Aldol condensation thermodynamic factors

For the other broad category of reaction conditions, the reaction proceeds under conditions of thermodynamic control. This can result from several factors. Aldol condensations can be effected for many compounds using less than a stoichiometric amount of base. Under these conditions, the aldol reaction is reversible, and the product ratio will be determined by the relative stability of the various possible products. Conditions of thermodynamic control also permit equilibration among all the enolates of the nucleophile. The conditions that permit equilibration include higher reaction temperatures, protic solvents, and the use of less tightly coordinating cations. 

The aldol condensation can be carried out under either of two broad sets of conditions which lead to the product being determined by either kinetic or thermodynamic factors. To achieve kinetic control the enolate which is to serve as the nucleophile is generated stoichiometrically, usually with lithium as the counterion in an aprotic solvent. Under these conditions, enolates are both structurally and stereochemically stable. The electrophilic carbonyl compound is then added. Under these conditions, the structure of the reaction product is determined primarily by two factors (1) the structure of the initial enolate and (2) the stereoselectivity of the addition to the electrophilic carbonyl group. 

The other broad category of reaction conditions results in thermodynamic control. This can result from several factors. Aldol condensations can be effected for many compounds using less than a stoichiometric amount of base. Under these conditions. 

It is important to put the thermodynamic aldol condensation into perspective. The actual product as well as the yield depends on the solvent, the base used, and the nature of the carbonyl substrate. When both a kinetic and a thermodynamic enolate are present, the equilibrium may favor the thermodynamic enolate, but steric hindrance makes its reaction much slower. In such a case, the kinetic enolate product may be the isolated product. When 2-pentanone (32) is refluxed with NaOMe in methanol and then treated with 20% sulfuric acid, for example, conjugated ketone 42 is the only isolated product, but in only 8% yield. This clearly makes the reaction confusing to understand. It is presented only to show that this reaction is an equilibrium-driven process and that the equilibrium may be shifted between kinetic and thermodynamic enolates by several factors. For the purposes of doing homework, assume that thermodynamic conditions lead to the thermodynamic aldol as the major product and that kinetic control conditions lead to the kinetic aldol as the major product. 

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