Hydrogen Abstraction by Chlorine Atom from Amino Acids: Remarkable Influence of Polar Effects on Regioselectivity

Quantum chemistry computations have been used to investigate hydrogen-atom abstraction by chlorine atom from protonated and N-acetylated amino acids. The results are consistent with the decreased reactivity at the backbone alpha-carbon and adjacent side-chain positions that is observed experimentally. The individual effects of NH3+, COOH, and NHAc substituents have been examined and reveal important insights. The NH3+ group in isolation is found to be deactivating at the alpha-position, while the acetamido group is activating. For the COOH group, polar effects lead to a contrathermodynamic deactivation of the thermodynamically most favorable alpha-abstraction. In the N-acetylamino acid, the alpha-position is deactivated by the combined inductive effect of the substituents and the presence of an early transition structure, again overriding the greater thermodynamic stability of the alpha-centered radical product. Deactivation of the alpha-, beta-, and gamma-positions results in a peculiar stability for amino acids and peptides and their derivatives with respect to radical degradation.