Carboxyl-directed, general α-site-selective deuteration of carboxylic acids by Pd1/CeOx single-atom catalyst

Carboxylic acids are ubiquitous structural motifs in bioactive molecules, making their site-selective deuteration a powerful tool for probing biochemical mechanisms and improving the pharmacokinetic properties of drug molecules. Late-stage H/D exchange offers superiority over de novo synthesis from deuterated precursors, but remains challenging. Here, we report, to our knowledge, the first α-site-selective deuteration method that is compatible with both free amino acids and general (non-amino-acid) carboxylic acids enabled by a regenerable Pd1/CeOx single-atom catalyst. Mechanistic studies reveal that, unlike previously established mechanisms, the reaction proceeds via a carboxyl-directed pathway, relying on synergistic interactions between Pd single atoms and the CeOx support: the CeOx surface anchors the carboxylate, while the Pd mediates α-C − H bond activation. This method features a broad substrate scope and excellent site-selectivity, underscoring its generality and establishing a versatile platform for late-stage isotopic labeling of pharmaceuticals and other complex molecules. Carboxylic acids are widely found moieties in feedstock chemicals as well as biomolecules, and as such, deuterations of scaffolds containing acid functionalities would be of synthetic use. Here the authors report a α-site-selective deuteration method that is compatible with both free amino acids and general (non-amino-acid) carboxylic acids enabled by a regenerable Pd1/CeOx single atom catalyst.