Deuteration of Arenes in Pharmaceuticals by S E Ar Mechanism with Heavy Water Using p TSA Catalyst

Aromatic rings are widely recognized in the realm of natural products and bioactive molecules, highlighting their importance in various applications. The development of deuterated analogues of pharmaceuticals is particularly significant in pharmaceutical and medicinal chemistry. In this study, we present a novel catalytic method for hydrogen/deuterium (H/D) exchange in aromatic compounds, using cost‐effective, readily available D 2 O as the deuterium source. This approach demonstrates impressive deuterium incorporation under mild reaction conditions, yielding good to excellent results in a single run. Utilizing para ‐toluenesulfonic acid as a catalyst, this metal‐free protocol exhibits broad applicability in the late‐stage deuteration of a variety of bioactive molecules, pharmaceuticals, and small molecules. Furthermore, our method is scalable; it has been successfully implemented at the gram‐scale with a reduced catalyst loading of 2.0 mol% for Tyrosol, illustrating its practical utility. Moreover, our thorough mechanistic studies and detailed density functional theory studies enhance our understanding of how the catalyst and solvent contribute to the aromatic electrophilic substitution process. This innovative method provides a sustainable alternative to traditional transition metal‐catalyzed H/D exchange techniques.