15.19:
Intramolecular Aldol Reaction
Dicarbonyl compounds like dialdehydes, diketones, and keto-aldehydes in the presence of an acid or base, undergo an intramolecular aldol reaction to yield stable five or six-membered cyclic products.
In diketones, the base can deprotonate four of the nucleophilic alpha-carbons to form the corresponding enolates.
In a symmetrical diketone, the enolates derived from carbons 1 and 6 are equivalent, as are those from carbons 3 and 4, resulting in two possible intramolecular attacks.
The nucleophilic attack on carbonyl carbon 5 by carbon 1 and carbonyl carbon 2 by carbon 4 generates cyclic five-membered and three-membered aldol products, respectively. While the strained three-membered aldol product is not formed, the five-membered aldol product dehydrates to give cyclopentenone.
In keto-aldehydes, the two electron-donating alkyl groups connected to the carbonyl carbon make it less electropositive in ketones as compared to aldehydes. Hence, the carbonyl of aldehyde is more electrophilic and attacked by the ketone enolate to form the stable cyclic product.
15.19:
Intramolecular Aldol Reaction
Intramolecular aldol reaction occurs in dicarbonyl compounds such as dialdehydes, diketones, and keto-aldehydes. The dicarbonyl compounds possess more than one nucleophilic ⍺ carbon for the base to deprotonate and form the enolates. For example, in symmetrical diketones, there are four ⍺ carbons. Hence, four types of enolates are possible when treated with a base. However, since the molecule is symmetrical, the enolates formed on either side of one carbonyl group are equivalent to those formed on either side of the other carbonyl. This is shown in figure 1, where the enolate derived from carbon 1 is equivalent to 6, and carbon 3 is equivalent to 4, thereby resulting in two possible distinct intramolecular nucleophilic attacks.
Figure 1. Possible enolates of a symmetrical diketone
As depicted in Figure 2, there are two possible intramolecular nucleophilic attacks. The attack on the carbonyl carbon 5 by the enolate formed at carbon 1 yields a stable five-membered ring. In contrast, the attack on the carbonyl carbon 2 by the enolate formed at carbon 4 generates a three-membered ring. As the three-membered ring is strained, the former intramolecular attack predominates to form a cyclic five-membered aldol product, which then dehydrates to yield the unsaturated cyclic product.
Figure 2. Two possible intramolecular nucleophilic attacks in a diketone molecule
In ketoaldehydes that possess an aldehyde group at one end and a ketone group at the other end, the positive inductive effect of the alkyl groups makes the ketone group less electropositive than the aldehyde. Hence, as shown in Figure 3, the enolates formed beside the ketone carbonyl group attack the aldehyde carbonyl group to form the stable six-membered cyclic product.
Figure 3. The intramolecular attack in a ketoaldehyde molecule