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Synthesis, structure, and antiproliferative activity of ruthenium(II) arene complexes with N,O-chelating pyrazolone-based β-ketoamine ligands.
Article
pubs.acs.org/IC
Synthesis, Structure, and Antiproliferative Activity of Ruthenium(II)
Arene Complexes with N,O-Chelating Pyrazolone-Based β‑Ketoamine
Ligands
Riccardo Pettinari,*,† Fabio Marchetti,‡ Claudio Pettinari,† Agnese Petrini,† Rosario Scopelliti,§
Catherine M. Clavel,§ and Paul J. Dyson§
†
School of Pharmacy and ‡School of Science and Technology, University of Camerino, via S. Agostino 1, 62032 Camerino, Macerata,
Italy
§
Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), 1015 Lausanne, Switzerland
S Supporting Information
*
ABSTRACT: Novel ruthenium half-sandwich complexes
containing (N,O)-bound pyrazolone-based β-ketoamine ligands have been prepared, and the solid-state structures of one
ligand and five complexes have been determined by singlecrystal X-ray diffraction. Some of the complexes display
moderate cytotoxicity toward the human ovarian cancer cell
lines A2780 and A2780cisR, the latter line having acquired
resistance to cisplatin.
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adducts on the histone proteins.9 In addition, arene−ruthenium
complexes containing σ-bonded ligands with aromatic side
arms10 or with π-bonded arenes11 may bind DNA also by
intercalation, where the planar part of the compounds undergo
noncovalent stacking interactions with DNA base pairs.
Intercalative interactions between metal complexes and DNA
introduce new mechanisms for attack on DNA and new
concepts for developing structure−activity relationships.12
Recently, we have shown that RuII arene complexes
containing pyrazolone-based β-ketoamine ligands are cytotoxic
to cancer cells including cisplatin-resistant cell lines, where
minor changes to the ligands result in considerable changes to
their cytotoxicity.13 These ligands represent an interesting class
in order to fine-tune the anticancer properties of the ruthenium
arene unit. On the basis of the observed results we have
hypothesized that tethering a DNA intercalator to the
ruthenium(II) arene unit may allow DNA intercalation,
enhancing the cytotoxic effect of the compounds. Herein, we
present a systematic investigation of half-sandwich Ru II
complexes with pyrazolone-based β-ketoamine ligands with
respect to their antiproliferative activity on human ovarian
cancer cells.
INTRODUCTION
Metal-based compounds are among the most widely used
chemotherapeutic agents and continue to play an important
role in the treatment of many cancers since the discovery of
cisplatin.1 Although platinum-based compounds are among the
most successful anticancer drugs employed in the clinic, they
are not without problems.2 In the search for anticancer agents
containing metals other than platinum, ruthenium compounds
have become promising alternatives to platinum-based drugs.3
Certain ruthenium complexes display specific activities
against different cancers and favorable toxicity and clearance
properties, and two RuIII compounds are presently undergoing
clinical trials.4 It has been proposed that their mode of action
involves in vivo reduction to the more reactive RuII species, and
this feature has led, at least in part, to the growing interest in
the medicinal properties of organometallic Ru II arene
complexes.5 The hydrophobic arene ligand is thought to
facilitate the diffusion through the lipophilic cell membrane,6
and the remaining three coordination sites comprise various
ligands including those that are relatively labile, to eventually
allow direct binding to a target biomolecule and more stable
ligands which help to modulate biological and pharmacological
properties of the compound.7 Nevertheless, the molecular
targets and mechanism of action of ruthenium(II)−arene
compounds are poorly understood.8 A recent study on two
prototypical ruthenium−arene agents, the cytotoxic antiprimary
tumor compound [Ru(cym)(ethylene-diamine)Cl]PF6 and the
relatively non-cytotoxic antimetastasis compound [Ru(cym)(1,3,5-triaza-7-phosphaadamantane)Cl2] (RAPTA-C), revealed
quite distinct targets for the two compounds: the former targets
the DNA of chromatin, while the latter preferentially forms
© XXXX American Chemical Society
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RESULTS AND DISCUSSION
Condensation of 4-acyl-5-pyrazolones (HQ′) with 1-naphthylamine or aniline affords the proligands (HL′; HLbiph,ph = (4Z)3-methyl-4-((phenylamino)(4-biphenyl)methylene)-1-phenyl1H-pyrazol-5(4H)-one, HLbiph,naph = (4Z)-3-methyl-4-((naphReceived: September 18, 2014
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in the free proligands. As expected, the 1H NMR spectra of
complexes 1, 2, and 3 containing the Lbiph,ph ligand display one
set of signals due to unhindered rotation of the phenyl ring.
The 1H NMR spectrum of 1 in CDCl3 contains a doublet for
each of the four p-cymene ring protons and two doublets
corresponding to the methyl groups of the isopropyl moiety.
One of the four proton resonances attributable to the p-cymene
ring is strongly shifted to higher frequency (3.52 ppm), whereas
the other three doublets are in the range 5.14−5.37 ppm, which
is typical of ruthenium arene systems.14 The above-mentioned
shift of one of the aromatic protons results from the close
vicinity of the phenyl group in the ammine moiety of the
ligand, as confirmed from X-ray diffraction studies (see below).
Also, in the 13C NMR spectra of 1, signals corresponding to
four different p-cymene ring carbons are observed in the range
79.2−87.0 ppm together with signals that may be attributed to
two different methyl groups of the isopropyl moiety at 21.2 and
23.7 ppm. A similar pattern is observed in the 1H and 13C NMR
of 4, 5, and 8, where, however, two sets of signals are detected,
due to the presence of two conformers (in 1:1 ratio) in
solution, differing in the orientation of the naphthyl group of
the chelating ligands with respect to the cymene moiety on the
Ru(II) center, as previously observed for similar compounds.11
In the 1H NMR spectra of 4, 5, and 8 in DMSO-d6, over the
temperature range 298−373 K, coalescence of the two sets of
resonances is observed. In detail, at 298 K the aromatic protons
of the p-cymene ring give rise to eight separate doublets
(integrating 1H each) and the methyl groups of the isopropyl
moiety give rise to two partially superimposed doublets. Above
363 K all the peaks attributable to the p-cymene ring protons
broaden, and at 373 K they coalesce to form four broad
resonances, presumably due to rapid isomerization between the
two forms on the NMR time scale. Solutions of the complexes
in [D6]DMSO and D2O were prepared and maintained at 37
°C for 7 days, and monitored by 1H NMR spectroscopy.
