关键词: 吡啶卤化, 间位选择性, 吡啶自由基阳离子, 自由基化学, 自旋密度, 本科化学教学

Abstract: meta-Selective C–H functionalization of pyridines and their derivatives has long remained a formidable challenge in organic synthesis. Classical directing effects dictate that electrophilic aromatic substitution (S_EAr) of pyridines occurs at the meta-position due to their intrinsic electronic properties; however, the low reactivity of pyridines necessitates harsh reaction conditions. Building on our recent study published in Nature Synthesis, this article provides a systematic overview of classical mechanisms and emerging strategies for pyridine halogenation from a pedagogical perspective. In that study, we reported a novel strategy for meta-selective halogenation via radical–radical cross-coupling mediated by pyridinium radical cations. Density functional theory (DFT) calculations reveal the spin density distribution of this radical species and its influence on the reactivity and selectivity of radical coupling. Furthermore, the experimentally observed preference for C5 over C3 functionalization is rationalized by π–π stacking interactions. From a teaching standpoint, we propose incorporating this cutting-edge example into undergraduate courses such as introductory organic chemistry. This approach aims to deepen students’ understanding of classical directing effects, establish a foundational knowledge of radical chemistry, and illustrate the unique regioselectivity of radical reactions, thereby fostering flexible critical thinking regarding organic reaction mechanisms.

Key words: Pyridine halogenation, Meta-Selectivity, Pyridinium radical cation, Radical chemistry, Spin density, Undergraduate chemistry course