Substituent effect on the radical scavenging activity of 6-chromanol derivatives

Several 6-chromanol derivatives with various substituents (one or two amino, acetylamino, chloro or nitro substituents at the 5-, 7-, 8- or 5,7-positions on the phenyl ring of 2,2-dimethyl-6-chromanol) were synthesized, and their second order rate constants (k) for a reaction that demonstrates radical scavenging activity (reaction with the galvinoxyl radical) were determined. Three monoacetylamino compounds, 8-nitro compound, and 5,7-diamino, 5,7-diacetylamino, and 5,7-dinitro compounds were newly synthesized. log k was plotted against the Hammett sigma (sigma(m)) or Taft sigma (sigma*) constants for the compounds containing each of the four substituents to obtain their reaction constants (rho) from the slopes. The sigma plots representing radical scavenging activity showed a linear correlation with negative rho values for all compounds with substituted positions. The results indicate that the electron-donating effect of the amino and acetylamino groups on the chroman ring enhanced radical scavenging activity, whereas the electron-withdrawing effect of the chloro and nitro groups decreased this activity. Furthermore, the magnitude of rho for the substituted compounds increased in the following order with respect to the substitution position: meta-substituted (-3.71 for 6a-d), ortho-monosubstituted (-0.86 for 4a-d, -0.87 for 5a-d), and ortho-disubstituted (-0.47 for 7a-d). The greater rho magnitudes for the meta-substituted compound indicated that the radical scavenging reactions were more sensitive to inductive substituent effects than for the ortho-substituent compounds. The rho values for ortho-mono- and ortho-disubstituted compounds were smaller than that for the meta-substituted compound, despite the fact that the k values for the ortho-substituted compounds were higher than those for the meta-substituted compounds. Thus, electron-donating groups in ortho-substituted 6-chromanols accelerate the reaction rate through resonance stabilization in addition to the inductive substituent effect.