Mechanistic Studies Of Lithium Diisopropylamide-Mediated Ortholithiations Under Nonequilibrium Conditions

Other Titles
Lithium diisopropylamide (LDA) plays an integral role in organic synthesis. In a comprehensive survey of over 500 total syntheses conducted by Reich, LDA emerged as the most commonly used reagent attesting to its broad range of synthetic applications. Its widespread utility led Collum to investigate mechanisms of LDA-mediated lithiation; a survey of these studies was assembled into a review that paints a coherent picture of generalized LDA-mediated reactions conducted at or above -40 °C. Fast LDA aggregate exchange inherent at high temperatures precludes detailed mechanistic understanding of aggregation dynamics by rendering substrate lithiation rate-limiting. By lowering the temperature to -78 °C, the rate of aggregate exchange can become comparable to the rate of metalation in THF. Time dependent decays exhibit linear and sigmoidal curvatures under pseudo-first order conditions, foreshadowing mechanistic complexity. Under this non-limiting regime, aggregates are no longer in full equilibrium, causing the reaction to become sensitive to autocatalysis, exogenous salts, and trace impurities. Subtle changes to reaction conditions, including isotopic substitution, can shift the rate-limiting step unpredictably. The work described herein presents two experimental accounts for elucidating mechanisms of lithiation: ortholithiation of 1,4-difluorobenzene and ortholithiation of 1,4-bis(trifluoromethyl)benzene. Given the highly substrate-dependent mechanisms, both substrates present different views of LDA deaggregation with internal consistency. i The third experimental account presents a fruitful collaboration with Zakarian aimed at understanding the underlying chemical basis for enantioselective alkylations of the enediolate of phenylacetic acid in the presence of a lithiated C2-symmetric tetraamine ligand. The high facial selectivity was traced to the formation of a densely functionalized mixed aggregate. ii
Journal / Series
Volume & Issue
Date Issued
Lithium Diisopropylamide; Nonequilibrium Kinetics; Reaction Mechanism
Effective Date
Expiration Date
Union Local
Number of Workers
Committee Chair
Collum, David B
Committee Co-Chair
Committee Member
Dichtel, William Robert
Lin, Hening
Degree Discipline
Chemistry and Chemical Biology
Degree Name
Ph. D., Chemistry and Chemical Biology
Degree Level
Doctor of Philosophy
Related Version
Related DOI
Related To
Related Part
Based on Related Item
Has Other Format(s)
Part of Related Item
Related To
Related Publication(s)
Link(s) to Related Publication(s)
Link(s) to Reference(s)
Previously Published As
Government Document
Other Identifiers
Rights URI
dissertation or thesis
Accessibility Feature
Accessibility Hazard
Accessibility Summary
Link(s) to Catalog Record