Metal-free alternative: Rethinking coupling methods for more sustainable organic synthesis

Coupling reactions are among the most transformative tools in organic chemistry, enabling the formation of crucial chemical bonds in pharmaceuticals, agrochemicals, and advanced materials. Since their introduction, they have been one of the backbones of modern organic synthesis. However, these methods have long relied on environmentally taxing transition metal catalysts, such as palladium, which are often scarce, costly, and generate unwanted byproducts.

The limitations of conventional coupling methods have prompted researchers to seek alternative strategies that better align with the principles of green and sustainable chemistry (GSC). Such alternatives aim to minimize waste, reduce reliance on rare metals, and lower energy consumption, all while maintaining high efficiency and selectivity. Addressing these challenges is essential for the development of more sustainable industrial and pharmaceutical synthesis methods.

Now, a research team, led by Professor Toshifumi Dohi from the College of Pharmaceutical Sciences, Ritsumeikan University, and Professor Yasuyuki Kita, Visiting Senior Researcher at the Research Organization of Science and Technology, Ritsumeikan University, has provided a comprehensive overview of recent advancements in transition metal-free coupling methods. Their review article published in the journal Chemical Reviews on March 26, 2025, highlights emerging strategies that enable the activation of aryl-iodide bonds under environmentally benign conditions.

The review particularly emphasizes coupling via the hypervalent iodine strategy, a field in which the authors have been leading contributors for decades. Other members of the team included Dr. Elghareeb Elshahat Elboray, Dr. Kotaro Kikushima, and Dr. Koji Morimoto, all from Ritsumeikan University.

The hypervalent iodine approach leverages the unique properties of diaryliodonium salts, which serve as highly reactive intermediates in coupling reactions. By strategically manipulating the oxidation state of iodine atoms, researchers have been able to generate aryl cation-like species, radicals, and aryne precursors that facilitate selective bond formation. This transition metal-free approach reduces reliance on costly catalysts while also enhancing the atom economy of coupling processes.

“Our study presents hypervalency strategy, an innovative next-generation approach for coupling which better aligns with GSC requirements, intended for use in the synthesis of pharmaceuticals, related molecules, and functional organic compounds,” remarks Prof. Dohi.

One of the key advantages of hypervalent iodine-mediated coupling is its broad substrate scope, which allows for the efficient synthesis of diverse molecular architectures. The method also exhibits high functional group tolerance, making it particularly attractive for applications in medicinal chemistry. Additionally, researchers have devised various strategies to recycle the aryl iodide byproducts generated in these reactions, addressing previous concerns about waste and enhancing the overall atom efficiency.

Beyond hypervalent iodine strategies, the review also discusses alternative transition metal-free activation methods, including base-promoted aryl–iodide dissociation, photoinduced activation, electrochemical activation, and electrophotochemical activation. Each of these approaches offers unique benefits, such as reducing energy consumption, utilizing mild reaction conditions, or eliminating the need for certain hazardous reagents. By compiling and analyzing recent advances, the authors wish to guide and inspire further research in this area.

“We hope that this review will be of interest to researchers aiming to develop new methods of solving the problems associated with this field of chemistry,” says Prof. Kita.

With the growing need for greener and more efficient chemical synthesis methods, the strategies outlined in this review have the potential to reshape the future of organic chemistry. By reducing environmental impact and lowering production costs, these methods may play a critical role in the long-term development of pharmaceuticals and other fine chemicals. As the field continues to evolve, the present contributions will hopefully serve as a foundation for future breakthroughs in sustainable chemistry.