Modulating Twisted Amide Geometry and Reactivity Through Remote Substituent Effects

The unusual reactivity of twisted amides has long been associated with the degree of amide distortion, though classical bridged bicyclic amides offer limited methods to further modify these parameters. Here, we report that the geometry and reactivity of a single twisted amide scaffold can be significantly modulated through remote substituent effects. Guided by calculated ground state geometries, a library of twisted amide derivatives was efficiently prepared through a divergent synthetic strategy. Kinetic and mechanistic investigations of these amides in the alkylation/halidere-bound ring-opening reaction with alkyl halides show a strong positive correlation between the electron donating ability of the substituent and distortion of the amide bond, leading to rates of nucleophilic substitution spanning nearly 2 orders of magnitude. The rate limiting step of the cascade sequence is found to be dependent on the nature of the substituent, and additional studies highlight the role of solvent polarity and halide ion on reaction pathway and efficiency.

Automated summary

This study demonstrates that the geometry and reactivity of twisted amide scaffolds can be significantly modulated by remote substituent effects. The electron-donating ability of the substituent shows a strong positive correlation with the distortion of the amide bond, impacting the rates of nucleophilic substitution. The nature of the substituent determines the rate-limiting step of the cascade sequence, while solvent polarity and halide ion also play a role in reaction pathway and efficiency.