An original concept for catalytic electrochemical dehydration has enabled a suite of acid substitutions, including amidation, esterification, and thioesterification, through a linchpin anhydride formed in situ. By avoiding stoichiometric dehydrating agents, this method addresses a leading challenge in organic synthesis and green chemistry. It also proceeds without acid additives at room temperature, accesses a diverse range of product structures, is easily scaled, and enabled the first example of catalytic peptide coupling at room temperature.