Enolates kinetic versus thermodynamic control

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the case of formation of enolate anions from unsymmetrical ketones. This is a very important matter for synthesis and will be discussed more fully in Chapter 1 of Part B. Most ketones, highly symmetric ones being the exception, can give rise to more than one enolate. Many studies have shown tiiat the ratio among the possible enolates that are formed depends on the reaction conditions. This can be illustrated for the case of 3-methyl-2-butanone. If the base chosen is a strong, sterically hindered one and the solvent is aptotic, the major enolate formed is 3. If a protic solvent is used or if a weaker base (one comparable in basicity to the ketone enolate) is used, the dominant enolate is 2. Enolate 3 is the kinetic enolate whereas 2 is the thermodynamically favored enolate. 

Before commencing this discussion, it is appropriate to consider briefly the issue of kinetic versus thermodynamic control in the reactions of preformed Group I and Group II enolates and to summarize the structure-stereoselectivity generalizations that have emerged to date. It is now welt established that preformed lithium, sodium, potassium and magnesium enolates react with aldehydes in ethereal solvents at low temperatures (typically -78 °C) with a very low activation barrier. For example, reactions can often be quenched within seconds of the addition of an aldehyde to a solution of a lithium enolate. ... 

The factors that govern the direction of enolate formation from such unsymmetrical ketones are numerous, but can be organized using the concept of kinetic versus thermodynamic control. 

Kinetic Versus Thermodynamic Control in Formation of Enolates... 

The idea of kinetic versus thermodynamic control can be illustrated by discussing briefly the formation of enolate anions from unsymmetrical ketones. A more complete discussion of this topic is given in Chapter 7 and in Part B, Chapter 1. Any ketone with more than one type of a-proton can give rise to at least two enolates when a proton is abstracted. Many studies, particularly those of House,have shown that the ratio of the two possible enolates depends on the reaction conditions. If the base is very strong, such as the triphenylmethyl anion, and there are no hydroxylic solvents present, enolate 6 is the major product. When equilibrium is established between 5 and 6 by making enolate formation reversible by using a hydroxylic solvent, however, the dominant enolate is 5. Thus, 6 is the product of kinetic control... 

What does all of this mean The reaction of 2-pentanone with LDA in THF at -78°C constitutes typical kinetic control conditions. Therefore, formation of the kinetic enolate and subsequent reaction with benzaldehyde to give 34 is predictable based on the kinetic versus thermodynamic control arguments. In various experiments, the reaction with an unsymmetrical ketone under what are termed thermodynamic conditions leads to products derived from the more substituted (thermodynamic) enolate anion. Thermodynamic control conditions typically use a base such as sodium methoxide or sodium amide in an alcohol solvent at reflux. The yields of this reaction are not always good, as when 2-butanone (37) reacts with NaOEt in ethanol for 1 day. Self-condensation at the more substituted carbon occurs to give the dehydrated aldol product 38 in 14% yield. Note that the second step uses aqueous acid and, under these conditions, elimination of water occurs. 

To tackle this problem, you have to invoke the principles of kinetic versus thermodynamic control (review Sections 11-6, 14-6, and 18-2) that is, which enolate is formed faster and which one is more stable Divide your team so that one group considers conditions A and the other conditions B. Use curved arrows to show the flow of electrons leading to each enolate. Then assess whether your set of conditions is subject to enolate equilibration (thermodynamic control) or not (kinetic control). Reconvene to discuss these issues and draw a qualitative potential-energy diagram depicting the progress of deprotonation at the two a sites. 

Results of molecular mechanics and quantum mechanical calculations are consistent with an interpretation of the base-dependent stereoselective intramolecular conjugate addition of amide enolates to Q ,j8-unsaturated esters in terms of thermodynamic versus kinetic control. ... 

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