Kinetic versus Thermodynamic Regiocontrol of Enolate Formation

Kinetic versus Thermodynamic Regiocontrol of Enolate Formation 

When starting with an unsymmetrical ketone such as 2-butanone, deprotonation at either alpha carbon will result in two possible enolates. Varying the reaction conditions can control the regioselectivity of enolate formation. When LDA is used at a low temperature, the irreversible deprotonation is controlled by kinetics, and the least sterically hindered proton is removed to form the so-called kinetic enolate. 

Deprotonation at the more substituted alpha carbon is slower since it is more crowded, but the resulting thermodynamic enolate is more stable since it has a more substituted double bond. The thermodynamic enolate is favored when the reaction is allowed to equilibrate using higher temperatures and either an excess of ketone or a weaker base allows the reverse reaction to occur. In another approach, an enolate is trapped with trimethyMyl chloride (TMSCl) to give the thermodynamic silyl enol ether. The reversible mechanism of the silyl enol ether formation, along with the warmer reaction conditions, promotes equilibration, and, therefore, favors the more stable product. 

Choice of Base/Reaction Conditions Determines Enolate Regiochemistry 

Treatment of the silyl enol ether with fluoride ion (tetrabutylammonium fluoride, TBAF) regenerates the enolate, making alkylation at the more substituted alpha carbon possible. 

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