Reactions Knoevenagel

Side Note 13.6. Knoevenagel Synthesis of Conjugated (Mono-) Carboxylic Acids 

2 equiv. pyridine (as a advent), room temp, or gentle heating 

It can be assumed that the small amount of piperidine in the reaction mixture is completely protonated by malonic acid because piperidine is more basic than pyridine. Hence, only the less basic pyridine is available for the formation of the malonic acid enolate D from free malonic acid and for the formation of the malonic acid dianion from the malonic acid mono-carboxylate C. The pKa value of malonic acid with regard to its C,H acidity should be close to the pKa value of malonic acid diethyl ester (p= 13.3). The pKa value of malonic acid monocarboxylate C with regard to its C,H acidity should be larger by at least a factor 10. Hence, the concentration of the malonic acid enolate D in the reaction mixture must be by many orders of magnitude higher than that of any malonic acid dianion. Due to the advantages associated with this enormous concentration D could be the actual nucleophile in Knoevenagel condensations. 

The Knoevenagel reaction has been carried out between aldehydes and acetonitrile in water. Thus, salicylaldehydes react with malononitrile at room temperature in the heterogeneous aqueous alkaline medium to give 

In case of phenylacetonitrile, a catalytic amount of CTABr (0.1 mole/ equiv) is used. The above reaction gives better yields in water compared to in ethanol. 

The Knoevenagel reaction between benzaldehydes and acetonitriles in water has recently been extensively investigated [6a, 14]. 

Salicylaldehydes react with malononitrile in heterogeneous aqueous alkaline medium at room temperature to give a-hydroxybenzylidenemalononi-triles, which are converted directly in high yield to 3-cyanocoumarins by acidification and heating of the reaction mixture [14]  

By using substituted acetonitriles, the addition reaction sometimes requires the presence of catalytic amounts of CTABr (Table 7.2). Comparison with reactions carried out in homogeneous alcoholic medium shows that the aqueous reaction gives better yields [14] (Table 7.2). 

The condensation of benzaldehyde with aryl acetonitriles does not occur in 

The presence of a cationic surfactant is also necessary to achieve a selective condensation between indene and benzaldehyde in water. A catalytic amount of CTACl favors the bis-condensation, while a large excess of surfactant allows the mono-adduct to be isolated quantitatively [6a]. 

Under homogeneous conditions, the reaction proceeds by addition of a carba-nionic species to the carbonyl group, then dehydration. 

In some special cases, the carbonyl function could be previously activated during the process [38]. The rate-controlling step could be either the ionization of the methylene-activated reactant or the addition of the so-formed carbanion to the carbonyl group the dehydration step is nearly always assumed not to be rate-determining [39]. 

Under heterogeneous conditions, the Knoevenagel reaction has been used as a well-adopted test reaction to check the activity of the basic sites of different solids, mainly basic zeolites such as alkali-exchanged zeolites [40] or zeolites containing occluded metal oxides [41]. The basic activity of alkali-containing MCM-41 [42] or binary cesium-lanthanum oxide supported on MCM-41 [43] has, moreover, also been evaluated in the Knoevenagel condensation. 

Kinetic investigations have shown that during heterogeneous catalysis performed with metal oxides the associated acid site (metal cation) can also activate the carbonyl group, leading to cooperative acid-base catalysis. With organic bases attached to a mineral support such an effect would not be so pronounced. 

In this respect, Brunei and co-workers compared grafted AMP-MTS [44] silica-grafted aminopropyl materials (AMPS) [45]. They found that AMP-MTS efficiently catalyzed the reaction of ethyl cyanoacetate and benzaldehyde, that the catalysts could be easily recovered and reused after a simple regeneration step, and that the activity was a simple linear function of catalyst loading within the limits 0.8-1.9 mmol g -the highest loading achievable with these materials. Tertiary amines attached via displacement of a halogen substituent with piperidine were 

Condensation of an aldehyde or ketone with an active methylene compound 

The prototype of a Knoevenagel reaction shown in the scheme above is the condensation of an aldehyde or ketone 1 with a malonic ester 2, to yield an a ,/3-unsaturated carboxylic ester 4. 

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. 

The corresponding anion 5, formed from 2 by deprotonation, subsequently adds to the carbonyl substrate to give the aldol-type intermediate 6. Loss of water from intermediate 6 leads to a primary o ,/3-unsaturated condensation product 3  

Named Organic Reactions, Second Edition T. Laue and A. Plagens 2005 John Wiley Sons, Ltd ISBNs 0-470-01040-1 (HB) 0-470-01041-X (PB) 

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The formation of ethyl isopropylidene cyanoacetate is an example of the Knoevenagel reaction (see Discussion before Section IV,123). With higher ketones a mixture of ammonium acetate and acetic acid is an effective catalyst the water formed is removed by azeotropic distillation with benzene. The essential step in the reaction with aqueous potassium cyanide is the addition of the cyanide ion to the p-end of the ap-double bond ... 

Knoevenagel reaction. The condensation of an aldehyde with an active methylene compound (usually malonic acid or its derivatives) in the presence of a base is generally called the Knoevenagel reaction. Knoevenagel found that condensations between aldehydes and malonic acid are effectively catalysed by ammonia and by primary and secondary amines in alcoholic solution of the organic amines piperidine was regarded as the best catalyst. 

The Doebner condensation (or reaction) is a slight modification of the Knoevenagel reaction and consists in warming a solution of the aldehyde and... 

Examples of the Knoevenagel reaction with aldehydes are given under crotonic acid (111,145), P-n-hexylacrylic acid (111,144), sorbic acid (111,145) and furylacryUc acid (V,10). 

