Kinetics of Resin-Supported Mitsunobu Esterification and Etherification Reactions

Abstract

Solid-phase Mitsunobu reaction is very useful in organic and parallel synthesis. In this work, we optimize the solid-phase Mitsunobu esterification and etherification reactions and investigated their kinetics by single-bead FTIR microspectroscopy method. Thirteen solid-phase Mitsunobu esterification reactions proceeded at rates between 2.5 x 10(-3) and 19 x 10(-3) s(-1), while five etherification reactions at generally slower rates between 3.3 x 10(-3) and 8.9 x 10(-3) s(-1). We discovered that reaction rates, as in solution phase Mitsunobu reactions, linearly correlated to pK(a) values of acids and phenols used in the reaction. By studying side reactions and intermediates, we found that the solid-phase reaction mechanism also bears remarkable similarities to that of solution phase Mitsunobu reaction.