The origins of the diverse reactivities of lithium dialkylamides used extensively throughout organic, medicinal, and natural products chemistry will be investigated. A comparative study will focus on the steric and electronic factors that determine the aggregation and solvation states of four different lithium amides - - lithium diisoprophylamide, lithium isopropylcyclohexylamide, lithium tetramethylpiperidide, and lithium hexamethyldislazide -- solvated by the standard donor solvents (diethyl ether, tetrahydrofuran, dimethoxyethane, hexamethylphosphoramide, and tetramethylethylenediamine). 6Li-15N double labelling studies will be pivotal in laying the structural foundations. Qualitative and quantitative studies of product feedback control mechanisms occurring through the intervention of mixed aggregates will be studied. Effects of ketone enolates and lithium halides on the structures, reactivities, and selectivities of the amide bases will receive considerable attention. Some of the more complex, synthetically important reactions of lithium dialkylamides will be investigated including: (1) N,N-dimethylhydrazone deprotonation, (2) orthometallation, (3) epoxide elimination, and (4) asymmetric deprotonation. The experimentally determined rate equations, taken in the context of the specific solvation and aggregation states of the predominant species, will provide a detailed description of the solvation and deaggregation steps leading to the rate and product determining transition state(s). Specific efforts to apply the mechanistic principles to the development of new reagents and strategies will include: (1) the adaptation of lithium dialkylamides into catalytic cycles to enhance the utility of expensive chiral amides and additives, and (2) the investigation of bis(lithium dialkylamides) as prototypes of highly ordered internally aggregation structures with well defined shapes and enhanced substrate recognition capabilities.
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