Enolate vs Nucleophile Reaction

Question

How do you know if a reaction will form an enolate or attack at the carbonyl carbon? For example, if I added -OCH2CH3, would this attack the carbon or take a hydrogen to form the enolate?

Answer 1

A simplified approach is this: a reagent that is both small and can act as either a base or nucleophile will do both runs (EtO- will do both) while a large reactant will be far more likely to act as a base. You can skew the run towards nucleophilic attack by making the carbonyl carbon more partially positive by having the carbonyl carbon attached to an electron-withdrawing group.

Answer 2

A number of different things would have to be considered when deciding which one would form preferentially. If, for example, you wanted to do nucleophilic acyl substitution (attacking the carbonyl), you'd have to have a fairly reactive carbonyl carbon (like a acyl chloride or acid anhydride) and a good nucleophile/base (like OH-, methoxide, cyanide, ethoxide, grignard reagent)

If you wanted to preferentially form an enolate, you would have to have a carbonyl compound with an acidic hydrogen (i.e diethyl malonate, ethyl acetoacetate, or 2,4-pentadione) and a good base. The base should be taken into consideration as well. A bulky base, like LDA (lithium Diisopropyl amide) couldnt attack at the carbonyl carbon, and so would deprotonate that acidic alpha hydrogen, perhaps potassium tert-butoxide could be used as well.

The thing is too, i'm sure the formation of the enolate and substitution product are in equilibrium, so that's why, if you wish to form a certain product, you should consider the starting reagents/conditions. So, if you want substitution, perhaps choose something fairly nucleophilic that can add to the carbonyl carbn, but not basic enough to deprotonate that alpha hydrogen. In your question, for example, the ethoxide is pretty basic, and would probably deprotonate the alpha hydrogen, especially of its a diketone of some sort with an acidic alpha hydrogen like 2,4-pentadione. If you wanted that ethoxy group added to the carbonyl carbon, you could do acid catalyzed acetal formation using ethanol, which is fairly nucleophilic, but not very basic.