With the support of the Organic Dynamics Program in the Chemistry Division, Professor Steven M. Bachrach at Trinity University will explore computational approaches towards incorporating the effects of solvents within quantum mechanical calculations of organic reactions. Modern computational techniques have become quite reliable in predicting gas phase properties; however, much of chemistry and all of biochemistry occurs within a solvent. In this proposal, Professor Bachrach will examine a number of different approaches towards accounting for solvation, including continuum fields and explicit consideration of a small number of solvent molecules. These techniques will be applied to a number of important chemical problems. Nucleophilic substitution at sulfur and selenium is critical for the activation of some novel anti-tumor and antibiotic agents. Gas phase studies suggest an addition-elimination mechanism, so these studies will be extended to determine the mechanism in the more biologically relevant aqueous environment. In particular, the activation step for the powerful anti-tumor agent calichaemicin and the antibiotic leinamycin will be examined with the hope that mechanistic insight may help to create more effective analogues with better pharmacokinetic properties. Hydrogen bonding solvents that will activate carbonyl species used in the Diels-Alder reaction will be examined. And, finally, solution NMR experiments will be used as an alternate approach to addressing the strength of aromaticity, which remains one of the cornerstone principles of organic chemistry. The principal broader aim of the proposal is to train undergraduate students in the science of computational chemistry and to motivate these students towards a career in the sciences.
The Organic and Macromolecular Chemistry Program in the Chemistry Division supports Professor Steven M. Bachrach who will undertake the project at Trinity University, which has a long history of attracting undergraduate students to the research program, including many women and students of Hispanic origin, groups that have been underrepresented in the sciences. Professor Bachrach will expose these students to the challenges, excitement and opportunities for careers in chemistry. Another societal benefit that may develop from the proposed research is added insight toward the activation of some novel antitumor and antibiotic agents. Greater understanding of how these compounds are "turned on" can provide guidance towards developing analogues that may serve as new drug treatments.
