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Reactivities of substituted α-phenyl-N-tert-butyl nitrones.

Rosselin M, Choteau F, Zéamari K, Nash KM, Das A, Lauricella R, Lojou E, Tuccio B, Villamena FA, Durand G - J. Org. Chem. (2014)

Bottom Line: The effect of N-tert-butyl substitution on the charge density and electron density localization of the nitronyl carbon as well as on the free energies of nitrone reactivity with O2(•-) and HO2(•) were computationally rationalized at the PCM/B3LYP/6-31+G**//B3LYP/6-31G* level of theory.Finally, the substituent effect was investigated in cell cultures exposed to hydrogen peroxide and a correlation between the cell viability and the oxidation potential of the nitrones was observed.Through a combination of computational methodologies and experimental methods, new insights into the reactivity of free radicals with nitrone derivatives have been proposed.

View Article: PubMed Central - PubMed

Affiliation: Avignon Université , Equipe Chimie Bioorganique et Systèmes Amphiphiles, 33 rue Louis Pasteur, F-84000 Avignon, France.

ABSTRACT
In this work, a series of α-phenyl-N-tert-butyl nitrones bearing one, two, or three substituents on the tert-butyl group was synthesized. Cyclic voltammetry (CV) was used to investigate their electrochemical properties and showed a more pronounced substituent effect for oxidation than for reduction. Rate constants of superoxide radical (O2(•-)) reactions with nitrones were determined using a UV-vis stopped-flow method, and phenyl radical (Ph(•)) trapping rate constants were measured by EPR spectroscopy. The effect of N-tert-butyl substitution on the charge density and electron density localization of the nitronyl carbon as well as on the free energies of nitrone reactivity with O2(•-) and HO2(•) were computationally rationalized at the PCM/B3LYP/6-31+G**//B3LYP/6-31G* level of theory. Theoretical and experimental data showed that the rates of the reaction correlate with the nitronyl carbon charge density, suggesting a nucleophilic nature of O2(•-) and Ph(•) addition to the nitronyl carbon atom. Finally, the substituent effect was investigated in cell cultures exposed to hydrogen peroxide and a correlation between the cell viability and the oxidation potential of the nitrones was observed. Through a combination of computational methodologies and experimental methods, new insights into the reactivity of free radicals with nitrone derivatives have been proposed.

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Correlationof the nitronyl carbon charge densities with (A) nitronylC chemical shifts of nitrones 2, 6, 7, 10, 11, and PBN (R2 = 0.965), excluding nitrones 1 and 8 (marked as ○) and 9 (which is not solublein CDCl3), (B) experimental relative rate constants ofO2•– addition to nitrones (ksN/kPR), including para-substituted nitrones (marked as ▲) fromDurand et al.20 (R2 = 0.451) and excluding nitrone 2 (marked as○), and (C) experimental relative rate constants of phenyladdition to nitrones (kpN/kTN) (R2 = 0.504).
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fig3: Correlationof the nitronyl carbon charge densities with (A) nitronylC chemical shifts of nitrones 2, 6, 7, 10, 11, and PBN (R2 = 0.965), excluding nitrones 1 and 8 (marked as ○) and 9 (which is not solublein CDCl3), (B) experimental relative rate constants ofO2•– addition to nitrones (ksN/kPR), including para-substituted nitrones (marked as ▲) fromDurand et al.20 (R2 = 0.451) and excluding nitrone 2 (marked as○), and (C) experimental relative rate constants of phenyladdition to nitrones (kpN/kTN) (R2 = 0.504).

Mentions: The effect of the nature of the substituent on thecharge density of the nitrone moiety was also studied using 1H and 13C NMR spectroscopy. Similar to the case for carbonylcompounds, nitrones are susceptible to nucleophilic addition reactions,and therefore, the electronic nature of the nitronyl C can affectits reactivity toward nucleophilic radicals such as O2•–. Figure 3A shows agood correlation between the 13C NMR chemical shift inCDCl3 of the nitronyl C and the calculated nitronyl C chargedensity, where there is a downfield shift with increasing positivecharge of the nitronyl C. This confirms the presence of a polar effectfrom the substituent in a β-position on the nitronyl chargedensity and suggests a stabilization of the mesomeric B form due tothe electron-withdrawing effect of the substituents. Only the mono-and dihydroxylated derivatives 1 and 8 wereout of the range likely due to the formation of intramolecular hydrogenbonds between the hydroxyl group and the nitronyl O,17 which may induce a downfield shift. An opposite trend wasobserved for the 1H NMR chemical shift in CDCl3 of the nitronyl H, where an upfield shift of the β-hydrogenwas observed with increased positivity of the nitronyl-C, furtherconfirming the polar effect from the N-tert-butyl substituents (Figure S12).


