Synthesis of 13C-labeled parabens from isotopically enriched phenols using the Houben–Hoesch reaction |
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Authors: | Keith P Reber John D Sivey Matthew Vollmuth Priyansh D Gujarati |
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Affiliation: | 1. Department of Chemistry, Towson University, Towson, Maryland, USA;2. Department of Chemistry, Towson University, Towson, Maryland, USA
Department of Chemistry, University of Oxford, Oxford, UK |
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Abstract: | Parabens are antimicrobial additives found in a wide array of consumer products. However, the halogenated compounds formed from parabens during wastewater disinfection are a potential environmental concern. In order to identify these transformation products and investigate their mechanism of formation, a synthetic route to ethyl parabens labeled with the stable isotope carbon-13 at specific positions within the benzene ring was developed. This efficient two-step procedure starts from commercially available 13C-labeled phenols and involves (1) initial acylation of the phenol via a Houben–Hoesch reaction with trichloroacetonitrile followed by (2) a modified haloform reaction of the resulting trichloromethyl ketone to afford the corresponding 13C-labeled ethyl parabens in 65%–80% overall yield. The scope of the modified haloform reaction was also investigated, allowing for the synthesis of other parabens derived from primary or secondary alcohols, including 13C- and deuterium-labeled esters. In addition, 4-hydroxybenzoic acid can be formed directly from the common trichloromethyl ketone intermediate upon treatment with lithium hydroxide. This protocol complements existing methods for preparing 13C-labeled paraben derivatives and offers the specific advantages of exhibiting complete regioselectivity in the Houben–Hoesch reaction (to form the para-disubstituted product) and avoiding the need for protecting groups in the modified haloform reaction that forms the paraben esters. |
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Keywords: | carbon-13 haloform Houben–Hoesch reaction paraben phenol water disinfection |
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