Fast reactivity of a cyclic Nitrone-Calix[4]pyrrole conjugate with superoxide radical anion: Theoretical and experimental studies

Shang U. Kim, Yangping Liu, Kevin M. Nash, Jay L. Zweier, Antal Rockenbauer, Frederick A. Villamena

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Nitrone spin traps have been employed as probes for the identification of transient radical species in chemical and biological systems using electron paramagnetic resonance (EPR) spectroscopy and have exhibited pharmacological activity against oxidative-stress-mediated diseases. Since superoxide radical anion (O2•-) is a major precursor to most reactive oxygen species and calix[4]pyrroles have been shown to exhibit high affinity to anions, a cyclic nitrone conjugate of calix[4]pyrrole (CalixMPO) was designed, synthesized, and characterized. Computational studies at the PCM/B3LYP/6-31+G(d,p)//B3LYP/6-31G(d) level suggest a pendant-type linkage between the calix[4]pyrrole and the nitrone to be the most efficient design for spin trapping of O2•-, giving exoergic reaction enthalpies (ΔH298K,aq) and free energies (ΔG298K,aq) of -16.9 and -2.1 kcal/mol, respectively. 1H NMR study revealed solvent-dependent conformational changes in CalixMPO leading to changes in the electronic properties of the nitronyl group upon H-bonding with the pyrrole groups as also confirmed by calculations. CalixMPO spin trapping of O 2•- exhibited robust EPR spectra. Kinetic analysis of O 2•- adduct formation and decay in polar aprotic solvents using UV-vis stopped-flow and EPR methods gave a larger trapping rate constant for CalixMPO and a longer half-life for its O2•- adduct compared to the commonly used nitrones. The unusually high reactivity of CalixMPO with O2•- was rationalized to be due to the synergy between the α-effect and electrostatic effect by the calix[4]pyrrole moiety on O 2•- and the nitrone, respectively. This work demonstrates for the first time the application of an anion receptor for the detection of one of the most important radical intermediates in biological and chemical systems (i.e., O2•-).

Original languageEnglish (US)
Pages (from-to)17157-17173
Number of pages17
JournalJournal of the American Chemical Society
Issue number48
StatePublished - Dec 8 2010
Externally publishedYes

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry


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