Unexpected reactivity of the antiseptic domiphen bromide

For nearly ten decades parabens have been employed as preservatives in a broad variety of preparations. Since parabens were detected in breast cancer cells[1] they have been under scrutiny for their putative role in promoting cancerogenesis. The food, pharmaceutical and cosmetic industries are yearning for alternatives to these benchmark preservatives and “paraben-free” claims have become popular advertising messages. From a technical stand point, parabens are: 1) very versatile species with a reliable antimicrobial efficacy; 2) easy to incorporate; 3) stable over a broad pH range. Domiphen bromide is an aromatic quaternary ammonium salt employed as antiseptic, antimicrobial and disinfectant. These properties combined with a good workability make domiphen a possible alternative for parabens. Anyhow, the co-presence of bromide as a counterion and aromatic ring highly reactive to electrophilic substitutions suggests that accidental bromide oxidation to bromine can lead to phenyl bromination. In this study we developed hyphenated analytical strategies combining HPLC, LC/MS and NMR to monitor such reactions. Indeed we found that domiphen bromide undergoes bromination even under mild conditions. In details, mild oxidant conditions at different pH values have been investigated in order to mimic the variability of preparations. HPLC analyses were carried out under conditions suitable for LC/MS, which clearly proved the formation of the bromo derivative. Moreover, NMR analyses indicated that halogenation occurred at the para position.