Pieter J. Nieuwland

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.

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.

Microreactortechnology: Real-Time Flow Measurements in Organic Synthesis

With the commercial availability of integrated microreactor systems, the numbers of chemical processes that are performed nowadays in a continuous flow is growing rapidly. The control over mixing efficiency and homogeneous heating in these reactors allows industrial scale production that was often hampered by the use of large amounts of hazardous chemicals. Accurate actuation and in line measurements of the flows, to have a better control over the chemical reaction, is of added value for increasing reproducibility and a safe production.

Optimisation and Scale-up of α-Bromination of Acetophenone in a Continuous Flow Microreactor

To expand the knowledge base for fundamental organic reactions in continuous flow, the a-bromination of acetophenone was successfully transformed from a known batch procedure to a continuous flow process in 99 % yield through D-optimal optimisation and subsequent scale-up of the validated optimum. Using a preparative scale system, a space-time yield of 0.26 kg/m3/s (comparable literature batch reaction 0.24 kg/m3/s) was achieved under conditions suitable for laboratory and small-scale industrial application where high yield or purity is required, e.g., when expensive substrates are used.

Flow Markers in Microreactors: A Generally Applicable Chromatographic Method for Monitoring Flow Rates During Reactions

Microreactors have found widespread use for continuous flow synthesis and reaction optimization. Flow rates are critical factors with respect to the latter application because they are used to set screening parameters such as reaction time and stoichiometric ratios. However, the set flow values of pumps for nanoliter to microliter volume reactors are quite often not sufficiently accurate. In this paper we present a generally applicable chromatographic method to analyze flow rates during microreactor reaction screening. By adding flow markers to all reactant and reagent flows and performing conventional GC analysis on all samples, an accurate flow rate was calculated. The deviation between the set flow values and the measured flow rates was shown for a standard continuous flow experiment. The implications of this deviation for reaction optimization were demonstrated via a model Swern-Moffatt oxidation reaction, which showed that accurately measured flow rates are critical for correct data interpretation.

Thrombin generation test in microfluidic systems

The thrombin generation test is one of the diagnostic tests currently in use as a universal method for measuring hemostatic disorders. We envisioned that conventional monitoring of thrombin generation could be miniaturized resulting in a time-saving, accurate, easy-to-operate, and cost-efficient test. For the translation of the conventional thrombin generation test to microfluidic devices, our focus was directed to parameters such as the detection limit, temperature, protein-surface interactions (i.e., hydrophilicity of microchannels), and mixing behavior. Scaling down to microchannels (e.g., capillaries) resulted in volume reduction and allowed us to study the effect of a microchannel surface (either hydrophilic or hydrophobic) on the thrombin activity. Finally, the use of a micromixer enabled us to perform efficient on-chip mixing, resulting in the successful measurement of a thrombin generation in a microfluidic device.

Cu-catalysed pyrazole synthesis in continuous flow

The synthesis of 1,4-disubstituted pyrazoles via the cycloaddition reaction of sydnones and terminal alkynes has been achieved employing silica-supported copper catalysts. Furthermore, this methodology has been successfully implemented in continuous flow conditions using prepacked stainless steel cartridges containing the solid-supported copper promoter. Finally, we demonstrate that this synthetic procedure can be successfully scaled up to produce practically useful amounts of pyrazole products within 2–5 hours.

Fischer Indole Reaction in Batch and Flow Employing a Sulfonic Acid Resin: Synthesis of Pyrido[2,3-a]carbazoles

An Amberlite IR 120 H-promoted one-pot Fischer indolization from a cis-decahydroquinoline using a range of phenylhydrazines led to compounds with the pyrido[2,3-a]carbazole scaffold. The process may be conducted either in batch mode or in a continuous manner in a flow reactor. The stereochemical course of the Fischer indole reaction changed in going from using free phenylhydrazine to the corresponding hydrochloride in batch conditions, whereas, with the short reaction times in continuous flow, no changes due to isomerization processes were observed.