To overcome solubility problems in organic chemistry



Scientists at Hokkaido University have developed a fast and efficient protocol for cross-coupling reactions, greatly expanding the pool of chemicals that can be used for the synthesis of useful organic compounds.

One of the compounds synthesized in this study, 3u, is strongly photoluminescent in solution (Tamae Seo, et al. Journal of the American Chemical Society, March 30, 2021).

Chemical reactions are a vital process in the synthesis of products for various purposes. For the most part, these reactions are carried out in the liquid phase, by dissolving the reagents in a solvent. However, there are a large number of chemicals which are partially or totally insoluble and therefore have not been used for synthesis. The starting materials required for the synthesis of many advanced organic materials, such as organic semiconductors and luminescent materials, are often poorly soluble, which poses problems in solution-based synthesis. Therefore, the development of a synthetic solvent-independent approach to overcome these long-standing solubility issues in organic synthesis is strongly desired to synthesize valuable new organic molecules.

In recent years, synthetic techniques using ball milling have been used to perform solid phase solvent-free reactions. It has been proposed that the use of ball milling would potentially solve the aforementioned solubility problems in synthetic chemistry, but a systematic study for this purpose has never been carried out.

A team of four scientists from the Institute for Chemical Reaction Design and Discovery (WPI-ICReDD) at Hokkaido University, led by Associate Professor Koji Kubota and Professor Hajime Ito, developed a rapid, efficient, and painless protocol. solvent for the cross coupling Suzuki – Miyaura reaction of insoluble aryl halides. The protocol was published in the Journal of the American Chemical Society.

Aryl halides are popular raw materials for the synthesis of functional organic molecules, primarily through the palladium-catalyzed Suzuki-Miyaura cross-coupling reaction – for which Professor Emeritus Akira Suzuki of Hokkaido University shared the prize. Nobel Prize in Chemistry 2010. Although cross-coupling reactions have been used for the synthesis of a wide range of interesting molecules, insoluble aryl halides are not suitable substrates because Suzuki-Miyaura cross-coupling reactions have been carried out mainly in solution.

Insoluble reagents are hardly reactive in solution, but can react in solvent-free systems using ball milling to cause solid state chemical reactions (Tamae Seo, et al. Journal of the American Chemical Society, March 30, 2021 ).

In view of this limitation, scientists focused on developing an efficient solid state Suzuki-Miyaura cross-coupling of a number of highly unreactive insoluble aryl halides. The key equipment consisted of a ball mill, to mix the reagents; a heat gun, to increase the temperature at which the reactions took place; and the use of a catalyst system composed of palladium acetate (the catalyst), SPhos (a high performance ligand for Suzuki-Miyaura cross-coupling reactions) and 1,5-cyclooctadiene (dispersant and stabilizer).

When the violet pigment 23, one of the predominantly insoluble aryl halides, was subjected to the reaction with an aryl boron nucleophile at 120 ° C in a ball mill in the presence of the palladium-based catalyst system, it was subjected to the reaction with an aryl boron nucleophile at 120 ° C in a ball mill in the presence of the palladium-based catalyst system. converted to a 3u product which was strongly photoluminescent when dissolved in dichloromethane (Tamae Seo, et al. Journal of the American Chemical Society. March 30, 2021).

The cornerstone of this study was the application of the solvent-free solid state reaction to predominantly insoluble aryl halides. These reagents gave no product in conventional solution-based reactions. Solid state reactions using high temperature ball milling, however, gave the desired products. Importantly, the team discovered a new, high photoluminescence material prepared from insoluble pigment violet 23.

“The high temperature ball milling technique and our catalytic system are essential for these insoluble aryl halide cross-coupling reactions, and the protocol we have developed expands the diversity of organic molecules derived from insoluble starting materials.” , explains Koji Kubota.

Hajime Ito (left), Tamae Seo (center) and Koji Kubota (right), authors of this study (Photo: Koji Kubota).

Original article:

Tamae Seo et al. Solving Solubility Problems in Organic Synthesis: Solid State Cross-coupling of Insoluble Aryl Halides. Journal of the American Chemical Society. March 30, 2021.

DOI: 10.1021 / jacs.1c00906


This work was supported by the KAKENHI Grants from the Japan Society for the Promotion of Science (JSPS) (18H03907, 17H06370, 19K15547, 20H04795), the Japan Science and Technology Agency (JST) via a CREST grant ( Core Research for Evolutional Science and Technology). (JPMJCR19R1), and the Institute for Chemical Reaction Design and Discovery (ICReDD), Hokkaido University, created by the World Premier International Research Initiative (WPI), Ministry of Education, Culture, Sports, Science and technology (MEXT), Japan.

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