ISSN print edition: 0366-6352 ISSN electronic edition: 1336-9075 Registr. No.: MK SR 9/7 Published monthly

Mitsunobu reaction in limonene

Aoi Tokutake and Hiromasa Goto

Department of Materials Science, Institute of Pure and Applied Sciences, University of Tsukuba, Tsukuba, Japan

E-mail: gotoh@ims.tsukuba.ac.jp

Received: 11 November 2025  Accepted: 16 February 2026

Abstract:

Mitsunobu reaction, which is a condensation of alcohols and carboxylic acids, has been usually carried out in tetrahydrofuran. Mitsunobu reactions are useful for the synthesis of pharmaceuticals, foods, and liquid crystals because of the high efficiency of stereo inversion. However, there are some problems, such as the need for a large amount of organic solvents and the lack of facile removal of highly crystalline phosphine oxide, which is by-products of the Mitsunobu reaction. In this study, limonene obtained from natural fruit was used for the condensation reaction. As a result of the Mitsunobu reaction in limonene, the by-product phosphine oxide could be instantly removed by paper filtration. Further, the Walden inversion by the S_N2 mechanism occurred with a high efficiency of 99%, confirming the stereo inversion of the chiral center. Limonene used as a solvent can be reused. These results could lead to a new approach to chemical reactions, using natural plant oils as solvents. They also suggest that all natural oils can be used as solvents in artificial chemical reactions.

Keywords: Chiral; Optical activity; Limonene; Mitsunobu reaction; Walden inversion

Full paper is available at www.springerlink.com.

DOI: 10.1007/s11696-026-04745-1

Chemical Papers 80 (5) 5731–5738 (2026)