Nature has a delicate system for catalysis due to optimization through evolution, which often displays unparalleled efficiency and selectivity. "Learning from nature" is a popular and effective approach in designing alternative reactions and catalysts when traditional strategies fail. Here, we demonstrate that it can be highly rewarding to consider nature's repertoire of catalysis during the effort to facilitate the challenging heterolytic C-O bond cleavage of methanol (MeOH). Inspired by MeOH metabolism by methyltransferase complex in certain methanogenic microorganisms that contain a Brønsted acid cluster flanked by a Zinc moiety, we successfully identify the combination of an easily available Brønsted acid and Zn(OTf)2 as a highly efficient and practical binary catalyst for cooperative MeOH activation. This strategy enables the direct application of MeOH in various important methylation reactions, including some of those carried out in large scale in industry with significantly increased selectivity under relatively less demanding conditions. Mechanistic studies and density functional theory (DFT) calculations suggest a synergy between the Brønsted acid and Zn(OTf)2, suggestive of that found in methanol-activating MtaBC complex in Methanosarcina barkeri.
© 2025. The Author(s).