Tuning the reactivity of mononuclear tridentate platinum (II) complexes : a detailed kinetic and mechanistic approach using Azole Nucleophiles.

Abstract

The kinetic substitution reactions of two different sets of mononuclear Platinum(II) complexes with heterocyclic bio-relevant azole nucleophiles, viz. Imidazole (Im), 1-methylimidazole (MIm), 1,2-Dimethylimidazole (DIm), 1,2,4-triazole (Trz) and pyrazole (Pyz). All substitution reactions were studied under pseudo-first order conditions as a function of the incoming nucleophiles concentration and temperature using stopped-flow techniques and UV/Visible spectroscopy. The first set of complexes included the tridentate polypyridine complexes, Pt(II)(2,2:6,2″-terpyridine)Cl]Cl.2H2O, (PtL1) Pt(II)(1,3-di(2-pyridyl)benzene)Cl, (PtL2) Pt(II)(2,6-di-(2’-quinolinyl)pyridine)Cl](Cl), (PtL3) and Pt(II)(1,3-di-(2’-quinolinyl)benzene)Cl (PtL4). The substitution of these complexes with the previously mentioned azoles showed that tuning electronic communication of the Pt(II) centre towards substitution through quinoline moieties has an opposed effect to that obtained through pyridine moieties, and verified that the trans-effect of a phenyl ring is much greater than that of a pyridine ring. The reactivity trend among the complexes was PtL2 > PtL4 > PtL1 > PtL3. Once the nucleophiles were categorised into two groups based on their structural similarities, reactivity trend observed amongst the nucleophiles was generally Im > Pyz > Trz, based on the basicity (electronic effects) and MIm > Im > DIm based on steric effects. The second series of complexes were tridentate [Pt(bis(2-pyridylmethyl)amine)OH2](ClO4)2, Ptdpa and [Pt(bis(2-pyridylmethyl)sulfide)OH2](ClO4)2, Ptdps of which the kinetics were studies in an aqua medium and at constant ionic strength (0.1 M). Ptdps was found to be more reactive (three magnitude higher) than Ptdpa. The rate of substitution of the aqua ligand is dependent on the strength of the σ-donor character and the π-acceptability of the atom situated trans to the leaving group. The observed reactivity for the azoles followed the trend, MIm > Im > DIm > Trz > Pyz. This reactivity trend is in accordance with the basicity, and reflects steric and electrophilic effects of the nucleophiles. This was supported by DFT calculations and the X-ray crystal structure of Ptdps_Cl. For all substitution reactions, the temperature dependent studies showed an associative activation. It is envisaged that the findings of this project will provide useful information for designing new drugs as part of a protracted search of effective anticancer drugs with a wider spectrum.