Pyramidalized N [sp behavior of DZEs is not reported. Thus, the model DZE 11 was prepared, and detailed analysis of 11 was conducted by X-ray crystallography as well as cyclic voltammetry (CV) (Figure , Figure ). Interestingly, X-ray crystallographic analysis revealed that the amide nitrogen is considerably pyramidalized due to the highly strained four-membered ring, a rare example of twisted amides. Furthermore, a cyclic voltammetric study clearly suggested that 11 is indeed redox-active, although the oxidation peak around 1 V is ill-defined under the cyclic voltammetric conditions. Bulk electrolysis of 11 in the presence of benzylamine afforded an amide product 12 in moderate yield without significant oxidation of benzylamine, suggesting compatibility to reactive nucleophilic residues in peptides and proteins. Only a trace amount of 12 was observable without electrolysis, indicating that 11 is mostly unreactive during the timescale of the control experiment (2.5 h). The formation of amides as well as deuterium incorporation at the α-position to the carbonyl support the hypothesis of a ketene as the reactive intermediate. Having demonstrated electrochemical activation of this latent functional group, we next designed a minimalist trifunctional monomer ( ) consisting of a carboxylic acid group for ligand attachment, a reporter handle, and a DZE warhead. The key DZE intermediate 14 can be conveniently accessed from the carboxylic acid 13 in one step by [2+2] cycloaddition between the corresponding ketene and di-t-butyl azodicarboxylate (Figure ). Amide bond formations and click reactions can be used for attaching various ligands and reporter tags as exemplified through the synthesis of nine small molecule ligand-based DZE probes (see SI for complete listing).