New Ru(II)-DMSO complexes of ON/SN chelates: Synthesis, behavior of Schiff bases towards hydrolytic cleavage of CN bond, electrochemistry and biological activities

Article abstract of DOI:10.1016/j.poly.2010.09.019

The reaction of cis-[RuCl₂(DMSO)₄] with salicylaldehyde semicarbazone in ethanol resulted in the chemoselective cleavage of the CN bond of the Schiff base, forming a complex in which the semicarbazide remains coordinated to the metal, as observed previously with trans-[RuCl ₂(DMSO)₄]. In another set of reactions of cis-[RuCl ₂(DMSO)₄] with 4-aminoantipyrine derivatives of salicylaldehyde, 2-hydroxy-1-naphthaldehyde and o-vanillin, CN cleavage was observed in all three cases yielding the same compound, [RuCl ₂(DMSO)₂(4-aminoantipyrine)]. However, when the reactions, under the same experimental conditions, were extended to unsubstituted/N- substituted thiosemicarbazones of salicylaldehyde and 2-hydroxy-1- naphthaldehyde, no cleavage was observed. All the new complexes were characterized by analytical and spectroscopic techniques. The structures of two of the complexes, [RuCl₂(DMSO)₂(semicarbazide)] ·2H₂O and [RuCl₂(DMSO)₂(4- aminoantipyrine)], were determined by single crystal XRD and are in support of the cleavage. The electrochemistry of the complexes was studied by cyclic voltammetry. Further, the preliminary DNA-binding ability and antibacterial activity of the complexes were studied.

Full text of DOI:10.1016/j.poly.2010.09.019

Polyhedron 29 (2010) 3363–3371
Contents lists available at ScienceDirect
Polyhedron
journal homepage: www.elsevier.com/locate/poly
New Ru(II)–DMSO complexes of ON/SN chelates: Synthesis, behavior of Schiff
bases towards hydrolytic cleavage of C@N bond, electrochemistry and biological
activities
Viswanathan Mahalingam a, Nataraj Chitrapriya a, Frank R. Fronczek b, Karuppannan Natarajan a,
⇑
a Department of Chemistry, Bharathiyar University, Coimbatore 641 046, India
b Department of Chemistry, Louisiana State University, Baton Rouge, LA 70803, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 9 June 2010
Accepted 16 September 2010
Available online 29 September 2010
The reaction of cis-[RuCl2(DMSO)4] with salicylaldehyde semicarbazone in ethanol resulted in the chemo-
selective cleavage of the C@N bond of the Schiff base, forming a complex in which the semicarbazide
remains coordinated to the metal, as observed previously with trans-[RuCl2(DMSO)4]. In another set of
reactions of cis-[RuCl2(DMSO)4] with 4-aminoantipyrine derivatives of salicylaldehyde, 2-hydroxy-1-
naphthaldehyde and o-vanillin, C@N cleavage was observed in all three cases yielding the same com-
pound, [RuCl2(DMSO)2(4-aminoantipyrine)]. However, when the reactions, under the same experimental
conditions, were extended to unsubstituted/N-substituted thiosemicarbazones of salicylaldehyde and 2-
hydroxy-1-naphthaldehyde, no cleavage was observed. All the new complexes were characterized by
analytical and spectroscopic techniques. The structures of two of the complexes, [RuCl2(DMSO)2(semi-
carbazide)]Á2H2O and [RuCl2(DMSO)2(4-aminoantipyrine)], were determined by single crystal XRD and
are in support of the cleavage. The electrochemistry of the complexes was studied by cyclic voltammetry.
Further, the preliminary DNA-binding ability and antibacterial activity of the complexes were studied.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Ru(II)–DMSO complexes
Thiosemicarbazones
C@N cleavage
Cyclic voltammetry
DNA-binding
1. Introduction
cytotoxicity of NAMI-A was significantly related only to DNA bind-
ing and not to intracellular ruthenium accumulation [5]. Similarly,
Metal complexes of ruthenium have been subjected to a num-
ber of studies concerning their chemical behavior and their poten-
tial role in medical applications. Particular emphasis has been
given to the examination of the antineoplastic properties of ruthe-
nium complexes with a number of ligands of biological interest [1].
Dimethylsulfoxide-coordinated ruthenium complexes have shown
high affinity for nitrogen donor ligands in vitro and as a result ex-
hibit various degrees of biological activities, including antitumor
action in vivo [2]. The Ru(III)–DMSO compound, [ImH][trans-
Cl4(Me2SO)(Im)Ru] (Im = imidazole, NAMI-A), is the first ruthe-
nium compound that successfully entered phase I clinical trials
and is scheduled to begin phase II clinical trials [3,4]. In the
in vitro studies in four human cancer cell lines, NAMI-A has shown
lower cytotoxicity than that of cisplatin, which can partly be
explained by its reduced reactivity to DNA in intact cells. The
the Ru(II)–DMSO complexes cis- and trans-[RuCl2(DMSO)4] have
shown anticancer activity [6,7] in several tumor models and are
the most widely used starting materials for the synthesis of other
ruthenium complexes [8–10]. Various ligand systems, such as het-
erocycles [11–14], semicarbazones [15,16], thiosemicarbazones
[17], hydrazones [18], carboxylic acids [19] and acid hydrazides
[20], have been reacted with these potential starting materials to
get new Ru(II)–DMSO complexes targeting various biological activ-
ities. Nevertheless, 4-amino antipyrine or its derivatives, known
for their diverse pharmaceutical activity [21,22] such as antibacte-
rial, antipyretic, analgesic and histaminic activities, have not been
reacted with Ru–DMSO complexes to-date, although a number of
other transition metal complexes of these ligands with Cu(II),
Ni(II), Co(II), Zn(II) and Mn(II) have long been studied since 1940
[23]. Similarly, thiosemicarbazones, a well known class of com-
pounds endowed with rich biological activities [24–27], have been
studied with Ru–DMSO complexes only to a lesser extent.
Abbreviations: TBAP, tetra butyl ammonium perchlorate; Tris, tris-(hydroxy-
methyl) aminomethane; UV–Vis, Ultraviolet–Visible; cfu, colony forming units;
NCIM, National Centre for Industrial Microorganisms; MTCC, Microbial Type
Culture Collection; NCCLS, National Committee for Clinical Laboratory Standards.
