Chemistry Magazine 2 by Catharine Snell

December 2021 Volume 2 Issue 1

Chemistry in Japan

› The Chemical Society of Japan: Striving for Chemical Sciences and Technology for a Sustainable Human Society, p6 › Peptide Cyclization Methodologies Amenable to in Vitro Display, p12 › Supramolecular Polymerization: Personal History and Outlook Towards a Sustainable Future, p20 › “Think Globally, Act Locally” An interview with Prof. Ryōji Noyori, p88 › A History of Chemistry in Japan, 1820-1955, p104 › Science Diplomacy: where chemistry is crucial, p114

Promoting the advancement and appreciation of chemistry

and the interests of Asia-Pacific

professional chemists

The Federation of Asian Chemical Societies (FACS) includes 32 chemical societies of countries and territories in the Asia Pacific whose membership consists of individual qualified chemists. For forty years the FACS has been fostering the development of chemistry in the Asia-Pacific region. Membership Membership of the Federation is open to all not-for-profit chemical societies whose membership consists largely of individual qualified chemists and which are national professional chemical societies of countries and territories in the Asia-Pacific. Individual membership is open to individual chemists from countries and territories that have societies within the Federation. ACES FACS is a supporting organization of the Asian Chemical Editorial Society (ACES) journals. ACES was founded in 2005 and is an organization of 13 major chemical societies in the Asia-Pacific region committed to scientific excellence, publishing ethics, and the highest standards in publication.

www.facs.website Federation Members: The Royal Australian Chemical Institute Bangladesh Chemical Society Brunei Chemical Society Cambodian Chemical Society Institute of Chemistry, Ceylon Chinese Chemical Society Hong Kong Chemical Society Chemical Research Society of India Indian Chemical Society Himpunan Kimia Indonesia Iraqi Chemists Union

Israel Chemical Society Chemical Society of Japan Jordanian Chemical Society Korean Chemical Society Kuwaiti Chemical Society Institiut Kimia Malaysia Mongolian Chemical Society Nepal Chemical Society New Zealand Institute of Chemistry Chemical Society of Pakistan The Institute of Chemists PNG

Integrated Chemists of the Philippines Mendeleev Russian Chemical Society Saudi Chemical Society Singapore National Institute of Chemistry Chemical Society of the South Pacific Chemical Society Located in Taipei, China Chemical Society of Thailand Chemical Society of Timor-Leste Turkish Chemical Society (TCS) Chemical Society of Vietnam

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ABSTRACT CALL: · Deadline for Oral Communications Presenters: 11th March, 2022 · Notification of Oral Communications Acceptance: 29th April, 2022 · Deadline for Poster Communications Presenters: 29th june, 2022 · Notification of Poster Communications Acceptance: 3st June, 2022 · Deadline for Student Grant Application: 29th April, 2022 REGISTRATION: · Standard Registration deadline: 17th June, 2022 · Late registration deadline: 5th August, 2022 twitter.com/EuChemS_Congres facebook.com/EuChemS2022

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PLENARY LECTURERS Cristina Nevado (Organic Synthesis/Medicinal Chemistry) University of Zurich, Switzerland Hanadi Sleiman (Chemistry and Biology) McGill University, Canada Joanna Aizenberg (Materials) Harvard University, USA João Rocha (Materials and Solids) University of Aveiro, Portugal Lutz Ackermann (Catalysis) University of Göttingen, Germany

Nicola Armaroli (Energy and Sustainability) National Research Council, Italy

Takuzo Aida (Polymer and Supramolecular Chemistry) The University of Tokyo, Japan

CONTENTS AsiaChem December 2021

Volume 2, Issue 1

https://doi.org/10.51167/acm10002

AsiaChem is produced biannually on behalf of the Federation of Asian Chemical Societies by: Publisher: Israel Chemical Society Editor-in-Chief: Prof. Ehud Keinan Marketing: Ms. Tali Lidor Layout & Design: Little Wing Designs, UK Printing: Gestelit Digital Ltd., Haifa, Israel Communications Director: Prof. Ehud Keinan

Science Frontiers The Chemical Society of Japan . . . . . . . . . . 6

Mitsuo Sawamoto (The Chemical Society of Japan) https://doi.org/10.51167/acm00017

Ribosomal Synthesis of Nonstandard Peptides . . . . . . . . . . . . . . . . 12 Hiroaki Suga and Ata Abbas (University of Tokyo) https://doi.org/10.51167/acm00018

Supramolecular Polymerization: Personal History and Outlook Towards a Sustainable Future . . . . . . . . . . . . . . . . . . 20

Takuzo Aida and Kiyoshi Morishita (University of Tokyo) https://doi.org/10.51167/acm00019

Cooperative Catalysis in Organic Synthesis . . . . . . . . . . . . . . . . . . . . 26 Yoshiaki Nakao (Kyoto University) https://doi.org/10.51167/acm00020

New Insights into Bond Homolysis Process and Discovery of Novel Bonding System (C–π–C) by Generating Long-lived Singlet Diradicals . . . . . . . . . . . . . . . . . . . . . 32 Manabu Abe, Zhe Wang, and Rikuo Akisaka (Hiroshima University)

https://doi.org/10.51167/acm00021

From Structural to Functional Materials: a Green Way to Produce Functional Biopolymers Based on Polypeptides . . . . . 42 Kousuke Tsuchiya and Keiji Numata (Kyoto University) https://doi.org/10.51167/acm00022

Nanoporous Chemical Plants: MOFs as Polymer Manufacturers . . . . . . . . 48 Takashi Uemura and Keat Beamsley (University of Tokyo) https://doi.org/10.51167/acm00023

Reactivity Prediction Through Quantum Chemical Calculations . . . . . . . . . 56

Satoshi Maeda, et al. (Hokkaido University) https://doi.org/10.51167/acm00024

On the Cover

This issue focuses on Chemistry in Japan through scientific articles, essays, interviews, a historical account, and the story of the Chemical Society of Japan, all highlighting both past and current scientific accomplishments of Japan’s chemistry community.

Therapeutic In Vivo Synthetic Chemistry by Glycosylated Artificial Metalloenyzmes for Innovative Biomedical Modality . . . . . . . . . . 64 Katsunori Tanaka and Tsung-Che Chang (Tokyo Institute of Technology) https://doi.org/10.51167/acm00025

Pillar-Shaped Macrocyclic Hosts Pillar[n]arenes: From Simple Receptors to Supramolecular Assemblies . . . . . . . . . . . . 72

Tomoki Ogoshi (Kyoto University) https://doi.org/10.51167/acm00026

Two-Electrode Solar Water Splitting Permitting H2 Separation at a Dark Cathode ��80 Hironobu Ozawa and Ken Sakai (Kyushu University) https://doi.org/10.51167/acm00027

Editorial

Interview

Chemistry in Japan ��5

Ryōji Noyori (Nagoya University) �� 88

https://doi.org/10.51167/acm00016

https://doi.org/10.51167/acm00028

Ehud Keinan

Essay Science Diplomacy: Where Chemistry is Crucial . . . . . . . . . . . . . . . . . . . . . . . . . 114 John M Webb, Thomas H Spurling, and Gregory W Simpson https://doi.org/10.51167/acm00031

4 | December 2021

104

Ehud Keinan (Israel)

Tête-à-tête with Eiichi Nakamura �� 96 Ehud Keinan (Israel)

https://doi.org/10.51167/acm00029

History

114

A History of Chemistry in Japan, 1820-1955 . . . . . . . . . . . . . . . . . . 104 Yoshiyuki Kikuchi and Yona Siderer https://doi.org/10.51167/acm00030

www.facs.website

Chemistry in Japan https://doi.org/10.51167/acm00016

Dear Reader,

I am happy to present you with the December 2021 edition of our AsiaChem magazine, which echoes the Federation of Asian Chemical Societies (FACS). Concluding from the success of the previous issue, I am sure that the new one will attract even greater attention worldwide. This issue starts a tradition of unique coverage of chemistry in specific member countries within the FACS expanse. As you can see from the wealth of topics covered by this issue, the decision to focus on one country is well justified. Japan has always been a science powerhouse, as reflected by the fact that it is the top Asian country based on Nobel and Wolf Prize records. Remarkably, of the 29 Japanese Nobel Prize Laureates, 21 received the prize since 2000. The rapidly increasing trend of awarding Asian scientists with major prizes parallels other trends. First, the center of gravity of the global scientific activity follows the apparent shift of the world economy from North America and Europe to Asia. Second, Asian countries notoriously known for their brain drain have become increasingly attractive to their scientists, thus, shifting the balance between brain drain and brain gain. And Nobel Prize Laureate Yuan-Tseh Lee has proposed to replace the term “brain drain” with “brain circulation” (https://doi.org/10.51167/acm00001). Asian scientists are increasingly taking leadership positions in meeting the global challenges of health and climate, which have recently gained much public attention. Nevertheless, the other challenges, including sustainable energy, water quality, the dwindling raw materials, food problems, and waste management, are no less significant. The common denominator of all global challenges is their chemical nature. Although politicians and governments cannot solve these problems, they still enhance media and public awareness, thus creating lucrative opportunities for science and technology. Undoubtedly, chemists will take a dominant role in these efforts, and Asian chemists of all disciplines will continue working together across political borders and cultural barriers to secure a better world for the next generations: https://www.euchems.eu/ newsletters/chemistry-in-europe-2021-4/ This issue comprises a broad variety of articles on cutting-edge science, history, essays, and interviews, serving a wide readership worldwide. The group of scientists represents the Japanese academic landscape regarding age and scientific interest. Mitsuo Sawamoto, Executive Director of the Chemical Society of Japan (CSJ), provides a concise overview and brief history of the CSJ, its missions, activities, and future goals. Hiroaki Suga and Ata Abbas of the University of Tokyo describe their innovative peptide cyclization methodologies amenable to in vitro display. Takuzo Aida and Kiyoshi Morishita of the University of Tokyo talk about supramolecular polymerization from a perspective of personal history and www.asiachem.news

a sustainable future. Yoshiaki Nakao of Kyoto University describes cooperative catalysis for organic synthesis. Manabu Abe, Zhe Wang, and Rikuo Akisaka of Hiroshima University provide new Insights into the bond homolysis process and the discovery of a novel bonding system (C–π–C). Keiji Numata and Kousuke Tsuchiya of Kyoto University describe a structural to functional materials journey, proposing a green way to produce functional biopolymers based on polypeptides. Takashi Uemura and Keat Beamsley of the University of Tokyo describe a novel opportunity of using MOFs as means for polymer manufacturing. Satoshi Maeda and colleagues of Hokkaido University predict chemical reactivity through quantum chemical calculations. Katsunori Tanaka and TsungChe Chang of the Tokyo Institute of Technology describe in vivo synthetic chemistry using glycosylated artificial metalloenzymes. Tomoki Ogoshi of Kyoto University, the discoverer of the pillar[n]arene macrocycles, reviews their properties from simple receptors to supramolecular assemblies. Ken Sakai and Hironobu Ozawa of Kyushu University describe a two-electrode solar water splitting permitting hydrogen gas separation at a dark cathode. I had the pleasure of interviewing Ryōji Noyori of Nagoya University, 2001 Nobel Prize Laureate, learning about his exciting career and unique views on science and education. My conversation (tête-à-tête) with Eiichi Nakamura of the University of Tokyo revealed a leading scientist and musician’s life experience and aspirations. Yoshiyuki Kikuchi of the Aichi Prefectural University and Yona Siderer of the university of Jerusalem provide a fascinating account of the history of chemistry in Japan during 1820-1955. Three Australian scientists, John M Webb, Thomas H Spurling, and Gregory W Simpson, conclude this issue, discussing science diplomacy, where chemistry is crucial. I wish to thank all these authors for opening a wide window to Japanese science and technology. Special thanks go to the graphics designer, Catharine Snell of Little Wing Designs (UK), for her contributions to the magazine’s layout and unique character. Enjoy your reading! Ehud Keinan Technion – Israel Institute of Technology President, Israel Chemical Society IUPAC, Vice President and President-elect AsiaChem, Editor-in-Chief FACS Communications Director

December 2021 | 5

The Chemical Society of

Striving for Chemical Sciences and for a Sustainable Human Society

Mitsuo Sawamoto

Executive Director, The Born in Japan (1951), he received his B.Sc. (1974), M.Sc. (1976), and Ph.D. (1979) in polymer chemistry from Kyoto University. After postdoctoral research at the University of Akron, USA (1980–81), he joined the Department of Polymer Chemistry, Kyoto University. In 2017, upon retiring from Kyoto, he joined the Frontier Research Institute at Chubu University. He serves as an Executive Program Director at the Japan Science and Technology Agency (JST), Member of the Science Council of Japan (SCJ), Executive Director of the

Chemical Society of Japan, and Chair of the International Organizing Committee Pacifichem 2021. He has published over 540 research papers, 50 reviews and book chapters, and 46 patents (with nearly 25,000 citations and an h-index of 71) in the areas of precision cationic and radical polymerizations, metal polymerization catalysts, precision synthesis of designed functional polymers, and sequence regulation in chain-growth polymerization. His long list of Awards and Honors includes the Arthur K. Doolittle Award of the ACS, the Macro Group UK Medal, the SPSJ Award for Outstanding Achievement in Polymer Science and Technology, the NIMS Award on Strong Future of Soft Materials, the 2015 Medal of Honor with Purple Ribbon (presented by Emperor Akihito and Prime Minister Shinzo Abe, Japan), the Alexander von Humboldt Research Award, and the Benjamin Franklin Medal in Chemistry (USA).

6 | December 2021

Brief History

The Chemical Society of Japan (CSJ), with a long history extending over 140 years and a membership of ca. 24,000, is one of the world’s largest, most active, and internationally recognized societies in chemistry. The history of CSJ dates back to 1878 (just ten years after the Meiji Restoration, where Japan was reborn), when about twenty motivated and enthusiastic young scholars launched a small organization, the Chemical Society, in Tokyo for the advancement of chemistry. In the following year the embryonic society was renamed The Tokyo Chemical Society and eventually the current name, The Chemical Society of Japan, in 1921. In 1948, shortly after the World War II, the then CSJ merged with the Society of Chemical Industry, founded in 1898, into an integrated organization with the same name: ”The Chemical Society of Japan”. The integration was in part symbolic in defining the renewed CSJ’s perspective: CSJ consists of comparable numbers of individual members from both academia and industry along with supporting company affiliates; its activities cover virtually all segments of pure and applied chemistry along with diverse interdisciplinary areas now extended to physics, biology, medicine, materials, and advanced technology. Since 2011 CSJ is a public interest incorporated association, a nonprofit tax-exempt organization legitimately certified and under the jurisdiction of the Japanese Cabinet. www.facs.website

Japan:

d Technology By Mitsuo Sawamoto https://doi.org/10.51167/acm00017

Missions

The prime mission of CSJ is to promote chemical sciences and technology in collaboration with other domestic and global chemistry-related societies and associations. Above all, the overriding objective is thus to contribute to the betterment of human life. The recently redefined CSJ mission statement goes: The Chemical Society of Japan, with diverse members in academia, industry, and government, will internationally play leading roles in promoting the progress in state-of-the-art fundamental research and the implementation of developments in chemical science and technology, and will thereby contribute to building a sustainable human society. In his inaugural address in June 2020, CSJ President Yoshimitsu Kobayashi said in excerpt: “The global society currently faces www.asiachem.news

three unprecedented trends: globalization, digitalization (or AI proliferation), and socialization. All three have the potential to rapidly overturn existing paradigms. Also, as we prepare for the challenges to come, we must continue to stay focused on the existing global challenges before us, namely global climate change, marine plastics, food and water shortages, and the yet uncontained COVID-19 pandemic. “As CSJ President, I believe that the vital missions of chemistry and our Chemical Society are to respond quickly and sensitively to these fast-developing trends and thereby to provide solutions for global challenges. In retrospect, the Japanese chemical industry’s bitter history in the 20th Century as a major aerial and oceanic polluter resulted in invaluable lessons learned. The industry, in turn, applied its knowledge and technology thus acquired to develop strategies

to prevent environmental hazards, eventually transitioned to a solution provider, and has successfully played active roles in multiple environmental improvement efforts, including the revitalizing crystal-clear blue oceans, firefly-living fresh water, and clean air. I believe that, through the power of chemistry, the industry as solution provider will be at the forefront to find solutions to all worldwide challenges and thereby to establish a sustainable society.”

Organization

The CSJ membership, total ca. 24,000 as of 2020, includes individual regular members in academia (ca. 9600) and industry (ca. 3700), student members (ca. 4300), teachers (ca. 1550), supporting company affiliates (420+), and institutional members December 2021 | 7

(such as libraries ; ca. 360). International membership grows steadily, particularly from China, Korea, and other Asian countries. The CSJ Office operates by the Board of Directors and the Secretariat: The Board of Directors is the second highest decision-making, management organization, under the CSJ General Assembly, and consists of President, Senior Vice President, four Vice Presidents, Executive Director, General Secretar y, 19 Directors, and four Auditors. The CSJ President, serving a two-year term, is elected by online general election by all the regular members; the position alternates for two consecutive terms from academia and the following third term from industry. The current President for fiscal 2020-2022 is Dr. Yoshimitsu Kobayashi (Figure 1), the Mitsubishi Chemical Holdings, and the President-Elect is Professor Hiroaki Suga, the University of Tokyo.

Figure 1. CSJ President: Dr. Yoshimitsu Kobayashi, Mitsubishi Chemical Holdings Organizationally, the CSJ comprises of a Secretariat (Headquarters), Departments, and Regional Sections. The CSJ Secretariat consists of about 20 staff members, under Executive Director, Secretary General, and three Managers who work in three Sections (General Affairs; Projects, Meetings, and International Exchange; and Publications and Information) related to the Departments described below; the General Affairs Section also deals with the Society’s finance. The CSJ Headquarters is located in a central academic area (Ochanomizu) of metropolitan Tokyo in the Chemistry Hall, a CSJ-owned building inaugurated in 1991 by members’ contributions and wholly renovated just last year in 2020 (Figure 2). The Departments are CSJ’s functional organizations: General Affairs, Research Exchange, Publications and Information, Academia-Industry Exchange, and Education and Public Relations). In accordance with their functions, these Departments hold total about 8 | December 2021

Figure 2. The Chemistry Building: The CSJ Headquarters and offices 30 Committees, such as Membership, Award Selection, International Exchange, Journal Publication, Research Promotion, etc. In addition to these Departments and Committees, since 2018 the CSJ comprises 21 Divisions for virtually all specific fields in chemistry, including analytical, inorganic, organic, macromolecular, and others. In parallel with Divisions are five Topical Groups, self-supporting research organizations currently focused on Colloids and Interfacial Chemistry, Chemo-informatics, Biofunctional Chemistry, Biotechnology, and Organic Crystals. Seven Regional Sections cover local CSJ activities geographically extended all over Japan. The Kanto Section (metropolitan Tokyo and its vicinity) is the largest with ca. 50 % of all CSJ membership; the Kinki (Osaka, Kyoto, Kobe, and vicinity) and the Tokai (centered in Nagoya) Sections are the second and the third largest Sections, respectively. Each Regional

Section runs a variety of activities including local membership promotion, regional symposia, and outreach events for young potential chemists (children and school pupils) and the general public in the region. The annual operating budget of CSJ in fiscal 2020 is about one billion Japanese yen (JPY) or nine million US dollars (USD), where the primary revenue comes from the membership fees (regular, student, and company affiliate fees).

Activities

Meetings. The CSJ holds two annual meetings: the CSJ Spring Annual Meeting in March and the CSJ Chemistry Festa in October. The Spring Meeting (Figure 3), perhaps one of the most important CSJ activities, usually involves ca. 8,000 participants and over 6,000 oral and poster papers presented in general sessions and special symposia, expositions, and www.facs.website

Figure 3. CSJ Spring Annual Meeting: Lectures and poster sessions www.asiachem.news

December 2021 | 9

public outreach events, where the General Assembly, Presidential lecture, and the Award Presentation Ceremony are also held. In contrast, the Chemistry Festa focuses on academia-industry exchange and collaboration, where a majority of the organizing committee members accordingly come from the industry. Coupled with carefully selected special topic symposia, exhibitions, and human networking events, the Festa provides excellent opportunities for industry-academia collaboration and for student job-hunting and recruiting. Along with the two annual nationwide meetings, the headquarter Departments and the Regional Sections organize a variety of symposia and workshops throughout a year. Publications. CSJ actively and internationally publishes two journals, two societal organs, and books (Figure 4). The two peer-reviewed journals are monthly published online in English. Bulletin of the Chemical Society of Japan (BCSJ), launched in 1926, publishes original articles, reviews, and accounts, in total ca. 200 papers per annum, with an impact factor 5.448 as of

2020, which steadily rising. Chemistry Letters (CL or ChemLett), launched in 1972, is for rapid current-awareness communications and short reviews, monthly with ca. 400 papers a year, with impact factor 1.389 as of 2020. The two organs, both primarily in Japanese and partially electronic, are windows to its members. Kagaku to Kogyo (Chemistry and Industry) is the CSJ’s primary monthly organ delivered online and by mail, and free of charge to all the members. It features hot-topics accounts, Regional Section and CSJ Division reports, meeting announcements, messages to the members, and help-wanted advertisements. Kagaku to Kyoiku (Chemistry and Education), as its title implies, is primarily directed to school teachers and those who interested in chemistry education. It focuses on fundamental topics in chemistry (such as the IUPAC-authorized periodic table and atomic weights, SI units, etc.), new experiment programs developed by the members, and reviews. In addition, The Chemical Record and Chemistry: An Asian Journal are joint publications with Wiley-VCH, covering more or

less personal research accounts. With several overseas chemistry-related societies, the CSJ has recently joined publishing a so-called preprint journal, ChemRxiv™, to follow a current trend of non-peer-reviewed online publication for the rapid exchange of ever proliferating research information. The CSJ also publishes books, such as Kagaku Binran (Chemistry Handbook), an authoritative compilation of chemistry data), and CSJ Current Reviews, a series of monographs covering hot topics, now in about 50 volumes. Awards and Research Grants. For recognition of members’ achievements and societal service, The Chemical Society annually presents ten awards, including the Award of the Chemical Society of Japan (the highest honor of research achievement), the Award for Creative Work, the Award for Young Chemists, the Award for Technical Development, the Award for Outstanding Young Women Chemists, and the Award for Chemical Education. Based on the private endowment by the 2019 Nobel Prize in Chemistry laureate, the Akira Yoshino Research Program provides a

Figure 4. CSJ publications: Journals, organs, and books: (first row from left) Bulletin of the Chemical Society of Japan, Chemistry Letters, Kagaku to Kogyo, Kagaku to Kyoiku; (second row from left) The Chemical Record, Chemistry: an Asian Journal, Kagaku Binran, CSJ Current Review. 10 | December 2021

www.facs.website

funding to a selected proposal on the topics annually specified by the donor, such as novel materials for lithium-ion batteries. In 2021, based on another private legacy endowment fund, CSJ has set a brand-new award, the Saburo Nagakura Award named after the donor, an honorary Society member, to recognize and promote a promising researcher either in academia or industry with original, creative, and novel research, development, and/or education. For the first time for the Society, the award presents a non-restricted cash prize of 10 million Japanese yen (ca. 100 thousand USD) to a single recipient a year to be selected from the awardees of the afore-mentioned CSJ Awards except for the Award of the Chemical Society of Japan. International Exchange. Quite naturally, the CSJ actively commits to international exchange activities (Figure 5) in collaboration with the chemistry-related societies and organizations worldwide, including the American Chemical Society (ACS), the Canadian Society for Chemistry (CSC), the Chinese Chemical Society (CCS), the Chemical Research Society of India (CRSI), the Chemical Society Located in Taipei (CSLT), German Chemical Society (GDCh), the Israel Chemical Society, (ICS), Korean Chemical Society (KCS), the New Zealand Institute of Chemistry (NZIC), the Royal Australian Chemical Institute (RACI), the Royal Society of Chemistry (RSC), and many others. The Japanese Chemical Society is an active member of international chemistry organizations, such as the International Pure and

Applied Chemistry (IUPAC) and the Federation of Asian Chemical Societies (FACS) (Figure 5). The CSJ, ACS, and CSC are the three founding societies of the International Chemical Congress of Pacific Basin Societies (Pacifichem). This Congress, held in every five years in Honolulu, HA, USA, is perhaps one of the largest and most comprehensive chemistry congresses with over 15,000 participants, co-organized by the seven Pacific Rim chemical societies (the founding members with CCS, KCS, NZIC, and RACI). Another interesting activity is the Chemical Sciences and Society Summit (CS3), a series of symposia jointly held by pairs of a chemical society and a funding agency in China, Germany, Japan, UK, and USA; the Japanese pair consists of CSJ and the Japan Science and Technology Agency (JST). Every 2-3 years CS3 provides a forum to discuss topics important for chemistry relative to the world society, such as sustainability, environment, climate change, water, etc., and the next meeting will be hosted by CSJ and JST. With the Korean (KCS) and the Taipei (CSLT) partners, the CSJ holds a bilateral exchange agreement. Alternatingly every year, one partner society invites the president and/or younger chemists of the other to its annual meeting for lectures and human networking. Outreach. To foster next generation chemists and strengthen the relationship with the general public, the CSJ Headquarters and the Regional Sections regularly hold outreach

events open to the public and particularly to school children and pupils. Of particular interest is the “I-Love-Chemistry Club” meeting, featuring chemistry experiments for kids, exhibitions, and Q&A sessions. To the delight of the CSJ members, juvenile participants show intense curiosity in chemical science and ask tough questions that often puzzle the instructors. For example, they may ask “Why does an orange-flavored jelly that looks a soft solid soon melt in our mouth and taste sweet?” To answer such questions, instrutors cannot use any technical terms, however commonly used by professional chemists, such as hydrogel and hydrogen bonding.

