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