Hydrogen Bond Directed Photocatalytic Hydrodefluorination: Overcoming Electronic Control

Abstract

The photocatalytic C–F functionalization of highly fluorinated arenes is a powerful method for accessing functionalized multifluorinated arenes. The decisive step in the determining regioselectivity in fluorine functionalization is fluoride fragmentation from the radical anion of the multifluorinated arene. To date, the availability of regioisomers has been dictated by the innate electronics of the fluorinated arene, limiting the synthetic utility of the chemistry. This study investigates the remarkable ability of a strategically located hydrogen bond to transcend the normal regioselectivity of the C–F functionalization event. A significant rate acceleration is additionally observed for hydrodefluorination of fluorines that can undergo intramolecular hydrogen bonds that form 5–8 membered cycles with moderately acidic N–Hs. The hydrogen bond is expected to facilitate the fragmentation not only by bending the C–F bond of the radical anion out of planarity, but also by increasing the exothermicity of the fluoride extrusion step through protonation of the naked fluoride. Finally, the synthetic utility of the method is demonstrated in an expedited synthesis of the trifluorinated α-phenyl acetic acid derivative required for the commercial synthesis of Januvia, an anti-diabetic drug. This represents the first synthesis of a commercially important multifluorinated arene via a defluorination strategy, and is significantly shorter than the current strategy.

Visible‐Light‐Induced Selective Defluoroborylation of Polyfluoroarenes, gem‐Difluoroalkenes, and Trifluoromethylalkenes

“…Theh ydrogen bond might facilitate the fragmentation step and direct the regioselectivity to overcome the innate electronics of the fluorinated arene substrates. [30] 5) Hydroborylation may occur to produce dearomatization products if aproton was located at the para-position of an electron-withdrawing group (1t,1x, 1y, and 1aa). Notably,i ns ome cases,s uch as 3c and 3j,t he regioselectivity is different from that obtained with the transition-metal-catalyzed processes where ortho defluoroborylation was observed, [9c, 10b,17] providing an orthogonal strategy for regioselective defluoroborylation of polyfluoroarenes.…”

Photocatalytic Hydrodehalogenation for the Removal of Halogenated Aromatic Contaminants

“…In an advantage over using traditional hydrogenation reagents (e. g., Si‐ or Al‐hydride), this method not only employed inexpensive amine as the hydrogen donor but also demonstrated excellent selectivity and functional group compatibility, with a turnover number up to 22500. Using this complex, the same group further controlled the regioselectivity of defluorination by introducing N‐acetylated functionality . The intramolecular hydrogen bond between the acidic N−H and the C−F bond enforces a configuration where the F is located outside the aromatic plane, facilitating bond breaking after electron transfer.…”

Light-driven activation of carbon-halogen bonds by readily available amines for photocatalytic hydrodehalogenation

“…Light-driven activation of carbon-halogen bonds (C-X) has become a powerful approach for constructing new chemical bonds in valuable pharmaceutical and industrial intermediates, as well as for the elimination of polyhalogenated aromatic pollutants [1][2][3][4][5][6][7][8]. Essentially, the process relies on high-energy excited states/intermediates that trigger electron transfer to cleave carbon-halogen bonds (C-X + e -→ C• + X -, dissociative electron transfer), affording carbon radicals that can engage in diverse reactions, including hydrogenation and cross coupling [9][10][11][12][13][14][15][16][17][18]. For a thermodynamically favored process, energy levels of the photogenerated species should locate above the an-ti-bonding σ* or π* orbital of halogenated substrates.…”