Arene ruthenium dichloro complexes containing isonicotinic ester ligands: Synthesis, molecular structure and cytotoxicity

Article abstract of DOI:10.1016/j.jorganchem.2012.10.016

A series of p-cymene ruthenium dichloro complexes containing isonicotinic ester ligands, [(arene)RuCl₂NC₅H₄-4-COO-C ₆H₄-p-O-(CH₂)_n-CH₃] (n = 1: 1, n = 3: 2, n = 5: 3, n = 7: 4, n = 9: 5, n = 11: 6, n = 13: 7, n = 15: 8), were prepared from p-cymene ruthenium dichloro dimer and the corresponding isonicotinic ester ligand. The single-crystal X-ray analysis of 1 shows the molecule to adopt the usual pseudo-tetrahedral piano-stool geometry, the isonicotinic ester ligand being coordinated through the nitrogen atom. The cytotoxicity of all complexes and of the free ligands was studied towards human ovarian cancer cells; high activities were observed only for n = 9 (presenting a chain with ten carbon atoms), both as far as the free ligands and the complexes are concerned. Based on this result, a new isonicotinic ester ligand with a C₁₀ substituent containing a terminal alcohol function, NC ₅H₄-4-COO-C₆H₄-p-O-(CH ₂)₁₀-OH, was synthesized by a four-step method, and arene ruthenium complexes thereof, [(arene)RuCl₂NC₅H ₄-4-COO-C₆H₄-p-O-(CH₂) ₁₀-OH] (arene = C₆H₆: 9a, arene = p-MeC ₆H₄Prⁱ: 9b, arene = C₆Me ₆: 9c) were prepared. The complexes 9a and 9b show indeed remarkable anticancer activities, the IC₅₀ values for human ovarian cancer cells being in the submicromolar range. The highest cytotoxicity was observed for complex 9b, with IC₅₀ values of 0.18 μM for A2780 and 3.04 μM for the cisplatin-resistant mutant A2780cisR.

Full text of DOI:10.1016/j.jorganchem.2012.10.016

Journal of Organometallic Chemistry 730 (2013) 49e56
Contents lists available at SciVerse ScienceDirect
Journal of Organometallic Chemistry
journal homepage: www.elsevier.com/locate/jorganchem
Arene ruthenium dichloro complexes containing isonicotinic ester ligands:
Synthesis, molecular structure and cytotoxicity
,
b
b
Farooq-Ahmad Khan a, Bruno Therrien a, Georg Süss-Fink a , Olivier Zava , Paul J. Dyson
*
a Institut de Chimie, Université de Neuchâtel, Avenue de Bellevaux 51, CH-2000 Neuchâtel, Switzerland
b Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne (EPFL), CH-1015 Lausanne, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of p-cymene ruthenium dichloro complexes containing isonicotinic ester ligands, [(arene)
RuCl2NC5H4-4-COOeC6H4ep-O-(CH2)n-CH3] (n ¼ 1: 1, n ¼ 3: 2, n ¼ 5: 3, n ¼ 7: 4, n ¼ 9: 5, n ¼ 11: 6,
n ¼ 13: 7, n ¼ 15: 8), were prepared from p-cymene ruthenium dichloro dimer and the corresponding
isonicotinic ester ligand. The single-crystal X-ray analysis of 1 shows the molecule to adopt the usual
pseudo-tetrahedral piano-stool geometry, the isonicotinic ester ligand being coordinated through the
nitrogen atom. The cytotoxicity of all complexes and of the free ligands was studied towards human
ovarian cancer cells; high activities were observed only for n ¼ 9 (presenting a chain with ten carbon
atoms), both as far as the free ligands and the complexes are concerned. Based on this result, a new
isonicotinic ester ligand with a C10 substituent containing a terminal alcohol function, NC5H4-4-COO
eC6H4ep-Oe(CH2)10eOH, was synthesized by a four-step method, and arene ruthenium complexes
thereof, [(arene)RuCl2NC5H4-4-COOeC6H4ep-Oe(CH2)10eOH] (arene ¼ C6H6: 9a, arene ¼ p-MeC6H4Pri:
9b, arene ¼ C6Me6: 9c) were prepared. The complexes 9a and 9b show indeed remarkable anticancer
activities, the IC50 values for human ovarian cancer cells being in the submicromolar range. The highest
Received 23 July 2012
Received in revised form
3 October 2012
Accepted 4 October 2012
Keywords:
Anticancer drugs
Bioorganometallic chemistry
Isonicotinic ester ligands
Arene ruthenium complexes
cytotoxicity was observed for complex 9b, with IC50 values of 0.18 mM for A2780 and 3.04 mM for the
cisplatin-resistant mutant A2780cisR.
Ó 2012 Elsevier B.V. All rights reserved.
1. Introduction
Isonicotinic acid (pyridine-4-carboxylic acid), an isomer of
nicotinic acid (pyridine-3-carboxylic acid), is widely used for the
synthesis of antibiotics and antituberculosis preparations [9], and it
has strong bactericide effects [10]. The encouraging pharmacolog-
ical profile of isonicotinic acid derivatives coupled with amphiphilic
arene ruthenium moieties makes this combination promising for
drug design. Thus, Liu et al. recently reported arene ruthenium
complexes containing isonicotinic acid, methyl isonicotinate and
5-fluorouracil-1-methyl isonicotinate (5-Fu) ligands, a synergistic
effect was observed in the case of the 5-Fu ligand and the p-cymene
ruthenium fragment [11]. Similar effect was observed by
Schobert et al. in a series of arene ruthenium dichloro complexes
containing N-coordinated oestrogen and androgen isonicotinates
Arene ruthenium complexes containing chlorido ligands are
often both lipophilic and water-soluble, which preconditions these
organometallics for bio-medical applications, in particular as anti-
cancer agents [1]. The field of antitumoral and antimetastatic arene
ruthenium complexes has, in recent years, received considerable
attention [2,3], following the first in vitro study of arene ruthenium
compounds as anticancer agents by Tocher et al. in 1992, who
observed a cytotoxicity enhancement by coordinating the anti-
cancer agent metronidazole [1-b-(hydroxyethyl)-2-methyl-5-
nitro-imidazole] to a benzene ruthenium dichloro fragment [4].
Prototype arene ruthenium(II) complexes evaluated for anticancer
properties include [(p-MeC6H4Pri)RuCl2(P-pta)] (pta ¼ 1,3,5-triaza-
7-phospha-tricyclo-[3.3.1.1]decane), termed RAPTA-C [5], and
ꢀ
[12]. However, Sipka et al. reported only low cytotoxic activity for
a series of arene ruthenium complexes with functionalized pyri-
dines including a p-cymene ruthenium derivative containing an
isonicotinic acid ligand viz. [(p-MeC6H4Pri)RuCl2NC5H4COOH] [13].
Another arene ruthenium complex containing isonicotinic acid as
a ligand, namely [(C6H6)RuCl2NC5H4COOH], was synthesized by
Ma1ecki et al., but the biological properties of this complex were not
reported [14]. We have been interested in the use of long-chain
isonicotinic esters as lipophilic components in order to increase
[(C6H5Ph)RuCl(N,N-en)][PF6] (en
¼
1,2-ethylenediamine) [6],
although many different classes have since been reported [7].
Recently, we reported highly cytotoxic diruthenium compounds
such as [(p-MeC6H4Pri)Ru2(S-p-C6H4Me)3]Cl [8].
* Corresponding author. Tel.: þ41 32 718 2405; fax: þ41 32 718 2511.
E-mail address: georg.suess-fink@unine.ch (G. Süss-Fink).
0022-328X/$ e see front matter Ó 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jorganchem.2012.10.016

50
F.-A. Khan et al. / Journal of Organometallic Chemistry 730 (2013) 49e56
the anticancer activity of arene ruthenium complexes. Recently, we
found that long-chain isonicotinic ester ligand-stabilized ruthe-
nium(0) nanoparticles, derived from the precursor complex [(p-
MeC6H4Pri)RuCl2NC5H4-4-COOeC6H4ep-Oe(CH2)9eCH3] (5) show
in vitro anticancer activity against human ovarian cancer cells [15].
In this paper we report a systematic study of this type of
complexes: the synthesis and characterization of p-cymene ruthe-
nium complexes containing isonicotinic ester ligands, (arene)
RuCl2[NC5H4-4-COOeC6H4ep-O-(CH2)n-CH3] (n ¼ 1: 1, n ¼ 3: 2,
n ¼ 5: 3, n ¼ 7: 4, n ¼ 9: 5, n ¼ 11: 6, n ¼ 13: 7, n ¼ 15: 8) with an even
number of carbon atoms in the aliphatic chain (including the known
complex 5 [15]), the synthesis and characterization of a new long-
chain isonicotinic ester ligand with a C10 substituent containing
a terminalalcoholfunction, NC5H4-4-COOeC6H4ep-Oe(CH2)10eOH,
and of the corresponding ruthenium complexes thereof, [(arene)
RuCl2NC5H4-4-COOeC6H4ep-Oe(CH2)10eOH] (arene ¼ C6H6: 9a,
arene ¼ p-MeC6H4Pri: 9b, arene ¼ C6Me6: 9c) as well as the cyto-
toxicities of these compounds for human ovarian cancer cells.
