Mechanistic insights on deoxyfluorination

Abstract

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). With the knowledge they gleaned about the mechanism, Ritter and Neumann teamed