Intermolecular Interactions in Crystalline Materials

In crystalline materials, the arrangement of molecular entities into ordered lattices is governed by a network of intermolecular forces that operate beyond formal chemical bonds, collectively defining the stability, morphology and function of the solid. Chief among these interactions are hydrogen bonds, π···π stacking and weaker contacts such as anion···π attractions and van der Waals forces. These noncovalent forces modulate crystal packing, directing the emergence of supramolecular assemblies with tailored porosity, optical response and mechanical resilience. Advances in experimental crystallography, surface‐mapping techniques and computational modelling have elucidated how subtle variations in electrostatic potential and atomic overlap drive the propensity of chemical species to associate. A thorough understanding of these phenomena underpins rational design of functional materials, from pharmaceutical polymorphs and organic semiconductors to coordination frameworks and metal–organic networks with bespoke properties.

Research from Nature Portfolio

Recent studies have combined high‐resolution X-ray diffraction with computational analysis to dissect the interplay between crystal packing and molecular conformation in drug-like triazole derivatives. Detailed Hirshfeld surface mapping has revealed that hydrogen bonding motifs, such as C–H···N and C–H···Cl contacts, dominate stabilisation, while π···π and anion···π interactions further enhance lattice cohesion. Parallel density functional theory investigations have demonstrated that crystal-packing forces can distort gas-phase minima, altering frontier orbital energies and thus electronic properties relevant to biological targeting. Together, these works underscore the necessity of accounting for solid-state noncovalent networks when predicting reactivity, ligand binding and material performance in crystalline pharmaceuticals and related molecular solids.

Intermolecular Interactions in Crystalline Materials publication trend

The graph below shows the total number of articles in intermolecular interactions in crystalline materials across all publications each year (not limited to Nature Index journals).

Technical terms

Hydrogen bond: A directional interaction between an electropositive hydrogen atom bonded to N or O and a lone-pair acceptor, crucial for crystal stabilisation.
π···π stacking: Attractive overlap between aromatic rings that contributes to the cohesion and ordering of molecular layers.
Anion···π interaction: Electrostatic attraction between an electron-rich anion and the π-system of an aromatic ring, directing lattice assembly.
Hirshfeld surface analysis: A computational method for partitioning space around a molecule in the crystal to visualise and quantify intermolecular contacts.
Enrichment ratio: A statistical measure comparing observed contact frequencies in a crystal with those expected at random, indicating preferred interaction partners.
Supramolecular assembly: Organisation of molecules into larger ordered architectures held together by noncovalent interactions.
Density functional theory (DFT): A quantum-mechanical modelling approach to calculate electronic structure and predict interaction energies.
Molecular electrostatic potential (MEP): A computed map of charge distribution used to rationalise sites favourable for noncovalent interactions.

References

1. Crystallographic Aspects, Photophysical Properties, and Theoretical Survey of Tetrachlorometallates of Group 12 Metals [Zn(II), Cd(II), and Hg(II)] with a Triply Protonated 2,4,6-Tris(2-pyridyl)-1,3,5-triazine Ligand. Inorganic Chemistry (2023).
2. Crystal structure, Hirshfeld surface analysis and DFT studies of 5-(adamantan-1-yl)-3-[(4-chlorobenzyl)sulfanyl]-4-methyl-4H-1,2,4-triazole, a potential 11β-HSD1 inhibitor. Scientific Reports (2019).
3. The enrichment ratio of atomic contacts in crystals, an indicator derived from the Hirshfeld surface analysis. IUCrJ (2014).
4. Coordination Polymers Based on Phthalic Acid and Aminopyrazine Ligands: On the Importance of N–H···π Interactions. Polymers (2018).