Fast Reactivity of a Cyclic Nitrone−Calix[4]pyrrole Conjugate with Superoxide Radical Anion: Theoretical and Experimental Studies†

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 u...