Lead Research Organisation: University of Warwick
Department Name: Chemistry


Transition metal systems play many vital roles in catalysis and biology. For the former, catalysts containing metal centres are used extensively for asymmetric organic synthesis. Here, molecules with specific chirality are prepared. Control over the chirality is critical as each form of the molecule may have dramatically different properties. One form may be a particularly efficacious pharmaceutical while the other may have dire side effects. Ruthenium compounds where the metal is bound to the face of a benzene or substituted benzene molecule have proved particularly useful for transferring hydrogen to both ends of a carbonyl group to generate the corresponding chiral alcohol. Interestingly, very similar Ru-arene compounds have shown anti-cancer activity and are being actively studied as potential replacements for existing metallodrugs such as cisplatin. In both cases, it is important to have a atomic-level understanding of how the molecules function. On the one hand, we want to know the intimate details of how hydrogen adds across the C=O bond and how we might design even better cataylsts while, on the other, we want to know how the Ru drug interacts with its biological target DNA and how we might design better drugs. Theory can provide a powerful tool for addressing these issues. However, computer modelling of systems containing transition metals is difficult. Metal centres tend to have complicated electronic structures which appear to demand an equally complicated theoretical method / specifically quantum mechanics (QM). The problem here is that the molecular systems we are interested in are too large and too numerous and QM is (relatively) too slow for a quantum approach to be viable. The alternative classical approach, molecular mechanics (MM), is much faster but requires extensive modification in order to be able to deal with metal centres. Hence, this proposal describes a scheme for extending MM to facilitate modelling Ru-arene systems and, in conjunction with the experimental groups of Wills and Sadler, its application to asymmetric hydrogen transfer reactions and Ru-DNA binding.


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Description Ruthenium arenes are versatile complexes with diverse applications in catalysis and biology. In order to better understand how these systems function, it is important to be able to generate atomistic computer models which can accurately describe their properties and interactions. This would normally involve high level, potentially very expensive quantum chemistry-based methods. In contrast, simple classical models essentially based on a balls-connected-by-springs idea, are very much faster but pi-bonded systems such as ruthenium arenes require a special treatment. We set about to extend our ligand field molecular mechanics (LFMM) method, previously successfully applied to 'classical' coordination complexes, to these 'non-classical' organometallic metal arenes. There were significant computer coding issues to be overcome since the hexagonal arene ring sits over the metal centre but is connected to it via a virtual bond with a dummy atom located at the ring centroid. The forces on this dummy atom have to be distributed to the actual carbon centres of the arene. Ultimately, we were able to code LFMM for Ru-arenes into our extended version of the Molecular Operating Environment software (MOE) and provide a validation for a set of test molecules in terms of optimised geometries and some simple molecular dynamics simulations. For the latter, it turns out that MOE is not an ideal vehicle so we ported LFMM to DL_POLY, the flagship MD code of CCP5. This, in turn, was not a straightforward process so we initially tested it on a more conventional coordination chemistry system involving the interaction of Pt(II) anti-cancer agents with double-stranded DNA. At this stage, the MD implementation was restricted in that no pressure-dependence was included hence we could not directly estimate Gibbs free energies. Consequently, we implemented the stress tensor for the LFMM. We thus now have a new computational tool with which to explore further the chemistry of organometallic systems in general and ruthenium arene species in particular.
Exploitation Route The ability to model arene complexes using an empirical method remains valuable. A new manuscript describing the use of bis {Ru-arene} complexes as anion sensors is currently in preparation.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology