Periodic Reporting for period 1 - ICAT-PACHO (Implementing Cationic Paths in Aliphatic C-H Oxidation)
Reporting period: 2023-05-01 to 2025-04-30
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.
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.
Over the course of the fellowship, major progress was made in advancing new ways to build useful chemical compounds. One important result was the publication of a scientific article in a top chemistry journal (The Journal of the American Chemical Society) and two in a pre-print open access platform (ChemRxiv). A second article is planned for submission at the end of the fellowship. The published work introduces valuable new strategies for controlling how chemical groups are transferred in the oxidation of C–H bonds within cyclopropane-containing molecules. These reactions led to the formation of novel compounds with good efficiency. This contributes important tools to the expanding field of selective C–H functionalization. As part of the fellowship, the researcher also spent time at the Max Planck Institute (MPI) für Kohlenforschung in Germany, working with Nobel Prize-winning chemist Prof. Benjamin List. There, they developed new ways to guide chemical reactions using small organic molecules as tools, instead of metals or harsh chemicals. This approach, called organocatalysis, was used to transform certain alcohol-based molecules into more complex and valuable structures—again by taking advantage of carbocationic intermediates.
The ICAT-PACHO project went beyond traditional approaches to chemical reactions by exploring a brand-new way to modify certain bonds in organic molecules—specifically, C–H bonds, which are very common but usually hard to change. This breakthrough involved using a unique cationic reaction pathway that had never been applied to these types of bonds before, opening up exciting new possibilities for creating useful chemical structures. From the start, the project focused on sustainability. All reactions were designed to be as environmentally friendly as possible. Instead of relying on rare or toxic metals, the researcher used catalysts made from earth-abundant elements and employed hydrogen peroxide—a green and safe oxidant. Thanks to this approach, valuable chemical products were created efficiently in a single reaction step, reducing both waste and the need for extra processing. The success of these reactions depended on carefully choosing the right catalysts and reaction conditions. This allowed researchers to guide the reaction in a precise way, encouraging the formation of a cationic intermediates. The method was especially effective on molecules containing cyclopropane rings. Because these cyclopropane units can be easily made from common building blocks, the findings from this project—such as the ability to build four-membered carbon rings in a controlled way—offer valuable tools also for other scientists. These results can now inspire and support new directions in chemical research, including the development of cleaner, more efficient ways to build complex molecules for use in medicine, materials, and beyond.