Base-catalyzed Claisen-Schmidt condensation

Substitution effects have been observed for both the homogeneously and heterogeneously base-catalyzed Claisen-Schmidt condensation of ketones and aldehydes with functional groups substituted in the para-position [5 -12], In this... 

Ba.se Catalyzed. Depending on the nature of the hydrocarbon groups attached to the carbonyl, ketones can either undergo self-condensation, or condense with other activated reagents, in the presence of base. Name reactions which describe these conditions include the aldol reaction, the Darzens-Claisen condensation, the Claisen-Schmidt condensation, and the Michael reaction. 

There are numerous examples of both acid- and base-catalyzed mixed aldol condensations involving aromatic aldehydes. The reaction is sometimes referred to as the Claisen-Schmidt condensation. Scheme 2.2 presents some representative examples. 

Hydrotalcite-derived materials also show good performances in analogous reactions, such as the Claisen-Schmidt condensation of substituted 2-hydroxyacetophe-nones with substituted benzaldehydes, the synthetic route to flavonoids and the condensation of 2,4-dimethoxyacetophenone with p-anisaldehyde to synthesize Vesidryl, a diuretic drug [270]. Another similar class of reactions in which HT-based materials give good results are Knoevenagel condensations [271]. An example is the synthesis of citronitrile, a perfumery compound with a citrus-like odor, which can be prepared by HT-catalyzed condensation of benzylacetone with ethyl cyanoacetate, followed by hydrolysis and decarboxylation (Figure 2.42b) [272]. 

The trivial name of the reaction was applied by Wurtz in 1872, and stems from the trivial name of the dimer resulting from the acid-catalyzed self-reaction of acetaldehyde (equation 1). In time, the term came to be applied to the analogous self-condensation reactions of ketones, the first known example of which was the acid-mediated dimerization of acetone, discovered in 1838. The first use of a base as a catalyst for the aldol reaction was in the reaction of furfural with acetaldehyde or acetone (equation 2). This example also illustrates the first example of a mixed aldol reaction, a process that came to be known as the Claisen-Schmidt condensation. ... 

Aldol addition and condensation reactions involving two different carbonyl compounds are called mixed aldol reactions. To be useful as a method for synthesis there must be some basis for controlling which carbonyl component serves as the electrophile and which acts as the enolate precursor. One of the most general mixed aldol condensations involves the use of aromatic aldehydes with alkyl ketones or aldehydes. There are numerous examples of both acid- and base-catalyzed mixed aldol condensations involving aromatic aldehydes. The reaction is sometimes referred to as the Claisen-Schmidt condensation. Aromatic aldehydes are incapable of enolization and cannot function as the nucleophilic component. Furthermore, dehydration is especially favorable because the resulting enone is conjugated with the aromatic ring. 

Besides the aldol reaction to form y0-hydroxyketone, 1,3-Dipolar Cycloaddition can also form similar molecules. In addition to the Mukaiyama Aldol Reaction, the following are also similar or closely related to the aldol reaction the Claisen-Schmidt Condensation (the aldol reaction between benzaldehyde and an aliphatic aldehyde or ketone in the presence of relatively strong bases to form an o, )0-unsaturated aldehyde or ketone), the Henry Reaction (base-catalyzed addition of nitroalkane to aldehydes or ketones), the Ivanov Reaction (the addition of enediolates or aryl acetic acid to electrophiles, especially carbonyl compounds), the Knoevenagel Reaction (the condensation of aldehydes or ketones with acidic methylene compounds in the presence of amine or ammonia), the Reformatsky Reaction (the condensation of aldehydes or ketones with organozinc derivatives of of-halo-esters), and the Robinson Annulation Reaction (the condensation of ketone cyclohexanone with methyl vinyl ketone or its equivalent to form bicyclic compounds). 

There are many examples of both acid- and base-catalyzed condensation reactions involving aromatic aldehydes. The name Claisen-Schmidt condensation is associated with this type of mixed aldol reaction. Entries 7-10 in Scheme 2.1 are a few of the hundreds of examples of this reaction that have been recorded. 

Figure 2.1. Transition states for base-catalyzed dehydration in Claisen-Schmidt condensations.

Claisen-Schmidt Condensation. The base-catalyzed condensation between an aromatic aldehyde and a ketone to yield an a ,/3-unsaturated ketone and a water molecule is known as the Claisen-Schmidt reaction (49,50). This reaction is mechanistically related to the Knoevenagel condensation, and in many aspects this reaction can be regarded as a particular case of it. 

The reaction of an aldehyde with a ketone employing sodium hydroxide as the base is an example of a mixed aldol condensation reaction, the Claisen-Schmidt reaction. Dibenzalacetone is readily prepared by condensation of acetone with two equivalents of benzaldehyde. The aldehyde carbonyl is more reactive than that of the ketone and therefore reacts rapidly with the anion of the ketone to give a /3-hydroxyketone, which easily undergoes base-catalyzed dehydration. Depending on the relative quantities of the reactants, the reaction can give either mono- or dibenzalacetone. 

Scheme 7.4 presents some representative examples of Claisen-Schmidt reactions. Entries 1 and 2 are typical base-catalyzed condensations at methyl groups. Entry 3 illustrates the use of a cyclic ketone, and reaction occurs at the methylene group, where dehydration is possible. The stereochemistry presumably places the furan ring trans to the carbonyl group for maximum conjugation. Entry 4 shows the use of phthalaldehyde to effect a cyclization. Entry 5 illustrates the preference for condensation at the more-substituted position under acidic conditions. 

Ba(OH)2 is known to cattdyze several base-catalyzed organic reactions in the solid form, Of the reactions, aldol condensation is the most common. In recent years, several organic reactions besides aldol condensation have been found to be effectively catalyzed by Ba(OH)2. These reactions are the Claisen-Schmidt reaction, esterification of acid chlorides, Williamson s ether synthesis, benzil-benzilic acid rearrangement, the synthesis of A -pyrazolines by the reaction of a,/3-unsaturated ketone with PhNHNHz Wittig-Homer reaction, and Michael addition. For these reactions, the Ba(OH)2 catalyst prepared from Ba(0H)2-8H20 by cidcination at 473 K shows the highest activity. 

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