Which conformations make stable crystal structures? Mapping crystalline molecular geometries to the conformational energy landscape

Abstract

Flexible organic molecules often do not adopt their lowest energy conformer in crystal structures. We find that there is a preference for molecules to crystallise with high surface area conformers.

Crystal structure of 7-methoxy-1-{[(E)-2,6-dimethylphenylimino] (phenyl)methyl}-2-naphthol: Clarification of non-covalent bonding interactions on the basis of spatial organization of single molecular structure and the molecular alignments

“…From this point of view, the naphthalene derivatives having aroyl groups at peri-positions, i.e., 1-aroyland 1,8-diaroylnaphthalene derivatives, are one of the good models for analysing non-covalent bonding interactions in crystal. Recently, the authors have found highly effective diaroylation at peri (1,8)-positions of 2,7-dialkoxynaphthalene [10,11]. Furthermore, functional group interconversion of 2-and/or 7-alkoxy group to hydroxyl group is also achievable [12].…”

“…However, flexibility of molecular structure often disturbs to grasp origin and role of respective non-covalent bonding interactions [8,9]. In organic crystals, organic molecules are aggregated through various non-covalent bonding interactions.…”

In Silico Prediction of Growth and Dissolution Rates for Organic Molecular Crystals: A Multiscale Approach

“…Despite the excessive ramification of approaches developed to date, the whole CSP process can generally be subdivided into three distinct steps, each with their own methodologies and challenges: (1) conformational exploration of the molecule(s), (2) generation of candidate packing arrangements and (3) (re-)ranking of candidate structures using some form of fitness function [64]. Successful crystal engineering relies on the knowledge of molecular conformation, i.e., the overall shape of molecular building-blocks, as well as the relative arrangement of functional groups within a molecule that can participate in structure-directing interactions [65]. Molecular shape can be easily predicted for rigid molecules, but becomes more challenging as molecular flexibility is increased and the molecules of interest have a choice of conformers when self-assembling into a crystal [65].…”

“…Successful crystal engineering relies on the knowledge of molecular conformation, i.e., the overall shape of molecular building-blocks, as well as the relative arrangement of functional groups within a molecule that can participate in structure-directing interactions [65]. Molecular shape can be easily predicted for rigid molecules, but becomes more challenging as molecular flexibility is increased and the molecules of interest have a choice of conformers when self-assembling into a crystal [65]. Different conformers may lead to very different crystal packing arrangements, ultimately influencing the properties of the crystal [65].…”

Binding energies of tyrosine kinase inhibitors: Error assessment of computational methods for imatinib and nilotinib binding

“…There can be severe steric clashes in the X-ray structure which are not easily apparent. It has been shown [17] that molecular strain can be induced by intermolecular interactions in single-component crystal structures of molecules with no intramolecular hydrogen bonding, resulting in some molecules being distorted by up to 5 kcal/mol by crystal packing forces. As inter-molecular hydrogen bonding is involved in inhibitor -protein binding, large distortions may occur due to crystal packing forces.…”