ICAT-PACHO · Implementing Cationic Paths in Aliphatic C-H Oxidation

Implementing Cationic Paths in Aliphatic C-H Oxidation

The oxidation of carbon-hydrogen (C–H) bonds in simple organic molecules is a key chemical transformation. This is because many biologically active and pharmaceutical compounds contain oxidized frameworks, and introducing carbon-oxygen (C–O) bonds into these molecules allows for the creation of a wide range of useful products. In recent years, scientists have made great progress in designing catalysts—substances that speed up chemical reactions—that mimic the behavior of natural enzymes, especially a class called oxygenases. These enzymes are particularly good at oxidizing C–H bonds in living organisms. Moreover, the use of environmentally friendly metals (such as manganese or iron) to synthesize these catalysts, making the process more sustainable. Oxygenase enzymes can carry out C–H oxidations through different mechanisms. One common route, called the rebound mechanism, involves replacing a hydrogen atom on the molecule with an oxygen atom. Another possible pathway involves an electron transfer, which creates a positively charged intermediate known as a carbocation. This carbocation can then lose a proton and form a new structure. A particularly useful trick involves the use of cyclopropyl groups—small three-carbon rings. These rings can make nearby C–H bonds more reactive through a process called hyperconjugation, which helps guide the reaction to a specific site on the molecule. Cyclopropyl groups also help stabilize carbocation intermediates, making it possible for reactions to proceed through carbocationic pathways. Until recently, however, there was no direct evidence that these carbocation-based pathways could lead to actual reaction products. In collaboration with Costas group, the fellow studied the oxidation of a cyclopropane substrate called 6-tert-butylspiro[2.5]octane. They discovered for the first time that the reaction produced one major product: a cyclobutane ring (a four-carbon ring), formed through a highly specific rearrangement involving a carbocation. These findings opened the door to designing more selective and efficient oxidation reactions using cyclopropane-containing compounds, with the potential to create new molecules in a greener and more controlled way. The main objectives of the project: 1. Create a wide range of valuable cyclobutane structures representing a major step forward in a key type of C–H bond oxidations. 2. This new method will be applied to more complex molecules, including natural products and medicines. Overall, this project is helping develop cleaner, smarter, and more precise ways to build molecules, paving the way for innovations in medicine, materials, and green chemistry.

Data: CORDIS, © European Union