Continuous synthesis of 1‐ethoxy‐2,3‐difluoro‐4‐iodo‐benzene in a microreactor system and the Gaussian and computational fluid dynamics simulations

A microreactor system consisting of membrane‐dispersion tube‐in‐tube microreactors and delay loops was developed for the continuous synthesis of 1‐ethoxy‐2,3‐difluoro‐4‐iodo‐benzene. Because of the high mass and heat transfer in the microreactor system, ortho‐ and halogen‐lithiation could be performed at −40 and −20°C, respectively, which are much higher than the temperature required (−70°C) for the batch reaction. In stirred tanks, the yield of 1‐ethoxy‐2,3‐difluoro‐4‐iodo‐benzene reaches 91.0% in 70 min. Nearly the same yield of 91.3% was achieved within a shorter time of 16 min in the microreactor system. Furthermore, the kinetics of ortho‐lithiation calculated by the Gaussian software, were used for the computational fluid dynamics (CFD) simulations of the reaction process in another microreactor system. Thus, a Gaussian‐CFD‐coupled‐method for efficiently predicting reaction kinetics and yield without experiments could be established. The predicted yield reached 88.7% at 1000 s, which is comparable with the experimental yield of 90.1% at 960 s.