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Aldol Reactions and Aldol-like Reactions

Aldol Reaction / Aldol Condensation

A carbonyl compound that contains an α hydrogen is in equilibrium with its own enol. The interconversion between a carbonyl compound and the corresponding enol or enolate, known as keto-enol tautomerism, may be catalyzed by a base or an acid. Due to its π electron system, the enol can act as a nucleophile, while the carbonyl carbon of the carbonyl compound is electrophilic. As keto-enol tautomerism is an equilibrium reaction, a carbonyl compound always also contains the corresponding enol. Thus, the carbonyl compound's carbonyl carbon may be nucleophilically attacked by the enol. As a result, a new carbon-carbon single bond between the enol's α carbon and the carbonyl compound's carbonyl carbon is formed. The resulting product is a β-hydroxycarbonyl compound, which is called an aldol. Thus, the reaction is known as aldol reaction or aldol addition reaction.

Base-catalyzed aldol reaction.
The name aldol is derived from "aldehyde" and "alcohol". An aldol is a β-hydroxycarbonyl compound.

Aldol reactions may be catalyzed by a base, as well as by an acid. In the base-catalyzed aldol reaction, the catalyst is a base, such as OH or aluminium t-butoxide. The attacking nucleophile is an enolate anion. In contrast, in the acid-catalyzed aldol reaction, only the poorly nucleophilic enol is available. However, protonation of the carbonyl compound's carbonyl oxygen increases the carbonyl carbon's electrophilicity just enough so that it can be nucleophilically attacked by the enol. Nevertheless, aldol reactions proceed more efficiently under basic conditions.

Acid-catalyzed aldol reaction.
Acid- and base-catalyzed aldol reactions yield the same product, namely a β-hydroxycarbonyl compound. Aldol reactions may be carried out with aldehydes, as well as ketones as long as they contain an α hydrogen atom.

Under acidic and basic conditions the aldol may be dehydrated during the course of the reaction. Dehydration can occur relatively easily, since the new double bond is in conjugation with the carbonyl group's double bond. Therefore, if no spontaneous dehydration takes place, it can be easily enforced under normal circumstances. When dehydration takes place, the entire reaction is called aldol condensation. Dehydration proceeds effectively under acidic conditions, as water is a good leaving group. In contrast, under basic conditions, dehydration rarely takes place during the reaction, as the hydroxide anion is not an adequate leaving group.

Acid-catalyzed dehydration.

Since hydroxide is a poor leaving group, dehydration is barely possible under basic conditions. However, when it does occur, it follows an E1cB mechanism, which is a unimolecular elimination with the aldol's conjugated base as an intermediate. First of all, the aldol's α hydrogen (proton) is abstracted by the base yielding the aldol's conjugated base. Subsequently, the carbanion eliminates the poor hydroxide leaving group. An E1cB mechanism is only possible when the leaving group is poor and the leaving group's vicinal hydrogen is relatively acidic, otherwise an E1, or E2, mechanism proceeds much more easily.

Base-catalyzed dehydration.
Summary: β-hydroxycarbonyl compounds and α,β-unsaturated carbonyl compounds are made available by the aldol reaction or aldol condensation. Dehydration is often controlable by the reaction conditions.

Aldol reactions and condensations are equilibrium reactions. Thus, β-hydroxycarbonyl compounds and α,β-unsaturated carbonyl compounds can be converted into the corresponding aldehydes or ketones by being treated with a base. The reaction is classified as retrograde aldol reaction. However, similar to aldol reactions and condensations, the yield depends on the position of the equilibrium. The product's yield in aldol reactions and condensations can be increased by removing the water, or the carbonyl product, from the reaction mixture and, thus, removing it from the equilibrium.

The aldol reaction proceeds much more efficiently in combination with aldehydes rather than with ketones. With aldehydes, the product's equilibrium concentration is higher than that of the starting product. Due to the +I effect of the additional alkyl substituent, the carbonyl carbon's electrophilicity in the case of ketones is lower than that of an aldehyde's carbonyl carbon. Furthermore, a kinetic inhibition, the result of the additional alkyl substituent's steric demand, then takes place. Consequently, the enolate's nucleophilic attack on the carbonyl carbon is hampered.

Equilibrium positions and kinetic inhibition in aldol reactions.

As mentioned above, the aldol reaction's and condensation's yield can be inreased by continually removing the water or carbonyl product from the reaction mixture and, thus, from the equilibrium altogether. As a result, the establishment of equilibrium is prevented and the product is continually formed, as the reaction mixture aspires to achieve equilibrium. In addition, if the carbonyl product is removed from the reaction mixture the retrograde aldol reaction is minimized, as the carbonyl product is separated from the base. Continual separation of the carbonyl product from the base is manageable with the help of a Soxhlet extractor, for one. However, in this case, the base must be insoluble in the reaction solvent.

Aldol reaction is a considerably valuable synthetic pathway, as ...

  • ... it is a method of forming new carbon-carbon bonds, and ...
  • ... the products of aldol reaction may be converted into a variety of subsequent products.

The double bond and the carbonyl group of an α,β-unsaturated carbonyl compound may be separately converted. The carbonyl group, for instance, can be selectively reduced with lithium aluminium hydride (LiAlH4), while sodium tetrahydridoborate (NaBH4) often additionally reduces the double bond, as the double bond is activated by the carbonyl group. The double bond can be selectively hydrogenated with H2/Pd/C.

Examples: Aldol reaction's products as starting products for a variety of syntheses.

Variations of aldol reaction

Many variations of aldol reaction were established. These work on the same principle as aldol reaction does, such as ...

  • ... intramolecular aldol reaction, which yields cyclic compounds.
  • ... crossed aldol condensation, in which two different carbonyl compounds are applied at the same time, resulting in a variety of products.
  • ... Knoevenagel reaction, in which particularly strongly CH-acidic compounds, such as 1,3-dicarbonyl compounds or nitroalkanes, are applied instead of a "simple" enolate.
  • ... Michael reaction, in which the conjugated base (anion) of a CH-acidic compound is added to the β carbon of an α,β-unsaturated carbonyl compound. If the CH-acidic compound is an aldehyde or a ketone, the Michael reaction yields a 1,5-dicarbonyl compound.

Exercise 1

Exercise 2

Exercise 3

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