Design and characterization of a cascade of continuous stirred-tank reactors for a Grignard reaction

Abstract

Currently, the pharmaceutical and fine chemical industry performs Grignard reactions in large semi-batch reactors. Due to the exothermic nature of this reaction, heat dissipation problems occur. This requires dosing of reagents and therefore a long reaction time. Also, each batch needs an initiation, causing varying product quality. A continuous-flow process improves heat dissipation, has only one transient startup initiation and decreases production area, which increases production capacity and stability. This Master's thesis describes the design and characterization of a continuous-flow Grignard process of which the research was executed in Lab4U and in collaboration with Janssen Pharmaceutica. Based on literature research a reactor setup was designed, consisting of two Continuously Stirred Tank Reactors (CSTRs) in series with a solids settler in between to keep magnesium in the first reactor. Next, the reactor setup and the reactions were characterized. The residence time distribution was measured for the CSTR cascade and separate CSTRs, showing that the solids settler had a clear influence on the residence time. Reaction characterisation was performed in an Easymax 102. The formation of phenylmagnesium bromide out of bromobenzene and magnesium powder was second order with an activation energy of 44.8 kJ/mol. A total yield of 70% 1,1-diphenylethanol was achieved when the reaction was carried out with acetophenone in the CSTR cascade at 1.2 l/h. No particles above 25 µm were found in the final product flow.