π is the key to hydration as researchers find non-classical hydrogen bonding is the (back-seat) driver of aromatic hydration
02 Sep 2026 - Rosie de Laune
A group of researchers from the University of Oxford, UCL, and ISIS have used total neutron scattering analysed using computational modelling, to reveal the molecular mechanisms underlying aromatic solubility in water. Their results provide key insights relevant to understanding biomolecular behaviour and the design of new pharmaceuticals.
Aromatic rings are key structures in organic chemistry. Derived from benzene, they have delocalised electrons whose distribution depends on the functional groups bonded to the ring. This provides an adaptable and rigid platform on which to build larger assemblies such as biomolecules like chlorophyll and pharmaceuticals such as ibuprofen.
The properties of these larger assemblies depend on their interaction with other molecules, notably water. Benzene and other simple aromatics are insoluble in water, a phenomenon commonly rationalised with the empirical ‘like dissolves like’ rule. Their scarce solubility in water stands in stark contrast to the ubiquity of aromatics in pharmacy and structural biology.
Unfortunately, due to this hydrophobicity, our current understanding of interactions between water and aromatics is restricted to solid state constrained geometries or gas phase dimers. These scenarios inherently lack the necessary complexities of the liquid phase, where subtle biological and chemical processes take place. In liquids, the dynamic bonds are mutually interdependent and rely on cooperative mechanisms to modulate solubility.
Researchers from the University of Oxford, UCL, and ISIS have used total neutron scattering on SANDALS and NIMROD alongside computational modelling to investigate the dominant forces behind aromatic hydration. They studied the solvation behaviour of three archetypal aromatics in water: phenol, aniline, and p-nitrophenol, comparing the effects of the OH, NH2, and NO2 on the hydration. To distinguish between specific sites in the molecules, they took advantage of the distinct neutron scattering properties of hydrogen and deuterium.
We propose a new way of thinking about aromatic hydration and solubility in water, in which it is the weak hydrogen bonding that drives solvation, rather than classical hydrogen bonding, dipole-dipole, or dispersion forces.
Camilla Di Mino, University of Oxford
In their work, recently published in Nature Communications, they were able to characterise the classical hydrogen bonding between the functional groups and water, as well as revealing the non-classical interactions with the delocalised electrons in the aromatic rings that can, and often do, form hydrogen bonds.
“We propose a new way of thinking about aromatic hydration and solubility in water, in which it is the weak hydrogen bonding that drives solvation, rather than classical hydrogen bonding, dipole-dipole, or dispersion forces,” explains Camilla Di Mino, from the University of Oxford and ISIS Springboard Award winner.
Their experiments show that both phenol and aniline form short, directional OH···π interactions where the water is hydrogen bonding to the electron density at the centre of the aromatic ring. However, these are virtually absent in p-nitrophenol where, despite strong classical hydrogen bonding between water and the substituents, the loss of these interactions coincides with an almost order-of-magnitude decrease in solubility.
“Moreover, this opens up the possibility of non-classical HO···π* bonds, where an oxygen lone-pair from water forms a close contact with the p-nitrophenol antibonding orbital,” says Camilla. “These interactions have only recently been identified in the solid and gas phases, and the existence of such motifs in the liquid state has been contentious, as until now direct evidence has been elusive. In this study, we provide unequivocal experimental evidence of HO···π* interactions in liquids, and we fully characterise their structure and geometry atomistically.”
The schematic, right, shows these two types of interactions.
Such a detailed analysis, afforded by unique ability of neutrons to resolve hydrogen locations at the molecular level, highlights the importance of solvation mechanisms in the understanding of weak competitive interactions and their effect on the macroscopic behaviour of solutions.
The full paper can be found at DOI: 10.1038/s41467-026-76528-x
Camilla’s research is funded by EPSRC, through their Doctoral Prize Fellowship (Postdoctoral Pathway) Scheme.
