Beyond Strain Release: Delocalization-Enabled Organic Reactivity

Journal article

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.

Authors: Sterling, AJ; Smith, RC; Anderson, EA; Duarte, F

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: American Chemical Society
• Journal: The Journal of Organic Chemistry
• Volume: 89
• Issue: 14
• Pages: 9979-9989
• Publication date: 2024-07-06
• Acceptance date: 2024-06-21
• DOI: 10.1021/acs.joc.4c00857
• EISSN: 1520-6904
• ISSN: 0022-3263
• Language: English