2. Results and discussion
Fig. 1. OREP diagram of complex 1 with 50% probability thermal ellipsoids.
2.1. Synthesis of the p-cymene ruthenium complexes 1e8
The dinuclear complex [(p-MeC6H4Pri)RuCl2]2 reacts in
dichloromethane with two equivalents of the isonicotinic ester
ligands NC5H4-4-COOeC6H4ep-O-(CH2)n-CH3 at room temperature
to give the neutral complexes [(p-MeC6H4Pri)RuCl2NC5H4-4-COOe
C6H4ep-O-(CH2)n-CH3] (n ¼ 1: 1, n ¼ 3: 2, n ¼ 5: 3, n ¼ 7: 4, n ¼ 9: 5,
n ¼ 11: 6, n ¼ 13: 7, n ¼ 15: 8) in quantitative yield, see Scheme 1.
All the complexes are obtained as air-stable yellow to yellow-
brownish powders, which are soluble in polar organic solvents, in
particular in dichloromethane and in chloroform. The complexes
are also sparingly soluble in water.
A2780 ovarian cancer cell line and cisplatin-resistant variant
A2780cisR using the MTT assay. It was found that the IC50 values for
both cell lines depend strongly on the length of the carbon chain in
the isonicotinic ester ligand (Fig. 2). In particular, complex 5
containing a ten-carbon-atom chain (n ¼ 9) exhibits a very high
cytotoxicity towards both cell lines, the IC50 values being compa-
rable to those of cisplatin [16]. Indeed, it has been shown previously
that arene ruthenium complexes with long aliphatic chains [17] or
long perfluorous chains [18] are often very cytotoxic.
Interestingly, the analogous pyridine complex [(p-MeC6H4Pri)
RuCl2(py)] is essentially inactive (IC50 ¼ 750
mM) under comparable
conditions in these cancer cell lines [19], suggesting that the
cytotoxicity of isonicotinic ester complexes may be due to the long-
chain isonicotinic ligand. This is supported by the low IC50 values
observed for the free ligands (Fig. 3).
2.2. Single-crystal X-ray structure analysis of 1
Orange crystals of 1 with X-ray diffraction quality were obtained
by slow evaporation of a dichloromethane solution. This compound
crystallizes in the monoclinic centrosymmetric space group P21/c.
The structure of this complex can be described as pseudo-
tetrahedral, having a “piano stool”-like geometry, in which the
ruthenium atom is coordinated to the p-MeC6H4Pri ligand, the two
chlorido ligands and to the nitrogen atom of the isonicotinic ester
ligand. The molecular structure of 1 is shown in Fig. 1, and char-
acteristic distances and angles are summarized in Table 1.
The remarkable dependence of the IC50 values on the length of
the carbon chain in both, the free isonicotinic ester ligands and of
the p-cymene ruthenium complexes thereof suggests that for the
highest anticancer activity ten carbon atoms in the substituent of
the isonicotinic ester are required. This observation prompted us to
synthesize a new isoniconitic ester containing a ten-carbon-atom
chain with an alcoholic function at the terminal carbon atom in
order to increase the hydrophilicity of the complex.
2.3. Anticancer properties of complexes 1e8 and of the free ligands
2.4. Synthesis of the isonicotinic ester NC5H4-4-COOeC6H4ep-Oe
(CH2)10eOH
The in vitro cytotoxicity of the complexes [(p-MeC6H4Pri)
RuCl2NC5H4-4-COOeC6H4ep-O-(CH2)n-CH3] (1e8) and of the cor-
responding free isonicotinic ester ligands NC5H4-4-COOeC6H4ep-
O-(CH2)n-CH3 (n ¼ 1, 3, 5, 7, 9, 11, 13, 15) was studied towards the
The long-chain isonicotinic ester NC5H4-4-COOeC6H4ep-Oe
(CH2)10eOH was synthesized using a classical four-step method,
Cl
Ru
Ru
Ru
Cl
N
1/2 Cl
Cl
Cl
N
+
Cl
O
O
(CH2)n
CH3
O
O
(CH2)n
CH3
O
O
n
=
1
3
5
7
9
11 13 15
1 2 3 4
5 6 7 8
Scheme 1.

F.-A. Khan et al. / Journal of Organometallic Chemistry 730 (2013) 49e56
51
Fig. 2. Cytotoxicities of arene ruthenium complexes 1e8 containing isonicotinic ester ligands and graphical representation of carbon atom chain length effect on IC50 values of these
complexes.
see Scheme 2: Starting by selective bromination of 1,10-decanediol
using 48% HBr solution in a liquideliquid extractor to give 10-
bromodecanol [20] (Step 1), the corresponding benzyl ether was
obtained by reaction with benzyl hydroquinone in the presence of
potassium carbonate and 18-crown-6, according to a literature-
modified etherification process [21] (Step 2). The benzyl group
was then removed with molecular hydrogen under pressure in the
presence of palladium on carbon [22] (Step 3). The isonicotinic
ester NC5H4-4-COOeC6H4ep-Oe(CH2)10eOH was obtained by
reacting isonicotinoyl chloride hydrochloride with the alcohol viz.
4-(10-hydroxydecyloxy)phenol (Step 4) [22]. The reaction is done
in the presence of triethylamine to bind the HCl eliminated. The full
characterization of this new isonictonic ester is presented in the
Experimental Part.
which the signals for the a-protons in the pyridine ring appear at
lower field as compared to those of the corresponding protons in
the free ligand. All complexes are obtained as air-stable yellow to
brownish-yellow powders, which are soluble in polar organic
solvents, in particular in dichloromethane and chloroform. The
complexes are also soluble in DMSO and sparingly soluble in water.
2.6. Anticancer properties of complexes 9aec and of the free ligand
The in vitro cytotoxicity of the complexes [(arene)RuCl2NC5H4-
4-COOeC6H4ep-Oe(CH2)10eOH] (arene ¼ C6H6: 9a, arene ¼ p-
MeC6H4Pri: 9b, arene ¼ C6Me6: 9c) and of the corresponding free
isonicotinic ester ligand NC5H4-4-COOeC6H4ep-Oe(CH2)10eOH
was studied towards the A2780 ovarian cancer cell line and
cisplatin-resistant variant A2780cisR using the MTT assay.
Surprisingly, the free ligand NC5H4-4-COOeC6H4ep-Oe(CH2)10e
2.5. Synthesis of the arene ruthenium complexes 9aec
OH is almost inactive (IC50 ¼ 162
for A2780cisR), in contrast to its non-hydroxylated analogue
NC5H4-4-COOeC6H4ep-Oe(CH2)9eCH3 (IC50 ¼ 5 M for A2780 and
IC50 ¼ 11 M for A2780cisR). However, the arene ruthenium
m
M for A2780 and IC50 ¼ 208
mM
The precursors [(C6H6)RuCl2]2, [(p-MeC6H4Pri)RuCl2]2 and
[(C6Me6)RuCl2]2 react in dichloromethane as expected with two
equivalents of the new isonicotinic ester ligand NC5H4-4-COOe
C6H4ep-Oe(CH2)10eOH to give the complexes [(arene)Ru-4-COOe
C6H4ep-Oe(CH2)10eOH] (arene ¼ C6H6: 9a, arene ¼ p-MeC6H4Pri:
9b, arene ¼ C6Me6: 9c) in quantitative yield, see Scheme 3.
The coordination of the ligand to the ruthenium centre can be
concluded from the 1H NMR spectra of the complexes 9aec, in
m
m
complexes containing the hydroxylated C10 ligand are very active,
see Table 2. In particular, the p-cymene ruthenium complex 9b
containing the hydroxylated C10 ligand is, towards the A2780 cell
line, ten times more active than the corresponding p-cymene
ruthenium complex 5 containing the non-hydroxylated C10 ligand;
towards the cisplatin-resistant A2780 cell line, the introduction of
a terminal hydroxyl function into the C10 isonicotinic ester ligand
increases the anticancer activity by a factor of 2.
Table 1
ꢀ
ꢁ
Selected bond lengths (A) and angles ( ) for 1.
