Regioselective hydrogen bonding phase transfer catalysis
The challenge of performing reactions with catalyst control over regioselectivity has not been met with a general solution. Here, we approach this longstanding problem in the field by addressing the specific question of how to regioselectively install fluorine - a key element in the agrochemical and pharmaceutical industries. By combining the charge-modulating properties of hydrogen bond donors with a phase transfer event, we propose that it will be possible to use simple fluoride salts in regioselective fluorination reactions. Using hydrogen bonding as an activation mode for cheap inorganic salts, we will address new challenges in site selectivity through catalyst design and an extensive interrogation of the potential energy landscape of the reactions. This research will demand catalysts that can control the charge density on a nucleophile and will require computational studies that enable the prediction of regioselectivity on the basis of a nucleophilicity index. To apply the lessons of these studies in the context of asymmetric catalysis, new high performance catalysts will be developed that are capable of kinetic resolution and enantioconvergent allylic fluorination. The ultimate test of the regioselective fluorination methods will be in the synthesis of novel PET tracers, where both time and operational simplicity are critical to achieving a high specific activity. Regioselective hydrogen bonding phase transfer catalysis will strongly influence the broader landscape of catalysis and yield mechanistic insight into a novel synthetic process while providing valuable biological probes from abundant feedstock chemicals. The interdisciplinary aim of this proposal is to connect computational chemists, synthetic organic chemists, radiochemists, and PET imaging specialists in a framework that allows the production of new tools to expedite clinical breakthroughs.