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 - selectivities in Et N/toluene (20:1), methyl- -butyl ether (MTBE, 10:1), -pentamethyldiethylenetriamine (PMDTA)/toluene (8:1), TMEDA/toluene (4:1)...

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Bibliographic Details
Published in:Journal of the American Chemical Society 2021-10, Vol.143 (42), p.17452-17464
Main Authors: Woltornist, Ryan A, Collum, David B
Format: Article
Language:English
Subjects:
Deuterium - chemistry
Kinetics
Models, Chemical
Organosilicon Compounds - chemistry
Pentanones - chemistry
Solvents - chemistry
Stereoisomerism
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Summary:Ketone enolization by sodium hexamethyldisilazide (NaHMDS) shows a marked solvent and substrate dependence. Enolization of 2-methyl-3-pentanone reveals - selectivities in Et N/toluene (20:1), methyl- -butyl ether (MTBE, 10:1), -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 Me SiCl/Et N requires warming to -40 °C whereas Me SiOTf reacts within seconds. In situ enolate trapping at -78 °C using preformed NaHMDS/Me SiCl mixtures is effective in Et N/toluene yet fails in THF by forming (Me Si) N. Rate studies show enolization via mono- and disolvated dimers in Et N/toluene, disolvated dimers in TMEDA, trisolvated monomers in THF/toluene, and free ions with PMDTA. Density functional theory computations explore the selectivities via the - and -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.
ISSN:0002-7863
1520-5126
1520-5126
DOI:10.1021/jacs.1c06529