Sequential Nucleophilic Substitution of Phosphorus Trichloride with Alcohols in a Continuous‐Flow Reactor and Consideration of a Mechanism for Reduced Over‐reaction through the Addition of Imidazole. Issue 37 (26th May 2022)

• Record Type: Journal Article
• Authors: Kitamura, Hiroshi; Otake, Yuma; Sugisawa, Naoto; Sugisawa, Hiroki; Ida, Tomonori; Nakamura, Hiroyuki; Fuse, Shinichiro
• Is Part Of: Chemistry. Volume 28:Issue 37(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-05-26
• Subjects: Berry pseudorotation -- continuous flow -- nucleophilic substitution -- phosphorus -- phosphotriester; Chemistry -- Periodicals; 540
• DOI: 10.1002/chem.202200932
• Languages: English
• ISSNs: 0947-6539

Abstract

Abstract: We demonstrate a sequential nucleophilic substitution of highly electrophilic and inexpensive phosphorus trichloride with three different alcohols in a continuous‐flow reactor. A variety of alcohols including ones that contained acid‐ and/or basic‐labile functionalities were rapidly reacted. A over nucleophilic substitution that occurred during reaction of the second alcohol was suppressed by the addition of imidazole. Density functional theory calculations of the sequential nucleophilic substitutions of alcohols were performed both with and without imidazole, and Berry pseudorotation was suggested as a rate‐limiting step in both cases. Herein, we discuss the reasons for the decreased selectivity in the absence of imidazole as well as those for improved selectivity in the presence of imidazole during the second nucleophilic substitution. Abstract : Micro‐flow technology enables a sequential nucleophilic substitution of highly electrophilic and inexpensive phosphorus trichloride with three different alcohols including ones that contain acid‐ and/or basic‐labile functionalities, and various asymmetric phosphotriesters were synthesized in good‐to‐high yields (53–83 %). Mechanistic study suggested that Berry pseudorotation was a rate‐limiting step in the nucleophilic substitution of phosphorus trichloride with alcohol.