Visible‐Light‐Induced ArC(sp³)−F Bond Activation in Aqueous Media: From DFT Study to Molecular Design

Trifluoromethylarenes (ArCF₃) are crucial bioisosteres in medicinal chemistry, but catalyst-free and controlled photo-activation of the ArC(sp³)-F bond remains a significant challenge. The photo-induced defluorination acyl fluoride exchange (photo-DAFEx) of m-trifluoromethylaniline, induced by ultraviolet light, emerges as a promising novel photo-click reaction for photoaffinity drug discovery. However, the photophysical properties of NMe₂PhF₂C(sp³)-F derivatives and factors affecting ArC(sp³)-F bond activation in photo-DAFEx are not yet fully understood, hindering the development of new photo-defluorination reagents with longer absorption wavelength for the photo-DAFEx. Herein, the photophysical properties, the related mechanism and their affecting factors of a series of ArCF₃ compounds are systematically studied using (TD)DFT methods. The skeleton of aromatic core is found to be intimately related to the absorption wavelength needed for ArC(sp³)-F bond activation. A photo-induced intramolecular single-electron activation model was proposed to rationalize the photo-activation of the ArC(sp³)-F bond. The transfer of excited electron to C(sp³)-F antibonding orbital determined the activation. Based on the above knowledge, three novel ArCF₃ reagents with extended excitation wavelength were designed and predicted, and the absorption spectra and photo-defluorination reactivity of two of them with visible absorption wavelength were validated experimentally, which provided a theoretical guidance for designing next-generation photo-DAFEx.