Aldol self-aldolization

An example of an intermolecular aldol type condensation, which works only under acidic catalysis is the Knoevenagel condensation of a sterically hindered aldehyde group in a formyl-porphyrin with a malonic ester (J.-H. Fuhrhop, 1976). Self-condensations of the components do not occur, because the ester groups of malonic esters are not electrophilic enough, and because the porphyrin-carboxaldehyde cannot form enolates. 

The selective intermolecular addition of two different ketones or aldehydes can sometimes be achieved without protection of the enol, because different carbonyl compounds behave differently. For example, attempts to condense acetaldehyde with benzophenone fail. Only self-condensation of acetaldehyde is observed, because the carbonyl group of benzophenone is not sufficiently electrophilic. With acetone instead of benzophenone only fi-hydroxyketones are formed in good yield, if the aldehyde is slowly added to the basic ketone solution. Aldols are not produced. This result can be generalized in the following way aldehydes have more reactive carbonyl groups than ketones, but enolates from ketones have a more nucleophilic carbon atom than enolates from aldehydes (G. Wittig, 1968). 

Difunctional target molecules are generally easily disconnected in a re/ro-Michael type transform. As an example we have chosen a simple symmetrical molecule, namely 4-(4-methoxyphenyl)-2,6-heptanedione. Only p-anisaldehyde and two acetone equivalents are needed as starting materials. The antithesis scheme given helow is self-explanatory. The aldol condensation product must be synthesized first and then be reacted under controlled conditions with a second enolate (e.g. a silyl enolate plus TiCl4 or a lithium enolate), enamine (M. Pfau, 1979), or best with acetoacetic ester anion as acetone equivalents. 

The situation is similar for other ketones Special procedures for aldol addition and self condensation of ketones have been developed but are rarely used... 

The carbon-carbon bond forming potential of the aldol condensation has been extended beyond the self condensations described in this section to cases in which two different carbonyl compounds react m what are called mixed aldol condensations... 

Mixed aldol condensations can be effective only if we limit the number of reaction pos sibilities It would not be useful for example to treat a solution of acetaldehyde and propanal with base A mixture of four aldol addition products forms under these condi tions Two of the products are those of self addition... 

Indeed formaldehyde is so reactive toward nucleophilic addition that it suppresses the self condensation of the other component by reacting rapidly with any enolate present Aromatic aldehydes cannot form enolates and a large number of mixed aldol con densations have been carried out m which an aromatic aldehyde reacts with an enolate... 

In practice this reaction is difficult to carry out with simple aldehydes and ketones because aldol condensation competes with alkylation Furthermore it is not always possi ble to limit the reaction to the introduction of a single alkyl group The most successful alkylation procedures use p diketones as starting materials Because they are relatively acidic p diketones can be converted quantitatively to their enolate ions by weak bases and do not self condense Ideally the alkyl halide should be a methyl or primary alkyl halide... 

Reaction of one mole of acetaldehyde and excess phenol in the presence of a mineral acid catalyst gives l,l-bis(p-hydroxyphenyl)ethane [2081-08-5], acid catalysts, acetaldehyde, and three moles or less of phenol yield soluble resins. Hardenable resins are difficult to produce by alkaline condensation of acetaldehyde and phenol because the acetaldehyde tends to undergo aldol condensation and self-resinification (see Phenolic resins). 

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. 

Examples include acetaldehyde, CH CHO paraldehyde, (CH CHO) glyoxal, OCH—CHO and furfural. The reaction is usually kept on the acid side to minimize aldol formation. Furfural resins, however, are prepared with alkaline catalysts because furfural self-condenses under acid conditions to form a gel. 

Thus, various kmds of bases are effective in inducing the Henry reaction The choice of base and solvent is not crucial to carry out the Henry reaction of simple nitroalkanes v/ith aldehydes, as summarized in Table 3 1 In general, sterically hindered carbonyl or nitro compounds are less reactive not to give the desired ni tro-aldol products in good yield In such cases, self-condensation of the carbonyl compound is a serious side-reaction Several mochfied procedures for the Henry reaction have been developed... 

The bicyclic ketoue shown below does not undergo aldol self-condensation even though it has two a hydrogen atoms. Explain. 

Derivatization of the optically active aldehydes to imines has been used for determination of their enantiomeric excess. Chi et al.3 have examined a series of chiral primary amines as a derivatizing agent in determination of the enantiomeric purity of the a-substituted 8-keto-aldehydes obtained from catalysed Michael additions. The imine proton signals were well resolved even if the reaction was not completed. The best results were obtained when chiral amines with —OMe or —COOMe groups were used [2], The differences in chemical shifts of diastereo-meric imine proton were ca. 0.02-0.08 ppm depending on amine. This method has been also used for identification of isomers of self-aldol condensation of hydrocinnamaldehyde. 

