Coupling and optimisation of online nuclear magnetic resonance spectroscopy and mass spectrometry for process monitoring to cover the broad range of process concentration

Abstract

Real time online monitoring of chemical processes can be carried out by a number of analytical techniques, including optical and vibrational spectroscopies, nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). As each technique has unique advantages and challenges, combinations are an attractive option. The combination of a 500-MHz H NMR and a small footprint mass spectrometer to monitor a batch reaction at process concentration was investigated. The mass spectrometer was coupled into the flow path of an online reaction monitoring NMR. Reaction mixture was pumped from a 100-ml vessel to an NMR flow tube before returning to the vessel. Small aliquots were diverted into a sampling make-up flow using an active flow splitter and passed to the mass spectrometer. Advantages of the combination were observed. H NMR was ideal for quantitation of high level components, whereas MS showed a greater capability for detecting those at low level. In preliminary experiments MS produced a limited linear relationship with concentration (0.02% to 2% relative concentration, 0.01 mg/ml-1.25 mg/ml), because of signal saturation at the higher concentrations. NMR was unable to detect components below 0.1% relative to concentration maximum. Optimisation of sample transfer to the MS extended the linearity to 10% relative to the concentration maximum. Therefore, the combination of online NMR and MS allows both qualitative and quantitative analysis of reaction components over the full process range. The application of the combination was demonstrated by monitoring a batch chemical reaction and this is described. Copyright © 2016 John Wiley & Sons, Ltd.

Intelligent Microfluidics: The Convergence of Machine Learning and Microfluidics in Materials Science and Biomedicine

“…The resultant data can then be analyzed via machine learning to optimize and study the contributions of experimental parameters, 14,42 for example via reinforcement learning. Mass spectrometry, 42 nuclear magnetic resonance, 21 Raman spectroscopy, 152 or infrared spectroscopy 153 can be used to monitor reactions in real time, 154 while brightfield microscopy can be used to monitor flow rates, 49 fluid properties, 52 chemical composition, 50 or mixing. 155 Other techniques must be adapted depending on the application; for example, infrared thermography was demonstrated effectively monitor Schematic of an intelligent microfluidic platform including microfluidic chips coupled to miniaturized instrumentation such as an in situ bio-electrochemical multisensor platform, 160 optical probing, mass spectrometry, 42 spectroscopy (e.g., nuclear magnetic resonance, 21 Raman, 152 or infrared), 153 and microscopy (e.g., brightfield or fluorescent).…”

Engineering aspects of FlowNMR spectroscopy setups for online analysis of solution-phase processes

“…In this article we shall focus on closed-loop FlowNMR setups for investigating batch processes, but many of the considerations discussed will be relevant to continuous flow application as well. 26,27 A number of flow devices have been developed that allow a continuous stream of sample solution to be pumped through the NMR active region of the spectrometer, [28][29][30][31][32][33][34][35][36] developments that actually date back to early days of NMR spectroscopy in the 1950s. 37 Recent examples include the use of FlowNMR coupled with oxygen probes in the elucidation of the mechanism of amination reactions, 38 the development of low-volume flow system containing biological organisms within the flow tip for solution-state in vivo NMR, 39 the use of ultra-fast single scan 2D NMR in flow 40 and the real-time monitoring of oxidative wastewater treatment.…”

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

“…In addition to traditional offline LC–MS reaction monitoring, online, direct MS analysis has proven to be a useful tool for characterizing many aspects of chemical reactions. Recently, the use of small footprint, portable mass spectrometers has attracted attention in the field of online reaction monitoring due to their compactness and versitility, with batch and flow reaction monitoring (including starting material, intermediate, and product) as well as kinetic profiling using online mini-MS having been demonstrated. , As shown in Table S1, mini-MS reaction monitoring has been applied in a wide variety of reaction types and substrates, including nitrogen-containing heterocycles, ethers, ketones, esters, and amides. However, most previous studies focused mainly on monitoring the abundance ratio of starting material (SM) versus product for reaction kinetic profiling, which is useful only for a rough estimation of the reaction conversion/kinetic profile and is unsuitable for more accurate reaction quantitation. − In general, the use of a reference standard (RS) in LC–MS is regarded as the best practice for quantitation.…”