Molecular modelling and NMR studies of the caffeine dimer

A survey of crystal structures containing the xanthine ring shows that caffeine-like molecules tend to stack in parallel in a variety of stacking geometries, suggesting that a stacked pair of caffeine molecules has many conformations of comparable energy. Molecular modelling suggests that the caffeine dimer, the major associated species in aqueous solution, may occur in nine distinct conformations. In agreement with the crystal survey and the modelling results, NMR spectra of caffeine solutions exhibit intermolecular nuclear Overhauser enhancements (NOEs), consistent with a dynamic equilibrium of several conformations of the dimer of comparable energies.