).
Water Solubility. During the course of this work, several
experimental observations strongly suggested that ruthenium−
arene complexes bearing imidazol(in)ium-2-dithiocarboxylate
ligands had a strong affinity toward water (vide supra). Hence,
we decided to investigate more thoroughly this remarkable
property by determining the aqueous solubility of monometallic complexes 2a−e and their bimetallic analogues 3a−e.
A simple and straightforward procedure was applied for these
tests. Distilled water was added in small portions (0.05 mL) to
5 μmol of each complex at room temperature. The mixture was
vigorously shaken after every addition, and the process was
repeated until no more solid was visible. Very gratifyingly,
millimolar concentrations of the various compounds under
investigation could be achieved in water (Table 7), and the
dark orange-brown solutions obtained were stable for extended
periods of time (up to several months) in the presence of
oxygen and light. It should be pointed out that the starting
azolium-2-dithiocarboxylate inner salts were insoluble in water
despite their zwitterionic nature. Except for the SIDip·CS2
ligand, dual anionic and cationic complexes 3a−d were
significantly more soluble than the corresponding mono16777
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by various analytical techniques, and the molecular structures
of two monometallic and two bimetallic complexes were solved
by X-ray diffraction analysis.
NMR titrations showed that the chelation of the
dithiocarboxylate ligands to afford cationic ruthenium−arene
complexes was quantitative and irreversible. Conversely, the
formation of the trichlorido(p-cymene)ruthenate anion was
limited by an equilibrium, and this species readily dissociated
into chloride anions and the [RuCl2(p-cymene)]2 dimer. The
position of the equilibrium was strongly influenced by the
nature of the solvent and was rather insensitive to the
temperature. At 25 °C in CDCl3, the dissociation constant of
[RuCl3(p-cymene)]− was Kd = 0.02 mol L−1.
Samples subjected to XRD analysis after recrystallization of
compounds 3a−e in water/organic solvent mixtures contained
either mono- or bimetallic complexes cocrystallized with H2O.
The presence of [RuCl2(p-cymene)]2 was also evidenced in
the crystal phase, thereby confirming the reversible dissociation
of the [RuCl3(p-cymene)]− anion. Furthermore, crystallography highlighted the existence of strong interactions between
the azolium ring protons of the [RuCl(p-cymene)(S2C·
NHC)]+ cations and neighboring n- or π-donor groups in
the solid state. These hydrogen bonds are most likely
responsible for the large differences of chemical shifts
evidenced by 1H NMR spectroscopy when monitoring the
resonances of the azolium backbone protons in solution. The
facile cocrystallization of compounds 3a−e with water
prompted us to determine their aqueous solubility. A 0.01 M
saturation concentration was reached with the [RuCl(pcymene)(S2C·IMes)][RuCl3(p-cymene)] complex (3a) at
room temperature. This corresponds to a 0.02 M concentration in metal species.
The in vitro antiproliferative activity of monometallic
complexes 2a−e and bimetallic salts 3a−e was evaluated on
K562 human leukemia cells. All the compounds tested were
highly cytotoxic against these tumorous cells (IC50 = 0.05−
7.10 μM). Furthermore, the SIDip-based complex 2e displayed
a remarkable selectivity toward cancerous vs normal cells.
Altogether, this study allowed us to better understand the
equilibrium that governs the formation of the [RuCl3(pcymene)]− anion and to devise an efficient synthetic protocol
for the synthesis of dual anionic and cationic ruthenium−arene
complexes. Bimetallic compounds of this type had seldom
been described in the literature and were isolated fortuitously
in most cases. We showed that the use of zwitterionic ligands
that form strong hydrogen bonds through their positively
charged azolium ring and the recourse to a ruthenate complex
instead of the more common halide counterions were two
factors contributing to a high solubility of ruthenium−arene
species in water. We also uncovered that mono- and bimetallic
ruthenium−arene complexes bearing imidazol(in)ium-2-dithiocarboxylate ligands were highly active and selective
cytotoxic agents. Further investigations to better appraise the
potentials of these compounds as metallodrugs are underway
and will be reported in due course.
Table 8. Half Maximal Inhibitory Concentration (IC50) for
K562 Erythroleukemic Cells, Cytotoxic Concentration
(CC50) for Mouse Splenocytes, and Selectivity Index (SI)
for the [RuCl(p-cymene)(S2C·NHC)]Cl Complexes (2a−e)
complex (NHC)
IC50 (μM)a
CC50 (μM)a
SIb
2a (IMes)
2b (IDip)
2c (ICy)
2d (SIMes)
2e (SIDip)
0.051 ± 0.021 (3)
0.308 ± 0.121 (3)
5.808 ± 1.627 (4)
1.014 ± 0.426 (4)
0.139 ± 0.004 (2)
0.068 ± 0.022 (3)
0.213 ± 0.139 (3)
3.075 ± 0.179 (2)
1.713 ± 0.624 (2)
4.489 ± 0.388 (2)
1.33
0.69
0.53
1.69
32.1
a
Numbers of independent experiments are given in parentheses. bSI =
CC50/IC50.
ingly, complex 2c bearing cycloalkyl groups on the nitrogen
atoms of its imidazolium ring was the least active cytotoxic
agent of our screening, and its selectivity was unfavorably
reversed. Complex 2e featuring the SIDip·CS2 ligand emerged
as the most promising candidate for further biological
investigations, as it exhibited a high cytotoxicity remarkably
targeted against the tumor cell line.
