Biocompatible ligand balancing in transition metal coordination enables benign in-cell protein arylation

Metal-mediated chemistries now find increasing application in in vitro biomolecule modification. However, the perceived and potential toxicity of some metals has limited the application of organometallic reagents in more complex biological settings such as inside living cells. Ligands play a crucial role in modulating both the reactivity and availability of transition metals. Here we reveal that organonickel-mediated S-arylation tolerates flexible chelation with biocompatible ligands without destroying the chemical reactivity of corresponding aryl-nickel reagents, enabling the creation of safe, site-selective C-S-bond-forming arylation manifolds. These balanced systems prove sufficiently benign for use on diverse protein substrates in vitro and in living prokaryotic and eukaryotic cells. This, in turn, enables deep chemical surveys of reactive cysteines in human cells with sensitivity sufficient to detect covalently targetable proteins from emerging intracellular viral and bacterial pathogens. Biocompatible ligand balancing thus offers a path to the broader use of transition metals in living systems.