Solvent effects aldol reactions

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. 

Asymmetric reactions using chiral copper Lewis acids are also performed in aqueous media. It has been reported that an asymmetric Diels-Alder reaction proceeds smoothly in water using Cu(OTf)2 and abrine as a chiral ligand (Scheme 49).214 The Cu -bis(oxazoline) system is effective in asymmetric aldol reactions in an aqueous solvent such as water/ethanol and even in pure water.215... 

On the other hand, Ln(OTf)3 compounds, which were found to be effective catalysts for the hydroxy-methylation in aqueous media, also activate aldehydes other than formaldehyde in aldol reactions with silyl enol ethers in aqueous solvents.1121 One feature of the present reactions is that water-soluble... 

Arnett and coworkers later examined the reaction of lithium pinacolone enoiate with substituted benzaldehydes in THE at 25 °C. The determination of the heat of reaction indicated that the Hammett p value for the process is 331. Although the aldol reaction was instantaneous in THF at 25 °C, the reaction with o- or p-methylbenzaldehyde could be followed using a rapid injection NMR method in methylcyclohexane solvent at —80 °C. Application of Eberson s criterion based on the Marcus equation, which relates the free energy of ET determined electrochemically and the free energy of activation determined by kinetics, revealed that the barriers for the ET mechanism should be unacceptably high. They concluded that the reaction proceeds via the polar mechanism . Consistent with the polar mechanism, cyclizable probe experiments were negative . The mechanistic discrepancy between the reactions of benzaldehyde and benzophenone was later solved by carbon kinetic isotope effect study vide infraf. ... 

The Kotsuki group investigated the effect of high-pressure conditions on the direct proline-catalyzed aldol reaction [79a], a process which, interestingly, does not require use of DMSO as co-solvent. Use of high-pressure conditions led to suppression of the formation of undesired dehydrated by-product and enhancement of the yield. Study of the substrate range with a range of aldehydes and ketones revealed that enantioselectivity was usually comparable with that obtained from experiments at atmospheric pressure. Additionally, proline catalyzed aldol reactions in ionic liquids, preferably l-butyl-3-methylimidazolium hexafluorophosphate, have been successfully carried out [79b,c]. 

Aldol reactions.2 This combination of catalysts is effective for promoting reaction of acetals with silyl enol ethers and ketene silyl acetals. It can also promote reaction of aldehydes or imines with ketene silyl acetals. The reactions occur in high yield at 25° either CH3CN or THF can be used as the solvent. 

Aldol reactions using catalyst 12 were also performed with water without any organic solvent (Table 2.9) [15]. In these examples, it is assumed that the reaction occurred in the organic phase composed of reactants and the catalyst separated from the water phase. A large excess of ketone was used in these reactions. Catalysts possessing a tert-butyldimethylsilyl (TBS) or a triisopropylsilyl (TIPS) group instead of the tert-butyldiphenylsilyl (TBDPS) group on 12 also effectively catalyzed the reaction with water, but hydroxyproline 2 did not catalyze the reaction under the same conditions this indicated that the hydrophobic substituents of... 

TABLE 13.2. Effect of solvents on LASC-catalysed aldol reaction. 

Simple, clear-cut examples of aldol reactions exhibiting such solvent effects are scarce. Heathcock et al. [526] have reported that the erythro threo equilibration of lithium aldolates via retro-aldol reaction) is much faster in pentane than in tetrahy-drofuran or diethyl ether. 

In an effort to understand the role of nomicotine in catalyzing aqueous aldol reactions, Noodleman and Janda examined the aldol reaction of acetaldehyde and acetone in an organic solvent (THF, tetrahydrofuran) and water. The calculations were performed at B3LYP/6-311-l-G(2d,2p)//B3LYP/6-311(d,p) and were corrected for ZPVE at HF/3-21G and the effects of solvent using the COSMO model at B3LYP/6-311(d,p). 

The importance of aqueous reactions is now generally recognized, and development of carbon-carbon bond-forming reactions that can be performed in aqueous media is now one of the most challenging topics in organic synthesis [59]. It has been found that Sc(OTf)3 was effective in aldol reactions of silyl enolates with aldehydes in aqueous media (water-THF Eq. 16) [4]. Reaction between aromatic and aliphatic aldehydes such as benzaldehyde and 3-phenylpropionaldehyde and silyl enolates have been performed successfully in aqueous solvents. In addition, direct treatment of aqueous solutions of water-soluble formaldehyde and chloroacetaldehyde with silyl enolates affords the corresponding aldol adducts in good yields. Water-sensitive silyl enolates could be used in aqueous solutions with Sc(OTf)3 as catalyst. 

For example, an effective procedure for the synthesis of LLB (where LL = lanthanum and lithium) is treatment of LaCls 7H2O with 2.7 mol equiv. BINOL dilithium salt, and NaO-t-Bu (0.3 mol equiv.) in THF at 50 °C for 50 h. Another efficient procedure for the preparation of LLB starts from La(0-/-Pr)3 [54], the exposure of which to 3 mol equiv. BINOL in THF is followed by addition of butyllithium (3 mol equiv.) at 0 C. It is worthy of note that heterobimetallic asymmetric complexes which include LLB are stable in organic solvents such as THF, CH2CI2 and toluene which contain small amounts of water, and are also insensitive to oxygen. These heterobimetallic complexes can, by choice of suitable rare earth and alkali metals, be used to promote a variety of efficient asymmetric reactions, for example nitroaldol, aldol, Michael, nitro-Mannich-type, hydrophosphonylation, hydrophosphination, protonation and Diels-Alder reactions. A catalytic asymmetric nitroaldol reaction, a direct catalytic asymmetric aldol reaction, and a catalytic asymmetric nitro-Mannich-type reaction are discussed in detail below. 

Solvent Effect on Montmorillonite-Catalyzed Aldol Reaction... 

Aldol reactions. Self-condensation of aldehydes as well as Robinson annulation are effected. The latter process is conducted in the presence of molecular sieves 4A in aprotic solvents such as toluene. 

It was also found that 5a worked well in water rather than in organic solvents. The effect of solvents on the aldol reaction is shown in Table 14-9. While the reaction proceeded smoothly in water, it is very slow in organic solvents. 

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