A survey of crystal structures containing the xanthine ring shows that
caffeine-like molecules tend to stack in parallel in a variety of sta
cking geometries, suggesting that a stacked pair of caffeine molecules
has many conformations of comparable energy. Molecular modelling sugg
ests 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 t
he dimer of comparable energies.