Rate Constants of Hydroperoxyl Radical Addition to Cyclic Nitrones:  A DFT Study

Abstract

Nitrones are potential synthetic antioxidants against the reduction of radical-mediated oxidative damage in cells, and as analytical reagent for the identification of HO 2 • and other such transient species. In this work, the PCM/B3LYP/6−31+G(d,p)//B3LYP/6−31G(d) and PCM/mPW1K/6−31 +G(d,p) density functional theory (DFT) methods were employed to predict the reactivity of HO 2 • with various functionalized nitrones as spin traps. The calculated second-order rate constants and free energies of reaction at both levels of theory were in the range of 10 0 −10 3 M −1 s −1 and 1 to −12 kcal mol −1 , respectively, and the rate constants for some nitrones are on the same order of magnitude as those observed experimentally. The trend in HO 2 • reactivity to nitrones could not be explained solely on the basis of the relationship of the theoretical positive charge densities on the nitronyl-C, with their respective ionization potentials, electron affinities, rate constants, or free energies of reaction. However, various modes of intramolecular H-bonding interaction were observed at the transition state (TS) structures of HO 2 • addition to nitrones. The presence of intramolecular Hbonding interactions in the transition states were predicted and may play a significant role towards a facile addition of HO 2 • to nitrones. In general, HO 2 • addition to ethoxycarbonyl-and spirolactamsubstituted nitrones, as well as those nitrones without electron-withdrawing substituents, such as 5,5-dimethyl-pyrroline N-oxide (DMPO) and 5-spirocyclopentyl-pyrroline N-oxide (CPPO), are most preferred compared to the methylcarbamoyl-substituted nitrones. This study suggests that the use of specific spin traps for efficient trapping of HO 2 • could pave the way toward improved radical detection and antioxidant protection.

Synthesis, structure, theoretical and experimental in vitro antioxidant/pharmacological properties of α-aryl, N-alkyl nitrones, as potential agents for the treatment of cerebral ischemia

“…31 On the other hand, the computational calculation of the energy reaction in the formation of the adduct-spin between nitrones and the hydroperoxyl Å OOH radical, has previously been used to predict its reactivity. 32 In the case of nitrones 7-12, 18, 19, 21, and 23, we have observed that the most stable conformation for the adductspin has an intramolecular OO-HÁ Á ÁO-N hydrogen bond (for nitrone 21, see Chart 5) with bond lengths of 1.84 and 2.19 Å. Similarly to the nitrone adducts-spin with radical OH Å , the spin density is now transferred and concentrated over the nitroxyl group N-O.…”

Theoretical considerations of secondary organic aerosol formation from H-abstraction of p-xylene

“…Previous studies showed that in the presence of OH radical the main reaction path is OH addition to the aromatic ring to form a xylene-OH adduct (consuming $90% of OH radicals) with Habstraction from one methyl group to form a methylbenzyl radical (consuming $10% of OH radicals) being the minor route [18,[31][32][33][34]. In addition, theoretical investigations have mainly focused on OH-addition to xylene and the fate of xylene-OH adducts and intermediates [15,26,31,[34][35][36], whereas the H-abstraction mechanism for p-xylene oxidation following the initial OH attack and subsequent products have only been studied experimentally [22,25,37,38].…”

Potential Implication of The Chemical Properties and Bioactivity of Nitrone Spin Traps for Therapeutics

“…The high reactivity of O 2 •− to DMPO in acidic pH was proposed to be due to the protonation of O 2 •− to form hydroperoxyl radical (HO 2 • ), since the pK a for O 2 •− and HO 2 • is 4.8 [137] and 4.4 [138], respectively, and that HO 2 • is a stronger oxidizer than O 2 •− ( E o′ = 1.06 and 0.94 V, respectively) [4]. The higher reactivity of HO 2 • to DMPO compared with O 2 •− was theoretically rationalized and the predicted rate constants in aqueous phase for the O 2 •− and HO 2 • addition to DMPO were found to be 5.9 × 10 −5 M −1 s −1 and 285 M −1 s −1 , respectively, at the PCM/B3LYP/6–31+G**//B3LYP/6–31G* level of theory [127,139]. At the same level of theory, the calculated thermodynamic data in aqueous phase also show a more facile addition of HO 2 • to DMPO compared with O 2 •− with Δ G rxn of -4.6 and 11.9 kcal/mol, respectively [139].…”

“…The higher reactivity of HO 2 • to DMPO compared with O 2 •− was theoretically rationalized and the predicted rate constants in aqueous phase for the O 2 •− and HO 2 • addition to DMPO were found to be 5.9 × 10 −5 M −1 s −1 and 285 M −1 s −1 , respectively, at the PCM/B3LYP/6–31+G**//B3LYP/6–31G* level of theory [127,139]. At the same level of theory, the calculated thermodynamic data in aqueous phase also show a more facile addition of HO 2 • to DMPO compared with O 2 •− with Δ G rxn of -4.6 and 11.9 kcal/mol, respectively [139]. …”