ipso‐Substitution: A General Biochemical and Biodegradation Mechanism to Cleave α‐Quaternary Alkylphenols and Bisphenol A

Abstract Sphingobium xenophagum Bayram is capable of metabolizing 4‐alkoxyphenols and endocrine disruptive α ‐quaternary 4‐nonylphenols by an ipso ‐substitution mechanism that involves ring hydroxylation at the site of the substituent. Here, we show that Bayram's ipso ‐hydroxylating activity was able to transform also bisphenol A (=dimethyl‐4,4′‐methylenediphenol; BPA) and 4‐isopropylphenol. We identified six metabolites when resting cells of strain Bayram were incubated with BPA. They were unambiguously characterized by HPLC‐UV, HPLC/MS, and HPLC/MS/MS as hydroquinone, 2‐(4‐hydroxyphenyl)isopropanol, 4‐isopropenylphenol, 4‐isopropylphenol, 4‐hydroxy‐4‐isopropenylcyclohexa‐2,5‐dien‐1‐one, and 4‐hydroxy‐4‐isopropylcyclohexa‐2,5‐dien‐1‐one. In experiments with 4‐isopropylphenol as a substrate, 4‐hydroxy‐4‐isopropylcyclohexa‐2,5‐dien‐1‐one, one of the metabolites from BPA, accumulated to a high degree. We could rationalize the formation of all metabolites by invoking ipso ‐hydroxylation and ipso ‐substitution mechanisms. On closer view, also classical bacterial metabolism of BPA can be well rationalized by an ipso ‐substitution mechanism, albeit with ipso ‐attack of an internal alkyl radical instead of an activated oxygen species. This highlights the important role of ipso ‐substitution as a versatile degradative principle utilized by diverse organisms to degrade α ‐quaternary 4‐nonylphenols, 4‐alkoxyphenols, and BPA.