Form II Caffeine: A Case Study for Confirming and Predicting Disorder in Organic Crystals

Caffeine is a challenge in the study of organic crystallization, as the single crystal X-ray structures for both anhydrous phases are disordered. The symmetry-adapted ensemble approach is used in the form recently introduced for organic crystals to model the static disorder of form II (β) caffeine, giving structural motifs, energy, and entropy associated with the disorder. To explore whether it could be predicted that caffeine would form disordered structures, the analysis of the crystal energy landscape for caffeine is contrasted with that for isocaffeine. This demonstrates that near-symmetry in the intermolecular interactions of a molecule may be correlated with sets of nearly equienergetic crystal structures, to suggest disorder components. Symmetry-adapted ensemble calculations can then provide guidance as to whether disorder may be thermodynamically feasible.