Selective enolate formation is straightforward if the protons on one side of the ketone are significantly more acidic than those on the other. This is what you have just seen with ethyl acetoacetate: it is a ketone, but with weak bases (pKa of the conjugate acid < 18) it only ever enolizes on the side where the protons are acidified by the second electron-withdrawing group. If two new substituents are introduced, in the manner you have just seen, they will always both be joined to the same carbon atom. This is an example of thermodynamic control: only the more stable of the two possible enolates is formed.

This principle can be extended to ketones whose enolates have less dramatic differences in stability. Since enols and enolates are alkenes, the more substituents they carry the more stable they are. So, in principle, even additional alkyl groups can control enolate formation under thermodynamic control. Formation of the more stable enolate requires a mechanism for equilibration between the two enolates, and this must be proton transfer. If a proton source is available—and this can even be just excess ketone—an equilibrium mixture of the two enolates will form. The composition of this equilibrium mixture depends very much on the ketone but, with 2-phenylcyclohexanone, conjugation ensures that only one enolate forms. The base is potassium hydride: it’s strong, but small (and so has no difficulty removing the more hindered proton) and can be used under conditions that permit enolate equilibration.

The more substituted lithium enolates can also be formed from the more substituted silyl enol ethers by substitution at silicon—a reaction you met in Chapter 20. The value of this reaction now becomes clear because the usual way of making silyl enol ethers (Me3SiCl, Et3N) typically produces, from unsymmetrical ketones, the more substituted of the two possible ethers. Because the silyl enol ether (unlike the enolate itself) can be purified, fully regio chemically pure enolates can be formed in this way.

One possible explanation for the thermodynamic regioselectivity in the enol ether-forming step is related to our rationalization of the regioselectivity of bromination of ketones in acid on p. 464. Triethylamine is too weak a base (pKa of Et3NH+ is about 10) to deprotonate the starting carbonyl compound (pKa ca. 20), and the fi rst stage of the reaction is probably an oxygen–silicon interaction. Loss of a proton now takes place through a cationic transition state, and this is stabilized rather more if the proton being lost is next to the methyl group: methyl groups stabilize partial cations just as they stabilize cations.

An alternative view is that reaction takes place through the enol: the Si–O bond is so strong that even neutral enols react with Me₃SiCl, on oxygen, of course. The predominant enol is the more substituted, leading to the more substituted silyl enol ether.

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مواضيع ذات صلة

The Claisen ester condensation and other self-condensations

Problems with acylation at carbon

Cross-condensations

The aldol reaction

Nitroalkanes are superb nucleophiles for conjugate addition

A variety of electrophilic alkenes will accept enol(ate) nucleophiles

Conjugate addition of silyl enol ethers leads to the silyl enol ether of the product

Enamines are convenient stable enol equivalents for conjugate addition

Alkali metal (especially Na, K) enolates can undergo conjugate addition

1,3-Dicarbonyl compounds undergo conjugate addition

Using Michael acceptors as electrophiles

Conjugate addition to enones gives enolates regiospecifically