Chlorine atom substitution influences radical scavenging activity of 6-chromanol

Keiko Inami, Yuko Iizuka, Miyuki Furukawa, Ikuo Nakanishi, Kei Ohkubo, Kiyoshi Fukuhara, Shunichi Fukuzumi, Masataka Mochizuki

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26 Scopus citations

Abstract

Synthetic 6-chromanol derivatives were prepared with several chlorine substitutions, which conferred both electron-withdrawing inductive effects and electron-donating resonance effects. A trichlorinated compound (2), a dichlorinated compound (3), and three monochlorinated compounds (4, 5, and 6) were synthesized; compounds 2, 3, and 6 were novel. The antioxidant activities of the compounds, evaluated in terms of their capacities to scavenge galvinoxyl radical, were associated with the number and positioning of chlorine atoms in the aromatic ring of 6-chromanol. The activity of compound 1 (2,2-dimethyl-6-chromanol) was slightly higher than the activities of compounds 2 (2,2-dimethyl-5,7-dichloro-6-chromanol) or 3 (2,2-dimethyl-5,7,8-trichloro-6- chromanol), in which the chlorine atoms were ortho to the phenolic hydroxyl group of 6-chromanol. The scavenging activity of compound 3 was slightly higher than that of 2, which contained an additional chlorine substituted in the 8 position. The activities of polychlorinated compounds 2 and 3 were higher than the activities of any of the monochlorinated compounds (4-6). Compound 6, in which a chlorine was substituted in the 8 position, exhibited the lowest activity. Substitution of a chlorine atom meta to the hydroxyl group of 6-chromanol (compounds 2 and 6) decreased galvinoxyl radical scavenging activity, owing to the electron-withdrawing inductive effect of chlorine. Positioning the chloro group ortho to the hydroxyl group (compounds 4 and 5) retained antioxidant activity because the intermediate radical was stabilized by the electron-donating resonance effect of chlorine in spite of the electron-withdrawing inductive effect of chlorine. Antioxidant activities of the synthesized compounds were evaluated for correlations with the O-H bond dissociation energies (BDEs) and the ionization potentials. The BDEs correlated with the second-order rate constants (k) in the reaction between galvinoxyl radical and the chlorinated 6-chromanol derivatives in acetonitrile. This indicated that the antioxidant mechanism of the synthesized compounds consisted of a one-step hydrogen atom transfer from the phenolic OH group rather than an electron transfer followed by a proton transfer. The synthesized compounds also exhibited hydroxyl radical scavenging capacities in aqueous solution.

Original languageEnglish
Pages (from-to)4049-4055
Number of pages7
JournalBioorganic and Medicinal Chemistry
Volume20
Issue number13
DOIs
StatePublished - 1 Jul 2012

Bibliographical note

Funding Information:
This work was partially supported by Grant-in-Aid (Nos. 23590064, 23750014 and 20108010) from the Ministry of Education, Culture, Sports, Science and Technology, Japan, the Global COE (center of excellence) program “Global Education and Research Center for Bio-Environmental Chemistry” of Osaka University from MEXT, Japan, and NRF/MEST of Korea through WCU (R31-2008-000-10010-0) and GRL (2010-00353) programs.

Keywords

  • Antioxidant
  • Chlorine
  • Chromanol
  • Electron-donating resonance effect
  • Electron-withdrawing inductive effect

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