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，我们将扩展我们正在进行的合作研究计划，利用流动核磁共振光谱学实时研究分子溶液的相变，特别是与过渡金属络合物的催化作用，目的是获得动力学和机械信息，使我们能够改进现有的过程和带来新的反应。通过先进的多核流动核磁共振技术及其与正交谱和光谱学技术的集成将是核心要素，与我们在巴斯的动态反应监测(DREAM)设备的持续开发相一致。第二个要素涉及对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曲线的即时评估来自动调整工艺参数，最终实现自优化反应装置。将这两个任务应用于以下三个具有学术意义和工业意义的催化反应包：1)Ru催化的甲酸不对称酮转移氢化反应。在该小组以前工作的基础上，建立对流动中这种对空气敏感的转变的监测，利用选择性激发脉冲序列来量化金属氢化物中间体。增加了主动加压采样回路，以抑制气泡对核磁共振采集的不利影响。与顶空气相色谱联用，跟踪甲酸分解副反应。2)二胺/双膦Ru催化剂对酮和亚胺的氢加氢反应。扩展设置以在二氢作为还原剂的压力下工作，建立交错定量1H和31P流动核磁共振技术，并与液相质谱和UV-Vis光谱相结合，以获得关于催化中间体的更多信息。3)用于酯和酰胺加氢的NPN和PNN Ru络合物。应用WP1&2中的知识和经验来了解导致酯和酰胺还原的复杂反应网络，这是精细化学工业中目前从机械上很难理解的一种备受瞩目的转变。连续流动模式下的自我调节和自我优化能力的工程方面将与WP1-3中的化学研究并行开发，并在任何系统工作后立即应用于该系统。虽然重点将放在方法开发上，但如果我们有任何发现，为如何通过特定的催化剂修饰来改善化学性能提供线索，上述合成工作也有空间。

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.