Azaaldol Condensation of a Lithium Enolate Solvated by <i>N,N,N′,N′</i>-Tetramethylethylenediamine: Dimer-Based 1,2-Addition to Imines

The lithium enolate of <i>tert</i>-amylacetate solvated by <i>N,N,N′,N′</i>-tetramethylethylenediamine (TMEDA) is shown to be a doubly chelated dimer. Adding the dimeric enolate to 4-fluorobenzaldehyde-<i>N</i>-phenylimine affords an N-lithiated β-amino ester shown to be monomeric using ⁶Li and ¹⁵N NMR spectroscopies. Rate studies using ¹⁹F 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 <i>trans-N,N,N′,N′</i>-1,2-tetramethylcyclohexanediamine showing analogous rates and rate law suggest that TMEDA is fully chelated

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