Photoelectrocatalytic Trifluoromethylation of Arenes via Trifluoroacetate Decarboxylation - PROJECT SUMMARY/ABSTRACT The incorporation of C–F bonds into small-molecule therapeutics can dramatically improve their pharmacokinetic properties, including bioavailability, lipophilicity, and metabolic stability. In accordance with the profound positive impacts of fluorine incorporation, approximately 20% of all pharmaceuticals contain fluorine. Aryl–CF3 linkages are a particularly common motif, present in approximately 15% of all fluorinated pharmaceuticals. Yet, a major drawback of current catalytic trifluoromethylation methods is that commonly employed CF3 sources can be very expensive, limiting the economic viability of trifluoromethylation reactions on large scales. Therefore, the development of an efficient trifluoromethylation protocol employing an inexpensive CF3 source would significantly improve the discovery and synthesis of new fluorinated pharmaceuticals. Trifluoroacetate (TFA), which is produced annually on multi-ton scale, could serve as the desired inexpensive CF3 source. However, the decarboxylation of TFA to generate reactive CF3 radicals (●CF3) is notoriously difficult, due to the strongly electron-withdrawing nature of the CF3 group. Recently, the Nocera group employed a silver(II) complex to achieve the first example of visible-light-induced TFA decarboxylation using a well-defined metal complex. However, this method’s use of stoichiometric silver(II), as well as the incompatibility of the reaction conditions with oxidatively sensitive substrates, limit the practicality of this advance. The objective of this proposal is the development of a practical, catalytic trifluoromethylation method. The stoichiometric, silver(II)-mediated method developed in the Nocera group will be modified to be catalytic in silver, with the catalyst turned over electrochemically. This method will be applied to the production of other difficult-to- generate radicals that are relevant to the synthesis of pharmaceuticals. Additionally, a rational ligand design campaign will be undertaken to develop silver(II) complexes that are compatible with oxidatively sensitive functional groups. Finally, the catalyst ligand environment will be modified to stabilize ●CF3 in the secondary coordination sphere, allowing for catalyst control over the precise delivery of ●CF3 to substrates. The proposed research is expected to constitute a significant synthetic advance in the field of radical trifluoromethylation. The Nocera laboratory at Harvard University is the ideal environment to accomplish the proposed research and training goals in preparation for a career in academia. The Nocera group will provide invaluable training in many areas of inorganic chemistry, particularly in the development of photo- and electrochemically driven redox reactions and in the deployment of mechanistic techniques, including transient absorption spectroscopy and photocrystallography. Moreover, Harvard will supply numerous opportunities for skill development in scientific education and mentoring through the Derek Bok Center for Teaching and Learning. These factors make Harvard the optimal institution to pursue ambitious research goals and prepare for a successful future academic career.