Radical Stability as a Guideline in C-H Amination Reactions

The stability of N-centered radicals and radical cations of potential relevance in C-H amidation reactions has been quantified using highly accurate theoretical methods. Combination with available C-H bond energies for substrate fragments allows for the prediction of reaction enthalpies in 1,5-hydrogen atom transfer (HAT) steps frequently encountered in reactions such as the Hofmann-Loffler-Freytag (HLF) reaction. Protonation of N-radicals is found to be essential in classical HLF reactions for thermochemically feasible HAT steps. The stability of neutral N-radicals depends strongly on the type of N-substituent. Among the electron-withdrawing substituents, the trifluoroacetyl (TFA) group is the least and the toluenesulfonyl (tosyl) group the most stabilizing. This implies that TFA-aminyl radicals have the broadest and tosyl-aminyl radicals the smallest window of synthetic applicability. In how far the intramolecular C-H amidation reactions compete with hydrogen abstraction from common organic solvents can be judged based on a comparison of reaction thermodynamics.