空気下、室温で実施可能な超高速メカノケミカルバーチ還元反応の開発

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空気下、室温で実施可能な超高速メカノケミカルバーチ還元反応の開発

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第518回のスポットライトリサーチは、北海道大学総合化学院有機元素化学研究室 (伊藤肇教授)の郜云鹏 (Gao Yunpeng)博士にお願いしました！

伊藤研では、有機化合物とさまざまな種類の元素を組み合わせた触媒や機能性材料の開発を行なっており、近年は特にそれらとメカノケミストリーを組み合わせたユニークな反応の開発に注力されています。メカノケミストリーでは、化学反応に物理的・機械的刺激を加えることでその反応性を制御することが可能となり、固体状態での触媒反応などを効率的に行うことができます。伊藤研究室は発足以降、素晴らしい成果をスピード感溢れるペースで発表され続けており、ケムステでも幾度と取り上げさせていただいております。

本プレスリリースの研究内容はメカノケミストリーについてで、ボールミルを使用したメカノケミカル法によって空気下及び室温で簡単に実施できるバーチ還元反応の開発に成功しました。この研究成果は、「Angewandte Chemie International Edition」誌に掲載され、プレスリリースにも成果の概要が公開されています。

Mechanochemical Approach for Air-Tolerant and Extremely Fast Lithium-Based Birch Reductions in Minutes

Yunpeng Gao, Koji Kubota, and Hajime Ito

Angew. Chem. Int. Ed. 2023, e202217723

DOI:doi.org/10.1002/anie.202217723

研究を指揮された伊藤肇教授ならびに久保田浩司准教授より、Gao博士についてコメントを頂戴しております！

久保田先生からのコメント

彼は北京大学のJianbo Wang先生の研究室で博士号を取得後、約２年半前に博士研究員として伊藤研に来てくれました。高度な実験技術、豊富な知識と経験で、伊藤研メカノチームの研究レベルを着実に引き上げてくれました。研究室の成果報告会では、毎回こちらの期待の上を行く結果を持ってくるので、いつも驚かされます。本当に頼もしい仲間です。益々のご活躍を期待しています。

伊藤先生からのコメント

Gao さんは非常に的確な研究計画を立て、緻密それでいて高速に実験を進められる優秀な研究者です。何よりも研究テーマにオリジナリティがあるかないかをきちんと理解して議論できるところに安心感があります。そろそろ次に向かって羽ばたく時期ですが、彼ならどこに行っても大活躍するでしょう。

Q1. 今回プレスリリースとなったのはどんな研究ですか？簡単にご説明ください。

First reported in 1944 by Prof. Arthur John Birch, Birch reduction has been widely used as a powerful dearomatizing method to reduce arenes to 1,4-cyclohexadienes. In every basic organic chemistry textbook, this reaction is introduced to undergraduate students when they meet with aromatic compounds for the first time. However, carrying out a traditional Birch reaction is a challenging task for beginners. Liquid ammonia is a powerful solvent as well as a suitable ligand for alkali metals to generate solvated electrons, which eventually undergo single electron transfer with aromatic rings. However, when treating caustic and toxic liquid ammonia, people must keep many tips in mind. Great efforts on set-up are needed to ensure inert and cryogenic conditions. Long time will be wasted on the distillation of liquid ammonia before the reaction and the careful dissipation after the reaction. To address these issues, chemists developed various ammonia-free variations of traditional Birch reduction. In 1950s, Benkeser et al. developed a representative example using lithium/organic amine system which suffered from over-reduction. Recently, Koide and co-workers reported that an ethereal solvent, such as THF, is a better choice for the lithium/ethylenediamine system. Despite these remarkable achievements, all solution-based protocols still require an inert atmosphere with complicated reaction setups.

Organometallic mechanochemistry is a longstanding research interest of our group. Recently, we have achieved the mechanical activation of magnesium, calcium, and manganese metals to generate organometallic species using a ball milling technique. The strong impact force would break down the raw metal efficiently to generate highly reactive, fresh metal surface in situ. Bulk solvents are no longer needed to promote the dissociation of solid metals. Meanwhile, the reduced contact of the reactive organometallic species with gaseous oxygen and water under solvent-less conditions leads to significant tolerance of atmospheric conditions.

