The term aldol condensation is also commonly used, especially in biochemistry, to refer to just the first (addition) stage of the process—the aldol reaction itself—as catalyzed by aldolases. However, the first step is formally an addition reaction rather than a condensation reaction because it does not involve the loss of a small molecule.
This section needs expansion with: actually discuss the dehydration mechanisms, not just present an image of them. You can help by adding to it. (June 2018)
The first part of this reaction is an Aldol reaction, the second part a dehydration—an elimination reaction (Involves removal of a water molecule or an alcohol molecule). 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 deprotonates the product to an enolate, which eliminates via the E1cB mechanism,[9][10] while dehydration in acid proceeds via an E1 reaction mechanism. Depending on the nature of the desired product, the aldol condensation may be carried out under two broad types of conditions: kinetic control or thermodynamic control.[11] Both ketones and aldehydes are suitable for aldol condensation reactions. In the examples below, aldehydes are used.
The mechanism for base-catalyzed aldol condensation can be seen in the image below. A mechanism for aldol condensation in basic conditions, which occurs via enolate intermediates and E1CB elimination.The process begins when a free hydroxide (strong base) strips the highly acidic proton at the alpha carbon of the aldehyde. This deprotonation causes the electrons from the C-H bond to shift and create a new C-C pi bond. The new pi bond then acts as a nucleophile and attacks the remaining aldehyde in the solution, resulting in the formation of a new C-C bond and regeneration of the base catalyst.
In the second part of the reaction, the presence of base leads to elimination of water and formation of a new C-C pi bond. The product is referred to as the aldol condensation product.
The mechanism for acid-catalyzed aldol condensation can be seen in the image below. A mechanism for aldol condensation in acidic conditions, which occurs through enol intermediates and an elimination reaction.
A crossed aldol condensation is a result of two dissimilar carbonyl compounds containing α-hydrogen(s) undergoing aldol condensation. Ordinarily, this leads to four possible products as either carbonyl compound can act as the nucleophile and self-condensation is possible, which makes a synthetically useless mixture. However, this problem can be avoided if one of the compounds does not contain an α-hydrogen, rendering it non-enolizable. In an aldol condensation between an aldehyde and a ketone, the ketone acts as the nucleophile, as its carbonyl carbon does not possess high electrophilic character due to the +I effect and steric hindrance. Usually, the crossed product is the major one. Any traces of the self-aldol product from the aldehyde may be disallowed by first preparing a mixture of a suitable base and the ketone and then adding the aldehyde slowly to the said reaction mixture. Using too concentrated base could lead to a competing Cannizzaro reaction.[12]
Ethyl 2-methylacetoacetate and campholenic aldehyde react in an Aldol condensation.[15] The synthetic procedure[16] is typical for this type of reaction. In the process, in addition to water, an equivalent of ethanol and carbon dioxide are lost in decarboxylation.
The reaction between menthone ((2S,5R)-2-isopropyl-5-methylcyclohexanone) and anisaldehyde (4-methoxybenzaldehyde) is complicated due to steric shielding of the ketone group. This obstacle is overcome by using a strong base such as potassium hydroxide and a very polar solvent such as DMSO in the reaction below:[19]
A Claisen–Schmidt reaction
The product can epimerize by way of a common intermediate—enolateA—to convert between the original (S,R) and the (R,R) epimers. The (R,R) product is insoluble in the reaction solvent whereas the (S,R) is soluble. The precipitation of the (R,R) product drives the epimerization equilibrium reaction to form this as the major product.
^Heathcock, C. H. (1991). Additions to C-X π-Bonds, Part 2. Comprehensive Organic Synthesis. Selectivity, Strategy and Efficiency in Modern Organic Chemistry. Vol. 2. Oxford: Pergamon. pp. 133–179. ISBN0-08-040593-2.
^Ethyl 2-methylacetoacetate (2) is added to a stirred solution of sodium hydride in dioxane. Then campholenic aldehyde (1) is added and the mixture refluxed for 15 h. Then 2N hydrochloric acid is added and the mixture extracted with diethyl ether. The combined organic layers are washed with 2N hydrochloric acid, saturated sodium bicarbonate and brine. The organic phase is dried over anhydrous sodium sulfate and the solvent evaporated under reduced pressure to yield a residue that is purified by vacuum distillation to give 3 (58%).
^Heat is usually added manually through the use of a hot plate, or is already present through the use of an exothermic catalyst reaction, such as when -OCH3 is used as the base.
This drives the second step, by removing water, it allows the reactions equilibrium to continually favor the dehydration mechanism, converting the temporary addition product present to its final condensation product. Otherwise a significant amount of unwanted aldol addition side product would be formed alongside the aldol condensation product.[1]
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