Benzaldehyde Claisen-Schmidt reaction

Sadvilkar et al. (1995) have studied condensation of benzaldehydes with acetophenones (Claisen-Schmidt reaction) in an aqueous medium, containing sodium butylmonoglycol sulphate and sodium salts of aromaticsulphonic acids as hydrotropes. A substantial improvement in the rate of reaction was realized, while product recovery was facilitated. 

Reaction between 2 -hydroxyacetophenone and benzaldehyde (Claisen-Schmidt condensation) in the absence of a solvent at 423 K giving 2 -hydroxy chalcones and flavanones has been successfully performed with MgO as a solid base catalyst/581 A conversion of 40 % after 1 h with 67 % selectivity to chalcone was achieved. The influence of the solvent and the effects of a substituent on the aromatic ring were investigated by Amiridis et a//59,6"1 The reaction was carried out on MgO at 433 K. Dimethyl sulfoxide (DMSO) showed a strong promoting effect on the reaction, which was attributed to the ability of this dipolar aprotic solvent to weakly solvate anions and stabilize cations so that both become available for reaction. In this case, a conversion of 2-hydroxyacetophenone of 47 % with a selectivity to flavanone of 78 % was achieved after 30 min in a batch reactor. Further investigations1611 showed that DMSO significantly increases the rate of the subsequent isomerization of the 2 -hydroxychalcone intermediate to flavanone. 

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. 

Many products synthesized by Claisen-Schmidt reactions find applications in the pharmaceutical industry. In particular, chalcones and fiavanones are intermediates in the synthesis of flavonoids. The basic structure of fiavonoids, that is, 2 -hydroxychalcone can be obtained by condensation of substituted 2-hydroxyacetophenone and substituted benzaldehyde at 323 K using basic zeolites as catalysts (46) or Mg-Al mixed oxides (47). 

In the real world of practical organic synthesis, one rarely needs to do a simple aldol condensation between two identical aldehydes or two identical ketones. Far more common is the necessity to do a crossed aldol between two different aldehydes, two different ketones, or an aldehyde and a ketone. As noted earlier, there are difficulties in doing crossed aldol reactions. Suppose, for example, that we want to condense 2-pentanone with benzaldehyde. Benzaldehyde has no a hydrogen, so no enolate can be formed from it. Some version of the Claisen-Schmidt reaction (p. 984) seems feasible. But 2-pentanone can form two enolates, and the first problem to solve is the specific formation of one or the other enolate (Fig. 19.127). 

Figure 9.52 Claisen-Schmidt reaction of benzaldehyde with 2-butanone showing the two possible condensation products 4-phenyl-3-methyl-3-buten-2-one (internal enone) and 1-phenyl-1-penten-3-one (terminal enone), as well as their precursor intermediate ketols.

The Claisen-Schmidt reaction between benzaldehyde and butanone was conducted in NCW over a temperature range of 250-300°C without the addition of added acid or base. A 10-fold molar excess of 2-butanone to benzaldehyde was used in order to minimize the formation of higher adducts. The results at temperature of 250,275, and 300°C are shown in Figs. 9.54, 9.55, and 9.56, respectively. 

The Claisen-Schmidt condensation of 2 -hydroxyacetophenone and different chlorinated benzaldehydes over MgO has been investigated through kinetic and FTIR spectroscopic studies. The results indicate that the position of the chlorine atom on the aromatic ring of the benzaldehyde substantially affects the rate of this reaction. In particular, the rate increases in the following order p-chlorobenzaldehyde < m-chlorobenzaldehyde < o-chlorobenzaldehyde. The difference between the meta and para-substituted benzaldehyde can be attributed to electronic effects due to the difference in the Hammett constants for these two positions. Steric effects were found to be responsible for the higher rate observed with the o-chlorobenzaldehyde. 

Aldol and related condensation reactions such as Knoevenagel and Claisen-Schmidt condensations are also widely used in the fine chemicals and specialty chemicals, e.g. flavors and fragrances, industries. Activated hydrotalcites have been employed as solid bases in many of these syntheses. Pertinent examples include the aldol condensation of acetone and citral [107, 108], the first step in the synthesis of ionones, and the Claisen-Schmidt condensation of substituted 2-hydroxyacetophenones with substituted benzaldehydes [109], the synthetic... 

MgO nanoparticles have proven to be very effective chemical reagents in the Claisen-Schmidt condensation, which is a very valuable C—C bond-formation reaction commonly employed in the pharmaceutical and fine chemical industries [295]. When MgO(lll) nanosheets were employed for the Claisen-Schmidt condensation of benzaldehyde and acetophenone, they were found to exhibit activity superior to other systems, such as AICI3, BE3, POCI3, alumina and other reported nano-crystaUine MgO samples [296]. This development is particularly noteworthy as it represents a potential heterogenization of the Claisen-Schmidt catalytic process, which offers numerous advantages including easier product recovery and catalyst recycling. 

