A target identification platform derived from the bioorthogonal activation of reactive species is described. We explore the reactivity of halogenated enamine N-oxides and report that the previously undisclosed α,γ-halogenated enamine N-oxides can be reduced biooorthogonally by diboron reagents to produce highly electrophilic α,β-unsaturated haloiminium ions suitable for labeling a range of amino acid residues on proteins in a 1,2- or 1,4-fashion. Affinity labeling reagents bearing this motif enable ligand-directed protein modification and afford highly sensitive and selective target identification in unbiased chemoproteomics experiments. Target identification is supported in both cell lysate and live cells.