Knoevenagel reaction limitation

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. 

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 benefits of the use of micromembranes for the selective removal of one or more products during reaction have been demonstrated for equdibrium-limited reactions [289]. For example, the performance of hydrophilic ZSM-5 and NaA membranes over multichannel microreactors prepared from electro-discharge micromachining of commercial porous stainless steel plates was studied by Yeung et al. in the Knoevenagel condensation [290,291] and andine oxidation to azoxybenzene [292]. For such kind of reactions, the zeolite micromembrane role consists of the selective removal of water, which indeed yields higher conversions, better product purity, and a reduction in catalyst deactivation in comparison to the traditional packed bed reactor. 

It must be emphasized that the scope and limitations of many of the new Knoevenagel catalysts have not been explored sufficiently. From the practising chemist s point of view the situation is somewhat confusing and the search for the appropriate reaction conditions is still largely a process of trial and error. 

Zeolite catalysts have promise in Knoevenagel and Michael reactions but are not yet widely applied because of the weakly basic character of ion-exchanged zeolites, or the rapid deactivation of over-exchanged zeolites by water and/or CO2. Another limitation of microporous systems is that bulky reactants are involved in many chemical processes. In this context, we note that the mesoporous molecular sieve MCM-41 is a promising candidate for the conversion of large molecules. Na- and Cs-exchanged MCM-41 have been found to be active catalysts in Knoevenagel and Michael reactions. 

Iminium triflates can also undergo nucleophilic addition with a broad spectrum of nucleophiles. For example, the activated amide can react with malonates in a Knoevenagel-t)tpe condensation reaction (96). Other nucleophiles include, but are not limited to, Grignard reagents to form ketones 56 qj. alkylamines, phosphites, amino acids, pyridines, and pyridine oxydes or alcohols to afford lactones via intramolecular cyclization (97). ... 

In addition, measurements of the intrinsic reaction rate (free of external and internal diffusion limitations) were achieved by the strict control of the thickness of SIM shell on SIM/alumina beads. The Hnearity observed between the variation of the MOF layer thickness and the conversion observed for the Knoevenagel condensation demonstrated that the reaction takes place inside the whole MOF layer through the porosity and not just at the external surface. 

PVRs equipped with hydrophilic membranes can be used for any liquid reaction where the water produced limits the equilibrium conversion or acts as an inhibiting agent. For example, PVRs have been studied for the dehydration reaction of butenediol to form tetrahydrofuran (Liu and Li, 2002), the synthesis of methylisobutylketone (Staudt-Bickel and Lichtenthaler, 1996), the Knoevenagel condensation reaction between benzaldehyde and ethyl cyanoacetate or ethyl acetoacetate or diethyl malonate (Zhang et al, 2004). Additional information can be found in reviews by Sanchez Marcano and Tsotsis (2002) and by Van der Bruggen (2010). 

The use of a heterogeneous catalyst not only iaciUtates its reutihzation but also provides certain heat and mass transfer limitations, which are known to modify selectivity and yield. As MSRs offer high spedfic siulaces, the influence of transfer phenomena on the overall reaction can be reduced partially or completely improving the catalytic performance. Some examples reported in the hterature are the Simiki coupling reactions, the Knoevenagel condensation reaction, enzymatic hydrolysis [10], and the esterification reaction [5]. 

Merck described the S5mthesis of PDE4 inhibitor 107 as a potential antiinflammatory drug, the synthesis of which involved a Knoevenagel condensation between aldehyde 105 and benzyl oxadiazole 106 as the key step. The researchers were concerned about the possibility of the formation of olefin isomers in the condensation, due to the similar sterics of the phenyl and ox diazole rings. They found however, that by performing the reaction in isopropanol (in which both the starting aldehyde 105 and product 107 have limited solubility) the initially-formed mixture of olefin isomers equilibrates, and the desired product crystallizes out of the mixture to provide exclusively the desired isomer. 

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