Within this period the 1H NMR spectra of 1−9 remained
unchanged. The ESI mass spectra of 1−9 in positive ion mode
contain peaks that may be attributed to the cationic fragment
[Ru(arene)(L′)] + , generated from loss of Cl − ligand.
Furthermore, the stability of compounds 1, 4, 5, and 8 in
water−methanol solution was assayed by ESI-MS and their
mass spectra remained essentially constant over the entire
incubation period. Only a small peak appears after 24 h, due to
the formation of a small amount of the dinuclear hydrolysis
product [Ru2(cym)2(μ-OCH3)3]+ (m/z 565.08), arising from β
ketoamine ligand dissociation, and bridging methoxy groups
from methanol molecules. However, we cannot exclude that
such β ketoamine ligand dissociation may be due to the soft
electrospray process, as previously reported.15
The crystal structures of HLph,naph, 1, 4, 5, 8, and 9 were
determined by X-ray crystallography (see Experimental Section
for details of the data collections and structure refinements).
The molecular structures are shown in Figure 1, and key bond
lengths and angles are given in the caption. The solid state
structure of the proligand HLph,naph shows an essentially planar
geometry for the phenyl-pyrazolone moiety with a rather short
intramolecular H-bond between the −NH and the −CO
moieties (N−H···O: 2.698(2) Å; 144(2)°), as observed in
related compounds.13,14 The orientations of the main
substituents on the central partial double bond (C3−C11,
1.398(2) Å) are shown by the torsion angles between the
−naphthyl and the −CNH groups (−26.6°), as well as by the
dihedral angle calculated between the phenyl and the −CNH
thalen-1-ylamino)(4-biphenyl)methylene)-1-phenyl-1H-pyrazol-5(4H)-one, HLph,naph = (4Z)-3-methyl-4-((naphthalen-1ylamino)(phenyl)methylene)-1-phenyl-1H-pyrazol-5(4H)-one,
HLhex,naph = (4Z)-3-methyl-4-(1-(naphthalen-1-ylamino) heptylidene)-1-phenyl-1H-pyrazol-5(4H)-one) in high yield
(Scheme 1).
Scheme 1. Synthesis of Proligands HL′
Compared to the ketoamine proligands previously investigated,13 the novel proligands HL′ are insoluble in water.
Complexes 1−9 were prepared by reacting [Ru(arene)Cl2]2
and the appropriate deprotonate ligand in methanol (Scheme
2). All complexes are air-stable in the solid state and in solution
Scheme 2. Synthesis of Complexes 1−9
and are highly soluble in most organic solvents, but insoluble in
water. Conductivity measurements indicate a slight dissociation
of the chloride ligand in DMSO at room temperature. The
extent of chloride loss increases with temperature, and at 353 K
dissociation is almost complete. The IR spectra of 1−9 show
the typical shift of the ν(CO) vibrations to lower frequency
upon coordination of the β-ketoamine proligands to the
ruthenium(II) ion. The 1H NMR spectra of 1−9 display
distinct changes in frequency for the resonances of the βketoamine protons in comparison with the equivalent protons
B
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Figure 1. Molecular structures of HLph,naph (a); 1, [Ru(cym)(Lbiph,ph)Cl] (b); 4, [Ru(cym)(Lbiph,naph)Cl] (c); 5, [Ru(cym)(Lph,naph)Cl] (d); 8,
[Ru(cym)(Lhex,naph)Cl] (e); and 9, [Ru(hmb)(Lhex,naph)Cl] (f). Selected bond lengths (Å) and angles (deg): HLph,naph, C1−O1 1.255(2), N1−N2
1.406(2), N3···O1 2.698(2), N3−H3···O1 144(2); 1, Ru1−O1 2.068(4), Ru1−N3 2.130(5), Ru1−Cl1 2.412(2), O1−Ru1−N3 87.45(18), O1−
Ru1−Cl1 85.05(15), N3−Ru1−Cl1 84.39(15); 4, Ru1−O1 2.073(2), Ru1−N3 2.148(2), Ru1−Cl1 2.420(1), O1−Ru1−N3 87.81(9), O1−Ru1−
Cl1 83.67(6), N3−Ru1−Cl1 87.28(8); 5, Ru1−O1 2.083(3), Ru1−N3 2.118(3), Ru1−Cl1 2.447(1), O1−Ru1−N3 88.74(13), O1−Ru1−Cl1
84.66(9), N3−Ru1−Cl1 83.89(10); 8, Ru1−O1 2.070(3), Ru1−N3 2.128(4), Ru1−Cl1 2.426(1), O1−Ru1−N3 88.91(13), O1−Ru1−Cl1
84.84(10), N3−Ru1−Cl1 84.43(11); 9, Ru1−O1 2.084(5), Ru1−N3 2.164(6), Ru1−Cl1 2.444(2), O1−Ru1−N3 89.37(19), O1−Ru1−Cl1
84.61(15), N3−Ru1−Cl1 81.67(16).
moieties (−63.2°). The observed twisting of the molecule is
presumably due to steric hindrance among the substituents.
Complexes 1, 4, 5, 8, and 9 adopt the expected piano-stool
coordination geometry around the ruthenium ion. Differences
in the backbone of the ligands arise from the different
substituents although they do not modify the bond distances
and angles (see the figure caption) around the metal center to a
large extent, and these values are comparable with those found
for similar compounds.13,16 The Ru−η 6-arene centroid
distances are 1.666(3) (1), 1.661(1) (4), 1.674(2) (5), 1.676
(8 which displays a disordered p-cymene), and 1.701(4) (9) Å,
suggesting that the metal−arene interaction is slightly weaker
for the hexamethylbenzene ring. This may also explain the
rather long Ru−N bond distance (2.163(7) Å) in 9.
