Toward crystal structure prediction for conformationally flexible molecules: The headaches illustrated by aspirin

A crystal structure prediction study was carried out on aspirin, based on an analysis of its gas phase conformers and multiple searches for minima in the lattice energy with the molecule held rigid in low energy conformations. Various high levels of ab initio theory were used to estimate the gas phase conformations and energy differences, and accurate distributed multipole-based electrostatic models were used to estimate the electrostatic contribution to the lattice energies. The molecular conformation adopted in the crystal structure is close to a local minimum found in the gas phase ab initio energy using a B3LYP/6-31G(d,p) calculation. A MP2 optimization gives larger differences from the solid state molecular structure. The calculation using the B3LYP molecular conformer predicts the observed crystal structure as one of the most thermodynamically stable and generally the most plausible crystal structure. Alternative molecular conformers, including the gas phase global minimum energy structure and planar transition states, were shown to give less favorable lattice energies. In contrast with a previous study with a flexible molecule force field, the possibility of a planar conformer of aspirin in a crystal structure appears to be unlikely because of the intramolecular energy cost. Although the use of ab initio optimized molecular conformers clearly shows promise for crystal structure prediction for some flexible molecules, the sensitivity of the lattice energies to small distortions of the molecular conformation shows that it can only be used with care when the conformational energy profile is suitable.