ꢁ
Bond lengths (A)
Angles (ꢀ)
3. Conclusions
Ru1eN1
Ru1eC1
Ru1eC2
Ru1eC3
Ru1eC4
Ru1eC5
Ru1eC6
Ru1eCl1
Ru1eCl2
2.142(3)
2.216(4)
2.181(4)
2.144(5)
2.177(4)
2.153(4)
2.188(4)
2.4251(12)
2.3934(11)
Cl1eRu1eN1
Cl2eRu1eN1
Cl1eRu1eCl2
e
e
e
e
e
e
85.53(11)
86.13(9)
88.02(4)
e
e
e
e
e
e
A
systematic series of p-cymene ruthenium dichloro
complexes containing an isonicotinic ester ligand, the carbon
chain length of which varying from 2 to 16 were prepared and
evaluated for anticancer activity towards human ovarian cancer
cells (A2780 and A2780cisR). A striking activity increase was
observed for the complex containing a C10 aliphatic chain. A new
isonicotinic ester was synthesized by introducing a terminal

52
F.-A. Khan et al. / Journal of Organometallic Chemistry 730 (2013) 49e56
Fig. 3. Cytotoxicity values of isonicotinic ester ligands NC5H4-4-COOeC6H4ep-O-(CH2)n-CH3 (n ¼ 1, 3, 5, 7, 9, 11, 13, 1) and correlation of IC50 values and carbon chain length.
hydroxy group at the end of the C10 chain, and the corresponding
p-cymene ruthenium dichloro complex turned indeed out to be
the most active compound. It is too early to say whether these
ruthenium compounds exert their cytotoxic effect via a similar
mechanism to cisplatin or whether different mechanisms are in
operation.
[26], the 4-(alkyloxy)phenyl isonicotinate ligands [27] (except the
new derivative for
7, see below) and [(p-MeC6H4Pri)
RuCl2NC5H4-4-COOeC6H4ep-Oe(CH2)9eCH3] (5) [15] were
n
¼
prepared according to published methods.
4.2. Cytotoxicity tests (MTT assay)
4. Experimental section
The cytotoxicity was determined using the MTT assay (MTT ¼ 3-
(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide).
4.1. General procedures
Cells were seeded in 96-well plates as monolayers with 100 ml of
cell solution (approximately 20,000 cells) per well and pre-
incubated for 24 h in medium supplemented with 10% FCS.
Compounds were added as DMSO solutions and serially diluted to
the appropriate concentration (to give a final DMSO concentration
Solvents were dried using appropriate drying agents and
distilled prior to use. RuCl3 $ n H2O (Johnson-Matthey), 1-
bromoalkanes (Sigma Aldrich), isonicotinoyl chloride hydrochlo-
ride (Sigma Aldrich), 4-benzyloxyphenol (Sigma Aldrich) were used
as received. NMR spectra were recorded on a Bruker DRX 400 MHz
spectrometer at 400.13 (1H) with SiMe4 as internal references and
coupling constants are given in Hz. Infrared spectra were recorded
on PerkineElmer FT-IR spectrometer as KBr pellets. UVeVis studies
were recorded on a UVIKON 930 spectrometer. The compounds
[(C6H6)RuCl2]2 [24], [(p-MeC6H4Pri)RuCl2]2 [25], [(C6Me6)RuCl2]2
of 0.5%). 100 ml of drug solution was added to each well and the
plates were incubated for another 72 h. Subsequently, MTT (5 mg/
ml solution in phosphate buffered saline) 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
+
HBr
OH
Br (CH2)10 OH
HO (CH2)10 OH
- H2O
BzO
+
Br (CH2)10
OH
OH
BzO
HO
N
O
(CH2)10
(CH2)10
- HBr
+ H2
OH
OH
OH
BzO
HO
O
O
(CH2)10
(CH2)10
O
- BzH
N
+
C
O
Cl
C
O
O
O
OH
(CH2)10
- HCl
Scheme 2.

F.-A. Khan et al. / Journal of Organometallic Chemistry 730 (2013) 49e56
53
arene
arene
Cl
Ru
Ru
Cl
N
1/2 Cl
Cl
N
+
Cl
Ru
Cl
O
O
(CH2)10
OH
O
O
(CH2)10
OH
arene
O
O
i
arene
C6H6 p-MeC6H4Pr
C6Me6
9a
9b
9c
Scheme 3.
of surviving cells, was quantified at 540 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.
using 10% Pd/C (0.4 mol eq) in a CH2Cl2/EtOH mixture (9:1). This
mixture was stirred overnight under H2 pressure (4 bar) at room
temperature. Then, Pd/C was removed by filtration, and the
solvents were evaporated under reduced pressure in order to give
a pale-white residue of 4-octyloxyphenol, yield: 2.1 g, 91%. 1H
NMR (400 MHz, CDCl3)
d ppm 6.77 (m, 4H, C6H4), 4.57 (s, 1H, OH),
3.98 (t, 3J ¼ 7 Hz, 2H, OCH2), 1.75 (quin, 3J ¼ 7 Hz, 2H, CH2), 1.44 (m,
2H, CH2), 1.28 (m, 8H, (CH2)4), 0.89 (t, 3J ¼ 7 Hz, 3H, CH3). 4-
Octyloxyphenol (1.26 g, 5.7 mmol) and Et3N (0.8 mL) were dis-
solved in CH2Cl2 (100 mL). Isonicotinoyl chloride hydrochloride
(1.06 g, 5.09 mmol) was then added. The reaction mixture was
stirred overnight at room temperature. The precipitate was filtered
off and discarded, and the solution was evaporated to dryness
under reduced pressure. The yellow residue obtained was recrys-
tallized several times from ethanol to give a white product, viz. 4-
(octyloxy)phenyl isonicotinate, yield: 1.04 g, 56%. (Found: C, 73.26;
H, 7.68; N, 4.31. Calc. for C20H25NO3 (M ¼ 327.42): C, 73.37; H, 7.70;
4.3. Crystal structure determination of compound 1
Single crystal X-ray data for 1 were collected at 173 K (ꢁ100 ꢀC)
on a Stoe Mark II-Image Plate Diffraction System equipped with
a two-circle goniometer and using MoK
a
graphite monochromated
ꢁ
radiation (
l
¼ 0.71073 A). The structure was solved by direct
methods using the program SHELXS-97 [28]. The refinement and
all further calculations were carried out using SHELXL-97 [28]. The
C-bound H-atoms were included in calculated positions and treated
as riding atoms. The non-H atoms were refined anisotropically,
using weighted full-matrix least-squares on F2. Crystallographic
details are summarized in Table 3. Fig. 1 was drawn with ORTEP
[29]. CCDC 853079 (1) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via ww.ccdc.cam.ac.
uk/data_request/cif.
N, 4.28%). IR (KBr, cmꢁ1): 3476(m), 2933(s,
CH2), 1738(s,
C ¼ O), 1596(w), 1563(w), 1514(s,
1296(m), 1254(m, OCH2), 1207(m), 1103(m), 1050(m), 877(m),
821(m), 753(m), 701(m, NC5H4), 553(w), 456(w). UVevis:
n
CH2CH3), 2856(m,
CNpy), 1410(m),
n
n
n
n
n
(2.30
ꢂ
10ꢁ5 M, CH2Cl2, 298 K): lmax 419 nm
(
3
¼ 1094 Mꢁ1 cmꢁ1), lmax 277 nm (
3
¼ 6660 Mꢁ1 cmꢁ1), lmax
229 nm (
3
¼ 8557 Mꢁ1 cmꢁ1
) d ppm
1H NMR (400 MHz, CDCl3)
4.4. Synthesis of the isonicotinic ester NC5H4-4-COOeC6H4ep-Oe
(CH2)7eCH3
8.87 (d, 3J ¼ 6 Hz, 2H, NC5H4), 8.01 (d, 3J ¼ 6 Hz, 2H, NC5H4), 7.13
4-Benzyloxyphenol (3 g, 15 mmol) and aqueous potassium
hydroxide (0.84 g, 15 mmol in 30 mL water) were stirred in
ethanol (125 mL). Then octyl bromide (15 mmol) was added
dropwise, and the mixture was refluxed overnight. The following
day, water and ethanol were removed under reduced pressure.
Dichloromethane (100 mL) was added to the residue, the insoluble
potassium bromide was filtered off and discarded. The filtrate was
purified by flash chromatography using dichloromethane as
mobile phase. The solvent was then removed by evaporation
under reduced pressure in order to get a brown residue of 1-
(benzyloxy)-4-(octyloxy)benzene, yield: 3.2 g, 68%. 1H NMR
Table 3
Crystallographic and structure refinement parameters for complex 1.
