Manganese-Porphyrin-Catalyzed C-H Fluorination: Hydrocarbons, But Not Drugs?

Transformation of C-H to C-F bonds in organic compounds can be used in drug design to easily diversify molecular series under exploration. A particularly attractive fluorination reaction is the recently discovered aliphatic C-H bonds fluorination catalyzed by manganese(Mn)-containing porphyrins, which proceeds under mild conditions and with high yields. However, this fluorination technique has been applied so far only to a narrow range of carbon rich organic substrates. In this preliminary study, based on quantum chemical modeling of several key stages in the presumed mechanism of this reaction, we put forward a hypothesis to explain difficulties of extending the Mn-porphyrin-catalyzed fluorination to nitrogen rich drug-like molecules, namely, a significant growth of the height of the activation barrier for drug-like substrates. Specifically, we demonstrate that reaction energies are comparable for various substrates, including those for which Mn-porphyrin-catalyzed fluorination occurs and those for which it does not occur, and hence, thermodynamic factors are unlikely to control the observed differences in the reactivity. Next, we carry out a first-pass modeling of fluorination reaction paths for two substrates, cyclohexane versus piperidine, as a representative of the type of nitrogen rich compound that can and cannot be fluorinated under recommended conditions, and found a significant difference in activation energies (~7 kcal/mol vs ~40 kcal/mol), which might point at the reason for the difference in the reactivity. Further computational modeling is required to reveal the limitations of the Mn-porphyrin-catalyzed fluorination, and, if possible, possible ways to overcome such limitations.