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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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EPR signals recorded in benzene by photolysis of 3 mol L–1 phenyl iodide solution in the presence of the nitrones 10 and 7 at two different ratios [10]/[TN]:(a) [10]/[TN] = 0.67 ([10] = 20 mmol L–1 and [TN] = 30 mmol L–1); (b) [10]/[TN] = 2 ([10] = 40 mmol L–1 and [TN] = 20 mmol L–1). The peaks marked with× correspond to the phenyl radical adduct of 10,while the other lines correspond to the phenyl radical adduct of TN.
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fig4: EPR signals recorded in benzene by photolysis of 3 mol L–1 phenyl iodide solution in the presence of the nitrones 10 and 7 at two different ratios [10]/[TN]:(a) [10]/[TN] = 0.67 ([10] = 20 mmol L–1 and [TN] = 30 mmol L–1); (b) [10]/[TN] = 2 ([10] = 40 mmol L–1 and [TN] = 20 mmol L–1). The peaks marked with× correspond to the phenyl radical adduct of 10,while the other lines correspond to the phenyl radical adduct of TN.

Mentions: Since some nitrones in the serieswere poorly water soluble or were found to be highly reactive towardHO•, the use of a Fenton system was precluded. Therefore,we chose to study phenyl radical (Ph•) trappingin benzene, where the corresponding adducts show high stability. 1,3,5-Tris[(N-(1-diethylphosphono)-1-methylethyl)-N-oxyaldimine]benzene (TN)29 was used asa competitive scavenger to examine the relative rates of trappingby the nitrones 1, 2, and 6–11 in comparison to PBN (Figure 4). It is worth noting that the adduct decay must be slow enoughto be neglected to obtain reliable results with this approach.30 The Ph• was generated by UVphotolysis of a solution containing a large excess of iodobenzenein the presence of TN and of the nitrone of interest, denoted as N.As previously observed,29 the possibilityof multiple trapping by TN was neglected, since the polyadducts werenever observed by EPR in our study. In this method, the Ph• spin trapping rate was monitored by measuring the intensities (asthe signal area) of the EPR signals of the corresponding adducts.The standard kinetic competition model employed as described elsewhere29 yielded eq 2. In thisequation, the second-order rate constants for Ph• trapping by the nitrones N and TN are denoted as kpN and kTN, respectively, while r and R representthe trapping rate by TN only in the presence of N and by both TN andN, respectively.2By plotting the R/r ratio as a function of the [N]/[N]ratio for each nitrone 1, 2, and 6–11, a straight line was obtained with a slopeequal to kpN/kTN. Fiveexperiments were performed at five different [N]/[TN] ratios keptbetween 1 and 4. The commercially available PBN was then employedinstead of N in order to determine the kpPBN/kTN ratio. From theseresults, the kpN/kpPBN ratio was calculated andthe values obtained for nitrones 1, 2, and 6–11 are reported in Table 3.


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)

EPR signals recorded in benzene by photolysis of 3 mol L–1 phenyl iodide solution in the presence of the nitrones 10 and 7 at two different ratios [10]/[TN]:(a) [10]/[TN] = 0.67 ([10] = 20 mmol L–1 and [TN] = 30 mmol L–1); (b) [10]/[TN] = 2 ([10] = 40 mmol L–1 and [TN] = 20 mmol L–1). The peaks marked with× correspond to the phenyl radical adduct of 10,while the other lines correspond to the phenyl radical adduct of TN.
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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4216227&req=5

fig4: EPR signals recorded in benzene by photolysis of 3 mol L–1 phenyl iodide solution in the presence of the nitrones 10 and 7 at two different ratios [10]/[TN]:(a) [10]/[TN] = 0.67 ([10] = 20 mmol L–1 and [TN] = 30 mmol L–1); (b) [10]/[TN] = 2 ([10] = 40 mmol L–1 and [TN] = 20 mmol L–1). The peaks marked with× correspond to the phenyl radical adduct of 10,while the other lines correspond to the phenyl radical adduct of TN.
Mentions: Since some nitrones in the serieswere poorly water soluble or were found to be highly reactive towardHO•, the use of a Fenton system was precluded. Therefore,we chose to study phenyl radical (Ph•) trappingin benzene, where the corresponding adducts show high stability. 1,3,5-Tris[(N-(1-diethylphosphono)-1-methylethyl)-N-oxyaldimine]benzene (TN)29 was used asa competitive scavenger to examine the relative rates of trappingby the nitrones 1, 2, and 6–11 in comparison to PBN (Figure 4). It is worth noting that the adduct decay must be slow enoughto be neglected to obtain reliable results with this approach.30 The Ph• was generated by UVphotolysis of a solution containing a large excess of iodobenzenein the presence of TN and of the nitrone of interest, denoted as N.As previously observed,29 the possibilityof multiple trapping by TN was neglected, since the polyadducts werenever observed by EPR in our study. In this method, the Ph• spin trapping rate was monitored by measuring the intensities (asthe signal area) of the EPR signals of the corresponding adducts.The standard kinetic competition model employed as described elsewhere29 yielded eq 2. In thisequation, the second-order rate constants for Ph• trapping by the nitrones N and TN are denoted as kpN and kTN, respectively, while r and R representthe trapping rate by TN only in the presence of N and by both TN andN, respectively.2By plotting the R/r ratio as a function of the [N]/[N]ratio for each nitrone 1, 2, and 6–11, a straight line was obtained with a slopeequal to kpN/kTN. Fiveexperiments were performed at five different [N]/[TN] ratios keptbetween 1 and 4. The commercially available PBN was then employedinstead of N in order to determine the kpPBN/kTN ratio. From theseresults, the kpN/kpPBN ratio was calculated andthe values obtained for nitrones 1, 2, and 6–11 are reported in Table 3.

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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