Applications and Development of Methodologies for Designing Hybrid Catalysts.

A catalyst is a substance that increases the rate at which a reaction occurs without being consumed. In this project organometallic catalysts (organic catalysts that contain a metal centre) and biomolecular catalysts (e.g. enzymes) are of particular interest. These two classes of catalysts have complementary characteristics and the aim of the current project is to combine these by embedding the metal center into an enzyme, resulting in a hybrid catalyst. The challenge that this idea invites is to find an appropriate enzyme with a binding site that can accommodate an organometallic complex and subsequently to fine-tune the catalytic ability of the hybrid catalyst for the desired reaction. In general, the binding sites of the enzymes we wish to investigate have not evolved to contain metals and thus the inclusion of the metal center will have unforeseeable implications on the structure and reactivity of both the enzyme and the organometallic catalyst. The role of this project is to predict what these changes in structure and reactivity will be and then to modify the original system to obtain the desired reactivity. This structure-based approach of designing molecules is known as rational design, whereby the surrounding residues (and consequently the molecular architecture) are mutated based on their known properties and orientation. The knowledge of the chemical and structural properties of the system is gained through computational modeling, which allows us to visualize the system and predict how it will react to certain chemical modifications. For this purpose we use a range of computational methods, including low-level methods (molecular mechanics) in order to analyze structural changes; and high-level methods (such as quantum mechanics) in order to analyze changes in the chemical properties of the system, such as activation barrier heights. Large systems, such as enzymes, are far too expensive, computationally, to be treated with quantum mechanical methods, thus a hybrid quantum mechanical/molecular mechanical (QM/MM) method is employed to study the reactivity of the resulting hybrid catalyst.Organometallic catalysts are used in a wide range of industrial processes; most notably in the production of finechemicals and pharmaceuticals. However, compared to enzymes, the rate at which these compounds catalyze reactions and the corresponding turnover numbers (i.e. amount of product produced per catalyst) is quite small. One of the advantages of using hybrid catalysts will be in the increase of the control of the reaction mechanism, which leads to faster rates. Furthermore, in the hybrid catalyst one may be able to obtain greater control over the specificity of the reaction; this implies that protecting groups (used to stop side reactions occurring in organometallic catalysis) are no longer necessary. By reducing the chance of side reactions we decrease the amount of starting material required to produce a given quantity of the actual product. Thus hybrid catalysts offer the possibility of performing chemically challenging syntheses in a much more efficient manner than is possible with traditional organometallic catalysts. This greater efficiency is achieved through a reduction in the amount of catalyst required, a reduction in the number of reactions steps required and an increase in the percentage yield of the desired product. With hybrid catalysts we get more product for less - which makes sense both economically and environmentally.