Theory and experiment are complementary tools in the search for fundamental understanding of chemical behaviour. In my research group, computational modelling is applied a variety of questions concerning organic reactivity, using a range of quantum-chemical techniques from simple to sophisticated; of current interest are new hybrid quantum-mechanical/molecular-mechanical methods. The common theme is the transition state, and specific topics include the following.
* Transition states for asymmetric induction in stereoselective processes.
Enantioselectivity in addition of hydride and carbon nucleophiles to carbonyl substrates
* Transition states for biochemical processes.
Catalysis by lactate dehydrogenase and serine proteases. Mechanisms for glycoside hydrolysis. Mode of action of neuraminidases. Design of transition-state analogues as inhibitors or as templates for catalytic antibodies.
* Transition-state structural variation and mechanistic change.
Exploration of the relationship between theoretical energy surfaces and experimental kinetic data. e.g. at the SN1/SN2 mechanistic borderline.
* Strain effects upon organic reactivity.
Topological electron-density analysis of reaction paths for strained molecules.
* What do empirical structure/reactivity correlations actually measure?
Theoretical modelling of transition states to assist the interpretation of experimental Bronsted coefficients.
* What do experimental kinetic isotope effects tell us?
How may they be reliably interpreted as measures of transition-state structure?
* Mechanistic aspects of H-, H., and H+ transfer processes.
To evaluate similarities and differences, to investigate stereoelectronic and isotopic effects, and to explore recent theories of reactivity.
* Degradation mechanisms of atmospheric CFCs and their proposed alternatives.
Characterization of intermediates and transition states.
Some recent publications:
1. "Transition-state structural variation and mechanistic change" JCS Faraday Trans. (1994) 90, 1709
2. "Computational elucidation of the catalytic mechanism for ketone reduction by an oxazaborolidine adduct" JCS Chem. Commun. (1994) 1651
3. "A theoretical investigation of hydride bridging in chiral oxazaborolidine-borane adducts: the importance of electron correlation" Tetrahedron Asymmetry (1994) 5, 813.
4. "Complete active space self-consistent field and density functional study of FNO" J. Chem. Phys. (1994) 100, 459.
5. "Interplay of theory and experiment in the determination of transition-state structure" Chem. Soc. Rev. (1993) 22, 277.
6. "Theoretical investigation of the origin of secondary alpha-deuterium kinetic isotope effects" JCS Chem. Commun. (1993) 1286.
7. "Transition-state structural variation in a model for carbonyl reduction by lactate dehydrogenase" J. Am. Chem. Soc. (1992) 114, 5423.