Knoevenagel reaction kinetics

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. 

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. 

Microwave-assisted synthesis is attractive to researchers for many reasons, including speed, yields, and the potential for reduced solvent use. Raman monitoring offers a convenient way to elucidate the chemical mechanism while instantly, continuously monitoring reaction kinetics. This enables rapid, data-driven process optimizations without concerns about safely and accurately sampling out of a microwave vessel stopped mid-reaction. Pivonka and Empheld of AstraZeneca Pharmaceuticals describe the continuous acquisition of Raman spectra of an amine or Knoevenagel coupling reaction in a sealed microwave reaction vessel at elevated temperatures and pressures [134]. 

The rate of the hydrolytic cleavage of Knoevenagel products (retro-Knoevenagel reaction) strongly depends on the pH of the aqueous solution - as well as on cosolvents such as DMSO and additional nucleophiles such as amines. The hydrolysis of these alkenes to CH2XY can be presented by equation (3) at pH < and by equation (4) at pH > Although the kinetics are related to the na-... 

If the ester is replaced by malonate (51), the specific enol equivalent, the condensation works very well. Malonate (51) enoiises completely under the reaction conditions whilst the aldehyde is only slightly enolised and the most electrophilic carbonyl group is still the aldehyde. A mixture of weak acid and weak base is often used as conditions should be as mild as possible to encourage only the fastest reaction (kinetic control). This is known as the Knoevenagel reaction. The product can be hydrolysed and decarboxylated in the usual way to give TM(49). 

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