Stereoinvertive SN1 Through Neighboring Group Participation

• Published in: Angewandte Chemie Vol. 136; no. 31
• Main Authors: Suresh, Rahul, Orbach, Noam, Marek, Ilan
• Format: Journal Article
• Language: English
• Published: Weinheim Wiley Subscription Services, Inc 29-07-2024
• Subjects: Acceleration; Configurations; inversion; neighboring group; Nucleophiles; nucleophilic substitution; participation; stereochemistry; Substitution reactions
• ISSN: 0044-8249; 1521-3757
• DOI: 10.1002/ange.202407602

Neighboring group participation, the assistance of non‐conjugated electrons to a reaction center, is a fundamental phenomenon in chemistry. In the framework of nucleophilic substitution reactions, neighboring group participation is known to cause rate acceleration, first order kinetics (SN1), and retention of configuration. The latter phenomenon is a result of double inversion: the first one when the neighboring group displaces the leaving group, and the second when a nucleophile substitutes the neighboring group. This powerful control of stereoretention has been widely used in organic synthesis for more than a century. However, neighboring group participation may also lead to inversion of configuration, a phenomenon which is often overlooked. Herein, we review this unique mode of stereoinversion, dividing the relevant reactions into three classes with the aim to introduce a fresh perspective on the different modes of stereoinversion via neighboring group participation as well as the factors that control this stereochemical outcome.
A novel classification for stereoinvertive nucleophilic substitution through neighboring group participation is presented. Three disctinct modes have been identified: Inversion via Rearrangements, Invertive Intermediate‐Retentive Ring‐opening and Retentive Intermediate‐Invertive Substitution. In each instance, we have elucidated the fundamental principles underlying the stereochemistry and provided representative examples to illustrate the concepts.