Carbonylations in flow: tube-in-tube reactor vs. gas–liquid slug flow†

In order to improve the performance of carbonylation reactions in flow, we compared the tube-in-tube system to a gas–liquid two-phase setup. We found that the two-phase slug flow reactor significantly improved the yield and throughput of the reactions tested. First, we performed a reference reaction, methoxycarbonylation of 4-chlorobenzonitrile, using conditions described in the literature and obtained 57% calculated yield in the biphasic setup and 16% in the tube-in-tube setup, with side product formation of 1% and 8% respectively. The reaction was further optimized in both apparatuses, improving the yield in the biphasic setup to 86%, while the tube-in-tube method was limited to about 34%. Finally, a 1.5 g scale-up of a project-relevant building block yielded 73% of the product in the tube-in-tube setup vs. 92% when two-phase flow was used, with more than a ten-fold increase in throughput in the biphasic method. Using gas–liquid flow enabled higher yield and throughput due to direct contact of gas and liquid, better control of CO equivalents and intensification of process conditions: higher temperature, pressure and concentration in the system and significant reduction of residence time.