Aldol condensation solvent effects

For the other broad category of reaction conditions, the reaction proceeds under conditions of thermodynamic control. This can result from several factors. Aldol condensations can be effected for many compounds using less than a stoichiometric amount of base. Under these conditions, the aldol reaction is reversible, and the product ratio will be determined by the relative stability of the various possible products. Conditions of thermodynamic control also permit equilibration among all the enolates of the nucleophile. The conditions that permit equilibration include higher reaction temperatures, protic solvents, and the use of less tightly coordinating cations. 

Aldol Condensation of 60 and 61 with Benzaldehyde (eq. [49,50]) Solvent and ligand Effects (6)... 

Aldol Condensation of Zinc Ester Enolates with Benzaldehyde Anil Solvent Effects (Scheme 16) (76)... 

Table 9.6 shows the effect of both the addition time and the polarity of the solvent, as well as the nature of the aldehyde, in the catalytic asymmetric aldol condensation promoted by tributyltin fluoride and a chiral diamine coordinated to tin(n) triflate. 

The compositionMeCo(PR3)4 isreahzed, apart from PMes, with various phosphines. The PPhs complex, however, has a lower coordination number, that is, MeCo(PPh3)3 is found in the solid, but it partially dissociates in solution into MeCo(PPh3)2, reminiscent of the behavior of RhCl(PPh3)3 (see Wilkinson s Catalyst). In protic solvents, this compound decomposes by proton abstraction, releasing methane, and this observation may explain its abihty to effect aldol condensation of certain ketones (acetone and methyl ethyl ketone) in an aprotic solvent (equation 36). 

Asymmetric aldol condensation (6, 410-411 7, 307). Terashima and coworkers have examined the effect of various (S)-amino acids on asymmetric cyclization of the acyclic triketone 1. The course of the cyclization is dependent on the solvent. In ether (R,S)-3 is formed preferentially in water (R,S)-2 is the major product. Several amino acids were found to effect asymmetric cyclization, particularly in the cyclization of 1 to 2. The most interesting result is that addition of (S)-phenylalanine gives (R)-2 in 56% enantiomeric excess and that addition of (S)-histidine gives (S)-2 in 54% enantiomeric excess. As expected (S)-proline exerted an effect, but rather slight. 

The crystalline aluminosilicate-catalyzed aldol condensation of acetophenone to form dypnone has been reported (27). As shown in Table XXIII, hydrogen zeolites were the most effective catalysts for this conversion. Operation at low temperatures in the liquid phase is critical for this reaction, to avoid both coke formation and condensation with aromatic solvents. Catalyst aging was rapid, however. Only transient conversions of acetone to mesitylene were obtained over REX or H-mordenite at 315° owing to rapid intracrystalline self-condensation and coke formation. 

Table 3. Effect of the solvent on the initial rate of the aldol condensation of benzaldehyde with acetone in the liquid phase at 273 K.

The base catalysts must be neutralized and/or washed out during the work-up procedure. The solid-acid Nafion H, on the other hand, can be reused. Table 10-2 shows that the most effective procedure with regard to mass efficiency and E factor can be carried out with catalyst d. Not only solvents and auxiliary materials can be saved, but the catalyst too, is reusable without having a negative effect on the yield. This leads to a further decrease in the E factor. In conclusion, Nafion H seems to be an efficient catalyst for performing aldol condensation to yield chalcone in an environmentally friendly manner, i.e. avoiding the use of water and reducing the amount of solvent. 

A soln. of 2-carbomethoxy-2-cyclohexenone in chloroform added during 25 min to a mixture of startg. p-ketoester and 0.47 eqs. CS2CO3 in the same solvent at room temp., 2.5 h later CS2CO3 removed, and the crude product refluxed with / -TsOH in benzene product. Y 70% (99.5% cis-cis isomer). Solvent effects and reaction mechanisms s. P. Deslongchamps, J.-F. Lavallee, Tetrahedron Letters 29, 5117-8 (1988) 14a-hydroxysteroids by sequential Michael addition-intramolecular aldol condensation s. ibid. 6033-6. 

Interestingly, although Knoevenagel demonstrated the effectiveness of amine bases in promoting aldol-type reactions and though, as noted above, he was particularly interested in pyridine, he overlooked this material s potential application to aldol condensations. It was left to Verley (1899) and Doebner (1900) to introduce successful modifications of the condensation in which pyridine appears to play a number of roles as a solvent, as a base, and assisting in the decarboxylation. 

In the formation of the first synthetic intermediate in Sequence D, the very effective Verley-Doebner modification of the fundamental Knoevenagel condensation is used. This modification uses malonic acid in place of the conventional ester to promote enoUzation. In addition, the heterocyclic amine, pyridine, functions as both the base catalyst and the solvent. A cocatalyst, P-alanine (an amino acid), is also introduced. Mechanistically, the reaction closely resembles the aldol condensation in that in both cases a carbanion is generated by abstraction, by base, of a proton alpha to a carbonyl group. The resulting carbanion is stabilized as an enolate anion (see below). 

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... 

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