Chemical formula
Formula weight
Crystal system
C24H27Cl2NO3Ru
549.44
Monoclinic
P21/c
Orange block
0.18 ꢂ 0.15 ꢂ 0.13
14.3079(9)
8.4712(4)
19.3588(9)
99.463(4)
2314.5(2)
4
Space group
Crystal colour and shape
Crystal size (mm)
ꢁ
a (A)
ꢁ
b (A)
ꢁ
c (A)
(ꢀ)
(400 MHz, CDCl3)
d
ppm 7.48e7.35 (m, 5H, C6H5), 6.91 (d, 3J ¼ 9 Hz,
b
3
ꢁ
V (A )
Z
2H, C6H4), 6.84 (d, 3J ¼ 9 Hz, 2H, C6H4), 5.01 (s, 2H, CCH2), 3.91 (t,
3J ¼ 7 Hz, 2H, OCH2), 1.75 (quin, 3J ¼ 7 Hz, 2H, CH2), 1.45 (m, 2H,
CH2), 1.28 (m, 8H, (CH2)4), 0.89 (t, 3J ¼ 7 Hz, 3H, CH3). 1-(Benzy-
loxy)-4-(octyloxy)benzene (3.2 g, 10.2 mmol) was deprotected
T (K)
173(2)
1.577
0.934
Dc (g cmꢁ3
)
m
(mmꢁ1
)
Scan range (ꢀ)
1.44 <
4107
q < 25.11
Unique reflections
Observed refls [I > 2
Rint
Final R indices [I > 2
R indices (all data)
Goodness-of-fit
s
(I)]
2909
0.1062
R1 0.0489, wR2 0.0563
R1 0.0877, wR2 0.0620
0.978
0.566, ꢁ0.699
Table 2
s
(I)]a
Cytotoxicity values of the arene ruthenium complexes 9aec.
Complex
A2780 IC50
[m
M]
A2780cisR IC50 [mM]
ꢁꢁ3
9a
9b
9c
0.60 ꢃ 0.24
0.18 ꢃ 0.07
3.00 ꢃ 1.23
3.56 ꢃ 1.43
3.04 ꢃ 1.12
9.57 ꢃ 2.14
Max., min. Dr (e A
)
a
Structures were refined on F20: R1 ¼ SrrFor ꢁ rFcrr/SrFor, wR2 ¼ [S [w (F02 ꢁ F2c)2]/
Sw (F20)2]1/2, where wꢁ1 ¼ [S(F02) þ (aP)2 þ bP] and P ¼ [max(F02, 0) þ 2F2c]/3.

54
F.-A. Khan et al. / Journal of Organometallic Chemistry 730 (2013) 49e56
(d, 3J ¼ 9 Hz, 2H, C6H4), 6.95 (d, 3J ¼ 9 Hz, 2H, C6H4), 3.98 (t,
3J ¼ 7 Hz, 2H, OCH2), 1.83 (quin, 3J ¼ 7 Hz, 2H, CH2), 1.46e1.30 (m,
10H, (CH2)5), 0.91 (t, 3J ¼ 7 Hz, 3H, CH3) ppm. 113C{1H} NMR
NCH), 143.7 (1C, CeO), 137.3 (1C, Cpy), 123.4 (2C, CHpy), 122.0 (2C,
CH), 115.1 (2C, CH), 68.4 (1C, OCH2), 63.0 (1C, CH2OH), 32.7e25.7
(8C, (CH2)8) ppm. MS (ESI) m/z: 372.4 [M þ H]þ.
(100 MHz, CDCl3):
d 164.1 (1C, C]O), 157.2 (1C, CeO), 150.8 (2C,
NCH), 143.7 (1C, CeO), 136.9 (1C, Cpy), 123.0 (2C, CHpy), 122.0 (2C,
CH), 115.1 (2C, CH), 68.4 (1C, OCH2), 31.8e22.6 (6C, (CH2)6), 14.1
(1C, CH3) ppm. MS (ESI) m/z: 327 [M þ H]þ.
4.6. Synthesis of the arene ruthenium dichloro isonicotinic ester
complexes
A mixture of the appropriate [(arene)RuCl2]2 and 2 equivalents
of the isonicotinic ester ligand in CH2Cl2 solution (25 mL) was
stirred for 3 h at room temperature. The solvent was then removed
under reduced pressure, and the residue was re-dissolved in EtOH
(30 mL). The solution was filtered and then evaporated to dryness,
and the final product was collected and dried in vacuo.
4.5. Synthesis of the isonicotinic ester NC5H4-4-COOeC6H4ep-Oe
(CH2)10eOH
10-Bromodecanol was synthesized by reported procedures [23].
A typical procedure for the synthesis of 10-bromodecanol is as
follows: 1,10-decandiol (25 g, 0.14 mol) and 48% HBr solution
(125 mL, 2.2 mol) in 380 mL ligroin were distilled in a liquideliquid
extractor. After 3 days, the organic layer was separated. The solvent
was then removed by evaporation under reduced pressure in order
to get a dark brown oily residue of 10-bromodecanol, yield: 22.9 g,
4.6.1. [(p-MeC6H4Pri)RuCl2NC5H4-4-COOeC6H4ep-OeCH2eCH3] (1)
Yield: 0.0816 g, >99%. (Found: C, 52.59; H, 5.08; N, 2.54. Calc. for
C
24H27NO3Cl2Ru (M ¼ 549.46): C, 52.46; H, 4.95; N, 2.55%). IR (KBr,
cmꢁ1): 3481(s), 2935(m,
CH2CH3), 2868(w, CH2), 2363(w), 1748(s,
C ¼ O), 1613(m), 1589(w), 1507(s, CNpy), 1417(m), 1273(m), 1190(s,
n
n
67.1%. 1H NMR (400 MHz, CDCl3)
d
ppm 3.64 (t, 3J ¼ 4 Hz, 2H, CH2Br),
n
n
n
3.41 (t, 3J ¼ 4 Hz, 2H, CH2OH), 1.88 (quin, 3J ¼ 8 Hz, 2H, CH2), 1.59
(quin, 3J ¼ 8 Hz, 2H, CH2), 1.52e1.29 (m, 12H, (CH2)6). A mixture of
4-benzyloxyphenol (5.0 g, 21 mmol), potassium carbonate (5.6 g,
41 mmol) and 18-crown-6 ether (0.2 g, 0.7 mmol) was stirred in dry
acetone (125 mL) for 30 min at room temperature. Then, 1-
bromodecanol (2.8 g, 14 mmol) in acetone (25) was added drop-
wise. This mixture was refluxed under inert atmosphere. After four
days, the solution was filtered to eliminate potassium carbonate,
and the solvent was removed by evaporation under reduced pres-
sure. The product was further purified by CH2Cl2/H2O extraction,
followed by recrystallization in isopropanol, which affords a light
brown product, viz. 10-(4-(benzyloxy)phenoxy)decanol, yield:
OCH2), 1100(s), 1089(s), 878(m), 826(m), 768(m), 696(w, nNC5H4),
607(w), 483(w). UVevis: (1.0 ꢂ 10ꢁ5 M, CH2Cl2, 298 K): lmax
337 nm (
lmax 229 nm (
d
3
¼ 5552 Mꢁ1 cmꢁ1), lmax 277 nm (
3
¼ 10,259 Mꢁ1 cmꢁ1),
3
¼ 21,320 Mꢁ1 cmꢁ1). 1H NMR (400 MHz, CDCl3)
ppm 9.32 (d, 3J ¼ 5 Hz, 2H, NC5H4), 7.99 (d, 3J ¼ 5 Hz, 2H, NC5H4),
7.12 (d, 3J ¼ 8 Hz, 2H, C6H4), 6.95 (d, 3J ¼ 8 Hz, 2H, C6H4), 5.48 (d,
3J ¼ 6 Hz, 2H, RuC6H4), 5.26 (d, 3J ¼ 6 Hz, 2H, RuC6H4), 4.05 (q,
3J ¼ 6 Hz, 2H, OCH2), 3.01 (sept, 3J ¼ 7 Hz, 1H, CH), 2.12 (s, 3H, CH3),
1.42 (t, 3J ¼ 7 Hz, 3H, CH3), 1.32 (d, 3J ¼ 7 Hz, 6H, (CH3)2). 13C{1H}
NMR (100 MHz, CDCl3):
d 162.9 (1C, C]O), 157.2 (1C, CeO), 156.0
(2C, NCH), 143.6 (1C, CeO), 138.3 (1C, Cpy), 123.8 (2C, CHpy), 122.0
(2C, CH), 115.3 (2C, CH), 103.9 (1C, Carene), 97.5(1C, Carene), 83.2(2C,
CHarene), 82.4(2C, CHarene), 63.9 (1C, OCH2), 30.8 (1C, CH(CH3)2),
22.3 (2C, (CH3)2) 18.3(1C, CH3),14.8 (1C, CH3) ppm.
