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Chapter: Organic Chemistry: Aldehydes and ketones

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Aldehydes and ketones: Reactions of enolate ions

Enolate ions are formed by treating aldehydes or ketones with a base. A proton has to be present on the α-carbon.

REACTIONS OF ENOLATE IONS

Key Notes

Enolate ions

Enolate ions are formed by treating aldehydes or ketones with a base. A proton has to be present on the α-carbon.

Alkylation

Enolate ions can be alkylated with an alkyl halide. O-Alkylation and C-alky-lation are both possible, but the latter is more likely and more useful. The reaction allows the introduction of alkyl groups to the α-carbon of alde-hydes and ketones. If there are two α-protons present, two different alkyla-tions can be carried out in succession. β-Ketoesters are useful starting materials since the α-protons are more acidic and the alkylation is targeted to one position. The ester group is removed by decarboxylation.

Aldol reaction

The Aldol reaction involves the dimerization of an aldehyde or a ketone. In the presence of sodium hydroxide, aldehyde or ketone is converted to an enolate ion, but not all the carbonyl molecules are converted and so the enolate ion can undergo a nucleophilic addition on ‘free’ aldehyde or ketone. The product is a β-hydroxyaldehyde or β-hydroxyketone. Aldehy-des react better than ketones in this reaction. If water is lost from the Aldol adduct, an α,β-unsaturated carbonyl structure is obtained.

Crossed Aldol reaction

The crossed Aldol reaction links two different aldehyde structures. The reaction works best if one of the aldehydes has no α-proton present and the other aldehyde is added slowly to the reaction mixture to prevent self-condensation. If a ketone is linked to an aldehyde, the reaction is known as the Claisen–Schmidt reaction. This works best if the aldehyde has no α-proton.

 

Enolate ions

Enolate ions are formed by treating aldehydes or ketones with a base. Anα-proton has to be present. Enolate ions can undergo a variety of important reactions including alkylation and the Aldol reaction.

Alkylation

Treatment of an enolate ion with an alkyl halide results in a reaction known as alkylation (Fig. 1). The overall reaction involves the replacement of anα-proton with an alkyl group. The nucleophilic and electrophilic centers of the enolate ion and methyl iodide are shown (Fig. 2). The enolate ion has its negative charge shared between the oxygen atom and the carbon atom due to resonance, and so both of these atoms are nucleophilic centers. Iodomethane has a polar C–I bond where the iodine is a weak nucleophilic center and the carbon is a good electrophilic center.


One possible reaction between these molecules involves the nucleophilic oxy-gen using one of its lone pairs of electrons to form a new bond to the electrophilic carbon on iodomethane (Fig. 3a). At the same time, the C–I bond and both elec-trons move onto iodine to give it a fourth lone pair of electrons and a negative charge. This reaction is possible, but in practice the product obtained is more likely to arise from the reaction of the alternative carbanion structure reacting with methyl iodide (Fig. 3b). This is a more useful reaction since it involves the forma-tion of a carbon–carbon bond and allows the construction of more complex carbon skeletons.


An alternative mechanism to that shown in Fig. 3b, but which gives the same result, starts with the enolate ion. The enolate ion is more stable than the carban-ion since the charge is on the electronegative oxygen and so it is more likely that the reaction mechanism will occur in this manner (Fig. 4). This is a very useful reaction in organic synthesis. However, there are limitations to the type of alkyl halide which can be used in the reaction. The reaction is SN2 with respect to the alkyl halide  and so the reaction works best with primary alkyl, primary benzylic, and primary allylic halides. The enolate ion is a strong base and if it is reacted with secondary and tertiary halides, elimination of the alkyl halide takes place to give an alkene.


α-Alkylation works well with ketones, but not so well for aldehydes since thelatter tend to undergo Aldol condensations instead.

The α-protons of a ketone such as propanone are only weakly acidic and so a powerful base (e.g. lithium diisopropylamide) is required to generate the enolate ion required for the alkylation. An alternative method of preparing the same prod-uct but using a milder base is to start with ethyl acetoacetate (a β-keto ester) instead (Fig. 5). The α-protons in this structure are more acidic since they are flanked by two carbonyl groups. As a result, the enolate can be formed using a weaker base such as sodium ethoxide. Once the enolate has been alky-lated, the ester group can be hydrolyzed and decarboxylated on heating with aqueous hydrochloric acid. The decarboxylation mechanism involves the β-keto group and would not occur if this group was absent (Fig. 6). Carbon dioxide is lost and the enol tautomer is formed. This can then form the keto tautomer by the normal keto–enol tautomerism.

