Catalytic site-selective functionalization of distal C–H bonds represents a formidable challenge in organic synthesis. Particularly, the precise functionalization of distal aromatic C(sp²)–H bonds remains largely unexplored. Here we present a highly para-selective acylation strategy to target ultraremote aryl C(sp²)–H bonds, eight chemical bonds away from an activated functionality, through radical N-heterocyclic carbene organocatalysis. This method is developed on the basis of a unique single-electron pathway involving the site-selective activation of aryl C–H bonds by a nitrogen-centred radical generated in situ. Importantly, this organocatalytic approach shows potential for the functionalization of drugs, amino acids and peptides, thus highlighting its importance for medicinal chemistry. Our investigation encompassed meticulous mechanistic studies, including control experiments and density functional theory calculations, to unravel the intricacies behind the observed site selectivity and shed light on the mechanism of radical N-heterocyclic carbene organocatalysis.

远端 C-H 键的催化位点选择性官能化是有机合成中的一个巨大挑战。特别是，远端芳香族 C( sp ² )–H 键的精确功能化在很大程度上仍未得到探索。在这里，我们提出了一种高度对位选择性酰化策略，通过自由基N-杂环卡宾有机催化，靶向超远程芳基C( sp ² )–H键，即距离活化官能团八个化学键。该方法是基于独特的单电子途径开发的，涉及通过原位产生的以氮为中心的自由基对芳基 C-H 键进行位点选择性激活。重要的是，这种有机催化方法显示出药物、氨基酸和肽功能化的潜力，从而凸显了其对药物化学的重要性。我们的研究包括细致的机理研究，包括控制实验和密度泛函理论计算，以揭示观察到的位点选择性背后的复杂性，并揭示自由基 N-杂环卡宾有机催化的机制。