Automating the Understanding of Catalytic Aldehyde Synthesis

醛类化合物是活性药物成分化学合成中的关键中间体。芳基醛通常是由芳基卤化物与s链试剂金属化，然后加入二甲基甲酰胺（Bouveault合成）制成的。这种方法有其缺点：它需要形成有机金属中间体，官能团耐受性有限，并且产生相当大的浪费。一种更有效的替代方法是用CO/H2混合物催化芳基卤化物甲酰化。尽管这种催化方法具有潜力，但由于对反应的了解有限，它并没有得到广泛的应用。目前，尚不清楚筛选新催化剂的最佳过程是什么，也不清楚应该关注哪些变量来扩大衬底范围，以及如何最好地扩大该过程的开放性问题仍然存在。如果对催化甲酰化的详细机理了解能够得到发展，它可以用于支持该方法在原料药合成中的更广泛应用。在这个项目中，我们将结合自动化，动力学分析（VTNA）， DFT计算和合成化学来深入了解钯催化甲酰化

Aldehydes are key intermediates in the chemical synthesis of active pharmaceutical ingredients (APIs). Aryl aldehydes are typically made by the metalation of an aryl halide with an s-block reagent followed by addition to dimethylformamide (Bouveault synthesis). This approach has its disadvantages: it requires the formation of organometallic intermediates, shows limited functional group tolerance, and it generates considerable waste. A more efficient alternative is the catalytic formylation of aryl halides with CO/H2 mixtures. Despite the potential of this catalytic approach, it does not find widespread use due to the limited understanding of the reaction. Currently, it is not clear what the best process is to screen for new catalysts, it is not obvious which variables to focus on to expand the substrate scope, and open questions remain as to how best to scale the process up. If a detailed mechanistic understanding of catalytic formylation could be developed it could be used to underpin a broader application of this method in the synthesis of APIs. In this project, we will use a combination of automation, kinetic analysis (VTNA), DFT calculations and synthetic chemistry to develop deep insight into the palladium catalysed formylation