Benchtop NMR spectrometers for the in-line monitoring of continuous flow reactions

Unlike biology, which has been making extensive use of automation techniques since the 1970s, synthetic chemistry has been more reluctant to open up to new technologies. While synthetic chemistry has benefited greatly from improvements in analytical tools, notably thanks to the appearance of nuclear magnetic resonance (NMR) spectrometers in research laboratories from the 1970s onwards, it has benefited little from technological tools for conducting chemical reactions. If Marcelin Berthelot (1827-1907), one of the most eminent French chemists of the 19th century, were to visit an organic chemistry research laboratory in the 21st century, he would discover that, like him 150 years ago, chemists are still using standardized glassware to conduct chemical reactions. This situation can be explained by the fact that synthetic chemists have naturally preferred to study the content (reaction mixture) rather than the container (reactor, experimental set-up...). Of course, this somewhat caricatured situation is tending to change more and more rapidly.

One of the first turning points was the use of automatic peptide synthesizers in the nineties, followed by the arrival of microwave reactors as alternative heating devices to traditional methods based on electrical convection. However, it wasn't until the 2000s that traditional synthesis techniques underwent profound change with the advent of miniaturized flow chemistry. The latter has revolutionized the way in which chemical reactions are carried out, particularly as it enables previously impossible reactivities to be achieved under safer conditions. Many academic and industrial laboratories are now equipped with commercial devices.

At the same time, NMR made a spectacular "return to the future" with the development and marketing of benchtop spectrometers operating at low fields between 40 and 80 MHz for the proton. These resonance frequencies were typical of those used in the 1970s, but with equipment that did not benefit from the miniaturization of modern benchtop spectrometers. To achieve this degree of miniaturization, the physics associated with these new devices has been significantly modified compared with traditional high-field devices. These new benchtop spectrometers hold out the promise of a revolution in various fields of chemical science, and in particular for the (near-)real-time analysis of chemical transformations.

This article deals with the use of bench-top (i.e. transportable) spectrometers operating at low magnetic fields for the reaction monitoring of transformations carried out in continuous flow reactors. This emerging field of research has already led to some spectacular advances, and should in the medium term lead to on-board or portable synthesis devices.

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