Integrated Multi-dimensional Real-Time Reaction Analysis for Accelerated Understanding and Automated Optimisation of Molecular Transformations in Solu

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In this joint project, we will expand our ongoing collaborative research programme into utilizing FlowNMR spectroscopy for real-time investigation of molecular solution phase transformations, catalysis with transition metal complexes in particular, with the aim of deriving kinetic and mechanistic information that will allow us to improve existing processes and bring about new reactivity.Reaction monitoring via advanced multi-nuclear FlowNMR techniques as well as its integration with orthogonal spectroscopic and spectrometric techniques will be a central element, tying in with the ongoing development of our Dynamic Reaction Monitoring (DReaM) Facility at Bath.A second element concerns the effective real-time analysis of the spectroscopic responses collected by the instruments, with the aim of utilising on-the-fly evaluation of activity and selectivity profiles to regulate process parameters in an automated way, ultimately enabling a self-optimising reaction setup.These two tasks will be achieved in applying them to the following three work packages exemplifying catalytic reactions of academic interest and industrial relevance:1) Ru-catalysed asymmetric ketone transfer hydrogenation from formic acid. Building on previous work in the group, establish monitoring of this air-sensitive transformation in flow, utilizing selective excitation pulse sequences to quantify metal-hydride intermediates. Addition of an actively pressurized sampling loop to suppress adverse gas bubble effects on NMR acquisition. Couple with head-space mass spectrometry to follow formic acid decomposition side reactions.2) Di-amine/bis-phosphine Ru catalysts for H2 hydrogenation of ketones and imines. Extend setup to work under pressures of dihydrogen as reductant, establish interleaved quantitative 1H and 31P FlowNMR techniques and integrate with liquid phase mass spectrometry and UV-vis spectroscopy to derive additional information on catalytic intermediates.3) NPN and PNN Ru complexes for ester and amide hydrogenation. Apply knowledge and experience from WP1&2 to understand the intricate reaction networks leading to ester and amide reduction, a high-profile transformation in the fine chemical industry which currently is poorly understood mechanistically.Engineering aspects of self-regulation and self-optimization capabilities in continuous flow mode will be developed in parallel to investigating the chemistry in WP1-3, and applied to any system as soon as it is working. Although the focus will be on method development there is also scope for synthetic work in the above should we make any discoveries that give us clues as to how to improve the chemistry through specific catalyst modifications.