Systematic conformational bias in small-molecule crystal structures is rare and explicable

Abstract

Analysis of the Cambridge Structural Database, together with DFT and crystal structure prediction calculations, show that the observation of higher-energy planar conformers of biphenyl (BP) and cyclobutane (CB) is possible because of improved intermolecular interactions in their crystal structures. Such intermolecular/intramolecular energy compensation almost always occurs when crystallographic and molecular symmetry elements coincide. For BP and CB, almost exclusively, a crystallographic inversion centre coincides with a centre of symmetry in a Ci-symmetric molecule. We conclude that the observation of higher energy conformers (with the compensation of conformational energies up to ≈8–10 kJ.mol.−1 above the global minimum) together with this symmetry coincidence is rare. The work shows that concerns, expressed by some drug discovery chemists and other scientists, that conformations observed in crystal structures are systematically biased due to ‘crystal packing effects’ is overstated: only 16% of BP and CB fragments are exactly planar in small-molecule crystal structures, while the remaining conformations are close to their gas-phase energy minima. Thus, crystal structure conformations are good guides to conformational preferences in other phases and in other applications, e.g. in conformer generation or in the study of protein–ligand binding.