(Radio)Fluorination and Other Nucleophilic Functionalizations Enabled by Photocatalytic Radical-Polar Crossover

With the support of the Chemical Synthesis (SYN) program in the Division of Chemistry, Professor Abigail Doyle of University of California, Los Angeles is developing new chemical reactions that will enable the synthesis of organofluorine compounds; namely those that contain a C-F bond. Such bond constructions are in high demand as C-F bonds are found in next-generation medicines, agrochemicals, and biomedical imaging agents.

The chemical reactions under development here use a catalyst that can harness the energy in visible light to generate a high-energy reactive intermediate, a carbocation, that is most often only accessible under harsh (thermal or strongly acidic or Lewis-acidic) conditions. Because the strategy being pursued by Professor Doyle and her students accesses this intermediate under the mild conditions associated with visible light irradiation, reactions are being developed that generate chemical structures that were previously challenging to access, starting from abundant and inexpensive reagents.

The researchers will use a variety of tools to help them understand how the reactions work at the molecular level such that this knowledge can be used to discover new processes and design improved reactions. Students conducting these research activities will have the opportunity to develop a broad skill set, both scientific in nature and with respect to communication, mentorship, leadership, and also with respect to embracing and building diversity, equity, inclusion and belonging, that will help them become leaders in their independent careers.

Broader impacts of this work also include the development of activities directed at recruitment and retention of students from underrepresented groups to science, technology, engineering, and mathematics (STEM). For example, the program includes the development of undergraduate teaching material to highlight scientific contributions from researchers of diverse backgrounds, experiences and perspectives and the design of workshops for entering graduate students on topics such as citation bias, conflict management, and micro-aggression.

Carbocations are reactive intermediates in a broad range of synthetic transformations because they undergo reaction with abundant and stable nucleophiles like water, alcohols, halides, amines, and olefins. Nevertheless, the generation of carbocation intermediates typically requires harsh reaction conditions and requires use of pre-oxidized precursors such as alkyl halides.

These limitations preclude applications in more complex settings, such as in the synthesis of bioactive compounds or radiolabelling, and access to desirable products. This program seeks to address these challenges by using a photocatalyst and light to convert abundant and stable C(sp3)–OH, –NH2 and –H precursors to radicals and then to carbocations (a so-called radical-polar crossover).

A focus of these efforts will be to use fluoride to trap the carbocation intermediates in order to generate organofluorine products that are useful in the pharmaceutical and agrochemical industries. Mechanistic studies will accompany these synthetic efforts and the most efficient strategies will also be adapted for the synthesis of 18-fluorine-radiolabelled small molecules for use in positron emission tomography (PET), an important diagnostic tool for detecting disease.

This research will provide a rigorous and multi-disciplinary training environment for a diverse group of graduate and undergraduate students and postdoctoral fellows.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.