Biocompatible 'ligand balancing' in transition metal coordination allows benign in-cell protein arylation - 90 min 1f-labelling EXPT - Fragpipe offset search for selectivity

organonickel-mediated S arylation tolerates flexible chelation with biocompatible ligands without ablating the chemical reactivity of corresponding aryl nickel reagents. This, critically, now allows the creation of safe, site-selective C–S-bond-forming arylation manifolds that mimic nature’s use of balanced ligand state. These prove sufficiently benign for use not only on diverse protein substrates in vitro but even on the surface of and inside living prokaryotic and eukaryotic cells. This, in turn, now allows the deepest chemical surveys of reactive cysteines in cells known to date, several-fold outstripping traditional organic reagents (e.g. ~11,000 in human embryonic kidney).