Metal-free hydrogenation of viologens to piperidine derivatives for bacterial inhibition

Abstract

The hydrogenation of aromatic viologens to their non-aromatic derivatives holds promise for biomedical and materials science applications. Conventional hydrogenation methods, however, rely on harsh reductants and high-cost metal catalysts. Here we report a safe, metal-free hydrogenation strategy that uses formic acid as a sustainable reductant, facilitated by an azeotropic mixture with N,N-dimethylformamide. This method enables the efficient conversion of diverse viologen derivatives into their reduced 4-(piperidin-4-yl)-3-piperideine counterparts. A key advantage of this process is the tendency of the products to undergo spontaneous crystallization, streamlining purification and enabling direct structural characterization. We demonstrate the broad applicability of this transformation across a range of architectures, including viologen-based small molecules, macrocyclic compounds and porous organic frameworks. Mechanistic investigations integrating mass spectrometry, single-crystal X-ray diffraction and density functional theory calculations reveal a reduction pathway analogous to the Eschweiler–Clarke and Lukeš reactions. In addition, several reduced scaffolds demonstrate antimicrobial activity. A metal-free hydrogenation method converts rigid aromatic viologen units into flexible piperidine-based structures using formic acid. The transformation induces pronounced conformational changes in macrocycles and extends across diverse architectures, providing access to functional piperidine materials with potential antimicrobial activity.