Abstract
In this work, two methods of high-resolution X-ray data refinement: multipole refinement (MM) and Hirshfeld atom refinement (HAR) - together with X-ray wavefunction refinement (XWR) - are applied to investigate the refinement of positions and anisotropic thermal motion of hydrogen atoms, experiment-based reconstruction of electron density, refinement of anharmonic thermal vibrations, as well as the effects of excluding the weakest reflections in the refinement. The study is based on X-ray data sets of varying quality collected for the crystals of four quinoline derivatives with Cl, Br, I atoms and the -S-Ph group as substituents. Energetic investigations are performed, comprising the calculation of the energy of intermolecular interactions, cohesive and geometrical relaxation energy. The results obtained for experimentally derived structures are verified against the values calculated for structures optimized using dispersion-corrected periodic density functional theory. For the high-quality data sets (the Cl and -S-Ph compounds), both MM and XWR could be successfully used to refine the atomic displacement parameters and the positions of hydrogen atoms; however, the bond lengths obtained with XWR were more precise and closer to the theoretical values. In the application to the more challenging data sets (the Br and I compounds), only XWR enabled free refinement of hydrogen atom geometrical parameters, nevertheless, the results clearly showed poor data quality. For both refinement methods, the energy values (intermolecular interactions, cohesive and relaxation) calculated for the experimental structures were in similar agreement with the values associated with the optimized structures - the most significant divergences were observed when experimental geometries were biased by poor data quality. XWR was found to be more robust in avoiding incorrect distortions of the reconstructed electron density as a result of data quality issues. Based on the problem of anharmonic thermal motion refinement, this study reveals that for the most correct interpretation of the obtained results, it is necessary to use the complete data set, including the weak reflections in order to draw conclusions.
Highlights
Quinoline is a planar heterocyclic compound consisting of a benzene ring fused with a pyridine ring, with the nitrogen atom at position 1
The considered data sets vary in quality [high-quality data sets PT-11(S-Ph) and PT-2(Cl) versus low-quality data sets PT8(Br) and PT-10(I)]; R and wR obtained in the course of Hirshfeld atom refinement (HAR)/X-ray wavefunction refinement (XWR)/multipole refinement (MM) refinement in all cases are low
A small increase in similarity to the theoretical values is observed in the case of MM for PT-10(I) and MM(freeXH) for PT-2(Cl) as well as a more significant improvement in the case of PT-11(SPh)(freeXH). Both of the studied refinement methods, XWR and MM, enabled successful refinement of positions and Atomic displacement parameters (ADPs) of heavy atoms, which was confirmed by comparison with theoretical bond lengths
Summary
Quinoline is a planar heterocyclic compound consisting of a benzene ring fused with a pyridine ring, with the nitrogen atom at position 1. As a result of its universal synthetic applications and owing to the fact that it shows a broad spectrum of pharmacological activity, belongs to the group of substances described as generic drug-like motifs (Musiol et al, 2011). These are, in turn, very versatile so-called privileged motifs (Evans et al, 1988) (molecular fragments that facilitate ligand binding to a certain type of receptor), which are very important starting points in the process of drug design. It is crucial to establish the way in which substituents with certain properties influence the qualities of the drug-like motif and change its therapeutic potential
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