Lithium diisopropylamide-mediated enolizations: Solvent-dependent mixed aggregation effects

Li-6 and N-15 NMR spectroscopic investigations of lithium diisopropylamide-mediated ester enolization in THF, t-BuOMe, HMPA/THF, and DMPU/THF (HMPA = hexamethylphosphoramide, DMPU = 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidone) reveal substantial concentrations of mixed aggregates. While previous quantitative rate studies revealed that the metalations by lithium diisopropylamide (LDA) homonuclear dimers proceed at nearly solvent-independent rates, the reactivities of the intermediate mixed aggregates are markedly lower and quite sensitive to the choice of solvent. The autoinhibition correlates with the relative stabilities of the mixed aggregates. However, the relative stabilities do not correlate in a simple fashion with the ligating properties of the solvent.