Fast Multidimensional Flow Nuclear Magnetic Resonance at High Field for Real-Time Reaction Monitoring and Flow Synthesis

Flow nuclear magnetic resonance (NMR) at high field is a powerful approach for the online monitoring of chemical reactions, which provides real-time quantitative and structural information. While 1D ¹H spectra are commonly collected for NMR monitoring applications, their information content is limited because of peak overlap and assignment ambiguity. 2D NMR methods provide an opportunity to resolve peaks that overlap in 1D spectra and obtain correlation information that helps assignment. Their fast implementations additionally have durations (from sub-second to minute) that remain compatible with a large range of online reaction monitoring applications. They are also expected to benefit flow synthesis applications in which a flow reactor is hyphenated with a high-field NMR spectrometer. Herein, a selection of fast 2D NMR methods that are compatible with flow NMR applications is described: ultrafast 2D NMR and fast diffusion-ordered NMR spectroscopy. After a description of an experimental setup and current best practices, the principle behind each method and the way in which it can be implemented for continuously flowing samples are described. Also, the flow effects that are specific to these methods, for different settings, are described. These fast 2D NMR methods should be useful to users of flow NMR with an interest in reaction monitoring.