4.46 g, 88.9%. 1H NMR (400 MHz, CDCl3)
d ppm 7.43e7.31 (m, 5H,
C6H5), 6.91 (d, 3J ¼ 9 Hz, 2H, C6H4), 6.84 (d, 3J ¼ 9 Hz, 2H, C6H4), 5.01
(s, 2H, C6H5CH2O), 3.91 (t, 3J ¼ 6 Hz, 2H, OCH2), 3.66 (m, 2H,
CH2OH), 1.78 (quin, 3J ¼ 7 Hz, 2H, CH2), 1.60 (quin, 3J ¼ 7 Hz, 2H,
CH2), 1.44e1.31 (m, 12H, (CH2)6). 10-(4-(Benzyloxy)phenoxy)dec-
anol (0.21 g, 0.6 mmol) was deprotected using 10% Pd/C (0.4 mol eq)
in a CH2Cl2/EtOH mixture (9:1). This mixture was stirred overnight
under H2 pressure (4 bar) at room temperature. Then, Pd/C was
removed by filtration, and the solvents were evaporated under
reduced pressure in order to give the white residue of 4-(10-
hydroxydecyloxy)phenol, yield: 0.15 g, 95.4%. 1H NMR (400 MHz,
4.6.2. [(p-MeC6H4Pri)RuCl2NC5H4-4-COOeC6H4ep-Oe(CH2)3eCH3]
(2)
Yield: 0.0908 g, >99%. (Found: C, 53.79; H, 5.50; N, 2.41. Calc. for
C
26H31NO3Cl2Ru (M ¼ 577.51): C, 54.07; H, 5.41; N, 2.43. IR (KBr,
cmꢁ1): 3480(s), 2935(s,
CH2CH3), 2867(m, CH2), 2366(w),
1748(s, CNpy), 1488(m), 1406(m),
C ¼ O), 1611(m), 1592(w), 1505(s,
1251(m), 1194(s,
n
n
n
n
n
OCH2), 1100(s), 1094(s), 878(m), 826(s), 691(w,
n
NC5H4), 607(w), 487(w). UVevis: (1.1 ꢂ10ꢁ5 M, CH2Cl2, 298 K): lmax
CDCl3)
d
ppm 6.77 (m, 4H, C6H4), 4.48 (s, 1H, OH), 3.91 (t, 3J ¼ 6, 2H,
337 nm (
3
¼ 4740 Mꢁ1 cmꢁ1), lmax 278 nm (
3
¼ 7900 Mꢁ1 cmꢁ1),
OCH2), 3.67 (m, 2H, CH2OH), 1.76 (quin, 3J ¼ 6 Hz, 2H, CH2), 1.58 (m,
2H, CH2), 1.48e1.21 (m, 12H, (CH2)6). 4-(10-Hydroxyde)phenol
(0.15 g, 0.6 mmol) and Et3N (0.08 mL) were dissolved in CHCl3
(20 mL). Isonicotinoyl chloride hydrochloride (0.1 g, 0.6 mmol) was
then added. The reaction mixture was stirred overnight at room
temperature. The yellow precipitate was filtered off and discarded,
and the solution was evaporated to dryness. The yellow residue
obtained was recrystallized several times from ethanol to give
a white product, viz. 4-(10-hydroxydecyloxy)phenyl isonicotinate,
yield: 1.04 g, 61.4%. (Found: C, 71.05; H, 7.95; N, 3.78. Calc. for
lmax 229 nm (
d
3
¼ 18,544 Mꢁ1 cmꢁ1). 1H NMR (400 MHz, CDCl3)
ppm 9.32 (d, 3J ¼ 5 Hz, 2H, NC5H4), 7.99 (d, 3J ¼ 5 Hz, 2H, NC5H4),
7.12 (d, 3J ¼ 8 Hz, 2H, C6H4), 6.95 (d, 3J ¼ 8 Hz, 2H, C6H4), 5.48
(d, 3J ¼ 6 Hz, 2H, RuC6H4), 5.26 (d, 3J ¼ 6 Hz, 2H, RuC6H4), 3.97
(t, 3J ¼ 6 Hz, 2H, OCH2), 3.01 (sept, 3J ¼ 7 Hz,1H, CH), 2.13 (s, 3H, CH3),
1.81 (quin, 3J ¼ 6 Hz, 2H, CH2),1.49 (m, 2H, CH2),1.34 (d, 3J ¼ 7 Hz, 6H,
(CH3)2), 1.00 (t, 3J ¼ 7 Hz, 3H, CH3). 13C{1H} NMR (100 MHz, CDCl3):
d
162.9 (1C, C]O), 157.4 (1C, CeO), 156.0 (2C, NCH), 143.5 (1C, CeO),
138.4 (1C, Cpy), 123.8 (2C, CHpy), 122.0 (2C, CH), 115.3 (2C, CH), 103.9
(1C, Carene), 97.5(1C, Carene), 83.2(2C, CHarene), 82.4(2C, CHarene), 68.2
(1C, OCH2), 31.3 (1C, CH(CH3)2), 30.7 (1C, CH2), 22.3 (2C, (CH3)2), 19.2
(1C, CH2), 18.3 (1C, CH3), 14.8 (1C, CH3) ppm.
C
22H29NO4 (M ¼ 371.48): C, 71.13; H, 7.87; N, 3.77%). IR (KBr, cmꢁ1):
3471(m), 2934(s,
nCH2CH3), 2856(m, nCH2), 2346(w), 1738(s,
n
C ¼ O), 1611(w), 1564(w), 1514(s,
nCNpy), 1410(m), 1295(m),
OCH2), 1207(m), 1103(m), 1052(m), 877(m), 824(m),
1255(m,
754(m), 701(m,
CH2Cl2, 298 K): lmax 277 nm (
(
n
4.6.3. [(p-MeC6H4Pri)RuCl2NC5H4-4-COOeC6H4ep-Oe(CH2)5eCH3]
(3)
n
NC5H4), 607(w), 483(w).UVevis: (1.5 ꢂ 10ꢁ5 M,
3
¼ 7386 Mꢁ1 cmꢁ1), lmax 229 nm
Yield: 0.0964 g, >99%. (Found: C, 55.75; H, 5.85; N, 2.34. Calc. for
3
¼ 8395 Mꢁ1 cmꢁ1). 1H NMR (400 MHz, CDCl3)
d
ppm 8.86 (s, 2H,
C
28H35NO3Cl2Ru (M ¼ 605.56): C, 55.54; H, 5.83; N, 2.31%). IR (KBr,
cmꢁ1): 3489(m), 2937(s,
CH2CH3), 2867(m, CH2), 2373(w), 1748(s,
CNpy),1488(m),1417(m),1251(m),
NC5H4), 8.03 (d, 3J ¼ 5 Hz, 2H, NC5H4), 7.13 (d, 3J ¼ 9 Hz, 2H, C6H4),
6.95 (d, 3J ¼ 9 Hz, 2H, C6H4), 3.98 (t, 3J ¼ 7 Hz, 2H, OCH2), 3.66 (t,
3J ¼ 7 Hz, 2H, CH2OH), 1.83 (quin, 3J ¼ 7 Hz, 2H, CH2), 1.9 (quin,
3J ¼ 7 Hz, 2H, CH2), 1.46e1.30 (m, 12H, (CH2)6). 13C{1H} NMR
n
n
n
C ¼ O),1611(m),1592(w),1505(s,
n
1190(s, nOCH2), 1099(s), 1089(s), 878(m), 826(s), 691(w, nNC5H4),
607(w), 486(w). UVevis: (0.7 ꢂ 10ꢁ5 M, CH2Cl2, 298 K): lmax 337 nm
(100 MHz, CDCl3):
d
163.9 (1C, C]O), 157.2 (1C, CeO), 150.3 (2C,
(
3
¼ 7176 Mꢁ1 cmꢁ1), lmax 278 nm (
3
¼ 11,960 Mꢁ1 cmꢁ1), lmax

F.-A. Khan et al. / Journal of Organometallic Chemistry 730 (2013) 49e56
55
229 nm (
3
¼ 28,073 Mꢁ1 cmꢁ1). 1H NMR (400 MHz, CDCl3)
d
ppm 9.31
1405(m), 1251(m), 1192(s,
n
OCH2), 1097(s), 1087(s), 877(m), 826(s),
(d, 3J ¼ 5 Hz, 2H, NC5H4), 7.99 (d, 3J ¼ 5 Hz, 2H, NC5H4), 7.12 (d,
3J ¼ 8 Hz, 2H, C6H4), 6.95 (d, 3J ¼ 8 Hz, 2H, C6H4), 5.48 (d, 3J ¼ 6 Hz, 2H,
RuC6H4), 5.26 (d, 3J ¼ 6 Hz, 2H, RuC6H4), 3.96 (t, 3J ¼ 6 Hz, 2H, OCH2),
3.01 (sept, 3J ¼ 7 Hz,1H, CH), 2.12(s, 3H, CH3),1.79 (quint, 3J ¼ 6 Hz, 2H,
CH2), 1.47 (m, 2H, CH2), 1.34e1.29 (m, 10H, (CH3)2 and (CH2)2), 0.92
795(w), 691(w,
n
NC5H4), 607(w), 483(w). UVevis: (0.7 ꢂ 10ꢁ5 M,
CH2Cl2, 298 K): lmax 337 nm (
3
¼ 5098 Mꢁ1 cmꢁ1), lmax 277 nm
(
3
¼ 9253 Mꢁ1 cmꢁ1), lmax 229 nm (
3
¼ 19,935 Mꢁ1 cmꢁ1). 1H NMR
(400 MHz, CDCl3)
d
ppm 9.32 (d, 3J ¼ 5 Hz, 2H, NC5H4), 7.99 (d,
3J ¼ 5 Hz, 2H, NC5H4), 7.12 (d, 3J ¼ 8 Hz, 2H, C6H4), 6.95 (d, 3J ¼ 8 Hz,
2H, C6H4), 5.48 (d, 3J ¼ 5 Hz, 2H, RuC6H4), 5.26 (d, 3J ¼ 5 Hz, 2H,
RuC6H4), 3.96 (t, 3J ¼ 6 Hz, 2H, OCH2), 3.01 (sept, 3J ¼ 7 Hz, 1H, CH),
2.13 (s, 3H, CH3), 1.79 (quin, 3J ¼ 6 Hz, 2H, CH2), 1.46 (m, 2H, CH2),
1.34e1.26 (m, 26H, (CH3)2 and (CH2)10), 0.88 (t, 3J ¼ 7 Hz, 3H, CH3).
