Backside versus Frontside S_N2 Reactions of Alkyl Triflates and Alcohols

Nucleophilic substitution reactions are elementary reactions in organic chemistry that are used in many synthetic routes. By quantum chemical methods, we have investigated the intrinsic competition between the backside S_N2 (S_N2-b) and frontside S_N2 (S_N2-f) pathways using a set of simple alkyl triflates as the electrophile in combination with a systematic series of phenols and partially fluorinated ethanol nucleophiles. It is revealed how and why the well-established mechanistic preference for the S_N2-b pathway slowly erodes and can even be overruled by the unusual S_N2-f substitution mechanism going from strong to weak alcohol nucleophiles. Activation strain analyses disclose that the S_N2-b pathway is favored for strong alcohol nucleophiles because of the well-known intrinsically more efficient approach to the electrophile resulting in a more stabilizing nucleophile-electrophile interaction. In contrast, the preference of weaker alcohol nucleophiles shifts to the S_N2-f pathway, benefiting from a stabilizing hydrogen bond interaction between the incoming alcohol and the leaving group. This hydrogen bond interaction is strengthened by the increased acidity of the weaker alcohol nucleophiles, thereby steering the mechanistic preference toward the frontside S_N2 pathway.