Unveiling Repulsion in Intramolecular H-Bonded Systems

Intramolecular H-bonds govern molecular conformation and play critical roles in pharmaceutical design, catalysis, and supramolecular chemistry. Despite this, the experimental influence of <i>ortho</i>-substituents on the energetics of an adjacent H-bond defies classical Hammett analysis. By using synthetic molecular balances, we show that substituents positioned <i>ortho</i> to an OH H-bond donor can compete strongly with H-bonding to an external acceptor. Computational dissection of the experimental trends reveals that this competition is rarely dominated by stabilizing OH···R H-bonds, but rather by the avoidance of repulsive HO···R interactions. We provide a framework for rationalizing the influence of <i>ortho</i>-substituents on molecular conformation and the energetics of intramolecular H-bonds. Our work challenges the intuitive bias of attributing close contacts to attractive interactions and highlights the critical role of repulsion in molecular design.