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Electrochemical methods for aryl etherification and amination demonstrate broad functional group tolerance and extended nucleophile scope compared to traditional methods. Nevertheless, there is a need for robust and scale\u2010transferable workflows for electrochemical compound library synthesis. Herein we describe a platform for automated electrochemical synthesis of C\u2212X arylation (X=NH, OH) in flow to access compound libraries. A comprehensive Design of Experiment (DoE) study identifies an optimal protocol which generates high yields across&gt;30 aryl halide scaffolds, diverse amines (including electron\u2010deficient sulfonamides, sulfoximines, amides, and anilines) and alcohols (including serine residues within peptides). Reaction sequences are automated on commercially available equipment to generate libraries of anilines and aryl ethers. The unprecedented application of potentiostatic alternating polarity in flow is essential to avoid accumulating electrode passivation. Moreover, it enables reactions to be performed in air, without supporting electrolyte and with high reproducibility over consecutive runs. Our method represents a powerful means to rapidly generate nucleophile independent C\u2212X arylation compound libraries using flow electrochemistry.<\/jats:p>","DOI":"10.1002\/anie.202413383","type":"journal-article","created":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T12:21:03Z","timestamp":1728476463000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Electrochemical C\u2212O and C\u2212N Arylation using Alternating Polarity in flow for Compound Libraries"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1210-7975","authenticated-orcid":false,"given":"Jennifer","family":"Morvan","sequence":"first","affiliation":[{"name":"Global Discovery Chemistry, Janssen Research and Development  Turnhoutseweg 30 2340 Beerse Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koen P. 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