The proposed research will involve the study of reactive electrophilic species. The objectives of the work include the generation of new electrophiles and the application of these chemical intermediates to the synthesis of biologically active products. The research will establish the importance of closely oriented, positive charge centers in determining the overall reactivity of electrophiles. It is proposed that certain organic functional groups have the tendency to form highly reactive dicationic electrophiles in acidic media. We will exploit the reactivity of these electrophilic species using electrophilic aromatic substitution chemistry to prepare anti-Parkinsonian drugs, anti-histamines, anti-depression drugs, anti-convulsant drugs, and anti-fungal drugs. Moreover, our studies will have implications toward the chemistry associated with epinephrine (adrenaline), the aromatic amino acids, and the NAD+/NADH redox system. In a typical experiment, a suitable pre-electrophile will be dissolved in a strong acid solution, protonation of the pre-electrophile will yield cationic or dicationic electrophiles, and the resulting electrophilic species will be reacted with an aromatic compound. The synthetic methods will also be applied to the combinatorial synthesis of libraries of anti-depression drugs and anti-Parkinsonian drugs. It is also proposed that novel derivatives of known drugs will be readily prepared using our new chemistry. Our synthetic studies will also be accompanied by kinetics experiments and theoretical analysis of the electrophilic intermediates. The theoretical studies will use semi-empirical and ab initio computational methods.
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