Mechanistic analysis is important for the development and optimization of catalytic reactions. Real-time reaction monitoring coupled with process analytical technology provides a broad perspective of the reaction system and its kinetics, which in turn allow for mechanistic elucidation. During the development of a Pd-catalyzed C-N coupling to access a chiral active pharmaceutical ingredient (API), an unexpected phenomenon was observed whereby higher Pd catalyst loadings apparently suppressed the epimerization of the product. The process by which this epimerization occurs, as well as how the Pd-catalyst could affect this epimerization remained unresolved.<br/>Using online HPLC-MS as a powerful tool to elucidate transient processes, we studied the epimerization of the target API as well as several model systems, to delineate both the mechanism of epimerization as well as the role the Pd-catalyst plays in mitigating this process. Online HPLC-MS time course profiles have enabled real-time quantification of the conversion between stereoisomers and Pd-suppressed epimerization under heterogeneous conditions. This technique has clarified several substrate decomposition processes, and allowed for new hypotheses to be proposed for the role of the Pd-catalyst. We have further shown that it is possible to interrogate the catalyst speciation via online HPLC-MS, giving the distribution of the Pd-precatalyst and its oxidative addition complexes over time. Altogether, this project demonstrates that online HPLC-MS is a unique and powerful tool for directly interrogating complex catalytic systems.

Applying online HPLC-MS to the mechanistic investigation of Pd-mediated processes

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