Chelation of 2-substituted-1-lithoxides: Structural and energetic factors of relevance to synthetic organic chemistry

Article abstract of DOI:10.1021/ja00016a045

A number of lithium 2-(methylamino)-, 2-(dimethylamino)-, 2-methoxy-, and 2-(isopropylthio)-substituted-1-phenyl-1-propoxides were studied as models for asymmetric synthetic strategies for which lithium chelation between two electronegative atoms has frequently been invoked. The heats of formation of these alkoxides were determined by deprotonating the alcohols with lithium bis(trimethylsilyl)amide in a solution calorimeter. Aggregation numbers for the substituted alcohols and their corresponding lithium alkoxides were obtained with freezing point depression and vapor pressure osmometry in THF, benzene, and dioxane. In several cases, solution structures were obtained through ¹H, ⁶Li, and 2D ⁶Li-¹H NOE (HOESY) NMR spectroscopy. Solid-state structures of lithium (+)-N-methylpseudoephedrate and (-)-N-methylephedrate (+)-N-methylpseudoephedrate and (-)-N-methylephedrate (as the benzene solvate) were obtained by X-ray crystallography, and both were found to be present as tetramers in which the dimethylamino nitrogen atoms were coordinated to the lithium cations to form five-membered chelate rings. The lithium alkoxides were either tetramers or hexamers in nonpolar solvents; however, the alkoxides' solution structures were very complex in THF as evidenced by several ⁶Li resonances observed in the ⁶Li NMR spectra at low temperatures. Intramolecular lithium chelation was found to occur in each alkoxide in dioxane and benzene. The enthalpies of chelational stabilization were estimated by comparing their heats of deprotonation with those of nonchelatable 2-alkyl-substituted analogues. The stabilization enthalpies ranged from 5 to 11 kcal/mol per alkoxide molecule.