Future Perspective

The CSJ has been consistently active and steadily growing in promoting the progress in chemical science and technology. Its activities have been expanding in scope to encompass not only chemistry per se but a wide variety of related fields as biology, physics, medicine, pharmacy, and materials science. As stated above in the CSJ’s missions, Chemistry for Sustainable Society and the World is an eminently important mission. As an expert group of professionals in molecules, substance transformation, materials creation, and process innovation, the Chemical Society of Japan has decided to meet the global challenges with concrete, viable, and implementable solutions, including sustainability, resilience, energy demand, food and water supply, global warming, and preserving the environment. ◆

Figure 5.CSJ’s international activities

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December 2021 | 11

Peptide Cyclization Methodologies Amenable to in Vitro Display

By Hiroaki Suga and Ata Abbas https://doi.org/10.51167/acm00018

Hiroaki Suga

Hiroaki Suga is a Professor of the Department of Chemistry, Graduate School of Science in the University of Tokyo. He received Ph.D. at MIT (1994) followed by post-doctoral fellow in MGH (1997). He was Assistant and tenured Associate Professor in the State University of New York, University at Buffalo (1997–2003) and Professor in the Research Center for Advanced Science and Technology in the University of Tokyo (2003–2010). Since 2010, he has the present position. He is the recipient of Akabori Memorial Award 2014, Max-Bergmann Medal 2016, Nagoya Medal Silver 2017, Vincent du Vigneaud Award 2019, Bohlmann Lecture 2019 and The Research Award of the Alexander von Humboldt Foundation 2020. He is also a co-founder of PeptiDream and MiraBiologics in Japan.

12 | December 2021

Ata Abbas

Ata Abbas was born and grew up in India. After receiving his MSc (organic chemistry) from Aligarh Muslim University, India, he worked for a pharmaceutical company for some time. He later went on to receive his PhD from Nanyang Technological University, Singapore in 2015. Currently he is a post-doctoral researcher in Suga lab at The University of Tokyo where his interests are new chemical reactions to diversify genetically encoded macrocyclic peptide libraries and RaPID mRNA display. He is particularly passionate about mild, water based chemistries that are applicable to biological systems.

Display technology platforms offer their own unique set of challenges for chemical transformations, at the heart of which lies peptide macrocyclization. The amenable reactions for peptide macrocyclization on this platform need to meet a number of criteria like high reactivity, selectivity, mild conditions, irreversibility and in many cases, a unique requirement to be assimilated into the translation machinery. Skillful utilization of these reactions has led to the formation of huge macrocyclic peptide libraries with varied linkages and topographies which have in turn led to the discovery of a number of hits for purposes such as drug discovery and others. Herein, we review those reactions which have mainly been applied in mRNA and phage display and discuss their technical characteristics and significance. GENETICALLY ENCODED LIBRARIES of peptides are an inexhaustible repertoire of therapeutic entities. They, however, generally work better when cyclized. Cyclic peptides are known to have two major advantages over their linear counterparts. Firstly, they are more resistant to proteases1 and hence have longer half-lives and better bioavailability2 for application as drugs etc. Secondly, they are more compact, have lesser degrees of freedom and

fewer available conformations due to which they bind more tightly to the target protein by saving on entropy cost.3 Moreover, they are indicated to possibly have better cell permeability than their linear counterparts.

The development of methodologies applicable to peptide cyclization under mild conditions constitutes an important and active area of research. Such methodologies must fulfil the requirement of application to not only diverse sequences but

www.facs.website

also structures consisting of one, two, three or even more cyclic motifs. Cyclization reactions become more complicated and challenging due to the presence of various reactive sidechains on proteinogenic amino acids. Even though there are various techniques for chemical synthesis of cyclic peptides on solid support based on traditional protection-deprotection chemistries4 and/or metal-catalyzed reactions,5 most of these reactions are not suitable for the use on display platforms because of the following reasons: they must be compatible to physiological-like conditions (e.g. at near-neutral pH) and high chemoselective to the aiming functional groups. This review deals with techniques of peptide cyclization as applied to in vitro display techniques, represented by the phage and mRNA displays.

Challenges

Display technologies6, 7 rely on the translation machinery consisting of ribosome, protein translation factors, various enzymes including aminoacyl-tRNA synthetases, amino acids, tRNAs, mRNAs, energy sources, and others. Thus, the cyclization chemistry needs to selectively work for the aimed peptides in the presence of all these bio- and small-molecules. Even a harder

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challenge is that their chemistry must efficiently take place regardless of peptide sequences originating from huge mRNA libraries and vast tertiary structures originating from the diverse peptide sequences. For the phage display, a classical and general method for generating cyclic peptides is disulfide bond formation via two cysteine (Cys) residues. This is simply because their genotype of mRNA or DNA sequence is packaged in the bacteriophage, the easiest way to cyclize the peptide sequences is to use the naturally occurring crosslinking bond(s) of disulfide. However, disulfide bond is a reducible bond, and therefore in consideration for physiological conditions this bond is not necessarily ideal for drug use. Even though such a disulfide bond can be elaborated to an alternative bond, but in such a case the activity of the parental peptide is often diminished. Thus, it is important to develop an alternative approach to produce macrocyclic peptides closed by a more physiologically stable bond from the initial library. For the mRNA display, the respective peptides are directly attached to the genotype sequences of mRNA via puromycin molecule. Occasionally, the mRNA sequence is reverse transcribed to cDNA sequence forming the

noncovalent annealing pair. This means that the peptide-mRNA/cDNA fusion contains not only the peptide motif but also ‘naked’ nucleic acids, and thereby the chemistry for cyclization is even more challenging than the phage case, where the cyclization must take place without unwanted reactions with sidechains of peptide nor with nucleic acid’s nucleobases/phosphates.

Cyclization strategies

Traditionally, peptide cyclization has been categorized as taking place between two ends of the peptide (head-to-end), two sidechains (sidechainto-sidechain) or one end to a sidechain (head-tosidechain and sidechain-to-end). However, for the sake of this review which deals mainly with those methods applied to display technologies, we will broadly categorize the strategies in two, i.e., cyclization without using genetic code manipulation and cyclization using genetic code manipulation.

Cyclization via chemical crosslinking

This strategy usually takes advantage of inherent reactivity of a native amino acid side chain and an external organic motif. Majority of groups have exploited nucleophilicity of thiol groups of

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Cys or amino groups of lysine (Lys) ε-sidechain (or occasionally N-terminus), which are present at fixed positions in the translated peptide that conjugate with a small organic motif added after translation. Thus, this strategy has been applied for the majority of phage display works.

interesting biological activities,8-10 many groups have tried to develop methods to create peptide libraries having similar topologies. Beginning of this was the report of Timmerman (Figure 1) that treating di-, tri-, and tetra-Cys containing peptides with bis-, tris-, and tetrakis(bromomethyl) benzene derivatives in aqueous ACN results in fast, one-step chemical synthesis of single-, double-, and triple loop peptides.11 In 2009, this reaction was later utilized by Winter et al.12 to produce bicyclic peptide libraries for phage display. They designed peptide libraries with three reactive Cys residues, each separated by several random amino acids and conjugated with tris(bromomethyl)benzene (TBMB) in aqueous solvents (Figure 2A). The conjugation reaction however posed several challenges including cross reactivity of TBMB with the disulfide bridges D1 and D2 domain in the phage PIII and a loss in phage infectivity due, probably, to the

Thioether bond formation

This has been a popular strategy due to its simplicity and the ability to yield macrocyclic peptides with more than one loop. Cys thiols at fixed positions react with organohalides forming thioether bonds in a SN2 reaction. The libraries have vast diversities consisting of proteinogenic amino acids only.

Using bis/tris/tetrakis (bromomethyl) benzenes

Inspired by some naturally occurring peptides with multiple fused rings and loops and having

C C

C HS

C S

Figure 1. Formation of peptide loops by reacting Cys-containing peptides with di-, tri-, or tetra-Cys reacting to bis-, tris-, or tetrakis-(bromomethyl)benzene as a crosslinking agent. Br

A Br

H2N

S O O

C SH

N Cl

F F F

H2N

F F

S O O

F S

F F

R Cl H2N

S N

C R = biotin mono-glycoside

Figure 2. Examples of peptide cyclizations using bromomethyl benzenes, amenable to display technologies. (A) Bicyclic peptide library using 1,3,5-tris(bromomethyl) benzene reported by Winter group. (B) Decafluoro-diphenylsulfone (DFS) cyclizaton and (C) Dichloro-oxime cyclization reported by Derda group. 14 | December 2021

crosslinking of the phage coat protein through lysine side chains. The problems were, however, solved by using a disulfide free gene-3-protein phage and using low concentration of TBMB. The phage display selection was successfully carried out to find an inhibitor ligand to human plasma kallikrein. This elegant approach represents that the appropriate engineering of the phage system allows to control selective crosslinking of Cys residues only appeared in the random library of displayed peptides. In 2012, Szostak group also utilized a similar strategy to cyclize highly modified peptides having two flanking cysteine residues using dibromoxylene.13 The peptide libraries having several non-proteinogenic amino acids were used for in vitro selection based on mRNA display against the target protease thrombin with successful isolation of binders with low nanomolar affinity.

Using perfluoroarenes

Perfluoroarenes react with a reactive thiol in peptide via nucleophilic aromatic substitution reaction SNAr, which has been used extensively for polymer arylation and bioconjugation.14-18 Derda et al.19 used decafluoro-diphenylsulfone (DFS) to crosslink Cys thiols yielding cyclic peptides in one of the fastest Cys conjugation reactions (Figure 2B). They improved the previously reported SNAr reagents such as 1-chloro-2,4-dinitrobenzene,20 perfluorobenzene21, 22 and perfluorobiphenyl22 which show low reactivity and poor solubility in aqueous systems. The group has demonstrated this reaction to be biocompatible and faster than most Cys conjugation reactions with the reaction rates up to 180 M-1S-1, although the rate is largely sequence dependent; e.g. positively charged residues such as arginine accelerated it while negatively charged aspartate supressed the rate. This unique reaction is fairly selective for Cys, but with large excess and prolonged exposure to DFS showed some cross-reactivity with amine groups. As for applicability of the reaction in phage display, a clone of M13 phage could be 60–70% modified with DFS in 5% DMF as cosolvent. The modification efficiency was decreased to 35% when a whole library containing 109 peptides was used. Interestingly, the crosslinked peptides generally exhibit higher oxidative resistance compared with the traditional α,α’-dibromo-meta-xylene.

Using Dichloro-oxime

In 2015, Dawson et al. reported side chain linking of cysteine or homocysteine thiols using dichloroacetone (DCA) to give stapled (macrocyclic) peptide with an acetone bridge.23 This linking not only stabilized the secondary structure of the peptides but also provided a ketone moiety to link various molecular tags through oxime ligation. Building further on this concept, Derda et al. used pre-formed dichloro-oxime (DCO) derivatives (Figure 2C) to cyclize phage displayed glycopeptide libraries.24 Reaction went on to completion giving approximately

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85% adduct in 3 hrs with a rate constant of 1.1 M-1S-1. Interestingly, it was found, unlike the reports of Heinis and Winter,12 that DCO modification did not result in losing phage infectivity and more than 80% of phage remained viable after modification. This suggests that crosslinking of phage coat protein is negligible with DCO.

Amide bond formation

In one of the first reports, Robert et al. reported a general route for post-translational cyclization of mRNA display libraries by treating translated peptide with disuccinimidyl glutarate (DSG) at pH 8.25 DSG reacted near-quantitively with N-terminal amine and an internal Lys ε-amino group crosslinked via two amide bonds. The same group then demonstrated mRNA display of DSG-linked library against Gαi1, successfully discovering a strong cyclic peptide binder with Kd = 2.1 nM.26

Disufide-rich loop formation

Disulfide bond formation was one of the first approaches developed to cyclize linear peptides displayed on phage but due to the instability of disulfide bond in reducing cellular environment, this approach finds little practical value for in vivo applications. However, plant-based cyclotides are a unique class of peptides having multiple loops in the form of cysteine knots. Their remarkable thermal and proteolytic stability and a wide range of biological activities make them ideal macrocycles to be screened as ligands for target proteins. There are several reports of selection of cyclotides with novel function using in vitro displays.27-30 As a recent demonstration, Wenyu et al. reported mRNA-display of a cyclotide library derived from Momordica cochinchinensis trypsin inhibitor-II (MCoTI-II), in which two loops, 1 and 5, were randomized. The selection campaign against human Factor XIIa (hFXIIa) successfully yielded an extraordinary potent and selective variant, referred to as MCoFx1, giving Ki of 0.37 nM to hFXIIa that is greater than three orders of magnitude selective over trypsin and other related proteases.31

Cyclization using genetic code reprogramming

Genetic code reprogramming is a powerful technique which enables incorporation of nonproteinogenic amino acids in translated polypeptides via codon reassignment32 or expansion.33, 34 The technique has evolved and matured over the years (for recent reviews see these references35, 36 ) in which task of reprogramming is achieved through a combination of an Escherichia coli reconstituted cell-free translation system and pre-aminoacylated tRNA with various nonproteinogenic amino acids facilitated by flexizymes. This system, referred to as FIT (Flexible In-vitro Translation), enables for devising many unique methods for macrocyclization of peptides discussed in the following sections.

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Thioether Bond Formation Thioether bond formation by nucleophilic substitution

Unlike the aforementioned strategy of adding an external organic moiety with multiple halogens, this strategy results in the formation of one thioether bond per cycle. The halo part is incorporated at the initiator position or at a suitable side chain through genetic code reprogramming.37 An intramolecular substitution reaction by a downstream Cys thiol results in the formation of a physiologically stable thioether linkage. Suga group has explored, evolved and exploited this technique thoroughly, resulting in a number of interesting macrocyclic libraries and successful selections against various targets (for recent representative examples see references37-45). In 2008, Goto et al. have used a methioninedepleted FIT system where the initiation codon AUG becomes vacant, and engineered the initiation event. To this sytem is added an aminoacyltRNA fMetCAU charged with N-chloroacetylated amino acid, such as tryptophan (ClAc-Trp) or tyrosine (ClAc-Tyr), prepared by a flexizyme (eFx).37 The ClAc-Trp-tRNAfMetCAU was set as an initiator, for example, for the peptide expression, ribosome elongates amino acids starting from the ClAc-Trp

mRNA•cDNA

L/D

mRNA•cDNA

O Cl

N H

according to mRNA template sequence, followed by a Cys residue at a downstream position. When the peptide synthesis is completed, the Cys thiol spontaneously reacts with the ClAc group to yield a thioether linked macrocyclic peptide (Figure 3A). It should be noted that other haloAc group, such as BrAc and IAc, yielded many byproducts originating from adducts of thiols present in the translation system, e.g. mercaptoethanol, DTT, and Cys. Thus, the ClAc group was the perfect reactivity toward the Cys thiol in peptide chain that effectively promotes the desired intramolecular reaction over undesired intermolecular reaction. This strategy has been applied to constructing mass libraries (over trillion members) of thioether macrocycles in combination with genetic code reprogramming for the incorporation of exotic amino acids46-48 including N-methyl-L-amino acids49,50, D-amino acids51-53, and β-amino acids54,55, etc. Suga group has integrated this strategy with mRNA display, referred to as RaPID (Random nonstandard Peptides Integrated Discovery) system, and enabled the ‘rapid’ discovery of various potent macrocycles56 against extracellular and intracellular proteins and has reported more than 35 successful selection outcomes with a range of low nM to pM KD values in the period of a decade.57-84

L/D

O S

N H

C HS HS

C W

Br SH

Urotensin-II

Urotensin-II analog

V C Y S

E T P D C F

fM P D Cab

Y W

O N H

C S

N H

V C S

fM P D Cab

K W F

GryA

HS O

Figure 3. Ribosomal synthesis of macrocycles closed by a thioether bond via nucleophilic substitution. (A) N-terminal ClAc-Trp installed by the genetic code reprogramming reacts with a downstream Cys. (B) Tricyclic peptide synthesis of the intramolecular N-terminal ClAc with the second downstream Cys in the combination with TBMB that crosslinks three remaining Cys residues. (C) The ClAc group on the sidechain of Cab installed by the genetic code reprogramming reacts with a downstream Cys. The sequence represents a sequence of human urotensin II. (D) Macrocyclization using thioether bond formation by intramolecular reaction between non-proteinogenic amino acid O2beY and Cys inside living bacterial cells via intein-based protein splicing. December 2021 | 15

Interestingly, the N-terminal ClAc group reacts with Cys thiol at almost any position, except for Cys at the adjacent downstream position to ClAc-initiator (i.e. at the second position). This is simply because Cys cannot sterically reach to the ClAc group. Thus, when there is a Cys residue at the second position, arbitrary sequence and length of peptide followed by a downstream Cys residue, the latter Cys thiol (generally the second Cys residue) selectively reacts with the N-terminal ClAc group to form thioether-macrocycle. This fact has allowed to build a strategy for ribosomal synthesis of tricyclic peptides (Figure 3B). In this scheme, a peptide contains a total of four Cys residues, where ClAc-Trp is followed by Cys and then the rest of peptide sequence has three Cys residues at various position. The second Cys spontaneously reacts with the N-ClAc group to afford a monocycle. Then, the treatment of TBMB crosslinks the remaining three Cys residues to form a topologically complex tricyclic peptide. This ClAc thioether strategy can be expanded to inter-sidechain cyclization by incorporating an Nγ-ClAc-α,γ-diaminobutylic acid (ClAc-Cab).85 Again, a downstream cysteine thiol reacts with the ClAc group to afford a macrocycle closed by the thioether bond. Application of this methodology was demonstrated by translating a known biologically active peptide human urotensin II which is a potent vasoconstrictor. Single disulfide bond between cysteine residues at position 5 and 10 was replaced with a thioether bridge between Cab at position 5 and a cysteine at position 10 (Figure 3C). The resulting peptide was shown to retain biological activity and remarkable stability towards proteinase K under reducing conditions.85

Michael Addition

Nucleophilicity of thiolate can also be exploited in Michael type addition reactions to yield thioether linkage. In fact, many biologically active natural lanthipeptides utilize this strategy for cyclization. For such ribosomally synthesized and posttranslationally modified peptides, dehydratase enzymes recognize the N-terminus of the precursor leader peptide and convert serine and threonine residues in the core peptide to dehydroalanine (Dha) and dehydrobutyrine (Dhb) respectively. The α,β-unsaturated moieties in Dha and Dhb acts as the electrophile where enzyme assisted Michael addition reaction by cysteine thiol generates a thioether linkage. The most

0.5 mM K3Fe(CN)6

WOH

In 2014, Fasan et al. developed a strategy of producing thioether linked macrocyclic peptides inside living bacterial cells (E.coli) which can be utilized on phage display platform (Figure 3D).86, 87 In order to supress cross reactivity with many other nucleophiles in the cellular environment, they ribosomally incorporated a rather slow reacting nonproteinogenic amino acid (O-(2bromoethyl)-tyrosine) termed O2beY. For proteolytic release of the cyclized peptide, they also incorporated an intein-based protein splicing element. Both features combined together, resulted in ribosomal production of a linear precursor peptide having a cysteine reactive nonproteinogenic amino acid O2beY and an intein splicing element. Remarkably, another cysteine present in the intein element did not show any reactivity towards cyclization reaction due to being partially buried within the active site. Yet, the practice of this approach for the disovery of de novo macrocyclic peptides has not been reported.

pH8, RT, 5 min

HO N H

WOH N H

NH2

Figure 4. Benzyl amine and hydroxyindole incorporated in translated peptides react rapidly under oxidative conditions, yielding a unique fluorogenic aromatic linkage.

fM G

H N

O N H

A G

L M G HS

N G

95°C

fM G

H N

O N H

A G

extreme case observed in natural products is biosynthesis of nisin. Inspired by this chemistry, Goto et al.88 used genetic code reprogramming to incorporate vinylglycine in translated peptides which was isomerized to dehydrobutyrine by simply heating the peptide at 95˚C for 30 minutes. This was followed by spontaneous Michael addition by a cysteine thiol to give methyllanthionine containing macrocyclic peptide. They later demonstrated the applicability of this reaction by synthesizing two ring segments of the natural bioactive peptide nisin (Figure 4). Due to high temprature requirement of this cyclization step, this approach is inapplicable to the display system; therefore, a better alternative approach is needed.

Oxidative Coupling

Genetic code reprogramming allows for incorporation of various nonproteinogenic amino acids including those with orthogonal reactive handles to accomplish click type ligation (vide infra). A practically useful application of this methodology was incorporation of benzylamine and 5-hydroxyindole.89 These functional groups are known to react instantly under oxidative conditions to yield a fluorescent heterocyclic moiety. This methodology (Figure 5), although not used for display technology yet, seems to offer immense practical utility and potential for application in display-based selection.

