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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\u201013 at specific positions within the benzene ring was developed. This efficient two\u2010step procedure starts from commercially available <jats:sup>13<\/jats:sup>C\u2010labeled phenols and involves (1) initial acylation of the phenol via a Houben\u2013Hoesch reaction with trichloroacetonitrile followed by (2) a modified haloform reaction of the resulting trichloromethyl ketone to afford the corresponding <jats:sup>13<\/jats:sup>C\u2010labeled ethyl parabens in 65%\u201380% 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 <jats:sup>13<\/jats:sup>C\u2010 and deuterium\u2010labeled esters. In addition, 4\u2010hydroxybenzoic acid can be formed directly from the common trichloromethyl ketone intermediate upon treatment with lithium hydroxide. This protocol complements existing methods for preparing <jats:sup>13<\/jats:sup>C\u2010labeled paraben derivatives and offers the specific advantages of exhibiting complete regioselectivity in the Houben\u2013Hoesch reaction (to form the <jats:italic>para<\/jats:italic>\u2010disubstituted product) and avoiding the need for protecting groups in the modified haloform reaction that forms the paraben esters.<\/jats:p>","DOI":"10.1002\/jlcr.3992","type":"journal-article","created":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T21:54:37Z","timestamp":1658526877000},"page":"254-263","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Synthesis of <sup>13<\/sup>C\u2010labeled parabens from isotopically enriched phenols using the Houben\u2013Hoesch reaction"],"prefix":"10.1002","volume":"65","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0407-9281","authenticated-orcid":false,"given":"Keith P.","family":"Reber","sequence":"first","affiliation":[{"name":"Department of Chemistry Towson University  Towson Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0472-7747","authenticated-orcid":false,"given":"John D.","family":"Sivey","sequence":"additional","affiliation":[{"name":"Department of Chemistry Towson University  Towson Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Matthew","family":"Vollmuth","sequence":"additional","affiliation":[{"name":"Department of Chemistry Towson University  Towson Maryland USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Priyansh D.","family":"Gujarati","sequence":"additional","affiliation":[{"name":"Department of Chemistry Towson University  Towson Maryland USA"},{"name":"Department of Chemistry University of Oxford  Oxford UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2022,7,26]]},"reference":[{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scitotenv.2021.146150"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/10408440490920104"},{"key":"e_1_2_7_4_1","doi-asserted-by":"publisher","DOI":"10.2478\/acph\u20102021\u20100001"},{"key":"e_1_2_7_5_1","doi-asserted-by":"publisher","DOI":"10.2166\/wst.2007.821"},{"key":"e_1_2_7_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.watres.2014.09.030"},{"key":"e_1_2_7_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhazmat.2015.06.060"},{"key":"e_1_2_7_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.aca.2006.05.068"},{"key":"e_1_2_7_9_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10311\u2010012\u20100367\u20101"},{"key":"e_1_2_7_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/03067310802272663"},{"key":"e_1_2_7_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.watres.2011.10.027"},{"key":"e_1_2_7_12_1","doi-asserted-by":"publisher","DOI":"10.1021\/es010076a"},{"key":"e_1_2_7_13_1","doi-asserted-by":"publisher","DOI":"10.1021\/jo01330a014"},{"key":"e_1_2_7_14_1","doi-asserted-by":"publisher","DOI":"10.1002\/recl.19891080405"},{"key":"e_1_2_7_15_1","doi-asserted-by":"publisher","DOI":"10.1515\/znb\u20101964\u20101205"},{"key":"e_1_2_7_16_1","first-page":"176","article-title":"Synthesis of [15N]\u2010, [1\u201013C]\u2010, [3\u201013C]\u2010, [ring\u20101,2\u201013C2]\u2010, and [ring\u20103,4,5\u201013C3]\u2010labelled DL\u2010tyrosine","volume":"6","author":"Baldwin JE","year":"1984","journal-title":"J Chem Research (S)"},{"key":"e_1_2_7_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/jlcr.1788"},{"key":"e_1_2_7_18_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00166913"},{"key":"e_1_2_7_19_1","doi-asserted-by":"publisher","DOI":"10.1055\/s\u20101998\u20102109"},{"key":"e_1_2_7_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/jlcr.1460"},{"key":"e_1_2_7_21_1","doi-asserted-by":"publisher","DOI":"10.15227\/orgsyn.078.0113"},{"key":"e_1_2_7_22_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja051386m"},{"key":"e_1_2_7_23_1","doi-asserted-by":"publisher","DOI":"10.1039\/b813991a"},{"key":"e_1_2_7_24_1","doi-asserted-by":"publisher","DOI":"10.1021\/ja907911y"},{"key":"e_1_2_7_25_1","unstructured":"KainoshoM TerauchiT.Stable isotope\u2010labeled aromatic amino acids method for incorporating them into target protein and method for analyzing protein structure by NMR. 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