Exploring the Binding of Barbital to a Synthetic Macrocyclic Receptor. A Charge Density Study

Experimental charge density distribution studies, complemented by quantum mechanical theoretical calculations, of a host-guest system comprised of a macrocycle (1) and barbital (2) in a 1:1 ratio (3) have been carried out via high resolution single crystal X-ray diffraction. The data was modelled using the conventional multipole model of electron density according to the Hansen-Coppens formalism. The asymmetric unit of macrocycle (1) contained an intraannular ethanol molecule and an extraannular acetonitrile molecule, while the asymmetric unit of (3) also contained an intraannular ethanol molecule. Visual comparison of the conformations of the macrocyclic ring shows the rotation by 180° of an amide bond attributed to competitive hydrogen bonding. It was found the intraannular and extraannular molecules inside were orientated to maximise the number of hydrogen bonds present, with the presence of barbital in (3) resulting in the greatest stabilisation. Hydrogen bonds ranging in strength from 4-70 kJ mol-1 were the main stabilising force. Further analysis of the electrostatic potential between (1), (2) and (3) showed significant charge redistribution when co-crystallisation occurred, which was further confirmed by a comparison of atomic charges. The findings presented herein introduce the possibility of high resolution X-ray crystallography playing a more prominent role in the drug design process.