Year: 2025
Type: article
Abstract: Intramolecular H-bonds govern molecular conformation and play critical roles in pharmaceutical design, catalysis, and supramolecular chemistry. Despite this, the experimental influence of ortho -substituents on the energetics of an adjacent H-bond defies classical Hammett analysis. By using synthetic molecular balances, we show that substituents positioned ortho 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 ortho -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.
DOI: 10.1021/jacs.5c00385
Authors: Ivan V. Smolyar, Scott L. Cockroft
Institution: University of Edinburgh
Language: English
Subfield: Physical and Theoretical Chemistry
Field: Chemistry
Domain: Physical Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
OpenAlex ID: W4409218717