During the course of our detailed exploration of reactions of cis-
[RuCl2(DMSO)4] with various ligands, at one point we observed
ruthenium mediated hydrolytic cleavage of the C@N bond in a sal-
icylaldehyde semicarbazone ligand, resulting in the formation of
[RuCl2(DMSO)2(semicarbazide)]Á2H2O, as observed earlier with
⇑
Corresponding author. Tel.: +91 4222428311; fax: +91 4222422387.
E-mail address: k_natraj6@yahoo.com (K. Natarajan).
0277-5387/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.poly.2010.09.019

3364
V. Mahalingam et al. / Polyhedron 29 (2010) 3363–3371
OH
N
N
O
H
C
N
N
H
NH2
N
O
Salicylaldehyde semicarbazone (ssc)
HO
Salicylaldehyde 4-aminoantipyrine (saap)
OH
S
N
N
H
N
H
N
Salicylaldehyde 4-phenylthiosemicarbazone (sptsc)
H
C
N
N
O
OH
S
HO
2-Hydroxy-1-naphthlaldehyde 4-aminoantipyrine (hnaap)
N
N
H
NH2
2-Hydroxy-1-naphthlaldehyde thiosemicarbazone (hntsc)
N
O
H
C
N
OH
S
N
N
N
H
NH
HO
OCH3
o-Vanillin 4-aminoantipyrine (ovaap)
2-Hydroxy-1-naphthlaldehyde 4-phenylthiosemicarbazone (hnptsc)
Chart 1. Structural drawings of various Schiff base ligands with their abbreviations.
trans-[RuCl2(DMSO)4] [16]. Later, again we observed hydrolytic
cleavage of the C@N bond in tetradentate Schiff bases derived from
diamines (o-phenylene diamine, ethylene diamine) and o-hydroxy
aldehydes (salicylaldehyde, 2-hydroxy-1-naphthaldehyde) with
cis-[RuCl2(DMSO)4], yielding complexes of the type [RuCl2(DM-
SO)2(diamine)] [28]. The results were interpreted on the basis of
reference [16] and a significant role of the structural o-hydroxy
motive in the reaction was suggested. With this background infor-
mation and experience, we selected three thiosemicarbazones of
salicylaldehyde/2-hydroxy-1-naphthaldehyde and three o-hydro-
xy Schiff base derivatives of 4-aminoantipyrine as ligand systems
to react with cis-[RuCl2(DMSO)4]. Thus, in the present paper we de-
scribe the behavior of o-hydroxy Schiff bases towards hydrolytic
cleavage, the synthesis of new Ru(II)–DMSO complexes, their char-
acterization, electrochemistry and biological activities, such as
DNA-binding and antibacterial activity. The structural drawings
of the ligands used in the study are presented in Chart 1.
[29]. The DNA concentration per nucleotide was determined by
absorption spectroscopy using the molar absorption coefficient
(6600 MÀ1 cmÀ1) at 260 nm [30]. Distilled dimethyl sulfoxide
was used in absorption titrations and to record the electronic spec-
tra of the complexes. Commercially available TBAP was properly
dried and used as an electrolyte for recording the cyclic voltammo-
grams of the ligands and the complexes. The starting complex cis-
[RuCl2(DMSO)4] was prepared according to the method reported
by Evans et al. [8], and the ligands were prepared by following lit-
erature procedures [22,27].
2.2. Physical measurements
Infrared spectra were recorded on a Nicolet Avatar Model FT-IR
spectrophotometer, while UV–Vis spectra were measured on a Sys-
tronics 119 UV–Vis spectrophotometer. 1H NMR spectra were ac-
quired on a Varian-Australia AMX-400 instrument. Microanalyses
were carried out on a Vario EL III Elementar elemental analyzer.
Cyclic voltammograms were obtained using a CHI 1120A Electro-
chemical analyzer. A three-electrode system was employed with
a Pt disc working electrode, a Pt wire counter electrode and an
Ag/Ag+ reference electrode.
2. Experimental
2.1. Reagents and materials
Analytical grade dimethyl sulfoxide and distilled ethanol were
used for synthetic purposes. Commercial RuCl3Á3H2O (Himedia)
was used without further purification. Protein free Herring sperm
ds DNA obtained from SRL chemicals was stored at 0–4 °C. All
the spectroscopic DNA titrations were carried out in Tris–HCl buf-
fer (5 mM Tris–HCl, 50 mM NaCl, pH 7.1) at room temperature. A
solution of herring sperm DNA (0.1 g) in Tris–HCl buffer (10 ml)
gave a ratio of UV absorbance at 260 and 280 nm of ca. 1.7–
1.8:1, indicating that the DNA was sufficiently free of protein
2.3. Syntheses
2.3.1. [RuCl2(DMSO)2(semicarbazide)]Á2H2O(1)
2.3.1.1. Method 1. cis-[RuCl2(DMSO)4] (0.1 g, 0.21 mmol) and the li-
gand salicylaldehyde semicarbazone (ssc) (0.038 g, 0.21 mmol)
were taken in ethanol (30 mL) and heated under reflux for 4 h.
The solution turned orange-red from yellow. The contents were re-
duced to half of the volume and kept for slow evaporation at room

V. Mahalingam et al. / Polyhedron 29 (2010) 3363–3371
3365
temperature. X-ray quality orange-yellow crystals separated after
24 h. Yield: 34 mg; 37%. Elemental analysis: Anal. Calc. for C5H21
Cl2N3O5RuS2 (439.34): C, 13.67; H, 4.82; N, 9.36; S, 14.80. Found:
C, 13.22; H, 4.36; N, 9.61; S, 14.33%. IR (KBr, cmÀ1):
(NH2)(asy+sym)
3420(w); (NH), 3186(w); (C@O), 1653(s); (S@O)s-bonded, 1071(s)
(asy, asymmetric; sym, symmetric; s, strong; w, weak). UV/Vis
(DMSO) k, nm (
, molÀ1 cmÀ1 L): 309 (8640), 398 (6750). 1H NMR
reflux for 5 h. The resulting solution was reduced to half its volume
and kept for slow evaporation at room temperature. X-ray quality
orange-yellow crystals separated after 48 h. Yield: 69–74 mg; 62–
-
m
,
66%. Elemental analysis: Anal. Calc. for
(531.48): C, 33.90; H, 4.74; N, 7.91; S, 12.07. Found: C, 33.49; H,
4.25; N, 7.83; S, 12.50%. IR (KBr, cmÀ1):
(NH2)(asy+sym), 3246(w);
(C@O)(cyclic keto group), 1582(s); (S@O)s-bonded, 1085(s). UV/
Vis (DMSO) k, nm (
C15H25Cl2N3O3RuS2
m
m
m
m
e
m
m
(DMSO-d6, d ppm): 3.14–3.33 (group of peaks, DMSO, 12H), 6.69
(s, O@C–NH2, 2H), 6.79 (s, –NH2–, 2H), 8.52 (s, –NH, 1H).