Table 1. Cytotoxicity of the Compounds and Cisplatin
Following Exposure to the Ovarian Carcinoma Cells A2780
and A2780cisR (Cisplatin-Resistant) for 72 h
IC50, μM
compound
A2780
A2780cisR
resistance factor
biph,ph
31 ± 3
109 ± 9
65 ± 3
108 ± 6
7.6 ± 1.3
16.7 ± 1.2
63.1 ± 1.2
96 ± 4
23 ± 2
20 ± 1
20 ± 1
31 ± 2
126 ± 14
1.0 ± 0.2
191 ± 6
261 ± 14
114 ± 10
102 ± 3
61 ± 5
13 ± 1
442 ± 20
243 ± 19
20 ± 1
21 ± 4
24 ± 3
30 ± 10
49 ± 1
25 ± 1
6.1
2.4
1.8
0.9
8.1
0.8
7.0
2.5
0.9
1.1
1.2
1.0
0.4
25
HL
HLbiph,naph
HLph,naph
HLhex,naph
1
2
3
4
5
6
7
8
9
cisplatin
■
CYTOTOXICITY STUDIES
The ligands and complexes were tested for their cytotoxicity to
human ovarian A2780 carcinoma cells and the A2780cisR
variant with acquired resistance to cisplatin. IC50 values of the
compounds were determined after exposure of the cells to the
compounds for 72 h using the MTT assay (see Experimental
Section). The IC50 values of the compounds are listed in Table
1.
It might be expected that the ligands would be cytotoxic as
the aromatic rings, i.e., phenyl, biphenyl, and naphthyl rings,
could intercalate with DNA. However, the ligands are not
appreciable cytotoxic with the exception of HLbiph,ph that has an
IC50 value of 31 ± 3 in the nonresistant A2780 cell line.
Complexes 1 and 5−8 are significantly more cytotoxic than the
ligands with the biphenyl-containing complex 1 showing the
highest levels of cytotoxicity to the nonresistant A2780 cell line
(IC50 = 7.6 ± 1.3) and 2, also with a biphenyl ring, being most
cytotoxic toward the resistant A2780cisR cell line (IC50 = 13 ±
1). Compounds 1 and 2 simply differ according to the nature of
the η6-arene ring, i.e., p-cymene in 1 and benzene in 2.
Surprisingly the hexamethylbenzene adduct is considerably less
cytotoxic toward both cancer cell lines.
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in combination with an Atlas CCD detector. The data reduction was
carried out by Crysalis PRO.21
The solutions and refinements were performed by SHELX.22 The
crystal structures were refined using full-matrix least-squares based on
F2 with all non-hydrogen atoms anisotropically defined. Hydrogen
atoms were placed in calculated positions by means of the “riding”
model.
Cell Culture and Inhibition of Cell Growth. The human A2780
and A2780cisR ovarian carcinoma and HEK (human embryonic
kidney) cells were obtained from the European Collection of Cell
Cultures (Salisbury, U.K.). A2780 and A2780R cells were grown
routinely in RPMI-1640 medium, while HEK cells were grown with
DMEM medium, with 10% fetal calf serum (FCS) and antibiotics at 37
°C and 5% CO2. Cytotoxicity was determined using the MTT assay
(MTT = 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium
bromide). Cells were seeded in 96-well plates as monolayers with
100 μL of cell solution (approximately 20 000 cells) per well and
preincubated for 24 h in medium supplemented with 10% FCS.
Compounds were prepared as DMSO solutions and then dissolved in
the culture medium and serially diluted to the appropriate
concentration, to give a final DMSO concentration of 0.5%. A 100
μL portion of the drug solution was added to each well, and the plates
were incubated for another 72 h. Subsequently, MTT (5 mg/mL
solution) was added to the cells and the plates were incubated for a
further 2 h. The culture medium was aspirated, and the purple
formazan crystals formed by the mitochondrial dehydrogenase activity
of vital cells were dissolved in DMSO. The optical density, directly
proportional to the number of surviving cells, was quantified at 590 nm
using a multiwell plate reader, and the fraction of surviving cells was
calculated from the absorbance of untreated control cells. Evaluation is
based on means from two independent experiments, each comprising
three microcultures per concentration level.
Syntheses and Characterization. HLbiph,ph. To a solution of
HQbiph (1-phenyl-3-methyl-4-biphenyl-5-pyrazolone, 2.00 g, 5.64
mmol) in ethanol (75 mL) was added dropwise a solution of aniline
(0.52 g, 5,64 mmol). The solution was stirred at reflux for 24 h. The
solvent was removed under reduced pressure, and dichloromethane
(10 mL) was added. The mixture was filtered, and n-hexane (20 mL)
was added to the solution to form a biphase, which was stored at 4 °C.
Yellow crystals were obtained and collected. The mixture was filtered
and the precipitate washed with ethanol (20 mL). The yellow
precipitate was recrystallized in methanol at 4 °C (2.23 g, 5.20 mmol,
yield 92%). The compound is soluble in diethyl ether, alcohols,
acetone, acetonitrile, DMSO, and chlorinated solvents. Mp: 175−177
°C. Anal. Calcd for C29H23N3O: C, 81.09; H, 5.40; N, 9.78. Found: C,
80.76; H, 5.37; N, 9.59. IR (cm−1): 3054w, 1615s, 1579s, 1519w
ν(CC; CN). 1H NMR (CDCl3, 298 K): δ, 1.62 (s, 3H, C3−
CH3), 6.85 (d, 2H), 7.00−7.74 (m, 15H), 8.10 (d, 2H), 13.00 (sbr,
1H, −NH). 13C NMR (CDCl3, 298 K): δ, 16.5 (s, C3−CH3), 101.7 (s,
C4), 119.5, 121.0, 124.0, 124.7, 126.2, 126.9, 127.2, 127.4, 127.6,
128.4, 128.8, 129.0, 129.2, 129.3, 130.4, 137.7, 139.1, 139.6, 143.4,
148.3, 162.2, 165.9 (s, ligand HLbiph,ph). ESI-MS (−) CH3OH (m/z,
relative intensity %): 429 [100] [Lbiph,ph]−.
