As with photochemistry, electrochemistry is one of the oldest methods for facilitating redox reactions, which still remains the most direct means for accomplishing oxidation and reduction. Presumably due to its heterogeneous nature and lack of protocols that reliably proceed in water, the application of electrochemistry to biomolecule functionalization in complex biological systems is limited. Several recent successful applications in this context rely on the anodic oxidation of triazolinediones, 18 phenothiazines 19 or N-oxyls to capture tyrosine or tryptophan residues in small oligopeptides and in vitro protein labeling. To our knowledge, there is no precedent for electrochemical protein labeling in complex cellular environments. To begin these studies, several criteria were set for a useful functional group for ECAL. To allow minimally invasive placement of a reactive group on drug binding motifs, 9 the desired functional group must be as small as possible, redox-active, stable under physiological conditions, and readily accessible (Figure ). It must also be easily incorporated into a trifunctional monomer that includes orthogonally reactive functional groups such as an alkyne and a carboxylic acid to enable modular incorporation of desired small molecule ligands as well as reporter groups. Most importantly, a highly reactive species should be generated through mild electrochemical activation that can be performed bioorthogonally in a complex cellular environment. Satisfying these criteria is challenging, since redox-active compounds are usually reactive or possess large π-systems, deviating from the ideal probe design. Moreover, the redox potential necessary for activation needs to be ideally within ± 1 V (vs Ag/AgCl), considering the cathodic limit by H2O reduction (around -1 V) and anodic limit by oxidatively labile amino acid residues (Trp 1.02 V, Tyr 0.93 V). On top of these difficulties, generating highly reactive species which rivals to carbenes (reactive species from photochemical activation of diazirines) through electrochemical redox under aqueous conditions in a biorthogonal manner is a demanding requirement. Not surprisingly, there is no such small motif known in the literature to satisfy all of these criteria. Accordingly, our explorations began by surveying a wide range of redox-active small molecules that could generate reactive species (Figure ). Some of them were inspired by existing literature, and others were designed based on first principles. For example, reductive means of activation on structures 1-3 were hypothesized to lead to reactive species such as vinylidene carbenes, 21 quinone methides, and carbenes, respectively. Unfortunately, these strategies were barely successful from the standpoint of stability, size, accessibility, and modularity. Oxidative modes of activation were also explored on structures 4-9 wherein reactive carbenes, diazonium, 24 benzynes, sulfeniums, and acyl pyridiniums 26 could potentially be formed. Yet, these precursors showed no promising reactivity in a model study and were not further optimized or explored due to similar issues facing the reductive approach. Nevertheless, the oxidative approach was further pursued considering the fact that reactive species generated under oxidative conditions would likely be electrophilic, suitable for targeting peptides or proteins in which reactive amino acid residues are usually nucleophilic. The lesson from these exploratory studies and literature precedent was that hydrazine-containing species might be a promising motif due to their ease of oxidation under mild conditions.