e
, molÀ1 cmÀ1 L): 327 (6320), 341 (6650), 386
(9310). 1H NMR (DMSO-d6, d ppm): 3.12–3.35 (group of peaks,
DMSO, 12H), 2H), 7.20–7.64 (multiplet, aromatic protons, 5H), 5.4
(s, –NH2–, 2H), 2.4 (s, N–CH3, 1H), 2.1 (s, C–CH3, 1H).
2.3.1.2. Method 2. Complex 1 could also be obtained by the reaction
of cis-[RuCl2(DMSO)4] (0.1 g, 0.21 mmol) and semicarbazide hydro-
chloride (0.023 g, 0.21 mmol) under same experimental condi-
tions. Analytical, spectroscopic and structural data correspond to
those reported for the complex isolated by Method 1.
2.3.5.2. Method 2. Complex 5 could also be obtained by the direct
reaction of cis-[RuCl2(DMSO)4] (0.1 g, 0.21 mmol) with 4-aminoan-
tipyrine (0.043 g, 0.21 mmol) under same experimental conditions.
Analytical, spectroscopic and structural data correspond to those
reported for the complex isolated by Method 1.
2.3.2. [RuCl2(DMSO)2(sptsc)](2)
cis-[RuCl2(DMSO)4] (0.1 g, 0.21 mmol) and the ligand salicylal-
dehyde 4-phenylthiosemicarbazone (sptsc) (0.057 g, 0.21 mmol)
were taken in ethanol (30 mL) and heated under reflux for 5 h.
The resulting solution was reduced to half of the volume. After
24 h, the complex precipitated as a dark brown solid, which was
washed with diethyl ether and dried under vacuum. Yield: 82 mg;
2.4. Crystallographic structure determination
X-ray diffraction measurements were performed on a Nonius
MACH3 (for 1)/Nonius Kappa CCD (with Oxford Cryostream) dif-
fractometer (for 5) with graphite monochromatized Mo Ka radia-
65%. Elemental analysis: Anal. Calc. for
(599.58): C, 36.06; H, 4.20; N, 7.01; S, 16.04. Found: C, 36.38; H,
4.01; N, 7.47; S, 15.82%. IR (KBr, cmÀ1):
(OH), 3400(w); (NH),
3256(w); (C@N), 1598(s); (S@O)s-bonded, 1086(s); (C@S), 750(s).
UV/Vis (DMSO) k, nm (
C
18H25Cl2N3O3RuS3
tion. The structure of 5 was solved by direct methods and
refinements were carried out by full-matrix least-square tech-
niques. The hydrogen atoms were treated by a mixture of indepen-
dent and constrained refinement. The following computer
programs were used: structure solution SIR-97 [31], refinement
SHELXL-97 [32], molecular diagrams, ORTEP-3 [33] for windows.
m
m
m
m
m
e
, molÀ1 cmÀ1 L): 314 (12280), 355 (9080).
1H NMR (DMSO-d6, d ppm): 3.31–3.43 (group of peaks, DMSO,
12H), 6.10–7.88 (multiplet, aromatic protons), 8.05 (s, –CH@N,
1H), 10.03 (s, –NH, 1H), 10.14 (s, Ph–NH, 1H), 10.27 (s, –OH, 1H).
2.5. Anti-microbial screening
2.3.3. [RuCl2(DMSO)2(hntsc)](3)
The bacterial strains, Escherichia coli NCIM 2831, Staphylococcus
aureus NCIM 2492, Staphylococcus epidermidis NCIM 2493,
Klebsiella pneumoniae NCIM 5082 and Shigella sonnei MTCC 2957
were used in the study. The agar-well diffusion method [34] was
employed for the determination of anti-microbial activities. MICs
(minimum inhibitory concentration) of the compounds against test
organisms were determined by the broth micro dilution method.
All the tests were performed in duplicate and repeated twice.
Modal values were selected.
The complex was prepared as described in Section 2.3.1 by the
reaction of cis-[RuCl2(DMSO)4] (0.1 g, 0.21 mmol) and the ligand 2-
hydroxy-1-naphthaldehyde thiosemicarbazone (hntsc) (0.052 g,
0.21 mmol). Yield: 76 mg; 63%. Elemental analysis: Anal. Calc. for
C
16H23Cl2N3O3RuS3 (573.54): C, 33.51; H, 4.04; N, 7.33; S, 16.77.
Found: C, 33.82; H, 4.42; N, 7.06; S, 16.52%. IR (KBr, cmÀ1):
m
m
(OH), 3409(w);
(C@N), 1608(s);
m
(NH2)(asy+sym)
(S@O)s-bonded, 1087(s);
e
, molÀ1 cmÀ1 L): 332 (9960), 407 (7160). 1H NMR
,
3461(w);
m(NH), 3248(w);
m
m
(C@S), 748(s). UV/Vis
(DMSO) k, nm (
(DMSO-d6, d ppm): 3.36–3.42 (group of peaks, DMSO, 12H),
7.00–8.15 (multiplet, aromatic protons), 8.90 (s, –CH@N, 1H), 9.5
(s, –NH, 1H), 10.8 (s, NH2, 1H), 11.98 (s, –OH, 1H).
