Site‐specific incorporation of deuterium into drug molecules to study and improve their biological properties is crucial for drug discovery and development. Herein, we describe a palladium‐catalyzed room‐temperature deuterogenolysis of carbon–oxygen bonds in alcohols and ketones with D2 balloon for practical synthesis of deuterated pharmaceuticals and chemicals with benzyl‐site (sp3 C−H) D‐incorporation. The highlights of this deoxygenative deuteration strategy are mild conditions, broad scope, practicability and high chemoselectivity. To enable the direct use of D2O, electrocatalytic D2O‐splitting is adapted to in situ supply D2 on demand. With this system, the precise incorporation of deuterium in the metabolic position (benzyl‐site) of ibuprofen is demonstrated in a sustainable and practical way with D2O.

Site‐specific incorporation of deuterium into drug molecules to study and improve their biological properties is crucial for drug discovery and development. Herein, we describe a palladium‐catalyzed room‐temperature deuterogenolysis of carbon–oxygen bonds in alcohols and ketones with D2 balloon for practical synthesis of deuterated pharmaceuticals and chemicals with benzyl‐site (sp3 C−H) D‐incorporation. The highlights of this deoxygenative deuteration strategy are mild conditions, broad scope, practicability and high chemoselectivity. To enable the direct use of D2O, electrocatalytic D2O‐splitting is adapted to in situ supply D2 on demand. With this system, the precise incorporation of deuterium in the metabolic position (benzyl‐site) of ibuprofen is demonstrated in a sustainable and practical way with D2O.