Trace palladium and copper as hidden catalysts in cross-coupling reactions: roles and analytical detection

Abstract

Palladium- and copper-catalyzed reactions are among the most widely employed methodologies in cross-coupling chemistry for the formation of key C–X (X = C, N, O, S) bonds, underpinning the synthesis of pharmaceuticals, agrochemicals, and complex natural products. Considerable efforts have been directed toward developing alternative catalytic systems based on inexpensive metals or organocatalysis; however, many such systems, including those reported as metal-free, are often not truly devoid of ultra-trace amounts of palladium and copper at ppm, ppb, or even ppt levels. This Review highlights systematic approaches for the detection and removal of hidden Pd/Cu impurities that can lead to misinterpretation of metal-free reactivity. It further examines how ultra-low loadings of these metals can still deliver high turnover numbers (TON), thereby influencing mechanistic understanding. This review article also provides a comprehensive framework for identifying trace Pd/Cu metal impurities and elucidating their unnoticed roles in cross-coupling chemistry.