Inline Reaction Monitoring of Amine-Catalyzed Acetylation of Benzyl Alcohol Using a Microfluidic Stripline Nuclear Magnetic Resonance Setup.

We present an in-depth study of the acetylation of benzyl alcohol in the presence of N, N-diisopropylethylamine (DIPEA) by nuclear magnetic resonance (NMR) monitoring of the reaction from 1.5 s to several minutes. We have adapted the NMR setup to be compatible to microreactor technology, scaling down the typical sample volume of commercial NMR probes (500 µL) to a microfluidic stripline setup with 150 nL detection volume. Inline spectra are obtained to monitor the kinetics and unravel the reaction mechanism of this industrially relevant reaction. The experiments are combined with conventional 2D NMR measurements to identify the reaction products. In addition, we replace DIPEA with triethylamine and pyridine to validate the reaction mechanism for different amine catalysts. In all three acetylation reactions, we find that the acetyl ammonium ion is a key intermediate. The formation of ketene is observed during the first minutes of the reaction when tertiary amines were present. The pyridine-catalyzed reaction proceeds via a different mechanism.

Continuous Flow 1H and 13C NMR Spectroscopy in Microfluidic Stripline NMR Chips.

Microfluidic stripline NMR technology not only allows for NMR experiments to be performed on small sample volumes in the submicroliter range, but also experiments can easily be performed in continuous flow because of the stripline's favorable geometry. In this study we demonstrate the possibility of dual-channel operation of a microfluidic stripline NMR setup showing one- and two-dimensional 1H, 13C and heteronuclear NMR experiments under continuous flow. We performed experiments on ethyl crotonate and menthol, using three different types of NMR chips aiming for straightforward microfluidic connectivity. The detection volumes are approximately 150 and 250 nL, while flow rates ranging from 0.5 µL/min to 15 µL/min have been employed. We show that in continuous flow the pulse delay is determined by the replenishment time of the detector volume, if the sample trajectory in the magnet toward NMR detector is long enough to polarize the spin systems. This can considerably speed up quantitative measurement of samples needing signal averaging. So it can be beneficial to perform continuous flow measurements in this setup for analysis of, e.g., reactive, unstable, or mass-limited compounds.

A microfluidic high-resolution NMR flow probe.

A microfluidic high-resolution NMR flow probe based on a novel stripline detector chip is demonstrated. This tool is invaluable for the in situ monitoring of reactions performed in microreactors. As an example, the acetylation of benzyl alcohol with acetyl chloride was monitored. Because of the uncompromised (sub-Hz) resolution, this probe holds great promise for metabolomics studies, as shown by an analysis of 600 nL of human cerebrospinal fluid.