Separation, synthesis and estrogenic activity of 4-nonylphenols: Two sets of new diastereomeric isomers in a commercial mixture

Two sets of new diastereomeric 4-nonylphenol (NP) isomers [4-(3,4-dimethylheptan-4-yl)phenol (344NP, NP-J, L) and 4-(3,4-dimethylheptan-3-yl)phenol (343NP, NP-K, P)] were separated from a commercial NP mixture. The mixture of these diastereomers was synthesized at the same time by a single Friedel–Crafts reaction of 3,4-dimethyl-4-heptanol and phenol, and the mixture was separated into individual NPs by HPLC equipped with Hypercarb column. For the first time, in this study the stereostructure–estrogenic activity relationship of NP diastereomers was investigated. The NP isomers (NP-L and NP-P) having the β-methyl group over the benzene ring were found to be 2–4 times more estrogenic than their diastereomers (NP-J and NP-K). In the case of the other set of diastereomer [4-(3,5-dimethylheptan-3-yl)phenol, (353NP, NP-E, G)] containing γ-methyl group in the molecule, the γ-methyl proton signal (δ 0.49) in the more estrogenic isomer (NP-G) also appeared in a higher field than the corresponding methyl signal (δ 0.76) of the less estrogenic isomer (NP-E).