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

在这个联合项目中，我们将扩大我们正在进行的合作研究计划，利用FlowNMR光谱技术实时研究分子溶液的相变，特别是过渡金属配合物的催化作用，目的是获得动力学和机理信息，使我们能够改进现有的工艺并带来新的反应性。通过先进的多核流核磁共振技术及其与正交光谱和光谱技术的集成进行反应监测将是一个核心要素，与我们在巴斯的动态反应监测（DReaM）设施的持续发展相结合。第二个要素涉及对仪器收集的光谱响应进行有效的实时分析，目的是利用活性和选择性概况的实时评估，以自动化的方式调节过程参数，最终实现自优化反应设置。这两项任务将通过将它们应用于以下三个工作包来实现，这些工作包将举例说明具有学术意义和工业意义的催化反应：1)钌催化甲酸的不对称酮转移加氢。在小组先前工作的基础上，利用选择性激励脉冲序列定量金属氢化物中间体，建立对流动中这种空气敏感转换的监测。增加了主动加压采样回路，以抑制不利的气泡对核磁共振采集的影响。结合头空质谱法跟踪甲酸分解副反应。2)二胺/双膦Ru催化剂用于酮和亚胺的H2加氢反应。扩展设置以在二氢作为还原剂的压力下工作，建立交叉定量1H和31P FlowNMR技术，并与液相质谱和紫外-可见光谱相结合，以获得催化中间体的额外信息。3)用于酯和酰胺加氢的NPN和PNN Ru配合物。运用wp1和wp2的知识和经验，了解导致酯和酰胺还原的复杂反应网络，这是精细化工行业备受瞩目的转变，目前对其机理知之甚少。工程方面的自我调节和自我优化能力将在研究WP1-3的化学性质的同时开发，并在任何系统工作时立即应用。虽然重点将放在方法开发上，但如果我们有任何发现，可以为我们提供如何通过特定催化剂改性来改善化学性质的线索，那么上述合成工作也有范围。

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.