Computer aided design has helped make the strongest synthetic sulfate-encapsulating receptor ever

Chemists in the US have made a self-assembling cage designed specifically to recognise sulfate anions. The receptor is strong enough to sequester sulfate from water, which could lead to new ways of cleaning up nuclear waste. 

Radu Custelcean and Ben Hay from Oak Ridge National Laboratory, Tennessee, used Hay’s ’HostDesigner’ computer software to construct an ideal binding environment for sulfate anions. ’Sulfate is a notoriously difficult anion to bind from water,’ explains Custelcean, ’because it can accept 12 hydrogen-bonds from water molecules, and to effectively bind sulfate we would have to replace all of them.’   

Hay had shown from molecular modelling studies that six urea molecules, arranged along the edges of a tetrahedron, could be perfectly set up to provide the necessary 12 hydrogen-bonds. What the group needed was a way of holding those urea groups in place. It was immediately obvious that making such a cage by multi-step organic synthesis would be inefficient, so they opted for a self-assembly approach. 

Nickel bipyridine complexes made an ideal choice for the corners of their tetrahedral cage, as they are very stable in water. ’The final task was to place all the components in the perfect arrangement and find ways to link them all together. This is where the HostDesigner software comes in: it can generate large numbers of possible structures very quickly (over 270,000 in this case), which we then screened [using molecular modelling] to identify a small number that formed rigid cages.’


Source: © Angew. Chemie Int. Ed.

The sulfate anion (red and yellow) is imprisoned by a tetrahedron of four nickel centres linked by self-assembling ligands (experimental - blue/predicted - yellow)

The team then selected the most synthetically accessible of these candidates and put the theory to the test. The cage formed as predicted, and the team used mass spectrometry and X-ray crystallography to confirm that it was stable in water and that a sulfate anion was bound in the centre.   

To measure the strength of the binding, they used barium nitrate to try and rip the sulfate out of the cage: ’Barium sulfate is very insoluble,’ Custelcean explains, ’so by measuring the amount of barium sulfate that precipitates in the presence of the cage, we can estimate the sulfate binding constant. It turns out that the affinity is truly exceptional - it surpasses all known synthetic receptors and even rivals the sulfate binding protein.’ 

Phil Gale, a specialist in supramolecular anion recognition and sensing from the University of Southampton, UK, applauds the group’s success: ’Not only is it a great achievement to make a sulfate receptor that works in water with such a high stability constant, but perhaps more importantly it shows the power of Ben Hay’s HostDesigner software and of using a computational approach to design.’ 

Looking to the future, Custelcean thinks that this computer-aided design process could be extended to create receptors for all sorts of other molecules with many potential applications. ’We are looking towards environmental decontamination and nuclear waste cleanup - although sulfate is not a major contaminant in nuclear waste, it does interfere with processing, so it would be useful to be able to remove sulfate before the waste is processed.’ He adds that this particular cage would not be particularly useful for sequestering sulfate, but that his group have some ideas about how to improve it. 

Phillip Broadwith