A stereoselective intramolecular aldol reaction of thiazolidinecarboxylate (39) proceeds with retention of configuration to give fused heterocycles (40a,b separable) and (41), the product of a retroaldol-acylation reaction. The selectivity is suggested to be directed by self-induced axial chirality, in which the enolate generated in the reaction has a stereochemical memory, being generated in an axially chiral form (42). The retroaldol step also exemplifies a stereoretentive protonation of an enolate. 

Sodium benzoate has been identified as a mild and efficient catalyst for the tandem Michael-aldol self-condensation of y,5-unsaturated-/3-keto esters, affording conjugated vinylcyclohexenonedicarboxylates, some of which exhibit biological activity against ectoparasites in cattle. 

D-Erythrose undergoes self-aldolization in alkali solution, to form d- / co-L- /3 C6 TO-3-octulopyranose by combination of the 1,2-enediol and aldehyde forms. In weak alkali at 105°, syrupy D-erythrose yields d- /ycero-tetrulose, jS-D-a/tro-L-g/ycero-l-octulofuranose, and a-Ti-gluco-i -g/ycero-3-octulopyranose. At 300° in alkali, the major products from syrupy D-erythrose were 1-5% of butanedione (biacetyl) with smaller proportions of pyrocatechol, 33, 2,5-dimethyl-2,5-cyclohexadiene-l,4-dione (2,5-dimethylbenzoquinone), and 2,5-dimethyl-1,4-benzenediol (2,5-dimethylhydroquinone). It was assumed that D-erythrose is reduced to erythritol by a Cannizzaro type of reaction, followed by dehydration of erythritol to form biacetyl. However, very low proportions (<1%) of biacetyl are formed from erythritol compared with D-erythrose itself. Apparently, some other mechanism predominates in the formation of biacetyl. 

Trost s group reported direct catalytic enantioselective aldol reaction of unmodified ketones using dinuclear Zn complex 21 [Eq. (13.10)]. This reaction is noteworthy because products from linear aliphatic aldehydes were also obtained in reasonable chemical yields and enantioselectivity, in addition to secondary and tertiary alkyl-substituted aldehydes. Primary alkyl-substituted aldehydes are normally problematic substrates for direct aldol reaction because self-aldol condensation of the aldehydes complicates the reaction. Bifunctional Zn catalysis 22 was proposed, in which one Zn atom acts as a Lewis acid to activate an aldehyde and the other Zn-alkoxide acts as a Bronsted base to generate a Zn-enolate. The... 

Figure 1. Kinetic parameters for the selection of antibody-catalyzed aldol and retro-aldol reactions, reflecting the biocatalyst s ability to accept substrates that differ clearly with respect to their molecular geometry. No background reaction was observed for the self-condensation of cyclopentanone. The indicated value for cyclopentanone addition to pentanal was estimated using the published kuncat value of 2.28 X 10 M s for the aldol addition of acetone to an aldehyde. Reproduced with permission of the authors and the American Association for the Advancement of Science.

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). 

II reaction under similar conditions at temperatures between 80 and 100°C and with a four-fold excess of 2-methylpentanal (to compensate for the low solubility), the selectivity for the Aldol II product (80%) was 20% higher in [BMIMJEF NaOH than in the water/NaOH system, both at 100% propanal conversion. The increased selectivity was attributed to the higher solubility of the reactant 2-methylpentanal in the ionic liquid phase than in the water phase. The higher solubility of 2-methylpentanal effectively suppressed the self-aldol condensation in the ionic liquid. 

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... 

The activated Ba(OH)2 was used as a basic catalyst for the Claisen-Schmidt (CS) condensation of a variety of ketones and aromatic aldehydes (288). The reactions were performed in ethanol as solvent at reflux temperature. Excellent yields of the condensation products were obtained (80-100%) within 1 h in a batch reactor. Reaction rates and yields were generally higher than those reported for alkali metal hydroxides as catalysts. Neither the Cannizaro reaction nor self-aldol condensation of the ketone was observed, a result that was attributed to the catalyst s being more nucleophilic than basic. Thus, better selectivity to the condensation product was observed than in homogeneous catalysis under similar conditions. It was found that the reaction takes place on the catalyst surface, and when the reactants were small ketones, the rate-determining step was found to be the surface reaction, whereas with sterically hindered ketones the adsorption process was rate determining. 

Figure 2 shows illustrated mechanism for acetone self-condensation over calcined hydrotalcites, where the enolate ion is formed in a first step followed by two possible kinetic pathways 1) In the first case the subtracted proton is attracted by the basic sites and transferred to the oxygen of the enolate ion to form an enol in equilibrium. 2) In the second case the enolate ion reacts with an acetone molecule in the carbonyl group, to produce the aldol (diacetone alcohol). Finally, the p carbon is deprotonated to form a ternary carbon and then loses an OH group to obtain the final products. 

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