Online High-Performance Liquid Chromatography Analysis Of Buchwald-Hartwig Aminations From Within An Inert Environment

Obtaining data-dense reaction profiles for reactions performed under an inert atmosphere remains a significant challenge obfuscating mechanistic analysis. To this end, we have developed a reaction monitoring platform capable of automated sampling and online HPLC analysis to generate temporal profiles for reactions performed from within a glovebox. The device allows for facile reaction progress analysis to aid in mechanistic studies of air-sensitive chemical transformations. The platform has demonstrated high reproducibility regarding sample mixing, dilution, delivery, and analysis. We employed the sampling platform to acquire temporal profiles for a series of Buchwald-Hartwig aminations. Parallel coupling reactions using iodobenzene and bromobenzene both exhibit complex kinetics. A competition reaction including both aryl halides demonstrated high selectivity for iodobenzene indicative of catalyst monopoly. The temporal profile for the difunctionalized substrate 1,4-iodobromobenzene was unexpected based on our parallel and competition studies and is indicative of a distinct underlying mechanism. We attribute this unanticipated reactivity to intramolecular catalyst transfer through the p system as seen in "living" polymerization transfer catalyst systems. The use of this automated sampling platform has greatly increased mechanistic understanding despite performing only a small number of experiments.