Simultaneous self-optimisation of yield and purity through successive combination of inline FT-IR spectroscopy and online mass spectrometry in flow reactions

Abstract

Self-optimisation constitutes a very helpful tool for chemical process development, both in lab and in industrial applications. However, research on the application of model-free autonomous optimisation strategies (based on experimental investigation) for complex reactions of high industrial significance, which involve considerable intermediate and by-product formation, is still in an early stage. This article describes the development of an enhanced autonomous microfluidic reactor platform for organolithium and epoxide reactions that incorporates a successive combination of inline FT-IR spectrometer and online mass spectrometer. Experimental data is collected in real-time and used as feedback for the optimisation algorithms (modified Simplex algorithm and Design of Experiments) without time delay. An efficient approach to handle intricate optimisation problems is presented, where the inline FT-IR measurements are used to monitor the reaction’s main components, whereas the mass spectrometer’s high sensitivity permits insights into the formation of by-products. To demonstrate the platform’s flexibility, optimal reaction conditions of two organic syntheses are identified. Both pose several challenges, as complex reaction mechanisms are involved, leading to a large number of variable parameters, and a considerable amount of by-products is generated under non-ideal process conditions. Through multidimensional real-time optimisation, the platform supersedes labor- and cost-intensive work-up procedures, while diminishing waste generation, too. Thus, it renders production processes more efficient and contributes to their overall sustainability. Graphical abstract

Rapid Kinetic Screening via Transient Timesweep Experiments in Continuous Flow Reactors

“…First, flow chemistry is most elegantly combined with online monitoring, removing the need to take samples in the first place (depending on the type of analysis intended). Infrared, [9][10][11] UV/Vis [12,13] or NMR [7,14] spectroscopy is nowadays readily available for direct flow online monitoring, and also HPLC [15][16][17] separation methods for detailed product analysis is available. Secondly, since reaction time is correlated via flow rate and volume, it is possible to directly monitor reaction progress along the axis of a flow reactor.…”

SnAKe: Bayesian Optimization with Pathwise Exploration

“…We substantially decrease experimental cost with respect to classical black-box optimization, e.g. as used by Fath et al [2021] and McMullen and Jensen [2011]. In the real-life SnAR benchmark, SnAKe spends 30-40% of the cost while making similarly strong predictions to classical BO.…”

A Review of Inline Infrared and Nuclear Magnetic Resonance Applications in Flow Chemistry

“…7 Fath et al's microreactor setup for organometallic synthesis with n-butyllithium. 16 Pharmaceutical Fronts © 2023. The Author(s).…”

“…This research presented a new method for solving complex multidimensional optimization problems and maximizing product yield and purity. 16…”

“…The highly sensitive mass spectrometry technique provides insights into the formation of by-products, enabling the study of complex optimization problems and the full discovery of the potential of inline analysis. 16…”