Organic Chemistry

Beyond strain release: Delocalisation-enabled organic reactivity

Authors

Abstract

Strain energy has long been recognised as a fundamental driving force for organic reactions. However, the release of strain alone is an insufficient predictor of reactivity, as seen in the equivalent strain energies but disparate reactivity of cyclopropane and cyclobutane. Here we show that electronic delocalisation is a key factor that operates alongside strain release to boost reactivity, significantly lowering the energy required for bond-breaking in cyclopropanes, cycloalkynes and cycloalkenes. Consideration of thermodynamic and delocalisation parameters explains the relative rates of reaction of molecules containing these functional groups, leading to a ‘hierarchy of delocalisation’ and a rule-of-thumb model that accurately predicts activation barriers. The implications of these principles are demonstrated in the context of the reactions of strained building blocks commonly encountered in total synthesis, medicinal chemistry, polymer science and bioconjugation.

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Supplementary material

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Supporting information
Additional analysis discussed in this paper
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Supporting material
Cartesian coordinates and energies of all stationary points. Script to generate all linear regression data