Molecular recognition and crystal energy landscapes : an X-ray and computational study of caffeine and other methylxanthines

We introduce a new approach to crystal-packing anal., based on the study of mutual recognition modes of entire mols. or of mol. moieties, rather than a search for selected atom-atom contacts, and on the study of crystal energy landscapes over many computer-generated polymorphs, rather than a quest for the one most stable crystal structure. The computational tools for this task are a polymorph generator and the PIXEL d. sums method for the calcn. of intermol. energies. From this perspective, the mol. recognition, crystal packing, and solid-state phase behavior of caffeine and several methylxanthines (purine-2,6-diones) have been analyzed. Many possible crystal structures for anhyd. caffeine have been generated by computer simulation, and the most stable among them is a thermodn., ordered equiv. of the disordered phase, revealed by powder X-ray crystallog. Mol. recognition energies between two caffeine mols. or between caffeine and water have been calcd., and the results reveal the largely predominant mode to be the stacking of parallel caffeine mols., an intermediately favorable caffeine-water interaction, and many other equiv. energy min. for lateral interactions of much less stabilization power. This last indetn. helps to explain why caffeine does not crystallize easily into an ordered anhyd. structure. In contrast, the mono- and dimethylxanthines (theophylline, theobromine, and the 1,7-isomer, for which we present a single-crystal X-ray study and a lattice energy landscape) do crystallize in anhyd. form thanks to the formation of lateral hydrogen bonds.