Mechanism
of Lithium Diisopropylamide-Mediated Ortholithiation
of 1,4-Bis(trifluoromethyl)benzene under Nonequilibrium Conditions:
Condition-Dependent Rate Limitation and Lithium Chloride-Catalyzed
Inhibition
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Abstract
Lithiation
of 1,4-bis(trifluoromethyl)benzene with lithium diisopropylamide
in tetrahydrofuran at −78 °C occurs under conditions at
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 is presented that captures the critical
features of the LiCl catalysis, focusing on the influence of LiCl-catalyzed
re-aggregation of the fleeting monomer that can reside above, at,
or below the equilibrium population without catalyst
