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

Enolates are important nucleophiles which react nicely with a variety of carbonyl compounds. In this case, the nucleophilic reactivity of the enolate and the electrophilic reactivity of the carbonyl group are well matched and a wide variety of products can be made.


Enolates are important nucleophiles which react nicely with a variety of carbonyl compounds. In this case, the nucleophilic reactivity of the enolate and the electrophilic reactivity of the carbonyl group are well matched and a wide variety of products can be made. The type of enolate (ketone, ester, etc.) and the type of carbonyl electrophile (aldehyde, ketone, ester, etc.) determine the structure of the final product. Furthermore these reactions are often named according to the two partners that are reacted and the type of product produced from them.

The aldol condensation is the reaction of an aldehyde or ketone enolate with an aldehyde or ketone to give a β-hydroxy aldehyde or ketone. A simple aldol reaction is one in which the enolate nucleophile is derived from the carbonyl electrophile. Very often the β-hydroxy carbonyl product dehydrates to give an ,β-unsaturated carbonyl compound; however, the aldol nature of the dehy-dration product can be discerned by disconnection of the double bond of the unsaturated product.

If the enolate nucleophile is derived from an aldehyde or ketone different than the carbonyl electrophile, a crossed-aldol condensation results. Normally best success is achieved if the carbonyl electrophile employed for the crossed-aldol condensation is more reactive than the carbonyl electrophile from which the enolate is derived. For example, ketone enolates react with aldehydes effectively, but aldehyde enolates do not give the crossed aldol with most ketones but self-condense instead.

The Claisen condensation is the reaction of the enolate of an ester with an ester electrophile. The product is a β-keto ester since the tetrahedral intermediate collapses by expulsion of an alkoxide.

A crossed Claisen is the reaction of an ester enolate with an aldehyde or ketone to produce a β-hydroxy ester. This works well because aldehydes and ketones are more reactive electrophiles than esters; thus the ester enolate reacts faster with the aldehyde or ketone than it condenses with itself, avoiding product mix-tures. Moreover, the aldehyde or ketone should not have α hydrogens so that proton transfer to the more basic ester enolate is avoided. This would lead to the formation of an aldehyde or ketone enolate in the mixture, and an aldol reaction would be a major competing reaction.

For the same reason it is generally not feasible to carry out a crossed-Claisen reaction between the enolate of one ester and a second ester which has α protons. This is due to the fact that if nucleophilic addition to the carbonyl group is not fast, proton exchange can occur, giving a mixture of enolates and thus a mixture of products.

There are many other named reactions that follow the same general features but differ as to the type of enolate or the carbon electrophile. These include the Reformatski reaction, the Darzens reaction, and the Dieckmann ring closure. They were in widespread use for many years and were named as a convenient way to characterize the reactants employed and type of product which results. The reason that there are so many variations on the same theme is that control of the reaction products depends on the ability to generate a particular enolate nucleophile and react it with a particular carbonyl electrophile. In earlier times alkoxide bases were the strongest bases routinely available to synthetic chemists. Since alkoxides have pKa = 15–19 while protons α to carbonyl groups have pKa = 20–25, the reaction of an alkoxide base with a carbonyl compound produces only a small amount of the enolate at equilibrium, and it is produced in the presence of the unreacted carbonyl compound, which is an electrophile. For simple aldol and Claisen reactions, this is the ideal situation for self-condensation.

If, however, it is necessary to generate a crossed product by the reaction of an enolate derived from one carbonyl compound with a second carbonyl compound as the electrophile, things can go bad rapidly. Because both carbonyl groups must be present in solution at the same time and each can form enolates to some extent, there can be four possible products from the various combinations of enolates and carbonyl compounds. This problem was illustrated for the crossed-Claisen condensation above. The number of products can be minimized if one carbonyl component lacks α protons and cannot form an enolate and is also a more reactive electrophile than the second carbonyl component. If these conditions are met, then crossed condensations can be carried out successfully using alkoxide bases. Many of the named reactions were developed so that product mixtures could be avoided.

Today reactions of enolates are usually carried out much differently by uti-lizing very strong, nonnucleophilic bases for generating the enolate nucleophile. Instead of having only small equilibrium concentrations of an enolate produced in solution, the use of strong, nonnucleophilic bases like LDA, KHMDS, and KH that have pKa’s >35 permits carbonyl compounds, whose α protons have pKa’s of 20–25, to be converted completely to enolate anions. Doing so completely converts the carbonyl compound into a nucleophile which cannot condense with itself and is stable in solution. This enolate can then be reacted with a second carbonyl compound in a subsequent step to give product:

Step 1

Step 2

As long as nucleophilic addition of the preformed enolate to the second carbonyl component is rapid and the carbonyl electrophile is added after the enolate is formed, the product is predictable and is not a mixture. The rule of thumb to ensure success is that the carbonyl electrophile should be more reactive than the carbonyl compound from which the enolate is derived. If this condition is met, the carbonyl electrophile can have α protons and the structural possibilities are increased tremendously. Typical enolate–carbonyl pairs that have been condensed by this methodology include the following:

Acetylides can also react as nucleophiles toward aldehydes and ketones to give propargylic alcohols, which provides a simple way to install the triple bond in molecules.

Esters, amides, and nitriles are relatively weak electrophiles. They react slug-gishly or not at all with enolates. Esters are more electrophilic than amides and nitriles and react readily with carbanionic-type reagents such as organolithiums or Grignard reagents. As seen previously, two equivalents of the organometallics are added and tertiary alcohols are produced. Tertiary amides and nitriles react with organolithiums (but not Grignard reagents) to give ketones after hydrolytic workup. A single nucleophilic addition occurs to give an anionic intermediate which is stable to further nucleophilic addition. The oxidation level is that of a ketone which is unmasked upon hydrolysis.

Carbonyl electrophiles are obviously a very important group of electrophiles that react successfully with a spectrum of carbon nucleophiles. Among carbonyl electrophiles, however, large differences in reactivity are observed. Acid chlorides are very reactive electrophiles whereas esters and amides are much weaker and fail to react with several classes of carbon nucleophiles. Aldehydes and ketones are probably the most widely utilized groups of carbonyl electrophiles and exhibit moderate electrophilic reactivity. No matter what carbonyl electrophile is used, however, it reacts by nucleophilic addition to the carbonyl carbon to produce a tetrahedral intermediate. The ultimate reaction product reflects subsequent chem-istry of the tetrahedral intermediate.

While the use of strong bases has changed the way in which many condensation reactions are carried out, it is important to remember the types of products that are produced from them. Recall that the aldol condensation yields β-hydroxy aldehydes or ketones which are easily dehydrated to α,β-unsaturated aldehydes or ketones.

It is thus possible to look at a molecule such as A below and recognize that it is a β-hydroxy ketone and thus could be formed in a crossed-aldol reaction between enolate B and aldehyde C. Likewise D could potentially be produced by dehydration of the aldol product of cyclohexanone

In addition to these intermolecular processes, intramolecular versions of the Claisen (Dieckmann) reaction and the mixed Claisen and the aldol reaction (Robinson annulation) are also well known. In all cases the same structural classes of products are formed.

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