Automating the Understanding of Catalytic Aldehyde Synthesis

醛是化学合成活性药物成分(API)的关键中间体。芳醛通常是由芳基卤化物在S嵌段试剂中金属化，然后添加到二甲基甲酰胺(Bouveault合成)得到的。这种方法有其缺点：它需要形成有机金属中间体，表现出有限的官能团耐受性，并且会产生相当大的废物。一种更有效的替代方法是芳基卤化物与CO/H2混合物的催化甲酰化反应。尽管这种催化方法很有潜力，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工艺是什么，也不清楚应重点关注哪些变量来扩大底物范围，如何最好地扩大工艺规模仍是悬而未决的问题。如果能够对催化甲酰化反应的机理有一个详细的了解，就可以用来支持该方法在原料药合成中的更广泛的应用。在这个项目中，我们将结合自动化、动力学分析(Vtna)、密度泛函计算和合成化学来深入了解钯催化的甲酰化反应。

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