Development of a continuous process: a perspective for Mitsunobu reaction
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Ó Indian Academy of Sciences Sadhana (0123456789().,-volV)FT3](0123456 789().,-volV)
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Development of a continuous process: a perspective for Mitsunobu reaction GIRISH BASAVARAJUa,b,*
and RAVISHANKAR RAJANNAb
a Process
Engineering, Syngene International Ltd., Bengaluru, India of Chemical Engineering, Dayanand Sagar College of Engineering, Bengaluru, India E-mail: [email protected]; [email protected] b Department
MS received 18 May 2020; revised 6 July 2020; accepted 6 July 2020
Abstract. 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. Keywords. Continuous flow chemistry; Mitsunobu reaction; tubular reactor; design of experiments (DoE).
1. Introduction The Mitsunobu reaction is widely practised in the synthetic chemistry area to achieve alkyl aryl ethers transformation.1–3 The reaction is quite successful in coupling a broad selection of alcohol and phenol substrates.4 These reactions, in general, are slow and offer specific advantages such as stereospecificity, mild reaction conditions, and scope of the chemistry.5 The chemical bonds such as C-O, C-N, C-S, C-C could be built with diisopropyl azodicarboxylate (DIAD) or diethyl azodicarboxylate (DEAD) under redox conditions.2,4 The azodicarboxylates, in general, are explosive compounds that undergo decomposition in the presence of elevated temperature,6 poses a safety risk in case of large-scale operations, especially under batch conditions. On the other side, azodicarboxylates simplify easy workup and purification during downstream processing.2,3 The Mitsunobu reaction is highly
acquainted with batch processing methods for several decades. In the last few years, there have been significant development and technological advancements being investigated to reap the benefits to improve safety, minimize cost, improve sel
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