Enantioconvergent halogenophilic nucleophilic substitution (SN2X) reaction by chiral phase-transfer catalysis

• Main Author: Zhang, Xin
• Other Authors: Tan Choon Hong
• Format: Theses and Dissertations
• Language: English
• Published: 2019
• Subjects: DRNTU::Science::Chemistry
• Online Access: https://hdl.handle.net/10356/103434; http://hdl.handle.net/10220/48077
• Institution: Nanyang Technological University

Bimolecular nucleophilic substitution (SN2) is a well-known textbook reaction and considered carbonophilic as the nucleophile (Nu) attacks the electrophile C-X bond from the ‘backside’ subsequently displacing X. Another form of substitution, that is less known, is the halogenophilic nucleophilic substitution (SN2X) reaction. The SN2X reaction occurs via attack of the ‘front’ X along the direction of the X-C bond, generating carbanion as a new nucleophile and Nu-X as a new electrophile. Their further reaction affords the product. Herein, we have achieved an enantioconvergent SN2X process whereby substitution of tertiary bromide by thiocarboxylate generates tertiary thioester under phase-transfer conditions. Chapter 1 introduces the development of phase-transfer catalysis and nucleophilic substitution reactions. We focus on the discussion of stereoselective SN1, SN2 and SRN1 reactions with different approaches and their inherent deficiencies. Enantioconvergent SN1 reactions through cation intermediates are achieved with chiral Lewis/ Brønsted acid catalysts, and SRN1 reactions through radical intermediates are achieved with chiral transition metal catalysts. SN2 reaction is not suitable for enantioconvergent transformation. Then less known SN2X reaction is introduced and representative examples are discussed. Chapter 2 discusses enantioconvergent SN2X reactions under phase-transfer conditions utilizing tertiary electrophiles, which are still challenging with SN1 and SRN1 approaches. We find brominated cyanoesters and cyanophosphonates are excellent tertiary bromides for SN2X reaction and the product tertiary thioesters were obtained with high enantioselectivities. Chapter 3 discusses the reaction mechanism. Both experimental and computational studies support SN2X mechanism. Computational modelling discloses the S···Br intermolecular halogen bonding between tertiary bromide and thiocarboxylate, which is crucial for the efficient halogenophilic reaction. Chapter 4 lists the experimental procedures and characterization data.