Are n-BuLi/TMEDA-Mediated Arene Ortholithiations Directed? Substituent-Dependent Rates, Substituent-Independent Mechanisms

Rate studies of the lithiation of benzene and related alkoxy-substituted aromatics by n-BuLi/TMEDA mixtures implicate similar mechanisms in which the proton transfers are rate limiting with transition structures of stoichiometry [(n-BuLi)₂(TMEDA)₂(Ar−H)]^⧧ (Ar−H = benzene, C₆H₅OCH₃, m-C₆H₄(OCH₃)₂, C₆H₅OCH₂OCH₃, and C₆H₅OCH₂CH₂N(CH₃)₂). Cooperative substituent effects and an apparent importance of inductive effects suggest a mechanism in which alkoxy−lithium interactions are minor or nonexistent in the rate-limiting transition structures. Supported by ab initio calculations, transition structures based upon triple ions of general structure [(n-Bu)₂Li]^-//⁺Li(TMEDA)₂ are discussed.