Deciphering the driving forces in crystal packing by analysis of electrostatic energies and contact enrichment ratios

Abstract

Hirshfeld surface analysis is a widely used tool for identifying the types of intermolecular contacts that contribute most significantly to crystal packing stabilization. One useful metric for analyzing these contacts is the contact enrichment descriptor, which indicates the types of contacts that are over- or under-represented. In this statistical study, enrichment ratios were combined with electrostatic energy (E elec) data for a variety of compound families. To compute the electrostatic interaction energy between atoms, charge density models from the ELMAM2 database of multipolar atoms were used. As expected, strong hydrogen bonds such as O/N—H...N and O/N—H...O typically display large enrichment values and have the most negative (i.e. favorable) electrostatic energies. Conversely, contacts that are repulsive from an electrostatic perspective are usually the most under-represented. Analyzing the enrichment ratio and electrostatic energy indicators was shown to help identify which favorable contacts are the most competitive with each other. For weaker interactions, such as hydrophobic contacts, the behavior is less clear cut and can depend on other factors such as the chemical content of the molecule. The anticorrelation between contact enrichment and E elec is generally lost for weaker contacts. However, we observed that C...C contacts are often enriched in crystal structures containing heterocycles, despite the low electrostatic attraction. For molecules with only weak hydrogen bond donors/acceptors and hydrophobic groups, the correlation between contact enrichment and E elec is still evident for the strongest of these interactions. However, there are some exceptions where the most favorable contacts from an electrostatic perspective are not the most over-represented. This can occur in cases where the shape of the molecule is complex or elongated, favoring dispersion forces and shape complementarity in the packing.

Quantifying the hydrogen-bond propensity of drugs and its relationship with Lipinski's rule of five

“…Numerous papers delve into the analysis of the roles and strengths of N and O in both intramolecular and intermolecular HB interactions. 10–12 For example, Klebe et al compared the strength of N and O atoms as hydrogen bond acceptors in crystalline oxazoles, isoxazoles, methoxypyridines, and oxime ethers. Their study revealed that, within the entire palette of N and O hydrogen-bond acceptors, specific instances exist where O atoms exhibit weaker hydrogen bond donor characteristics compared to N atoms in molecule⋯H 2 O complexes.…”

“…13 Jelsch et al observed that strong hydrogen bonds, such as O/N–H⋯N and O/N–H⋯O, exhibit significant enrichment values and possess the most negative electrostatic energies. 10 Hydrogen bonds between HX (X = N, O) donors and push–pull or saturated aminoketone and aminoester molecular fragments exhibit more frequency on oxygen compared to amino nitrogen. 14 Additionally, the presence of different functional groups and specific molecular contexts can further influence the strength and significance of hydrogen bonding interactions.…”

Approaches for the Efficient Removal of Fluoride from Groundwater: A Comprehensive Review

“…The interaction between fluoride and nanomaterials is usually carried out by electrostatic forces, surface attraction, chemical dissociation, or hydrogen interactions. These interactions cause the adsorption of fluoride by nanomaterials and the separation of the fluoride from the water [22].…”