Monitoring Pd-Catalyst Speciation in Biphasic Suzuki Reactions: Insights from Flow-NMR and Online HPLC-MS

High Resolution Image Download MS PowerPoint Slide Pd-catalyzed cross-coupling reactions are versatile reactions widely used across industrial and academic settings. Pd catalysts display dynamic speciation throughout the course of a reaction. This speciation is often a key factor governing reaction outcomes. However, difficulties in the direct observation of such dynamic low-concentration species limit our ability to optimize reactions guided by this speciation. Herein, we report the use of DirectInject-LC and high-field flow-NMR to study the Pd speciation during a Suzuki cross-coupling. Biphasic reaction conditions representative of industrially relevant Suzuki processes were selected; by extending our phase-selective sampling platform to integrate both NMR and HPLC analysis, we enabled a comprehensive kinetic interrogation of catalyst and reagent speciation across aqueous and organic phases. Complementary time course data obtained from both HPLC-MS and NMR allowed the optimization of catalyst activation, reaction execution, and elucidation of the main transmetalation pathway in the reaction studied herein. The ability to obtain phase-selective speciation data was key in the generation of a kinetic model that verified the final mechanistic conclusions.