In the above reaction one molecular proportion of sodium ethoxide is employed this is Michael s original method for conducting the reaction, which is reversible and particularly so under these conditions, and in certain circumstances may lead to apparently abnormal results. With smaller amounts of sodium alkoxide (1/5 mol or so the so-called catal3rtic method) or in the presence of secondary amines, the equilibrium is usually more on the side of the adduct, and good yields of adducts are frequently obtained. An example of the Michael addition of the latter type is to be found in the formation of ethyl propane-1 1 3 3 tetracarboxylate (II) from formaldehyde and ethyl malonate in the presence of diethylamine. Ethyl methylene-malonate (I) is formed intermediately by the simple Knoevenagel reaction and this Is followed by the Michael addition. Acid hydrolysis of (II) gives glutaric acid (III). 

Knoevenagel reaction Knorr pyrrole synthesis. Kolbe>Schmitt reaction Leuckart reaction Mannich reaction... 

Phenyl-7-aminocoumarin is obtained by a Knoevenagel reaction of substituted saUcylaldehydes with phenylacetic acid or ben2yl cyanide. Further synthesis of the individual end products is carried out by usual procedures. 

The Knoevenagel reaction is unsatisfactory for the direct preparation of these reaction products. 

Knoevenagel reaction. Addition of the cyanomethyl group has been accom-... 

Knoevenagel reaction is the synthesis of a, p-unsaturated acids by reaction of aldehydes and compounds with active methylene groups in the presence of an organic base... 

The manufacture of alkyl cyanoacrylate monomers, 1, involves the Knoevenagel reaction of formaldehyde, 2, with an alkyl cyanoacetate, 3, and a base, such as a secondary amine, as the catalyst, shown in Eq. 1. 

Literature articles, which report the formation and evaluation of difunctional cyanoacrylate monomers, have been published. The preparation of the difunctional monomers required an alternative synthetic method than the standard Knoevenagel reaction for the monofunctional monomers, because the crosslinked polymer thermally decomposes before it can revert back to the free monomer. The earliest report for the preparation of a difunctional cyanoacrylate monomer involved a reverse Diels-Alder reaction of a dicyanoacrylate precursor [16,17]. Later reports described a transesterification with a dicyanoacrylic acid [18] or their formation from the oxidation of a diphenylselenide precursor, seen in Eq. 3 for the dicyanoacrylate ester of butanediol, 7 [6]. 

Virtually any aldehyde or ketone and any CH-acidic methylene compound can be employed in the Knoevenagel reaction however the reactivity may be limited due to steric effects. Some reactions may lead to unexpected products from side-reactions or from consecutive reactions of the initially formed Knoevenagel product. 

Because of the mild reaction conditions, and its broad applicability, the Knoevenagel reaction is an important method for the synthesis of a ,/3-unsaturated carboxylic acids. Comparable methods are the Reformatsky reaction, the Perkin reaction, as well as the Claisen ester condensation. The Knoevenagel reaction is of greater versatility however the Reformatsky reaction permits the preparation of a ,/3-unsaturated carboxylic acids that are branched in a-position. 

A more recent application of the Knoevenagel reaction is its use in domino reactions. The term domino reaction is used for two or more subsequent transformations, where the next reaction step is based on the functionality generated in the preceding step. Such reactions are also called tandem reactions or cascade reactions. 

Various competitive reactions can reduce the yield of the desired Michael-addition product. An important side-reaction is the 1,2-addition of the enolate to the C=0 double bond (see aldol reaction, Knoevenagel reaction), especially with a ,/3-unsaturated aldehydes, the 1,2-addition product may be formed preferentially, rather than the 1,4-addition product. Generally the 1,2-addition is a kinetically favored and reversible process. At higher temperatures, the thermodynamically favored 1,4-addition products are obtained. 

The aldol-like reaction of an aromatic aldehyde 1 with a carboxylic anhydride 2 is referred to as the Perkin reaction. As with the related Knoevenagel reaction, an o ,/3-unsaturated carboxylic acid is obtained as product the /3-aryl derivatives 3 are also known as cinnamic acids. 

The Knoevenagel reaction is a carbonyl condensation reaction of an ester with an aldehyde or ketone to yield an a,j8-unsaturated product. Show the mechanism of the Knoevenagel reaction of diethyl malonate with benzaldchyde. 

El reaction and, 392 E2 reaction and, 386 S l reaction and, 373-374 Sjxj2 reaction and, 362-363 Kishner, N. L. 715 Knoevenagel reaction, 913 Knowles, William S., 734, 1027 Kodel, structure of, 1222 Koenigs-Knorr reaction, 990 mechanism of, 990 neighboring-group effect in, 990-991... 

With most of these reagents the alcohol is not isolated (only the alkene) if the alcohol has a hydrogen in the proper position. However, in some cases the alcohol is the major product. With suitable reactants, the Knoevenagel reaction, like the aldol (16-2), has been carried out diastereoselectively and enantioselectively. ... 

When the reactant is of the form ZCH2Z, aldehydes react much better than ketones and few successful reactions with ketones have been reported. However, it is possible to get good yields of alkene from the condensation of diethyl malonate, CH2(COOEt)2, with ketones, as well as with aldehydes, if the reaction is run with TiCU and pyridine in THF. In reactions with ZCH2Z, the catalyst is most often a secondary amine (piperidine is the most common), though many other catalysts have been used. When the catalyst is pyridine (to which piperidine may or may not be added) the reaction is known as the Doebner modification of the Knoevenagel reaction. Alkoxides are also common catalysts. 

A number of special applications of the Knoevenagel reaction follow ... 

When aliphatic nitro compounds are used instead of aldehydes or ketones, no reduction occurs, and the reaction is essentially a Knoevenagel reaction, though it is usually also called a Tollens reaction ... 

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