Knoevenagel reaction solvents

The term Knoevenagel reaction however is used also for analogous reactions of aldehydes and ketones with various types of CH-acidic methylene compounds. The reaction belongs to a class of carbonyl reactions, that are related to the aldol reaction. The mechanism is formulated by analogy to the latter. The initial step is the deprotonation of the CH-acidic methylene compound 2. Organic bases like amines can be used for this purpose a catalytic amount of amine usually suffices. A common procedure, that uses pyridine as base as well as solvent, together with a catalytic amount of piperidine, is called the Doebner modification of the Knoevenagel reaction. 

Recently Bogdal [48] observed, using kinetic studies, greater MW rate enhancements when the Knoevenagel reaction of salicylaldehyde with ethyl malonate (vide supra, Scheme 4.15) was performed in toluene than when ethanol was used as the solvent. The calculated rate constants in toluene solution were more than three times higher under MW irradiation than under conventional conditions, whereas the rate constants of the reaction in ethanol were the same, within experimental error, under both heating methods. 

As mentioned earlier, a number of reactions initially observed to show MW rate enhancements compared with conventionally heated reactions at the same temperature, have since, with more careful comparison, been shown to occur at the same rate under the two heating modes. Other reactions, such as Knoevenagel reactions in ethanol solution (vide supra, Schs. 15 and 16), have been shown to have modest rate enhancements, occurring typically 2 or 3 times faster under MW heating than under conventional heating at the same temperature. These rate increases are not surprising considering that solvents superheat by 10 °C or more on MW reflux, particularly as the reaction mixtures were not stirred. 

Microwave activation and solvent-free PTC have been shown to be of prime efficiency for the synthesis of new benzylidene cineole derivatives (UV sunscreens) by the Knoevenagel reaction. When performed classically by use of KOH in ethanol at room temperature for 12 h (Eqs. 43 and 44) the yield was 30%. This was improved to 90-94% within 2-6 min under PTC + MW conditions (Tabs 5.17 and 5.18) [27, 28],... 

An organic base in an ionic liquid was also found to be effective for a Knoevenagel reaction. Glycine was added to the ionic liquid [HMIMjPFs as the base catalyst. The reaction proceeded at room temperature in air without the need for rigorous drying of the ionic liquid. Glycine and the reactants malononitrile and benzaldehyde dissolved readily in the ionic liquid. The product was extracted from the ionic liquid phase with an immiscible co-solvent, toluene 110). 

Ionic liquids are also alternative reaction media considered as green, mostly because of their lack of vapor pressure and the possibility of reuse [68, 69]. Base-catalyzed Knoevenagel reactions have been described in these media [70-73]. The development of task specific ionic liquids in which the solvent and promoter are coupled is a real breakthrough in the field and some of them have been used in the Knoevenagel condensation [74—81]. 

Preliminary data on the reactivity of these materials in a typical Knoevenagel reaction (cyclohexanone and ethyl cyanoacetate) indicates a general trend towards higher activity with increasing water content in the material preparation system. This is complicated by some irregularities in the data from the samples prepared from solvents with roughly comparable water ethanol volume ratios. While many systems have been described where the catalytic activity correlates with changes in textural properties[9], the trends in activity found in this study correlate best with an increase in framework mesopore diameter, and do not follow the... 

Wit tig, Wittig-Homer, and Knoevenagel reactions These reactions can be carried out with A1203 or KF supported on A1203 without solvent, but addition of water catalyzes both Wittig and Wittig-Homer reactions. Under these conditions trimethylsulfonium iodide undergoes reaction to form epoxides (equation I). 

The reaction of diethyl cyanomethylphosphonate in the presence of A1203 with aliphatic or aromatic aldehydes in the absence of solvent results mainly in the product of Knoevenagel reaction (equation II). 

The amorphous silica-supported amine systems show promising selectivity and recyclability for the heterogeneous catalysis of the Knoevenagel reaction (scheme 1). However they also demonstrate distinct limitations on the choice of solvent for the reaction and moderate turnover numbers.3 Materials prepared via grafting of HMS or in-situ preparation of organo-functionalised HMS will hopefully overcome these limitations. 

The catalytic activity of proton sponge in the Knoevenagel reaction has been studied227. It was shown that benzaldehyde, in the presence of 2 mol% of 1, reacts with ethyl cyanoacetate and ethyl acetoacetate (equation 22). The condensation is accelerated in polar solvents (especially in DMSO) and does not occur in the case of diethyl malonate, as its CH-acidity is too low (pK = 13.3). 

Condensations. Alumina promotes the formation of a-hydroxyphosphonate esters from aromatic aldehydes and dialkyl phosphonates, and the adducts are converted to a-aminophosphonate esters on reaction with ammonia. A solvent-free synthesis of a-nitro ketones comprises mixing nitroalkanes, aldehydes, and neutral alumina and oxidizing the adducts with wet, alumina-supported CrOj (15 examples, 68-86%). The Knoevenagel reaction, the Michael addition of nitromethane to gcm-diactivated alkenes, and the formation of iminothiazolines from thioureas and a-halo ketones are readily effected with alumina under microwave irradiation. 

This variation of the Knoevenagel reaction will give somewhat higher yields of product than the preceding method. The reason for the higher yield is the use in this method of toluene as solvent, and the placement of a Dean Stark trap above the flask to remove water from the mixture as it is formed. Removal of water favors the formation of greater quantities of nitroalkene. 

Other applications include the Knoevenagel reaction under microwave irradiation in a solvent-free reaction. With this technique, benzaldehyde reacts in a few minutes with diethyl cyanomethylphosphonate in the presence of carefully controlled amounts of piperidine to give diethyl 1-cyano-... 

The Knoevenagel reaction is strongly solvent-dependent. The first step, the formation of the enolate from the 1,3-dicarbonyl and its addition to the carbonyl (or imine) is facilitated in solvents of high polarity and the second step, 1,2-elimination, is inhibited by protic solvents. Thus, dipolar aprotic solvents such as dimethylformamide are especially useful in Knoevenagel condensations. - ... 

The Knoevenagel reaction is a synthetic method with a broad scope. The educts are simple and cheap, reaction conditions are mild, and a wide variety of solvents can be used. In addition, the Knoevenagel products are reactive compounds and may be employed in sequential transformations (see also Section 1.1.1.4). This is why the Knoevenagel reaction is widely employed, especially in the formation of heterocycles. The most used active methylene in these reactions is malonodinitrile. In many syntheses of natural products, drugs, dyes and other compounds, the condensation of a carbonyl group with an activated methylene compound is found. It is beyond the scope of this review to discuss all examples described in the literature, so only a few recent examples are given in this section. 

The majority of work on organically modified solids as solid bases has been carried out on the simple 3-aminopropyl-derivatised silica. This material is established as an efficient catalyst for the Knoevenagel reaction.136-138 There are several interesting features about this application. One of these is the solvent, a... 

Figure 4.20 Solvent effects in the Knoevenagel reaction using (a) aminopropyl silica and (b) aminopropyl HMS catalysts...

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