Ligand HLbiph,naph. The synthesis was performed as for HLbiph,ph
using 1-phenyl-3-methyl-4-biphenyl-5-pyrazolone (2.00 g, 5.64 mmol)
and 1-naphthylamine (0.80 g, 5.64 mmol). The compound is soluble
in diethyl ether, alcohols, acetone, acetonitrile, DMSO, and
chlorinated solvents. Mp: 266−268 °C. Anal. Calcd for C33H25N3O:
C, 82.67; H, 5.21; N, 8.76. Found: C, 82.60; H, 5.33; N, 8.71. IR
(cm−1): 3063w, 1604w, 1575w, 1538s ν(CC; CN). 1H NMR
(CDCl3, 298 K): δ, 1.71 (s, 3H, C3−CH3), 6.89 (d, 2H), 7.14−7.64
(m, 4H), 7.83 (d, 1H), 8.10 (d, 2H), 8.29 (d, 1H), 13.40 (sbr, 1H,
−NH). 13C NMR (CDCl3, 298 K): δ, 16.5 (s, C3−CH3), 102.0 (s,
C4), 119.6, 122.4, 124.1, 124.8, 125.1, 126.9, 127.1, 127.4, 127.6,
128.3, 128.6, 129.0, 129.1, 129.5, 130.4, 133.5, 134.1, 139.1, 139.6,
143.1, 148.3, 164.2, 166.4 (s, ligand HLbiph,naph). ESI-MS (−) CH3OH
(m/z, relative intensity %): 478 [100] [Lbiph,naph]−.
Ligand HLph,naph. The synthesis was performed as for HLbiph,ph using
1-phenyl-3-methyl-4-benzoyl-5-pyrazolone (1.57 g, 5.64 mmol) and 1naphthylamine (0.80 g, 5.64 mmol). The compound is soluble in
In comparison to the previous series of compounds we
reported,13 in which the C atom derivatived with the biphenyl
group in 1−4 was derivatized with a naphthyl group, IC50
values tend to be quite similar. However, the most cytotoxic
compound from both series in the A2780 cell line is the pcymene derivative with three phenyl rings attached to the
bidentate N,O− ligand (IC50 = 7.6 ± 1.1) and the most
cytotoxic compound toward the resistant A2780cisR cell line is
the benzene derivative also with three phenyl rings on the
bidentate N,O− ligand. Combined, these results imply that
intercalative interactions do not play a significant role in
mechanism of action of these types of compounds.
■
CONCLUSIONS
Ruthenium(II) arene complexes with pyrazolone-based βketoamine ligands containing phenyl, biphenyl, and naphthyl
groups in varying positions were prepared in order to evaluate
the influence of aromatic substituents on their in vitro
anticancer activity. Ruthenium(II) arene compounds may
coordinate directly to the DNA or histone core in chromatin,
and it is known that protruding aromatic ligands may
intercalate DNA.11 However, the ligands were not cytotoxic,
indicating that DNA intercalation is unlikely. Nevertheless,
some of the resulting compounds are reasonably cytotoxic and,
interestingly, in the A2780cisR cell line 2 is significantly more
cytotoxic than cisplatin (IC50 values of 13 ± 1 and 25 ± 1,
respectively) and 5 and 6 are marginally more cytotoxic than
cisplatin to this resistant cell line. Overall, the cytotoxicity of 1,
2, 5, and 6 is similar to that observed for many other series of
organoruthenium compounds.
■
EXPERIMENTAL SECTION
Materials and Methods. The dimers [Ru(arene)Cl2]2 (arene =
cym, benz, or hmb) were purchased from Aldrich. The acylpyrazolone
ligands HQph, HQbiph, and HQhex were synthesized using literature
methods.17 All other materials were obtained from commercial sources
and were used as received. IR spectra were recorded from 4000 to 600
cm−1 on a PerkinElmer Spectrum 100 FT-IR instrument. 1H and 13C
NMR spectra were recorded on a 400 Mercury Plus Varian instrument
operating at room temperature (400 MHz for 1H and 100 MHz for
13
C) relative to TMS. Positive and negative ion electrospray mass
spectra were obtained on a series 1100 MSI detector HP spectrometer
using methanol as the mobile phase. Solutions (3 mg/mL) for
electrospray ionization mass spectrometry (ESI-MS) were prepared
using reagent-grade methanol. Masses and intensities were compared
to those calculated using IsoPro Isotopic Abundance Simulator,
version 2.1.28. Melting points are uncorrected and were recorded on a
STMP3 Stuart scientific instrument and on a capillary apparatus.
Samples for microanalysis were dried in vacuo to constant weight (20
°C, ca. 0.1 Torr) and analyzed on a Fisons Instruments 1108 CHNS-O
elemental analyzer. Electrical conductivity measurements (ΛM,
reported as S cm2 mol−1) of acetonitrile and dichloromethane
solutions of the complexes were recorded using a Crison CDTM
522 conductimeter at room temperature.
X-ray Crystallography. The diffraction data of compounds 4 and
8 were measured at low temperature [100(2) K] using Mo Kα
radiation on a Bruker APEX II CCD diffractometer equipped with a
kappa geometry goniometer. The data sets were reduced by
EvalCCD18 and then corrected for absorption.19 The data collections
of compounds HLph, naph, 5, and 9 were collected at low temperature
[140(2) K] using Mo Kα radiation on a mar345dtb system in
combination with a Genix Hi-Flux small focus generator (marμX
system). The data reduction was carried out by automar.20 The data
collection of compound 1 was performed at room temperature using
Cu Kα radiation on an Agilent Technologies SuperNova dual system
D
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Hbiph,ph). ESI-MS (+) CH3OH (m/z, relative intensity %): 608
[100][Ru(benz)(Lbiph,ph)]+.
[Ru(hmb)(Lbiph,ph)Cl] (3). The synthesis was performed as for 1
using [Ru(hmb)Cl2]2. 3 is soluble in alcohols, acetone, acetonitrile,
DMSO, and chlorinated solvents. Mp: 248−250 °C. Anal. Calcd for
C41H40N3RuClO: C, 67.71; H, 5.54; N, 5.78. Found: C, 67.27; H,
5.46; N, 5.59. Λm (DMSO, 298 K, 10−4 mol/L): 18 S cm2 mol−1. IR
(cm−1): 3056w, 1601w, 1587m, 1567s, 1527m ν(CC; CN). 1H
NMR (CDCl3, 298 K): δ, 1.23 (s, 3H, C3−CH3), 1.78 (s, 18H,
C6(CH3)6), 6.73−7.94 (m, 19H). 13C NMR (CDCl3, 298 K): δ, 15.2
(s, C3−CH3), 16.1 (s, C6(CH3)6), 92.0 (s, C6(CH3)6), 102.8 (s, C4),
119.5, 120.9, 121.8, 124.0, 124.9, 125.0, 126.7, 127.1, 127.7, 128.4,
128.6, 128.9, 129.6, 136.1, 139.4, 140.1, 140.3, 149.5, 154.5, 160.3,
169.4 (s, ligand Hbiph,ph). ESI-MS (+) CH3OH (m/z, relative intensity
%): 692 [100][Ru(hmb)Ru(Lbiph,ph)]+.
