X-ray Charge Density Study of Drug Methimazole with Zʹ = 2: Differences in the Electronic Structure of Thiourea Core due to Crystal Packing Effects

Herein we present a detailed experimental charge-density study for the low-temperature polymorph of antithyroid drug methimazole crystallized with two crystallographically independent molecules lacking conformational freedom. Quantum-topological analysis of experimental electron density allowed us to detect the distinctive differences in the electron distribution within their thiourea groups, arising primarily from crystal packing effects. Sulfur atom S(1a) features two separate regions of positive deformation density, whilst the other atom S(1b) is found to be more diffuse with positive density taking a toroidal form. In contrast to S(1a), the couple of the lone pairs of S(1b) derived by non-bonding charge concentrations takes a more significant turn relative to the molecular plane and proves to be distorted. We also report an ambiguous electronic structure of the heteroatoms, i.e. appearance of “false” Laplacian CPs (3, +3) or splitting of true ones, which is caused by neglecting or excessive use of Gra...