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

Abstract

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 α-carbon and adjacent side-chain positions that is observed experimentally. The individual effects of NH(3)(+), COOH, and NHAc substituents have been examined and reveal important insights. The NH(3)(+) group in isolation is found to be deactivating at the α-position, while the acetamido group is activating. For the COOH group, polar effects lead to a contrathermodynamic deactivation of the thermodynamically most favorable α-abstraction. In the N-acetylamino acid, the α-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 α-centered radical product. Deactivation of the α-, β-, and γ-positions results in a peculiar stability for amino acids and peptides and their derivatives with respect to radical degradation.

An ONIOM investigation of the effect of conformation on bond dissociation energies in peptides

“…From a biological perspective, we note that peptide backbones are in general relatively more inert than side chains toward attack by electrophilic radicals . This has been attributed to a kinetic effect of polar destabilization, that is, the effect of polar substituents on a polar transition structure (formed between an electron‐rich and an electron‐poor reactant) that lead to further charge separations .…”

“…In a series of studies in recent years, we have also used computational quantum chemistry to examine bond dissociation energies, including some that are biologically relevant . In addition, we have examined reaction barriers for bond dissociation processes that result from radical attack . While our earlier studies did not examine conformational effects in detail, we have recently investigated more thoroughly the qualitative and quantitative effects of conformation on the formation of small peptide radicals .…”

Theoretical study on SH2 reaction of methyl radical with three‐membered ring

“…It is well known that bimolecular reactions probably involve complexes along the reaction path . Especially, when the complex is lower in energy than the isolated species, it should be regarded as a reference point for the calculation of reaction barrier.…”

Direct Trifluoromethylthiolation of Unactivated C(sp3)H Using Silver(I) Trifluoromethanethiolate and Potassium Persulfate

“…Among several common solvents that we screened, CH 3 CN stood out as the best one and water was harmful for the reaction (Table 1, entries 8-13). A reaction temperature higher than 50 8C was required for an effective transformation, as no obvious conversion of AgSCF 3 was observed at lower temperatures (Table 1, entries [14][15][16][17][18]. Interestingly, when the reaction was conducted at 50 8C, a longer reaction time (12 h) was required, as no reaction occurred within 4 h (Table 1, entry 16).…”

“…Similarly, the direct C(sp 3 )ÀH trifluoromethylthiolation occurred predominantly at tertiary C À H bonds. Cyclopentanone and cyclohexanone were not suitable substrates for the reaction, as only trace amounts of the desired products were observed, however, the reaction of cycloheptanone and cyclooctanone successfully resulted in the desired products (14)(15)(16)(17). Various acyclic ketones underwent the trifluoromethylthiolation to give the desired products in acceptable yields (18)(19)(20)(21)(22)(23)(24)(25).…”