Lithium amides are some of the most important reagents in organic synthesis. The pharmaceutical industry uses these reagents frequently and on very large scales. In this proposal we describe efforts to understand the underlying chemistry of the most important reactions of lithium amides with the goal of improving existing synthetic methods and developing new ones. We continue to focus on the three most important amides: lithium hexamethyldisilazide, lithium diisopropylamide, and lithium tetramethylpiperidide. The case studies to be investigated include: (1) ketone and ester enolizations; (2) imine lithiations;(3) epoxide eliminations; (4) ortholithiations; (5) N-alkylations; (6) N-arylations; and (7) N-acylations. These case studies touch on the preponderance of the chemistry of lithium amides. Each poses unique questions and offers unique opportunities. Through an understanding of the mechanistic principles we learn to control reactivity and selectivity. We use a uniquely integrated approach allowing a combination of NMR spectroscopy, solution kinetics, and computational chemistry to be brought to bear on the problems. By bringing synthetic organic, physical organic, analytical, and computational chemistry together under one roof, we reveal the consequences of soIvation and aggregation with an unprecedented clarity. ? ?
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