August 22, 2011
Improve a Knoevenagel condensation reaction. Esters such as 5 are effective UV absorbers that are used as light stabilizers in plastic products or as sunscreens in cosmetics. These esters can be prepared by using a Knoevenagel condensation between cyanoacetic esters and carbonyl compounds. Depending on the catalyst, however, the processes require long reaction times and produce unwanted byproducts, or they give low conversions.
J. Huang and co-inventors achieve better results with the same route by using a specific mol ratio of reagents in the presence of ammonium ion and a carboxylic acid. The figure outlines the route used to prepare 5 from cyano ester 3 and benzophenone (4). This sequence also produces amide 6 as a byproduct. Because 6 and 5 have similar boiling points, they cannot be separated by distillation, so the formation of 6 is minimized by controlling the reaction temperature.
The first step of the process is the esterification of alcohol 1 with aqueous cyano carboxylic acid 2 to give 3 with p-toluenesulfonic acid as the catalyst. Water is removed azeotropically under increasing vacuum. The preparation of ≈400 g 3 takes ≈8 h; the product is isolated by vacuum distillation in 92% yield.
The condensation of 3 and 4 is catalyzed by NH4OAc and EtCO2H. The inventors carried out two series of experiments to determine the optimum 3/4 mol ratio and the best amount of NH4OAc to use. The results indicated that the optimum 3/4 mol ratio is 0.7:1.
In the catalyst experiments, they used the methyl ester corresponding to 2-ethylhexyl ester 3. The results showed that increasing the amount of catalyst increases the product yield but decreases the conversion of 4. Using a catalyst/4 mol ratio of 0.4:1, the conversion of 4 is 80.1%; but the yield is only 28.0%. Increasing the mol ratio to 0.6:1 gives a 92.4% yield with a 73.2% conversion of 4. At a mol ratio of 0.85:1, the yield remains at 92.4%, and the conversion is slightly higher at 77.2%.
The inventors’ example for preparing 5 from 3 and 4 uses a catalyst/4 mol ratio of 0.41:1. NH4OAc is added in portions to the reaction mixture. The yield of byproduct amide 6 is minimized by keeping the reaction temperature <100 °C. The water formed in the condensation reaction is removed by azeotropic distillation with EtCO2H and the reaction solvent n-heptane. The temperature is kept at ≈95 °C by reducing the pressure; this maintains the reaction at reflux. The control and maintenance of reaction reflux by this procedure is covered in the patent’s claims. The crude product contains 0.04% of the amide; after distillation, the yield of 5 is 68% with an amide content of 0.38%.
Varying the pressure to maintain reflux and remove water without increasing temperature is an engineering solution that R&D chemists may not always consider. The process improves a known method and gives a high yield of the product with minimal byproducts. (DSM IP Assets B.V. [Heerlen, The Netherlands]. US Patent 7,985,870, July 26, 2011; Keith Turner)