Unprecedented Pt(II) complex of an asymmetric 2,6-diacetylpyridine bis(4N-substituted thiosemicarbazone) ligand

Article abstract of DOI:10.1016/j.inoche.2012.10.022

Reaction of 2,6-diacetylpyridine bis(⁴N-o- tolylthiosemicarbazone), H₂L¹, with K₂PtCl ₄ and further recrystallization in DMSO/MeOH of the [PtL¹] complex obtained, led to the isolation of the novel platinum complex, [PtL ²], which was structurally characterized by single crystal X-ray diffraction. The molecular structure shows that the ligand has undergone an unexpected chemical transformation viz. reduction of one of the terminal phenyl rings into cyclohexyl. The resulted asymmetrical ligand acts a dianionic tetradentate donor, coordinating to the platinum(II) center in a square planar geometry through the N_pyridinic atom and the N_iminic and the S atoms from one thiosemicarbazone arm, the fourth coordination position is occupied by the N_hydrazinic atom of the other arm.

Full text of DOI:10.1016/j.inoche.2012.10.022

Inorganic Chemistry Communications 27 (2013) 5–8
Contents lists available at SciVerse ScienceDirect
Inorganic Chemistry Communications
journal homepage: www.elsevier.com/locate/inoche
Unprecedented Pt(II) complex of an asymmetric 2,6-diacetylpyridine bis
(4N-substituted thiosemicarbazone) ligand
⁎
Ana I. Matesanz, Pilar Souza
Departamento de Química Inorgánica (Módulo 07), Facultad de Ciencias, c/ Francisco Tomás y Valiente nº 7, Universidad Autónoma de Madrid, 28049-Madrid, Spain
a r t i c l e i n f o
a b s t r a c t
Reaction of 2,6-diacetylpyridine bis(4N-o-tolylthiosemicarbazone), H2L1, with K2PtCl4 and further recrystalliza-
tion in DMSO/MeOH of the [PtL1] complex obtained, led to the isolation of the novel platinum complex, [PtL2],
which was structurally characterized by single crystal X-ray diffraction. The molecular structure shows that
the ligand has undergone an unexpected chemical transformation viz. reduction of one of the terminal phenyl
rings into cyclohexyl. The resulted asymmetrical ligand acts a dianionic tetradentate donor, coordinating to
the platinum(II) center in a square planar geometry through the Npyridinic atom and the Niminic and the S atoms
from one thiosemicarbazone arm, the fourth coordination position is occupied by the Nhydrazinic atom of the
other arm.
Article history:
Received 10 July 2012
Accepted 13 October 2012
Available online 23 October 2012
Keywords:
Asymmetric N3S coordination
Bis(thiosemicarbazone)
2,6-diacetylpyridine
Platinum(II) complexes
Thiol function
© 2012 Elsevier B.V. All rights reserved.
X-ray diffraction
Thiosemicarbazones (R1R2C_N\NH\C(S)\NR3R4) are an im-
portant and versatile type of ligands due to the potential donor
atoms that they possess, among which sulfur is of paramount im-
portance in the metal–ligand linkage. Moreover the π delocalization
and configurational flexibility create the possibility of a variety of
coordination modes [1–3].
showing [7+7], [6+6], [6+4] and [4+4] coordination environ-
ments [8–11]. However no structural information about d8 metal
complexes bearing 2,6-diacetylpyridine bis(thiosemicarbazone)
ligands has been encountered in the bibliography.
As a part of a program concerning the behavior of α-N-heterocyclic
bis(thiosemicarbazones) we have published structural studies of a series
of palladium(II) and platinum(II) complexes derived from 3,5-diacetyl-
1,2,4-triazol-bis(thiosemicarbazones)[12–18]. In these complexes, the
square-planar coordination geometry of the central metal ions is provid-
ed by one N atom of the heterocyclic ring, the Niminic and S atoms of one
thiosemicarbazone arm and the S of the other thiosemicarbazone arm
(dimer complexes) or the P atom of the PPh3 coligand (mononuclear
complexes).
To extend the knowledge in this research field, particularly with re-
spect to the coordination properties of the α-N-heterocyclic bis(thiosemi-
carbazones) and the stereochemistry and molecular structure of the
complexes, we undertook the study of platinum(II) complexes derived
from 2,6-diacetylpyridine bis(4N-substituted thiosemicarbazones). Here
we report on the synthesis, characterization and crystal structure of a
new Pt(II) complex derived from an asymmetric 2,6-diacetylpyridine
bis(4N-substituted thiosemicarbazone) ligand.
The coordination capacity of thiosemicarbazones can be further in-
creased, if the parent aldehyde or ketone contains additional functional
group in a position suitable for chelation. Particularly, compounds in
which the thiosemicarbazone side-chain is attached in the α position
to an N-heterocyclic ring, namely α-N-heterocyclic thiosemicarbazones,
are strong metal chelating agents and have been reported to be among
the most effective ribonucleotide reductase (RR) inhibitors yet identified
[4]. Pyridine-2-carbaldehyde thiosemicarbazone was the first member of
this class reported to have carcinostatic effects and since then many
α-N-heterocyclic thiosemicarbazones and their metal complexes have
shown anticancer activity against a wide spectrum of tumor cell lines.
Currently, the 3-aminopyridine-2-carboxaldehyde thiosemicarbazone
(Triapine, Vion Pharmaceuticals, New Haven, CT) is being evaluated in
human phase II clinical trials as an antineoplastic therapeutic [5–7].
Although not as intensely studied as the mono(thiosemicarbazones),
the α-N-heterocyclic bis(thiosemicarbazones) having the two thiosemi-
carbazone moieties positioned possess a variety of flexible donor sets
and are capable of adopting various coordination modes, leading to
enormous structural diversity of their complexes. For example, in the
literature a series of dinuclear zinc complexes have been found
derived from 2,6-diacetylpyridine bis(thiosemicarbazone) ligands
The novel ligand 2,6-diacetylpyridine bis(4N-o-tolylthiosemicarba-
zone), H2L1, was synthesized by refluxing an ethanolic solution (20 mL)
of 2,6-diacetylpyridine (1 mmol) with 4N-o-tolylthiosemicarbazide
(2 mmol), which was prepared as described in reference [18], for 5 h
and then was left to stand in ambient temperature. The solution was re-
duced to half volume and the pale yellow solid formed was filtered,
washed with cold EtOH and Et2O and dried in vacuo. The ligand was
characterized by elemental analysis and FAB spectrometry as well as by
IR and 1H NMR spectroscopy [19].
⁎
Corresponding author. Tel.: +34 914975146; fax: +34 914974833.
E-mail address: pilar.souza@uam.es (P. Souza).
1387-7003/$ – see front matter © 2012 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.inoche.2012.10.022