In this study, we have achieved the first mechanochemical approach for lithium-based ammonium-free Birch reduction in air at room temperature using a ball mill. The entire synthetic procedure can be conducted under atmospheric conditions without any special precautions or elaborate synthetic techniques. Owing to the in-situ mechanical activation of lithium metal, the mechanochemical Birch reduction was extremely fast and completed within one minute for a broad range of substrates. Our method is 20-150 times faster than the conventional solution-based methods without calculating the time for set-up and work-up. The gram-scale reduction within one minute succeeded in affording Birch-type product in excellent yield, implying the possibility of highly efficient scaled-up synthesis. The following picture shows the general workflow of our method, which is extremely time-economic and operationally simple. We expect our study could provide a practical choice to conduct this classical and important name reaction in the lab, and, hopefully, in industry.

Q2. 本研究テーマについて、自分なりに工夫したところ、思い入れがあるところを教えてください。

The first point is their good air tolerance. In a conventional solution-based Birch reduction, a strictly inert atmosphere is required to avoid the side reactions of solvated electrons. But in our mechanochemical approach, all procedures are conducted in the air. Although air still exists in the closed jar, the solventless conditions significantly reduce the contact between the in-situ-generated organometallic species and air. The high reaction rate also prevents other side reactions.

The second point is the extremely shortened reaction time. Alkali metal must be solvated before reduction under solution-based conditions. But under ball milling conditions, the dissociation of zero-valent metal is no longer a problem. Lithium is a relatively soft solid. The strong mechanical impact continuously generates reactive, fresh metal surfaces in situ. Thanks to the high-speed ball milling technique, one minute of ball milling delivers 1800 vibrations (30 Hz), which is enough to totally crush the metal. Meanwhile, the high concentration of the substrates inside the jar further accelerates the reduction.

Combining the above two points, we get the third unique point of our method: the simple operation. As long as you have a ball mill, Birch reduction could be carried out without any precautions in a pretty short time. In our gram-scale reduction shown in the above picture, all the procedures (from set-up to isolation) only take less than 45 min, which is difficult to imagine for a traditional Birch reduction.

Q3. 研究テーマの難しかったところはどこですか？またそれをどのように乗り越えましたか？

To demonstrate the synthetic utility of this method, I tested the reactivity of 40 arenes with different substitutions and electron properties. The biggest challenge during this process is that no general conditions could be found for all substrates. For each category of substrates, sometimes for each substrate, different parameters must be screened to ensure the best results. The only way to overcome this difficulty is to try more. The mostly screened parameter is the loading of lithium and amine. For some substrates that could be easily over-reduced, I need to tune the dosage of reagents and additives carefully. Whether liquid additives (tBuOH and THF) should be used is also a problem. Mechanistically, tBuOH should be added in the reduction of electron-rich arenes as an additional proton source. But for substrates with fused aromatic rings, when tBuOH is added, product selectivity issues arise to generate a complex mixture of reduced products. Interestingly, removing tBuOH leads to the selective reduction of the most reactive ring. A small amount of THF additive has some unique effects on the reduction of specific substrates. It can avoid side reactions in the case of aryl ethers. For a drug molecule (S)-(+)-ibuprofen, racemization was prevented when THF was added. All these results were obtained after massive trials.

Q4. 将来は化学とどう関わっていきたいですか？

My PhD studies in Peking University have no relations with ball mills at all. After 2.5 years in Hokudai, I have become a skilled researcher of this fascinating technique. Scientific research is a kind of encounter. I hope I can meet with new knowledge, understand them, and finally create new science from them. I am willing to get another postdoc position in Europe or America. “Do the science, see the world.” Then I hope to start my independent research in academia, to meet with more knowledge, and to create more science.

Q5. 最後に、読者の皆さんにメッセージをお願いします。

I love playing Japanese RPG games. In my opinion, scientific research is somewhat similar to a game. First, you need to know what’s your “main quest” and the meaning of completing this “quest.” After you start your “adventure”, you will confront the “monsters” with different levels. You might be defeated, but you will still get the “experience” and the “knowledge”. You will find your own way to defeat them and “level up”. Repeating this process might be boring, but if you continue striving, you will finally complete the “main quest”, namely, your research project. You will also be awarded the “trophy”- your research paper. Scientific research is even better than a game. Your “trophy” is not just for showing off. Other “villagers” will benefit from your achievements, giving you a deep sense of accomplishment. Don’t forget to pick up some “side quests” during your journey, which might be an unexpected side product or some counterintuitive data. Perhaps this “side quest” will become your next “main quest”. Please keep your passion in your research life no matter what you encounter. Remember, this is your own adventure, and enjoy it!

Finally, I would like to express my gratitude to Ito-sensei and Kubota-sensei. I benefit a lot from every discussion with them. Their rigorous style and creative thoughts on research really impressed me. Also, I would like to say thanks to everyone in Ito lab and Chem-Station.