"Harnessing the Dynamic Nature of Nucleophilic Aromatic Substitution for Pyridine-Based Macrocycle Construction"
Nucleophilic aromatic substitution (SNAr) is one of the most widely employed reactions in medicinal chemistry, traditionally regarded as an irreversible transformation. However, recent studies have demonstrated that SNAr can, under appropriate conditions, exhibit dynamic reversibility, enabling error correction and high-yield synthesis of complex architectures and yield advanced properties such as recyclability and malleability in polymer materials. Despite this emerging potential, the extent to which reaction conditions, nucleophilicity, and electrophile electronics govern SNAr reversibility remains underexplored, particularly in the context of dynamic organic material design. Here, we investigate the dynamic nature of SNAr in pyridine-containing systems to establish fundamental principles governing its reversibility. By systematically varying reaction conditions and electronic properties of nucleophiles and electrophiles, we aim to demonstrate the feasibility of constructing heteroatom-bridged, conjugated macrocycles via dynamic SNAr.