Theoretical Study of the Spin Trapping of Hydroxyl Radical by Cyclic Nitrones: A Density Functional Theory Approach

Frederick A. Villamena, Christopher M. Hadad, Jay L. Zweier

Research output: Contribution to journalArticle

Abstract

The hydroxyl radical (•OH) is an important mediator of biological oxidative stress, and this has stimulated interest in its detection. 5,5-Dimethyl-1-pyrroline N-oxide (DMPO) and its alkoxycarbonyl and alkoxyphosphoryl analogues have been employed as spin traps for electron paramagnetic resonance (EPR) spectroscopic radical detection. Energies of optimized geometries of nitrones and their corresponding •OH adducts were calculated using density functional theory (DFT) at the B3LYP/6-31+G* *//B3LYP/6-31G* level. Calculations predict that the trans adduct formation is favored in alkoxycarbonyl nitrones, while cis adducts with intramolecular H-bonding is favored for alkoxyphosphoryl nitrones. Addition of •OH to a phosphoryl-substituted nitrone is more exoergic than the carbonylated nitrones. Charge and spin densities on the nitrone spin traps were correlated with their rates of addition with •OH, and results show that the charge density on the nitronyl C, the site of •OH addition, is more positive in phosphorylated nitrones compared to DMPO and the alkoxycarbonyl nitrones. The dihedral angle between the β-H and nitroxyl O bonds is smaller in phosphorylated nitrones, and that aspect appears to account for the longer half-lives of the spin adducts compared to those in DMPO and alkoxycarbonyl nitrones. Structures of nitrones with trifluoromethyl-, trifluoromethylcarbonyl-, methylsulfonyl-, trifluoromethylsulfonyl-, amido-, spiropentyl-, and spiroester substituents were optimized and their energies compared. Amido and spiroester nitrones were predicted to be the most suitable nitrones for spin trapping of •OH due to the similarity of their thermodynamic and electronic properties to those of alkoxyphosphoryl nitrones. Moreover, dimethoxyphosphoryl substitution at C-5 was found to be the most efficient substitution site for spin trapping of •OH, and their spin adducts are predicted to be the most stable of all of the isomeric forms.

Original languageEnglish (US)
Pages (from-to)1816-1829
Number of pages14
JournalJournal of the American Chemical Society
Volume126
Issue number6
StatePublished - Feb 18 2004
Externally publishedYes

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Spin Trapping
Hydroxyl Radical
Density functional theory
Theoretical Models
Oxides
Substitution reactions
Oxidative stress
Dihedral angle
Charge density
Electronic properties
Paramagnetic resonance
Thermodynamic properties
Geometry
nitrones
Electron Spin Resonance Spectroscopy
Thermodynamics

ASJC Scopus subject areas

  • Chemistry(all)

Cite this

Theoretical Study of the Spin Trapping of Hydroxyl Radical by Cyclic Nitrones : A Density Functional Theory Approach. / Villamena, Frederick A.; Hadad, Christopher M.; Zweier, Jay L.

In: Journal of the American Chemical Society, Vol. 126, No. 6, 18.02.2004, p. 1816-1829.

Research output: Contribution to journalArticle

Villamena, Frederick A. ; Hadad, Christopher M. ; Zweier, Jay L. / Theoretical Study of the Spin Trapping of Hydroxyl Radical by Cyclic Nitrones : A Density Functional Theory Approach. In: Journal of the American Chemical Society. 2004 ; Vol. 126, No. 6. pp. 1816-1829.
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