Kinetic vs. Thermodynamic Control in Enolate and Enol Formation

4 Kinetic vs. Thermodynamic Control in Enolate and Enol Formation 

When a carbonyl has two different R groups with a-hydrogens, there are two possible enols and enolates. Furthermore, deprotonation of an acyclic structure with a-hydrogens can lead to enol and enolate isomers (E and Z). By judicious choices of reaction conditions 

By analogy to olefin chemistry, we expect that the more stable enolate, the thermodynamic enolate, will be the one with the more heavily substituted C=C double bond. Deprotonation under equilibrating conditions will produce the thermodynamic enolate. The same trend is seen for enols that is, the more substituted double bond gives the more stable enol. 

Another issue is the ratio of enolate E and Z isomers that can form in appropriate systems. In general, Z-enolates are more stable than -enolates due to lower steric interactions with the R group on the carbonyl carbon. For example, in the deprotonation of 3-pentanone with lithium tetramethylpiperidide (LTMP) at low temperature, the -enolate is formed preferentially (Eq. 11.7). In contrast, the use of LTMP with added HMPA (hexamethyl-phosphoramide, which binds cations) at ambient temperature preferentially gives the thermodynamic enolate (Eq. 11.8). The HMPA assists in breaking up the aggregates mentioned above, and in the exchange of enolate deprotonation sites. 

We noted above the tendency for enolates to aggregate. The aggregates are organized in large part by the counterion of the base, Li in the case of LDA or LTMP. To the side, prototypical dimers and tetramers are shown. In the absence of ligands such as HMPA, diamines, and THF, even larger aggregates exist. 

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