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 literature and obtained 57% calculated yield in 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 product in the tube-in-tube setup vs 92% when two-phase flow was used, with more than 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.