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

• Published in: Chemistry : a European journal Vol. 28; no. 37; pp. e202200932 - n/a
• Main Authors: Kitamura, Hiroshi, Otake, Yuma, Sugisawa, Naoto, Sugisawa, Hiroki, Ida, Tomonori, Nakamura, Hiroyuki, Fuse, Shinichiro
• Format: Journal Article
• Language: English
• Published: WEINHEIM Wiley 01.07.2022; Wiley Subscription Services, Inc
• Subjects: Alcohols; Berry pseudorotation; Chemistry; Chemistry, Multidisciplinary; Chlorides; continuous flow; Density functional theory; Imidazole; nucleophilic substitution; Phosphorus; phosphotriester; Physical Sciences; Reactors; Science & Technology; Selectivity; Substitution reactions; ORGANOPHOSPHORUS FLAME RETARDANTS; continuous flow; ACTIVATION; phosphotriester; FLASH CHEMISTRY; Berry pseudorotation; BASICITY; PHOSPHONATES; nucleophilic substitution; PHOSPHATES; ACETONITRILE; DERIVATIVES; TECHNOLOGY; PLASTICIZERS; phosphorus
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.202200932

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. 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.