Lithium diisopropylamide-mediated lithiation of 1,4-difluorobenzene under nonequilibrium conditions: role of monomer-, dimer-, and tetramer-based intermediates and lessons about rate limitation.

Lithiation of 1,4-difluorobenzene with lithium diisopropylamide (LDA) in THF at -78 °C joins the ranks of a growing number of metalations that occur under conditions in which the rates of aggregate exchanges are comparable to the rates of metalation. As such, a substantial number of barriers vie for rate limitation. Rate studies reveal that rate-limiting steps and even the choice of reaction coordinate depend on subtle variations in concentration. Deuteration shifts the rate-limiting step and markedly alters the concentration dependencies and overall rate law. This narrative is less about ortholithiation per se and more about rate limitation and the dynamics of LDA aggregate exchange.

Solution structures of lithium amino alkoxides used in highly enantioselective 1,2-additions.

Lithium ephedrates and norcarane-derived lithium amino alkoxides used to effect highly enantioselective 1,2-additions on large scales have been characterized in toluene and tetrahydrofuran. The method of continuous variations in conjunction with (6)Li NMR spectroscopy reveals that the lithium amino alkoxides are tetrameric. In each case, low-temperature (6)Li NMR spectra show stereoisomerically pure homoaggregates displaying resonances consistent with an S4-symmetric cubic core rather than the alternative D2d core. These assignments are supported by density functional theory computations and conform to X-ray crystal structures. Slow aggregate exchanges are discussed in the context of amino alkoxides as chiral auxiliaries.

Azaaldol condensation of a lithium enolate solvated by N,N,N',N'-tetramethylethylenediamine: dimer-based 1,2-addition to imines.

The lithium enolate of tert-amylacetate solvated by N,N,N',N'-tetramethylethylenediamine (TMEDA) is shown to be a doubly chelated dimer. Adding the dimeric enolate to 4-fluorobenzaldehyde-N-phenylimine affords an N-lithiated ß-amino ester shown to be monomeric using (6)Li and (15)N NMR spectroscopies. Rate studies using (19)F NMR spectroscopy reveal reaction orders consistent with a transition structure of stoichiometry [(ROLi)2(TMEDA)2(imine)](‡). Density functional theory computations explore several possible dimer-based transition structures with monodentate and bidentate coordination of TMEDA. Supporting rate studies using trans-N,N,N',N'-1,2-tetramethylcyclohexanediamine showing analogous rates and rate law suggest that TMEDA is fully chelated.