Ipso-substitution — the hidden gate to xenobiotic degradation pathways

• Ipso-substitution is often overlooked in transformations of environmental pollutants.
• Ipso-substitution can be enzymatically initiated by different reaction mechanisms.
• Ipso-substitution reactions can also be of interest for green chemistry approaches.
• Enzyme evolution can lead to new catabolic pathways, for example, ipso-substitution.
• Substrate conformation, favoring ipso-substitution has to be further elucidated.

Screening for metabolites of environmental pollutants, the focus is often on transformation products based on well-known pathways. Hydroxylation at unsubstituted positions of the aromatic ring or side chain modifications, followed by meta ring-cleavage pathways are usually considered, whereas less obvious mechanisms are often ignored. Here, a glimpse of the multitude of transformations involving ipso-substitution events, which are often overlooked as such, is presented. These reactions can be catalyzed by a variety of enzymes, proceed via several mechanisms and will often result in metabolites that are not expected to arise from generally known pathways. Hence, there is a future need when looking into transformations of emerging pollutants, to stray from the ‘beaten pathways’ and explore the possibilities of less obvious mechanisms.

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