Azide-Alkyne Coupling

Copper catalyzed Azide-Alkyne Click (CuAAC) reaction90, 91 needs no introduction and remains one of the most versatile and practically useful bioconjugation reaction (for some reviews see92-97). It has been exploited widely for peptide cyclization in solid phase 98 and solution phase peptide synthesis.9 9 -101 Its underutilization in macrocyclization of peptides for display technologies, however, is, in part, due to the lack of compatibility with nucleotides102-104 (with RNA in particular). RNA is susceptible to oxidation and degrades quickly in presence of Cu in aqueous medium.105 Use of acetonitrile as cosolvent, Cu stabilizing ligands and degassing buffer solutions are some of the ways to prevent mRNA degradation when using CuAAC reaction. Additionally, since double incorporation of both azide and alkyne bearing unnatural amino acids is rather tedious and low yielding, the use of this strategy for preparing monocyclic peptide

L M G HS

A L M NH G S G

O HN

N G

Figure 5. Cyclization via Michaels addition. Model peptide with vinylglycine isomerising to dehydrobutyrine on heating to 95˚C and subsequent intramolecular Michael addition by cysteine thiol to give the macrocycle. 16 | December 2021

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libraries is virtually unreported. This strategy has been proven to be valuable for producing bicyclic libraries in particular. Suga lab in 2008 reported first double incorporation of azide and alkyne106 bearing unnatural amino acids azidohomoalanine (Aha) and propargylglycine (Pgl) respectively using Leu codon CUC for Aha and Thr codon ACC for Pgl. This orthogonal pair was expressed along with another reacting pair 4-(2-Chloroacetyl)aminobutyric acid (Cab) and cysteine to generate a bicyclic peptide scaffold (Figure 6). Hartman’s group utilized the CuAAC reaction generating bicyclic peptide library for mRNA display.107 β-azidohomoalanine (AzHA) and p-ethynyl phenylalanine (F-yne) were incorporated in place of methionine and phenylalanine, respectively. The second cycle was formed by two cysteine thiols reacting with dibromoxylene. They further carried out a competitive mRNA selection on streptavidin target using a library of linear, monocyclic and bicyclic peptides to investigate the effect of different ring sizes and topologies on selection results and they found all the selection winners were linear peptides. This raised the question as to why all selection winners were linear peptides with only µM KD values even though some cyclic peptides capable of exhibiting nM KD values were known. For a detailed discussion on this see.108

Backbone Cyclization

Formation of backbone cyclized peptide libraries for in vitro display technologies coupled with ribosomal translation is not possible directly because the C-terminus of the peptide is involved in genotype-phenotype linkage and is not available for cyclization reaction. This intrinsic limitation had hindered devising a display strategy of backbone cyclized peptide. This means that a new strategy is required to covalently trap peptide phynotype to the cognate genotype via non-C-terminus. To break this technical hinderance, Takatsuji et al. has devised a two-step rearrangement strategy by utilizing genetic code reprogramming to incorporate three nonproteinogenic amino acids in the peptide.109 Peptide is expressed with a thiazolidine-Cys (Thz-Cys) dipeptide initiator charged onto tRNAfMetCAU and ClAc-Cab are installed in the N-terminal region of peptide by the genetic code reprogramming (Figure 7). Continuing the elongation of arbitrary sequence of peptide (p2-W8-SFCl9), an a-thio-p-chlorophenyl-lactic acid (HSFCl) is installed to form a thioester in the backbone and Cys residue at a downstream position (generally dipeptide, e.g. Ile-Gly, are inserted between HSFCl and Cys). Upon the completion of ribosomal peptide synthesis, the Cys thiol spontaneously exchanges with the thioester bond of HSFCl, to yield an intermediate (p2-W8-sC12). The thiol group of HSFCl then reacts with the ClAc group on Cab to give a covalent thioether linkage (tcp2-W8-SC12). In the second step, mild deprotection of the Thz group on the initiator Cys gives an N-methyl-Cys residue at the

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N-terminus (tcp2-W8-SC12:deprptected), whose thiol sidechain immediately undergoes intramolecular thioester exchange followed by transfer to the N-methyl-amino group on Cys (similar to native chemical ligation) to yield backbone-cyclized peptide (bcp2-W8). Most importantly, it was demonstrated that this entire process allows to maintain the C-terminal region of peptide covalently attaching to the backbone-cyclized peptide via the thioether linkage between ClAcCab and HSFCl groups (Figure 7). Since this leaves C-terminal peptide region remaining as carboxyl group, the strategy is compatible to the RaPID display via the puromycin molecule attached to cognate mRNA, as demonstrated in this work.109

Macrocyclic Depsipeptide Formation

Cyclic depsipeptides (CDPs) are a class of naturally occurring peptides which contain one or more ester bonds and exhibit wide range of biological activities.110 The O-acyl isopeptide bond, usually formed between the hydroxyl sidechain

of serine or threonine residues and the carboxyl group of the C-terminus amino acid is stable towards esterases and proteases. Because of biological significance of CDPs, several methods for the chemical synthesis of CDPs have been developed, but none of them is applicable to the conditions required for translation where the chemistry must work at near neutral pH and mild temperature. Nagano et al. conducted a selection campaign for self-esterifying peptide species from random peptide libraries using a thioester acyl-donor, and discovered a peptide containing a short SerProCysGly (SPCG) motif that can effectively esterify on the Ser residue. It turns out that trans-thioesterification between the acyl-donor and thiol sidechain of Cys residue in the SPCG motif firstly takes place, and the resulting acyl group on Cys rapidly transfers to the hydroxyl group of Ser (Figure 8A).111 This unique chemistry was then applied for CDP synthesis. Linear peptide is expressed, where the SPCG motif in the N-terminal region, arbitrary peptide sequence,

Pgl

Aha

TCEP, Cu(I) C

SH Cl

Cab HN

Pgl

Cab

HN S

N N N

Figure 6. Cyclization of peptide via azide-alkyne coupling. Double incorporation of both azide and alkyne in translated peptides via genetic code reprogramming by Suga group and subsequent formation of bicyclic peptide in conjugation with thioether bond formation.

Figure 7. Backbone cyclization amenable to the RaPID display. (A) Non-proteinogenic thioacid HSFCl. (B) mRNA sequence coding the arbitrary peptide p2-W8. (C) Thioester exchange followed by thioether bond formation between ClAc-Cab and HSFCl groups keeps the C-terminal peptide region to the sidechain of backbone-macrocyclic peptide. Deprotection of Thz-Cys followed by spontaneous thiol-thioester exchange leads to native chemical ligation which yields the backbone cyclized peptide attached to its genotype. December 2021 | 17

References

and HSFCl are installed by the genetic code reprogramming in the FIT system. Since the thioester bond originating from the incorporation of HSFCl acts as a thioester donor, the intramolecular trans-thioesterification occurs at the Cys residue in SPCG to afford an intermediate of cyclic thiolactone; and then rapidly rearranges into the CDP (Figure 8B). In-depth studies on mutants of the SPCG motif have revealed that this motif can be relaxed to SXCX (X can be nearly any amino acids). Since this method of CDP synthesis can proceed in one-pot and also on a wide variety of peptide sequences between the SPCG and HSFCl, it is applicable to the RaPID system to screen bioactive CDPs against protein targets of interest.

extremely strong binding macrocyclic peptide ligands against a wide range of intracellular and extracellular targets. The success of FIT and other genetic code reprogramming approaches have empowered researchers to explore newer and more challenging approaches for peptide macrocyclization in order to diversify the field and break through various barriers and limitations. Many valuable bioconjugation reactions like Michael addition to α,β-unsaturated systems and various ‘click’ type reactions remain underutilized on this platform and offer great opportunity for expanding the scope and pushing boundaries of this active field. ◆

Conclusions

Acknowledgements

It becomes evident that so far, majority of chemical space for peptide macrocyclization on display platform is occupied by either bi/tri/ tetra functional crosslinker induced cyclization or thioether bond formation by incorporating N-chloroacetyl group at the initiator position using genetic code reprogramming. The later one, in particular, has been tremendously successful in producing selection results against a variety of interesting targets yielding

This work was supported by the Japan S o c i et y fo r th e Pro m oti o n of Sc i e nc e (JSPS) Grant-in-Aid for Scientific Research S (26220204) and Spe cially Promote d Research (20H05618), and Japan Agency for Medical Research and Development (AMED), Pl at fo r m Pro j e c t fo r S u p p o r ti n g D r u g Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research, JP19am0101090) to H.S.

Figure 8. One-pot ribosomal synthesis of cyclic depsipeptides (CDPs). (A) Discovery of the SPCG motif that rapidly proceed the intramolecular S-to-O acyl-transfer reaction. (B) One-pot synthesis of CDP via intramolecular trans-thioesterification followed by the intramolecular S-to-O acyl-transfer reaction. 18 | December 2021

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61. K. Sakai, T. Passioura, H. Sato, K. Ito, H. Furuhashi, M. Umitsu, J. Takagi, Y. Kato, H. Mukai, S. Warashina, M. Zouda, Y. Watanabe, S. Yano, M. Shibata, H. Suga and K. Matsumoto, Nature Chemical Biology, 2019, 15, 598-606. 62. K. Ito, K. Sakai, Y. Suzuki, N. Ozawa, T. Hatta, T. Natsume, K. Matsumoto and H. Suga, Nature Communications, 2015, 6, 6373. 63. X. Song, L.-y. Lu, T. Passioura and H. Suga, Organic & Biomolecular Chemistry, 2017, 15, 5155-5160. 64. Y. Hayashi, J. Morimoto and H. Suga, ACS Chemical Biology, 2012, 7, 607-613. 65. T. Kawakami, T. Ishizawa, T. Fujino, P. C. Reid, H. Suga and H. Murakami, ACS Chemical Biology, 2013, 8, 1205-1214. 66. H. Hirose, T. Hideshima, T. Katoh and H. Suga, ChemBioChem, 2019, 20, 2089-2100. 67. K. Iwasaki, Y. Goto, T. Katoh, T. Yamashita, S. Kaneko and H. Suga, Journal of Molecular Evolution, 2015, 81, 210-217. 68. S. A. K. Jongkees, S. Caner, C. Tysoe, G. D. Brayer, S. G. Withers and H. Suga, Cell Chemical Biology, 2017, 24, 381-390. 69. H. Yu, P. Dranchak, Z. Li, R. MacArthur, M. S. Munson, N. Mehzabeen, N. J. Baird, K. P. Battalie, D. Ross, S. Lovell, C. K. S. Carlow, H. Suga and J. Inglese, Nature Communications, 2017, 8, 14932. 70. T. Passioura, K. Watashi, K. Fukano, S. Shimura, W. Saso, R. Morishita, Y. Ogasawara, Y. Tanaka, M. Mizokami, C. Sureau, H. Suga and T. Wakita, Cell Chemical Biology, 2018, 25, 906-915.e905. 71. T. E. McAllister, T. L. Yeh, M. I. Abboud, I. K. H. Leung, E. S. Hookway, O. N. F. King, B. Bhushan, S. T. Williams, R. J. Hopkinson, M. Münzel, N. D. Loik, R. Chowdhury, U. Oppermann, T. D. W. Claridge, Y. Goto, H. Suga, C. J. Schofield and A. Kawamura, Chemical Science, 2018, 9, 4569-4578. 72. T. Passioura, W. Liu, D. Dunkelmann, T. Higuchi and H. Suga, Journal of the American Chemical Society, 2018, 140, 11551-11555. 73. V. A. Haberman, S. R. Fleming, T. M. Leisner, A. C. Puhl, E. Feng, L. Xie, X. Chen, Y. Goto, H. Suga, L. V. Parise, D. Kireev, K. H. Pearce and A. A. Bowers, ACS Medicinal Chemistry Letters, 2021, 12, 18321839. 74. M. Nawatha, J. M. Rogers, S. M. Bonn, I. Livneh, B. Lemma, S. M. Mali, G. B. Vamisetti, H. Sun, B. Bercovich, Y. Huang, A. Ciechanover, D. Fushman, H. Suga and A. Brik, Nature Chemistry, 2019, 11, 644-652. 75. S. T. P. Tran, C. J. Hipolito, H. Suzuki, R. Xie, H. D. Kim Tuyen, P. t. Dijke, N. Terasaka, Y. Goto, H. Suga and M. Kato, Biochemical and Biophysical Research Communications, 2019, 516, 445-450. 76. Y. Huang, M. Nawatha, I. Livneh, J. M. Rogers, H. Sun, S. K. Singh, A. Ciechanover, A. Brik and H. Suga, Chemistry – A European Journal, 2020, 26, 8022-8027. 77. M. E. Otero-Ramirez, K. Matoba, E. Mihara, T. Passioura, J. Takagi and H. Suga, RSC Chemical Biology, 2020, 1, 26-34. 78. J. Johansen-Leete, T. Passioura, S. R. Foster, R. P. Bhusal, D. J. Ford, M. Liu, S. A. K. Jongkees, H. Suga, M. J. Stone and R. J. Payne, Journal of the American Chemical Society, 2020, 142, 9141-9146. 79. Q. Xie, M. M. Wiedmann, A. Zhao, I. R. Pagan, R. P. Novick, H. Suga and T. W. Muir, Chemical Communications, 2020, 56, 11223-11226. 80. K. Patel, L. J. Walport, J. L. Walshe, P. D. Solomon, J. K. K. Low, D. H. Tran, K. S. Mouradian, A. P. G. Silva, L. Wilkinson-White, A. Norman, C. Franck, J. M. Matthews, J. M. Guss, R. J. Payne, T. Passioura, H. Suga and J. P. Mackay, Proceedings of the National Academy of Sciences, 2020, 117, 26728. 81. N. K. Bashiruddin, M. Hayashi, M. Nagano, Y. Wu, Y. Matsunaga, J. Takagi, T. Nakashima and H. Suga, Proceedings of the National Academy of Sciences, 2020, 117, 31070. 82. J. M. Rogers, M. Nawatha, B. Lemma, G. B. Vamisetti, I. Livneh, U. Barash, I. Vlodavsky, A. Ciechanover, D. Fushman, H. Suga and A. Brik, RSC Chemical Biology, 2021, 2, 513-522.

83. D. J. Ford, N. M. Duggan, S. E. Fry, J. Ripoll-Rozada, S. M. Agten, W. Liu, L. Corcilius, T. M. Hackeng, R. van Oerle, H. M. H. Spronk, A. S. Ashhurst, V. Mini Sasi, J. A. Kaczmarski, C. J. Jackson, P. J. B. Pereira, T. Passioura, H. Suga and R. J. Payne, Journal of Medicinal Chemistry, 2021, 64, 78537876. 84. E. Stefan, R. Obexer, S. Hofmann, K. Vu Huu, Y. Huang, N. Morgner, H. Suga and R. Tampé, Elife, 2021, 10, e67732. 85. Y. Sako, Y. Goto, H. Murakami and H. Suga, ACS Chemical Biology, 2008, 3, 241-249. 86. N. Bionda, A. L. Cryan and R. Fasan, ACS Chemical Biology, 2014, 9, 2008-2013. 87. N. Bionda and R. Fasan, Methods Mol Biol, 2017, 1495, 57-76. 88. Y. Goto, K. Iwasaki, K. Torikai, H. Murakami and H. Suga, Chemical Communications, 2009, 34193421. 89. Y. Yamagishi, H. Ashigai, Y. Goto, H. Murakami and H. Suga ChemBioChem, 2009, 10, 1469-1472. 90. V. V. Rostovtsev, L. G. Green, V. V. Fokin and K. B. Sharpless, Angewandte Chemie International Edition, 2002, 41, 2596-2599. 91. C. W. Tornøe, C. Christensen and M. Meldal, The Journal of Organic Chemistry, 2002, 67, 30573064. 92. S. I. Presolski, V. P. Hong and M. G. Finn, Current Protocols in Chemical Biology, 2011, 3, 153-162. 93. C. J. Pickens, S. N. Johnson, M. M. Pressnall, M. A. Leon and C. J. Berkland, Bioconjugate Chemistry, 2018, 29, 686-701. 94. R. Breinbauer and M. Köhn, ChemBioChem, 2003, 4, 1147-1149. 95. Cancer Biotherapy and Radiopharmaceuticals, 2009, 24, 289-302. 96. H. C. Kolb and K. B. Sharpless, Drug Discovery Today, 2003, 8, 1128-1137. 97. L. Liang and D. Astruc, Coordination Chemistry Reviews, 2011, 255, 2933-2945. 98. R. A. Turner, A. G. Oliver and R. S. Lokey, Organic Letters, 2007, 9, 5011-5014. 99. A. Le Chevalier Isaad, A. M. Papini, M. Chorev and P. Rovero, Journal of Peptide Science, 2009, 15, 451-454. 100. R. Jagasia, J. M. Holub, M. Bollinger, K. Kirshenbaum and M. G. Finn, The Journal of Organic Chemistry, 2009, 74, 2964-2974. 101. D. Pasini, Molecules, 2013, 18, 9512-9530. 102. R. L. Weller and S. R. Rajski, Organic Letters, 2005, 7, 2141-2144. 103. J. Gierlich, G. A. Burley, P. M. E. Gramlich, D. M. Hammond and T. Carell, Organic Letters, 2006, 8, 3639-3642. 104. M. W. Kanan, M. M. Rozenman, K. Sakurai, T. M. Snyder and D. R. Liu, Nature, 2004, 431, 545-549. 105. E. Paredes and S. R. Das, ChemBioChem, 2011, 12, 125-131. 106. Y. Sako, J. Morimoto, H. Murakami and H. Suga, Journal of the American Chemical Society, 2008, 130, 7232-7234. 107. D. E. Hacker, J. Hoinka, E. S. Iqbal, T. M. Przytycka and M. C. T. Hartman, ACS Chemical Biology, 2017, 12, 795-804. 108. D. E. Hacker, N. A. Abrigo, J. Hoinka, S. L. Richardson, T. M. Przytycka and M. C. T. Hartman, ACS Combinatorial Science, 2020, 22, 306-310. 109. R. Takatsuji, K. Shinbara, T. Katoh, Y. Goto, T. Passioura, R. Yajima, Y. Komatsu and H. Suga, Journal of the American Chemical Society, 2019, 141, 2279-2287. 110. X. Wang, X. Gong, P. Li, D. Lai and L. Zhou, Molecules, 2018, 23, 169. 111. M. Nagano, Y. Huang, R. Obexer and H. Suga, Journal of the American Chemical Society, 2021, 143, 4741-4750.

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Supramolecular Polymerization:

Personal History and Outlook

Takuzo Aida

Takuzo Aida obtained his D.Eng. in Polymer Chemistry from The University of Tokyo in 1984 and began his academic career, working on precision polymer synthesis as an assistant professor at the same university. In 1996, he was promoted to full professor of Chemistry and Biotechnology in the School of Engineering at the University of Tokyo. Since 2013, he has been serving as Deputy Director of the RIKEN Center for Emergent Matter Science. He is recognized as a pioneer in the field of supramolecular polymers and has expanded the basic concept into a diverse range of functional materials such as “bucky gels”, “aqua materials”, and self-healable polymers. He has been recognized by numerous awards, including the Japan Academy Prize (2018), the Royal Netherlands Academy of Arts and Sciences (2020), and the U. S. National Academy of Engineering (2021).

20 | December 2021

Kiyoshi Morishita

Kiyoshi Morishita was born and raised in Canada and received his B.A.Sc. in Nanotechnology Engineering from the University of Waterloo, Canada in 2016. Thereafter he moved to Japan to pursue his graduate studies with Professor Takuzo Aida at the University of Tokyo. He obtained his M.Eng. in 2019 and is now a doctoral student, with a Research Fellowship for Young Scientists (DC1) from the Japan Society for the Promotion of Science (JSPS). His research interests include supramolecular, nanoparticle, and polymer chemistry and the functionalization and assembly of proteins. His current project is focused on the supramolecular assembly of the biomolecular machine GroEL into materials with various structures. Outside of the lab he enjoys dragon boat racing, cycling and photography.

2020 was a very special year for polymer science as the 100-year anniversary of its initiation by Staudinger. The past 100 years have been a prosperous time for polymer science, filled with discovery and innovation. Since plastics are lightweight, mechanically robust, and cheap, their use has proliferated, becoming pervasive in all sectors of society and ushering in the so-called heyday of plastics. At the same time however, the plastics and rubbers developed by polymer science have caused catastrophic damage to the environment as long-lasting wastes continue to accumulate in the disposable age. Incinerating these materials generates carbon dioxide, which accelerates global warming, while dumping them into the ocean results in their eventual disintegration into microplastics, small pieces that are consumed and accumulate in the food chain. As of 2015, only 9% of the 6300 million metric tons of plastics produced had been recycled,1 and unless farreaching policies are adopted in the next decade to change the social structure that has so far been dependent on disposable polymers, global warming will continue to accelerate and it will certainly be difficult to pass on a livable earth to future generations. Although this crisis is widely acknowledged, society has thus far been unable to give up such convenient and cheap materials. If we fail to shift our economic priorities or invent new materials as alternatives, it will be impossible to escape from this plastic world. www.facs.website

Towards a Sustainable Future

By Takuzo Aida and Kiyoshi Morishita https://doi.org/10.51167/acm00019

WHY ARE TRADITIONAL polymeric materials so pervasive? Because the constituent monomer units that make up polymeric materials are covalently linked, these materials are chemically and mechanically tough, benefiting many applications, but significantly slowing their breakdown. If the constituent monomers were connected by noncovalent bonds, the resulting polymers could be readily depolymerized back to the monomers and recycled. Such polymers are called “supramolecular polymers” and were invented three decades ago. Because of their intrinsically dynamic nature, supramolecular polymers are self-repairable and reconfigurable, meaning that the monomer sequence in a copolymer may in principle be transformable into a different sequence, for example by applying external energy. One can then anticipate that such materials are adaptive, exhibiting intelligent structural transformations in response to changes in the surrounding environment. For supramolecular polymerization, a diverse range of monomers such as biomolecular machines that are not amenable to conventional polymerization can be used (Fig. 2e). Supramolecular polymer materials have long been considered fragile, weak, and unsuitable as structure-forming materials due to the dynamic nature of noncovalent bonds that connect their constituent monomer units. www.asiachem.news

However, as these concerns are addressed, they may gradually replace traditional plastics to a certain extent in various applications. The reconfigurable and self-repairable nature of supramolecular polymers and their ability to readily be recycled to the monomer state will result in extended product lifespans, reducing energy and raw materials demands in manufacturing, and also reductions in the generation of the pervasive plastic and microplastic wastes that currently harm the environment. In 1988, 68 years after polymer science was established as a new research field, Aida published, as the first author, a short paper featuring a polymer-like one-dimensional assembly as a prototype of supramolecular polymers, in which the constituent monomer units are connected by a van der Waals interaction (Fig. 1b).2 Before this work, he had been involved in a project for developing precision covalent polymerization using specially designed metal complexes as polymerization initiators. During the course of this study, he developed “immortal polymerization”, a catalytic version of living polymerization, in which polymers with uniform molecular weights are catalytically produced when protonic compounds as chain transfer reagents are present in combination with his special initiator for the living polymerization. In immortal polymerization, polymer chains are formed quantitatively from protonic

compounds. Hence, he envisioned the incorporation of a polymer chain of predetermined length into protonic groups in functional compounds and succeeded in the synthesis of an amphiphilic porphyrin with four water-soluble polyether side chains using tetrakis(p-hydroxyphenyl)porphyrin as a protonic compound (Fig. 1a). Due to the water-solubility of the side chains, the amphiphilic compounds with long side chains appeared to be soluble in water. However, those with shorter side chains turned out to stack in a face-to-face manner via the core porphyrin, forming a 1D polymeric assembly. One month after this work was published, Aida noticed that the lid of the flask containing an aqueous solution of this supramolecular polymer had come off. Examining the flask, he was surprised to find the appearance of numerous cracks, which were not actually cracks but rather thin fibers of the supramolecular polymer generated by the evaporation of water from its aqueous solution. Although fascinated by the beauty of the large number of uniform fibers with a metallic luster, he never published this interesting observation or related papers, as he did not have an opportunity to follow up until he became an independent PI. In the meantime, the concept of supramolecular polymers began to take hold. Many early works focused on the assembly of molecules with December 2021 | 21

complementary H-bonding moieties. Onedimensional H-bonded chains were shown to form in the solid state by the assembly of a dipyridone with non-self-complimentary H-bonding units by Wuest,3 melamine and cyanuric acid derivatives by Whitesides,4 and triaminopyrimidine and barbituric acid derivatives by Lehn.5 Lehn also extended supramolecular polymers to the liquid crystalline state with a triple H-bonded design of monomers that assemble into chiral fiber-like structures.6 Ghadiri expanded on the scope of monomers by introducing the H-bond directed stacking of cyclic peptides.7 Percec reported on the columnar supramolecular polymerization of branched oligomers as monomers.8 Finally, Meijer reported his seminal 1997 paper on a supramolecular polymer consisting of a quadruple hydrogen-bonding interaction9 and pushed the research field to the forefront of chemistry by disclosing for the first time the viscoelastic properties of supramolecular polymers in solution and under dry conditions. Aida reinitiated the project on supramolecular polymerization nearly 10 years after his pioneering paper in 1988 and reported the first self-sorting phenomenon in the stereochemical copolymerization of two enantiomers of a chiral monomer in 2002.10 In 2004, he reported one of his seminal works featuring the nanotubular supramolecular polymerization of an amphiphilic molecular graphene to obtain electronically conductive nanotubes with a very high structural integrity (Fig. 2b).11 Despite the prevalence of supramolecular polymers with H-bonding interactions, analogous to his original work published in 1988, he employed only a van der Waals interaction to connect the monomer units, and further obtained radial

and linear supramolecular block copolymers in 200612 and 2011,13 respectively. In 2020, Aida had the opportunity to jointly write a review article with Bert Meijer on supramolecular polymers for a special issue of the Israel Journal of Chemistry in celebration of the 100-year anniversary of polymer science.14f The joint review article daringly included the special subtitle, “We’ve Come Full Circle”, as a reference to the historical background of polymer science. Before polymer science was launched as a new field of research in 1920, there had been a long-term debate between two groups, pushing the “macromolecular theory” by Staudinger and the “colloidal theory” by van’t Hoff, Fischer, Wieland, et al. After Staudinger experimentally substantiated the existence of long and gigantic molecules in 1920,15 the “colloid theory” declined. However, it is meaningful to consider the idea of supramolecular polymerization, which started in 1988, to be a modernized version of the “colloid theory” with a flavor of physical organic chemistry. Over the past 30 years, supramolecular polymerization has grown into a very hot research field,14 in which our group has enjoyed contributing to its progress and conceptual expansion. Our major achievements include nanotubular supramolecular polymerization (Fig. 2b),11-13,16,17 living chain-growth supramolecular polymerization (Fig. 2f),18 supramolecular block copolymerization,13,19 stereoselective supramolecular polymerization,16a and thermally bisignate supramolecular polymerization.20 These concepts are integral to conventional polymer science and our contributions filled in the critical gap between supramolecular and conventional

