Most efforts to covalently inhibit tyrosine phosphatases have focused on phenyl-based scaffolds, building on the structure of the endogenous substrate phosphotyrosine. As noted above, our assessment of chloroacetamides suggests that some heterocyclic scaffolds may be preferable over a phenyl scaffold (Figure ). A comparison of phenyl, benzyl, phenylethyl, and cyclohexyl chloroacetamides showed that an aromatic ring is beneficial near the warhead, mostly likely both for active site binding as well as chloroacetamide activation through inductive effects (Figure ). Our data also revealed that the classical PTP active site cannot tolerate steric bulk close to the chloroacetamide warhead. Substitution of the amide nitrogen with large substituents diminished activity in a variety of contexts (Figure and Figure ), as did introduction of large functional groups at the ortho-position relative to the chloroacetamide (Figure ). For example, we examined a few tertiary alkyl amides that have been used in protein-wide cysteine ligandability studies (compounds 31 and 32) and found that they were not as potent as structurally similar secondary aryl amides, despite their high intrinsic reactivity (Figure ). Recent work in this realm has focused on the development of fragment libraries with even more sterically crowded electrophiles to yield lead fragments with proteome-level selectivity. Our data suggest that the compounds in these libraries may not be optimal for targeting the active sites of tyrosine phosphatases.