Accidental Degeneracy in Crystalline Aspirin: New Insights from High-Level ab Initio Calculations

We perform the first high-level ab initio calculations (MP2) on crystalline aspirin using a newly developed fragment-based QM/MM method. Contrary to earlier density functional theory predictions, the two polymorphs are virtually degenerate, which is consistent with experimentally observed intergrowth structures. This near-degeneracy arises “accidentally” from a competition between intramolecular relaxation (form I) and intermolecular hydrogen bonding (form II).