A new method streamlines the design and effectiveness of ligands used in chemical reactions in catalysis and drug delivery.

Researchers at Hokkaido University in Japan have developed a technique called Virtual Ligand-Assisted Optimization, or VLAO, to enhance the design and effectiveness of ligands, which are important molecules used in chemical reactions, especially in catalysis. The study, published in the journal ACS Catalysis, details the new approach that streamlines the complex and time-consuming process of ligand engineering.

Ligands bind to central metal atoms during chemical reactions, influencing how these metals interact with other substances. Properties such as their size, shape, and charge can greatly affect the speed of reactions and the types of products produced. Ligands are used in a wide range of domains, from industrial manufacturing to targeted medical therapies.

Optimizing ligands for a reaction has traditionally been a labor-intensive process. Scientists design ligands based on established measurements, such as the arrangement of electrons and the physical shape of the ligand. However, this approach needs extensive experimentation and often fails to capture complex correlations between a ligand’s property and its performance in a target reaction, making it slow and challenging.

VLAO addresses these issues by analyzing ligands through computer simulations instead of relying solely on physical experiments. Researchers can create virtual models of ligands and assess their properties in a simulated environment. This makes it possible to quickly test different designs so researchers can rapidly identify the properties of a ligand which best catalyzes the desired reaction. This means they can optimize ligands more efficiently, which will improve the outcomes of chemical reactions.

"VLAO enables us to see how well ligands help produce specific products while keeping those products pure," explains Professor Satoshi Maeda of the Institute for Chemical Reaction Design and Discovery (WPI-ICReDD) at Hokkaido University, who led the study. "By adjusting the structure of the ligands, we were able to make big improvements in their performance, even for some that didn’t initially work very well."

The VLAO method has already shown promise in practical applications. The team optimized various types of phosphine ligands and found a highly effective ligand for a specific chemical reaction. This demonstrates that the method can be used to enhance the efficiency of chemical processes.

Transition metal catalysis is a key area where VLAO can have a significant impact. It involves using transition metals, which are elements that can speed up chemical reactions by forming temporary bonds with other molecules, which reduces the energy required for reactions to occur. As the demand for more efficient and selective catalysts continues to grow, VLAO holds the potential to transform this field, as well as pharmaceuticals and materials science.

“Our findings revealed highly effective ligands that surpass those developed through traditional methods,” says the study’s first author, Assistant Professor Wataru Matsuoka of Hokkaido University’s Institute for Chemical Reaction Design and Discovery (WPI-ICReDD). “While finding highly selective ligands remains a challenge, this new approach opens promising opportunities for future advancements.”

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Funding:
This work was supported by the Japan Science and Technology Agency (JST) ERATO (JPMJER1903) and Grant-in-Aid for Early-Career Scientists (JP24K17649); and the Institute for Chemical Reaction Design and Discovery (ICReDD), which was established by the World Premier International Research Initiative (WPI), Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT).