2.6. Acid vs. Base Catalysis for Enol Reactions

Enol reactions are commonly catalyzed by either acids or bases. When acid catalysis is used the catalyst performs two tasks. First, it catalyzes keto-enol tautomerism to keep the amount of enol in solution high. Second, as with most acid catalysis the electrophile becomes cationic, which decreases the amount of electron density and, by extension, increases the electrophilicity; acid catalysis works by making the electrophile stronger.

As an example, carbonyl-containing compounds like acetone can undergo acid-catalyzed keto-enol tautomerism and then attack another carbonyl-containing molecule (Scheme 2.11). The specific type of reaction (see Section 2.10) is not important at this stage. The uncatalyzed mechanism relies on the enol, a weak to moderate nucleophile with very low concentration, attacking a carbonyl, a weak to moderate electrophile. As a result, this reaction is very (very) slow. When acid catalysis is used the amount of nucleophile in solution increases AND the electrophile switches from being a carbonyl to a protonated carbonyl, a strong electrophile. As a result, the acid-catalyzed reaction is much faster.

Scheme 2.11 – Generalized Reaction Mechanism for Acid-Catalyzed Enol Formation and Subsequent Acid-Catalyzed Activation of the Electrophile.

When base catalysis is used the catalyst performs two tasks. First, it catalyzes keto-enol tautomerism to keep the amount of enol in solution high. Second, as with most base catalysis the nucleophile becomes anionic, which increases the amount of electron density and, by extension, the nucleophilicity; base catalysis works by making the nucleophile stronger.

As an example, carbonyl-containing compounds like acetone can undergo base-catalyzed keto-enol tautomerism and then attack another carbonyl-containing molecule (Scheme 2.12). The specific type of reaction (see Section 2.10) is not important at this stage. The uncatalyzed mechanism relies on the enol, a weak to moderate nucleophile with very low concentration, attacking a carbonyl, a weak to moderate electrophile. As a result, this reaction is very (very) slow. When base catalysis is used the amount of nucleophile in solution increases AND the nucleophile switches from being an enol to an enolate, a strong nucleophile. As a result, the base-catalyzed reaction is much faster.

Scheme 2.12 – Generalized Reaction Mechanism for Base-Catalyzed Enol Formation and Subsequent Base-Catalyzed Activation of the Nucleophile.

It is important to recognize that using a very strong base such as LDA is not catalysis; while LDA does generate the enolate (viz. it forms the same activated nucleophile) it is not regenerated at the end of the reaction.