Photocatalytic Activation of Aryl(trifluoromethyl) Diazos to Car-benes for High-Resolution Protein Labeling with Red Light

State-of-the-art methods in photo-proximity labeling center on the targeted generation and capture of short-lived re-active intermediates to provide a snapshot of local protein environments. Diazirines are the current gold standard for high-resolution proximity labelling, generating short-lived aryl(trifluoromethyl) carbenes. Here, we present a meth-od to access aryl(trifluoromethyl) carbenes from a stable diazo source via tissue penetrable, deep red (DR) to near-infrared (NIR) light (600-800 nm). The operative mechanism of this activation involves Dexter energy transfer from photoexcited osmium(II) photocatalysts to the diazo, thus revealing an aryl(trifluoromethyl) carbene. The labeling preferences of the diazo probe with amino acids are studied, showing high reactivity towards heteroatomH bonds. Upon synthesis of a biotinylated diazo probe, labeling studies are conducted on native proteins as well as proteins conjugated to the Os photocatalyst. Finally, we demonstrate that conjugation of a protein inhibitor to the photocatalyst also enables selective protein labeling in the presence of spectator proteins.