9.6: Intramolecular Aldol Reactions

Intramolecular aldol reaction

Molecules which contain two carbonyl functionalities have the possibility of forming a ring through an intramolecular aldol reaction. The term “Intramolecular” means “within the same molecule.” In this case, it means that the enolate donor and the electrophilic acceptor of an aldol reaction are contained in the same molecule such as dialdehydes, keto aldehydes, or diketones. In these cases, the small distance between the donor and acceptor leads to faster reaction rates for intramolecular condensations making intermolecular condensations (which require two molecules to collide in solution) less favorable. For example, base treatment of a 1,4-diketone such as 2,5-hexanedione yields a cyclopentenone product, and base treatment of a 1,5-diketone such as 2,6-heptanedione yields a cyclohexenone.

The mechanism of intramolecular aldol reactions is similar to that of intermolecular reactions. The only difference is that both the nucleophilic carbonyl anion donor and the electrophilic carbonyl acceptor are now in the same molecule. One complication, however, is that intramolecular aldol reactions might lead to a mixture of products, depending on which enolate ion is formed. For example, 2,5-hexanedione might yield either the five-membered-ring product 3-methyl-2-cyclopentenone or the three-membered-ring product (2-methylcyclopropenyl) ethanone (Figure \(\PageIndex{1}\)). In practice, though, only the cyclopentenone is formed.

The selectivity observed in the intramolecular aldol reaction of 2,5-hexanedione is due to the fact that all steps in the mechanism are reversible, so an equilibrium is reached. Thus, the relatively strain-free cyclopentenone product is considerably more stable than the highly strained cyclopropene alternative. For similar reasons, intramolecular aldol reactions of 1,5-diketones lead only to cyclohexenone products rather than to the more strained acylcyclobutenes.