5.10: Intramolecular Aldol Reactions
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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.
In most cases multiple sets of α-hydrogens need to be considered when determining the donor/acceptor roles for the reaction, which might lead to a mixture of products. The intramolecular aldol reaction of a 1,5-diketone, 2,6-heptanedione, could possibly yield either the six-membered ring product, 3-methyl-2-cyclohexenone, or the four-membered ring product, (2-methylcyclobutenyl)ethanone. However, the cyclohexanone product is exclusively formed.
This product selectivity is possible due to all of the steps of the mechanism being reversibly, which tends to produce the most stable product. As with most ring forming reactions, five and six membered rings are preferred due to their relative lack of ring strain compared to other sized rings (See Sections 4.4 & 4.5). Once equilibrium is reached, the relatively strain free and therefore more thermodynamically stable, cyclohexanone product will be preferably formed.
Example
Similar analysis can be used to predict the products of other intramolecular aldol reactions. In a similar reaction, 1,4-diketones, such as 2,5-hexanedione, only form the five-membered ring product, ex. 3-methyl-2-cyclopentenone, without any of the possible cyclopropane product forming.
Example
Please draw the expected product of an intramolecular aldol condensation with the following molecule:
- Answer
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Analysis: 6-Oxoheptanal has three unique sets of alpha-hydrogens which could be deprotonated to form an enolate. Selecting the correct set involves analyzing the carbonyl reactivity’s along with the possible ring sizes of the products.
Solution: Once the preferred alpha-hydrogens are determined go through the steps discussed in the previous sections to determine the aldol condensation product. Remember to form the aldol intermediate first.