[Ru(cym)(Lbiph,naph)Cl] (4). The synthesis was performed as for 1
using HLbiph,naph. 4 is soluble in alcohols, acetone, acetonitrile, DMSO,
and chlorinated solvents. Mp: 248−249 °C. Anal. Calcd for
C43H38N3RuClO: C, 68.93; H, 5.11; N, 5.61. Found: C, 68.79; H,
5.01; N, 5.50. Λm (DMSO, 298 K, 10−4 mol/L): 17 S cm2 mol−1. IR
(cm−1): 3041w, 1589m, 1570s, 1509m ν(CC; CN).). 1H NMR
(CDCl3, 298 K): δ, 1.18 (d, 6H, C3−CH3), 1.24 and 1.34 (m, 12H,
CH3−C6H4−CH(CH3)2), 1.90 (s, 6H, CH3-C6H4−CH(CH3)2), 2.75
(m, 2H, CH3−C6H4−CH(CH3)2), 2.94 (d, 1H, 3J = 5.6 Hz, CH3−
C6H4−CH(CH3)2), 3.27(d, 1H, 3J = 5.6 Hz, CH3−C6H4−CH(CH3)2), 4.71 (d, 1H, 3J = 5.6 Hz, CH3−C6H4−CH(CH3)2), 4.91 (d,
1H, 3J = 5.6 Hz, CH3−C6H4−CH(CH3)2), 4.97 (d, 1H, 3J = 5.6 Hz,
CH3−C6H4−CH(CH3)2), 5.10 (d, 1H, 3J = 5.6 Hz, CH3−C6H4−
CH(CH3)2), 5.30 (d, 1H, 3J = 5.6 Hz, CH3−C6H4−CH(CH3)2), 5.38
(d, 1H, 3J = 5.6 Hz, CH3−C6H4−CH(CH3)2), 6.90−8.20 (m, 20H),
9.11 (d,2H). 13C NMR (CDCl3, 298 K): δ, 15.7, 15.8 (s, C3−CH3),
18.7, 18.9 (s, CH3−C6H4−CH(CH3)2), 21.2, 21.4 and 23.8, 23.9 (s,
CH3−C6H4−CH(CH3)2), 30.8, 30.9 (s, CH3−C6H4−CH(CH3)2),
80.2, 80.3, 83.7, 83.8, 84.3, 84.5, 87.0,87.2, 96.5, 96.7, 101.2, 101.4 (s,
CH3−C6H4−CH(CH3)2), 102.4, 102.6 (s, C4), 120.6, 121.0,
124.7,124.8, 124.9, 152.1, 125.2, 125.9, 126.1, 126.6, 126.8, 127.1,
127.3, 127.4, 128.2, 128.7, 128.9 129.0, 129.5, 135.0, 135.4, 139.6,
139.9, 140.2, 140.5, 140.6, 149.2, 149.4, 156.0, 156.2, 159.9, 160.4,
168.3, 168.6 (s, ligand Hbiph,naph). ESI-MS (+) CH3OH (m/z, relative
intensity %): 714 [100][Ru(cym)(Lbiph,naph)]+.
[Ru(cym)(Lph,naph)Cl] (5). The synthesis was performed as for 1
using HLph,naph. 5 is soluble in alcohols, acetone, acetonitrile, DMSO,
and chlorinated solvents. Mp: 213-215 °C. Anal. Calcd for
C37H34N3RuClO: C, 66.01; H, 5.09; N, 6.24. Found: C, 65.86; H,
5.00; N, 6.20. Λm (DMSO, 298 K, 10−4 mol/L): 15 S cm2 mol−1. IR
(cm−1): 3033m, 1587m, 1567s, 1527m ν(CC; CN). 1H NMR
(CDCl3, 298 K): δ, 1.12−1.30 (d, 12H, CH3−C6H4−CH(CH3)2 3J =
7.2 Hz, CH3−C6H4−CH(CH3)2), 1.19−1.34 (d, 6H, CH3−C6H4−
CH(CH3)2 3J = 6.8 Hz, CH3−C6H4−CH(CH3)2), 1.66 (s, 3H, C3−
CH3), 1.80 (s, 6H, C3−CH3), 2.08 (s, 3H, CH3−C6H4−CH(CH3)2),
2.11 (s, 6H, CH3−C6H4−CH(CH3)2), 2.75 (m, 3H, CH3−C6H4−
CH(CH3)2), 2.90 (d, 1H, 3J = 5.6 Hz, CH3−C6H4−CH(CH3)2), 3.23
(d, 2H, 3J = 5.6 Hz, CH3−C6H4−CH(CH3)2), 4.67 (d, 1H, 3J = 5.6
Hz, CH3−C6H4−CH(CH3)2), 4.88 (d, 2H, 3J = 5.6 Hz, CH3−C6H4−
CH(CH3)2), 4.93 (d, 2H, 3J = 5.6 Hz, CH3−C6H4−CH(CH3)2), 5.07
(d, 1H, 3J = 5.6 Hz, CH3−C6H4−CH(CH3)2), 5.26 (d, 1H, 3J = 5.6
Hz, CH3−C6H4−CH(CH3)2), 5.34 (d, 1H, 3J = 5.6 Hz, CH3−C6H4−
CH(CH3)2), 6.73−9.04 (m, 51H). 13C NMR (CDCl3, 298 K): δ, 15.5,
15.7 (s, C3−CH3), 18.7, 18.8 (s, CH3−C6H4−CH(CH3)2), 21.4, 21.5
and 23.4, 23.6 (s, CH3−C6H4−CH(CH3)2), 31.0, 31.2 (s, CH3−
C6H4−CH(CH3)2), 80.0, 80.1, 83.9, 84.4, 84.6, 84.9, 87.0, 87.2, 96.5,
96.7, 101.0, 101.2 (s, CH3−C6H4−CH(CH3)2), 102.2, 103.3 (s, C4),
120.4, 121.2, 124.7, 124.7, 124.9, 152.0, 125.6, 125.9, 126.3, 126.5,
126.8, 127.1, 127.3, 127.6, 128.6, 128.7, 129.0, 129.5, 135.0, 135.4,
139.6, 139.9, 140.2, 140.5, 140.6, 149.2, 149.4, 156.0, 156.2, 160.7,
161.4, 170.2, 170.6 (s, ligand Hph,naph). ESI-MS (+) CH3OH (m/z,
relative intensity %): 638 [100][Ru(cym)Ru(Lph,naph)]+.
