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

Abstract

Herein we present a detailed experimental charge-density study for the low-temperature polymorph of the 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. The sulfur atom S(1a) features two separate regions of positive deformation density, while 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 nonbonding 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., the appearance of "false" Laplacian critical points (CPs) (3, +3) or splitting of true ones, which is caused by neglecting or excessive use of Gram−Charlier coefficients. Further, the turn of lone pairs, behavior of source function within the thiourea fragment, and atomic charges indicate decreased bond order of the formally double CS bond and increased contribution of the [CH 3 −]N (+) C−S (−) canonical structure into π-conjugation. Moreover, intermolecular hydrogen bonds N−H•••S and head-to-head interactions CS•••SC are described.

Orbital‐Free Quantum Crystallographic View on Noncovalent Bonding: Insights into Hydrogen Bonds, π⋅⋅⋅π and Reverse Electron Lone Pair⋅⋅⋅π Interactions

“…In turn, the covalency of interaction can be described with the donor-acceptor type of ED sharing. 58 In the case of the strongest hydrogen bond O2•••H9, the region of ( ) at the atom O2 (LP) is oriented exactly at the region of negative ( ) near the H9 atom (vacancy). In contrast, the two hydrogen atoms H7a and H11c share the other LP (Figure 4b), which becomes evident from the bond path trajectories in Figure 4a.…”

“…As are classical hydrogen bonds, nonclassical ones possess the property of directionality, which is reflected in a bond path trajectory and the mutual orientation of positive and negative regions, corresponding to electron lone pairs and ED deficiency or vacancies, respectively. In turn, the covalency of interaction can be described with the donor‐acceptor type of ED sharing [59] . In the case of the strongest hydrogen bond O2⋅⋅⋅H9, the region of positive at the atom O2 (Figure 4b), i. e., a lone pair, is oriented exactly at the region of negative near the H9 atom (vacancy).…”

“…The dispersion and exchange effects, which represent the Coulomb electron correlation and same spin electron‐electron interaction owing to Pauli exclusion principle, respectively, as well as atomic polarization and charge redistribution within and between the interacting molecules, i. e., charge transfer, need to be also taken into account [58] . More commonly, hydrogen bonds are described as an interaction of an electron lone pair (LP) of a heteroatom (H‐bond acceptor) and an electron deficiency region near the hydrogen atom, which can be ascribed to a donor‐acceptor (Lewis) mechanism of formation [59] . This provides the directionality of bonding, [60,61] which is however not a strict condition for a nonclassical H‐bond.…”

“…[58] More commonly, hydrogen bonds are described as an interaction of an electron lone pair (LP) of a heteroatom (H-bond acceptor) and an electron deficiency region near the hydrogen atom, which can be ascribed to a donor-acceptor (Lewis) mechanism of formation. [59] This provides the directionality of bonding, [60,61] which is however not a strict condition for a nonclassical H-bond.…”

Real-Space Interpretation of Interatomic Charge Transfer and Electron Exchange Effects by Combining Static and Kinetic Potentials and Associated Vector Fields

“…15,46 Lastly, the von Weizsäcker potential 𝜑 𝑊 (𝒓) or related one-electron potential is an alternative to the Laplacian of ED ∇ 2 𝜌(𝒓), 15,42,62,63,77,78 which is just the empirical measure of electron concentration or depletion via ED topology. 79 Modest attempts have been made to link the behavior of the potentials with essential chemical concepts, such as interatomic interaction, charge transfer, electron lone pair, and donor-acceptor (Lewis) mechanism of noncovalent bonds. 15 In this work, we generalize the described methodology to different kinds of chemical bonds present in a diverse set of selected crystals, including polar and nonpolar covalent bonds, ionic ones, classical and nonclassical hydrogen bonds, as well as several weak to moderate intermolecular interactions.…”