Aldol condensation
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An Aldol condensation is an organic reaction in which an enolate ion reacts with a carbonyl compound to form a β-hydroxyaldehyde or β-hydroxyketone, followed by dehydration to give a conjugated enone.
Aldol condensations are important in organic synthesis, providing a good way to form carbon–carbon bonds. The Robinson annulation reaction sequence features an aldol condensation; the Wieland-Miescher ketone product is an important starting material for many organic syntheses. Aldol condensations are also commonly discussed in university level organic chemistry classes as a good bond-forming reaction that demonstrates important reaction mechanisms.[1][1][1] In its usual form, it involves the nucleophilic addition of a ketone enolate to an aldehyde to form a β-hydroxy ketone, or "aldol" (aldehyde + alcohol), a structural unit found in many naturally occurring molecules and pharmaceuticals.[1][1][1]
The name aldol condensation is also commonly used, especially in biochemistry, to refer to the aldol reaction itself, as catalyzed by aldolases. However, the aldol reaction is not formally a condensation reaction because it does not involve the loss of a small molecule.
The reactions between a ketone and an aldehyde (crossed aldol condensation) or between two aldehydes also go by the name Claisen-Schmidt condensation after two of its pioneering investigators Rainer Ludwig Claisen and J. G. Schmidt who independently published on this topic in 1880 and 1881 [1] [1] [1], for example, the synthesis of dibenzylideneacetone.
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Mechanism
The first part of this reaction is an aldol reaction, the second part a dehydration—an elimination reaction. Dehydration may be accompanied by decarboxylation when an activated carboxyl group is present. The aldol addition product can be dehydrated via two mechanisms; a strong base like potassium t-butoxide, potassium hydroxide or sodium hydride in an enolate mechanism,[1] or in an acid-catalyzed enol mechanism.
Condensation types
It is important to distinguish the Aldol condensation from other addition reactions to carbonyl compounds.
- When the base is an amine and the active hydrogen compound is sufficiently activated the reaction is called a Knoevenagel condensation.
- In a Perkin reaction the aldehyde is aromatic and the enolate generated from an anhydride.
- A Claisen condensation involves two ester compounds.
- A Dieckmann condensation involves two ester groups in the same molecule and yields a cyclic molecule
- A Henry reaction involves an aldehyde and an aliphatic nitro compound.
- A Robinson annulation involves a α,β-unsaturated ketone and a carbonyl group who first engage in a Michael reaction prior to the Aldol condensation
- In the Guerbet reaction an aldehyde, in situ formed from an alcohol, self-condenses to the dimerized alcohol
Aldox process
In industry the Aldox process developed by Royal Dutch Shell and Exxon, converts propylene and syngas directly to 2-Ethylhexanol via hydroformylation to butyraldehyde, aldol condensation to 2-ethylhexenal and finally hydrogenation [1].
In one study crotonaldehyde is directly converted to 2-ethylhexanal in a palladium / Amberlyst / supercritical carbon dioxide system [1]:
Scope
Ethyl 2-methylacetoacetate and campholenic aldehyde react in an Aldol condensation.[1] The synthetic procedure [1] is typical for this type of reactions. In the process in addition to water, an equivalent of ethanol and carbondioxide are lost in decarboxylation.
Ethyl glyoxylate 2 and diethyl 2-methylglutaconate 1 react to isoprenetricarboxylic acid 3 (isoprene skeleton) with sodium ethoxide. This reaction product is very unstable with initial loss of carbon dioxide and followed by many secondary reactions. This is believed to be due to steric strain resulting from the methyl group and the carboxylic group in the cis-dienoid structure.[1]
Occasionally an aldol condensation is buried in a multistep reaction or in catalytic cycle such as the one sketched below:[1]
In this reaction an alkynal 1 is converted into a cycloalkene 7 with a ruthenium catalyst and the actual condensation takes place with intermediate 3 through 5. Support for the reaction mechanism is based on isotope labeling.[1]
The reaction between menthone and anisaldehyde is complicated due to steric shielding of the ketone group. The solution is use of a strong base such as potassium hydroxide and a very polar solvent such as DMSO in the reaction below [1]:
Due to epimerization through a common enolate ion (intermediate A) the reaction product has (R,R) cis configuration and not (R,S) trans as in the starting material. Because it is only the cis isomer that precipitates from solution this product is formed exclusively.
