Breakthrough in aromatic molecule research
30 Jun 2010



New experimental data by from the ISIS neutron source on how ring-shaped molecules pack together in liquids could lead to more efficient drug design.

​​Benzene - structure and arrrangements

A team of scientists from University College London and the Science and Technology Facilities Council’s ISIS Neutron Source have demonstrated how aromatic molecules arrange themselves in liquids. Aromatic molecules contain very stable atomic rings, of which benzene is the most famous example.

The data has shown that the current view underpinning many biological calculations may need significant rethinking. The impact will be profound as interactions between aromatic molecules are a factor in the self-assembly of many important biological molecules including DNA, RNA, proteins and peptides

Much of the early drug design process for a particular condition is based on molecular modelling using calculations and computer simulation to determine the likely nature of the interactions between the drug molecule and the biological molecule of interest, such as a protein.

This new knowledge should lead to more efficient drug design by the more accurate selection of the lead drug molecule, thereby potentially reducing the time and cost of developing new drugs to market

Aromatic π-π interactions are important in many biological processes, but current models are based on theoretical calculations. SANDALS was used to obtain the first detailed experimental data, and showed that one of the theoretical assumptions is incorrect. This research, today’s cover article in the top chemistry journal JACS, has profound implications.

“SANDALS was ideal for us because we could use isotope substitution, which enabled us to investigate distance and orientation of the molecules as they interacted,” says Prof Neal Skipper from UCL.

Benzene and toluene were investigated as they are the archetypal aromatic liquids and the simplest molecules with which to attempt to understand structures resulting from intermolecular π-orbital interactions. They are also important nonpolar organic solvents, used in a wide range of laboratory and industrial processes.

The structure of liquids is complex, but scientists typically visualise benzene via four ‘motifs’ (arrangements of molecule) – S (sandwich), PD (parallel displaced), T-shaped, and Y-shaped.

Current theory found that T and PD had the lowest energies, and so predicted that they would be the most common. But the experiment shows that PD and Y-shaped are most common – this makes sense as they are more efficient at ‘stacking’ when there are many molecules together. The current theoretical calculations are limited as they use assumptions from gas phase data and are mainly based on how two molecules interact, rather than many molecules packing together as seen in liquids.

The experiment

A combination of high-resolution neutron diffraction and isotopic substitution of hydrogen for deuterium was used to determine the detailed structure of liquid benzene and toluene. Data analysis resulted in a full six-dimensional spatial and orientational picture of the liquids.

The experiment found that that the nearest neighbour coordination shells contain approximately 12 molecules. When viewed as a whole these shells are orientationally isotropic, but detailed analysis reveals that the favoured molecule arrangements is PD at the smaller separations (<5 Å) and Y-shaped at the larger separations.


Understanding the aromatic π-π interactions of benzene-like chemical groups is extremely important for developing models of their biochemical interactions.  Aromatic π-π interactions play a role in: the stereochemistry of organic reactions, organic host-guest chemistry and crystal packing, protein folding and structure, DNA and RNA base stacking, protein-nucleic acid recognition, drug design and development, and asphaltene (heavy crude oil) aggregation and fouling.

The new knowledge provided by the present study has a number of important implications in drug design and development.

“π-π interactions are a factor in the self-assembly of many important biological molecules including DNA, RNA, proteins and peptides," says Jayne Lawrence, Professor of Biophysical Pharmaceutics in the Pharmacy Department at King's College London. “The discovery that our current understanding of these interactions is incorrect will have a number of far reaching implications ranging from basic chemistry through to our understanding of the self-assembly of biological molecules, eg protein folding."

Drug design – Molecular modelling is an important component in modern drug design. A first step is to establish whether drug candidates will interact with (or fit in) the target site of the biological molecule of interest (generally a protein but also molecules such as DNA).

The accuracy of theoretical calculations used to determine this interaction is critically dependent on being able to correctly model candidate drug interaction with the target site. Only then will theory successfully select the lead molecule for development.

This experimental data shows that our understanding of the likely interaction between a drug candidate and a target biological molecule involving aromatic rings needs to be urgently re-assessed in order to better design and select the most therapeutically active molecules for development.

Drug activity – Many classes of drug molecule contain a benzene-type functional unit within their structure. For example, pain-killers such as aspirin, ibuprofen, and codeine all contain such a unit, despite their otherwise relatively simple molecular form.

In many cases the presence of the benzene-type functional unit in the drug molecule is essential for its biological activity, because the drug interacts with the target biological molecule (usually an enzyme), by aromatic π-π interactions. Better understanding the nature of such interactions will improve our understanding of the mechanisms by which drugs exert their activity.

This project was part of lead author Tom Headen's PhD, which was funded by NERC.

Research date: April 2010

Further Information

SANDALS is a diffractometer especially built for investigating the structure of liquids and amorphous materials. It uses isotopic substitution to perform in depth structural studies on the atomic scale. The combination of an intense pulsed neutron source and a large number of detectors at low angles make SANDALS ​particularly useful for measuring structure factors containing light atoms such as hydrogen and deuterium.​