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 SN2 (SN2-b) and frontside SN2 (SN2-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 SN2-b pathway slowly erodes and can even be overruled by the unusual SN2-f substitution mechanism going from strong to weak alcohol nucleophiles. Activation strain analyses disclose that the SN2-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 SN2-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 SN2 pathway.</p

Mapping the effect of configuration and protecting group pattern on glycosyl acceptor reactivity

The reactivity of the acceptor alcohol can have a tremendous influence on the outcome of a glycosylation reaction, both in terms of yield and stereoselectivity. Through a systematic survey of 67 acceptor alcohols in glycosylation reactions with two glucosyl donors we here reveal how the reactivity of a carbohydrate acceptor depends on its configuration and substitution pattern. The study shows how the functional groups flanking the acceptor alcohol influence the reactivity of the alcohol and show that both the nature and relative orientation play an essential role. The empiric acceptor reactivity guidelines revealed here will aid in the rational optimization of glycosylation reactions and be an important tool in the assembly of oligosaccharides