Mechanistic Insight into Site-Selective Tritiation of Aryl Hydrogen without Directing Groups: Origin of Palladium-Catalyzed Cleavage of Dihydrogen

Tritium labeling has become an important tool for studying the pharmacokinetics and pharmacodynamics properties of drugs. Recently, a molecular palladium-catalyzed homogeneous hydrogenolysis reaction was reported. Despite the great efforts made by the experimental group, details regarding the mechanism remain unclear. In this work, detailed density functional theory calculations were carried out to elucidate the principal features of this transformation. The results reveal that the following. (1) The H–H bond dissociation of aryl palladium dihydrogen is the rate-determining step of the protocol with a total energy barrier of 22.3 kcal/mol. (2) In this system, the hydrogen molecule forms η2-dihydrogen complexes with metallic palladium via σ donor–receptor interaction. (3) Aryl thianthrene salts are critical to this strategy. Easier oxidative addition of aryl halides to metallic palladium severely inhibits the coordination of hydrogen molecules to palladium and is detrimental to the subsequent dissociation of the H–H bond. (4) The counterion BF4– can effectively promote the conversion and lower the potential barrier, but the halide negative ion prevents the combination of palladium with hydrogen due to its stronger binding to palladium, resulting in low yields of the main product.