QMMMKIES · Can QM/MM calculations reproduce experimental kinetic isotope effects

Final Activity Report Summary - QMMMKIES (Can QM/MM calculations reproduce experimental kinetic isotope effects)

The transition state (TS) is of strategic importance within the field of chemical reactivity, determining both the direction and the rate of chemical change. There are important practical reasons for investigating it, leading potentially to cleaner, greener, cheaper chemical processes in industry. Mechanisms-based approaches to drug design are directed towards the synthesis of TS analogues as inhibitory substrates for enzymes controlling key biochemical processes; this requires knowledge of the TS structure to be mimicked. The design of synthetic catalysts for specific chemical processes is aided by knowledge of the TS structure in order that its structural complement may be constructed. One of the most powerful experimental techniques for probing the nature of the TS is the measurement of a kinetic isotope effect (KIE), reflecting the extent by which substitution at a particular position in a molecule by a heavier isotope (e.g. deuterium with mass 2 instead of normal hydrogen with mass 1) affects the rate of chemical reaction. Its value provides information about the changes in chemical bonding occurring during the reaction. However, the interpretation of a KIE as a measure of TS structure requires a sound theoretical framework. Previously, qualitative theories have allowed qualitative conclusions to be drawn, but the development of quantum-mechanical techniques for the study of organic reaction mechanisms now poses questions regarding whether meaningful quantitative information can be obtained from KIEs. Many workers had previously assumed an optimistic stance on this question, but a recent important paper (by scientists in Poland, Sweden and Canada) cast a ray of cold, bright light upon the issue: it concluded that the current portfolio of conventional quantum-mechanical methods was not capable of reproducing the range of KIEs measured experimentally for isotopic substitution at multiple positions in a prototypical organic chemical reaction. This fact is an awkward reality that sits uneasily alongside the ambition of computational chemistry to provide reliable models for the rationalisation of known chemical behaviour and the prediction of unknown behaviour. Hybrid methods, in which that part of a molecular system involving significant changes in chemical bonding is described by quantum-mechanics, but the surrounding environment is described by a classical mechanics, are a promising way to approach modelling of increasingly large and complex systems; their application should allow us to investigate the role of solvation upon KIEs. This project is timely not only because of new theoretical developments but also because of recent questioning of the orthodox view of KIEs in reactions of organic compounds with solvents. The underlying assumptions of the prevailing theory have been challenged by a much simpler scheme involving both solvent and structural effects on KIEs for heterolysis. The key reactions in the new view now demand computational simulation in order to discriminate between the two opposing theories. We have not yet accomplished all that we set out to achieve in the project, but we have determined a significant and unexpected dependence of isotope effects upon the nature of the solvent in which the reaction takes place. This preliminary finding, which requires further investigation, has considerable significance for the way in which experimental KIEs are interpreted as indicators of reaction mechanism, favouring the new view over the old.

Data: CORDIS, © European Union