Figure 1. (a) Synthetic scheme for the synthesis of an amphiphilic porphyrin with PEG side chains of well-defined chain lengths. (b) 1D polymeric assembly of an amphiphilic porphyrin in water as a prototype of supramolecular polymerization.2 22 | December 2021

polymerizations. Furthermore, we extended the basic concept of supramolecular polymerization to the development of a variety of innovative soft materials such as bucky gels (Fig. 2a),21 carbon nanotubes noncovalently crosslinked by ionic liquids, and their use in the first metal-free stretchable electronics22 and battery-driven dry actuators,23 aquamaterials (Fig. 2c),24 robust and dynamic materials consisting mostly of water, with small amounts of additives, ATP-responsive nanotubular DDS carriers using the biological machine GroEL as the monomer (Fig. 2e),25 and stimuli-responsive columnar liquid crystalline materials (Figs. 2d and 2g).26 In 2018, our group also reported a major advancement towards mechanically robust materials with self-repairable features.27a We showed that low molecular weight ether thiourea oligomers (Fig. 3a), which can quickly and easily self-heal under ambient temperatures by swapping H-bonded thiourea pairs at fractured edges, display high mechanical robustness due to a dense nonlinear array of H-bonds (Fig. 3b). This work swept away the preconceptions that mechanically robust polymers necessarily have ultra-high molecular weights and are unable to self-heal due to the sluggish diffusion of such long polymer chains. We recently reported an updated version of this material in which copolymerization with dicyclohexylmethane thiourea units imparts humidity resistance to the material, expanding the potential range of usage conditions (Figs. 3c and 3d).27b Considering the short polymer chains employed in these reports, the next target is to further reduce their molecular weights into a range of ordinary monomers, which may unlock the full potential of supramolecular polymer materials in terms of complete reconfigurability and recyclability. Lastly, we highlight our new achievement, “solvent-free autocatalytic supramolecular polymerization (SF-ASP)” (Fig. 4),19 its significance in the field and relevance to the emergent environmental issues caused by plastic waste introduced above. Historically, supramolecular polymerization has been extensively studied in solution, with its mechanical interpretations being greatly elaborated in the last decade. Nevertheless, much work remains when considering the practical applications of supramolecular polymers. One common concern is that the structure of a supramolecular polymer in solution is not guaranteed to be the same as that in the dry state. This concern would be avoided if supramolecular polymers were synthesized under solvent-free conditions. Note also that solvent-free chemical manufacturing is an awaited green technology for the realization of a sustainable society, because of its reductions in raw materials usage, pollution and CO2 emission. However, there exists a preconception that supramolecular polymerization under solvent-free conditions may proceed heterogeneously, www.facs.website

resulting in polymeric assemblies of poor structural integrity. Our new finding of SF-ASP casts aside this preconception and features two unexpected advantages, that under solvent-free conditions, the monomer is produced in an autocatalytic manner from its precursor and that polymerization occurs in a living

manner without any inhibition to afford block copolymers. We serendipitously found the basic principle of SF-ASP while investigating the ferroelectric nature of H-bonding phthalonitrile derivatives (PNC4). Upon heating a powdery sample of PNC4 sandwiched between glass plates, we

noticed that, approximately 4 h after heating at 160°C, numerous thin, green-colored fibers composed of the corresponding phthalocyanine (PCC4) (Fig. 4b) began to appear and rapidly elongate (Fig. 4c). After 24 h, the reaction mixture no longer included the precursor PNC4 and we obtained analytically pure PCC4

Figure 2. Major achievements in supramolecular polymerization and related materials. (a) Bucky gels, materials made from the dispersion of carbon nanotubes in ionic liquid – adapted from Science.21a (b) Nanotubular supramolecular polymerization – adapted from Science.11 (c) Aquamaterials, mechanically robust materials made from water with a small amounts of additives.24 (d) Ferroelectric columnar liquid crystal – adapted from Science.26a (e) Nanotube made by the chaperonin protein GroEL and its use as an ATP-responsive drug delivery system – adapted from Nature Chemistry.25 (f) Living chain growth (ring opening) supramolecular polymerization – adapted from Science.18 (g) Supramolecular polymerization in mesogenic media affording a stimuli responsive coreshell columnar liquid crystal – adapted from Science.26b

www.asiachem.news

December 2021 | 23

in an exceptionally high yield of 83% by simply washing the reaction mixture with methanol. This value far exceeds the 20 to 25% yield reported for the typical solution-phase synthesis of phthalocyanine derivatives. As illustrated in Fig. 4a, the crystalline fibers preorganize the monomer precursor PNC4 on Figure 3 (left): Seal-healable and mechanically robust polymers. (a) Chemical structure and demonstration of the quick self-healing of poly(ether thiourea) at ambient temperatures.27a (b) Nonlinear H-bonding arrays ensure the mechanical robustness of the polymer. (c) Chemical structure of the humidity resistant, self-healable, and mechanically robust poly(ether thioureaco-dicyclohexylmethane thiourea).27b (d) Image of the material shown in (c). Figure 4 (below): (a) Schematic representation of solvent-free autocatalytic supramolecular polymerization (SF-ASP).19 (b) Chemical structures of the phthalonitrile precursor, PNC4, and the phthalocyanine monomer, PCC4, formed at the cross-sectional ends of the polymer chain. (c) Optical images of PNC4, sandwiched between glass plates at 160°C, at different reaction times – adapted from Nature Materials.

24 | December 2021

www.facs.website

their cross-sectional ends via H-bonding and dipole–dipole interactions, thereby enabling reductive cyclotetramerization of PNC4 into PCC4, the monomer for supramolecular polymerization, in an autocatalytic manner. The newly formed PCC4 monomer remains at the cross-sectional ends and likewise autocatalyzes the next cycle of reductive cyclotetramerization of PNC4 into PCC4. The repetition of these elementary steps results in elongation of the crystalline fibers of supramolecularly polymerized PCC4. Terminal coupling of the crystalline fibers, which would lead to a decrease in the total cross-sectional area for autocatalysis, barely took place in SF-ASP, likely due to their very sluggish diffusion in the hot melt of PNC4 under solvent-free conditions. When metal oleates are present, SF-ASP produces metallophthalocyanines as crystalline fibers again in exceptionally high yields, which grow in both directions without terminal coupling until the phthalonitrile precursors are completely consumed. Taking advantage of the living nature of this supramolecular polymerization, multistep SF-ASP without/with metal oleates results in the precision synthesis of ABA and ABCBA types of multi-block supramolecular copolymers. The finding of all of these qualities of SF-ASP that occur only under environmentally friendly solvent-free conditions was beyond our expectations. This demonstrates the significant potential of supramolecular polymerization to bring about change in chemical manufacturing processes and in the utilization of polymeric materials for the realization of a sustainable society. We hope that this report will encourage polymer chemists to focus much needed attention on the solid-state properties of supramolecular polymers. Certainly, to have a chance at finding widespread practical use and replacing traditional polymers, supramolecular polymer materials showing mechanical robustness under a range of usage conditions must be realized. Although dynamicity and mechanical robustness of polymeric materials have been considered mutually exclusive, by an advanced molecular design, one might sweep away this preconception, and make mechanically robust polymers that are recyclable or structurally reorganizable at the monomer level under particular conditions. We envision a world in which society overcomes its chronic dependency on traditional plastics, through the gradual adoption of supramolecular polymers and other green materials. The intrinsically reversible nature of noncovalent bonds affords supramolecular polymers the potential for self-healing, reconfigurability and complete recycling, enabling materials whose lifespan can be extended and whose properties can be enhanced in subsequent life cycles. ◆ www.asiachem.news

References

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H. Beijer, L. Brunsveld, B. J. B. Folmer, J. H. K. Ky Hirschberg, R. F. M. Lange, J. K. L. Lowe, and E. W. Meijer, Science 1997, 278, 1601–1604. 10. Homochiral Supramolecular Polymerization of an “S”-Shaped Chiral Monomer: Translation of Optical Purity into Molecular Weight Distribution. Y. Ishida and T. Aida, J. Am. Chem. Soc. 2002, 124, 14017–14019. 11. Self-Assembled Hexa-peri-hexabenzocoronene Graphitic Nanotube. J. P. Hill, W. Jin, A. Kosaka, T. Fukushima, H. Ichihara, T. Shimomura, K. Ito, T. Hashizume, N. Ishii, and T. Aida, Science 2004, 304, 1481–1483. 12. Photoconductive Coaxial Nanotubes of Molecularly Connected Electron Donor and Acceptor Layers. Y. Yamamoto, T. Fukushima, Y. Suna, N. Ishii, A. Saeki, S. Seki, S. Tagawa, M. Taniguchi, T. Kawai, and T. Aida, Science 2006, 314, 1761–1764. 13. Supramolecular Linear Heterojunction Composed of Graphite-Like Semiconducting Nanotubular Segments. W. Zhang, W. Jin, T. Fukushima, A. Saeki, S. Seki, and T. Aida, Science 2011, 334, 340–343. 14. (a) Supramolecular Polymerization. T. F. A. De Greef, M. M. J. Smulders, M. Wolffs, A. P. H. J. Schenning, R. P. Sijbesma, and E. W. Meijer, Chem. Rev. 2009, 109, 5687–5754. (b) Functional Supramolecular Polymers. T. Aida, E. W. Meijer, and S. I. Stupp, Science 2012, 335, 813–817. (c) Supramolecular Polymers: Historical Development, Preparation, Characterization, and Functions. L. Yang, X. Tan, Z. Wang, and X. Zhang, Chem. Rev. 2015, 115, 7196–7239. (d) Supramolecular polymerization through kinetic pathway control and living chain growth. M. Wehner and F. Würthner, Nat. Rev. Chem. 2020, 4, 38–53. (e) Supramolecular Polymerization: A Conceptual Expansion for Innovative Materials. P. K. Hashim, J. Bergueiro, E. W. Meijer, and T. Aida, Prog. Polym. Sci. 2020, 105, 101250– 101268. (f) Supramolecular Polymers – we’ve Come Full Circle. T. Aida and E.W. Meijer, Isr. J. Chem. 2020, 60, 33–47. 15. Über Polymerisation. H. Staudinger, Ber. Dtsch. Chem. Ges. 1920, 53, 1073–1085. 16. (a) Self-assembled graphitic nanotubes with one-handed helical arrays of a chiral amphiphilic molecular graphene. W. Jin, T. Fukushima, M. Niki, A. Kosaka, N. Ishii, and T. Aida, Proc. Natl. Acad. Sci. USA 2005, 102, 10801–10806. (b) Ambipolar-transporting coaxial nanotubes with a tailored molecular graphene–fullerene heterojunction. Y. Yamamoto, G. Zhang, W. Jin, T. Fukushima, N. Ishii, A. Saeki, S. Seki, S. Tagawa, T. Minari, K. Tsukagoshi, and T. Aida, Proc. Nat. Acad. Sci. USA 2009, 106, 21051–21056. 17. Manipulation of Discrete Nanostructures by Selective Modulation of Noncovalent Forces. T. Fukino, H. Joo, Yuki Hisada, M. Obana H. Yamagishi, T. Hikima, M. Takata, N. Fujita, and T. Aida, Science 2014, 344, 499–504. 18. A rational strategy for the realization of chain-growth supramolecular polymerization. J. Kang, D. Miyajima, T. Mori, Y. Inoue, Y. Itoh, and T. Aida, Science 2015, 347, 646–651. 19. Solvent-free autocatalytic supramolecular polymerization. Z. Chen, Y. Suzuki, A. Imayoshi, X. Ji, K. V. Rao, Y. Omata, D. Miyajima, E. Sato, A. Nihonyanagi, and T. Aida, Nat. Mater. 2021, in press. 20. Thermally bisignate supramolecular polymerization. K. V. Rao, D. Miyajima, A. Nihonyanagi, and T. Aida, Nat. Chem. 2017, 9, 1133–1139. 21. (a) Molecular Ordering of Organic Molten Salts Triggered by Single–Walled Carbon Nanotubes. T. Fukushima, A. Kosaka, Y. Ishimura, T. Yamamoto, T. Takigawa, N. Ishii, and T. Aida, Science 2003, 300, 2072–2074. (b) Ultrahighthroughput exfoliation of graphite into pristine ‘single-layer’ graphene using microwaves and molecularly engineered ionic liquids. M. Matsumoto, Y. Saito, C. Park, T. Fukushima, and T. Aida, Nat. Chem. 2015, 7, 730–736. 22. (a) A Rubberlike Stretchable Active Matrix Using Elastic Conductors. T. Sekitani, Y. Noguchi, K. Hata, T. Fukushima, T. Aida, and T. Someya, Science 2008, 321, 1468–1472. (b) Stretchable active-matrix organic light-emitting diode display using printable elastic conductors. T. Sekitani, H. Nakajima, H. Maeda, T. Fukushima, T. Aida, K. Hata, and T. Someya, Nat. Mater. 2009, 8, 494–499. 23. Fully Plastic Actuator through Layer-by-Layer Casting with Ionic-Liquid-Based Bucky Gel. T. Fukushima, K. Asaka, A. Kosaka, and T. Aida, Angew. Chem. Int. Ed. 2005, 44, 2410–2413. 24. (a) High-water-content mouldable hydrogel by mixing clay and a dendritic molecular binder. Q. Wang, J. L. Mynar, M. Yoshida, E. Lee, M. Lee, K. Okuro, K. Kinbara, and T. Aida, Nature 2010, 463, 339–343. (b) An anisotropic hydrogel with electrostatic repulsion between cofacially aligned nanosheets. M. Liu, Y. Ishida, Y. Ebina, T. Sasaki, T. Hikima, M. Takata, and T. Aida, Nature 2015, 517, 68–72. (c) Thermoresponsive actuation enabled by permittivity switching in an electrostatically anisotropic hydrogel. Y. S. Kim, M. Liu, Y. Ishida, Y. Ebina, M. Osada, T. Sasaki, T. Hikima, M. Takata, and T. Aida, Nat. Mater. 2015, 14, 1002–1007. 25. Biomolecular robotics for chemomechanically driven guest delivery fueled by intracellular ATP. S. Biswas, K. Kinbara, T. Niwa, H. Taguchi, N. Ishii, S. Watanabe, K. Miyata, K. Kataoka, and T. Aida, Nat. Chem. 2013, 5, 613–620. 26. (a) Ferroelectric Columnar Liquid Crystal Featuring Confined Polar Groups Within Core–Shell Architecture. D. Miyajima, F. Araoka, H. Takezoe, J. Kim, K. Kato, M. Takata, and T. Aida, Science 2012, 336, 209–213. (b) Nematic-to-columnar mesophase transition by in situ supramolecular polymerization. K. Yano, Y. Itoh, F. Araoka, G. Watanabe, T. Hikima, and T. Aida, Science 2019, 363, 161–165. 27. (a) Mechanically robust, readily repairable polymers via tailored noncovalent cross-linking. Y. Yanagisawa, Y. Nan, K. Okuro, and T. Aida, Science 2018, 359, 72–76. (b) Mechanically Robust, Self-Healable Polymers Usable under High Humidity: Humidity-Tolerant Noncovalent Cross-Linking Strategy. Y. Fujisawa, A. Asano, Y. Itoh, and T. Aida, J. Am. Chem. Soc. 2021, 143, 15279–15285.

December 2021 | 25

Cooperative Catalysis for Organic Synthesis

By Yoshiaki Nakao https://doi.org/10.51167/acm00020

Yoshiaki Nakao

Yoshiaki Nakao studied chemistry at Kyoto University (PhD in 2005 under the tutelage of Profs. Tamejiro Hiyama and Eiji Shirakawa), Yale University (Prof. John F. Hartwig), and the MaxPlanck-Institut für Kohlenforschung (Prof. Manfred T. Reetz). He has been a faculty member at Kyoto University since 2002 and is currently a full professor. He is interested in developing new reactions, reagents, and catalysts in order to streamline organic synthesis. He has received Mitsui Chemicals Catalysis Science Award of Encouragement in 2009, Merck–Banyu Lectureship Award in 2010, The Chemical Society of Japan Award for Young Chemists in 2011, The Young Scientist’s Prize from the Ministry of Education, Culture, Sports, Science and Technology in 2011, Tetrahedron Young Investigator Award in 2015, Mukaiyama Award in 2017, David Ginsburg Memorial Lectureship in 2018, and JSPS Prize in 2019 among others.

26 | December 2021

Metal catalysis has driven innovation in organic synthesis during the last half-century. An alternative to the traditional strategy of developing catalysts with a single metal center is the combined use of more than one metal complex and design of their cooperative action to achieve new synthetic transformations. With the rich chemistry of metal catalysis that has been developed over the last five decades, as well as recent advancements in organocatalysis and emerging photoredox catalysis, one can imagine that cooperativity of these known catalytic approaches could enable novel synthetic transformations that have been highly challenging via conventional single-site metal catalysis. METAL CATALYSIS IS indispensable in contemporary organic synthesis for the production of useful substances, such as materials and drugs, for modern human life. Many useful metal-catalyzed organic reactions have enabled the cleavage and formation of covalent bonds, which is otherwise challenging, and led to innovation in organic synthesis through providing atom- and step-economical routes to target molecules. The potential of metal catalysts to further unveil novel chemical transformations is infinite because of the different reactivities of the metal elements of the periodic table and the diversity of ligands to finely tune the reactivity of the metal centers. Nevertheless, the development of totally new metal catalysts to allow novel and useful chemical reactions is often laborious. Transition metal complexes show a variety of different types of reactions, such as oxidative addition, transmetalation, olefin insertion, reductive elimination, etc. The reactivity and selectivity of these elemental reactions depend heavily on the electronic and steric features of the metal complexes and can be precisely controlled by their formal oxidative states and the ligands binding to the metal centers. Consequently, a variety of single-metal-based catalysts bearing different transition metals

and ligands have been identified to achieve useful reactions such as cross-coupling, olefin metathesis, olefin/ alkyne-functionalization, and oxidation/reduction reactions, among others. These catalytic reactions consist of various elemental reactions such as those mentioned above. For example, the catalytic cycle of Pd-catalyzed cross-coupling reactions can be expressed roughly via three steps: oxidative addition of an electrophile, transmetalation with a nucleophile, and C–C bond-forming reductive elimination (Scheme 1). Each step favors different electronic and steric characteristics with regard to the Pd center. The initial oxidative addition proceeds faster with electron-rich Pd species, and thus electron-donating ligands are favored to make the Pd center nucleophilic, whereas electrophilic Pd(II) undergoes transmetalation efficiently. Although the rate of the reductive elimination step does not usually affect the overall reaction rate, it can be accelerated by ligands with electron-withdrawing π-accepting nature. Accordingly, an optimum catalyst must have well-balanced electronic and steric characteristics to enable the overall catalytic cycle. This may limit the scope of electrophiles and nucleophiles that can participate in the cross-coupling reactions. www.facs.website

Cooperative synergistic catalysis

To avoid this dilemma and promote catalytic cycles requiring distinct electronic properties in each step, the use of two different metal catalysts can be considered.1 One possible scenario is the use of a metal catalyst that activates electrophiles with another that preferentially reacts with nucleophiles. The thus-formed organometallic intermediates would react with each other to afford the products. This type of synergistic cooperative metal catalysis (Scheme 2a) has emerged as a powerful strategy to significantly expand the scope of cross-coupling reactions in recent years.2 The pioneering contribution of this type of synergistic cooperative metal/metal catalysis for cross-coupling was reported in 1975 by Japanese chemists Sonogashira, Tohda, and Hagihara (Scheme 2b).3 This reaction, which is now commonly called the Hagihara–Sonogashira coupling reaction, allows the coupling of organic halides and pseudo-halides with terminal alkynes via cooperative Pd/Cu catalysis. Pd(0) activates the organic halides through oxidative addition to give an electrophilic Pd(II) species, whereas Cu(I) reacts with terminal alkynes to generate Cu(I) acetylides as nucleophilic organometallic intermediates. These react with each other to give diorgano-Pd(II) intermediates that afford the product through C–C bond-forming reductive elimination. After 30 years, the scope of substrates for the Cu cycle was expanded to arenecarboxylic acids, which undergo decarboxylation to generate arylcopper nucleophiles. The decarboxylative coupling of carboxylic acids with organic electrophiles was established using cooperative Pd/Cu catalysis by Gooßen and coworkers (Scheme 2c).4 The Cu(I) cycle was then further developed to accommodate multi-step transformations to generate organocopper nucleophiles. We demonstrated the first example of such a system by integrating the functionalization of alkenes in the Cu(I) cycle to develop an arylboration reaction (Scheme 2d).5 This reaction can be useful to give highly functionalized organoboron compounds, which play versatile and important roles in modern organic synthesis. Combinations of other transition metals for cooperative synergistic catalysis have also been reported. A pioneering example was reported by Sawamura, Sudoh, and Ito, who showed that the combination of Pd www.asiachem.news

and Rh, both bearing chiral ligands, effectively catalyzed the allylation of α-cyanoesters to construct quaternary carbon stereocenters (Scheme 3a).6 It is essential for both metal catalysts to be optically pure to obtain high enantioselectivity in the allylation reaction. Catalytic C–H functionalization is one of the most important and extensively studied organic transformations in modern organic synthesis.7 Cooperative synergistic catalysis involving C–H activation represents an ideal strategy to expand the scope of C–H functionalization, because metal complexes effective for C–H activation are not always competent for the subsequent functionalization events, in which the other metal catalyst could play a role in cooperative catalysis. Chang and coworkers reported a pioneering example using cooperative Pd/Ru catalysis (Scheme 3b).8 The Ru cycle is likely responsible for the C–H activation, and a cross-coupling-type reaction proceeds on Pd. Another challenging and useful transformation in current synthetic organic chemistry is the so-called cross-electrophile coupling reaction,9 in which two different electrophiles must be distinguished. Weix and coworkers demonstrated that cooperative synergistic Pd/Ni catalysis allowed the selective reductive cross-coupling of aryl halides and aryl triflates (Scheme 3c).10

Scheme 1: A simplified single-metal-based catalytic cycle for cross-coupling reactions. December 2021 | 27

Examples of cooperative metal/organo synergistic catalysis are also available as a result of the extensive studies on organocatalysis in the last two decades.11 Krische reported an early example in which a nucleophilic phosphine catalyst was integrated into the intramolecular Pd-catalyzed allylic alkylation reaction (Scheme 4a).12 An intermolecular variant employing an enamine catalyst was then reported by Córdova (Scheme 4b)13. More recently, carbene catalysts have been shown to participate in Pd chemistry to enable the allylic acylation reaction through the reaction of π-allylpalladium with the Breslow intermediate, as demonstrated by Ohmiya and coworkers (Scheme 4c)14. Photoredox catalysis in organic synthesis has been developed significantly in the last ten years.15 This strategy can also be successfully combined with transition metal catalysis to enable highly challenging cross-coupling-type transformations. Molander,16 Doyle, and MacMillan17 pioneered cooperative Ni/Ir photoredox catalysis to achieve novel cross-coupling-type reactions. For example, simple amino acids can participate in the Ni-catalyzed cross-coupling reaction through oxidative decarboxylation to generate radical species, which react with arylnickel intermediates to provide the products upon C–C bond-forming reductive elimination (Scheme 5). Although the proposed catalytic cycle does not involve reaction between two distinct organometallic intermediates, this particular type of cooperative catalysis has found to be highly general to overcome the limitations of cross-coupling chemistry.18

Cooperative double activation catalysis

Another effective cooperative catalytic strategy is the use of two metal complexes that react with a single substrate (double activation) to promote bond-cleaving and/or -forming events that are inaccessible or sluggish using a conventional single metal catalyst (Scheme 6a).

Scheme 2: The concept behind cooperative synergistic catalysis, and examples of Pd/Cu catalysis.

Scheme 3: Other examples of cooperative synergistic metal/ metal catalysis. 28 | December 2021

Scheme 4: Cooperative synergistic Pd/organo catalysis. www.facs.website

Combinations of Lewis-acidic metal catalysts and late transition metal catalysts have been established for cooperative double activation catalysis. Epoxides are highly versatile organic building blocks that are frequently used in organic synthesis. They have a Lewis-basic functionality that undergoes ring-opening reactions, often catalyzed by Lewis acids. Thus, the combination of Lewis acids and low-valent transition metal complexes can be envisaged for the development of novel ring-opening reactions of epoxides catalyzed uniquely via cooperative catalysis. The development of cooperative double activation catalysis for epoxides was pioneered by Coates and coworkers using an anionic cobalt catalyst bearing cationic aluminum as a Lewis-acidic counterion for the reaction of epoxides with carbon monoxide to give b-lactone products (Scheme 6b).19 The epoxides form Lewis pairs with the cationic Al center and react with the nucleophilic anionic cobalt complex to give a metallacycle intermediate, in which CO insertion into the C–Co bond

Scheme 5: Cooperative synergistic Ni/Ir photoredox catalysis.

Scheme 6: The concept behind cooperative double activation catalysis, and pioneering examples. www.asiachem.news

takes place. The lactone products are ejected to regenerate the cooperative catalyst system. Alkynes and alkenes can also serve as Lewis bases via their π-electrons. Some metal complexes are known to act as Lewis acids to form Lewis pairs with alkynes and alkenes, which in turn can act as electrophiles to react with electron-rich low-valent transition metal complexes. In an early example, the regioselective dimerization of styrene was reported by Tsuchimoto, Shirakawa, and coworkers using Pd/In as a cooperative double activation catalyst (Scheme 6c).20 Styrene is likely activated by an In Lewis acid to act as an electrophile for the Pd(0) species; the subsequent carbopalladation reaction across another styrene gives an alkylpalladium intermediate, which undergoes b-hydride elimination to afford the dimerization products. Cooperative double activation catalysis has proved to be effective for catalytic C–H functionalization. As an early example, we reported that cooperative Ni/Zn catalysis allowed C2-alkenylation of pyridine (Scheme 7a).21 Pyridine coordinates to the Lewis-acidic Zn catalyst, and is then activated by the electron-rich Ni(0). Cooperative Ni/Al catalysis with bulky ligands was shown to be useful not only for the acceleration of the C–H functionalization, but also for controlling the site-selectivity. The steric repulsion between bulky Ni and Al catalysts likely induces the high C-4 selectivity of the alkylation reaction (Scheme 7b).22 The Ni/Al catalysis was then applied to site-selective C–H functionalization of substituted benzenes. Para-selective alkylation of benzamides with alkenes was achieved using a similar bulky Ni/Al catalysis system (Scheme 7c).23 Coordination of the Lewis-basic aminocarbonyl functionality to the bulky Al Lewis acid accelerates the rate and controls the para-selectivity of C–H activation by the bulky Ni catalyst. This is in stark contrast to

Scheme 7: Cooperative double activation Ni/Al catalysis for siteselective C–H alkenylation and alkylation. December 2021 | 29

conventional single metal catalysis, which commonly proceeds at the ortho-position through directed C–H metalation, in which the carbonyl groups bind to the metal catalyst to promote C–H activation at the proximal ortho-position.24 Cooperative double activation catalysis thus offers unique opportunities for the promotion of C–H functionalization as well as control of the site-selectivity, which have been elusive by single-site catalysts. The acceleration and the control of the para-selectivity of the bulky Ni/Al catalysis system for C–H functionalization reactions has been extended to other metal-catalyzed C–H functionalizations. Ir-catalyzed arene C–H borylation has been established, and its utility and reliability have been developed over the last three decades.25 This is because the site-selectivity of the reaction can be controlled by steric factors in a highly predictable manner. For example, 1,3-di-substituted benzenes can be borylated selectively at the 5-position. However, controlling the site-selectivity can be difficult with certain arenes, such as mono-substituted and 1,2-di-substituted benzenes, because of the less-biased steric environments at the possible reaction sites; this issue has attracted great attention from synthetic organic chemists.26 We revealed that cooperative Ir/Al catalysis could provide high para-selectivity for the C–H borylation of benzamides.27 Again, the use of the bulky Al Lewis acid and an Ir catalyst bearing ligands with peripheral bulk was crucial (Scheme 8a). As in the case of cooperative Ni/Al catalysis, the Al catalysts play key roles in terms of steric repulsion and rate-acceleration to induce the para-selectivity through making the arene core electrophilic towards the Ir catalysts under much milder reaction conditions than those in single-center Ir catalysis. We could even achieve

Scheme 8: Cooperative double activation Ir/Al catalysis for siteselective C–H borylation.

meta-selectivity in the arene C–H borylation using a catalyst with tethered Ir and Al centers (Scheme 8b).28 Notably, the benzene ring bearing the aminocarbonyl group was functionalized with high meta-selectivity exclusively over a phenyl substituent, which could also be borylated otherwise. The Ir/Lewis acid cooperative catalysis was also effective to achieve site-selective borylation of pyridine derivatives. The activation and functionalization of C–C bonds have attracted great attention in organic synthesis recently, as they could enable innovative transformations.29 The key to such transformations is the activation of the C–C bonds, which are commonly less kinetically and thermodynamically reactive. Successful and useful examples of C–C bond functionalization involving 3- and 4-membered compounds have been achieved via single site metal catalysts through the relief of ring strain as a major driving force to promote the C–C bond activation. Cooperative double activation catalysis has become a powerful strategy to expand the scope of C–C bond activation for organic synthesis. The C–CN bonds of nitriles are thermodynamically stable, but can reportedly be activated and functionalized by several transition metal catalysts.30 We expected that C–CN bond activation followed by the addition reaction of the organic and cyano fragments across unsaturated compounds, namely, the carbocyanation reaction, could be useful for organic synthesis, and initially performed the transformation using a single Ni catalyst. We then found that the scope of nitriles participating in this reaction could be significantly expanded using cooperative Ni/ Al catalysis.31 The cooperative double activation catalysis allows the activation of even acetonitrile to achieve the methylcyanation reaction (Scheme 9).32 Experimental and theoretical studies revealed that the cyano group coordinated to the Al Lewis acid at the N atom, while the p-bond bound to the Ni catalyst to significantly lower the barrier of the oxidative addition of the C–CN bonds. Cooperative transition metal/organic catalysis has also been developed to enable difficult C–H and C–C functionalizations that have been unavailable via single metal catalysts.33 A pioneering work was reported by Jun in 1997, who demonstrated the hydroacylation of alkenes via cooperative Rh/2-aminopicoline catalysis through formyl C–H bond activation (Scheme 10a).34 The amine catalyst reacts with aldehydes to give imines bearing a 3-methylpyridyl group, which serve as a coordinating directing group to bring the Rh catalyst close to the proximal formyl C–H bond, which undergoes oxidative addition to the Rh center. The ketone products are generated through the subsequent olefin insertion followed by C–C bond-forming reductive elimination. Hydroacylation via Rh catalysis alone has been limited to aldehyde and/ or alkene substrates bearing a coordinating functional group to prevent unwanted decarbonylation through its intramolecular coordination to the Rh center. The cooperative Rh/2-aminopicoline system has recently been further developed to achieve the direct a-alkylation of ketones with olefins (Scheme 10b).35 In this reaction, the enamine species bearing the pyridyl directing group is likely responsible for the directed C–H activation at the Rh center. Jun’s cooperative Rh/2-aminopicoline catalysis also effects the highly challenging catalytic C–C bond activation of ketones (Scheme 10c).36 Temporarily formed imines bearing the directing pyridyl group undergo the oxidative addition of the proximal C–C bond to the Rh(I) center. The reaction of phenylethyl ketones with 1-alkenes proceeds to afford alkyl ketones and styrene through C–C bond activation followed by exchange of the alkyl groups through b-H elimination. Cooperative double activation catalysis has recently been applied to the ring-expansion reaction of cyclopentanones through sequential C–C and C(sp2)–H bond activation (Scheme 10d).37

Conclusion

Scheme 9: Cooperative double activation Ni/Al catalysis for C–C functionalization. 30 | December 2021

In conclusion, the principles and representative examples of cooperative metal catalysis have been introduced, with a particular focus on new reactions that are difficult to achieve using conventional single metal catalysis. Taking advantage of cooperative synergistic catalysis, the scope and versatility of cross-coupling-type transformations have been significantly improved via the generation of nucleophilic organometallic www.facs.website

intermediates via one catalytic cycle and their successful integration into the product-forming cycle, which operates using another metal. Synthetic transformations based on cooperative double activation catalysis have also been briefly surveyed. The combination of common Lewis acids and late transition metal catalysts is powerful, particularly for the functionalization of otherwise less-reactive C–H and C–C bonds. Steric repulsion or tethering between the transition metal and Lewis acid have also been utilized to control the site-selectivity of C–H functionalization. Cooperative catalysis can also incorporate organocatalysis to generate transient substrates bearing a directing group to coordinate to the metal complex, enabling selective bond activation/formation processes at the proximal site. Given the large variety of possible combinations of catalysis systems based on different principles that have been developed in organic synthesis during the last half century, cooperative catalysis should be a useful and promising strategy for synthetic chemists to design novel and efficient organic reactions, which are greatly needed to establish sustainable chemical processes ◆.

References 1. 2. 3. 4. 5. 6. 7.

8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

Allen, A. E. and MacMillan, D. W. C. (2012). Synergistic catalysis: A powerful synthetic strategy for new reaction development. Chem. Sci. 3, 633–658. Pye, D. R. and Mankad, N. P. (2017). Bimetallic catalysis for C–C and C–X coupling reactions. Chem. Sci. 8, 1705–1718. Sonogashira, K., Tohda, Y. and Hagihara, N. (1975). A convenient synthesis of acetylenes: catalytic substitutions of acetylenic hydrogen with bromoalkenes, iodoarenes and bromopyridines. Tetrahedron Lett. 16, 4467–4470. Gooßen, L. J., Deng, G. and Levy, L. M. (2006). Synthesis of biaryls via catalytic decarboxylative coupling. Science 313, 662–664. Semba, K. and Nakao, Y. (2014). Arylboration of alkenes by cooperative palladium/copper catalysis. J. Am. Chem. Soc. 136, 7567–7570. Sawamura, M., Sudoh, M. and Ito, Y. (1996). An enantioselective two-component catalyst system: Rh–Pd-catalyzed allylic alkylation of activated nitriles. J. Am. Chem. Soc. 118, 3309–3310. Rogge, T., Kaplaneris, N., Chatani, N., Kim, J., Chang, S., Punji, B., Schafer, L. L., Musaev, D. G., Wencel-Delord, J., Roberts, C. A., Sarpong, R., Wilson, Z. E., Brimble, M. A., Johansson, M. J. and Ackermann, L. (2021). C–H activation. Nat. Rev. Methods Primers 1, 43. Ko, S., Kang, B., Chang, S. (2005). Cooperative catalysis by Ru and Pd for the direct coupling of a chelating aldehyde with iodoarenes or organostannanes. Angew. Chem. Int. Ed. 44, 455–457. Goldfogel, M. J., Huang, L. and Weix, D. J. (2020). Cross-electrophile coupling: principles and new reactions. in Nickel Catalysis in Organic Synthesis (ed. Ogoshi, S.) 183–222 (WileyVCH). Ackerman, L. K. G., Lovell, M. M. and Weix, D. J. (2015). Multimetallic catalysed crosscoupling of aryl bromides with aryl triflates. Nature 524, 454–457. Afewerki, S. and Córdova, A. (2016). Combinations of aminocatalysts and metal catalysts: a powerful cooperative approach in selective organic synthesis. Chem. Rev. 116, 13512–13570. Jellerichs, B. G., Kong, J.-R. and Krische, M. J. (2003). Catalytic enone cycloallylation via concomitant activation of latent nucleophilic and electrophilic partners: merging organic and transition metal catalysis. J. Am. Chem. Soc. 125, 7758–7759. Ibrahem, I. and Córdova, A. (2006). Direct catalytic intermolecular α-allylic alkylation of aldehydes by combination of transition-metal and organocatalysis. Angew. Chem. Int. Ed. 45, 1952–1956. Yasuda, S., Ishii, T., Takemoto, S., Haruki, H. and Ohmiya, H. (2018). Synergistic N-heterocyclic carbene/palladium-catalyzed reactions of aldehyde acyl anions with either diarylmethyl or allylic carbonates. Angew. Chem. Int. Ed. 57, 2938–2942. Romero, N. A. and Nicewicz, D. A. (2016). Organic photoredox catalysis. Chem. Rev. 116, 10075–10166. Tellis, J. C., Primer, D. N. and Molander, G. A. (2014). Single-electron transmetalation in organoboron cross-coupling by photoredox/nickel dual catalysis. Science 345, 433–436. Zuo, Z., Ahneman, D. T., Chu, L., Terrett, J. A., Doyle, A. G. and MacMillan, D. W. C. (2014). Merging photoredox with nickel catalysis: Coupling of α-carboxyl sp3-carbons with aryl halides. Science 345, 437–440. Twilton, J., Le, C., Zhang, P., Shaw, M. H., Evans, R. W. and MacMillan, D. W. C. (2017). The merger of transition metal and photocatalysis. Nat. Rev. Chem. 1, 0052. Getzler, Y. D. Y. L., Mahadevan, V., Lobkovsky, E. B. and Coates, G. W. (2002). Synthesis of β-lactones: A highly active and selective catalyst for epoxide carbonylation. J. Am. Chem. Soc. 124, 1174–1175. Tsuchimoto, T., Kamiyama, S., Negoro, R., Shirakawa, E. and Kawakami, Y. (2003). Palladium-catalyzed dimerization of vinylarenes using indium triflate as an effective cocatalyst. Chem. Commun. 852–853. Nakao, Y., Kanyiva, K. S. and Hiyama, T. (2008). A strategy for C–H activation of pyridines: Direct C-2 selective alkenylation of pyridines by nickel/Lewis acid catalysis. J. Am. Chem. Soc. 130, 2448–2449. Nakao, Y., Yamada, Y., Kashihara, N. and Hiyama, T. (2010). Selective C-4 alkylation of pyridine by nickel/Lewis acid catalysis. J. Am. Chem. Soc. 132, 13666–13668. Okumura, S., Tang, S., Saito, T., Semba, K., Sakaki, S. and Nakao, Y. (2016). Para-selective alkylation of benzamides and aromatic ketones by cooperative nickel/aluminum catalysis. J. Am. Chem. Soc. 138, 14699 –14704. Murai, S., Kakiuchi. F., Sekine, S., Tanaka, Y., Kamatani, A., Sonoda, M. and Chatani, N. (1993). Efficient catalytic addition of aromatic carbon–hydrogen bonds to olefins. Nature 366, 529–531. Mkhalid, I. A. I., Barnard, J. H., Marder, T. B., Murphy, J. M. and Hartwig, J. F. (2010). C–H activation for the construction of C–B bonds. Chem. Rev. 110, 890–931. Kuroda, Y. and Nakao, Y. (2019). Catalyst-enabled site-selectivity in the iridium-catalyzed C–H borylation of arenes. Chem. Lett. 48, 1092–1100. Yang, L., Semba, K. and Nakao, Y. (2017). Para-selective C–H borylation of (hetero)arenes by cooperative iridium/aluminum catalysis. Angew. Chem. Int. Ed. 56, 4853–4857. Yang, L., Uemura, N. and Nakao, Y. (2019). Meta-selective C–H borylation of benzamides and pyridines by an iridium–Lewis acid bifunctional catalyst. J. Am. Chem. Soc. 141, 7972–7979. Dong, G. (ed) (2014). C–C bond activation (Springer, Berlin). Nakao, Y. (2021). Metal-mediated C–CN bond activation in organic synthesis. Chem. Rev. 121, 327–344.

31. Nakao, Y. (2012). Nickel/Lewis acid-catalyzed carbocyanation of unsaturated compounds. Bull. Chem. Soc. Jpn. 85, 731–745

Scheme 10: Cooperative double activation Rh/organo catalysis for C–H and C–C functionalization. www.asiachem.news

32. Nakao, Y., Yada, A., Ebata, S. and Hiyama, T. (2007). A dramatic effect of Lewis acid catalyst on nickel-catalyzed carbocyanation of alkynes. J. Am. Chem. Soc. 129, 2428–2429. 33. Kim, D.-S., Park, W.-J. and Jun, C.-H. (2017). Metal–organic cooperative catalysis in C–H and C–C bond activation. Chem. Rev. 117, 8977–9015. 34. Jun, C.-H., Lee, H. and Hong, J.-B. (1997). Chelation-assisted intermolecular hydroacylation: direct synthesis of ketone from aldehyde and 1-alkene. J. Org. Chem. 62, 1200–1201. 35. Mo, F. and Dong, G. (2014). Regioselective ketone α-alkylation with simple olefins via dual activation. Science 345, 68–72. 36. Jun, C.-H. and Lee, H. (1999). Catalytic carbon–carbon bond activation of unstrained ketone by soluble transition-metal complex. J. Am. Chem. Soc. 121, 880–881. 37. Xia, Y., Lu, G., Liu, P. and Dong, G. (2016). Catalytic activation of carbon–carbon bonds in cyclopentanones. Nature 539, 546–550.

December 2021 | 31

In recent years, low-valent chemical species such as radicals and carbenes, which have been recognized as short-lived intermediates, have been isolated by appropriate molecular design, and their chemical properties have been investigated in detail experimentally. In particular, the discovery of isolable carbenes, which are now widely used as indispensable ligands in coordination chemistry and synthetic organic chemistry, has enabled the development of novel highly active catalysts. Manabu Abe

Manabu Abe was born in Osaka, Japan. He received his Ph.D. from the Kyoto Institute of Technology with Professor Akira Oku, in 1995. In 1995, he became a faculty staff at Osaka University (Prof. Masatomo Nojima’s group). From 199 to 1998, he was an Alexandervon-Humboldt fellow with Professor Dr. Waldemar Adam at the Universität Würzburg. He was also a visiting researcher at the LMU München (Professor Dr. Herbert Mayr) in 2007. He moved to Hiroshima and became a full-time professor of Organic Chemistry at the Department of Chemistry, Hiroshima University in 2007. His research focuses on reactive intermediates chemistry, especially on diradicals.

Zhe Wang

Zhe Wang was born in Qingdao, P.R.China. He received his bachelor’s degree (B.Eng.) in chemical engineering from China University of Petroleum (East China) in 2017. He then joined the research group of Prof. Abe at Hiroshima University. He received his master’s degree (M.Sc.) in chemistry from Hiroshima University in 2019 under the supervision of Prof. Dr. Manabu Abe. He is currently a Ph.D. student at Hiroshima University. His research focuses on the kinetic stabilization of singlet 2,2-dimethoxycyclopentane1,3-diyl diradicals using stretch effect induced by macrocyclic structures.

Rikuo Akisaka

Rikuo Akisaka was born in Kashiwa city, Japan. He received his bachelor’s degree in chemistry from University of Tsukuba in 2016. He received his master’s and Ph.D. degree in chemistry from Hiroshima University under supervision of Professor Manabu Abe in 2018 and 2021, respectively. He currently works with Professor Petr Klan at Masaryk University in Czech Republic as postdoctoral researcher. His current research focuses on the photo-reactivity of a dipyrrinone.

IN OUR RESEARCH, we have focused on the singlet state of radical pairs that are always involved in the homolysis of bonds but are difficult to observe directly because of their extremely short lifetimes (Scheme 1); moreover, we have been working to elucidate their chemical properties and develop their functions by increasing their lifetimes. In this article, we first review the chemistry of localized singlet 1,3-diradicals intervening in the bond homolysis process of carbon-carbon bonds. Further, we discuss our recent findings on (1) controlling the ground state spin multiplicity (singlet versus triplet); (2) a novel bonding mode (C–π–C); (3) effects of substituents, macrocycles, and solvent viscosity; (4) the nitrogen-atom effect; and (5) the third intermediate in the bond homolysis process.

homolysis

transition state

singlet radical pair

Scheme 1 Bond homolysis. 32 | December 2021

www.facs.website

New Insights into

Bond Homolysis Process and Discovery of Novel Bonding System (C–π–C) by Generating Long-lived Singlet Diradicals By Manabu Abe, Zhe Wang, and Rikuo Akisaka

https://doi.org/10.51167/acm00021

Chemistry of Localized Singlet Diradicals (singlet radical pair)

It has recently been discovered that in some cases, three energy minima may be observed in the bond homolysis process; nevertheless, it is generally believed that there are two energy minima in this process. For example, homolytic cleavage of the carbon–carbon σ-bond of the ethane molecule (CH3–CH3) generates a singlet radical pair of two methyl radicals (·CH3) (Scheme 1) whose energy difference is approximately equal to the bond dissociation energy of the σ bond, approximately 85 kcal mol–1. If we can directly observe the thermal equilibrium process between these two states, we can examine the solvent and substituent effects on the equilibrium process and clarify the details of the bond homolysis process experimentally. However, since the activation energy of the σ-bond formation reaction between methyl radicals is almost zero, it is extremely difficult to directly observe the singlet radical pair in a simple manner. To achieve the direct observation of singlet radical pairs based on kinetic stabilization, the authors focused on singlet diradicals in a cyclic framework (Scheme 2). Prior to the study on singlet diradicals by the present authors, Kistiakowsky1, Hoffmann2,3, C l o s s 4, 5 , S c h a efe r 6 , B e r s o n 6 , Ad a m 7, Dougherty8,9, and Borden10 reported on the reactivity and ground state of 1,3-diradicals in the 1930s, 1960s, 1970s, 1980s, and 1990s, respectively. The role of 1,3-diradicals in the www.asiachem.news

thermal isomerization of cyclopropane to propene was first proposed by Kistiakowsly et al. (Scheme 2), and theoretical and experimental studies were performed by Hoffmann and Berson et al. The triplet ground states of cyclobutane-1,3-diyl-diradical 1 and cyclopentane-1,3-diyl-diradical 2 were discovered by Closs, Adam, and Dougherty, and the ground state of 2,2-difluoro-1,3-diradical 3 was found to be singlet by Borden et al. To study the reactivity of singlet 1,3-diradicals experimentally and to clarify the bonding homolysis process, the present authors deemed it essential to extend the lifetime of the singlet diradicals by stabilizing them kinetically. In the latter half of the 1990s, we began to study 1,3-diradicals 4 with oxygen functional groups at the 2-position, keeping in mind that the molecular design of long-lived singlet diradicals requires (1) a singlet ground state and (2) the easy synthesis of a variety of derivatives. As a result, we succeeded in generating localized singlet diradicals DR that can be easily observed by time-resolved spectroscopy owing to their strong absorption peak around 600 nm in the visible region, which quantitatively gives the σ-bonded product CP.11–13

Ground state spin multiplicity of 1,3-diradicals

Closs et al. found that when the substituents at the C2 position of 1,3-diradicals are hydrogen atoms (X = H), the most stable spin

multiplicity of the diradical is a triplet (Table 1).4,5 This is because the energy difference between the two orbitals ψ S and ψA, which the two electrons of the 1,3-diradical occupy, becomes small due to the orbital interaction between ψS and the pseudo-π orbital σCH at the second position.3 The triplet state becomes energetically stable when one electron occupies ψS,H and ψA,H each according to Hund’s rule (Figure 1). In other words, by increasing the energy

1 2 triplet ground state

DR ~600 nm ( ~5000 M–1cm–1) max

singlet ground state

Scheme 2 Localized 1,3-diyl diradicals in cyclic structures. December 2021 | 33

levels of the two orbitals occupied by two electrons, diradicals can be created with a singlet ground state. Indeed, Borden et al. found that diradical 3 with an electron-withdrawing fluorine atom at the C2 position (X = F, singlet-triplet energy difference ΔEST = –9.7 kcal mol–1)14 is a singlet-state molecule. We focused on the oxygen functional group, for which an increased number of derivatives are possible, and examined the most stable spin multiplicity of 4 (Table 1). As a result, we found that 4a (X = OH) with an oxygen functional group is indeed a singlet ground-state molecule that is a candidate for the experimental verification of the π-single bond (vide infra). Interestingly, 5 (X = SiH3) with an electron-donating substituent, SiH3, was also found to have a singlet ground state.15 These substituent effects can be explained by the pseudo-π orbital interaction at the C2-position of the 1,3-diradical and the spiro-conjugation effect (Figure 2). In the case of the oxygen functional group, the interaction between ψS and the pseudo-π orbital σCO* at the C2 position stabilizes the ψS orbital (Figure 2a, left), resulting in a singlet ground state with π-single bonding wherein two electrons selectively occupy the ψS,OR orbital. In the case of 4a with X = OH, a CASSCF(2,2) calculation shows that the two electrons are accommodated

in the ψS,OR orbital with 81% probability, and the bond order between C1 and C3 is 0.62. The electronic absorption spectrum was predicted by TD-DFT calculations, and 4a was found to be a species exhibiting strong absorption at 420 nm (oscillator intensity (f) = 0.32); furthermore, the absorption at 420 nm was found to be due to the π  π* transition of the π single bond.16 In addition to the pseudo π interaction, spiroconjugation plays a role in increasing the energy gap between ψS,OR and ψA,OR, thereby increasing it to the energy spacing ΔEST of 4b (Table 1, Figure 2a). In the case of 5 with the introduction of electron-donating silicon functional groups, the singlet was estimated to be the most stable spin multiplicity (Table 1), and CASSCF calculations revealed that an electron configuration in which the electrons occupied the antibonding orbital (π*) ΨA,Si with 71% probability was favorable (Figure 2b). This substituent effect was attributed to the strong interaction of the electron-donating σCSi with the ψS orbital, resulting in ψA,Si as the HOMO and ψ S,Si as the LUMO. This indicates that the singlet state of 5 exists without π-single bonding in the frontier orbitals, in contrast to the case of 4a,b, where π-single bonding is introduced by the electron-withdrawing substituents.

Table 1 Substituent effect on ground-state spin multiplicity

H,H

+0.9

triplet

F,F

–9.7

singlet

–6.7

singlet

–12.2

singlet

–5.2

singlet

OH,OH

EST* in kcal mol–1 ground state

X,X

SiH3,SiH3

H S,H

A A,H

Figure 1 Orbital interaction of

with

* EST = ES – ET. ES : singlet energy; ET : triplet energy

spiroconjugation

(a)

OR OR

S,Si

nO S,OR

singlet state with -single bonding

SiH3 S

SiH3

Si *

CSi

H Si

pseudo interaction

singlet state with no -single bonding

Figure 2. (a) alkoxy group effect and (b) silyl group effect on the singlet ground state of 1,3-direadicals

34 | December 2021

The present author’s research group has been promoting research with the aim of not only understanding the process of bond homolysis, but also developing new chemistry based on the unexpected discoveries made in such research. In this regard, an unexpected finding in our research was that the localized singlet diradical exhibited strong absorption in the visible region (around 600 nm in the case of diradical 6), whereas the corresponding triplet diradical 7 showed absorption in the ultraviolet region (around 350 nm). (Figure 3). To investigate the origin of the remarkable spin multiplicity effect on the absorption wavelength of the diradical species, we computed the orbitals corresponding to the electronic transitions using quantum chemical calculations (Figure 3). The absorption in the visible region around 600 nm is computed to be mainly due to the electronic transition from the π-bonding orbital (π) to the antibonding orbital (π*) between C1 and C3 based on a highlevel ab initio method (CAS(2,2)+DDCI3) (Figure 3). Thus, the singlet diradical 6 entails π-bonding between C1 and C3, although an open-shell singlet structure exists. In other words, the localized singlet 1,3-diradical with an electron-withdrawing substituent at the C2-position has a novel bonding system with a π-single bond (C–π–C) between C1 and C3. This new group of compounds has a planar four-coordinated carbon atom, which is different from the generally known molecular structure. Very recently, a new bonding system has been reported for heterocyclic systems.20–28 In addition, despite a small π-electron system, they exhibit strong absorption in the visible region and are expected to provide new photoantenna sites that absorb abundant solar energy. Furthermore, as recently proposed by Nakano and co-workers,29 the open-shell π-bond is expected to have a high two-photon absorption capacity because of the third-order nonlinear effect; once π-single bond (C–π–C) compounds are isolated, they may function as next-generation optical materials.

Kinetic Stabilization of π-SingleBonded Compounds based on Substituents and Solvent Viscosity

SiH3 A,Si

SiH3 SiH3

pseudo interaction

H3Si

O A,OR

CO*

(b)

Novel π-Single Bond (C-π-C)17–19

The singlet diradical 6 is stable for at least a day in the low-temperature matrix state (77 K) but has a lifetime of approximately 200 ns at room temperature.13 Therefore, it is difficult to handle the chemical species at room temperature. To extend the lifetimes of π-single-bonded compounds, we investigated the substituent effects of the alkoxy and aryl groups, which can be relatively easily modified (Figure 4). Although diradical 8, which has a planar cyclic acetal skeleton at the C2 position, www.facs.website

has a large singlet–triplet energy gap and absorbs light at around 500 nm, its lifetime is two orders of magnitude shorter than that of 6, which is approximately 2 ns. This indicates that the steric hindrance between the acetal skeleton and the phenyl group at the C2-position raises the energy barrier for the transformation from the π-bond to the more stable σ-bond. In the case of 9 with OC3H7, the lifetime was one order of magnitude longer than that of 6. When the aryl group was also modified with substituents that increased the steric hindrance, relatively long-lived singlet diradicaloids 10 and 11 with lifetimes of 5 and 24 μs, respectively, were obtained. Thus, the introduction of a bulky aryl group and an alkoxy group enables the elongation of the lifetime of the π-single-bonded species. Recently, the present author’s group observed a notable effect of viscosity on the lifetime of the singlet diradicaloid 11, which increased to 2 s in 2,4-dicyclohexyl-2-methyl pentane (DCMP, η = 38.7) at 4000 atm and 293 K.30 This phenomenon is understood as the dynamic solvent effect. That is, for reactions that require a large reaction space, the logarithm of the reaction rate is proportional to the logarithm of the reciprocal of the viscosity.31 The bond formation process of 11 should involve the movement of bulky aryl groups having a large space. This implies that the reaction requires sufficient reaction space. In fact, when the viscosity of the solvent was increased at atmospheric pressure, the lifetime of 11, which is the inverse of the reaction rate, became longer (Figure 5a). Under high pressure conditions with viscous solvents, which are known to increase in viscosity with increasing pressure, the logarithm of the lifetime of 11 was proportional to the induced pressure (Figure 5b).

(a)

MeO

OMe

max

OMe

~350 nm

max

~600 nm

Figure 3. Electronic absorption characteristic in the singlet and triplet diradicals.

MeO

OMe

6 200 ns Ar’ Ar

2 ns

5.4 μs

OMe

Ar = OMe

OC3H7

1899 ns

Ar’ O

C 3H 7 O

EtO

OEt

23.8 μs

iPr

Ar = iPr

at 293 K in benzene Figure 4. Substituent effect on the lifetime of singlet diradicaloids with π-single bond

(b)

Figure 5. (a)The solvent dependency of the lifetime of 11 at 293 K and atmospheric pressure. (b)The pressure dependency of the lifetime of 11 at 293 K in DCMP.

www.asiachem.news

December 2021 | 35

Kinetic Stabilization of π-Single Bonded Chemical Species Using Macrocyclic Stretching Effect32

We further aimed to determine whether the longevity of π-single-bonded chemical species can be achieved by kinetic stabilization through a novel molecular design. In this context, inspired by recent synthetic studies on cyclic paraphenylene,33–36 we designed a molecule with a diradical skeleton in the macrocyclic ring (Scheme 3)37. Specifically, the diradical skeleton has a planar structure and a larger macrocyclic ring than the corresponding ring-closing structure; therefore, we expected it to be less molecularly distorted and thus more kinetically stabilized in the reaction yielding the ring-closed product. The distorted macrocyclic skeleton was expected to have a stretching effect, pulling the C1–C3 bonds of the ring closure outward. As a model molecule, we designed a ring skeleton at the meta-position of the phenyl group in the radical moiety to minimize thermodynamic stabilization. Further, the macrocyclic effect

on the kinetic stabilization of diradical 12 was investigated using quantum chemical calculations. In the case of 12a (R = H), which has a biphenyl group as a substituent, the ringclosed compound 13a was found to be more stable than 12a by 9.6 kcal mol–1. In the case of 13b, in which a benzene ring was introduced between the biphenyl groups, the energy difference was slightly smaller, estimated to be 7.0 kcal mol –1. When a naphthyl group with a more planar π-system was introduced, the energy difference between the diradical structure 12c and the ring-closed structure 13c was found to be much smaller, 1.0 kcal mol–1, indicating that the kinetic stabilization of the diradical 12c was expected. The stretching effect of the ring-closing structure was suggested by the fact that the C1–C3 bond distance of 13c was calculated to be 162 pm, which was longer than that of 13a (158 pm). Furthermore, the transition state energy of the ring-closing reaction was estimated to be 5.8 kcal mol–1 for the transformation from 12a to

concept of stretch effect

macrocycle

str

etc

2 1

macrocycle h 1

etc

str

2 3

1 12

13 R H (a) (b)

(c)

E13-12 (kcal mol–1)

C1–C3 (pm)

–9.6

158

–7.0

161

–1.0

162

at (U)B3LYP/6-31G(d) Scheme 3 Concept of “stretch effect” for the kinetic stabilization of singlet diradical. 36 | December 2021

13a, but it was 9.2 kcal mol–1 for the cyclization from 12c to 13c. It is clear that the introduction of the macrocyclic ring kinetically stabilized the diradical. Recently, we succeeded in synthesizing azo compounds 14a37and 14b,38 which can experimentally verify the macrocyclic effect on the kinetic stabilization of diradicals, and examined its reaction behavior (Scheme 4). When we attempted to generate diradicals 15 from 14 by the lase-flash-photolysis (LFP) method, we observed an absorption maximum around 600 nm, which is characteristic of singlet diradical species. Further, transient species with an absorption maximum around 600 nm, characteristic of singlet diradical species, were successfully observed (Figure 6). The lifetimes of the transient species 15a and 15b were determined to be 14.0 and 156 μs at 293 K, respectively, which are two-three orders of magnitude longer than that of 6. The transient species near 600 nm was identified as the singlet diradical 15; this is because the photodenitration of 14 produced a quantitative ring-closed product 16 and the signal near 600 nm was not quenched by molecular oxygen. The macrocyclic stretching effect could not be directly estimated from the reaction energy because the thermal equilibrium process between 15 and its ring-closed form 15b could not be observed, as in the case of diradical 28 (Figure 9). A close examination of the reactivity of ring-closed compound 15b showed that its chemical reactivity was strongly influenced by the stretching effect of the macrocyclic ring. Thus, 15b was stable at room temperature under degassed conditions but gradually transformed into oxidation products 18-20 under an oxygen atmosphere. Under the same conditions, 21 was stable, suggesting that the high reactivity of 15b was due to the macrocyclic effect. The dynamic solvent effect (viscosity effect) has also been confirmed for the case of macrocyclic singlet diradicaloild 16. Diradicaloid 16 lasts up to 400 μs in the high-viscosity solvent triacetin (GTA, π* = 0.63 kcal mol-1, η = 23.0 cP), which is 2.5 times longer than in benzene (π* = 0.55 kcal mol-1, η = 0.65 cP) at 293 K. On the other hand, in low-viscosity acetone (π* = 0.62 kcal mol-1, η = 0.32 cP), whose polarity is very close to that of GTA, the lifetime 16 was as short as 27.9 μs. This indicates that the viscosity of the solvent plays an important role in determining the lifetime of the singlet diradical. During the ring closure reaction, the movement of the macrocyclic skeleton is inhibited in the viscous solvent, resulting in a longer lifetime of the singlet diradicaloid 16.

Nitrogen Atom Effect on the Reactivity of Singlet Diradicals

As typified by N-heterocyclic carbenes (NHCs), the reaction behavior of carbenes is known to change dramatically with the www.facs.website

adjacent nitrogen functional groups.40–44 Considering this, we investigated the effect of nitrogen atoms on the reactivity of localized 1,3-diradicals (Figure 7).45,46 As mentioned above, diradical 2 is a triplet ground-state molecule, but the ground state of 22 changes to a singlet when nitrogen atoms are introduced in the five-membered ring, as in carbene. However, the ground state of carbene is a closed-shell singlet, while the ground state of 22 (ΔEST = ES – ET = –2.7 kcal mol–1 in C2) is an open-shell singlet. Diradicals 23 and 24, with highly electronegative F or OH groups introduced on the carbon sandwiched between the radical moieties of 22, show larger singlet–triplet energy differences, ΔEST = –19.7 and –14.9 kcal mol –1 in C2, respectively; moreover, an increase in these energy differences suggests that the singlet becomes more stable upon introducing the electron-withdrawing groups. X

N N

the singlet-ground-state diradical. Surprisingly, the 1,3-diradical with an electron-withdrawing substituent at the C2-position was found to be more energetically stable than the corresponding closed-ring form. To experimentally investigate the effect of nitrogen on the reactivity of 1,3-diradicals, we attempted to synthesize azo compounds 27 that can clean the diradical (Scheme 5). The cycloaddition of pyrazole with PTAD afforded azo compound 27 in a quantitative yield, and the denitrogenation of 27 led to the generation of derivative 28 of diradical 26.

MeO

OMe

N 14

22: X = H 23: X = F 24: X = OH

N H 25: X = H triplet ground state

singlet ground state

26: X = OH singlet ground state

macrocycle

MeO

Ph trans-21

MeO OMe

b 155.9 μs

14.0 μs

OMe Ph

Figure 7. Nitrogen-atom effect on the Figure 7. Nitrogen-atom effect on the ground ground state spin-multiplicity.

OMe

MeO OMe

–N2

MeO

macrocycle

h (355 nm)

N N H

The reaction dynamics of diradical 28 were investigated by the laser flash photolysis (LFP) of 27 (Figure 9). As a result, we observed a chemical species exhibiting a strong absorption peak near 650 nm in the visible region, which is characteristic of singlet diradical species (Figure 9a). Interestingly, the species with absorption around 650 nm entailed two decay processes: a fast decay process (microseconds) and a slow decay process (milliseconds), as shown in Figure 9b. The species was determined to be the singlet diradical 28 because it was not quenched by molecular oxygen and

at 293 K in benzene

state spin-multiplicity.

N N 22

A’

N nN

O MeO H NOE

CO2Me 19

+ H

O OMe OMe 20

Scheme 4. Generation of 15 with a macrocyclic structure.

S’ S

15a

n N’

16a

Figure 8. effecteffect on theon singlet Figure 8.Nitrogen-atom Nitrogen-atom theground state singlet ground state

The nitrogen-atom effect can be understood by the fact that the interaction between the orbitals nN and ψA increases the energy difference of ψs and ψA occupied by the two radical electrons, as shown in Figure 8. This is supported by the shorter nitrogen–nitrogen bond distance of diradical 22 (1.355 Å) than that of pyrazolidine (1.521 Å). The orbital interaction shown in Figure 8 is also proved by the fact that the triplet becomes the ground state for diradical 25, in which the electron-withdrawing group is introduced on the nitrogen atom. Interestingly, diradical 26, in which the electron-withdrawing substituent is introduced at the C2 position of the 1,3-diradical, changes to www.asiachem.news

Figure 6. LFP study on 15a at 293 K in benzene.

December 2021 | 37

was electron spin resonance (EPR)–silent, which is consistent with the prediction of quantum chemical calculations that 28 exhibits strong absorption at around 700 nm. Product analysis of the photo-denitrogenation reaction of 27 showed that the cyclized product 29 of 28 was not isolated, but the product 30 obtained by methoxy group rearrangement was identified as the main product. This experimental result is consistent with the fact that cyclized compound 29 is more energetically unstable than 28, as mentioned above. From the results of this product analysis and quantum chemical calculations, the reaction behavior of 28 observed by the LFP method can be understood by the reaction mechanism shown in Scheme 5. Diradical 28 generated by the LFP method from 27 first reaches thermal equilibrium with the ring-closing compound 29 within a lifetime of approximately microseconds, and then gives the rearrangement product 30 in a reaction lasting for approximately milliseconds (Scheme 5). Therefore, nanosecond time-resolved infrared absorption (IR) spectra were measured to confirm the formation of ring-closing compound 29 in the reaction system. The fast decay process of 28 was experimentally identified as a radical recombination process to yield compound 29,

and the activation parameters ΔH‡ and ΔS‡ of the ring-closing reaction were found to be 37.6 kJ mol–1 and –2.6 J K –1 mol–1 in toluene and 36.4 kJ mol–1 and –4.6 J K–1 mol–1 in acetonitrile, respectively. These results are in good agreement with the activation energy of 42.4 kJ mol–1 obtained by quantum chemical calculations. The thermal equilibrium process (K = k29/k28) between the singlet diradical and σ-bonded product was experimentally observed for the first time in this study. Although the solvent effect on the equilibrium constant K was small, it was found to be smaller for the polar solvent acetonitrile (ACN) than for the nonpolar solvent toluene (TOL); KTOL = 1.54, KACN = 0.72, and the zwitterionic nature of the singlet diradical was experimentally clarified (Scheme 5). Because the contribution of the zwitterionic structure of the singlet diradical was further enhanced by the nitrogen atom adjacent to the radical site, the energy difference between the singlet diradical and its ring-closed form became small, and the bonding homolysis process could be directly observed.

Third Energy Minimum of the Bond Homolysis Process47

In general, there are two energy minima in the bond homolysis process: the singlet radical pair

MeO

N N

OMe

N N

MeO OMe O Ph Ph N N N N O N Ph 27

OMe Ph N N

O Ph

N 30

MeO Ph

k14

MeO

OMe Ph

OMe

MeO Ph

OMe Ph

k29

Ph 29

k28

–N2

N N O

N H

max

0.2 μs

12 28 ~650 nm

3.4 μs 70 μs

K = k13/k12

28 ~650 nm

K = k13/k12

MeO Ph

OMe Ph

N N O

355 nm

OMe Ph

~μs

N N O

MeO Ph

N N

max

N N

~ms

OMe

–N2

MeO OMe O Ph N N N N O N Ph 27 11

N Ph

and the sigma-bonded compound. Herein, we describe the recent discovery of a third energy-minimum structure in the bond homolysis process, a puckered-type intermediate 33. The discovery of this intermediate allows us to understand the spin-multiplicity effect on the stereoselectivity of the ring-closing product 32 produced in the denitrogenation of azo compound 31 and the emission observed from 32 at unusually long wavelengths (Scheme 6). As shown in Scheme 6, when the photo-denitrogenation of 31 was performed by the direct electronic excitation of the azo functional group (-N=N-), trans-32, which retains the stereochemistry of 32, is preferentially obtained (trans/ cis-28 = 85/15), whereas the denitration of the excited triplet of the azo moiety using a triplet sensitizer such as benzophenone yielded cis32 exclusively. To investigate the effect of spin multiplicity on the stereoselectivity of this radical coupling reaction, the reaction behavior of the previously known planar singlet diradical 6 was first investigated by quantum chemical calculations using the broken symmetry method (BS-DFT) (Figure 10). As a result, even though trans-32 is more stable thermodynamically than cis-32, the transition state cis-TS giving cis-32 is approximately 20 kJ mol –1 more stable than the

[13]

[12]

Scheme 5 (above). Generation of singlet diradical 28 and its reactivity.

at 273 K

kfast = k12 + k13 kslow = k14·k12/(k12 + k13)

Figure 9.(right) (a) LFP study on 28 at 293 K in toluene; (b) Time profile of 633 nm species after LFP of 27.

38 | December 2021

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transition state trans-TS giving trans-32, indicating that cis-32 is kinetically favored. These calculations indicate that cis-32 was formed exclusively in the triplet-sensitized denitrogenation of 31 because of the intersystem crossing (ISC) of the planar triplet diradical 3 6 to the more stable 6, which selectively leads to cis-32. Experimentally, the activation energy barrier of the radical coupling reaction in 6 was found to be 41.4 kJ mol–1, which is similar to the activation energy barrier for the transformation from 6 to cis-32 determined by quantum chemical calculations. When we started the IRC calculation from trans-TS, it was suggested that there is a third intermediate 33 between trans-32 and trans-TS, which had not been observed in the bonding homolysis process. Quantum chemical calculations (BS-UB3LYP/6-31G(d)) showed that the energy of 33 was approximately 36.8 kJ mol–1 higher than that of 6. It was also found that there was almost no energy barrier to trans32, and trans-32 was quickly obtained when 33 was generated (Figure 10). In other words, in the direct excitation of 31, 134 generated in the stepwise denitration process preferentially gives trans-32 via the puckered-type intermediate 33 (Scheme 7). By contrast, in the triplet sensitization reaction, cis-32 is exclusively generated from the triplet intermediate 334, which has a long lifetime and can change its conformation to the most stable planar diradical 36. After intersystem crossing to 6, cis-32 was selectively formed in the ring-closing reaction. As shown in scheme 7, the mystery of the remarkable spin multiplicity effect on stereoselectivity observed in the photo-denitration reaction of 31 seems to be solved by assuming the intervention of a previously unobserved puckered-type singlet diradical. However, there is no direct experimental evidence for the existence of such a diradical, and the analogy is based on DFT calculations, which are inherently unable to treat open-shell singlet diradicals with theoretical precision. The present author aimed to experimentally capture the third structure 33 intervening in the bond homolysis process. Therefore, we attempted to stabilize the puckered structure by introducing a bulky substituent, as is usual, and directly observed the derivative of 33 (λcald = 480 nm), which is expected to appear at wavelengths shorter than those of 6 (λcald = 580 nm) in our calculations (Figure 11). Azo compound 35 was synthesized by introducing –OCH2Ph as a bulky substituent in the alkoxy moiety and a meta-dimethoxyphenyl group (–C6H3(OMe)2) as an aryl group. The photodenitrogenation reaction was conducted in a low-temperature organic glass matrix using 2-methyltetrahydrofuran (MTHF, melting point 137 K). At 110–120 K, where a soft matrix was obtained, a strong absorption around 580 nm corresponding to a planar singlet diradical was observed and attributed www.asiachem.news

Anomalous long wavelength emission from trans-32

to 37. At temperatures below 98 K, where the matrix is hard, no absorption near 580 nm was observed, and a chemical species with electronic absorption near a shorter wavelength of 450 nm was observed instead of 37. Because of the good agreement with the calculated absorption wavelength of 36 and the silence in the electron paramagnetic resonance (EPR) spectrum, the absorption near 450 nm was assigned to the third minimum-energy structure, a puckered-type singlet diradical 36.

The puckered-type diradical 33 is the third minimal-energy structure found in the groundstate bond homolysis process and is an important intermediate that controls the stereoselectivity of radical coupling reactions. To determine whether the puckered-type structure exists in the bond dissociation process in an electronically excited state, we measured the emission spectrum of trans-32 (Figure 12).47

MeO direct (singlet) photolysis MeO

77 K

MeO

tripletsensitization

ﬂuorescence ~300 nm + 515 m

trans-32

OMe Ph

OMe

MeO

OMe Ph

puckered diradical 33

cis-32

Scheme 6. Puckered diradical 33 as a new intermediate of bond homolysis.

H 3C O

Hrel in kJ mol-1 H

MeO

O Ph

CH3 H

OMe

trans-TS 65.4

O CH3

CH3 O

cis-TS

43.9

36.8

ISC 0.0

Ph OMe

–28.8 MeO

OMe

OMe Ph

–13.3 Ph

planar singlet diradical 6 at (U)B3LYP/6-31G(d)

OMe

MeO cis-32

trans-32 Figure 10 Computational study on reactivity of planar singlet diradical 6. December 2021 | 39

The fluorescence spectrum (250 nm excitation) of a solution of trans-32 (1.5 × 10 –5 M) in 3-methylpentane (3-MP) was measured at liquid nitrogen temperature (77 K). Interestingly, fluorescence corresponding to a phenyl-group-derived vibrational structure was observed around 280–360 nm (lifetime 8.7 ns, Figure 12a) and broad fluorescence with no vibrational structure was noticed at 460–660 nm (lifetime 7.9 ns, Figure 12b). The excitation spectra of these two types of emission (Figures 12a and 12b) were consistent with the absorption OMe

MeO

Ph Ph 134

N N

–N2

Ph 33

OMe

planar diradical

MeO

ISC

OMe

Ar OCH2Ph

37 ~580 nm

max

117 K

OMe

MeO

OMe

0.10

94 K

0.05

cis-32

OMe –N2

350

PhOMe

MeO

fluorescence emissions

2 kcal mol–1

trans-32*

650

OMe

2-Naph 2-Naph

trans-39

OMe Ph

trans-40

Figure 12 Fluorescence spectra from trans-32 in 3-MP at 250 nm at 77 K. Short-wavelength emission (a) at around 320 nm and long-wavelength emission (b) at around 520 nm.

~450 nm

MeO

~515 nm

~320 nm

~580 nm MeO

2-Naph

OMe Ph OMe

~250 nm

total electronic energy

emission (a) t = 8.7 ns

trans-38

600

33*

emission (b) t = 7.9 ns

550

> 10 kcal mol–1

MeO

500

OMe

trans-32

450

Figure 11. Detection of puckered diradical 36 and planar diradical 37 in the photolysis of 35.

Scheme 7. Mechanism for the stereoselectivity in the denitrogenation of 31.

400

wavelength /nm

334

40 | December 2021

0.00

Ph N Ph N

Ar Ar 36 max ~450 nm

–N2 MTHF low-temperature matrix

OCH2Ph Ar

OCH2Ph

0.15

sensitized h (triplet) MeO

PhH2CO

Ar =

Ph OMe

N Ar 35

OMe

trans-32

MeO

OMe

Similar long-wavelength fluorescence was not observed for trans-38, an analog of 32; only fluorescence from the phenyl group (260–355 nm, 9.2 ns) was observed. The substituent effect on the emission spectra observed in trans-32 and 38 was also observed in trans-39 and 40, wherein the phenyl group was replaced by a naphthyl group. To understand these emissions, the reaction potentials of the electronic excited states of trans-32 and 38 were calculated using the state-averaged complete active space self-consistent field

OCH2Ph Ar

puckered diradical

direct h (singlet) MeO

PhH2CO

OMe

absorbance

MeO

spectrum of trans-32. These observations indicate that not only the fluorescence at shorter wavelengths but also the fluorescence with emission maxima around 515 nm originates from the electronically excited state of trans-32. Considering the results of quantum chemical calculations shown below, we conclude that the long-wavelength emission originates from the electronically excited state 33* of the Packard-type diradical, which is generated from the electronically excited state of trans-32 via an adiabatic σ-bond cleavage process.

