Clean 1H NMR Spectra of Products Directly from Batch and Flow Reaction Mixtures

Abstract

Nuclear magnetic resonance (NMR) spectroscopy is widely used for the monitoring of chemical reactions. Flow NMR methods are being increasingly used to monitor reactions carried out in either batch or flow synthesis mode. Kinetic information is commonly obtained by integration of assigned peaks across a series of spectra. However, the complexity of NMR spectra in reaction mixtures can result in peak overlap and assignment issues, which make it difficult to recover the clean complete spectrum of compounds involved in the reaction. Multiway analysis methods can in principle be used to separate information on compounds in a mixture, but they are demanding on the quality and form of the input data. Herein, it is shown how the multiway analysis of time-resolved diffusion NMR data can yield the clean spectrum of newly formed compounds, for a selection of click reactions carried out in batch and in flow, when monitored by flow NMR. The use of a fast and robust diffusion NMR approach, together with careful processing, yields high-quality data, even for continuously flowing samples, which was previously inaccessible. Multiway analysis then yields 1D ¹H spectra together with concentration changes. The proposed approach is expected to be particularly useful for reaction monitoring applications.