The Limit of Intramolecular H-bonding

Thomas A. Hubbard, Alisdair J. Brown, Ian A. W. Bell, Scott L. Cockroft

Research output: Contribution to journalArticlepeer-review


Hydrogen bonds are ubiquitous interactions in molecular recognition. The energetics of such processes are governed by the competing influences of pre-organization and flexibility that are often hard to predict. Here we have measured the strength of intramolecular interactions between H-bond donor and acceptor sites separated by a variable linker. A striking distance-dependent threshold was observed in the intramolecular interaction energies. H-bonds were worth less than –1 kJ mol–1 when the interacting groups were separated by ≥6 rotating bonds, but ranged between –5 and –9 kJ mol–1 for ≤5 rotors. Thus, only very strong external H-bond acceptors were able to compete with the stronger internal H-bonds. In addition, a constant energetic penalty per rotor of ~5-6 kJ mol–1 was observed in less strained situations where the molecule contained ≥4 rotatable bonds.
Original languageEnglish
JournalJournal of the American Chemical Society
Early online date6 Nov 2016
Publication statusE-pub ahead of print - 6 Nov 2016


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