Ph OMe Ph trans-32

~650 nm

OMe

Ph OMe

6 at SA-CASSCF(10,10)/6-31G(d)

Figure 13. Ground state and excited state potential energy surfaces in trans-32, calculated at the SA-CASSCF(10,10)/631G(d) level of theory.

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(SA-CASSCF) method (Figure 13). Although the SA-CASSCF method entails a large computational cost, it is able to obtain the electronic states and energies of the multiconfigurational singlet diradicals with an open-shell nature more precisely. As shown in Figure 13, the activation energy of the adiabatic bond-homolysis process to give the puckered-type intermediate 33* from the electronically excited state trans-32* was found to be very small, approximately 2 kcal mol–1, and the two fluorescence peaks observed in the emission spectrum of trans-32 were from trans-32* and 33*. The activation energy from 33* to 6* is as high as 10 kcal mol–1, which is consistent with the experimental observation that the emission from 6* (~650 nm) was not observed. A similar adiabatic excited-state cleavage reaction was performed for trans38*, and the energy barrier for the bond homolytic cleavage process was as high as approximately 6 kcal mol –1, consistent with the fact that only phenyl-group-derived fluorescence was observed from trans-38*. Thus, the existence of a third minimal-energy structure in the bond homolysis process of trans-32 even in the electronically excited state was revealed.

Conclusion

In this article, we elucidate the kinetic stabilization of localized singlet diradicals entailed in the bond homolysis process to extend their lifetime and investigate their chemical properties. By thoroughly studying the bond homolysis process, which is a fundamental chemical reaction, we propose novel bonding styles and new reaction intermediates. We hope that more research will be conducted using these new chemical concepts in the future. Finally, since we are often asked about the difference between “diradical” and “biradical,” we will explain the definition of “diradical” used in this paper. According to the IUPAC Gold Book, a diradical is a chemical species with two strongly interacting radicals in a molecule and two spin multiplicities, a singlet (↑↓) and a triplet (↑↑); by contrast, when two radicals are far apart in a molecule, the spin interaction is small, and they are judged to be two doublet species (2 × ↑), they are called biradicals. We would like to express our sincere gratitude to the students who have graduated from the Graduate School of Engineering, Osaka University, and the Graduate School of Science, Hiroshima University, who had devoted themselves to the research summarized herein. Part of this work was supported by the Ministry of Education, Culture, Sports, Science and Technology (MEXT), the Japan Society for the Promotion of Science (JSPS), and the Japan Science and Technology Agency (JST). ◆ www.asiachem.news

References

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Kishi, R.; Murata, Y.; Saito, M.; Morita, K.; Abe, M.; Nakano, M. Theoretical Study on Diradical Characters and Nonlinear Optical Properties of 1,3-Diradical Compounds. Journal of Physical Chemistry A 2014, 118 (45), 10837–10848. https://doi.org/10.1021/jp508657s. 30. Akisaka, R.; Ohga, Y.; Abe, M. Dynamic Solvent Effects in Radical– Radical Coupling Reactions: An Almost Bottleable Localised Singlet Diradical. Physical Chemistry Chemical Physics 2020, 22 (48), 27949–27954. https://doi.org/10.1039/d0cp05235c. 31. Asano, T. Kinetics in Highly Viscous Solutions: Dynamic Solvent Effects in “slow” Reactions. Pure and Applied Chemistry 1999, 71 (9), 1691–1704. https://doi.org/10.1351/pac199971091691. 32. Abe, M.; Furunaga, H.; Ma, D.; Gagliardi, L.; Bodwell, G. J. Stretch Effects Induced by Molecular Strain on Weakening σ-Bonds: Molecular Design of Long-Lived Diradicals (Biradicals). Journal of Organic Chemistry 2012, 77 (17), 7612–7619. https://doi.org/10.1021/jo3016105. 33. Jasti, R.; Bhattacharjee, J.; Neaton, J. B.; Bertozzi, C. R. Synthesis, Characterization, and Theory of [9]-, [12]-, and [18] Cycloparaphenylene: Carbon Nanohoop Structures. Journal of the American Chemical Society 2008, 130 (52), 17646–17647. https://doi.org/10.1021/ja807126u. 34. Takaba, H.; Omachi, H.; Yamamoto, Y.; Bouffard, J.; Itami, K. Selective Synthesis of [12]Cycloparaphenylene. Angewandte Chemie International Edition 2009, 48 (33), 6112–6116. https://doi.org/10.1002/anie.200902617. 35. Yamago, S.; Watanabe, Y.; Iwamoto, T. Synthesis of [8] Cycloparaphenylene from a Square-Shaped Tetranuclear Platinum Complex. Angewandte Chemie International Edition 2010, 49 (4), 757–759. https://doi.org/10.1002/anie.200905659. 36. Miyazawa, Y.; Wang, Z.; Matsumoto, M.; Hatano, S.; Antol, I.; Kayahara, E.; Yamago, S.; Abe, M. 1,3-Diradicals Embedded in Curved Paraphenylene Units: Singlet versus Triplet State and In-Plane Aromaticity. Journal of the American Chemical Society 2021, 143 (19), 7426–7439. https://doi.org/10.1021/jacs.1c01329. 37. Abe, M.; Furunaga, H.; Ma, D.; Gagliardi, L.; Bodwell, G. J. Stretch Effects Induced by Molecular Strain on Weakening σ-Bonds: Molecular Design of Long-Lived Diradicals (Biradicals). Journal of Organic Chemistry 2012, 77 (17), 7612–7619. https://doi.org/10.1021/jo3016105. 38. Harada, Y.; Wang, Z.; Kumashiro, S.; Hatano, S.; Abe, M. Extremely Long Lived Localized Singlet Diradicals in a Macrocyclic Structure: A Case Study on the Stretch Effect. Chemistry - A European Journal 2018, 24 (55), 14808–14815. https://doi.org/10.1002/chem.201803076. 39. Wang, Z.; Akisaka, R.; Yabumoto, S.; Nakagawa, T.; Hatano, S.; Abe, M. Impact of the Macrocyclic Structure and Dynamic Solvent Effect on the Reactivity of a Localised Singlet Diradicaloid with π-Single Bonding Character. Chemical Science 2021, 12 (Scheme 1), 613–625. https://doi.org/10.1039/d0sc05311b. 40. Arduengo, A. J.; Bertrand, G. Carbenes Introduction. Chemical Reviews 2009, 109 (8), 3209–3210. https://doi.org/10.1021/cr900241h. 41. Arduengo, A. J.; Harlow, R. L.; Kline, M. A Stable Crystalline Carbene. Journal of the American Chemical Society 1991, 113 (1), 361–363. https://doi.org/10.1021/ja00001a054. 42. Igau, A.; Baceiredo, A.; Trinquier, G.; Bertrand, G. [Bis(Diisopropylamino)Phosphino]Trimethylsilylcarbene: A Stable Nucleophilic Carbene. Angewandte Chemie International Edition in English 1989, 28 (5), 621–622. https://doi.org/10.1002/anie.198906211. 43. Bourissou, D.; Guerret, O.; Gabbaï, F. P.; Bertrand, G. Stable Carbenes. Chemical Reviews 2000, 100 (1), 39–91. https://doi.org/10.1021/cr940472u. 44. Jazzar, R.; Soleilhavoup, M.; Bertrand, G. Cyclic (Alkyl)- And (Aryl)-(Amino)Carbene Coinage Metal Complexes and Their Applications. Chemical Reviews 2020, 120 (9), 4141–4168. https://doi.org/10.1021/acs.chemrev.0c00043. 45. Yoshidomi, S.; Abe, M. 1,2-Diazacyclopentane-3,5-Diyl Diradicals: Electronic Structure and Reactivity. Journal of the American Chemical Society 2019, 141 (9), 3920–3933. https://doi.org/10.1021/jacs.8b12254. 46. Yoshidomi, S.; Mishima, M.; Seyama, S.; Abe, M.; Fujiwara, Y.; Ishibashi, T.-A. Direct Detection of a Chemical Equilibrium between a Localized Singlet Diradical and Its σ-Bonded Species by Time-Resolved UV/Vis and IR Spectroscopy. Angewandte Chemie - International Edition 2017, 56 (11), 2984–2988. https://doi.org/10.1002/anie.201612329. 47. Abe, M.; Kanahara, K.; Kadowaki, N.; Tan, C.-J.; Tsai, H.-H. G. Unusually Long-Wavelength Emissions of Cyclopropanes: New Insight into C−C Bond Homolysis. Chemistry - A European Journal 2018, 24 (30), 7595–7600. https://doi.org/10.1002/chem.201800671.

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From Structural to Functional Materials: a Green Way to Produce Functional Biopolymers Based on Polypeptides Green synthesis catalyzed by proteases

Kousuke Tsuchiya

Kousuke Tsuchiya received his Ph.D. in polymer chemistry in 2007 from the Tokyo Institute of Technology after engaging in the synthesis of functional polymers under the supervision of Prof. Mitsuru Ueda. He then was appointed an assistant professor at the Tokyo University of Agriculture and Technology, where he worked on the development of functional polymeric materials for optic and electronic devices. In 2015, he began conducting more biochemical research at the RIKEN Center for Sustainable Resource Science as a senior research scientist. He currently engages a project associate professor at the Kyoto University. His current work focuses on sustainable syntheses of bio-based polymers including polypeptides, and he has been recognized by awards such as Award for Encouragement of Research in Polymer Science from the Society of Polymer Science, Japan, and Polymer Chemistry Emerging Investigator 2020 from the Royal Society of Chemistry.

42 | December 2021

Keiji Numata

Keiji Numata is currently Full Professor at Department of Material Chemistry, Kyoto University, and Team Leader at the Biomacromolecules Research Team, RIKEN Center for Sustainable Resource Science, Japan. He is also Research Director for JST-ERATO Numata Organellar Reaction Cluster Project and leads the Precision Polymer Degradation, Grant-inAid for Transformative Research Area, in Japan. He investigates biosynthesis and material design of structural proteins, polypeptide, and poly(amino acid). He previously worked as JSPS Postdoctoral Fellow for Research Abroad at Tufts University (Medford, MA, United States), where he studied biosynthesis of silk-based polymers via bacterial pathways, as well as biomedical application of silk-based polymers. Dr. Numata has received numerous awards for his work and is currently one of the associate editors of ACS Biomaterials Science and Engineering.

Renewable polymeric materials produced from natural bioresources are fascinating alternatives to chemical products derived from petroleum that can fulfill the needs of future sustainable societies. Biodegradability and/ or recyclability are key features for the development of sustainable materials to meet this requirement. The United Nations (UN) adopted 17 sustainable development goals (SDGs) in 2015 to achieve sustainable development by 2030. These SDGs aim to tackle an urgent call for action by all countries in a global partnership, and most of them relate to environmental issues. To realize these criteria, developing an environmentally benign manufacturing process and producing novel biobased polymeric materials to replace petroleum-based materials are inevitably important. Various biopolymers derived from natural resources, such as poly(lactic acid), polyhydroxyalkanoate, and cellulose, have extensively been applied to practical use in commercial products. Polypeptides are another attractive biopolymer in terms of versatility in the molecular design of amino acid sequences. A rational choice of amino acid residues in polypeptide sequences offers a desired functionality. Polypeptides are conventionally prepared by chemical synthesis, such as solid phase peptide synthesis and ring-opening polymerization of amino acid N-carboxyanhydride (NCA), or biosynthesis in host microbes as a form of protein, which generally suffers from tedious purification steps.

We have pursued ideal synthetic methods for functional biopolymers, including polypeptides, through engineered pathways utilizing natural machinery. Enzymatic synthesis of polypeptides, named chemoenzymatic polymerization, can be used to build peptide bonds with the aid of proteases, which naturally cleave the peptide bonds in proteins (Figure 1). An appropriate combination of proteases and amino acid monomers enables us to synthesize various types of polypeptides.1-2 Chemoenzymatic polymerization possesses tremendous advantages over traditional synthetic methods. The polymerization, which generally involves just mixing amino acid monomers with a protease, proceeds in aqueous buffer solutions instead of organic solvents. Because of the substrate specificity of proteases, the resulting polypeptides have regioand stereoselectively well-defined structures. The leaving group is only a small alcohol molecule such as ethanol during polymerization, which can achieve excellent atom economy compared with conventional chemical syntheses using condensing agents. Collectively, chemoenzymatic polymerization offers green, facile synthesis of polypeptides with distinct structures. We have previously polymerized a variety of amino acid monomers, mostly in ester forms, via chemoenzymatic polymerization to provide polypeptides with a wide range of functional groups. In addition to amino acid monomers, oligopeptide ester derivatives are also candidate materials for polymerizable monomers. Di- or tripeptides with appropriate www.facs.website

By Kousuke Tsuchiya and Keiji Numata https://doi.org/10.51167/acm00022

amino acid combinations offer complex periodic sequences through chemoenzymatic polymerization. Our targets are functional polypeptides for a wide range of applications, from biomimetic structural materials to bioactive peptides for biotechnology. Proteases cleave amide bonds of specific proteins. The catalytic center in proteases attacks an amide bond to form an activated tetrahedral intermediate followed by hydrolytic reaction, resulting in scission of proteins. If we can exploit the reverse reaction of enzymatic hydrolysis, polymerization of amino

acids proceeds in a chemoselective manner regulated by spatial information for the catalytic pocket in enzymes.3 Although the equilibrium for enzymatic hydrolysis is biased toward cleavage, moderate activation of amino acids by modification with ester groups on the C-terminus kinetically facilitates protease-mediated formation of the tetrahedral intermediate and subsequent aminolysis reaction. The catalytic pocket in proteins consists of a series of subsites, each of which has distinct specificity to amino acid substrates. We harnessed chemoenzymatic polymerization by selecting

a reasonable combination of substrate-specific proteins and amino acid monomers, which was assisted by theoretical predictions using several techniques, including molecular dynamics simulations.4 Even an amino acid that mismatches the substrate specificity of proteases can be incorporated into polypeptides when it is inserted into an oligopeptide monomer with an elaborate sequence design to mitigate the mismatch. This technique motivates us to design and synthesize novel artificial polypeptides with more complicated sequences for further functionalization.

Structural proteins

Figure 1. Chemoenzymatic polymerization catalyzed by proteases (papain). The amino acid ester monomer is activated by acylation with a catalytic cysteine residue in papain to produce a tetrahedral intermediate, which subsequently undergoes aminolysis with another amino acid ester monomer. www.asiachem.news

Proteins and polypeptides play critical roles in living bodies. Versatile functions of proteins are determined by sequential variety, which are assembled into functional higher-order structures, and proteins are roughly categorized into structural proteins and globular functional proteins such as enzymes. In particular, structural proteins often possess long repetitive sequences to fold into specific higher-order structures that build up supportive frameworks in body tissues.5 To mimic such repetitive sequences as found in silk fibroin, collagen, elastin, and resilin, our synthetic technique for designing and controlling periodic sequences via chemoenzymatic polymerization is useful to offer artificial biomimetic polypeptide materials with physical and physiological functionality. We designed polypeptides containing specific short peptide motifs that are thought to govern the physical properties of structural proteins December 2021 | 43

to mimic their functionality using artificial polypeptide materials. The chemoenzymatic polymerization of amino acids or short oligopeptide motifs can be used to realize the facile synthesis of biomimetic artificial polypeptides for these structural proteins. Silk proteins are produced by some animals, such as silkworms and spiders, to construct silk fibers for multiple tasks. Spider silk exhibits excellent mechanical properties that occasionally compete with those of artificial high strength fiber or even steel.6 A dragline silk, which is the most well-studied type of spider silk, primarily consists of major ampullate spidroins (MaSp) and shows high strength and toughness.7 Polyalanine motifs repeatedly appear in the amino acid sequences of MaSp proteins and form β-sheet crystallites in silk fibers. The β-sheet nanocrystals align along the fiber axis during the spinning process, resulting in the high tensile strength of the silk fiber. On the other hand, glycine-rich complex motifs

alternate with polyalanine motifs in the highly repeating domain, which are responsible for the extensibility of silk fibers. We have focused on these motifs to assemble multiblock polypeptides that possess a sequence similar to that of spider dragline silk proteins (Figure 2).8 Chemoenzymatic polymerization of alanine ethyl ester was performed in the presence of papain, a cysteine protease with broad substrate specificity, in phosphate buffer at mild temperature, and polyalanine was obtained as a precipitate within an hour. Structural analysis revealed that the obtained polyalanine spontaneously forms a β-sheet structure similar to that of natural spider silks. Similarly, the glycine-rich motif in spider silk proteins was imitated by a random sequence of glycine and leucine obtained by papain-catalyzed copolymerization of these amino acid monomers. Ligation of the resulting polypeptide motifs with condensing agents afforded a specific amino acid sequence in which crystalline polyalanine

Figure 2. Synthesis of a multiblock polypeptide mimicking a repetitive sequence of spider silk proteins via chemoenzymatic polymerization. Reproduced from Ref. 8 with permission from the American Chemical Society.

and amorphous poly(glycine-random-leucine) motifs are tandemly flanked. For a crystalline/ random composition ratio that is similar to that of natural spider silk, the multiblock polypeptide was found to exhibit a secondary structure containing β-sheet crystallites and the ability to simultaneously form nanofibers. A great advantage of the chemoenzymatic synthesis approach used to construct spider silk-mimetic sequences is easy tuning of the polypeptide motifs. Random polypeptides of glycine with other amino acids, such as serine and tyrosine, are also available for an amorphous motif, and reactive hydroxy side groups of these motifs can be exploited for further modification or cross linking. Another example of the chemoenzymatic synthesis of biomimetic polypeptides is elastin. Elastin repeatedly contains a valine-proline-glycine-valine-glycine (ValProGlyValGly) motif in the hydrophobic region of its amino acid sequence, and the high elastic property of elastin arises from the tandem sequence of these motifs with cross linking. 9 The ValProGlyValGly motifs in the elastin sequence undergo a temperature-induced reversible phase transition above a transition temperature, which has tremendous potential for use in thermoresponsive biomaterials.10 To construct the repetitive sequence of elastin, solid phase peptide synthesis is generally used for the synthesis of elastin-mimetic polymers. We utilized a chemoenzymatic polymerization technique to synthesize a repetitive sequence containing the thermoresponsive motif of elastin (Figure 3).11 Papain-catalyzed copolymerization of ValProGly tripeptide and ValGly dipeptide ester monomers in aqueous buffer affords a polypeptide with an elastin-mimetic sequence. The polypeptide with a tandem ValProGly-random-ValGly sequence showed a temperature-dependent structural transition. Interestingly, when the valine residue was substituted with a glycine residue, the resulting analogous sequence of GlyProGly-randomValGly did not show any temperature-dependent structural transition. Such a trivial difference in sequences drastically changes the physical properties of the polypeptides, indicating the significant importance of specific motifs that structurally and physically determine the properties of proteins.

Unnatural polypeptides

Figure 3. Papain-catalyzed polymerization of VPG and VG monomers for the synthesis of elastin-mimetic polypeptide. The polypeptide possessing VPGVG repetitive motifs exhibits a reversible structural transition in a temperature-dependent manner, as shown by the circular dichroism (CD) spectra. Reproduced from Ref. 11 with permission from the Royal Society of Chemistry. 44 | December 2021

In addition to 20 proteinogenic amino acids, some nonproteinogenic amino acids also exist in the amino acid sequences of proteins and broaden the scope of protein functionality. Such nonproteinogenic residues are generally assembled in proteins not by enzymatic ligation in the central dogma but by epigenetic postmodification of proteinogenic amino acid residues in protein sequences. Although the assembly of unnatural amino acids into polypeptides via chemoenzymatic polymerization is fascinating, things are not www.facs.website

that simple. Thanks to the substrate specificity, we can chemoselectively polymerize natural amino acid monomers by chemoenzymatic polymerization. However, unnatural amino acid monomers are tightly excluded during the enzymatic reaction. Our initial attempt to polymerize unnatural amino acid esters in the presence of various proteases was not satisfactory: the amount of unnatural amino acids that can be incorporated into polypeptide sequences is quite limited,12 which motivated us to design unnatural amino acid-containing oligopeptide ester monomers. Sandwiching the unnatural amino acids amid natural amino acids allows proteases to recognize such species in the substrate pocket, leading to successful polymerization of these oligopeptide monomers (Figure 4).13-15 A typical unnatural amino acid, 2-aminoisobutyric acid (Aib), is an α,α-disubstituted amino acid with bulky side groups. Introduction of Aib residues in polypeptides is known to strongly induce a helical conformation due to the bulky structure. We prepared a tripeptide ethyl ester with an alanine-Aib-alanine (AlaAibAla) sequence for the monomer for chemoenzymatic polymerization.15 Neither Aib nor a Aib-containing dipeptide monomer was found to be able to polymerize in the presence of papain because the Aib unit has a poor affinity for papain. In contrast, the papain-catalyzed polymerization of the Aib-containing tripeptide monomer afforded a polypeptide that periodically contains Aib every three residues. The resulting polypeptide adopts an α-helix conformation, whereas polyalanine with no Aib units shows a β-strand structure in circular dichroism spectroscopic analysis. We expanded this “tripeptide” strategy to various types of unnatural amino acids from N-alkyl amino acids to monomer units of synthetic polyamides such as nylon and aramide polymers. The periodic introduction of nylon units (ω-aminoalkanoic acid) provides polypeptides with melting behavior below their decomposition temperature, promising improvement in the processability of polypeptide materials with thermal plasticity.13 On the other hand, aromatic monomers can also be inserted in polypeptides via chemoenzymatic polymerization of tripeptide monomers containing 4-aminobenzoic acid residues.14 Fusing the polypeptide backbone with an aromatic structure can increase the thermal stability of polypeptides, which is reminiscent of the thermal properties of synthetic aromatic polyamides such as Kevlar. Notably, periodic introduction of such an aromatic structure, by which an unnatural secondary structure distinct from natural polypeptide forms, is important for improving the physical properties. The random introduction of 4-aminobenzoic acid in the polypeptide backbone was found to conversely deteriorate the thermal stability. Therefore, the introduction of unnatural amino acids shows synergy with secondary structures derived from periodic www.asiachem.news

sequences to improve the physical properties of polypeptide materials.

Functional polypeptides for plant modification

Aligning functional side groups of polypeptides by rationally designed sequences can lead to assembly into specific higher-order structures with unique functionality. Such

polypeptides have been applied to pharmaceutical and biomedical fields, including drug delivery systems, due to their physiological functions. In particular, our interest lies in plantbased sustainable bioproduction of bulk polymeric materials. Material production using plants has been studied in a broad range of fields, such as drug discovery, energy production, food production, and materials synthesis.

Figure 4. 2-Aminoisobutyric acid (Aib), an unnatural amino acid showing a poor affinity for proteases, can be recognized in the catalytic center of papain by “sandwiching” with natural amino acids. Various unnatural amino acids can be introduced in periodic sequences via chemoenzymatic polymerization using tripeptide esters flanking natural amino acids. Reproduced from Ref. 15 with permission from the Royal Society of Chemistry.

Figure 5. Material delivery into plant cells mediated by peptide carriers. Cationic polypeptides are used as carriers to complex with cargo materials (DNA, proteins), and the complex is further functionalized by various peptides to overcome several barriers for internalization into desired organelles. December 2021 | 45

Gene delivery is a powerful biotechnology for engineering plants based on modifying plant organelles (nucleus, chloroplasts, and mitochondria) to acquire desired traits for material production. To date, plant modification has been mainly achieved via agrobacterium-mediated or biolistic transformation, which suffers from several limitations for plant species and organelles. We have utilized functional polypeptides synthesized by chemoenzymatic polymerization as tools to modify plants (Figure 5). Exogenous genes, in the form of plasmid DNA (pDNA), double-stranded DNA (dsDNA), or RNA, electrostatically interact with a cationic peptide carrier to form a peptide/DNA complex.16 The peptide carrier consists of two or more functional sequences, including cationic DNA condensing domains, cell-penetrating peptides (CPPs), and organellar transit

peptides, to efficiently translocate cargoes into plant cells. The peptide/DNA complex is typically delivered into plant cells to engineer organelles by immersing plants (tissues) into the complex solution or direct infiltration using a syringe. We have rationally designed functional polypeptides that individually match requirements for overcoming barriers for internalization into target organelles that we aim to modify. For this purpose, chemoenzymatic synthesis is a useful technique to synthesize such functional sequences. As a sophisticated carrier that enables DNA cargoes to enter plant cells, we developed lysine-based cationic peptides ligated with a terminal-functionalized oligo(ethylene glycol) (Figure 6).17 By mixing the cationic peptide with DNA, a micellar complex immediately forms by electrostatic interaction, and the resulting

Figure 6. Infiltration of the peptide/DNA micelle complex into plant cells. The micelle complex, which displays reactive functional groups (maleimides) on its surface, can be postfunctionalized with various functional peptides, including cell penetrating peptides and organellar transit peptides, via a click reaction.