[Ru(benz)(Lph,naph)Cl] (6). The synthesis was performed as for 2
using HLph,naph. 6 is soluble in alcohols, acetone, acetonitrile, DMSO,
and chlorinated solvents. Mp: 298−300 °C. Anal. Calcd for
diethyl ether, alcohols, acetone, acetonitrile, DMSO, and chlorinated
solvents. Mp: 175−176 °C. Anal. Calcd for C27H21N3O: C, 80.34; H,
5.25; N, 10.42. Found: C, 80.48; H, 5.32; N, 10.41. IR (cm−1): 3043w,
1615s, 1587s, 1571s, 1532m, 1514w, 1503w ν(CC; CN). 1H
NMR (CDCl3, 298 K): δ, 1.60 (s, 3H, C3−CH3), 6.84 (d, 1H), 7.11−
7.63 (m, 12H), 7.82 (d, 1H), 8.08 (d, 2H), 8.26 (d, 1H), 13.31 (sbr,
1H, −NH). 13C NMR (CDCl3, 298 K): δ, 16.3 (s, C3−CH3), 101.9 (s,
C4), 119.6, 122.3, 124.0, 124.7, 125.0, 126.9, 127.4, 127.5, 128.4,
128.5, 128.6, 129.0, 129.5, 130.4, 131.6, 133.4, 134.1, 139.1, 148.3,
164.4, 166.3 (s, ligand HLph,naph). ESI-MS (−) CH3OH (m/z, relative
intensity %): 402 [100] [Lph,naph]−.
Ligand HLhex,naph. The synthesis was performed as for HLbiph,ph
using 1-phenyl-3-methyl-4-hexenyl-5-pyrazolone (1.61 g, 5.64 mmol)
and 1-naphthylamine (0.80 g, 5.64 mmol). The compound is soluble
in diethyl ether, alcohols, acetone, acetonitrile, DMSO, and
chlorinated solvents. Mp: 166−168 °C. Anal. Calcd for C27H29N3O:
C, 78.80; H, 7.10; N, 10.21. Found: C, 78.86; H, 7.26; N, 10.16. IR
(cm−1): 3058w, 1623s, 1585s, 1572s, 1538s ν(CC; CN). 1H
NMR (CDCl3, 298 K): δ, 0.71 (t, 3H, CH2CH2CH2(CH2)2CH3),
0.94−1.06 (m, 4H, CH2 CH2CH2 (CH 2)2CH3), 1.12 (m, 2H,
CH2CH2CH2(CH2)2CH3), 1.47 (m, 2H, CH2CH2CH2(CH2)2CH3),
2.47 (s, 3H, C3−CH3), 2.57 (m, 2H, CH2CH2CH2(CH2)2CH3),
7.16−7.97 (m, 10H), 8.05 (d, 2H), 13.29 (sbr, 1H, −NH). 13C NMR
(CDCl3, 298 K): δ, 14.0 (s, (CH2)6CH3), 17.2 (s, C3−CH3), 22.3,
29.2, 29.5, 29.6, 31.0 (s, (CH2)6CH3), 99.8 (s, C4), 119.5, 122.7, 124.6,
125.3, 127.2, 127.8, 128.6, 129.0, 130.3, 133.1, 133.2, 134.5, 139.3,
147.1, 166.6, 169.8 (s, ligand). ESI-MS (−) CH3OH (m/z, relative
intensity %): 410 [100] [Lhex,naph]−.
[Ru(cym)(Lbiph,ph)Cl] (1). To the proligand HLbiph,ph (280.0 mg,
0.652 mmol) dissolved in methanol (20 mL) was added KOH (36.5
mg, 0.652 mmol). The mixture was stirred for 1 h at room
temperature, and then [Ru(cym)Cl2]2 (200.0 mg, 0.326 mmol) was
added. The resulting solution was stirred under reflux for 24 h. The
solvent was removed under reduced pressure, dichloromethane (10
mL) was added, and the mixture was filtered to remove potassium
chloride. The solution was concentrated to ca. 2 mL and stored at 4
°C, affording red crystals (360.0 mg, 0.514 mmol, yield 79%) that are
soluble in diethyl ether, alcohols, acetone, acetonitrile, DMSO, and
chlorinated solvents. Mp: 247−249 °C. Anal. Calcd for
C39H36N3RuClO: C, 66.99; H, 5.19; N, 6.01. Found: C, 67.00; H,
5.02; N, 5.94. Λm (DMSO, 298 K, 10−4 mol/L): 18 S cm2 mol−1. Λm
(DMSO, 313 K, 10−4 mol/L): 40 S cm2 mol−1. Λm (DMSO, 333 K,
10−4 mol/L): 61 S cm2 mol−1. Λm (DMSO, 353 K, 10−4 mol/L): 74 S
cm2 mol−1. IR (cm−1): 3034w, 1599m, 1588s, 1572s, 1530w ν(CC;
CN). 1H NMR (CDCl3, 298 K): δ, 1.24 (d, 3H, 3J = 6.8 Hz, CH3−
C6H4−CH(CH3)2), 1.28 (s, 3H, C3−CH3), 1.31 (d, 6H, 3J = 6.8 Hz,
CH3−C6H4−CH(CH3)2), 2.06 (s, 3H, CH3-C6H4−CH(CH3)2), 2.74
(sept, 1H, 3J = 7.2 Hz, CH3−C6H4−CH(CH3)2), 3.52 (d, 1H, 3J = 5.6
Hz, CH3−C6H4−CH(CH3)2), 5.14 (d, 1H, 3J = 5.6 Hz, CH3−C6H4−
CH(CH3)2), 5.17 (d, 1H, 3J = 6.4 Hz, CH3−C6H4−CH(CH3)2), 5.37
(d, 1H, 3J = 6.4 Hz, CH3−C6H4−CH(CH3)2), 6.82−7.96 (m, 19H).
