Hydrogen Bonding in Molecular Design

Hydrogen bonding underpins a vast array of strategies in molecular design, from drug discovery to advanced materials. At its core, a hydrogen bond arises when a hydrogen atom covalently bound to an electronegative donor (typically N, O or F) engages an electron-rich acceptor site. This directional, moderately strong interaction governs molecular recognition, conformational stability and self-assembly processes. In medicinal chemistry, tuning hydrogen-bond donors and acceptors influences solubility, bioavailability and target affinity, enabling the optimisation of lead compounds. In supramolecular systems, patterns of hydrogen bonds drive host–guest complexation, gel formation and molecular machines. Materials science exploits hydrogen bonding to impart mechanical resilience, stimuli-responsive behaviour and selective adsorption in polymers and frameworks. Computational methods have matured to predict hydrogen-bond strengths via quantum-chemical descriptors, electrostatic potentials and machine-learning models, bridging theory and experiment. By modulating donor–acceptor geometries, chemists can engineer molecular scaffolds with bespoke properties, such as enzyme inhibitors that exploit networked hydrogen bonds at active sites or porous materials that selectively capture greenhouse gases. Harnessing these interactions in a rational, design-led manner continues to expand the frontiers of functional molecular systems with global significance in health, energy and the environment.

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Hydrogen Bonding in Molecular Design publication trend

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Technical terms

Hydrogen bond donor: An electronegative atom bearing a hydrogen atom that participates in hydrogen bonding.

Hydrogen bond acceptor: An electron-rich atom or group capable of interacting with a hydrogen bond donor.

Electrostatic potential: The spatial distribution of charge around a molecule, used to predict sites of non-covalent interaction.

Molecular interaction field (MIF): A three-dimensional map describing a molecule’s ability to interact via various forces, including hydrogen bonding.

Gibbs free energy: A thermodynamic quantity combining enthalpy and entropy changes to predict spontaneity of molecular interactions.

References

1. Hydrogen bonding to graphene surface: A comparative computational study. Inorganica Chimica Acta (2023).
2. Calculation of Hydrogen Bonding Enthalpy Using the Two-Parameter Abraham Equation. Liquids (2024).
3. Combining machine learning and quantum mechanics yields more chemically aware molecular descriptors for medicinal chemistry applications. Journal of Computational Chemistry (2021).