Quantitative Perspective on Online Flow Reaction Profiling Using a Miniature Mass Spectrometer

Abstract

Online mass spectrometry has proven to be a useful tool for characterizing many aspects of chemical reactions. However, to the best of the authors' knowledge, no reference standard (RS) quantitation approach has been applied in online MS profiling work to date. In this study, we present a RS approach for online quantitation of an aerobic oxidation reaction in flow using a miniature mass spectrometer, with both internal RS and external RS quantitation approaches being evaluated. Quinoline, a structurally similar and chemically inert compound under these reaction conditions, was chosen as the RS to quantify the pyridine aldehyde product. To investigate the optimal RS concentration and instrument attenuation, calibration curves were established by plotting the product/RS peak intensity ratio against the theoretical product yield at different attenuation (dilution factor) values. The MS quantitation results for the actual flow reactions were validated with conventional offline 1 H NMR analysis.

Development of setups for real-time analysis of the effluent of a microreactor by mass spectrometry

“…To be robust, the coupling of a µR with an MS detector for real-time monitoring requires designing adapted set-ups allowing high adaptability (concentration level of reagents, nature of the reaction solvent, nature and number of monitored compounds…) while maintaining the performance of the mass analyzer. Different studies related to the use of MS to monitor a chemical reaction have already been published (1,3,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) (see Table S1 in supplementary materials). Most of the oldest studies involved directing the entire flow from the µR directly into the MS ionization source (1,(7)(8)(9).…”

“…Some of these studies described the use of solvents, such as dichloromethane (DCM) or toluene, which are not recommended in MS as they are too volatile to be infused at 100% in the ionization source, but which were sufficient for the identification of reaction products, their quantitation of being not the objective of these studies. The introduction of a single T-piece to dilute the µR effluent with an MS-compatible solvent (10) and of a second T-piece allowing to split the effluent and then decrease the flow-rate entering the ionization source was also proposed (3,11,12,(15)(16)(17). Even if the objective was only a qualitative monitoring of the produced compounds, one of this study showed that the composition of this MS-compatible solvent (proportion of acetonitrile (ACN) in water and nature of the acid additive) strongly affects the MS signal of the monitored compounds (3).The dilution of the whole µR effluent was also achieved by digital microfluidic by merging droplets (14).…”

“…Even if the objective was only a qualitative monitoring of the produced compounds, one of this study showed that the composition of this MS-compatible solvent (proportion of acetonitrile (ACN) in water and nature of the acid additive) strongly affects the MS signal of the monitored compounds (3).The dilution of the whole µR effluent was also achieved by digital microfluidic by merging droplets (14). Other studies consisted in developing devices to transfer to MS only a fraction of the reactor content with a solvent chosen for its miscibility with the synthesis solvent and its better compatibility with MS. For this, some groups proposed to use conventional switching valves equipped with a 60 nL- (15) or a 5 µl-loop (12), whereas others used an available commercial "mass rate attenuator" (MRA, Rheodyne) device allowing to pick-up and transfer three different aliquots of a fixed volume (22, 100, and 300 nL), with switching frequencies that range from 0.2 to 2.0 Hz, using a transfer solvent thus allowing a dilution factor of 1,000 to 6,666, the resulting effluent being next split before entering into the MS ionization source (3,16,17). In conclusion, more or less complicated setups allowing the monitoring of chemical reactions were developed.…”

“…Moreover, most of the studies reported in literature (77% of the cited works) concern qualitative or semi-quantitative analysis, the latest consisting in studying the evolution of the signal when varying some experimental parameters such as the temperature of the µR (3) or for kinetic studies (8,12) and polymer growth (11). Concerning the two quantitative studies [15,17], only the loop and then the dilution/divider assembly were at the miniaturized scale as opposed to the reactor in the first one (15). In the second one, the set-up was based on the commercial MRA system, which allows to transfer an aliquot of the reaction mixture to MS while ensuring a dilution step with a MS compatible solvent (17).…”

Online monitoring of small volume reactions using compact liquid chromatography instrumentation

“…More recently, a compact LC‐UV‐MS instrument was coupled to commercial reaction vessels and larger reaction workstations, primarily focused on online process monitoring in a pharmaceutical industry setting [11]. The same compact MS has also been coupled directly to a reaction vessel for sampling, using an in‐line membrane‐based phase separator rather than a chromatographic separation [23]. In this study, an integrated compact LC platform using capillary column cartridges was implemented for online monitoring of smaller reaction volumes (on the order of 10–30 mL) with a standard syringe pump for sampling, representing a common strategy that may be used in academic and small‐scale R&D environments as an alternative to some larger‐scale automated samplers [24].…”