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Abstract Imidazole‐1‐sulfonyl and ‐sulfonate (imidazylate) are widely used in synthetic chemistry as nucleofuges for diazotransfer, nucleophilic substitution, and cross‐coupling reactions. The utility of these reagents for protein bioconjugation, in contrast, have not been comprehensively explored and important considering the prevalence of imidazoles in biomolecules and drugs. Here, we synthesized a series of alkyne‐modified sulfonyl‐ and sulfonate‐imidazole probes to investigate the utility of this electrophile for protein binding. Alkylation of the distal nitrogen activated the nucleofuge capability of the imidazole to produce sulfonyl‐imidazolium electrophiles that were highly reactive but unstable for biological applications. In contrast, arylsulfonyl imidazoles functioned as a tempered electrophile for assessing ligandability of select tyrosine and lysine sites in cell proteomes and when mated to a recognition element could produce targeted covalent inhibitors with reduced off‐target activity. In summary, imidazole nucleofuges show balanced stability and tunability to produce sulfone‐based electrophiles that bind functional tyrosine and lysine sites in the proteome.