Web Date: March 19, 2018
Astatine forms halogen bonds
Studying the infinitesimally rare element astatine can feel like chasing shadows. All of its isotopes are radioactive, the most stable having a half-life of 8 hours, and the estimated stock of astatine in Earth’s crust amounts to less than 30 grams.
But thanks to some meticulous chemistry, researchers at the University of Nantes have shown experimentally that astatine can form a special kind of attraction known as a halogen bond (Nature Chemistry 2018, DOI: 10.1038/s41557-018-0011-1). The team hopes that these bonds could be exploited to stabilize radiotherapy agents that rely on astatine-211.
Halogen bonds are similar in strength and character to hydrogen bonds. They form when an electron-pair donor—a Lewis base—hooks up with a halogen that bears a patch of partial positive charge. All of the garden-variety halogens from fluorine to iodine make halogen bonds, with larger halogens forming stronger bonds. Computational studies had suggested that astatine’s halogen bonds should be even stronger, and the Nantes researchers have now confirmed that.
They created astatine-211 by smashing alpha particles into bismuth-209 targets at the Arronax cyclotron in Nantes, and used it to make an aqueous solution of astatine monoiodide (AtI). Adding cyclohexane to the mixture extracted some AtI into the organic phase. This two-phase setup would allow them to track astatine’s moves in response to potential halogen bonding partners.
However, using subnanomolar solutions of astatine made it impossible to use standard spectroscopic techniques to look for any halogen bonding. “The chemistry of astatine is difficult to understand because you don’t have the usual chemical tools available,” says Gilles Montavon, part of the research team. Instead, they used the element’s radioactivity to track its behavior.
The team tested nine different Lewis base partners, such as diethyl ether and tributyl phosphate, which were more soluble in cyclohexane than in water. As the concentration of the Lewis base increased, it pulled more AtI—and its radioactivity—out of the aqueous phase and into the cyclohexane, evidence for halogen bonding.
Measuring how the distribution of astatine changed during the experiments allowed the researchers to calculate the strength of the interaction between each Lewis base and astatine. When they compared these with the halogen bonds between the same Lewis bases and diiodine (I2), they found that astatine’s halogen bonds were stronger, and followed the same trend in strength from one Lewis base to the next. The researchers also used density functional theory calculations to show that astatine in AtI would have a more pronounced patch of positive charge than iodine, making it the more likely location for the halogen bond to form.
“It’s not too surprising because we knew all the other halogens had this ability, but it’s nice to get a confirmation,” says Scott Wilbur at the University of Washington. He is part of a collaboration that launched a clinical trial of astatine radiotherapy a few months ago, focusing on cancers that originate from the blood-generating haematopoietic stem cells in bone marrow. The trial employs an antibody that carries astatine-211 to target and kill those cells, prior to a stem cell transplant. Astatine-211’s high-energy alpha particles travel less than 100 µm in tissue, focusing the damage on the targeted cells, and the isotope’s 7.2 hour half-life means that its radioactivity has declined to almost nothing by the time the transplant happens a few days later. “Astatine just fits in a nice window,” Wilbur says.
The astatine halogen bond also completes a periodic set that has attracted growing interest in recent years. Mate Erdelyi at the University of Gothenburg says that halogen bonding is now being used strategically to improve the affinity and selectivity of new drugs, and to direct supramolecular self-assembly. “Halogen bonding has gone from being interesting for a few nerds to something that can be widely used in medicines, materials, and catalysis,” he says.
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