Recyclable Palladium-Polysiloxane Catalyst with Ultra-Low Metal Leaching for Drug Synthesis.

A carbon-supported palladium-containing polysiloxane macrocatalyst (Pd-PDMS) was developed for pharmaceutical-grade cross-coupling reactions. The catalyst demonstrates exceptional year-long stability at room temperature while maintaining full catalytic activity. Pd-PDMS efficiently promotes three pharmaceutically relevant reactions: Suzuki coupling (80% yield), copper-free Sonogashira coupling (90% yield at 55 °C), and Heck coupling (80% yield at 90 °C). The copper-free Sonogashira protocol eliminates toxic copper cocatalysts, phosphine ligands, and organic bases while operating under mild conditions. Most significantly, palladium contamination in products reaches ultra-low levels of 22 ppb (Sonogashira, Suzuki) and 167 ppb (Heck), representing a 60-450-fold improvement over European Medicines Agency requirements (10 ppm). The catalyst exhibits excellent recyclability without activity loss over multiple cycles, with simple washing protocols between uses. Scanning electron microscopy and X-ray photoelectron spectroscopy confirmed uniform Pd-PDMS coating on carbon fibers, while density functional theory calculations revealed specific coordination interactions between the palladium complex and carbon support at 3.26 Å distance. This convergence of pharmaceutical-grade metal contamination control, exceptional stability, and multi-reaction versatility establishes a significant advancement for sustainable cross-coupling catalysis in pharmaceutical applications.