Towards Allosteric Receptors: Adjustment of the Rotation Barrier of 2,2 '-Bipyridine Derivatives

Quantum-chemical calculations at the BP86/TZVP level of theory were performed to determine the energy differences between the syn and the anti conformers, as well as the energy barrier for the rotation of the aryl-aryl bond of 2,2'-bipyridine molecules and a number of disubstituted derivatives. Substitutents with hydrogenbond donor (or electron acceptor) functions or hydrogen-bond acceptors (or electron donors) are generally found to have large effects on the difference and the barrier. Substitution with a hydrogen-bond donor (or an electron acceptor) at position 6 and 6' leads to a decrease owing to a charge transfer from the pyridine nitrogen lone pair to the donor, which is caused by the formation of weak intramolecular hydrogen bonds and/or dipolar interactions, respectively. Conversely, substitution at position 4 and 4' causes an increase in the energy barrier. Substitution with a hydrogen-bond acceptor (or an electron donor) shows the opposite behavior. which can be explained by the weak intramolecular interactions. Interestingly, even very weak CH hydrogen-bond donors (electron acceptors) such as methyl groups have a significant influence. This indicates the importance of such weak interactions for the structure and energetics of supramolecular systems. The energy differences are mainly governed by the substituents directly attached to the bipyridine core as the introduction of sterically demanding groups in the periphery hardly influences the barriers or energy differences of the conformers. These findings are important for the design of heterotropic positive cooperative allosteric receptors with 2,2'-bipyridines as the allosteric centre.