Review Selected Examples of High-Pressure Reactions in Glass Microreactors Recent examples of high-pressure organic reactions in (flow) glass microreactors of micrometer dimensions are described. Different types of reactions such as Diels-Alder and nucleophilic aromatic substitution reactions performed in a capillary microreactor gave rate enhancements of 1.5–2.7 at 600 bar. Specifically designed flow glass microreactors, that withstand pressures of 140–690 bar, were used to study Diels-Alder and oxidation reactions. The use of supercritical fluids gives rise to considerable rate enhancements, while the use of a transparent mi- croreactor allows to visualize phase transitions. Keywords: Capillary microreactor, Diels-Alder reaction, Miniaturization, Supercritical fluids Received: July 16, 2009; revised: September 1, 2009; accepted: September 2, 2009 DOI: 10.1002/ceat.200900369 1 Introduction Application of (high) pressure is a well-known methodology to enhance the reaction rate of different types of organic reac- tions [1]. In general, reactions accompanied by a decrease in molar activation volume (DV ≠ ) are accelerated by pressure. High-pressure chemistry is regarded as a technique that re- quires specialized equipment with strict safety precautions. Miniaturization of the reaction system is expected to relax safety regulations, so that high-pressure experimentation will become more readily available. The advantages and the use of microreactors to study organ- ic reactions have been described in several reviews [2–5]. To our best knowledge there are no reviews mainly dealing with high-pressure reactions in flow microreactors of lm dimen- sions. In this review, we mainly describe our results of the ap- plication of glass microreactors for pressurized organic reac- tions, together with recent results from other groups. The use of microchips for pressure-driven liquid chromatography [6] is not included. 2 Capillary Microreactors A simple miniaturization step is the construction of a capillary microreactor. A schematic representation of such a microreac- tor is given in Fig. 1. It consists of a fused-silica capillary, vol- ume 3 lL, running through a stainless-steel cross, a six-port valve for sample inlet and outlet, and an HPLC pump as pres- sure generator. The course of the reactions was followed via an optical fiber, connecting the silica capillary and a UV/Vis spec- trophotometer. With this simple silica fiber microreactor reac- tions can be easily monitored up to 600 bar. The disadvantage of this system is that it does not operate in a continuous-flow mode. Using this setup, the nucleophilic aromatic substitution re- action of p-halonitrobenzenes 1a–c with cyclic amines 2a–c to give the p-N,N-dialkylamino-nitrobenzenes 3a–c has been in- vestigated under pseudo first-order conditions at pressures up to 600 bar (see Scheme 1). As an illustration, Fig. 2 shows the rate constants k of the reaction of 1-fluoro-4-nitrobenzene 1a versus pressure for the three different amines 2. It clearly shows the expected order in reactivity between the amines 2, viz. pyrrolidine > piperidine > morpholine, having rate en- hancements of 2.7, 1.7, and 1.5, respectively, at 600 bar. From © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim http://www.cet-journal.com Willem Verboom 1 1 Laboratory of Molecular Nanofabrication, University of Twente, MESA + Research Institute for Nanotechnology, Enschede, The Netherlands. – Correspondence: Dr. Willem Verboom (w.verboom@utwente.nl), Laboratory of Molecular Nanofabrication, University of Twente, MESA + Research Institute for Nanotechnology, P. O. Box 217, NL-7500 AE Enschede, The Netherlands. 600bar UV/Vis analyzer HPLC pressure generator Sample injection Plug Valve Silica fiber fiber optic Sample outlet Figure 1. Schematic representation of the capillary microreactor setup. Reproduced with permission of the Royal Society of Chemistry. Chem. Eng. Technol. 2009, 32, No. 11, 1695–1701 1695