Late-stage deuteration and tritiation through bioinspired cooperative hydrogenolysis

Hydrogenolysis, a fundamental chemical process with broad applications, has traditionally been performed using heterogeneous catalysis at high temperatures and pressures with limited selectivity. Recent advancements highlight the potential of homogeneous catalysis as a promising alternative, offering improved selectivity under milder conditions. However, the development of a general homogeneous catalysis approach capable of hydrogenolysing carbon-halogen bonds-one of the most fundamental, versatile and extensively studied functional groups-remains an unresolved challenge. Here we present a comprehensive rationale for the fundamental mechanistic prerequisites crucial to achieving general homogeneous carbon-halogen bond hydrogenolysis, with a particular focus on the tritiation of challenging yet abundant alkyl chlorides. We demonstrate how cooperative interplay of bioinspired carbon-halogen activation and hydrogenation can efficiently catalyse the selective hydrogenolysis of unactivated organohalides. The utility of this approach is demonstrated through its capability to enable deuteration and tritiation of pharmaceutically relevant organohalides with simultaneous control over reactivity and selectivity.