Synthesis and characterisation of new Schiff base chelates of platinum group metals.
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Date
2011
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Abstract
The principal goal of this work was to synthesise and fully characterise a range of
platinum group metal chelates of bis(pyridine-imine) ligands. These four-nitrogen donor
Schiff base ligands are underdeveloped relative to their salen (ONNO donor)
counterparts. The purified metal complexes were to be tested for their cytotoxicity
against cancer cell lines and their mode of interaction (expected to be intercalation)
studied.
The syntheses, spectroscopic and structural properties of some novel and some already
known bis(pyridine-imine) ligands are described. Furthermore, UV-Vis, IR and NMR
spectroscopy, as well as electrospray ionisation mass spectrometry, have been used to
characterize the ligands and comparisons were made with relevant literature. Fifteen
Schiff base ligands were successfully condensed from a 2-formyl or 2-ketopyridine
starting material and a diamine bridging group, while the attempted syntheses of a
further three are described. Literature methods or variations thereof were employed in
the syntheses of these derivatives, which generally resulted in good yields. X-ray quality
crystals were obtained and X-ray structures were determined for four novel ligands and
five unexpected cyclised hexahydropyrimidine- and imidazole-containing bidentate
ligands, of which three were novel structures.
The series of bicationic palladium and platinum complexes synthesised here were
analysed by NMR, IR and UV-Vis techniques, as well as X-ray crystallography when
possible. The complexes were prepared by reacting the free ligands with platinum group
metal salts in refluxing acetonitrile. The complexes exhibit infrared bands for the imine
C=N stretch between 1604–1670 cm-1; around 15–40 cm-1 lower than the free ligands.
The 1H NMR spectra in the CH=N chemical shift region also display shifts (0.1 to 0.8
ppm for the palladium complexes or 0.4 to 0.9 ppm for the platinum complexes) which
are consistent with metallation.
X-ray crystal structures were obtained for eight novel metal complexes, which all
crystallised in the monoclinic crystal system. The solid state analysis shows changes in
the free ligands upon introduction of the metal ions, caused by the coordination process.
Metallation of the free ligands led to twisting of the ligands due to size effects and the
spatial restrictions of the coordination geometry of the central metal ions. The structures
were generally solved by direct methods and refined to R1 = 0.0729 or less. Singlecrystal
X-ray diffraction analysis confirmed that the mononuclear complexes exhibit a
distorted square planar coordination sphere composed of the four donor nitrogen atoms
(two imine and two pyridyl nitrogen atoms) from the Schiff base ligands. The complexes
were generally very stable and differed by the type of metal ion (platinum(II) or
palladium(II)) and the diamine bridging group (2-carbon or 3-carbon linking chain with
various substituted groups). A range of unconventional F···H−C contacts is revealed to
play an important role in the overall bonding and crystal packing of many complexes.
To better understand our measured data and to separate the intrinsic properties of our
molecules from intermolecular interactions, theoretical calculations at the DFT (B3LYP)
level were carried out. These calculations predict the structural and spectroscopic
properties for the free ligands and their metallated counterparts. DFT simulations were
performed for the fifteen synthesised ligands (B3LYP functional, 6-31G** basis set), as
well as three projected ligands that could not be synthesised, and for all proposed thirtysix
metal complexes (B3LYP functional, SDD basis set). DFT simulations were used to
obtain theoretical IR frequency data which was compared to the literature and used to
prove the location of a local minimum energy structure in the geometry optimisation
rather than a transition state. Our results collectively showed the B3LYP level of theory to
be useful in the prediction of IR frequencies for these Schiff base ligands as well as the
platinum(II) and palladium(II) complexes.
Geometry optimisations performed using density functional theory for the free ligands
and metal complexes were compared, where possible, with X-ray data. For the free
ligands the main structural differences were observed for the position of the pyridyl-imine
"arms" of the ligands with relatively good agreement between the two structures for the
bridging groups. On the other hand, the metal complexes showed greater discrepancies
for the bridging groups rather than for the pyridine rings. These differences were also
affected by the length of the carbon bridge; the longer the carbon bridge, the less
variation was observed. The trends in the variation of bond distances and angles with the
metal ion identity and ligand structure delineated by DFT simulations were matched by
similar trends in the X-ray data.
Differences between the gas phase calculated geometries and those determined by Xray
diffraction were attributed to packing effects in the solid state and intermolecular
interactions not being accounted for during DFT computations. The impressive similarity
observed between the structures obtained from X-ray crystallography and computed by
DFT shows the applicability of these computations at the B3LYP level of theory. They
were able to accurately predict structural and spectroscopic properties for the ligands
and complexes presented in this work.
The in vitro cytotoxicities of some of the metal complexes were evaluated against two
mouse cancer cell lines. The compounds tested had lower than expected cytotoxicity
towards the cell lines studied with IC50 values > 100 μM. The interaction of the
complexes with calf thymus DNA has been explored by using absorption studies. From
the observed changes in absorption possible modes of binding to DNA have been
proposed for the metal complexes. Significant changes were observed in the absorption
spectra upon interaction of the complexes with DNA, from which large binding constants
were determined. The changes were, however, not as intense as expected nor were the
spectral variations typical of intercalating drugs. There were also no bathochromic shifts
nor any isobestic points observed for most of the metal complexes, except one. For the
cationic PGM chelates studied, the lack of shift in the wavelength of the visible range
MLCT band maximum and small changes in the band intensity were more indicative of
weak electrostatic interactions. Our spectral data were thus interpreted as being
consistent with non-intercalative binding; either simple electrostatic adduct formation or
major/minor groove binding.
The binding constant values (Kb) of the metal complexes estimated from the titration with
calf thymus DNA monitored by absorption spectroscopy were all in the range of 105 M-1.
This is within the range of those reported for other platinum(II) and palladium(II) metal
complexes that have shown intercalation and/or groove binding. With the lack of
inhibition of growth of the selected cancer cell lines it is possible that the compounds do
not reach nuclear DNA in living cells or that such compounds are possibly substrates for
efflux transporters. All the metal complexes in this work were determined to not be pure
DNA intercalators as had been expected; however, in some cases partial intercalation
cannot be ruled out from the spectral data.
Description
Thesis (Ph.D.)-University of KwaZulu-Natal, Pietermaritzburg, 2011.
Keywords
Schiff bases., Chelates., Platinum compounds., Theses--Chemistry.