6
A.I. Matesanz, P. Souza / Inorganic Chemistry Communications 27 (2013) 5–8
Scheme 1. Structure of the 2,6-diacetylpyridine bis(4N-o-tolylthiosemicarbazone) ligand and its platinum(II) complex synthesized.
Reaction of methanolic suspension (20 mL) of H2L1 ligand
planar geometry through the Npyridinic atom and the Niminic and the
(1.0 mmol) with K2PtCl4 (1.0 mmol) in water for 5 h at room tem-
perature yielded a brown precipitate which was filtered, washed
with MeOH and Et2O, purified by crystallization from DMSO and
dried in vacuo. Analytical and spectroscopic characterization [20]
was consistent with the formation of the expected neutral [PtL1]
complex (Scheme 1).
S atoms from one thiosemicarbazone arm. The fourth coordination
position is occupied by the Nhydrazinic atom of the other arm generating
two typical five membered (PtSCNN and PtNCCN) and one six mem-
bered (PtNNCCN) chelate rings. Coordination by the Nhydrazinic instead
of the Niminic atom, although uncommon, has been found in the bibliog-
raphy for some palladium and nickel bis(thiosemicarbazone) com-
plexes [28–30].
The Pt\N [1.979(7), 2.021(8) and 2.023(8) Å] and Pt\S [2.289(2) Å]
bond distances are comparable with those reported for Pt(II) thiosemi-
carbazone complexes.
Since the two thiosemicarbazone moieties coordinate in a differ-
ent fashion it would expect that in the bidentate-N∧S arm, the C\S
distance undergoes significant evolution from the thione to the
thiol form [C\S distance of 1.752(9) Å] but it is important to
note that the monodentate-Nhydrazinic thiosemicarbazone arm also
presents thiol C\S bond [1.81(3) Å] as well as an unexpected S\H
bond.
It is well known that compounds containing thiosemicarbazone func-
tional groups exhibit thiol–thione tautomerism, but unsubstituted and
monosubstituted ones, >C_N\NH\C(S)\NHR, are capable of stabiliz-
ing a third thiol form (Scheme 2). This is consistent with the C(15)\N(5)
and C(17)\N(7) bond lengths [1.309(17) and 1.295(17) Å respectively]
which correspond formally to double bonds while the C(17)\N(6) bond
length is longer, 1.408(13) Å.
Further recrystallization of [PtL1] from DMSO/MeOH led to the iso-
lation of good quality single crystals which were studied by X-ray dif-
fraction techniques [21]. The structural analysis allowed us to identify
a new platinum(II) complex, [PtL2], in which the 2,6-diacetylpyridine
bis(4N-o-tolylthiosemicarbazone) ligand has undergone an unexpected
chemical transformation viz. reduction of one of the terminal phenyl
rings into cyclohexyl.
Conventional hydrogenation reactions have implicit use of hydrogen
as a reactant. However it is possible that in the presence of a metal com-
plex, a hydrogen donor molecule transfers hydrogen to a substrate
which acts as an acceptor. The donor molecules, which undergo dehy-
drogenation are often the reaction solvents and the catalysts are usually
derived from platinum group metals bearing nitrogen or phosphorus do-
nating ligands with the Wilkinson's catalyst [RhCl(PPh3)3] being the
most prominent example [22–24].
By inspection of the literature a few examples of thiosemi-
carbazone metal complexes exhibiting catalytic activity have been
found. The fundamental features of these catalysts are the presence,
in the complexes, of stabilizing five membered chelate rings as well
as the presence of a labile coordinating bond prone to dissociate to
provide an available coordination site [25–27].
On the other hand, along the bidentate thiosemicarbazone arm and
as consequence of the extensive delocalization of electron density, the
In our case, the platinum complex [PtL1] contains two five mem-
bered chelate rings as well as a more rigid and therefore less stable
six membered chelate ring. Although further studies are necessary
in order to identify the reductant, a possible candidate could be
MeOH employed as solvent.
Since we have noticed that platinum(II) complexes derived of
3,5-diacetyl-1,2,4-triazol bis(4N-o-tolylthiosemicarbazone) ligand have
shown a notable antitumor activity [17] we analyzed the cytotoxic prop-
erties of the new complex [PtL2] by testing its antiproliferative activity in
vitro against five human cancer cell lines: NCI-H460 (non-small cell lung
cancer), HepG2 (hepatocellular carcinoma), MCF-7 (breast cancer),
A2780 and A2780cisR (epithelial ovarian cancer) which are among the
lines used in the NCI to identify novel potential anticancer drugs. Surpris-
ingly, the platinum(II) complex [PtL2] shows at 100 μM concentration,
a very low cellular growth inhibition (b50%) and therefore did not
have evaluable cytotoxicity (IC50 >100 μM). The substitution of the
N-heterocyclic ring (1,2,4-triazol versus pyridine) as well as the hydro-
genation on the peripheral tolyl substituent seems to be factors that
influence both structure and cytotoxicity.
The molecular structure of the neutral complex [PtL2], which crys-
tallized with one DMSO molecule in the monoclinic P21 space group,
together with the atom labeling scheme is shown in Fig. 1.
The transformed asymmetrical ligand acts a dianionic tetradentate
N,N,N,S-donor, coordinating to the platinum(II) center in a square
Fig. 1. Molecular structure of platinum(II) complex [PtL2].

