Synthesis of defined endocrine-disrupting nonylphenol isomers for biological and environmental studies

Nonylphenols are very important environmentally relevant substances in the focus of the world-wide endocrine disrupter research for over 25 years. Thus, they are among the 10 priority hazardous substances of the new European Union Water Framework Directive. They consist of a very complex mixture of isomers representing therefore a multi-component problem like dioxins or PCBs. As estrogenic effect and degradation behavior in the environment of individual 4-nonylphenols are heavily dependent on the structure and bulkiness of the side chain, it is absolutely necessary to consider the nonylphenol problem from an isomer-specific viewpoint. Therefore a range of 28 differently branched nonylphenol isomers were synthesized for biological and environmental studies. Nonylphenols with a quaternary α-carbon, like 4-(1,1,3,4-tetramethylpentyl)phenol (4-NP95) and 4-(1-ethyl-1,3,3-trimethylbutyl)phenol (4-NP170), were obtained by Friedel–Crafts alkylation of anisole with tertiary nonyl bromides and demethylation with BI3. Nonylphenols with a tertiary α-carbon, such as 4-(1,2-dimethylheptyl)phenol (4-NP10) and 4-(1,2,4-trimethylhexyl)phenol (4-NP41), were accessible via coupling of p-methoxyphenylmagnesium bromide with ketones. Nonylphenols bearing a quaternary β-carbon, like 4-(2,2-dimethylheptyl)phenol (4-NP15) and 4-(1,2,2-trimethylhexyl)phenol (4-NP39), were synthesized starting from 4′-methoxyisobutyrophenone. The compounds were characterized by GC–MS and NMR-spectroscopy. The individual isomers were designated according to the Juelich Nomenclature.