2.5.1. Agar-well diffusion method
Compounds were weighed and dissolved in dimethyl sulfoxide
(DMSO). The compounds were filter sterilized using a 0.45 lm
membrane filter. Each microorganism was suspended in sterile sal-
ine and diluted at ca. 106 colony forming units (cfu/ml). They were
flood inoculated onto the surface of Mueller–Hinton Agar (MHA).
The wells (8 mm in diameter) were cut from the agar and 0.1 mL
of solution was delivered into them. After incubation for 24 h at
37 °C, all the plates were examined for any zones of growth inhibi-
tion, and the diameter of these zones were measured in
millimeters.
2.3.4. [RuCl2(DMSO)2(hnptsc)](4)
The complex was prepared as described in Section 2.3.1 by the
reaction of cis-[RuCl2(DMSO)4] (0.1 g, 0.21 mmol) and the ligand 2-
hydroxy-1-naphthaldehyde 4-phenylthiosemicarbazone (hnptsc)
(0.067 g, 0.21 mmol). Yield: 93 mg; 68%. Elemental analysis: Anal.
Calc. for C22H27Cl2N3O3RuS3 (649.64): C, 40.67; H, 4.19; N, 6.47;
S, 14.81. Found: C, 41.11; H, 4.32; N, 6.25; S, 14.39%. IR (KBr,
cmÀ1):
(C@N), 1602(s);
m
(OH), 3385(w);
m
(NH), 3088(w);
m(S@O)s-bonded, 1091(s);
m
m(C@S), 747(s). UV/Vis (DMSO) k, nm
(e,
2.5.2. Determination of minimum inhibitory concentration (MIC)
A micro dilution broth susceptibility assay was used as recom-
mended [35] by NCCLS for determination of the MIC. All the tests
were performed in Mueller–Hinton Broth (MHB) supplemented
with Tween 80 detergent (final concentration of 0.5% (v/v)). Bacte-
rial stains were cultured overnight at 37 °C in MHA. Test strains
were suspended in MHB to give a final density of 5 Â 105 cfu/ml
and these were confirmed by viable counts. Geometric dilutions
of the compounds were prepared in a 96-well microtiter plate,
including one growth control (MHB + Tween 80) and one sterility
control (MHB + Tween 80 + compound). The plates were incubated
under normal atmospheric conditions at 37 °C for 24 h. The MICs of
molÀ1 cmÀ1 L): 337 (10920), 419 (7400). 1H NMR (DMSO-d6, d
ppm): 3.28–3.40 (group of peaks, DMSO, 12H), 6.8–7.9 (multiplet,
aromatic protons), 8.4 (s, –CH@N, 1H), 10.1 (s, Ph–NH, 1H), 10.8 (s,
–NH, 1H), 12.0 (s, –OH, 1H).
2.3.5. [RuCl2(DMSO)2(4-aminoantipyrine)](5)
2.3.5.1. Method 1. cis-[RuCl2(DMSO)4] (0.1 g, 0.21 mmol) and the
ligand salicylaldehyde 4-aminoantipyrine (saap) (0.065 g, 0.21
mmol)/2-hydroxy-1-naphthaldehyde 4-aminoantipyrine (hnaap)
(0.075 g, 0.21 mmol)/o-vanillin 4-aminoantipyrine (ovaap) (0.071
g, 0.21 mmol) were taken in ethanol (30 mL) and heated under

3366
V. Mahalingam et al. / Polyhedron 29 (2010) 3363–3371
Kanamycin and Oxytetracycline were individually determined in
parallel experiments in order to control the sensitivity of the test
organisms. The bacterial growth was indicated by the presence of
a white ‘‘pellet” on the well bottom.
behind salicylaldehyde is the key factor that made us undertake
this study with two more varieties of o-hydroxy Schiff bases de-
rived from unsubstituted/N-substituted thiosemicarbazides and
from 4-aminoantipyrine. Although the main thrust of this paper
is the synthesis of new Ru(II)-DMSO complexes, we have also made
an attempt to study the cleavage phenomenon to support our
observations that the o-hydroxy Schiff bases of thiosemicarbazides
did not undergo any cleavage and coordinate to the metal as neu-
tral bidentate ligands through the azomethine nitrogen and thio-
carbonyl sulfur atoms, with an intact OH group, whereas all the
o-hydroxy Schiff bases of 4-amino antipyrine, under same experi-
mental conditions, underwent hydrolytic cleavage and yielded
the same complex [RuCl2(DMSO)2(4-aminoantipyrine)]. This could
be explained based on the works of Vieites et al. [16], who sug-
gested the possible enolimine and ketoamine tautomerism in the
o-hydroxy Schiff bases theoretically and Sosa et al. [36] who stud-
ied the equilibrium and factors affecting such tautomerism spec-
troscopically. It is presumed from their studies that if the
experimental conditions favor the ketoamine tautomeric form,
then the Schiff base, after coordinating to the metal center, will
be more susceptible to nucleophilic attack by water and may un-
dergo hydrolytic cleavage across the C@N bond leading to the coor-
dination of the NH2 nitrogen to the metal, liberating the parent
aldehyde. On the other hand, when the enolimine form becomes
predominant, then the ligand will not undergo any cleavage. The
actual cause of stabilizing one of the tautomeric forms under given
experimental conditions has not been clearly understood, though
the ability of hydrogen bond formation, nature of the substituents
3. Results and discussion
3.1. Synthesis and hydrolytic cleavage
All the reactions were carried out in ethanol (Scheme 1) in order
to study the stability of the coordinated Schiff base ligands towards
hydrolytic cleavage. Although the complex [RuCl2(DMSO)2(semi-
carbazide)]Á2H2O has already been reported by Vieites et al. [16]
starting with trans-[RuCl2(DMSO)4], we could get the same com-
plex by employing
a simple procedure starting from cis-
[RuCl2(DMSO)4], which can be prepared easily. A similar simple
synthetic procedure followed for other complexes yielded a crys-
talline product only in the case of 5, and crystalline products of
the thiosemicarbazone complexes 2, 3 and 4 were not successfully
isolated, though these latter products were analytically pure com-
plexes. Also, the crystallization of complexes 2, 3 and 4 by different
techniques was unproductive. All of the complexes were stable to
air and light and soluble in organic solvents such as DMSO and
DMF. The microanalytical data of the complexes conform to the
proposed molecular formula (data given in Section 2.3).
