Lithium Diisopropylamide-Mediated Lithiation of 1,4-Difluorobenzene under Nonequilibrium Conditions: Role of Monomer‑, Dimer‑, and Tetramer-Based Intermediates and Lessons about Rate Limitation

Lithiation of 1,4-difluorobenzene with lithium diisopropylamide (LDA) in THF at −78 °C joins the ranks of a growing number of metalations that occur under conditions in which the rates of aggregate exchanges are comparable to the rates of metalation. As such, a substantial number of barriers vie for rate limitation. Rate studies reveal that rate-limiting steps and even the choice of reaction coordinate depend on subtle variations in concentration. Deuteration shifts the rate-limiting step and markedly alters the concentration dependencies and overall rate law. This narrative is less about ortholithiation per se and more about rate limitation and the dynamics of LDA aggregate exchange

Lithium Diisopropylamide-Mediated Ortholithiation of 2‑Fluoropyridines: Rates, Mechanisms, and the Role of Autocatalysis

Lithium diisopropylamide (LDA)-mediated ortholithiations of 2-fluoropyridine and 2,6-difluoropyridine in tetrahydrofuran at −78 °C were studied using a combination of IR and NMR spectroscopic and computational methods. Rate studies show that a substrate-assisted deaggregation of LDA dimer occurs parallel to an unprecedented tetramer-based pathway. Standard and competitive isotope effects confirm post-rate-limiting proton transfer. Autocatalysis stems from ArLi-catalyzed deaggregation of LDA proceeding via 2:2 LDA–ArLi mixed tetramers. A hypersensitivity of the ortholithiation rates to traces of LiCl derives from LiCl-catalyzed LDA dimer–monomer exchange and a subsequent monomer-based ortholithiation. Fleeting 2:2 LDA–LiCl mixed tetramers are suggested to be key intermediates. The mechanisms of both the uncatalyzed and catalyzed deaggregations are discussed. A general mechanistic paradigm is delineated to explain a number of seemingly disparate LDA-mediated reactions, all of which occur in tetrahydrofuran at −78 °C