(t, 3J ¼ 7 Hz, 3H, CH3).13C{1H} NMR (100 MHz, CDCl3):
d 162.9 (1C, C]
O), 157.4 (1C, CeO), 156.0 (2C, NCH), 143.5 (1C, CeO), 138.4 (1C, Cpy),
123.8 (2C, CHpy), 122.0 (2C, CH), 115.3 (2C, CH), 103.9 (1C, Carene),
97.5(1C, Carene), 83.2(2C, CHarene), 82.4(2C, CHarene), 68.5 (1C, OCH2),
31.6 (1C, CH(CH3)2), 30.7e22.6 (4C, (CH2)4), 22.3 (2C, (CH3)2),18.3 (1C,
CH3), 14.1 (1C, CH3) ppm.
13C{1} NMR (100 MHz, CDCl3):
d 162.9 (1C, C]O), 157.4 (1C, CeO),
156.0 (2C, NCH), 143.5 (1C, CeO), 138.4 (1C, Cpy), 123.8 (2C, CHpy),
122.0 (2C, CH), 115.3 (2C, CH), 103.9 (1C, Carene), 97.5(1C, Carene),
83.2(2C, CHarene), 82.4(2C, CHarene), 68.5 (1C, OCH2), 31.8 (1C,
CH(CH3)2), 30.7e22.7 (12C, (CH2)12), 22.3 (2C, (CH3)2), 18.3 (1C,
CH3), 14.2 (1C, CH3) ppm.
4.6.4. [(p-MeC6H4Pri)RuCl2NC5H4-4-COOeC6H4ep-Oe(CH2)7eCH3]
(4)
Yield: 0.1052 g, >99%. (Found: C, 57.08; H, 6.23; N, 2.23. Calc. for
C
30H39NO3Cl2Ru (M ¼ 633.62): C, 56.87; H, 6.20; N, 2.21%). IR (KBr,
cmꢁ1): 3477(s), 2933(s,
CH2CH3), 2865(m, CH2), 2367(w), 1748(s,
CNpy), 1456(m), 1405(m),
n
n
4.6.7. [(p-MeC6H4Pri)RuCl2NC5H4-4-COOeC6H4ep-Oe(CH2)15eCH3]
(8)
n
C ¼ O), 1613(m), 1589(w), 1496(s,
n
1251(m), 1192(s,
nOCH2), 1099(s), 1086(s), 878(m), 826(s), 691(w,
Yield: 0.1219 g, >99%. (Found: C, 61.33; H, 7.34; N, 1.89. Calc. for
n
NC5H4), 607(w), 488(w). UVevis: (0.8 ꢂ 10ꢁ5 M, CH2Cl2, 298 K):
C
38H55NO3Cl2Ru (M ¼ 745.83): C, 61.20; H, 7.43; N, 1.88%). IR (KBr,
cmꢁ1): 3481(m), 2926(s,
CH2CH3), 2856(m, CH2), 2361(w), 1749(s,
C ¼ O), 1612(m), 1587(w), 1506(s, CNpy), 1417(m), 1251(m), 1191(s,
lmax 337 nm (
3
¼ 3747 Mꢁ1 cmꢁ1), lmax 278 nm (
3
¼ 6673 Mꢁ1 cmꢁ1),
n
n
lmax 229 nm (
d
3
¼ 16,052 Mꢁ1 cmꢁ1). 1H NMR (400 MHz, CDCl3)
n
n
n
ppm 9.31 (d, 3J ¼ 5 Hz, 2H, NC5H4), 7.98 (d, 3J ¼ 5 Hz, 2H, NC5H4),
OCH2), 1097(m), 1087(m), 877(m), 826(m), 766(w), 691(w, nNC5H4),
7.12 (d, 3J ¼ 8 Hz, 2H, C6H4), 6.94 (d, 3J ¼ 8 Hz, 2H, C6H4), 5.49 (d,
3J ¼ 6 Hz, 2H, RuC6H4), 5.26 (d, 3J ¼ 6 Hz, 2H, RuC6H4), 3.95 (t,
3J ¼ 6 Hz, 2H, OCH2), 3.01 (sept, 3J ¼ 7 Hz, 1H, CH), 2.12 (s, 3H, CH3),
1.80 (quin, 3J ¼ 6 Hz, 2H, CH2), 1.47 (m, 2H, CH2), 1.32e1.26 (m, 14H,
(CH3)2 and (CH2)4), 0.91 (t, 3J ¼ 7 Hz, 3H, CH3). 13C{1H} NMR
607(w), 472(w). UVevis: (0.8 ꢂ 10ꢁ5 M, CH2Cl2, 298 K): lmax 337 nm
(
(
3
¼ 4118 Mꢁ1 cmꢁ1), lmax 277 nm (
3
¼ 7569 Mꢁ1 cmꢁ1), lmax 229 nm
3
¼ 17,483 Mꢁ1 cmꢁ1). 1H NMR (400 MHz, CDCl3)
d ppm 9.32 (d,
3J ¼ 5 Hz, 2H, NC5H4), 7.99 (d, 3J ¼ 5 Hz, 2H, NC5H4), 7.12 (d, 3J ¼ 8 Hz,
2H, C6H4), 6.95 (d, 3J ¼ 8 Hz, 2H, C6H4), 5.48 (d, 3J ¼ 6 Hz, 2H,
RuC6H4), 5.26 (d, 3J ¼ 6 Hz, 2H, RuC6H4), 3.96 (t, 3J ¼ 6 Hz, 2H, OCH2),
3.01 (sept, 3J ¼ 7 Hz, 1H, CH), 2.13 (s, 3H, CH3), 1.79 (qint, 3J ¼ 6 Hz,
2H, CH2), 1.46 (m, 2H, CH2), 1.34e1.26 (m, 30H, (CH3)2 and (CH2)12),
(100 MHz, CDCl3):
d 162.9 (1C, C]O), 157.4 (1C, CeO), 156.0 (2C,
NCH), 143.5 (1C, CeO), 138.4 (1C, Cpy), 123.8 (2C, CHpy), 122.0 (2C,
CH), 115.3 (2C, CH), 103.9 (1C, Carene), 97.5(1C, Carene), 83.2(2C,
CHarene), 82.4(2C, CHarene), 68.5 (1C, OCH2), 31.8 (1C, CH(CH3)2),
30.7e22.7 (6C, (CH2)6), 22.3 (2C, (CH3)2), 18.3 (1C, CH3), 14.1 (1C,
CH3) ppm.
0.88 (t, 3J ¼ 7 Hz, 3H, CH3). 13C{1H} NMR (100 MHz, CDCl3):
d 162.9
(1C, C]O), 157.4 (1C, CeO), 156.0 (2C, NCH), 143.5 (1C, CeO), 138.4
(1C, Cpy), 123.8 (2C, CHpy), 122.0 (2C, CH), 115.3 (2C, CH), 103.9 (1C,
C
arene), 97.5(1C, Carene), 83.2(2C, CHarene), 82.4(2C, CHarene), 68.5 (1C,
4.6.5. [(p-MeC6H4Pri)RuCl2NC5H4-4-COOeC6H4ep-Oe(CH2)11eCH3]
OCH2), 31.8 (1C, CH(CH3)2), 30.7e22.7 (14C, (CH2)14), 22.3 (2C,
(6)
(CH3)2), 18.3 (1C, CH3), 14.2 (1C, CH3) ppm.
Yield: 0.1087 g, >99%. (Found: C, 59.27; H, 6.81; N, 2.04. Calc. for
C
34H47NO3Cl2Ru (M ¼ 689.73): C, 59.21; H, 6.87; N, 2.03%). IR (KBr,
cmꢁ1): 3485(s), 2927(s,
CH2CH3), 2862(m, CH2), 2362(w),
1749(m, CNpy), 1454(m),
C ¼ O), 1611(m), 1591(w), 1496(s,
1405(m), 1251(m), 1192(s,
4.6.8. [(C6H6)RuCl2NC5H4-4-COOeC6H4ep-Oe(CH2)10eOH] (9a)
Yield: 0.2536 g, >99%. (Found: C, 52.70; H, 5.62; N, 2.25. Calc. for
n
n
n
n
C
28H35NO4Cl2Ru , 0.25 CH2Cl2 (M ¼ 642.09): C, 52.79; H, 5.57; N,
2.18%). IR (KBr, cmꢁ1): 3471(s), 2931(s,
CH2CH3), 2862(m, CH2),
2361(w), 1743(m, CNpy),
C ¼ O), 1613(m), 1583(w), 1496(s,
1405(m), 1253(m), 1192(s,
n
OCH2), 1099(s), 1088(s), 878(m), 826(s),
n
n
691(w,
298 K): lmax 337 nm (
(
n
NC5H4), 607(w), 485(w). UVevis: (0.7 ꢂ 10ꢁ5 M, CH2Cl2,
n
n
3
¼ 6535 Mꢁ1 cmꢁ1), lmax 277 nm
nOCH2), 1096(s), 1053(s), 877(m), 825(s),
3
¼ 13,238 Mꢁ1 cmꢁ1), lmax 229 nm (
3
¼ 25,689 Mꢁ1 cmꢁ1). 1H
691(w,
n
NC5H4), 607(w), 486(w). UVevis: (0.8 ꢂ 10ꢁ5 M, CH2Cl2,
NMR (400 MHz, CDCl3)
d
ppm 9.31 (d, 3J ¼ 5 Hz, 2H, NC5H4), 7.99 (d,
298 K): lmax 328 nm (
3
¼ 4937 Mꢁ1 cmꢁ1), lmax 277 nm
3J ¼ 5 Hz, 2H, NC5H4), 7.12 (d, 3J ¼ 8 Hz, 2H, C6H4), 6.95 (d, 3J ¼ 8 Hz,
2H, C6H4), 5.48 (d, 3J ¼ 6 Hz, 2H, RuC6H4), 5.26 (d, 3J ¼ 6 Hz, 2H,
RuC6H4), 3.96 (t, 3J ¼ 6 Hz, 2H, OCH2), 3.01 (sept, 3J ¼ 7 Hz, 1H, CH),
(
3
¼ 6502 Mꢁ1 cmꢁ1), lmax 229 nm (
3
¼ 19,597 Mꢁ1 cmꢁ1). 1H NMR
(400 MHz, CD2Cl2)
d
ppm 9.38 (d, 3J ¼ 7 Hz, 2H, NC5H4), 8.01 (d,
3J ¼ 7 Hz, 2H, NC5H4), 7.13 (d, 3J ¼ 9 Hz, 2H, C6H4), 6.95 (d, 3J ¼ 9 Hz,
2H, C6H4), 5.71 (s, 6H, C6H6), 3.98 (t, 3J ¼ 7 Hz, 2H, OCH2), 3.67 (dt,
3J ¼ 6 Hz, 3J ¼ 7 Hz, 2H, CH2OH), 1.79 (quin, 3J ¼ 7 Hz, 2H, CH2), 1.58
(m, 2H, CH2), 1.46e1.33 (m, 12H, (CH2)6), 1.20 (t, 3J ¼ 6 Hz, 1H, OH).
3
2.13 (s, 3H, CH3), 1.79 (quin, J ¼ 6 Hz, 2H, CH2), 1.46 (m, 2H, CH2),
1.33e1.26 (m, 22H, (CH3)2 and (CH2)8), 0.88 (t, 3J ¼ 7 Hz, 3H, CH3).
13C{1H} NMR (100 MHz, CDCl3):
d 162.9 (1C, C]O), 157.4 (1C, CeO),
156.0 (2C, NCH), 143.5 (1C, CeO), 138.4 (1C, Cpy), 123.8 (2C, CHpy),
122.0 (2C, CH), 115.3 (2C, CH), 103.9 (1C, Carene), 97.5(1C, Carene),
83.2(2C, CHarene), 82.4(2C, CHarene), 68.5 (1C, OCH2), 31.8 (1C,
CH(CH3)2), 30.7e22.7 (10C, (CH2)10), 22.3 (2C, (CH3)2), 18.3 (1C,
CH3), 14.2 (1C, CH3) ppm.
13C{1H} NMR (100 MHz, CDCl3):
d 162.8 (1C, C]O), 157.5 (1C, CeO),
156.4 (2C, NCH), 143.5 (1C, CeO), 128.4 (1C, Cpy), 124.2 (2C, CHpy),
122.0 (2C, CH), 115.3 (2C, CH), 85.0 (6C, C6H6), 68.5 (1C, OCH2), 63.1
(1C, CH2OH), 32.8e25.8 (8C, (CH2)8) ppm.
4.6.9. [(p-MeC6H4Pri)RuCl2NC5H4-4-COOeC6H4ep-Oe(CH2)10eOH]
(9b)
4.6.6. [(p-MeC6H4Pri)RuCl2NC5H4-4-COOeC6H4ep-Oe(CH2)13eCH3]
(7)
Yield: 0.2219 g, >99%. (Found: C, 56.13; H, 6.29; N, 2.08. Calc. for
Yield: 0.1237 g, >99%. (Found: C, 60.30; H, 7.08; N, 1.98. Calc. for
C
32H43NO4Cl2Ru , 0.1 CH2Cl2 (M ¼ 685.56): C, 56.19; H, 6.35; N,
2.04%). IR (KBr, cmꢁ1): 3474(s), 2930(s,
CH2CH3), 2862(m, CH2),
2367(w),1747(s, CNpy),1454(m),
C ¼ O),1612(m),1589(w),1496(s,
1404(m), 1251(m), 1192(s, OCH2), 1100(s), 1054(s), 877(m), 825(s),
C
36H51NO3Cl2Ru (M ¼ 717.78): C, 60.24; H, 7.16; N, 1.95%). IR (KBr,
cmꢁ1): 3476(m), 2927(s,
CH2CH3), 2858(m, CH2), 2359(w),
1749(m, CNpy), 1456(m),
C ¼ O), 1612(m), 1589(w), 1505(s,
n
n
n
n
n
n
n
n
n

56
F.-A. Khan et al. / Journal of Organometallic Chemistry 730 (2013) 49e56
691(w,
n
NC5H4), 608(w), 484(w). UVevis: (0.6 ꢂ 10ꢁ5 M, CH2Cl2,
References
298 K): lmax 329 nm (
3
¼ 5530 Mꢁ1 cmꢁ1), lmax 277 nm
¼ 9914 Mꢁ1 cmꢁ1), lmax 229 nm (
3
¼ 24,297 Mꢁ1 cmꢁ1). 1H NMR
[1] (a) G. Süss-Fink, Dalton Trans. 39 (2010) 1673;
(
3
(b) A.M. Pizarro, A. Habtemariam, P.J. Sadler, Top. Organomet. Chem. 32 (2010)
21.
[2] P.J. Dyson, Chimia 61 (2007) 698.
[3] S.J. Dougan, P.J. Sadler, Chimia 61 (2007) 704.
[4] L.D. Dale, J.H. Tocher, T.M. Dyson, D.I. Edwards, D.A. Tocher, Anti-cancer Drug
Des. 7 (1992) 3.
[5] C.S. Allardyce, P.J. Dyson, D.J. Ellis, S.L. Heath, Chem. Commun. (2001) 1396.
[6] R.E. Morris, R.E. Aird, P.d.S. Murdoch, H. Chen, J. Cummings, N.D. Hughes,
S. Pearsons, A. Parkin, G. Boyd, D.I. Jodrell, P.J. Sadler, J. Med. Chem. 44 (2001)
3616.
[7] P. Govender, B. Therrien, G.S. Smith, Eur. J. Inorg. Chem. (2012) 2853.
[8] (a) F. Giannini, G. Süss-Fink, J. Furrer, Inorg. Chem. 50 (2011) 10552;
(b) M. Gras, B. Therrien, G. Süss-Fink, O. Zava, P.J. Dyson, Dalton Trans. 39
(2010) 10305.