13
C NMR (CDCl3, 298 K): δ, 15.7 (s, C3−CH3), 18.7 (s, CH3−
C6H4−CH(CH3)2), 21.2 and 23.8 (s, CH3−C6H4−CH(CH3)2), 30.9
(s, CH3−C6H4−CH(CH3)2), 79.2, 80.3, 82.5, 83.7, 84.3, 86.9 (s,
CH3−C6H4−CH(CH3)2), 102.4 (s, C4), 120.6, 124.7, 124.9, 125.2,
125.9, 126.8, 127.1, 127.3, 127.4, 128.7, 128.9, 129.0, 129.5, 135.0,
139.6, 140.2, 140.6, 149.4, 156.2, 160.4, 168.3 (s, ligand Hbiph,ph). ESIMS (+) CH3OH (m/z, relative intensity%): 664 [100][Ru(cym)(Lbiph,ph)]+.
[Ru(benz)(Lbiph,ph)Cl] (2). The synthesis was performed as for 1
using [Ru(benz)Cl2]2. 2 is soluble in alcohols, acetone, acetonitrile,
DMSO, and chlorinated solvents. Mp: 240−242 °C. Anal. Calcd for
C35H28N3RuClO: C, 65.36; H, 4.39; N, 6.53. Found: C, 65.16; H,4.43;
N, 6.31. Λm (DMSO, 298 K, 10−4 mol/L): 16 S cm2 mol−1. IR (cm−1):
3066w, 1590s, 1568s, 1526m ν(CC; CN). 1H NMR (CDCl3, 298
K): δ, 1.27 (s, 3H, C3−CH3), 5.21 (s, 6H, C6H5), 6.89−7.95 (m,
19H). 13C NMR (CDCl3, 298 K): δ, 15.6 (s, C3−CH3), 84.6s (s,
C6H6), 102.8 (s, C4), 102.4 (s, C4), 119.5, 120.8, 124.8, 124.9, 125.3,
125.8, 126.8, 127.0, 127.3, 127.5, 128.5, 128.5 129.3, 129.2, 134.8,
139.4, 140.1, 140.7, 143.4, 149.5, 156.6, 160.6, 168.5 (s, ligand
E
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15.4 (s, C6(CH3)6), 17.9 (s, C3−CH3), 22.3 (s, −CH2(CH2)4CH3),
29.0, 29.4, 31.0, 31.7, 33.0 (s, −(CH2)5CH3), 91.6 (s, C6(CH3)6),
101.2 (s, C4), 119.5, 121.1, 122.5, 122.7, 123.5, 124.0, 124.6, 124.8,
125.4, 126.6, 127.2, 127.7, 128.3, 128.6, 128.8, 128.9, 129.1, 130.2,
133.9, 139.4, 147.4, 151.4, 160.9, 169.7, 175.2 (s, ligand Hhex,naph). ESIMS (+) CH3OH (m/z, relative intensity %): 674 [100][Ru(hmb)(Lhex,naph)]+.
C33H26N3RuClO: C, 64.23; H, 4.25; N, 6.81. Found: C, 64.06; H,
4.20; N, 6.71. Λm (DMSO, 298 K, 10−4 mol/L): 18 S cm2 mol−1. IR
(cm−1): 3070w, 1585m, 1566s, 1523m, 1505w ν(CC; CN). 1H
NMR (CDCl3, 298 K): δ, 1.13 (s, 6H, C3−CH3), 1.15 (s, 3H, C3−
CH3), 4.94 (s, 6H, C6H6), 5.03 (s, 12H, C6H6), 6.80−9.12 (m, 51H).
13
C NMR (CDCl3, 298 K): δ, 15.1, 15.2 (s, C3−CH3), 84.3, 84.5 (s,
C6H6), 103.2, 105.1 (s, C4), 119.5, 120.6, 120.7, 122.8, 123.7, 124.0,
124.6, 124.9, 125.4, 125.9, 126.1, 126.3, 126.4, 126.8, 126.9, 127.5,
127.6, 127.7, 127.9, 128.2, 128.5, 128.7, 129.3, 129.9, 133.3, 133.6,
135.3, 136.1, 139.3, 143.2, 149.4, 149.5, 152.7, 153.1, 161.2, 162.4,
168.9, 170.3 (s, ligand Lph,ph). ESI-MS (+) CH3OH (m/z, relative
intensity %): 582 [100][Ru(benz)(Lph,naph)]+.
[Ru(hmb)(Lph,naph)Cl] (7). The synthesis was performed as for 3
using HLph,naph. 7 is soluble in alcohols, acetone, acetonitrile, DMSO,
and chlorinated solvents. Mp: 248−250 °C. Anal. Calcd for
C39H38N3RuClO: C, 66.80; H, 5.46; N, 5.99. Found: C, 66.57; H,
5.34; N, 5.78. Λm (DMSO, 298 K, 10−4 mol/L): 20 S cm2 mol−1. IR
(cm−1): 3055w, 1600w, 1584m, 1563s, 1525m ν(CC; CN). 1H
NMR (CDCl3, 298 K): δ, 1.04 (s, 3H, C3−CH3), 1.06 (s, 6H, C3−
CH3), 1.54 (s, 6H, C6(CH3)6), 1.60 (s, 12H, C6(CH3)6), 6.57−7.94
(m, 45H), 8.01 (d, 4H) 8.01 (d, 2H). 13C NMR (CDCl3, 298 K): δ,
15.2, 15.4 (s, C3−CH3), 16.1, 16.2 (s, C6(CH3)6), 92.0, 93.4 (s,
C6(CH3)6), 102.8, 103.0 (s, C4), 119.5, 120.2, 120.9, 121.8, 124.0,
124.9, 125.1, 125.6, 125.8, 126.2, 126.6, 126.9, 127.1, 127.5, 127.7,
127.9, 128.1, 128.4, 128.6, 128.9, 129.3, 129.6, 136.1, 136.6, 139.4,
140.1, 140.3, 149.2 149.5, 153.6, 154.5, 160.3, 161.7, 169.4, 170.0 (s,
ligand Hph,naph). ESI-MS (+) CH3OH (m/z, relative intensity %): 666
[100][Ru(hmb)Ru(Lph,naph)]+.
