Small Molecule X-ray Crystal Structures at a Crossroads

Refinement of ‘small molecule’ crystal structures from X-ray diffraction benefits from advances in methods derived from quantum crystallography. After outlining some pertinent principles and reasons for needed improvements in the theoretical structure model, the author′s experience in implementing Hirshfeld Atom Refinement using the NoSpherA2 option in the popular Olex2 crystallographic GUI is outlined. The method allows the placement of hydrogen atoms with accuracy comparable to neutron diffraction. Moreover, the average precisions of bonds involving light atoms is found to improve in most cases, with the degree of improvement correlating strongly with the overall quality of the diffraction data and the refinement model. A suggested workflow for HAR with NoSpherA2 is provided. A call is made for wide-spread adoption, along with a community-wide development of ‘standard protocols for the use of aspherical form factors in chemical crystallography’.