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Flow chemistry today: practical approaches for optimisation and scale-up

corresponding

RENÉ BECKER1*, KASPAR KOCH1, PIETER J. NIEUWLAND1, FLORIS P.J.T. RUTJES2*
*Corresponding authors
1. FutureChemistry Holding B.V., Toernooiveld 100, 6525 EC Nijmegen, The Netherlands
2. Radboud University Nijmegen, Institute for Molecules and Materials, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands

Abstract

A general methodology is presented as a practical approach to the design of a continuous flow process and its subsequent optimisation and up scaling. Three examples of such designs are shown. The continuous flow Swern-Moffatt oxidation shows that even for ultrafast reactions, the same methodology is still feasible, resulting in an 8.5 g/h synthesis rate. Also, the continuous flow synthesis of explosive azides shows that preparative-scale safety issues at a 1 g/h synthesis rate can be more adequately dealt with. Lastly, as an example of what process automation can accomplish, we present the novel application of an automated screening of a model reaction (the Fischer esterification) with on-line gas-chromatographic analysis. Using this set-up, we found optimal reaction conditions within a working day using minimal amounts of reagents and labour, resulting in the continuous production of the target ester at a 67 mL/h rate.


INTRODUCTION

As continuous flow chemistry is now maturing into a well-established and accepted technology (1-5) it becomes useful for researchers to define a common set of tasks to systematically design continuous flow processes and identify the optimal reaction conditions to successfully synthesise the target molecules on a preparative laboratory or industrial scale.
In this article we present the methodology we developed over the years and which is now routinely employed in our research groups on a large variety of reactions. This methodology is highlighted by a selection of three chemical reactions which were successfully converted into continuous flow processes, thereby exemplifying some major advantages over the corresponding batch processes: (i) th