Enolate Regioisomers

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Chapter: Organic Chemistry : Carbon-Carbon Bond Formation Between Carbon Nucleophiles and Carbon Electrophiles

Enolates are commonly used as the nucleophilic component in carbon–carbon bond-forming reactions. By using strong, nonnucleophilic bases, both esters and ketones are easily converted to their enolates.


Enolates are commonly used as the nucleophilic component in carbon–carbon bond-forming reactions. By using strong, nonnucleophilic bases, both esters and ketones are easily converted to their enolates. Ketones, however, are problematic with regard to the regioselectivity of enolate formation if they are unsymmetric. As seen in the following example, two regioisomeric enolates can be produced by the removal of the nonequivalent α protons of 2-pentanone by base, and thus two regioisomeric aldol products are possible.

Regiochemical control of enolate formation is thus an important consideration when planning ways to construct a carbon–carbon bond using a ketone enolate. There are several strategies for controlling the regiochemistry of proton removal.

The first is to take advantage of the fact that the less-substituted α position has slightly more acidic protons. If a ketone is added slowly to a cold solution of LDA, the more acidic proton will be removed preferentially. The resulting enolate is termed the kinetic enolate because the more acidic proton is removed faster than the less acidic proton. Both steric and electronic factors contribute to the more rapid removal of protons from the less highly substituted α carbon.

The enolate that is the most stable usually has the most highly substituted dou-ble bond and is called the thermodynamic enolate. If a slight excess of the ketone is used or a trace of protic impurities is present, equilibrium between the enolates is established and isomerization to the more highly substituted enolate occurs.

The thermodynamic enolate is lower in energy so it is the one favored if equilib-rium is achieved. For this reason, great care must be taken in the preparation and reaction of the kinetic enolate so that equilibration does not occur. On the other hand, preparation and reaction of the thermodynamic enolate is much easier and demands less rigorous reaction conditions.

Besides the direct formation of kinetic or thermodynamic enolates of ketones, other strategies can be employed to produce regiospecific products. An older and extremely valuable strategy for making the synthetic equivalent of a particular regiospecific enolate utilizes some group (G) to acidify a proton α to a ketone so that it is removed preferentially by base. The resulting enolate is used as a carbon nucleophile and then the group (G) is removed. In this way it appears that one α position of a ketone has been regioselectively transformed when, in fact, the group G has guided the chemistry in the reactant but is not present in the product.

The most common group G is an ester function (although many other groups have been employed as well). The starting β-ketoester, which can be prepared easily by a Claisen-type reaction of an ester enolate and an acid chloride, has a very acidic α proton (pKa 9–10) which is easily removed (i.e., 1 equiv. NaH or 1 equiv. EtO).

The resulting enolate is used as a nucleophile to form a new carbon–carbon bond. The ester is then hydrolyzed and CO2 is thermally ejected to provide an α-substituted ketone. This strategy is simple, efficient, and convenient and is widely used. This synthesis is commonly referred to as the acetoacetic ester synthesis since the most simple starting material is an ester of acetoacetic acid if R1 = H.

A third strategy for controlling enolate formation is to convert the carbonyl group to a N ,N -dimethylhydrazone. The hydrazone is less reactive than the carbonyl group, and removal of an α proton by a strong base takes place at the least hindered α position. Alkylation followed by hydrolysis gives back carbonyl product that is the same as the result of kinetic control of enolate formation. However, this method does not have the problems of equilibration as found for simple enolate formation. The regioselectivity of proton removal from the hydrazone is probably related to the geometry of the hydrazone. The dimethylamino group is pointed toward the least hindered α position for steric reasons and directs the base to that position by coordination with the lone pairs on nitrogen.

The use of hydrazones is particularly important to form the enolate equivalents of aldehydes. Aldehydes are quite reactive as electrophiles, so as soon as some enolate has been formed, it reacts with the unreacted aldehyde present in solution. Conversion of the aldehyde to its N ,N -dimethylhydrazone (=NNMe2) lowers the electrophilicity so that α-proton removal can take place and then the electrophile of choice can be added. Hydrolysis gives back the aldehyde. In this case the geometry of the hydrazone is unimportant since aldehydes have only one α position from which protons can be removed by base.

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