Crossed aldol condensation reaction

Crossed aldol condensation reactions may present a problem because multiple products can be formed. For example, a mixture of carbonyl A and carbonyl B can give two different enolates, each of which can then attack either an A or a B molecule. Therefore, four products are possible (Ag, A + B, B + A, and B2). 

Several NaOH-treated ionic liquids for self- and cross-aldol condensation reactions of propanal provide an interesting example illustrating improved product selectivity in a system in which competing reactions take place (109). In the self-aldol condensation reaction of propanal, 2-methylpent-2-enal is formed. The reaction progresses through an aldol intermediate and produces the unsaturated aldehyde. The NaOH-treated ionic liquid [BDMIM]PF gave the highest product... 

When self-condensation of one of the reactants competes with the desired inter-molecular reaction, such as, 2A C and A + B E, where E is the desired product, it is obvious that the rate of the second reaction is improved by increasing the availability (or solubility) of B in a solvent. The principle has been demonstrated with a cross aldol condensation reaction, as shown in Scheme 17 109). 

Several cross-aldol condensations have been performed with alkaline earth metal oxides, including MgO, as a base catalyst. A general limitation of the cross-aldol condensation reactions is the formation of byproducts via the self-condensation of the carbonyl compounds, resulting in low selectivities for the cross-aldol condensation product. For example, the cross-condensation of heptanal with benzalde-hyde, which leads to jasminaldehyde (a-K-amylcinnamaldehyde), with a violet scent... 

Liquid phase aldol condensation reaction between heptanal and benzaldehyde is studied over two series of oxynitride catalysts aluminium phosphate oxynitrides AlPON and mixed aluminium gallium phosphate oxynitrides AlGaPON , with increasing nitrogen contents (0-14 wt.% for AlPON and 0 - 16 wt. % for AlGaPON ). The main products are jasminaldehyde and 2-pentyl-2-nonenal. Jasminaldehyde is formed via the cross-aldol condensation reaction between heptanal and benzaldehyde and 2-pentyl-2-nonenal is formed via the self-condensation reaction of heptanal. 

Tables 1 and 2 show some examples of self- or cross-aldol condensation reactions followed by dehydration to obtain a,/3-unsaturated carbonyl compounds. Also in Table 1, a review of methyl isobutyl ketone (a saturated ketone) synthesis in the presence of hydrogen is included (10). In Table 2, some examples of fine chemicals obtained by aldol-type reactions are shown.

The coupling of a secondary alcohol 1 with a primary alcohol 2 is achieved by the temporary removal of from each substrate which generates the ketone 3 and aldehyde 4 intermediates. A crossed aldol condensation occurs under the reaction conditions by the enolate derived from ketone 3 undergoing nucleophilic addition... 

Crossed aldol condensations, where both aldehydes (or other suitable carbonyl compounds) have a-H atoms, are not normally of any preparative value as a mixture of four different products can result. Crossed aldol reactions can be of synthetic utility, where one aldehyde has no a-H, however, and can thus act only as a carbanion acceptor. An example is the Claisen-Schmidt condensation of aromatic aldehydes (98) with simple aliphatic aldehydes or (usually methyl) ketones in the presence of 10% aqueous KOH (dehydration always takes place subsequent to the initial carbanion addition under these conditions) ... 

In the crossed aldol condensation between carbonyl partners there are four possible product stereoisomers (eq. [1]). Consequently, there are two stereochemical aspects associated with the reaction The first deals with internal stereochemical control or diastereoselec-tion [A( ) vs. B( )], and the second deals with absolute stereochemi-... 

A possible mechanism for the P-alkylation of secondary alcohols with primary alcohols catalyzed by a 1/base system is illustrated in Scheme 5.28. The first step of the reaction involves oxidation of the primary and secondary alcohols to aldehydes and ketones, accompanied by the transitory generation of a hydrido iridium species. A base-mediated cross-aldol condensation then occurs to give an a,P-unsaturated ketone. Finally, successive transfer hydrogenation of the C=C and C=0 double bonds of the a,P-unsaturated ketone by the hydrido iridium species occurs to give the product. 

The Claisen-Schmidt reaction (Figure 11-17) produces an a,P-unsaturated aldehyde or ketone, the general structure of which is shown in Figure 11-18. The Claisen-Schmidt reaction is a crossed aldol condensation. 

The Knoevenagel condensation is a cross-aldol condensation of a carbonyl compound with an active methylene compound leading to C-C bond formation (Scheme 7). This reaction has wide application in the synthesis of fine chemicals and is classically catalyzed by bases in solution (146,147). 

Recently, cross-aldol condensation of benzaldehyde with n-heptaldehyde to give jasminaldehyde (Scheme 13) has been reported a mesoporous molecular sieve Al-MCM-41 with supported MgO was the catalyst. The reactions were carried out in a stirred autoclave reactor with a molar benzaldehyde/heptanal ratio of 10 at 373-448 K (236). The results show that Al-MCM-41 is catalytically active, and its activity is significantly increased by the deposition of MgO (Table V). Increasing the amount of deposited MgO on Al-MCM-41 decreases the surface area but enhances the catalyst basicity. The basicity is well correlated with the catalytic activity, although the selectivity to jasminaldehyde is not the selectivity is essentially independent of temperature, pressure, time of the reaction, and conversion. 

