At first sight formaldehyde (methanal, CH₂=O) seems the ideal electrophilic partner in a mixed aldol reaction. It cannot enolize. (Usually we are concerned with α hydrogen atoms in an aldehyde. Formaldehyde does not even have α carbon atoms.) And it is a super aldehyde. Aldehydes are more electrophilic than ketones because a hydrogen atom replaces one of the alkyl groups. Formaldehyde has two hydrogen atoms. The trouble is that it is too reactive. It tends to react more than once and to give extra unwanted reactions as well. You might think that condensation between acetaldehyde and formaldehyde in base would be quite simple. The acetaldehyde alone can form an enolate, and this enolate will attack the more electrophilic carbonyl group, which is form aldehyde. In each reaction the only possible enolate attacks another molecule of form aldehyde. By now you have got the idea so we simply draw the next enolate and the structure of the third aldol.

This aldol is formed all right but it is not the final product of the reaction because, with an electrophile as powerful as formaldehyde, a second and a third aldol follow swiftly on the heels of the first.

Even this is not all. A fourth molecule of formaldehyde reacts with hydroxide ion and then reduces the third aldol. This reduction is known as the Cannizzaro reaction, and is described in the box below. The final product is the highly symmetrical ‘pentaerythritol’, C(CH₂OH)₄, with four CH₂OH groups joined in a tetrahedral array about the same carbon atom. The over all reaction uses four molecules of formaldehyde and can give a high yield (typically 80% with NaOH but as much as 90% with MgO) of the product.

A general solution to using formaldehyde in aldol reactions is to use the Mannich reaction. A typical example is shown in the margin: the reaction involves an enolizable aldehyde or ketone (here we use cyclohexanone), a secondary amine (here dimethylamine), the Mannich reaction formaldehyde as its aqueous solution, and catalytic HCl. The product is an amino ketone from the addition of one molecule each of formaldehyde and the amine to the ketone. The mechanism involves the preliminary formation of an imine salt from the amine and formaldehyde. The amine is nucleophilic and attacks the more electrophilic of the two car bonyl compounds available, which is, of course, formaldehyde. No acid is needed for this addition step, but acid-catalysed dehydration of the addition product gives the imine salt. In the normal Mannich reaction, this is just an intermediate but it is quite stable and the corres ponding iodide is sold as Eschenmoser’s salt for use in Mannich reactions.

The electrophilic salt can now add to the enol (we are in acid solution) of the ketone to give the product of the reaction, an amine sometimes called a Mannich base.

By using this reaction, you can add one molecule of formaldehyde—and one only—to car bonyl compounds. You might, of course, reasonably object that the product is not actually an aldol product at all—indeed, if you wanted the aldol product, the Mannich reaction would be of little use to you. It nevertheless remains a very important reaction. First of all, it is a simple way to make amino-ketones and many drug molecules belong to this class. Secondly, the Mannich products can be converted to enones. The most reliable method for making the enone is to alkylate the amine product of the Mannich reaction with MeI and then treat the ammonium salt with base. Enolate ion formation leads to an E1cB reaction rather like the dehydration of aldols, but with a better leaving group.

Enones like this, with two hydrogen atoms at the end of the double bond, are called exo methylene compounds; they are very reactive and cannot easily be made or stored. They certainly cannot be made by aldol reactions with formaldehyde alone as we have seen. The solution is to make the Mannich product, store that, and then to alkylate and eliminate only when the enone is needed. If the enone is wanted, any secondary amine will do as it does not end up in the molecule so the more convenient (less volatile and less smelly) cyclic amines, pyrrolidine, and piperidine, are often used. The very electrophilic enones with monosubstituted double bonds can be made in this way.

مواضيع ذات صلة

The Robinson annelation

Intramolecular aldol reactions

How to control aldol reactions of aldehydes

How to control aldol reactions of esters

Specifi c enol equivalents from 1,3-dicarbonyl compounds

Conjugated Wittig reagents as specific enol equivalents

Silyl enol ethers in aldol reactions

Lithium enolates in aldol reactions

Base-promoted halogenation

Halogenation

Racemization

Thermodynamically stable enols: 1,3-dicarbonyl compounds