Mechanism of Lithium Diisopropylamide-Mediated Ortholithiation of 1,4-Bis(trifluoromethyl)benzene under Nonequilibrium Conditions: Condition-Dependent Rate Limitation and Lithium Chloride-Catalyzed Inhibition

Abstract

Lithiation of 1,4-bis(trifluoromethyl)benzene with lithium diisopropylamide (LDA) in tetrahydrofuran at −78 °C occurs under conditions in which the rates of aggregate exchanges are comparable to the rates of metalation. Under such nonequilibrium conditions, a substantial number of barriers compete to be rate limiting, making the reaction sensitive to trace impurities (LiCl), reactant concentrations, and isotopic substitution. Rate studies using the perdeuterated arene reveal odd effects of LiCl, including catalyzed rate acceleration at lower temperature and catalyzed rate inhibition at higher temperatures. The catalytic effects are accompanied by corresponding changes in the rate law. A kinetic model that captures the critical features of the LiCl catalysis focusing on the influence of LiCl-catalyzed reaggregation of the fleeting monomer that can reside above, at, or below the equilibrium population without catalyst.

Lithium Diisopropylamide: Nonequilibrium Kinetics and Lessons Learned about Rate Limitation

“…We often observe instances in which two aggregation events appear to be competing for rate limitation as evidenced by non-integer LDA orders; 6,8 competing dimer- and tetramer-based aggregation events akin to those in Section 2.8 are emblematic. A composite LDA order between first and second order implicates two pathways of comparable barriers either in series (Figure 6) or in parallel (Figure 7).…”

“…We have documented autocatalysis as well as LDA-mediated metalations that fail to autocatalyze because one of the two prerequisites was not satisfied. 8 …”

“…For example, in our first detailed study (see Section 2.1), autocatalysis produced nearly perfect linear decays that were not zeroth order. 8a We routinely probe for mild autocatalysis using a standard control experiment. At the end of an experiment using excess organolithium reagent, a second aliquot of substrate is added.…”

“…The relative rate law assumes special importance for documenting the origins of minor impurities or selectivities when the influence of the minor pathway on the rates cannot be measured directly. 8d,25 …”

“…8 LDA, however, is only one part of a three-part story. Section 1 is a tutorial that delineates the methods and tactics used to untangle the interwoven mechanistic pathways, in particular, when rate-limiting steps routinely change.…”