The developments around flow processing technology have paved the way for new avenues and perspectives to consider in the field of organic chemistry and engineering. In this study, customized flow equipment was utilized to develop and optimize the Mitsunobu reaction. The flow reactor was a prototype of a simple tubular reactor based on the plug flow reactor concept. The experimentation methodology was designed through the statistical design of experiments approach to minimize the number of experiments. The molar ratios of cyclohexanol (1) and o-cresol (2) and interaction effects of triphenylphosphine, diisopropyl azodicarboxylate were studied in detail. The reaction profile of flow experiments agreed with the batch conditions adding noteworthy improvements to the overall reaction time, selectivity, and yield towards the desired product 1-(cyclohexyloxy)-2-methylbenzene (3). The Mitsunobu reaction in batch condition would take on an average of 3 to 5 h, which was effectively accomplished in 30 to 45 mins in this flow reactor. The generated mathematical model is in good agreement with the reaction conditions. We believe that the process could be executed continuously without a break, readily scaled to kilogram quantities in a short time without further development.
Volume 133, 2021
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