A Combined Kinetic and Computational Analysis of the Palladium-Catalysed Formylation of Aryl Bromides

Aryl aldehydes are key synthetic intermediates in the manufacturing of active pharmaceutical ingredients. They are generated on scale (>1000 kg) through the palladium-catalysed formylation of aryl bromides using syngas (CO:H2). The best-in-class catalyst system for this reaction employs di-1-adamantyl-n-butylphosphine (cataCXium A), palladium(II) acetate, and tetramethylethylenediamine. Despite nearly 20 years since its initial report, a mechanistic understanding of this system remains incomplete. Here we use automation, kinetic analysis, and DFT calculations to develop a new mechanistic model for this best-in-class catalyst. We show that a combination of the migratory insertion step and dihydrogen activation step are likely involved in the turnover-limiting sequence. The reaction kinetics are responsive to the nature of the substrate, with electron-rich aryl bromides reacting faster and more selectively than their electron-poor counterparts due to the influence of electronics in the migratory insertion step. Our findings overturn the current paradigm and provide new mechanistic insight into palladium-catalysed formylation of aryl bromides.