Beyond Strain Release: Delocalization-Enabled Organic Reactivity

The release of strain
energy is a fundamental driving force for
organic reactions. However, absolute strain energy alone is an insufficient
predictor of reactivity, evidenced by the similar ring strain but
disparate reactivity of cyclopropanes and cyclobutanes. In this work,
we demonstrate that electronic delocalization is a key factor that
operates alongside strain release to boost, or even dominate, reactivity.
This delocalization principle extends across a wide range of molecules
containing three-membered rings such as epoxides, aziridines, and
propellanes and also applies to strain-driven cycloaddition reactions.
Our findings lead to a “rule of thumb” for the accurate
prediction of activation barriers in such systems, which can be easily
applied to reactions involving many of the strained building blocks
commonly encountered in organic synthesis, medicinal chemistry, polymer
science, and bioconjugation. Given the significance of electronic
delocalization in organic chemistry, for example in aromatic π-systems
and hyperconjugation, we anticipate that this concept will serve as
a versatile tool to understand and predict organic reactivity.