Potential Safety Hazards Associated with Pd-Catalyzed Cross-Coupling Reactions

The potential safety hazards associated with Pd-catalyzed cross-coupling reactions have been underappreciated and inadequately discussed. These hazards have not been universally recognized in the past decades, perhaps overshadowed by the ubiquity of this class of chemistry and the desire to pursue new scientific advancements. The awareness of these hazards is further limited by the fact that synthetic chemists who develop these types of reactions on small scales are not typically trained in reactive chemistry hazard evaluation, and existing studies from industrial chemists and chemical engineers are often not published in journals that are commonly read by academic groups and synthetic chemists that typically work on small scales. This review summarizes observations of the exothermic behavior associated with the Pd-catalyzed α-arylation, Buchwald–Hartwig amination, Kumada–Corriu, Mizoroki–Heck, Negishi, Sonogashira, and Suzuki–Miyaura cross-coupling reactions. This exothermic behavior is consistently observed across each subset of cross-coupling reactions and appears to be relatively independent of the nucleophile, electrophile, base, solvent, and catalyst system employed. The magnitude of the exotherms poses potential safety hazards that could result in runaway scenarios in cases where the maximum temperature of a synthesis reaction (MTSR) exceeds the solvent boiling point and/or the onset temperature for reaction mixture decomposition. This contribution will serve as an educational resource to encourage researchers to conduct reaction safety evaluations and to develop control strategies accordingly to mitigate such potential safety risks prior to practicing Pd-catalyzed cross-coupling as well as other transition-metal-catalyzed cross-coupling reactions.