Catalytic α‐Site‐Selective Hydrogen‐Deuterium Exchange of Benzylic Alcohols by Palladium Single‐Atom Catalyst

Abstract Catalytic hydrogen‐deuterium exchange (HDE) has emerged as a valuable tool for achieving site‐selective deuteration and the precision labeling of bioactive molecules. Incorporation of deuterium at metabolically labile positions, enabled by such methods, can potentially improve drug efficacy through the kinetic isotope effect. However, achieving precise, site‐selective incorporation of deuterium at specific molecular positions remains challenging. Herein, we report a highly efficient α‐site‐selective HDE of benzylic alcohols via a palladium single‐atom catalyst (Pd SAC). By using the Pd SAC, exceptional activity and selectivity in HDE reactions were achieved, delivering up to 95% deuterium incorporation (D‐inc.) at the α‐position while effectively suppressing undesired pathways (e.g., α,β‐multisite deuteration). Mechanistic investigations reveal that the Pd SAC promotes site‐selective HDE through two distinct surface pathways: (i) a previously unreported direct C─H bond activation and (ii) a modified borrowing hydrogen process in which high‐pressure hydrogen inhibits the keto enol tautomerization, thereby largely circumvents α,β‐multisite deuteration. The catalyst exhibits robust stability, reusability, and broad substrate compatibility, underscoring its potential for practical applications. This work marks a significant advance in heterogeneous single‐atom catalytic methodologies for site‐selective deuteration, offering a complementary solution to longstanding challenges in catalytic organic synthesis.