Online Screening of Homogeneous Catalyst Performance using Reaction Detection Mass Spectrometry

Abstract

An integrated online screening system was developed to rapidly screen homogeneous catalysts for activity toward a selected synthesis. The continuous-flow system comprises standard HPLC pumps for the delivery of substrates, an HPLC autosampler for the injection of homogeneous catalysts, a thermostated reactor to mediate synthesis, and a single-stage quadrupole mass spectrometer (MS) equipped with atmospheric pressure chemical ionization for the determination of product formation. MS detection offers sensitivity, specificity, and speed when applied to the analysis of dynamic processes in the condensed phase. By applying the present methodology for the study of substrate conversion mediated by homogeneous catalysts, the concentration of substrates and reaction product could be monitored while information about the catalysts could also be obtained. In an initial screening application, the performance of a selected number of Lewis acids in the multicomponent synthesis of a highly substituted 2-imidazoline was determined. Limit of detection and limit of quantitation were determined by injecting different concentrations of 2-imidazoline standards and proved to be 1.6 and 5.2 nM, respectively. The results obtained with the new screening method were in good agreement with a traditional bench-scale experiment. Moreover, the system was capable of determining catalyst performance with very low catalyst and solvent consumption while the ruggedness of the system was exhibited with a 24-h continuous analysis of 280 successive catalyst injections with a peak area variation within 7% relative standard deviation.

The Flow’s the Thing…︁Or Is It? Assessing the Merits of Homogeneous Reactions in Flask and Flow

“…Microflow operation has also been employed to advantage for rapid screening of catalysts, substrates, and reaction types. [19] High throughput resulting from "scale-out", the setting up of multiple flow reactors in parallel, has also been suggested as an advantage, although, as demonstrated in the example above, this may not be practical in every case and may be more advantageous for the continuous long-term operation more often associated with the production of bulk chemicals rather than pharmaceuticals. These points must be weighed against the added cost of construction and technical complexity of such systems.…”

“…[22] The ability to monitor reaction progress virtually continuously in a flask reactor by a variety of methods (commonly including immersible spectroscopic probes and reaction calorimetry) has become commonplace over the past several decades, while in situ detection remains a key challenge for microflow reactor systems. In the absence of special construction or implementation of special analytical devices, [19] microflow systems rely on discrete sample collection at the reactor outlet followed by analysis, typically by HPLC or an ex situ spectroscopic technique.…”

High‐Throughput Reaction Optimisation and Activity Screening of Ferrocene‐Based Lewis Acid–Catalyst Complexes by Using Continuous‐Flow Reaction Detection Mass Spectrometry

“…The temperature dependence of this MCR to give 5 has been investigated previously. [7] By introducing the AgOTf catalyst at different temperatures, an optimum temperature curve was obtained. Although the highest temperature yielded …”

“…[6] Recently, a continuous-flow reaction detection screening system was introduced that was used for the determination of catalyst performance in synthetic conversions. [7] The feasibility of using this approach for the assessment of catalyst activity towards a selected synthetic conversion was demonstrated by the performance screening of a selected number of homogeneous Lewis acid catalysts for a synthetic conversion in tetrahydrofuran (THF). The results proved to be comparable to the results obtained with a traditional benchscale experiment.…”

Der Fluss ist das Ding …︁ oder ist er es? Ein Vergleich homogener Reaktionen in Reaktionskolben und Durchflussreaktoren

“…Mikrodurchflussverfahren wurden auch sehr erfolgreich für das schnelle Screening von Katalysatoren, Substraten und Reaktionsmechanismen eingesetzt. [19] Der parallelisierte Einsatz von Durchflussreaktoren im Hochdurchsatz wurde ebenfalls vorgeschlagen, wenngleich dies -wie im obigen Beispiel gezeigt -nicht in jedem Fall praktikabel sein dürfte und sich eher für kontinuierliche Prozesse anbietet, wie sie oft in der Produktion von Großchemikalien angewendet werden, nicht aber von Pharmazeutika. Diese möglichen Vorzüge müssen gegen die zusätzlichen Kosten für den Aufbau solcher Systeme abgewogen werden.…”