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

Abstract

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/CeO_x 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 CeO_x support: the CeO_x 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.