Organic Chemistry

Beyond strain release: Delocalisation-enabled organic reactivity

Authors

Abstract

The release of strain energy is a fundamental driving force for organic reactions. However, strain release 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 bond delocalisation is a key factor that operates alongside strain release to boost and even dominate reactivity, significantly lowering the energy required for bond-breaking in cyclopropanes and cycloalkynes. Thermodynamic and delocalisation parameters explain the relative reaction rates of molecules containing these functional groups, leading to a ‘rule-of-thumb’ that accurately predicts activation barriers. These principles are demonstrated in the context of the reactions of strained building blocks commonly encountered in organic synthesis, medicinal chemistry, polymer science and bioconjugation. By introducing delocalisation as a means to control reactivity profiles, these findings will transform the use of strain as a design concept in synthesis.

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Content

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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

Supplementary weblinks

supporting information material
Cartesian coordinates and energies of all stationary points. Script to generate all linear regression data