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 degrees C whereas Me3SiOTf reacts within seconds. In situ enolate trapping at -78 degrees C using preformed NaHMDS/Me3SiCl mixtures is effective in Et3N/toluene yet fails in THF by forming (Me3Si)(3)N. 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.

Automated summary

The enolization of ketones by sodium hexamethyldisilazide (NaHMDS) displays significant solvent and substrate dependence, leading to varied reaction rates, stereoselectivity, and mechanisms. Different solvents result in different products and reaction pathways for enolization of ketones, highlighting the complex interplay between NaHMDS, solvents, and substrates.