The distal effect of N-electron-withdrawing groups on the stability of peptide carbon radicals

The effect of electron-withdrawing substituents, hydrogen bonding and protonation at amide nitrogen on the stability of radicals formed by loss of either a distal CH adjacent to the amide carbonyl or one proximal to the amide nitrogen for a series of acetamides and diketopiperazines has been studied via high-level ab initio methods. These studies show that the effect is to destabilize the radicals formed by abstraction of the proximal hydrogens, typically by 10-20kJmol^-1, and stabilize the distal radicals typically by 5-10kJmol^-1, but only if the distal radicals are polarized by another dative substituent. The different radical stabilities are not directly mirrored in calculated activation energies or experimental rates of radical formation in bromination reactions, because there is significant charge development in these reaction transition states.