Mechanism-Based Regiocontrol in S_NAr: A Case Study of <i>Ortho</i>-Selective Etherification with Chloromagnesium Alkoxides

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