Serendipitous observation of metal center mediated water as-
sisted cleavage of C = N of salicylaldehyde semicarbazone and sub-
sequent coordination of the semicarbazide to ruthenium leaving
OSMe2
NH2
Cl
SOMe2
Cl
Ru
Cl
O C
Me2OS
Me2OS
Ethanol
OH
Ru
+
NH
Reflux 4 h
O
C
N
C N
H
SOMe2
SOMe2
Cl
H2
N
H
NH2
R'
NH
OSMe2
Cl
Ru
Cl
S C
Me2OS
Me2OS
Cl
SOMe2
Ethanol
S
R C N
H
H
NH
N
C
Reflux 4-6 h
+
Ru
N
C
N R'
H
SOMe2
SOMe2
H
Cl
R
R = o-C6H4OH; R' = C6H5, R = o-C10H6OH; R' = H, R = o-C6H4OH; R' = C6H5.
OSMe2
SOMe2
H3C
Cl
Cl
Ru
Cl
CH3
N
N
Me2OS
Me2OS
O
CH3
N
Ethanol
N
+
Ru
Reflux 4-6 h
N
CH
N
CH3
SOMe2
SOMe2
O
H2
Cl
R
OH
OH
OH
,
OCH3
=
R
,
Scheme 1. Reactions of various o-hydroxy Schiff bases with cis-[RuCl2(DMSO)4].

V. Mahalingam et al. / Polyhedron 29 (2010) 3363–3371
3367
in the amine part, temperature, pH and nature of the solvent have
been taken into account [36,37–42]. Thus, we opine that the thio-
semicarbazone ligands used in this study tend to be in the enoli-
mine form and hence are stable towards hydrolytic cleavage
under the experimental conditions and this is supported by litera-
ture evidence [43] that longer reaction times of ca. 20 h are re-
quired to hydrolyze coordinated acetonethiosemicarbazone to
give acetone and coordinated thiosemicarbazide.
SO)3(DMSO)] by the ligands, which is in accord with our earlier
works [17,18,20].
The electronic spectra of the complexes were studied in
DMSO. The absorption maximum and molar extinction coeffi-
cients are given in Section 2. All the complexes present two or
three bands between 419 and 309 nm which can be fairly as-
signed to dp(Ru) ? p*(L) MLCT transitions in accordance with
previous observations made for similar octahedral Ru(II)–DMSO
The ligands ssc, saap, hnaap and ovaap did not yield the respec-
tive aldehydes upon refluxing them in the same solvent (ethanol)
for 4 h without the metal complex cis-[RuCl2(DMSO)4], which
shows that the cleavage is metal mediated. The mechanism for
the hydrolytic cleavage proposed by Vieites et al. [16] is thought
to be suitable for the present cases and hence is not discussed
further.
complexes[11,44,45].
3.3. 1H NMR spectra
The 1H NMR spectra of the complexes were recorded after dis-
solution in [D6]-DMSO with TMS as the internal standard. The nat-
ure and the position of the signals were typical for diamagnetic
Ru(II) complexes. Careful analysis of the 1H NMR spectra evinced
a possible mode of coordination of the ligands and provided addi-
tional support regarding the hydrolytic cleavage of C@N of the
coordinated Schiff base ligands. In all of the complexes, the group
of peaks appearing around d 3.12–3.43 ppm is attributable to the
methyl resonances of S-bonded DMSO ligands. Since no peaks
could be observed for any of the complexes at d 2.7 ppm due to
O-bonded DMSO, it can be conceived that the complexes contain
only S-bonded DMSO ligands, as evidenced by the XRD studies of
complexes 1 and 5. The aromatic protons in complexes 2, 3, 4
and 5 were observed as multiplets around d 6.1–7.9 ppm. All the
NH protons in 1–4 appeared in the expected regions. Complex 1
showed two singlets at d 6.79 and 6.69 ppm, assigned to the pro-
tons of NH2 (hydrazinic) and NH2 (amide). The NH2 protons of 5
resonated as a singlet at d 5.4 ppm and the two methyl resonances
(N–CH3 and C–CH3) of the pyrazolinone ring were observed as
singlets at d 2.4 and 2.1 ppm, respectively. When the spectra of free
semicarbazide and 4-aminoantipyrine are compared with that of 1
and 5, a downfield shift is observed for the hydrazinic NH2 signal
3.2. IR and electronic spectra
A comparison of IR spectra of the free ligands with that of the
new Ru(II) complexes is not only essential in assigning the coordi-
nation mode but also helpful in studying the C@N cleavage phe-
nomenon. All the free o-hydroxy Schiff base ligands exhibited the
characteristic m
(OH) peak between 3427 and 3385 cmÀ1, showing
that all the ligands are in the enolimine form in the solid state.
The weak bands appearing at 3256 and 3263 cmÀ1 in the free li-
gands ssc and hntsc respectively can be assigned to combined sym-
metric and asymmetric stretching vibrations of the NH2 group. All
the ligands, except the ones derived from 4-aminoantipyrine, dis-
played m
(NH) peaks around 3250–3090 cmÀ1. The ligand ssc exhib-
ited a sharp peak at 1684 cmÀ1, characteristic of
m(C@O) of a
semicarbazone. A sharp peak at around 1595 cmÀ1 observed in
the IR spectra of 4-aminoantipyrine based ligands is assigned to
m
(C@O) (cyclic keto group) of the pyrazolinone moiety [22]. In all
the ligands, a sharp peak appearing around 1652–1612 cmÀ1 is
unequivocally assigned to (C@N), which is characteristic of Schiff
bases. A medium intensity band around 782–747 cmÀ1 appearing
in the spectra of the thiosemicarbazone ligands is due to (C@S).
(C@O) peak was shifted towards lower
m
Table 1
Crystal data for [RuCl2(DMSO)2(4-aminoantipyrine)] (5).
m
Crystal data
5
In the IR spectra of 1, the
m
wavenumber by 30 cmÀ1. This suggested that one point of attach-
ment to the metal is through the oxygen atom of the C@O group.