[Ru(cym)(Lhex,naph)Cl] (8). The synthesis was performed as for 1
using HLhex,naph. 8 is soluble in alcohols, acetone, acetonitrile, DMSO,
and chlorinated solvents. Mp: 200−202 °C. Anal. Calcd for
C37H42N3RuClO: C, 65.23; H, 6.21; N, 6.17. Found: C, 65.20; H,
6.29; N, 6.13. Λm (DMSO, 298 K, 10−4 mol/L): 17 S cm2 mol−1. IR
(cm−1): 3052w, 1590s, 1573s, 1520m ν(CC; CN). 1H NMR
(CDCl3, 298 K): δ, 0.68 (m, 3H, CH2CH2CH2CH2CH2CH3), 0.89
(m, 2H, CH2CH2CH2CH2CH2CH3), 1.01 (m, 2H,
CH2CH2CH2CH2CH2CH3), 1.10, 1.21 (d, 3H, 3J = 7.2 Hz, CH3−
C6H4−CH(CH3)2), 1.16, 1.31 (d, 3H, 3J = 6.8 Hz, CH3−C6H4−
CH(CH3)2), 1.42 (m, 2H, CH2CH2CH2CH2CH2CH3), 1.55, 1.59 (s,
3H, CH3-C6H4−CH(CH3)2), 1.94 (m, 2H,
CH2CH2CH2CH2CH2CH3), 2.33, 2.24 (s, 3H, C3−CH3), 2.42 (m,
2H, CH 2 CH2 CH 2 CH 2 CH 2 CH 3 ), 2.63 (m, 1H, CH 3 −C 6 H 4 −
CH(CH3)2), 2.95 (d, 1H, 3J = 5.6 Hz, CH3−C6H4−CH(CH3)2),
3.09 (d, 1H, 3J = 5.6 Hz, CH3−C6H4−CH(CH3)2), 4.75 (d, 1H, 3J =
5.6 Hz, CH3−C6H4−CH(CH3)2), 4.86 (d, 1H, 3J = 5.6 Hz, CH3−
C6H4−CH(CH3)2), 4.89 (d, 1H, 3J = 6.4 Hz, CH3−C6H4−
CH(CH3)2), 4.92 (d, 1H, 3J = 6.4 Hz, CH3−C6H4−CH(CH3)2),
5.23 (d, 1H, 3J = 6.4 Hz, CH3−C6H4−CH(CH3)2), 5.33 (d, 1H, 3J =
6.4 Hz, CH3−C6H4−CH(CH3)2), 7.15−8.79 (12, H). 13C NMR
(CDCl3, 298 K): δ, 14.0 (s, −(CH2)5CH3), 17.2, 17.6 (s, CH3−C6H4−
CH(CH3)2), 18.0 (s, C3−CH3), 20.8 and 23.8, 23.0.9, and 23.7 (s,
CH3−C6H4−CH(CH3)2), 22.3 (s, −CH2(CH2)4CH3), 29.3, 29.4, 29.9,
30.6, 30.7, 30.8, 31.8. 31.1, 32.4, 32.9 (s, CH3−C6H4−CH(CH3)2 and
−(CH2)5CH3), 76.2, 80.0, 82.6, 83.5, 84.6, 84.7, 87.8, 92.9, 93.5, 101.1
(s, CH3−C6H4−CH(CH3)2), 102.9, 103.3 (s, C4), 119.6, 120.3, 120.9,
122.1, 123.5, 124.6, 124.7, 126.0, 126.2, 126.7, 127.2, 127.4, 127.9,
128.1, 128.5, 128.9, 129.1, 129.4, 131.2, 133.8, 134.3, 139.6, 147.5,
147.6, 151.9, 152.9, 161.0, 171.2, 172.9 (s, ligand Hhex,naph). ESI-MS
(+) CH3OH (m/z, relative intensity %): 646 [100][Ru(cym)(Lhex,naph)]+.
[Ru(hmb)(Lhex,naph)Cl] (9). The synthesis was performed as for 3
using HLhex,naph. 9 is soluble in alcohols, acetone, acetonitrile, DMSO,
and chlorinated solvents. Mp: 250−252 °C. Anal. Calcd for
C39H46N3RuClO: C, 66.04; H, 6.54; N, 5.92. Found: C, 65.97; H,
6.46; N, 5.79. Λm (DMSO, 298 K, 10−4 mol/L): 15 S cm2 mol−1. IR
(cm−1): 3056w, 1601w, 1587m, 1567s, 1527m ν(CC; CN).). 1H
NMR (CDCl3, 298 K): δ, 0.66 (s, 3H, −(CH2)5CH3), 0.80−1.04 (m,
6H, −(CH2)5CH3), 1.45 (m, 2H, −(CH2)5CH3), 1.53 (s, 3H, C3−
CH3), 1.55 (s, 18H, C6(CH3)6), 2.30 (m, 2H, −(CH2)5CH3), 7.13−
8.27 (m, 12H). 13C NMR (CDCl3, 298 K): δ, 14.0 (s, −(CH2)5CH3),
■
ASSOCIATED CONTENT
S Supporting Information
*
Table of crystal data and details of the structure determination.
Crystallographic data in CIF format. This material is available
free of charge via the Internet at http://pubs.acs.org.
■
AUTHOR INFORMATION
Corresponding Author
*E-mail: riccardo.pettinari@unicam.it. Tel: +39 0737402338.
Notes
The authors declare no competing financial interest.
■
■
ACKNOWLEDGMENTS
We thank the Swiss National Science Foundation (CMM) and
the University of Camerino for financial support.
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Inorganic Chemistry
Article
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dx.doi.org/10.1021/ic502274b | Inorg. Chem. XXXX, XXX, XXX−XXX