A team at the University of Vienna, led by chemist Nuno Maulide, has developed a groundbreaking method for controlling chemical reactions in a more targeted and efficient manner. At the heart of this is the concept of 'cation sampling': specially selected groups (ketones), in a sense, function as molecular signposts for randomly migrating positive charges, enabling reactions to take place at sites on a molecule that were previously difficult to access. The method allows carbon-hydrogen bonds (C–H bonds) to be specifically modified. The study was published in the prestigious Journal of the American Chemical Society.
Organic molecules form the basis of almost all biological processes. They consist mainly of carbon and hydrogen – and hydrogen atoms in particular are very common in such molecules. "If you want to alter the properties of a molecule, you often have to specifically replace individual hydrogen atoms," explains Philipp Spieß, a former PhD student in the Maulide group and one of the study’s lead authors.
The precise modification of C–H bonds is therefore considered one of the key challenges of modern synthetic chemistry. It plays an important role in the development of new drugs, functional materials and more efficient chemical processes.
Scanning of positive charges enables precise control
"Imagine a molecule as a string of beads: the first few beads are easy to count, but the further back you go, the harder it becomes," says Miloš Vavrík, a PhD student in the Maulide group and co-first author of the paper. "It’s similar with atoms along a molecular chain: nearby positions are easy to reach, distant ones much harder."
This is precisely where the new method comes in. It uses positive charges that randomly travel along the molecular chain. "The undirected charges are scanned by a specific functional group contained in the molecule and are selected with high precision," explains Nuno Maulide. "This means that our method intervenes precisely at the moment the desired position is reached." This enables reactions at sites that were previously accessible only with great effort, or not at all.
More efficient and sustainable synthetic chemistry
"Our work shows that cations do not simply behave in an uncontrolled manner, but can be specifically controlled," says Maulide. What is particularly remarkable is that the researchers can determine where on the molecule the reaction takes place –by simply controlling the reaction temperature.
"To stick with the image of the string of beads: we can specifically choose which bead is altered," says Maulide. This opens up new possibilities for the production of complex molecules, ranging from active pharmaceutical ingredients to functional materials.
The method also does not require complex transition-metal catalysts, which are often needed in comparable processes. In the long term, this could help make chemical syntheses more efficient and sustainable.
A new method with enormous potential
The results presented stem directly from Maulide’s C-HANCE research project, which has been awarded an ERC Advanced Grant by the EU (the first Advanced Grant in the field of chemistry for the University of Vienna).
"The method is still in its infancy," says Maulide. "But it opens up a new way of precisely controlling chemical reactions using migrating charges. There is enormous potential in this."
Summary:
- The precise modification of carbon-hydrogen bonds is one of the key challenges facing modern synthetic chemistry.
- In the new method, positive charges move along the carbon chain of the molecule, are scanned and intercepted at the desired position, ultimately enabling targeted intervention.
- This makes it possible to carry out reactions at sites that were previously accessible only with great difficulty, or not at all.
- In the long term, this will make synthetic chemistry more efficient and sustainable.
- Synthetic chemistry plays a vital role in the development of new medicines and functional materials.
About the University of Vienna:
At the University of Vienna, curiosity has been the core principle of academic life for more than 650 years. For over 650 years the University of Vienna has stood for education, research and innovation. Today, it is ranked among the top 100 and thus the top four per cent of all universities worldwide and is globally connected. With degree programmes covering over 180 disciplines, and more than 10,000 employees we are one of the largest academic institutions in Europe. Here, people from a broad spectrum of disciplines come together to carry out research at the highest level and develop solutions for current and future challenges. Its students and graduates develop reflected and sustainable solutions to complex challenges using innovative spirit and curiosity.
Original publication:
Cation sampling enables regiodivergent distal functionalization of ketones
Philipp Spieß, Milos Vavrík, Jakob Frey, Uroš Vezonik, Daniel Kaiser und Nuno Maulide. In Journal of the American Chemical Society 2026.
DOI: 10.1021/jacs6c05299