The assignment of other point of attachment to the metal would
have been a complete mess unless the complex was characterized
Empirical formula
Formula weight
T (K)
Wavelength (Å)
Crystal color, habit
Crystal dimensions (mm)
Crystal system
Lattice type
Space group
Unit cell dimensions
a (Å)
b (Å)
c (Å)
C
15H25Cl2N3O3RuS2
531.47
100
0.71073
orange, plate fragment
0.20 Â 0.13 Â 0.07
orthorhombic
primitive
by X-ray crystallography, because the m(C@N) peak, characteristic
of a Schiff base, completely disappeared in the IR spectra and there
appeared a weak and broad band at 3240 cmÀ1 assignable to
Pca21
m
(NH2). Thus, with the help of single crystal XRD studies, the other
point of attachment was determined to be the hydrazinic NH2
nitrogen atom. This is the same in the spectrum of complex 5, syn-
thesized by using three different Schiff bases, where also only one
point of attachment through the oxygen atom of the cyclic keto
group could be determined by the observation that the peak due
to this group was shifted to lower wavenumber (1582 cmÀ1) [22]
and the other coordination site was determined to be the aminic
nitrogen atom of 4-aminoantipyrine by XRD studies. The IR spectra
of complexes 2, 3 and 4 were not complicated and all the assign-
ments could be made in a straight forward manner, with the ob-
14.159(3)
10.279(4)
30.007(8)
90
90
90
4367(2)
8
1.617
2.5–26
1.173
2160
13040/4079
2762
a
(°)
b (°)
c
(°)
V (Å3)
Z
Dcalc (mg mÀ3
h Range (°)
)
Absorption coefficient
l
(Mo K
a
) (mmÀ1
)
F (0 0 0)
served negative shift of
implying the coordination of the azomethine nitrogen and thiocar-
bonyl sulfur atoms. Further, the peaks due to (OH) in the spectra
m(C@N) and m
(C@S) by ca. 25–30 cmÀ1
Reflections collected/unique reflections
Reflections [I > 2 (I)]
r
Completeness to hmax
Refinement method
Data/restraints/parameters
93.4%
m
Full-matrix least squares on F2
of 2, 3 and 4 remain practically unaltered, indicating the non-coor-
dination of the phenolic oxygen atom and neutral bidentate nature
of the thiosemicarbazone ligands. All the new complexes displayed
4079/1/355
0.056
0.143
0.068
1.009
R [F2 > 2
wR [F2]
Rint
r
(F2)]
a band around 1091–1071 cmÀ1 characteristic of
m(SO)(S-bonded
Goodness-of-fit on F2
DMSO) that substantiates the replacement of one O-bonded DMSO
and one S-bonded DMSO from the precursor cis-[RuCl2(DM-
Largest peak and hole (e ÅÀ3
)
1.77 and À1.23

3368
V. Mahalingam et al. / Polyhedron 29 (2010) 3363–3371
and amine NH2 signal, confirming the coordination of the nitrogen
atoms of these groups in the respective complexes [20]. Complexes
2, 3 and 4 exhibited a singlet (1H) at around d 8.05–8.90 ppm,
which could be assigned to the azomethine proton, whereas this
characteristic peak (1H singlet) around this region is not observed
for complexes 1 and 5, indicating the stability of the thiosemicar-
bazone Schiff bases towards hydrolytic C@N cleavage. Further,
the presence of singlet (1H) signals due to OH protons in the com-
plexes 2, 3 and 4 around d 10.2–12.0 ppm supports this point and
shows the non-participation of the OH group in coordination.
When the spectra of the free thiosemicarbazone ligands are com-
pared with that of their corresponding complexes 2, 3 and 4, the
signal due to the azomethine proton in the complexes has been
shifted downfield, indicating the coordination of the azomethine
nitrogen to ruthenium [46]. All of the above points are in compli-
ance with the interpretation of the IR spectra, suggesting neutral
bidentate coordination of the ligands to ruthenium, and support
the results of the XRD studies.
3.4. X-ray crystallography of complexes 1 and 5
On solving the structure of 1, we found that it is exactly the
same as that reported earlier. The unit cell dimensions, space
group, geometry and the important bond lengths and bond angles
around ruthenium were not significantly different from the data
for the same compound reported by Vieites et al. [16], who pre-
pared the complex from trans-[RuCl2(DMSO)4], and hence the OR-
TEP diagram and crystal data of 1 are not provided. The details
regarding the data collection and structure refinement of 5 are gi-
ven in Table 1. Relevant geometrical data and hydrogen bonding
geometries are given in Tables 2 and 3, respectively. Fig. 1 shows
the ORTEP diagram of 5.
Table 2
Selected geometrical parameters for 5.
Bond distances (Å)
Bond angles (°)
Single crystals of 5 were obtained directly by the slow evapora-
tion of the solvent in the reaction mixture after refluxing for a suf-
ficient time as orange fragments after 48 h. From the unit cell
dimensions, it is clear that the crystal system is orthorhombic,
belonging to the space group Pca21. The asymmetric unit consists
of two independent complexes with almost similar geometrical
parameters. The ruthenium(II) ion in the complex is hexacoordi-
nated with NOS2Cl2 donor atoms and is slightly distorted from a
regular octahedral geometry. The equatorial plane consists of two
S atoms of the two DMSO ligands in mutual cis positions and the
ON chelate of the 4-aminoantipyrine ligand. The octahedron is
completed by two chloride ligands in the axial plane. The essential
bond distances, Ru–N [Ru1–N1 = 2.189(9); Ru2–N4 = 2.179(9) Å],
Ru–O [Ru1–O1 = 2.188(9); Ru2–O4 = 2.180(9) Å], Ru–Cl [mean va-
lue 2.39 Å] and Ru–S [mean value 2.20 Å] and bond angles Cl–
Ru–Cl [Cl1–Ru1–Cl2 = 169.42(14)°; Cl3–Ru2–Cl4 = 169.72(13)°],
S–Ru–S [S1–Ru1–S2 = 89.58(14)°; S3–Ru2–S4 = 89.90(13)°] and
the bite angle N–Ru–O [N1–Ru1–O1 = 82.3(3)°; N4–Ru2–
O4 = 82.4(3)°] are very close to previously observed values for sim-
ilar Ru(II)–DMSO complexes [16–18,20]. The complex is stabilized
by an intermolecular hydrogen bonding network with the N atom
of the coordinated NH2 group acting as a donor and Cl and S atoms
of an adjacent DMSO molecule acting as the acceptors.