It is possible for two different alkylations to be carried out on ethyl acetoacetate since there is more than one α-proton present (Fig. 7).


β-keto esters such as ethylacetoacetate are also useful in solving a probleminvolved in the alkylation of unsymmetrical ketones. For example, alkylating butanone with methyl iodide leads to two different products since there are α-protons on either side of the carbonyl group (Fig. 8). One of these products isobtained specifically by using a β-keto ester to make the target alkylation site more acidic (Fig. 9).


The alternative alkylation product could be obtained by using a different β-keto ester (Fig. 10).

Aldol reaction

Enolate ions can also react with aldehydes and ketones by nucleophilic addition. The enolate ion acts as the nucleophile while the aldehyde or ketone acts as an electrophile. Since the enolate ion is formed from a carbonyl compound itself, and can then react with a carbonyl compound, it is possible for an aldehyde or ketone to react with itself. We can illustrate this by looking at the reaction of acetaldehyde with sodium hydroxide (Fig. 11). Under these conditions, two molecules of acetaldehyde are linked together to form a β-hydroxyaldehyde.


In this reaction, two separate reactions are going on – the formation of an enolate ion from one molecule of acetaldehyde, and the addition of that enolate to a second molecule of acetaldehyde. The mechanism begins with the formation of the enolate ion. It is important to realize that not all of the acetaldehyde is converted to the enolate ion and so we still have molecules of acetaldehyde present in the same solution as the enolate ions. Since acetaldehyde is susceptible to nucleophilic attack, the next stage in the mechanism is the nucleo-philic attack of the enolate ion on acetaldehyde (Fig. 12). The enolate ion has two nucleophilic centers – the carbon and the oxygen – but the preferred reaction is at the carbon atom. The first step is nucleophilic addition of the aldehyde to form a charged intermediate. The second step involves protonation of the charged oxygen. Since a dilute solution of sodium hydroxide is used in this reaction, water is available to supply the necessary proton. (Note that it would be wrong to show a free proton (H+) since the solution is alkaline.)


If the above reaction is carried out with heating, then a different product is obtained (Fig. 13). This arises from elimination of a molecule of water from the Aldol reaction product. There are two reasons why this can occur. First of all, the product still has an acidic proton (i.e. there is still a carbonyl group present and an α-hydrogen next to it). This proton is prone to attack from base. Secondly, thedehydration process results in a conjugated product which results in increased stability. The mechanism of dehydration is shown in Fig. 14. First of all, the acidic proton is removed and a new enolate ion is formed. The electrons in the enolate ion can then move in such a fashion that the hydroxyl group is expelled to give the final product – an α,β-unsaturated aldehyde. 


In this example, it is possi-ble to vary the conditions such that one gets the Aldol reaction product or the α,β-unsaturated aldehyde, but in some cases only the α,β-unsaturated carbonylproduct is obtained, especially when extended conjugation is possible. The Aldol reaction is best carried out with aldehydes. Some ketones will undergo an Aldol reaction, but an equilibrium is set up between the products and starting materials and it is necessary to remove the product as it is being formed in order to pull the reaction through to completion.

Crossed Aldol reaction

So far we have talked about the Aldol reaction being used to link two molecules of the same aldehyde or ketone, but it is also possible to link two different carbonyl compounds. This is known as a crossed Aldol reaction. For example, benzaldehyde and ethanal can be linked in the presence of sodium hydroxide (Fig.15). In this example, ethanal reacts with sodium hydroxide to form the enolate ionwhich then reacts with benzaldehyde. Elimination of water occurs easily to give an extended conjugated system involving the aromatic ring, the double bond, and the carbonyl group.


This reaction works well because the benzaldehyde has no α-protons and cannot form an enolate ion. Therefore, there is no chance of benzaldehyde under-going self-condensation. It can only act as the electrophile for another enolate ion. However, what is to stop the ethanal undergoing an aldol addition with itself as previously described (Fig. 11)?

This reaction can be limited by only having benzaldehyde and sodium hydrox-ide initially present in the reaction flask. Since benzaldehyde has no α-protons, no reaction can take place. A small quantity of ethanal can now be added. Reaction with excess sodium hydroxide turns most of the ethanal into its enolate ion. There will only be a very small amount of ‘free’ ethanal left compared to benzaldehyde and so the enolate ion is more likely to react with benzaldehyde. Once the reaction is judged to have taken place, the next small addition of ethanal can take place and the process is repeated.

Ketones and aldehydes can also be linked by the same method – a reaction known as the Claisen–Schmidt reaction. The most successful reactions are those where the aldehyde does not have anα-proton (Fig. 16).

 

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