The cross aldol condensation of citral (Millennium Chemicals, 40 % cis-isomer + 55 % trans-isomer) with acetone (Merck, PA) was carried out at 353 K in N2 atmosphere under autogenous pressure ( 250 kPa) in a batch PARR reactor, using an acetone/citral = 49 (molar ratio) and a catalyst/(citral+acetone) = 1 wt.% ratio. Catalysts were pre-treated ex-situ in flowing N2 at 773 K for 2 h to remove adsorbed water and carbon dioxide and then quickly transferred to the reactor without exposing them to air. Reaction products were analyzed by gas chromatography. Selectivities (Sj, mol of producty /mol of citral reacted) were calculated as (%) = Cj X 100/ TCj where Cj is the concentration of product j. Product yields rjj, mol of product y/mol of citral fed) were calculated as Tfj = SjXat- Thirteen samples of the reaction mixture were extracted and analyzed during the 6-hour reaction. The main reaction product of citral conversion was pseudoionone, PS (cis- and trans- isomers). 

Aldol condensations.1 Under usual conditions, 1 is not useful for crossed-aldol condensation because of predominant self-condensation. However in the presence of pyridine and acetic acid 1 undergoes aldol condensation with aromatic and a,p-unsaturated aldehydes. Yields are moderate to high if the concentration of 1 is kept low (inverse addition). This reaction can be used to obtain all-trans-19,19,19- and 20,20,20-trifluororetinal (2). 

Aldol condensations of enones with a-ketols.2 ZnCl2 promotes the crossed-aldol condensation of enones with protected a-ketols. This reaction has been used for a short synthesis of frontalin (1). 

Triene complexes of rhodium have been prepared by a crossed aldol condensation with acetophenone (211) or by Wittig reactions [Eq. (29)] (212). 

Another example of cross-aldol condensation is the reaction between citral and acetone, which yields pseudoionone, an intermediate in the production of vitamin A. Noda et a/.[56] working at 398 K with a 1 1 molar ratio of reagents and 2 wt % of catalyst, obtained high conversions (98 %) with selectivities to pseudoionone close to 70 % with CaO and an Al-Mg mixed oxide catalyst these pseudoionone yields are greater than those reported for the homogeneous reaction. MgO exhibited poor activity, and under these conditions only 20 % citral conversion was obtained after 4 h in a batch reactor. Nevertheless, Climent et a/./571 working with 16 wt % MgO as a catalyst, a molar ratio of acetone to citral close to 3 and at 333 K, achieved 99 % conversion and 68 % selectivity to pseudoionone after 1 h. 

Fig. 12.18. Hydroxyalkylation of an enamine (—> hydroxy-enamine C), followed by in-situ-dehydration (—> dienamine F) and acidic workup (—> ft,/i-unsatu rated ketone E). Since the enamine A is produced from cyclopentanone, the figure shows the second part of a two-step reaction, which is an alternative to the base-mediated crossed aldol condensation (see Section 13.4.1).

Only one of the aldol condensations of Table 13.7 (top, center) concerns the reaction of a carbonyl compound with itself. In all other reactions of Table 13.7, the ,/i-unsaturated carbonyl compounds are formed by two different carbonyl compounds. Such aldol condensations are referred to as crossed aldol condensations (cf. the discussion of crossed aldol additions in Section 13.3.1). 

Crossed aldol condensations between aliphatic aldehydes on the one hand and benzaldehyde or cinnamic aldehyde or their derivatives on the other also are possible. The reaction components can even be mixed together. The aldol adducts are formed without chemo-... 

Crossed aldol condensations between aliphatic aldehydes on the one hand and benzaldehyde or cinnamic aldehyde or their derivatives on the other also are possible. The reaction components can even be mixed together. The aldol adducts are formed without chemoselectivity, as a mixture of isomers, but their formations are reversible. The Elcb elimination to an a,/3-unsaturated carbonyl compound is fast only if the newly created C=C double bond is conjugated to an aromatic system or to another C=C double bond already present in the substrate. This effect is due to product-development control. All the starting materials thus react in this way via the most reactive aldol adduct. 

When the enolate of one aldehyde (or ketone) adds to the carbonyl group of a different aldehyde or ketone, the result is called a crossed aldol condensation. The compounds used Crossed Aldol in the reaction must be selected carefully, or a mixture of several products will be formed. Condensations Consider the aldol condensation between ethanal (acetaldehyde) and propanal shown below. Either of these reagents can form an enolate ion. Attack by the enolate of ethanal on propanal gives a product different from the one formed by attack of the enolate of propanal on ethanal. Also, self-condensations of ethanal and propanal continue to take place. Depending on the reaction conditions, various proportions of the four possible products result. 

The following two reactions are successful crossed aldol condensations. The aldol products may or may not undergo dehydration, depending on the reaction conditions and the structure of the products. 

The general principles for proposing reaction mechanisms, first introduced in Chapter 4 and summarized in Appendix 3 A, are applied here to a crossed aldol condensation. This example emphasizes a base-catalyzed reaction involving strong nucleophiles. In drawing mechanisms, be careful to draw all the bonds and substituents of each carbon atom involved. Show each step separately, and draw curved arrows to show the movement of electrons from the nucleophile to the electrophile. 

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