If there are two carbonyl compounds present, then a cross condensation might occur, but usually it is of little synthetic value as there are four possible products. However, if one of the carbonyl compounds lacks an a-hydrogen, then the reaction might prove useful, because this compound cannot form the enol intermediate. An example is the Claisen-Schmidt condensation involving an aromatic aldehyde, e.g. benzaldehyde, with a simple aldehyde or ketone,... 

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]. 

Rates for competing processes such as self-condensation of cyclohexanone and Cannizzaro or Tishchenko reactions of benzaldehyde are negligible compared with the Claisen-Schmidt condensation of aldehyde with ketone. 

The propensity for Claisen-Schmidt condensation to afford bis-adducts [e.g., ( , )-2,6-dibenzylidenecyclohexanone from benzaldehyde and cyclohexanone] virtually exclusively, even in the presence of excess ketone (as mentioned in Section 6.2.3), was the cornerstone of our strategy for the preparation of symmetrical adducts (i.e., those with a two-fold axis through the C=O group as viewed in the plane of the page)." Such condensations occur sequentially, as mono-condensed products tend to be more reactive than the parent cycloalkanones under the reaction conditions, making them transient intermediates prepared for further reaction. 

The Cs+-exchanged zeolites, which are the most basic, have been shown to catalyse the Claisen Schmidt condensation between substituted 2-hydroxy-acetophenones and substituted benzaldehyde to give the 2 -hydroxychalcone structure (Reaction 3).30... 

C liment.. MJ Garcia. H Primo. J Conna. A. Zeolites as catalysts in organic reactions. Claisen-Schmidt condensation of acetophenone with benzaldehyde. Catalysis Letters, 1990 4.85-91. 

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). 

As mentioned earlier, the increase in the in HTW and SCW produces equivalent quantities of and OH and therefore the increase in the observed rate of reaction could also arise from base catalysis. Eckert et al. observed base catalysis in HTW in the Claisen-Schmidt condensation of benzaldehyde and 2-butanone. The product outcome of this reaction under normal aqueous conditions depends upon whether the reaction is acid or base catalysed in acid catalysis a monosubstituted enone is formed whereas the base-catalysed route yields a disubstituted enone as the favoured product (Scheme 3.6). The disubstituted enone was found to be the dominant product for the Claisen-Schmidt condensation in HTW indicating base catalysis as the dominant pathway in HTW. 

Calcined barium hydroxide is an efficient catalyst for a number of base-mediated reactions. Among these, the Claisen-Schmidt condensation of acetophenones with benzaldehydes occurs in times as short as 10 min at room temperature (Eq. 15). The acetophenone enolate (detected by IR spectroscopy) is formed on the catalyst surface, where the reaction with the aldehyde takes place. The higher activity of the ketone enolate is interpreted by the authors as the result of "an increased vibrational state of the lattice", a formulation close to the mechano-chemical explanation. With the help of selective poisoning experiments, it is concluded that the enolate forms via a SET mechanism. 

A variety of condensation reactions have been explored in NCW in order to elucidate the catalytic behavior of this medium. Nolen et al. have reported the results of the Claisen-Schmidt condensation between benzaldehyde and butanone to form a,/3-unsaturated ketones. Due to the asymmetry of the butanone with respect to the carbonyl group, two products are formed (Fig. 9.52). It has been reported that under traditional acidic... 

Obtained by reaction of benzaldehyde with 2,4-diacetyl-resorcinol in ethanol in the presence of concentrated aqneons potassium hydroxide at r.t. (Claisen-Schmidt condensation), for 48 h (34%) [5661] or for 24 h (9%) [5658]. 

Flavanones 25 are often synthesized by Claisen-Schmidt condensation followed by intramolecular Michael addition reaction of the corresponding chalcone derivative. Climent et al. reported a new environment-friendly method to prepare flavanones 25 by the reaction of 5-substituted-2-hydroxyacetophenones and benzaldehydes using hydro-talcites as basic catalysts (Scheme 16) [81]. Substitution over both aromatic rings influenced the reaction coxu-se leading to flavanones 25 in 7-45% of yields in only Ih of reaction time. 

Dilute sodium hydroxide was used as a condensing ent by J. G. Schmidt and the method was applied by Claisen and collaborators to the s3mthesis (Claisen reaction) of aromatic ketonic esters, e.g. benzylidene acetone and di-benzylidene acetone from benzaldehyde and acetone. An alternative method was the use of an aromatic aldehyde or ketone with acetoacetic ester in presence of hydrogen chloride. Benzoylacetic ester, CgHgCO CHe-COOCoHs, was obtained by condensing benzoic and acetic esters in presence of sodium ethoxide, and j8-diketones by condensing ketones and acid esters, e.g. acetyl-acetone CHaCO-CHaCOCHg."... 

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