Ru1–N1
Ru1–O1
Ru1–S1
Ru1–S2
Ru1–Cl1
Ru1–Cl2
Ru2–N4
Ru2–O4
Ru2–S3
Ru2–S4
Ru2–Cl3
Ru2–Cl4
S1–O2
2.189(9)
2.188(9)
2.219(4)
2.203(3)
2.399(4)
2.390(5)
2.179(9)
2.180(9)
2.209(4)
2.209(3)
2.400(3)
2.392(5)
1.495(11)
1.494(10)
1.459(10)
1.478(10)
Cl1–Ru1–Cl2
S1–Ru1–S2
N1–Ru1–O1
Cl3–Ru2–Cl4
S3–Ru2–S4
N4–Ru2–O4
C12–S1–C13
C14–S2–C15
C27–S3–C28
C29–S4–C30
C12–S1–O2
C13–S1–O2
C14–S2–O3
C15–S2–O3
C27–S3–O5
C28–S3–O5
C29–S4–O6
C30–S4–O6
169.42(14)
89.58(14)
82.3(3)
169.72(13)
89.90(13)
82.4(3)
98.6(7)
101.7(7)
99.0(7)
100.1(7)
105.4(6)
106.5(7)
106.3(6)
105.2(6)
106.7(6)
107.9(6)
106.8(6)
105.3(6)
S2–O3
S3–O5
S4–O6
Table 3
Hydrogen-bonding distances (Å) and angles (°) for 5.
D–HÁ Á ÁA
D–H
HÁ Á ÁA
DÁ Á ÁA
D–HÁ Á ÁA
N1–H12NÁ Á ÁCl3
N1–H11NÁ Á ÁO3i
N4–H41NÁ Á ÁCl1
N4–H42NÁ Á ÁO6ii
0.92
0.92
0.92
0.92
2.37
1.94
2.35
1.97
3.257(12)
2.853(13)
3.236(11)
2.883(13)
163.2
171.0
161.6
172.9
As expected in view of previous observations [17,18,20], the Cl
ligands in complexes 1 and 5 are trans to each other, whilst origi-
nally being mutually cis in the precursor cis-[RuCl2(DMSO)4].
Symmetry codes: (i) x À ½, Ày, Àz; (ii) ½ + x, 1 À y, z.
Fig. 1. Asymmetric unit of 5 with anisotropic displacement ellipsoids at 50% probability. Hydrogen atoms are omitted for clarity.

V. Mahalingam et al. / Polyhedron 29 (2010) 3363–3371
3369
3.5. Cyclic voltammetric studies
to-peak separation of 50 mV), which can be assigned to the Ru(III)/
Ru(II) redox process [49]. Complex 5 exhibited a quasireversible
oxidation couple with an E1/2 value of 1.14 V (peak-to-peak
The redox properties of the ligands and new Ru(II) complexes
were determined by cyclic voltammetry with DMSO solutions
(ꢀ1 Â 10À3 M) using 0.1 M TBAP as the supporting electrolyte in
the selected potential window of 1.8 V at a scan rate of 0.1 V/s,
and all the potentials were referenced to the Ag/Ag+ electrode.
The electrochemical data of the ligands and their complexes are gi-
ven in Table 4 and Fig. 2 shows a representative voltammogram.
Except for 2, all the complexes displayed one-electron Ru(II)/
Ru(I) redox waves with E1/2 values in the range À0.74 to À1.10 V
that agree well with literature values [47,48]. The peak-to-peak
separation values of this redox process ranges from 80 to 200 mV
and the process is best described as a reversible/quasireversible
electron transfer. While complex 1 did not show any oxidation re-
Table 5
Change in UV–Vis spectra of the complexes upon gradual addition of herring sperm
DNAa.
Complex kmax/nm (emax
)
r = 0
r = 1
r = 2
r = 3
r = 4
1
2
3
4
5
319 6420)
322 (6680) 324 (7120) 325 (7430) 327 (7860)
326 (7340) 328 (7900) 330 (8150) 331 (8430) 332 (8990)
332 (5540) 334 (5800) 337 (6060) 339 (6580) 341 (6840)
337 (2800) 338 (3030) 339 (3490) 341 (3950) 343 (4180)
323 (3880) 325 (4740) 326 (5600) 327 (6460) 329 (6890)
a
Concentration of the complexes ꢀ10–4 M in DMSO + buffer; concentration of
sponse, complexes
Epc = 0.62 V and Epa = 0.53 V, respectively. Complex 4 showed a
reversible oxidation couple with an E1/2 value of 0.56 V (peak-
2 and 3 showed uncoupled peaks with
DNA = 3.7878 Â 10À3 M in Tris–HCl buffer (pH 7.1); r = [DNA]/[complex]; emax is
given in L molÀ1 cmÀ1
.
Table 4
Cyclic voltammetric data of the new Ru(II)–DMSO complexes.
Compound
Peak potential (V)
Epa Epa
Half-wave potential (V) (peak-to-peak separation in mV)
1
2
Epa
3
Epc1
Epc
2
Epc
3
E1/2 (DEp)
Semicarbazide
sptsc
hntsc
hnptsc
0.81
0.43
0.31
0.38
1.25
–
À0.24
À0.44
À0.44
–
0.46
À0.23
–
–
–
–
–
–0.53
–
À0.88
À0.50
À0.83
–
–
–
–
–
–
–
–
À0.52
–
–
–
À0.54
À1.10
À0.64a
4-Aminoantipyrine
À0.64
1
–
2
–
3
–
4
5
À0.84a
–
À0.74 (200)a
–
À0.14
À0.19
–
0.62
–
–
–
–
–
0.53
À1.14a
À1.06a
À1.10 (80)a
0.59b
1.23c
À0.14
À0.24
À1.18a
À1.09a
0.54b
1.04c
–
–
À1.02a
À0.94a
À1.10 (160)a, 0.56 (50)b
À1.02 (150)a, 1.14 (190)c
a
b
c
Ru(II)/Ru(I) redox couple.
