Mechanism-Based Regiocontrol\nin S<sub>N</sub>Ar: A\nCase Study of <i>Ortho</i>-Selective Etherification with\nChloromagnesium Alkoxides

Although nucleophilic aromatic substitution (S<sub>N</sub>Ar) is\nroutinely employed as a practical alternative to transition-metal-catalyzed\ncross-coupling, the mechanistic basis for reactivity and regioselectivity\nremains underexplored and is an active area of research. This article\nreports a S<sub>N</sub>Ar-based etherification of 2,4-difluoroarylcarboxamides\nas a model system and shows that the <i>ortho</i>/<i>para</i> regioselectivity spans >500:1 to 1:∼20 simply\nby varying the reaction conditions via high-throughput experimentation\n(HTE). An in-depth characterization of the <i>ortho</i>-selective\nlead conditions is presented, and these insights are used to build\na reactivity model that self-consistently accounts for the regioselectivity\nand reaction scope. This article discusses synthetic implications\nof condition-dependent magnesium coordination and Schlenk equilibria\nand demonstrates that consideration of molecular-level stoichiometry\nand isomerism is an essential prerequisite for rationalizing reactivity\nand regioselectivity in S<sub>N</sub>Ar.