Alkylation of Aldehydes and Ketones18-4

Alkylation of enolates can be difficult to control.The alkylation of an aldehyde or ketone enolate is an example of a nucleophilic substitution reaction.

The alkylation of aldehydes and ketones is complicated by several unwanted side reactions.

E2 elimination: Enolate ion is a fairly strong base. Alkylation is normally feasible using only halomethanes or primary haloalkanes.

Condensation Reactions: Aldehyde alkylations usually fail because their enolate ions undergo a highly favorable condensation reaction.

Multiple Alkylations: Even ketones may lose a second -hydrogen and become alkylated a second time.

Regioisomeric Products: If the starting ketone is unsymmetrical, either -carbon may be alkylated.

An example of a successful alkylation of a ketone:

The ketone possesses a single -hydrogen and the primary allylic halide is an excellent SN2 substrate.

Enamines afford an alternative route for the alkylation of aldehydes and ketones.

Secondary amines react with aldehydes or ketones to produce enamines.

The nitrogen substituent renders the enamine carbon-carbon double bond electron-rich.

This electron density is concentrated at the -carbon, which makes it nucleophilic.

As a result of its nucleophilicity, electrophiles may attack the -carbon of the enamine.

Enamines will react with haloalkanes resulting in alkylation at carbon to produce an iminium salt.

The iminium salt is hydrolyzed during aqueous work-up, liberating the newly alkylated aldehyde or ketone and the original secondary amine.

Alkylation of an enimine is far superior to the alkylation of an enolate.

Minimizes multiple alkylations: The iminium salt formed after the first alkylation is unable to react with additional haloalkane.

It can be used to prepare alkylated aldehydes (aldehyde enolates undergo aldol condensation reactions).

Attack by Enolates on the Carbonyl Function: Aldol Condensation

18-5

Aldehydes undergo base-catalyzed condensations.Treating an aldehyde at low temperature with a small amount NaOH results in the formation of dimer, which, when heated, is converted into an ,-unsaturated aldehyde.

This reaction is known as an aldol condensation. It is general for aldehydes and sometimes succeeds with ketones.

The hydroxide ion serves as a catalyst for the reaction.

The overall reaction is not very exothermic and yields are only 50-60%.

At elevated temperatures, the aldol is converted into its enolate ion, which loses hydroxide (normally a poor leaving group) to form the relatively stable final product.

The aldol condensation yields different products depending upon the reaction temperature.

Low temperatures: a -hydroxycarbonyl compound

Higher temperatures: an ,-unsaturated carbonyl compound

Ketones can undergo aldol condensation.The driving force of the aldol reaction of ketones is less than that of aldehydes because of the greater stability of ketones (about 3 kcal mol-1). The reaction is endothermic.

The reaction can be driven towards completion by the continuous extraction of alcohol, or under more vigorous conditions, dehydration and the removal of water.

Crossed Aldol Condensation18-6An aldol condensation between the enolate of one aldehyde and the carbonyl of another results in a crossed aldol condensation.

Enolates of both aldehydes will be present and may react with the carbonyl groups of either starting compound.

A single aldol product can be obtained from the reaction of two different aldehydes when one of them has no enolizable hydrogen atoms.

The reaction is carried out by slowly adding the enolizable aldehyde to an excess of the nonenolizable reactant in the presence of a base.

Intramolecular Aldol Condensation18-7

An intramolecular aldol condensation results from the reaction of an enolate ion and a carbonyl group within the same molecule.

Reaction between different aldehyde molecules is minimized by running the reaction in a dilute solution.

The kinetics of intramolecular 5-membered ring formation are also favorable.

Intramolecular ring closures of ketones are a ready source of cyclic and bicyclic ,-unsaturated ketones.

Usually the least strained ring is formed (typically 5- or 6-membered).

Intramolecular aldol condensations of ketones succeed while intermolecular condensations fail because of the more favorable entropy change for ring closure (1 molecule 1 molecule rather than 2 molecules 1 molecule).