In a final series of experiments, we assessed the antitumoral
activity of bimetallic complexes 3a−e toward the K562
erythroleukemic cells. As discussed above (cf. Figure 5),
aquation and solvation reactions are expected to occur in
buffered culture media containing DMSO and water.25,26 At
this point, however, the actual species present in solution
remain unknown. It should be kept in mind, also, that a double
dose of ruthenium is available from the association of an
[RuCl(p-cymene)(S2C·NHC)]+ cation with the [RuCl3(pcymene)]− anion. Nonetheless, when starting from bimetallic
salts 3b, 3d, or 3e, we obtained lower IC50 values than those
recorded for the corresponding monometallic complexes 2b,
2d, and 2e (Table 9). The opposite trend was observed when
comparing the 2a/3a and 2c/3c pairs. Thus, no clear-cut
tendency could be deduced to predict the influence of the
anionic counterion.
Table 9. Half Maximal Inhibitory Concentration (IC50) for
K562 Erythroleukemic Cells of the Monometallic [RuCl(pcymene)(S2C·NHC)]Cl Complexes (2a−e) and the
Bimetallic [RuCl(p-cymene)(S2C·NHC)][RuCl3(pcymene)] Complexes (3a−e)
complex
IC50 (μM)a
complex
IC50 (μM)a
2a
2b
2c
2d
2e
0.051 ± 0.021 (3)
0.308 ± 0.121 (3)
5.808 ± 1.627 (4)
1.014 ± 0.426 (4)
0.139 ± 0.004 (2)
3a
3b
3c
3d
3e
0.485 ± 0.254 (4)
0.151 ± 0.130 (3)
7.102 ± 0.043 (1)
0.559 ± 0.319 (2)
0.095 ± 0.046 (3)
Article
a
Numbers of independent experiments are given in parentheses.
■
CONCLUSION AND PERSPECTIVES
An efficient synthetic protocol was devised for the preparation
of five cationic ruthenium−arene complexes bearing imidazol(in)ium-2-dithiocarboxylate ligands from the [RuCl2(p-cymene)]2 dimer and 2 equiv of an NHC·CS2 zwitterion. When the
metal source was reacted with only 1 equiv of a dithiolate
betaine, a set of five bimetallic salts with the generic formula
[RuCl(p-cymene)(S2C·NHC)][RuCl3(p-cymene)] was obtained in quantitative yields. These novel, dual anionic and
cationic ruthenium−arene complexes were fully characterized
■
ASSOCIATED CONTENT
sı Supporting Information
*
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.inorgchem.1c02648.
Experimental procedures and analytical data for
compounds 2a−e and 3a−e (PDF)
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Inorganic Chemistry
pubs.acs.org/IC
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with [Ru3(CO)12]: Remarkable Reactivity of These Betaines
Computational details for determination of Kd (XLS)
Accession Codes
CCDC 2037518−2037521 contain the supplementary crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
■
AUTHOR INFORMATION
Corresponding Author
Lionel Delaude − Laboratory of Catalysis, MolSys Research
Unit, Institut de Chimie Organique (B6a), Université de
Liège, 4000 Liège, Belgium; orcid.org/0000-0002-11342992; Email: l.delaude@uliege.be
Authors
Mohammed Zain Aldin − Laboratory of Catalysis, MolSys
Research Unit, Institut de Chimie Organique (B6a),
Université de Liège, 4000 Liège, Belgium
Guillermo Zaragoza − Unidade de Difracción de Raios X,
RIAIDT, Universidade de Santiago de Compostela, 15782
Santiago de Compostela, Spain; orcid.org/0000-00022550-6628
William Deschamps − Department of Molecular Biology,
Institute for Molecular Biology and Medicine, Université Libre
de Bruxelles, 6041 Gosselies, Belgium
Jean-Claude Didelot Tomani − Department of Molecular
Biology, Institute for Molecular Biology and Medicine,
Université Libre de Bruxelles, 6041 Gosselies, Belgium
Jacob Souopgui − Department of Molecular Biology, Institute
for Molecular Biology and Medicine, Université Libre de
Bruxelles, 6041 Gosselies, Belgium
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.inorgchem.1c02648
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS
Financial support from the Fonds de la Recherche Scientifique
- FNRS under Grant CDR J.0155.18 is gratefully acknowledged. The authors would like to thank Dr. Nicolas Smargiasso
for the ESI-MS analyses, Mr. Stéphane Luts and Prof. Gauthier
Eppe for the FT-IR analyses, and RIAIDT-USC for the use of
its analytical facilities.
■
Article
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