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.

Chemoenzymatic flow cascade for the synthesis of protected mandelonitrile derivatives.

A chemoenzymatic two-step cascade process, with both steps having incompatible reaction conditions, was successfully performed in continuous flow. The chemoenzymatic aqueous formation of cyanohydrins was integrated with a subsequent organic phase protection step in a single flow process utilising a membrane-based phase separation module. The wider applicability of our setup was demonstrated with the synthesis of nine protected cyanohydrin derivatives, all obtained in good yields and high to excellent enantioselectivity.

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.

Prilezhaev dihydroxylation of olefins in a continuous flow process.

Epoxidation of both terminal and non-terminal olefins with peroxy acids is a well-established and powerful tool in a wide variety of chemical processes. In an additional step, the epoxide can be readily converted into the corresponding trans-diol. Batch-wise scale-up, however, is often troublesome because of the thermal instability and explosive character of the peroxy acids involved. This article describes the design and semi-automated optimization of a continuous flow process and subsequent scale-up to preparative production volumes in an intrinsically safe manner.

Flash chemistry extensively optimized: high-temperature Swern-Moffatt oxidation in an automated microreactor platform.

The generally accepted benefits of small lateral dimensions of microreactors (1 microm to 1 mm) enable a different way of performing synthetic chemistry: Extremely short contact times in the millisecond range can circumvent the need for performing highly exothermic and fast reactions at very low temperatures. In order to fully exploit this technology, such fast processes need to be redesigned and investigated for optimal reaction conditions, which can differ drastically from the ones traditionally applied. In a comprehensive study, we optimized the selective Swern-Moffatt oxidation of benzyl alcohol to benzaldehyde by varying five experimental parameters, including reaction time and temperature. Employing an ultrashort mixing and reaction time of only 32 ms, the optimal temperature was determined to be 70 degrees C, approximately 150 degrees C higher than in the conventional batch conditions. This remarkable difference shows both the potency of continuous-flow chemistry as well as the urgency of a paradigm shift in reaction design for continuous-flow conditions.