Intermolecular Interaction Analysis in Molecular Crystals

Intermolecular interaction analysis in molecular crystals lies at the heart of crystal engineering, materials science and pharmaceutical development. By dissecting the forces that govern molecular assembly—hydrogen bonding, π–π stacking, halogen and chalcogen bonding, electrostatic complementarity and dispersion interactions—researchers can predict and tailor crystal structures with desired mechanical, optical and electronic properties. Modern approaches combine high-resolution X-ray and neutron diffraction with computational techniques such as density functional theory and ab initio calculations to quantify pairwise interaction energies and visualise three-dimensional packing landscapes. Tools like Hirshfeld surface analysis and energy frameworks enable a direct link between local contact motifs and bulk behaviour, illuminating how subtle changes in electron density distribution can drive polymorphism, influence solubility and affect charge transport. The convergence of experimental and computational methodologies has thus transformed our ability to rationalise and manipulate the architecture of molecular crystals for applications ranging from organic semiconductors to active pharmaceutical ingredients.

Research from Nature Portfolio

A recent high-pressure study of a prototypical aromatic hydrocarbon employed in situ synchrotron X-ray diffraction together with ab initio modelling to explore phase behaviour up to 35 GPa. The work revealed successive polymorphic transitions—pyrene-I to pyrene-II, IV and V—with unprecedented molecular curvature and compaction under compression. Quantitative bonding analysis showed how electrostatic attraction and dispersion forces evolve to stabilise metastable phases well beyond ambient conditions. These insights advance the fundamental understanding of pressure-induced modulation of intermolecular interactions and offer a roadmap for tuning crystal packing in organic functional materials.

Research from all publishers

One foundational contribution introduced a cross-platform software for comprehensive Hirshfeld surface analysis, two-dimensional fingerprint plotting and quantitative energy frameworks. By interfacing with quantum-mechanical engines, this tool rapidly computes interaction energies—including electrostatic, dispersion and repulsion components—and visualises void spaces, greatly facilitating the study of organic salts, solvates and coordination compounds. Complementing this, a conceptual review synthesised qualitative and quantitative perspectives on non-covalent contacts beyond hydrogen bonds—halogen, chalcogen, pnicogen and tetrel interactions—demonstrating their common origin in electron density redistribution. By integrating electron-density topology, molecular electrostatic potential and energy decomposition, the review established a unified framework linking contact motifs to crystal properties and guiding the design of materials with tailored functionality.

Intermolecular Interaction Analysis in Molecular Crystals publication trend

The graph below shows the total number of articles in intermolecular interaction analysis in molecular crystals across all publications each year (not limited to Nature Index journals).

Technical terms

Hirshfeld surface analysis: A method to map and quantify intermolecular contacts on a molecule’s electron-density isosurface, facilitating visualisation of close interactions.

Energy framework: A graphical representation of three-dimensional networks of interaction energies, decomposed into electrostatic, dispersion and repulsion contributions.

Non-covalent interaction (NCI): A weak, directional contact—such as hydrogen, halogen or chalcogen bonding—arising from electrostatic and dispersion forces without shared electron pairs.

π–π stacking: A face-to-face or offset overlap of aromatic rings leading to stabilising dispersion and electrostatic interactions between delocalised π systems.

Ab initio calculation: A first-principles computational approach that solves the Schrödinger equation for a molecular system without empirical parameters.

References

1. Polymorphism of pyrene on compression to 35 GPa in a diamond anvil cell. Communications Chemistry (2024).
2. CrystalExplorer: a program for Hirshfeld surface analysis, visualization and quantitative analysis of molecular crystals. Journal of Applied Crystallography (2021).
3. Intermolecular interactions in molecular crystals: what’s in a name?. Faraday Discussions (2017).