In 2011, when Tobias Ritter reported a reagent—now known as PhenoFluor—that could swap the hydroxyl group on a phenol for a fluoride, he was cautiously optimistic that the work might someday be used to make radiotracers with 18F. After all, the deoxyfluorination reaction, which proceeds via nuclear aromatic substitution, opened up more options. It worked on phenols that were electron-rich, whereas other such reactions worked only on electron-poor arenes.
But the radiolabeling version of the reaction proved elusive.
So Ritter and graduate student Constanze N. Neumann, both at Harvard University at the time, decided to dig into the reaction mechanism. They discovered that the deoxyfluorination takes place in a concerted fashion: The fluoride goes onto the aromatic ring at the same time the oxygen leaves the ring in the form of a urea compound (Nature 2016, DOI: 10.1038/nature17667).
This is unusual for nucleophilic aromatic substitutions, which usually take place in a stepwise manner. Those stepwise reactions can occur only on electron-poor arenes because a negative charge builds up and needs to be stabilized. That’s not the case with the concerted reaction.
With the knowledge they gleaned about the mechanism, Ritter and Neumann teamed up with Jacob M. Hooker, of Massachusetts General Hospital, to tweak PhenoFluor so that it could work with 18F. “This new reaction is much more robust, tolerates air and water, and, most importantly, is really easy to perform,” says Ritter, who recently moved to the Max Planck Institute for Coal Research.
Guy Lloyd-Jones, a fluorination expert at the University of Edinburgh calls the work “a major practical advance in the synthesis of 18F-aryl radiochemicals.” Furthermore, he adds, the work used “a very elegant physical organic study to identify the mechanistic process that allows the new methodology to be so effective.”