Kinetic analysis and improvement of the Williamson reaction for the synthesis of poly(ethylene glycol) propionaldehyde

Poly(ethylene glycol) (PEG) propionaldehyde is an important polymer derivative used in protein modification; it is usually synthesized by the Williamson reaction of 3‐chloropropionaldehyde diethyl acetal (CPADA) with PEG alkoxide followed by hydrolysis to deprotect the aldehyde group. However, the side reaction of the Williamson reaction has been a severe drawback leading to a low‐aldehyde‐content product. In this study, we established a kinetic model to depict the competition of the Williamson reaction and its side reaction. Based on a kinetic analysis, experiments were performed to systemically investigate the influence of the process parameters on the yield of PEG aldehyde, including the reaction solvents, reaction temperature, and molar equivalents of CPADA. The best reaction solvent was determined to be dioxane because the conversion of methoxy pol(ethylene glycol) in dioxane was higher than that in other solvents and because dioxane has low toxicity and is easily handled. The reaction temperature was set as the refluxing point of dioxane to effectively convert PEG into its alkoxide. The equivalents of CPADA were optimized to be 15 to obtain a quantitative yield of mPEG propionaldehyde and avoid wasting the reagent. The quantitative yield of mPEG propionaldehyde was achieved under these optimum conditions. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2009