Reactivities of substituted α-phenyl-N-tert-butyl nitrones.

Rosselin M, Choteau F, Zéamari K, Nash KM, Das A, Lauricella R, Lojou E, Tuccio B, Villamena FA, Durand G - J. Org. Chem. (2014)

Correlationof the nitronyl carbon charge densities with (A) nitronylC chemical shifts of nitrones 2, 6, 7, 10, 11, and PBN (R2 = 0.965), excluding nitrones 1 and 8 (marked as ○) and 9 (which is not solublein CDCl3), (B) experimental relative rate constants ofO2•– addition to nitrones (ksN/kPR), including para-substituted nitrones (marked as ▲) fromDurand et al.20 (R2 = 0.451) and excluding nitrone 2 (marked as○), and (C) experimental relative rate constants of phenyladdition to nitrones (kpN/kTN) (R2 = 0.504).
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fig3: Correlationof the nitronyl carbon charge densities with (A) nitronylC chemical shifts of nitrones 2, 6, 7, 10, 11, and PBN (R2 = 0.965), excluding nitrones 1 and 8 (marked as ○) and 9 (which is not solublein CDCl3), (B) experimental relative rate constants ofO2•– addition to nitrones (ksN/kPR), including para-substituted nitrones (marked as ▲) fromDurand et al.20 (R2 = 0.451) and excluding nitrone 2 (marked as○), and (C) experimental relative rate constants of phenyladdition to nitrones (kpN/kTN) (R2 = 0.504).
Mentions: The effect of the nature of the substituent on thecharge density of the nitrone moiety was also studied using 1H and 13C NMR spectroscopy. Similar to the case for carbonylcompounds, nitrones are susceptible to nucleophilic addition reactions,and therefore, the electronic nature of the nitronyl C can affectits reactivity toward nucleophilic radicals such as O2•–. Figure 3A shows agood correlation between the 13C NMR chemical shift inCDCl3 of the nitronyl C and the calculated nitronyl C chargedensity, where there is a downfield shift with increasing positivecharge of the nitronyl C. This confirms the presence of a polar effectfrom the substituent in a β-position on the nitronyl chargedensity and suggests a stabilization of the mesomeric B form due tothe electron-withdrawing effect of the substituents. Only the mono-and dihydroxylated derivatives 1 and 8 wereout of the range likely due to the formation of intramolecular hydrogenbonds between the hydroxyl group and the nitronyl O,17 which may induce a downfield shift. An opposite trend wasobserved for the 1H NMR chemical shift in CDCl3 of the nitronyl H, where an upfield shift of the β-hydrogenwas observed with increased positivity of the nitronyl-C, furtherconfirming the polar effect from the N-tert-butyl substituents (Figure S12).

Bottom Line: The effect of N-tert-butyl substitution on the charge density and electron density localization of the nitronyl carbon as well as on the free energies of nitrone reactivity with O2(•-) and HO2(•) were computationally rationalized at the PCM/B3LYP/6-31+G**//B3LYP/6-31G* level of theory.Finally, the substituent effect was investigated in cell cultures exposed to hydrogen peroxide and a correlation between the cell viability and the oxidation potential of the nitrones was observed.Through a combination of computational methodologies and experimental methods, new insights into the reactivity of free radicals with nitrone derivatives have been proposed.

View Article: PubMed Central - PubMed

Affiliation: Avignon Université , Equipe Chimie Bioorganique et Systèmes Amphiphiles, 33 rue Louis Pasteur, F-84000 Avignon, France.

ABSTRACT
In this work, a series of α-phenyl-N-tert-butyl nitrones bearing one, two, or three substituents on the tert-butyl group was synthesized. Cyclic voltammetry (CV) was used to investigate their electrochemical properties and showed a more pronounced substituent effect for oxidation than for reduction. Rate constants of superoxide radical (O2(•-)) reactions with nitrones were determined using a UV-vis stopped-flow method, and phenyl radical (Ph(•)) trapping rate constants were measured by EPR spectroscopy. The effect of N-tert-butyl substitution on the charge density and electron density localization of the nitronyl carbon as well as on the free energies of nitrone reactivity with O2(•-) and HO2(•) were computationally rationalized at the PCM/B3LYP/6-31+G**//B3LYP/6-31G* level of theory. Theoretical and experimental data showed that the rates of the reaction correlate with the nitronyl carbon charge density, suggesting a nucleophilic nature of O2(•-) and Ph(•) addition to the nitronyl carbon atom. Finally, the substituent effect was investigated in cell cultures exposed to hydrogen peroxide and a correlation between the cell viability and the oxidation potential of the nitrones was observed. Through a combination of computational methodologies and experimental methods, new insights into the reactivity of free radicals with nitrone derivatives have been proposed.

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