The increasing interest in the inhibition of radical reactions, which have been associated with lipid oxidation and cell aging processes, inspired computational modeling of novel antioxidants. Based on those computational results, compounds were designed containing an electron rich pyridine ring, followed by a semi-industrial scale synthesis. The key compound, 2-amino-3,4,6-trimethylpyridin-5-ol hydrochloride (1), was obtained from commercially available vitamin B₆ in four steps. N-Monoalkylated derivatives of 1 were found to possess better radical scavenging properties than corresponding dialkylamino substituted structures. This unexpected behavior was most likely observed due to a steric interaction between the 3-methyl substituent and the relatively bulky 2-dialkylamino group. Multi-gram scale preparation of these monoalkylated compounds was accomplished via N,O-diacyl derivatization followed by borane-tetrahydrofuran reduction. In addition, some biheterocyclic pyridinols, the best chain-breaking antioxidants known, were also obtained from pyridoxyl hydrochloride. Reactivity of these various vitamin B₆ derivatives with peroxyl radicals was investigated in an aqueous environment as well as in an organic medium. A peroxyl radical clock has recently been developed utilizing the competition between β-fragmentations of non-conjugated peroxyl radicals and trapping by a hydrogen atom donor in fatty ester oxidations. Using this system, the rate that these compounds donate hydrogen atoms to peroxyl radicals was measured to determine their scavenging ability. The stoichiometric factors (n) for all molecules tested were close to 2 in benzene, whereas in aqueous buffer in all cases n < 2. The relative decrease of n values in the aqueous medium was attributed to the ability of water to favor electron transfer reactions and ability of p-aminopyridoxyl radicals to undergo them.

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