This alternative solution is often better. With the right starting material, the tetrahedral inter mediate can become stable enough not to collapse to a ketone during the reaction; it therefore remains completely unreactive towards nucleophiles. The ketone is formed only when the reaction is finally quenched with acid but the nucleophile is also destroyed by the acid and none is left for further addition.

We can illustrate this concept with a reaction of an unlikely looking electrophile, a lithium carboxylate. Towards the beginning of the chapter we said that carboxylic acids were bad electrophiles and that carboxylate salts were even worse. Well, that is true, but with a sufficiently powerful nucleophile (an organolithium) it is just possible to get addition to the car bonyl group of a lithium carboxylate.

We could say that the affinity of lithium for oxygen means that the Li–O bond has considerable covalent character, making the CO2Li less of a true anion. And the intermediate after addition of MeLi is probably best represented as a covalent compound too. Anyway, the product of this addition is a dianion of the sort that we met during one of the mechanisms of base-catalysed amide hydrolysis. But in this case, there is no possible leaving group, so there the dianion sits. Only at the end of the reaction, when water is added, are the oxygen atoms protonated to give a hydrated ketone, which collapses immediately (remember Chapter 6) to give the ketone that we wanted. The water quench also destroys any remaining organo lithium, so the ketone is safe from further attack.

This method has been used to make some ketones that are important starting materials for making cyclic natural products known as macrolides.

Another good set of starting materials that lead to non-collapsible tetrahedral intermediates is known as the Weinreb amides, after their inventor, S. M. Weinreb. Addition of organo lithium or organ magnesium reagents to N-methoxy-N-methyl amides gives the tetrahedral intermediate shown, stabilized by chelation of the magnesium atom by the two oxygen atoms. Chelation means the coordination of more than one electron-donating atom in a molecule to a single metal atom.

This intermediate collapses to give a ketone only when acid is added at the end of the reaction.

The mechanism looks complicated but the reaction is easy to do:

This strategy even works for making aldehydes, if the starting material is dimethylformamide (DMF, Me₂NCHO). This is an extremely useful way of adding electrophilic CHO groups to organometallic nucleophiles. Once again, the tetrahedral intermediate is stable until acid is added at the end of the reaction and the protonated tetrahedral intermediate collapses.

A final alternative is to use a nitrile instead of an ester. The intermediate is the anion of an imine (see Chapter 12 for more about imines), which is not electrophilic at all—in fact, it’s quite nucleophilic, but there are no electrophiles for it to react with until the reaction is quenched with acid. It gets protonated and hydrolyses (we’ll discuss this in the next chapter) to the ketone.

مواضيع ذات صلة

Cyanide will attack iminium ions: the Strecker synthesis of amino acids

Lithium aluminium hydride reduces amides to amines

Iminium ions can react as electrophilic intermediates

Secondary amines react with carbonyl compounds to form enamines

Iminium ions and oxonium ions

Some imines are stable

Imines are usually unstable and are easily hydrolysed

Imines are the nitrogen analogues of carbonyl compounds

Amines react with carbonyl compounds

Modifying reactivity using acetals

Cyclic acetals are more stable than acyclic acetals

Acetals hydrolyse only in the presence of acid