Ru(III)/Ru(II) redox couple.
4-Aminoantipyrine based redox couple; E1/2 = 0.5 (Epc + Epa) and
D
Ep = Epc À Epa
.
Fig. 2. Cyclic voltammogram of 3 in DMSO.

3370
V. Mahalingam et al. / Polyhedron 29 (2010) 3363–3371
Table 6
Antibacterial activity data of ligands and their Ru(II)–DMSO complexes.
Compound
Escherichia coli
Shigella sonnei
Staphylococcus aureus
Staphylococcus epidermidis
Klebsiella pneumoniae
WDa
MICb
WD
MIC
WD
MIC
WD
MIC
WD
MIC
Semicarbazide
1
sptsc
2
hntsc
3
hnptsc
4
4-aminoantipyrine
5
Oxytetracycline
Kanamycin
13
16
14
16
14
18
14
17
12
15
30
32
64
57
76
72
77
72
62
56
71
65
15
18
14
20
13
17
13
17
15
18
14
17
37
48
61
52
81
68
83
69
64
59
67
55
8
13
19
12
16
15
17
13
16
13
17
32
40
67
56
78
57
86
70
71
63
74
62
7
14
17
15
17
14
19
11
15
15
19
44
60
74
63
91
78
89
71
83
76
68
61
8
15
17
12
15
12
14
13
16
14
15
30
35
66
61
98
86
93
85
79
68
92
85
8
9
10
11
10
a
WD, disc diffusion method as recommended by NCCLS. Diameter of zone of inhibition (mm) including well diameter 8 mm  100
were used.
lg of both compound and antibiotics
b
MIC, minimum inhibitory concentration. Values given as lg/ml for both compounds and antibiotics.
separation of 190 mV). This can be safely assigned to a ligand based
redox process on comparing with the electrochemical data of
4-aminoantipyrine. The other uncoupled peaks in the range
À0.14 to À0.24 V in the voltammogram of the complexes are not
metal-centered, which is also evident from the redox potentials
of the free ligands.
3.7. Antibacterial activity
The antibacterial activity of all the ligands (semicarbazide,
sptsc, hntsc, hnptsc and 4-aminoantipyrine) and their correspond-
ing Ru(II)–DMSO complexes as DMSO sol against three Gram neg-
ative (E. coli, K. pneumoniae, S. sonnei) and two Gram positive
(S. aureus, S. epidermidis) pathogenic bacteria were studied by mea-
suring the diameter of the zone of growth inhibition and minimum
inhibitory concentration. Oxytetracycline and Kanamycin were
used as standards. The data of the inhibition zone of growth (in
3.6. UV–Vis spectra of the complexes in the presence of buffered
herring sperm DNA solution
mm) and minimum inhibitory concentration (in
lg/L) are given
The binding of small molecules to DNA is one possible approach
to controlling gene expression [50,51], and is also very important
in the development of new therapeutic reagents. Inert transition
metal complexes, particularly those containing ruthenium(II)
centers, have been extensively used to study the principles of
DNA recognition and as DNA sequence and structure selective
binding agents [52,53]. Metal complexes containing planar polycy-
clic aromatic ligands bind strongly to DNA by intercalation, while
complexes with non-planar ligands may bind to DNA through
non-intercalative modes. Thus, in order to study their preliminary
DNA-binding abilities, absorption titrations of the new complexes
with herring sperm DNA were studied. The absorption titration
was carried out with the respective complex with a final concen-
tration of ꢀ1 Â 10À4 M and varying the concentration of the her-
ring sperm DNA. The concentration of the DNA stock solution
was calculated to be 3.7878 Â 10À3 M. The addition of DNA to
the complex was achieved by adding buffered DNA in different
mixing ratios (r = [DNA]/[Ru-complex]) to the complex (0.3 ml)
while maintaining a constant total volume (3 ml). The titrations
were carried out until no further change was seen in the spectra.
The complex-DNA mixture was allowed to stand for a uniform
time of 5 min to get consistent and comparable results.
in Table 6. The results show that the complexes exhibited better
activity than their corresponding ligands, although they could
not reach the effectiveness of the standards used in the study.
4. Conclusions
A series of new Ru(II)–DMSO complexes with ON/SN chelates
have been synthesized and characterized by analytical and spec-
troscopic techniques. Two ON chelates have been characterized
by single crystal XRD studies. One of the ON chelates,
[RuCl2(DMSO)2(semicarbazide)]Á2H2O, has already been reported,
though the present synthesis uses a slightly a different route which
is better in terms of affordability of the precursor, reaction time
and yield. The o-hydroxy Schiff base derivatives of thiosemicarbaz-
ides used in this study have been shown to be stable to hydrolytic
C@N cleavage under the experimental conditions, unlike the deriv-
atives of semicarbazide and 4-aminoantipyrine. The redox proper-
ties of the complexes have been studied by cyclic voltammetry.
The preliminary DNA-binding ability and antibacterial activity of
the complexes have also been studied.
All the complexes displayed a prominent peak in Tris–HCl buffer
in the range 319–337 nm due to a dp(Ru) ? p*(L) MLCT transition.
Appendix A. Supplementary data
This prominent peak was chosen to study the binding of the com-
plexes by monitoring the change in wavelength and absorbance
as calculated increasing amounts of DNA were added to the com-
plex solution. The changes observed in absorbance and kmax due
to addition of DNA solution are recorded in Table 5. In general,
intercalative DNA binding involving a strong stacking interaction
between aromatic chromophores and the base pairs of DNA is char-
acterized by large hypochromism accompanied by a fair red shift
(bathochromism) during absorption titration [54]. However, the
complexes studied in this work showed a considerable red shift
(6–9 nm) and hyperchromism, which is indicative of an interaction
between the complexes and herring sperm DNA in any one of the
non-intercalative modes observed for similar complexes.
CCDC 288121 and 654123 contains the supplementary crystal-
lographic data for compounds 1 and 5. These data can be obtained
free of charge via http://www.ccdc.cam.ac.uk/conts/retriev-
ing.html, or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; fax: (+44) 1223-336-033;
or e-mail: deposit@ccdc.cam.ac.uk.
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