Ketone Enolization with Sodium Hexamethyldisilazide: Solvent- and Substrate-Dependent E–Z Selectivity and Affiliated Mechanisms

Ketone enolization by sodium hexamethyldisilazide (NaHMDS) shows a marked solvent and substrate dependence. Enolization of 2-methyl-3-pentanone reveals E-Z selectivities in Et₃N/toluene (20:1), methyl-t-butyl ether (MTBE, 10:1), N,N,N',N″,N″-pentamethyldiethylenetriamine (PMDTA)/toluene (8:1), TMEDA/toluene (4:1), diglyme (1:1), DME (1:22), and tetrahydrofuran (THF) (1:90). Control experiments show slow or nonexistent stereochemical equilibration in all solvents except THF. Enolate trapping with Me₃SiCl/Et₃N requires warming to -40 °C whereas Me₃SiOTf reacts within seconds. In situ enolate trapping at -78 °C using preformed NaHMDS/Me₃SiCl mixtures is effective in Et₃N/toluene yet fails in THF by forming (Me₃Si)₃N. Rate studies show enolization via mono- and disolvated dimers in Et₃N/toluene, disolvated dimers in TMEDA, trisolvated monomers in THF/toluene, and free ions with PMDTA. Density functional theory computations explore the selectivities via the E- and Z-based transition structures. Failures of theory-experiment correlations of ionic fragments were considerable even when isodesmic comparisons could have canceled electron correlation errors. Swapping 2-methyl-3-pentanone with a close isostere, 2-methylcyclohexanone, causes a fundamental change in the mechanism to a trisolvated-monomer-based enolization in THF.