Continuous Flow Microreactor Systems for Intensified Synthesis of Fine Chemical Intermediates

Abstract

The position of fine chemical intermediates in manufacturing economics is a difficult one: They are too large in volume to be efficiently processed in batch flasks; too small in volume to justify an economical continuous process; and often must be produced by a transformation that is violently exothermic and unstable species are involved or must be produced in a manner that is so selective that it is hard to achieve in a continuous process. This position is directly reversed by continuous flow microreactor systems. They decrease channel sizes to the micro- or millimetre size scale, increase surface/volume ratios by many orders of magnitude, and shorten diffusion paths to the micrometre scale, which means that transport and safety become no longer the limiting factors in the potential selectivity that can be achieved. This review discusses the engineering principles underlying this intensification, reactor formats used and reported performance of flow systems in the synthesis of fine chemical intermediates. The three mechanisms by which intensification is achieved are discussed: mixing in a matter of milliseconds, operation of strongly exothermic steps near isothermally and near-ideal plug-flow residence time distributions. The role of telescoped multistep sequences, in-line work-up and hazardous intermediate generation are discussed in the context of documented examples, and scale-up strategies of numbering-up and dimension enlargement are compared, including their economics. Automation and statistical optimisation are seen as the development-speed multiplier, that makes the flows competitive at intermediate scale. As a result, the review highlighted the following: transport intensification is now well established, and the limiting factors are binding constraints related to separation science, solids handling, and absence of validated life-cycle and techno-economic data.