Although hydrogen bonds are fundamental to the formation of many different materials, these directional interactions invariably depend on the smaller, lighter elements of the periodic table, usually nitrogen and oxygen. Over the last few years Tomislav Friščić, an associate professor in McGill University’s Department of Chemistry, has examined how halogens could build molecular assemblies with larger atoms. He and his colleagues were able to do just that, describing in Nature Communications how they introduced such atoms to one another in solid-state structures that represent unusual, supramolecular amalgamations of elements such as iodine and antimony, as well as a new approach to materials science.

“We have an unexplored type of interaction involving really heavy atoms,” says Friščić, who describes the result as “beautifully unnatural”. “This is a way of creating supramolecular structures that don’t want to get involved in hydrogen bonding.”
The inspiration for this work was the cocrystal, a crystalline solid composed of different compounds in a way that produces neither a solvate nor a salt. Cocrystals have been a laboratory oddity since they were first highlighted as a route to new materials in the mid-19th century, but over the past decade they have been a subject of intense interest for the pharmaceutical industry. Drugs with desirable medical properties often have undesirable physical properties that prevent these agents from being taken into the human body.

Ball mill with steel ball is milling iron oxide and potassium nitrate.

Milling with steel ball yields unique compounds for study.

“There are lots of properties you can modify simply by changing the crystal structure of the compound and cocrystallization is a great way to do that,” explains Friščić. “You can take a low-solubility drug candidate and cocrystallize it with something that is more biologically acceptable, like sugar. It essentially changes the material property of the drug, making it easier to make tablets, for instance, without having to do any chemistry on the drug.”

Working with Dominik Cinčić, a long-time colleague from the University of Zagreb, Croatia, Friščić was less interested in any particular application than simply answering the question of whether it would be possible to entice heavier atoms into similarly novel cocrystal arrangements. More specifically, they wondered if members of the halogen family, such as iodine or bromine, would associate with non-halogen elements that typically did not form hydrogen bonds. By subjecting various ingredients to ball milling and grinding, Friščić’s team was in fact able to obtain just such halogen-bonded versions of phosphorus, arsenic, and antimony.

chematic view of the halogen bond donor 1,3,5-trifluoro-2,4,6-triiodobenzene (tftib) and the acceptors NPh3, PPh3, AsPh3, SbPh3, and BiPh3.

Schematic view of the halogen bond donor 1,3,5-trifluoro-2,4,6-triiodobenzene (tftib) and the acceptors NPh3, PPh3, AsPh3, SbPh3, and BiPh3.

A team led by David Bryce, a professor in the University of Ottawa’s Department of Chemistry and Biomolecular Sciences, has independently carried out a parallel stream of this same research. They studied an instance of phosphine becoming a halogen bond acceptor, which enabled them to create (Ph3P)·(sym-C6F3I3), which they claimed to be the first example of a cocrystal deliberately designed to form a phosphorus-iodine bond. Their work, which was published last year in Chemical Communication, focuses more on the use of nuclear magnetic resonance as a way of analyzing this kind of new molecular combinations.

“This fundamental spectroscopy attracted the interest of some leaders in the burgeoning area of halogen bonding,” says Bryce. “We have been trying to understand the nature of these interactions and what NMR could tell us about them.”

Friščić adds that the properties of these compounds could lend themselves to some remarkable uses. Since they do not rely on hydrogen bonds, for example, these materials could be used to make materials with interesting electronic features of metals while remaining highly resistant to water or humidity. He cautions that the explorations of such properties is just beginning, as evidenced by the fact that not all of the halogen bonding attempts were successful. The immediate way forward, he concludes, is pure science.

“This is really a matter of making molecules recognize each other using something that so far has not been observed in nature,” he says.