The Limit of Intramolecular H‑Bonding

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.