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光谱实时研究分子溶液相变，特别是过渡金属络合物的催化作用，目的是获得动力学和机理信息，使我们能够改进现有工艺并带来新的反应性。通过先进的多功能反应监测系统，核流动NMR技术以及其与正交光谱和光谱测定技术的集成将是一个中心要素，与我们在美国麻省理工学院的动态反应监测（DReaM）设施的正在进行的开发相结合。第二个要素涉及对由仪器收集的光谱响应的有效实时分析，目的是利用对活性和选择性的动态评估，以自动化的方式调节工艺参数，最终实现自我优化的反应设置。这两项任务将通过将其应用于以下三个工作包来实现，这些工作包举例说明了具有学术兴趣和工业相关性的催化反应：1）Ru催化的甲酸不对称酮转移氢化。在小组先前工作的基础上，建立对流动中这种空气敏感转变的监测，利用选择性激发脉冲序列来量化金属氢化物中间体。增加主动加压采样回路，以抑制气泡对NMR采集的不利影响。结合顶空质谱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。将装置扩展到在氢气作为还原剂的压力下工作，建立交错的定量1H和31 P 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更多信息。3）NPN和PNN Ru络合物用于酯和酰胺氢化。应用WP 1和WP 2的知识和经验，了解导致酯和酰胺还原的复杂反应网络，这是精细化工行业的一种备受瞩目的转化，目前在机理上了解甚少。连续流模式下的自我调节和自我优化能力的工程方面将与WP 1 -3的化学研究平行发展，并在任何系统运行时立即应用。虽然重点将放在方法开发上，但如果我们有任何发现，为我们提供如何通过特定催化剂改性改善化学性质的线索，则上述合成工作也有余地。

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.