5-Aryl-2-(3,5-dialkyl-4-hydroxyphenyl)-4,4-dimethyl-4 H-imidazole 3-Oxides and Their Redox Species: How Antioxidant Activity of 1-Hydroxy-2,5-dihydro-1 H-imidazoles Correlates with the Stability of Hybrid Phenoxyl-Nitroxides

Abstract

Cyclic nitrones of the imidazole series, containing a sterically hindered phenol group, are promising objects for studying antioxidant activity; on the other hand, they can form persistent hybrid phenoxyl-nitroxyl radicals (HPNs) upon oxidation. Here, a series of 5-aryl-4,4-dimethyl-4H-imidazole 3-oxides was obtained by condensation of aromatic 2-hydroxylaminoketones with 4-formyl-2,6-dialkylphenols followed by oxidation of the initially formed N-hydroxy derivatives. It was shown that the antioxidant activity of both 1-hydroxy-2,5-dihydroimidazoles and 4H-imidazole 3-oxides increases with a decrease in steric volume of the alkyl substituent in the phenol group, while the stability of the corresponding HPNs generated from 4H-imidazole 3-oxides reveals the opposite tendency.

Keywords: 4H-imidazole 3-oxides; antioxidants; cyclic hydroxylamines; electron paramagnetic resonance; hybrid phenoxyl–nitroxides; sterically hindered phenols.

Scheme 1

Chemical structures of nitrones with a lateral or exocyclic C=N⁺O⁻ group.

Scheme 2

Examples of cyclic nitrones with an endocyclic C=N⁺O⁻ group.

Scheme 3

Examples of spin traps, antioxidants, and neuroprotectors containing α,α′-dialkyl–substituted phenolic or nitrone groups.

Scheme 4

Synthesis of initial 4-formylphenols 23.

Scheme 5

Synthesis of key compounds: 2,4-diaryl-1-hydroxy-2,5-dihydroimidazoles 20, 2,5-diaryl-4H-imidazole 3-oxides 21, and HPNs 22. Reagents and conditions: (i) R³ = OH: (Z)-PhCH=NOH, EtONa (2 equiv), EtOH_abs, 0 °C → 20 °C, 72 h, 65%; (ii) R³ = H, F, Br: NH₂OH⋅HCl (5 equiv), MeONa (4 equiv), MeOH, rt→Δ (6–8 h), 60–85%; (iii) R³ = OH: NH₂OH⋅HCl, EtOH, rt, 48 h, then 25% aq NH₃, 80%; (iv) R³ = H, F, Br: HCl_conc, Δ, 25–50 min, 75–85%; (v) R³ = H, F, Br, OH: NH₄OAc (6–10 equiv), 4-formylphenol 23, MeOH (or EtOH_abs), rt, 6–12 h, then 0 °C, 12 h, 68–98%; (vi) R³ = H, F, Br, OH: Cu(OAc)₂⋅H₂O (20 mol%), 16% aq NH₃, O₂, MeOH, rt, 1–6 h, 81–100%; (vii) R³ = H, F, Br: CHCl₃, PbO₂, 296 K, 1 min, then dilution with PhMe, argon, 75–85% for 22e,j,o.

Scheme 6

Possible oxidative transformations of 1-hydroxy-2,5-dihydroimidazoles under the action of peroxide radicals as exemplified by diisopropyl substituted derivative 20h. Colored circles indicate the sites where the predominant attack of the peroxide radical occurs.

Figure 1

Chemical structures of HPNs 22a–o.

Figure 2

EPR spectra recorded for diluted and oxygen-free toluene solutions of HPNs at 295 K: (a) 22a, (b) 22b, (c) 22c, and (d) 22d. Black curve: experimental spectra; red curve: simulated spectra with the parameters listed in Table 3.

Figure 3

EPR spectra acquired for diluted and oxygen-free toluene solutions of HPNs at 295 K: (a) 22e, (b) 22j, and (c) 22o.

Figure 4

Mulliken atomic spin populations for (a)22e, (b)22j, (c)22o calculated at the UB3LYP/6-31G(d) level of theory.

Figure 5

A time-dependent EPR spectrum recorded for a diluted and oxygen-free solution of HPN 22a in PhMe: (a,d) immediately after radical formation; (b,e) at 1 h after radical formation; (c,f) 2 h after radical formation. The figure shows spectra that are normalized to the maximum on the y-axis (a,b) as well as non-normalized spectra (d–f).

Figure 6

Kinetics of decomposition of HPNs 22c and 22d in diluted and oxygen-free toluene solutions.