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Using Visible-Light and Photocatalysts to Illuminate Organic Synthesis

Just in the past ten years, the field of photoredox catalysis has emerged as a powerful mode of reactivity in a chemist’s toolbox. At the core of this field is the ability to photo-excite electrons in a photocatalyst, which turns light into chemical energy that can be used to activate molecules with single-electron chemistry to access interesting reactivities. The applications of photoredox has spanned across the pharmaceutical and agrochemical industries, functioning as a mild and robust way to synthesize drug and agrochemical candidates.

More specifically, one such moiety that has been hard to access with classic two-electron strategies is fluorinated motifs. Fluorinated substituents are crucial components of an increasing number of pharmaceutically active molecules because of fluorine’s small atomic size and physicochemical properties, in which C-F bonds resemble C-H bonds. Fluorine’s ability to improve the absorption, bioactivity, and resistance to unwanted metabolism in pharmacologically active materials has driven its frequent incorporation into drugs.

Although fluorine favorably enhances the medicinal properties of compounds and is present in over 25% of commercialized drugs, there are significant challenges toward installing fluorinated motifs in organic substructures. Precedented strategies use highly reactive organometallic or other pyrophoric reagents in two-electron pathways, thereby compromising functional group tolerance. Thus, there is a need for synthesis pathways that occur under milder conditions to allow incorporation of valuable fluorinated groups.

Our group, the Molander group at UPenn, has worked significantly on C-F activation, or bond scission, which is generally hard to perform due to the strength of the C-F bond. In this vein, we have reported a couple strategies to do photoredox-mediated C-F activation. In 2017, we reported the mild visible-light photoredox catalyzed synthesis of gem-difluoroalkenes from diverse trifluoromethyl alkenes in concert with various carbon-radical precursors. In 2019, we demonstrated another method whereby pharmaceutically-relevant benzylic gem-difluoroalkenes could be accessed via the photochemical C−F activation of α-trifluoromethyl alkenes.

Overall, the process of photoredox catalysis and organic synthesis more generally involves rounds of optimization of the reaction conditions. This often involves running several small-scale reactions, varying the reagents, solvents, catalysts, light source intensities, as well as the stoichiometry of the conditions. These reactions are analyzed by different modes of spectroscopy, such as nuclear magnetic resonance (NMR) spectroscopy, gas chromatography – mass spectroscopy (GC-MS), and liquid chromatography – mass spectroscopy (LC-MS). Using knowledge of the location of atoms or masses of the fragments of a desired product, the approximate reaction yield for each condition can be determined. Once the yields are achieved, the conditions can be compared to determine which was the most effective.

The second stage of organic research involves exploring the scope of the reagents. For example, for reactions with two components, each component can be varied with diverse organic structures to assess the functional group tolerance of the reaction. If the scope explores a larger chemical space, the utility of the synthetic method dramatically increases. All of the reactions are placed in chambers with stir plates and either LED or Kessil lights of the appropriate irradiation wavelengths.

Generally, photoredox has emerged as a modern synthetic tool to explore pharmaceutically-interesting scaffolds. Visible light can be harnessed in such a way that bonds that, otherwise would be unreactive, can be broken! Modulating reaction conditions can dramatically change the efficiency of the reaction and adding in new components could pave the route towards new functionalization reactions.

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