Theoretical investigations of conformational aspects of polymorphism. Part 1: O-acetamidobenzamide

o-Acetamidobenzamide crystallises in two polymorphs designated alpha and beta. In the alpha-polymorph an intramolecular hydrogen bond is present, which is not found in the conformation adopted in the beta-polymorph. The geometries of the molecules found in the crystal structures have been studied in detail using molecular mechanics, semi empirical and ab initio quantum chemistry techniques. Conformational energy differences have been evaluated, and gas phase potential energy surfaces generated to explore the conformational freedom of o-acetamidobenzamide. It has been found that both observed solid state conformations occur close to, but not actually at, minima on the calculated gas phase potential energy surfaces. Conformational energy differences of 8-10 kcal mol(-1) have been found between the conformers found in the crystals, depending on the method used for the calculation. Based on lattice energy calculations for both polymorphs it would appear that the less stable conformation is not compensated for by an equivalent stabilisation of the crystal lattice. The total (intra-and inter-molecular) energy difference between polymorphs is greater than that conventionally accepted. The difficulties of using theoretical tools in conformational studies and the implications of our findings for ab initio crystal structure prediction are discussed.