Molecules containing carbon fluorine bonds are industrially prevalent as approximately 30% of all agrochemicals and 20% of all pharmaceuticals contain fluorine. The incorporation of fluorine into pharmaceuticals can enhance lipophilicity, bioavailability, metabolic stability, and can alter the strength of a compound's interaction with a target protein. For example, the highly successful drugs Lipitor (hypercholesterolemia), Ciprobay (antibiotic), and Risperdal (antipsychotic) boast an aryl fluorine bond. Additionally, the radioactive isotope 18F is widely used for molecular positron emission tomography (PET) in oncology imaging. While fluorine has widespread use, the traditional methods to incorporate it into an aromatic framework generally require harsh reaction conditions that do not tolerate many functional groups. Because of these restrictions, strategically advantageous late-stage approaches are generally abandoned, and the desired fluorine atoms are introduced into aromatics at an early synthetic stage. Catalysis, however, enables mild reaction conditions and selective transformations by providing lower energy pathways for the conversion of reactants into products. Specifically, transition metal-catalyzed cross-coupling reactions-the joining of two fragments by way of a metal catalyst-are widespread in modern synthesis. By selection of the correct ligand, Pd has been shown to catalyze Ar-F bond formation, albeit with limited substrate scope. The reaction is believed to proceed though a Pd(0)/Pd(II) catalytic cycle and mechanistic studies revealed that reductive elimination is the problematic step. Decreasing the electron density of the metal center (or formal oxidation) is known to accelerate reductive elimination. This proposal aims at developing several bulky monophosphine ligands that contain a ferrocene unit to reversibly control the electron density on the catalytically metal center, allowing for mil and specific Ar-F bond formation.

Public Health Relevance

Fluorine atoms are key components in many pharmaceuticals;however, incorporating them is generally difficult and requires harsh reaction conditions. This proposal develops a mild and selective method to introduce fluorine into a variety of molecules.

National Institute of Health (NIH)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Barski, Oleg
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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