(400 MHz, CDCl3)
d
ppm 9.32 (d, 3J ¼ 6 Hz, 2H, NC5H4), 8.00 (d,
3J ¼ 6 Hz, 2H, NC5H4), 7.13 (d, 3J ¼ 9 Hz, 2H, C6H4), 6.95 (d, 3J ¼ 9 Hz,
2H, C6H4), 5.49 (d, 3J ¼ 6 Hz, 2H, RuC6H4), 5.26 (d,3J ¼ 6 Hz, 2H,
RuC6H4), 3.98 (t, 3J ¼ 6 Hz, 2H, OCH2), 3.66 (dt, 3J ¼ 6 Hz, 3J ¼ 7 Hz, 2H,
CH2OH), 3.02 (sept, 3J ¼ 7 Hz, 1H, CH), 2.13 (s, 3H, CH3), 1.79 (quin,
3J ¼ 6 Hz, 2H, CH2), 1.60 (m, 2H, CH2), 1.48e1.28 (m, 18H, (CH3)2 and
(CH2)6), 1.21 (t, 3J ¼ 6 Hz, 1H, OH). 13C{1H} NMR (100 MHz, CDCl3):
d
162.9 (1C, C]O), 157.4 (1C, CeO), 156.1 (2C, NCH), 143.5 (1C, CeO),
138.3 (1C, Cpy), 123.9 (2C, CHpy), 122.0 (2C, CH), 115.3 (2C, CH), 103.8
(1C, Carene), 97.6(1C, Carene), 83.3(2C, CHarene), 82.6(2C, CHarene), 85.0
(6C, C6H6), 68.5 (1C, OCH2), 63.1 (1C, CH2OH), 32.8e25.8 (8C, (CH2)8),
30.8 (1C, CH(CH3)2), 22.4 (2C, (CH3)2), 18.4 (1C, CH3) ppm.
[9] G.V. Tsarichenko, V.I. Bobrov, M.V. Smarkov, Pharm. Chem. J. 11 (1977) 481.
[10] M.C.S. Lourenço, M.V.N. Souza, A.C. Pinheiro, M.L. Ferreira, R.S.B. Gonçalves,
T.C.M. Nogueira, M.A. Peraltab, ARKIVOC 15 (2007) 181.
[11] K.-G. Liu, X.-Q. Cai, X.-C. Li, D.-A. Qin, M.-L. Hu, Inorg. Chim. Acta 338 (2012) 78.
[12] R. Schobert, S. Seibt, K. Effenberger-Neidnicht, C. Underhill, B. Biersack,
G.L. Hammond, Steroids 76 (2011) 393.
4.6.10. [(C6Me6)RuCl2NC5H4-4-COOeC6H4ep-Oe(CH2)10eOH] (9c)
Yield: 0.2136 g, >99%. (Found: C, 57.16; H, 6.70; N, 2.02. Calc. for
ꢀ
ꢂ
ꢂ
ꢀ ꢂ
ꢂ
ꢂ
ꢂ
[13] S.G. Sipka, I. Ivanovic, G. Rakic, N. Todorovic, N. Gligorijevic, S. Radulovic,
C
34H47NO4Cl2Ru , 0.1 CH2Cl2 (M ¼ 714.21): C, 57.35; H, 6.66; N,1.96%).
IR (KBr, cmꢁ1): 3481(s), 2929(s,
CH2CH3), 2861(m, CH2), 2356(w),
1746(s, CNpy), 1454(m), 1404(m),
C ¼ O), 1611(m), 1587(w), 1496(s,
1278(m), 1250(m), 1188(s,
ꢀ
V.B. Arion, B.K. Keppler, Z.L. Tesic, Eur. J. Med. Chem. 45 (2010) 1051.
[14] J.G. Ma1ecki, R. Kruszynski, M. Jaworska, P. Lodowski, Z. Mazurak,
J. Organomet. Chem. 693 (2008) 1096.
[15] G. Süss-Fink, F.-A. Khan, L.J. Jeanneret, P.J. Dyson, A.K. Renfrew, J. Cluster Sci.
21 (2010) 313.
[16] M. Auzias, B. Therrien, G. Süss-Fink, P. Stepnicka, W.H. Ang, P.J. Dyson, Inorg.
Chem. 47 (2008) 578.
[17] A.K. Renfrew, L. Juillerat-Jeanneret, P.J. Dyson, J. Organomet. Chem. 696 (2011)
772.
n
n
n
n
n
OCH2), 1090(s), 1053(s), 877(m), 825(s),
689(w,
n
NC5H4), 607(w), 482(w). UVevis: (1.0 ꢂ 10ꢁ5 M, CH2Cl2,
ꢀ
ꢀ
ꢀ
298 K): lmax 329 nm (
3
¼ 2318 Mꢁ1 cmꢁ1), lmax 277 nm
(
3
¼ 5422 Mꢁ1 cmꢁ1), lmax 229 nm (
3
¼ 14,890 Mꢁ1 cmꢁ1). 1H NMR
(400 MHz, CDCl3)
d
ppm 9.10 (d, 3J ¼ 6 Hz, 2H, NC5H4), 7.97 (d,
[18] A.K. Renfrew, R. Scopelliti, P.J. Dyson, Inorg. Chem. 49 (2010) 2239.
[19] C.A. Vock, C. Scolaro, A.D. Phillips, R. Scopelliti, G. Sava, P.J. Dyson, J. Med.
Chem. 49 (2006) 5552.
3J ¼ 6 Hz, 2H, NC5H4), 7.13 (d, 3J ¼ 9 Hz, 2H, C6H4), 6.95(d, 3J ¼ 9 Hz, 2H,
C6H4), 3.98 (t, 3J ¼ 6 Hz, 2H, OCH2), 3.66 (dt, 3J ¼ 5 Hz, 3J ¼ 6 Hz, 2H,
CH2OH), 2.02 (s,18H, C6(CH3)6),1.79 (quin, 3J ¼ 6 Hz, 2H, CH2),1.59 (m,
2H, CH2),1.47e1.26 (m, 12H, (CH2)6),1.22 (t, 3J ¼ 5 Hz,1H, OH).13C{1H}
[20] (a) D.J. Goldschmith, E. Kennedy, R.G. Campbello, J. Org. Chem. 40 (1995) 3571;
(b) S.K. Kang, W.S. Kim, B.H. Moon, Synthesis 12 (1985) 1161;
(c) A. Ravikrishnan, P. Sudhakara, P. Kannan, J. Mater. Sci. 45 (2010) 435;
(d) J.M. Chong, M.A. Heuft, P. Rabbat, J. Org. Chem. 65 (2000) 5837.
[21] Y. Fu, Y. Li, J. Li, S. Yan, Z. Bo, Macromolecules 37 (2004) 6395.
[22] T.W. Green, P.G.M. Wuts, Protective Groups in Organic Synthesis, Wiley-
Interscience, New York, 1999, pp. 76e86 and pp. 708e711.
[23] K.I. Nättinen, K. Rissanen, Cryst. Growth Des. 3 (2003) 339.
[24] T. Arthur, T.A. Stephenson, J. Organomet. Chem. 208 (1981) 369.
[25] M.A. Bennett, G.B. Robertson, A.K. Smith, J. Organomet. Chem. 43 (1972) C41.
[26] M.A. Bennett, T.W. Matheson, G.B. Robertson, A.K. Smith, P.A. Tucker, Inorg.
Chem. 10 (1980) 1014.
NMR (100 MHz, CDCl3): d 163.0 (1C, C]O),157.3 (1C, CeO),155.7 (2C,
NCH),143.2 (1C, CeO),137.6 (1C, Cpy),123.6 (2C, CHpy),121.9 (2C, CH),
115.2 (2C, CH), 91.6 (6C, (C6), 68.4 (1C, OCH2), 63.0 (1C, CH2OH), 32.8e
25.7 (8C, (CH2)8), 15.4 (6C, (CH3)6) ppm.
Acknowledgements
[27] (a) M. Marcos, M.B. Ros, J.L. Serrano, M.A. Esteruelas, E. Sola, L.A. Oro,
J. Barberà, Chem. Mater. 2 (1990) 748;
(b) M. Auzias, G. Süss-Fink, P. Stĕpnicka, J. Ludvik, Inorg. Chim. Acta 360
(2007) 2023.
[28] G.M. Sheldrick, Acta Crystallogr. A64 (2008) 112.
Financial support of this work from the Swiss National Science
Foundation (grant no 200021-115821) is gratefully acknowledged.
We also thank the Johnson Matthey Research Centre for a generous
loan of ruthenium(III) chloride hydrate.
[29] L.J. Farrugia, J. Appl. Crystallogr. 30 (1997) 565.