A.I. Matesanz, P. Souza / Inorganic Chemistry Communications 27 (2013) 5–8
7
Scheme 2. Tautomeric forms of unsubstituted and monosubstituted thiosemicarbazones.
C\N and N\N bond distances are intermediate between formal single
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Appendix A. Supplementary material
Full crystallographic details have been deposited in CIF format
with the Cambridge Crystallographic Data Centre. CCDC 890162 con-
tains the supplementary crystallographic data for this paper. These
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conts/retrieving.html, or from the Cambridge Crystallographic Data
Centre, 12 Union Road, Cambridge CB21EZ, UK; fax: +44 1223 336
408; e-mail: deposit@ccdc.cam.ac.uk. Supplementary data to this arti-
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[19] Ligand H2L1: Yield (73%). Anal. % found: C, 61.00; H, 5.55; N, 19.85; S, 12.90.
C
25H27N7S2 requires: C, 61.35; H, 5.50; N, 20.05; S, 13.10. MS(FAB+ with mNBA
matrix), m/z=490 for [H2L1+H]+. IR (KBr, cm−1), υ=3308, 3238, 3151 (s, NH);
υ=1589 (s, CN), υ=1520 (s, CN-thioamide I), υ=878 (m, CS-thioamide IV). 1H
NMR (300 MHz, d6-DMSO, ppm), δ=10.65 [s, N(2) and N(6), 2H]; 10.10 [s, N(1)
and N(7), 2H]; δ=8.55 [d, C(11) and C(13), 2H]; 7.75 [t, C(12), 1H]; δ=7.30–7.20
(m, aromatic-thiosemicarbazide, 8H); δ=2.50 (s, CH3-thiosemicarbazide, 6H);
δ=2.25 (s, CH3-diacetylpyridine, 6H).
[20] Complex [PtL1]: Yield (55%). Anal. % found: C, 42.35; H, 3.95, N, 13.00; S 12.25; C25H31-
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Fig. 2. View of platinum(II) complex [PtL2] showing the parallel disposition of the
molecules as a result of π–π stacking interactions.

8
A.I. Matesanz, P. Souza / Inorganic Chemistry Communications 27 (2013) 5–8
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