Figure 7. Zwitterionic polypeptides for dissociation of cellulose networks in cell walls. High-speed atomic force microscopy reveals that polypeptide treatment of cultured plant cells leads to partial dissociation of the cellulose network and amorphous pectin layer in cell walls. Bars show 50 nm. Reproduced from Ref. 23 with permission from the American Chemical Society. 46 | December 2021

micelle complex exhibits reactive functional groups such as maleimide and alkyne on its surface. We can exploit the surface reactive groups to further modify the micelle complex with another functional peptide or a peptide cocktail with multiple functionalities. The thiol-maleimide click reaction using cysteine-terminated functional peptides easily postfunctionalizes the micelle complex at the surface after the complexation process, and the types of functions and the reaction degree can be tuned on demand. Our fundamental experiments reveal that postfunctionalization with CPP doubles the gene delivery efficiency of a functionalized peptide/DNA complex compared with a nonfunctionalized micelle complex in a model plant (Arabidopsis thaliana). Furthermore, when the complex is modified with two peptides, CPP and endosome disrupting peptide (EDP), at an optimized ratio of 1 to 1, the gene delivery efficiency is further increased.18 The doubly functionalized complex with CPP and EDP can effectively deliver the DNA cargo into cells via CPP-mediated endocytosis and subsequently release it from the endosome to the cytosol. This success in improving delivery efficiency strongly implies that multiple functionalizations to address each barrier during the internalization process are essential to achieve high gene delivery efficiency. The most important function for internalization into cells is the membrane penetration property. CPPs have been developed as biological tools to deliver biomolecules into cells, initially for animal cells. We screened known CPPs originally used for material delivery into animal cells for internalization into plant cells to assess their availability for plant modification.19 Among the three categories of CPPs, namely, cationic, hydrophobic, and amphiphilic peptides, some amphiphilic CPPs were found to show a high internalization ability for model plant cells, although we found no remarkable correlation between the type/sequence of CPPs and the plant species that was used. In particular, no CPP was found that could be adapted to all plant species. The screening results for the CPP library motivated us to develop a novel artificial CPP suitable for versatile use across all plant species and tissue types. The most suitable candidate CPP in the peptide library was found to be an amphiphilic peptide adopting a helical conformation, which is assumed to be the key feature to penetrate cell membranes. We attempted to introduce a bulky nonproteinogenic Aib www.facs.website

residue into the sequence of CPP because it is known to strongly induce helix structures. Novel periodic peptides were synthesized by the chemoenzymatic polymerization of tripeptide esters containing cationic lysine and Aib residues.20 The resulting peptide with a repetitive sequence of the LysAibAla motif, designated the KAibA peptide, exhibited not only excellent membrane permeability but also long-term stability in plant cells compared with conventional amphiphilic or cationic CPPs. The KAibA peptide was applicable to various plants from model plants such as A. thaliana and tobacco (Nicotiana benthamiana) and crops such as rice (Oryza sativa) to practical plants such as kenaf (Hibiscus cannabinus, a fast-growing tall plant offering highstrength fibers) regardless of the type of tissue, including leaves and calli. Plant cells, unlike animal cells, have a cell wall in addition to a cell membrane. Cell walls are a relatively rigid tissue with hierarchical, dense network structures consisting mainly of cellulose and other polysaccharides, such as hemicellulose and pectin.21-22 Therefore, in contrast to cell membranes with dynamic lipid-layered structures, cell walls afford a major physical barrier for the transport of materials into plant cells. We focused on the cellulose network in cell walls and attempted to dissociate the network to maximize the penetration efficiency of the peptide/DNA complex through the cell wall. Cellulose, which suffers from poor processability due to its low solubility and nonmelting property, is known to dissolve in certain ionic liquids. Imidazolium-type ionic liquids with high hydrogen bond accepting ability interact and cleave the intermolecular hydrogen bonds of cellulose, resulting in complete dissolution of cellulose. We introduced such an imidazolium zwitterion structure similar to cellulose-dissolving ionic liquids into periodic polypeptides via chemoenzymatic polymerization (Figure 7).23 A tripeptide ester consisting of histidine flanked with glycine residues was polymerized in the presence of papain, and imidazole side groups of the resulting periodic polypeptide were converted to a zwitterionic structure. Based on in vitro experiments, bundles of cellulose nanocrystals derived from tunicates are found to be dissociated into smaller cellulose crystallites by treatment with zwitterionic polypeptides under mild conditions. Cultured tobacco plant cells (BY-2 cells) were also treated with zwitterionic polypeptides to investigate the effect of the polypeptide on the cellulose network in the cell wall. The zwitterionic polypeptide interacts with both the cellulose network and the amorphous pectin layers of BY-2 cells at a low www.asiachem.news

polypeptide concentration, which leads to the formation of large pores. Compared with the ionic liquid that dissolves cellulose, zwitterionic polypeptide shows almost no cytotoxicity at the efficacious concentration. We are trying to improve the material delivery efficiency into plant cells using such a novel “cell-wall permeable peptide” that helps polypeptide carriers penetrate cell walls.

Conclusion

Based on multifaceted approaches to produce polypeptide materials, we have developed protease-catalyzed green synthesis of polypeptide materials.24 Designing suitable amino acid sequences to construct specific secondary to higher-order structures that provide desired functionality allows us to synthesize various polypeptides that are expected to be widely applicable ranging from

References

1. Tsuchiya, K.; Miyagi, Y.; Miyamoto, T.; Gudeangadi, P. G.; Numata, K., Synthesis of Polypeptides. In Enzymatic Polymerization towards Green Polymer Chemistry, Kobayashi, S.; Uyama, H.; Kadokawa, J., Eds. Springer Singapore: Singapore, 2019; pp 233-265. 2. Tsuchiya, K.; Numata, K., Chemoenzymatic Synthesis of Polypeptides for Use as Functional and Structural Materials. Macromol. Biosci. 2017, 17 (11), 1700177. 3. Bordusa, F., Proteases in Organic Synthesis. Chem. Rev. 2002, 102 (12), 4817-4868. 4. Gimenez-Dejoz, J.; Tsuchiya, K.; Numata, K., Insights into the Stereospecificity in PapainMediated Chemoenzymatic Polymerization from Quantum Mechanics/Molecular Mechanics Simulations. ACS Chem. Biol. 2019, 14 (6), 12801292. 5. Numata, K., How to define and study structural proteins as biopolymer materials. Polym. J. 2020, 52 (9), 1043-1056. 6. Malay, A. D.; Sato, R.; Yazawa, K.; Watanabe, H.; Ifuku, N.; Masunaga, H.; Hikima, T.; Guan, J.; Mandal, B. B.; Damrongsakkul, S.; Numata, K., Relationships between physical properties and sequence in silkworm silks. Sci. Rep. 2016, 6 (1), 27573. 7. Xu, M.; Lewis, R. V., Structure of a protein superfiber: spider dragline silk. Proc. Natl. Acad. Sci. USA 1990, 87 (18), 7120. 8. Tsuchiya, K.; Numata, K., Chemical Synthesis of Multiblock Copolypeptides Inspired by Spider Dragline Silk Proteins. ACS Macro Lett. 2017, 6 (2), 103-106. 9. Urry, D. W.; Hugel, T.; Seitz, M.; Gaub, H. E.; Sheiba, L.; Dea, J.; Xu, J.; Parker, T., Elastin: a representative ideal protein elastomer. Philos. Trans. R. Soc. B Biol. Sci. 2002, 357 (1418), 169 -184. 10. Weller, D.; McDaniel, J. R.; Fischer, K.; Chilkoti, A.; Schmidt, M., Cylindrical Polymer Brushes with Elastin-Like Polypeptide Side Chains. Macromolecules 2013, 46 (12), 4966-4971. 11. Gudeangadi, P. G.; Tsuchiya, K.; Sakai, T.; Numata, K., Chemoenzymatic synthesis of polypeptides consisting of periodic di- and tri-peptide motifs similar to elastin. Polym. Chem. 2018, 9 (17), 2336-2344. 12. Yazawa, K.; Gimenez-Dejoz, J.; Masunaga, H.; Hikima, T.; Numata, K., Chemoenzymatic synthesis of a peptide containing nylon monomer units for thermally processable peptide material application. Polym. Chem. 2017, 8 (29), 4172-4176.

structural to functional materials. A simple protocol for chemoenzymatic polymerization leads to cost-effective, large-scale production of functional polypeptide materials. Ecofriendly chemical synthesis using enzymes has huge potential to replace the existing materials derived from exhaustible resources. From the perspective of energy reduction, enzymatic synthesis will also contribute to sustainable material production because it proceeds at mild temperatures. Our goal is to establish an innovative material manufacturing system that enables carbon-neutral cycles for a sustainable society. The novel synthetic method based on chemoenzymatic polymerization will be a key technology that plays an important role in the material ecocycle system. Recent advancements using enzyme-utilized synthesis will shed light on the potential for innovative materials based on polypeptides. ◆ 13. Gudeangadi, P. G.; Uchida, K.; Tateishi, A.; Terada, K.; Masunaga, H.; Tsuchiya, K.; Miyakawa, H.; Numata, K., Poly(alanine-nylon-alanine) as a bioplastic: chemoenzymatic synthesis, thermal properties and biological degradation effects. Polym. Chem. 2020, 11 (30), 4920-4927. 14. Tsuchiya, K.; Kurokawa, N.; Gimenez-Dejoz, J.; Gudeangadi, P. G.; Masunaga, H.; Numata, K., Periodic introduction of aromatic units in polypeptides via chemoenzymatic polymerization to yield specific secondary structures with high thermal stability. Polym. J. 2019, 51 (12), 12871298. 15. Tsuchiya, K.; Numata, K., Chemoenzymatic synthesis of polypeptides containing the unnatural amino acid 2-aminoisobutyric acid. Chem. Commun. 2017, 53 (53), 7318-7321. 16. Watanabe, K.; Odahara, M.; Miyamoto, T.; Numata, K., Fusion Peptide-Based Biomacromolecule Delivery System for Plant Cells. ACS Biomater. Sci. Eng. 2021, 7 (6), 2246-2254. 17. Miyamoto, T.; Tsuchiya, K.; Numata, K., Block Copolymer/Plasmid DNA Micelles Postmodified with Functional Peptides via Thiol–Maleimide Conjugation for Efficient Gene Delivery into Plants. Biomacromolecules 2018. 18. Miyamoto, T.; Tsuchiya, K.; Numata, K., Endosomeescaping micelle complexes dually equipped with cell-penetrating and endosome-disrupting peptides for efficient DNA delivery into intact plants. Nanoscale 2021, 13 (11), 5679-5692. 19. Numata, K.; Horii, Y.; Oikawa, K.; Miyagi, Y.; Demura, T.; Ohtani, M., Library screening of cell-penetrating peptide for BY-2 cells, leaves of Arabidopsis, tobacco, tomato, poplar, and rice callus. Sci. Rep. 2018, 8 (1), 10966. 20. Terada, K.; Gimenez-Dejoz, J.; Miyagi, Y.; Oikawa, K.; Tsuchiya, K.; Numata, K., Artificial Cell-Penetrating Peptide Containing Periodic α-Aminoisobutyric Acid with Long-Term Internalization Efficiency in Human and Plant Cells. ACS Biomater. Sci. Eng. 2020, 6 (6), 3287-3298. 21. Zhang, Y.; Yu, J.; Wang, X.; Durachko Daniel, M.; Zhang, S.; Cosgrove Daniel, J., Molecular insights into the complex mechanics of plant epidermal cell walls. Science 2021, 372 (6543), 706-711. 22. Yilmaz, N.; Kodama, Y.; Numata, K., Revealing the Architecture of the Cell Wall in Living Plant Cells by Bioimaging and Enzymatic Degradation. Biomacromolecules 2020, 21 (1), 95-103. 23. Tsuchiya, K.; Yilmaz, N.; Miyamoto, T.; Masunaga, H.; Numata, K., Zwitterionic Polypeptides: Chemoenzymatic Synthesis and Loosening Function for Cellulose Crystals. Biomacromolecules 2020, 21 (5), 1785-1794. 24. Numata, K., Biopolymer Science for Proteins and Peptides. Elsevier: Amsterdam, 2021.

December 2021 | 47

Keat Beamsley

Keat T. Beamsley received his B.S. in Chemistry from the University of Canterbury, New Zealand. He is currently pursuing his M.S. in Applied Chemistry at the University of Tokyo, and is working with Professor Takashi Uemura on the controlled synthesis of polymers in Metal-Organic Frameworks.

Takashi Uemura

Takashi Uemura received his Ph.D. degree at Department of Polymer Chemistry, Kyoto University in 2002. He then began his academic career as Assistant Professor (2002) and then Associate Professor (2010) at Kyoto University and was promoted to Professor at the University of Tokyo in 2018. He has received a number of awards, including JSPS Prize, the Chemical Society of Japan (CSJ) Award for Young Chemists, The CSJ Award for Creative Works, the Commendation for Science and Technology by the Minister of Education, Culture, Sports, Science, and Technology. He has been appointed as Associate Editor of several international journals, such Dalton Trans. (RSC), Chem. Lett. (CSJ), and Bull. Chem. Soc. Jpn. (CSJ). His research interest is preparation of synergistic nanohybrids between coordination compounds and polymeric materials, in particular, polymer chemistry in coordination nanospaces.

48 | December 2021

Nanoporous Chem MOFs as Polymer M Our technology-driven society continues to advance, and with it the demand for various high-function plastics also advances, calling for precision-engineered polymers with few defects in their structures even at the molecular level. People’s lives have come to strongly rely upon these plastics, but in recent decades have we also come to recognize their negative aspects in the form of the environmental and resource crises. It is against this backdrop that a new method of efficient and precise control over polymer structure has been developed - the use of porous materials called ‘MOFs’ as nano-sized ‘factories’. With this new technology, desired polymers can be supplied and utilized effectively, and we envision a future where they may also be reclaimed post-use then re-circulated. www.facs.website

mical Plants: Manufacturers By Keat Beamsley and Takashi Uemura https://doi.org/10.51167/acm00023

POLYMERS, ALONGSIDE METALS and ceramics, make up one of the three fundamental types of materials that enable our modern way of life. Owing to their characteristic light weight and customizable physical properties, the range of applications for polymers is continually expanding, calling for the development of polymeric materials which exhibit excellent functionality of any and all kinds. However, when we synthesize polymers, we typically do so in a flask or reactor – a macro-scale vessel. In this case, we may obtain polymeric materials at low cost and in great quantity, but their www.asiachem.news

polymer chains are unavoidably entangled, and control over their molecular structures is often difficult. If instead we were to use a reaction vessel of a scale that matches the individual size of target polymer chains, we should be able to precisely control the orientation, position, distance, and electronic state of the ingredient monomers. Thus, the vessel itself is expected to exert great influence on the polymerization reaction, and may be able to precisely control the resulting polymer structure and aggregation state from the moment it is formed.

In recent years, structurally regular porous materials formed from the self-assembly of metal ions and organic ligands – metal-organic frameworks or “MOFs” - have gathered much attention1-3. The number of combinations of metal ions and ligands in these organic-inorganic hybrids are limitless, so by choosing the structural ingredients appropriately one can not only control the pore space and its dimensionality, but also its shape and the presence or absence of functional groups (Figure 1). Further, by tuning the electronic structure of these building blocks, it is possible December 2021 | 49

to impart not only a spatial structure but also electronic properties and chemical reactivity. They therefore have value as vessels for the construction of custom polymers with tailor-made structures and functionality. MOFs, first developed in the 1990s, have mostly seen applications using gases and solvents, aiming for the adsorption and separation of these micromolecules. In contrast, this article describes MOF nanospaces’ ability to produce functional macromolecular (polymeric) materials. 500 publications per year now involve some combination of MOFs and polymers together, and it’s not hard to see why as it becomes increasingly clear that the skillful use of MOFs allows nano-level chemical manipulation of not only organic polymers, but biological and inorganic polymers as well. As the possibilities for combinations of MOFs and polymers are endless, this area will continue to expand into a wide-reaching field with strong

impact on various academic disciplines and industries4-8.

Controlling polymer primary structures

DNA and proteins show us that biological systems can exert such strict control over their polymerizations’ regiochemistry, stereoregularity, molecular weight, and sequence that they can’t help but seem like the ultimate system when measured by the standards we currently apply to synthetic polymerization. Life’s key to producing this kind of elaborate polymer structure is the highly accurate transcription of the molecular information held by nucleic acids, and it is within the organized nanospaces of enzymes that it does this. Similarly, when the micropores of MOFs are used as a vessel for polymerization, precise control over the structures of the polymers that come out becomes possible

Figure 1: Schematic representation of MOFs.

Figure 2: Polymerizations in MOFs allow multi-level controls over the structures of polymers, depending on the nanoporous structures of MOF templates. 50 | December 2021

(Figure 2)4-6. The history of this effort starts in 2005, with our development of the first polymerization method using a MOF nanospace9. Using the 1D channels of [M2(L)2(ted)] (M = Cu 2+ or Zn 2+, L = terephthalate or n its derivatives, ted = triethylenediamine), it became clear that radical polymerization of vinyl monomers in their pores proceeds in a manner resembling living radical polymerization9,10. Recently, Schmidt and Antonietti have also reported that they can exert greater control over the molecular weight by carrying out reversible addition-fragmentation chain transfer (RAFT) polymerization inside MOF spaces11. Atom transfer radical polymerization (ATRP) utilizing the metals inside MOFs has also become possible, with developments progressing into precision polymerization systems using recoverable catalysts12.

When copolymerization is carried out in a MOF, monomer reactivities differ greatly to their behavior in solution. Recently, it was observed that immobilizing monomers on a MOF framework through coordinate or covalent bonding caused wideranging changes to the makeup of the resulting copolymer Polymerization of vinyl monomers in MOF pores brings about polymers with stereoregularity that sensitively responds to the size and shape of the MOF space, as well as the presence or absence of unsaturated coordination sites10,13,14. This makes the formation of highly isotactic polymers, which are otherwise difficult to achieve by radical polymerization, possible. By also using unsaturated coordination sites as polymerization catalysts, Dinca and co-workers achieved highly stereospecific polymerization of butadiene monomers using a MOF possessing cobalt-substituted metal sites15. Combining the aforementioned RAFT www.facs.website

and ATRP methods, simultaneous control over molecular weight, stereoregularity, and terminal structure has also become possible16. When several kinds of monomers are simply mixed together and polymerized, the monomers usually connect randomly to one another, resulting in copolymers with no particular predetermined sequence. In contrast, when copolymerization is carried out in a MOF, monomer reactivities differ greatly to their behavior in solution. Recently, it was observed that immobilizing monomers on a MOF framework through coordinate or covalent bonding caused wide-ranging changes to the makeup of the resulting copolymer17,18. For example, mixing 5-vinylisophthalate (S) and copper ions gives a MOF with a perfectly repeating space of 0.68nm between the S units which are to act as monomers (Figure 3a)18. After introducing acrylonitrile (A) into the 1D channels of this MOF, carrying out copolymerization between the host and guest, and finally digesting the MOF, a polymer is obtained which has a structure consisting of perfectly repeating AAAS units (Figure 3b)18. This implies that precisely three A monomers fit and polymerize between each S embedded regularly along the 1D pores, and is a fascinating system for imprinting the periodicity of a MOF into a polymer. Recently, Sada and co-workers found that the step-growth polymerization of immobilized monomers in a MOF is also capable of controlling the molecular weight of polymers, in contrast to solution processes19. Between all these studies, it has become clear that polymerization within MOF pores can play a strong part in the precision-controlled synthesis of polymers, regardless of the polymerization mechanism.

To that end, a polystyrene network wherein polymer chains are perfectly aligned along one axis was synthesized by partially introducing divinylated ligands – species capable of bridging the styrene chains – into the walls of a 1D channel MOF, then polymerizing styrene within22. In this system, polymer networks were crosslinked while completely aligned in a MOF space, so the alignment of the polymer chains was conserved after MOF destruction, and even withstood heat and solvent treatment. Recently, the synthesis of ultrathin-film 2D polymers of monomolecular thickness has been demonstrated by crosslinking within the

2D space of a ‘pillared-layer MOF’ (Figure 4)23. These polymers display unique viscoelastic properties due to their unique topological structure, which completely excludes any interweaving of polymer chains. While the control over polymer network structures such as functional gels and adsorbent materials holds great importance to advanced materials science and technology, the standard polymerization reactions carried out in solution inevitably form randomly arranged crosslinks, making such control difficult. By using a MOF possessing 3D connected pores as a template, however,

Figure 3: a) Formation of a MOF with styryl groups (S) periodically aligned along the 1D channels. b) Copolymerization of acrylonitrile with the MOF provides sequenceregulated copolymers reflecting on the periodicity of the MOF channels.

Aligning polymer chains

Polymers synthesized within MOF pores form in a state where their orientation is perfectly restricted by the crystalline space. If, perhaps, the template MOF could be removed without disturbing that state, it follows that it would be possible to control the aggregation structure of the polymers inside according to the dimensionality of the MOF used. Following this principle, it was discovered that polythiophene synthesized in a MOF’s 1D pores give rod-shaped particles when said MOF is removed20. Polymer chains in these particles are highly aligned along their long axis, and possess electrical conductivity on the order of 1000 times higher than that of polythiophene synthesized in solution. Further, when polythiophene chains are inserted into a chiral MOF, it has been shown that even upon removal of the MOF mold (that is, in the complete absence of a source of chirality), the isolated polythiophene continues to exhibit chirality21. While this method of control over orientation and conformation is effective with respect to rigid, conjugated polymers, it remains unsuitable for the control of soft, vinyl polymers. www.asiachem.news

Figure 4: a) Crystal structure of a pillared-layer MOF and an MD simulation snapshot of the MOF containing styrene monomers. b) AFM image and height profile of ultrathin polystyrene film obtained from the MOF. December 2021 | 51

control of various polymer network structures becomes possible. For example, if the synthesis of a polysaccharide is carried out within the 3D channels of [Cu3(btc)2] (btc = benzene-1,3,5-tricarboxylate), polymeric particles possessing mesopores are obtained24. As this type of material efficiently takes up guests such as drugs and peptide molecules, it is hoped to see use in biological applications such as drug delivery systems. Research is also being carried out into the precise control over bridged structures by carrying out host–guest cross-polymerization between monomer guests and reaction sites embedded into MOF ligands. For example, a ‘click’ coupling reaction proceeds efficiently between a tetraalkynyl guest and a MOF host possessing two azide groups on each of its ligands25. Upon removal of the MOF’s metal atoms, a polymer particle with a shape reflecting that of the original MOF particle is obtained, and exposing this particle to solvent then expands it isotropically into a gel. More recently, success has also been found in designing anisotropically-expanding gels by using pillared-layer 2D MOFs as templates26. If all different types of polymeric material were mutually miscible, we could freely tune the functional properties of these polymers by simply mixing them, bringing about possibilities that would be unobtainable with mere homopolymers. However, the vast majority are instead mutually immiscible, resulting in the spontaneous phase separation of polymer mixtures. In our work, we have shown that mutually immiscible polymer species (such as polystyrene and methyl methacrylate) can be mixed on the molecular level by using the non-equilibrium approach of encapsulating different species of polymer inside a MOF’s pores, then removing the MOF27.

Integrating MOF-polymer functions

By introducing polymer chains into MOF nanospaces, one can precisely control the

By enclosing conductive polymers like polythiophene in MOF pores, changes in hole mobility could be induced depending on the number of polymer chains aggregated together number of interacting polymer chains, their alignment, and their surrounding environment. Accordingly, it becomes possible to characterize the physical properties of either one or several polymer chains in isolation, which are distinct from those in the bulk state. Accordingly, we have revealed that the nanoconfinement in MOF channels has marked effects on the dynamics as well as the thermal behaviors of the encapsulated polymer chains28,29. By enclosing conductive polymers like polythiophene in MOF pores, changes in hole mobility could be induced depending on the number of polymer chains aggregated together30. Preparing such a host–guest complex gives a material possessing a combination of both porosity and conductivity, and this was further developed into sensor materials capable of detecting guest NO2 gas at the ppb level by measuring their impact on host conductivity31. It has also been shown that donor-acceptor structures can be rationally assembled at the molecular level by forcing them to reflect anisotropic MOF framework structures. By first preparing a MOF with

titanium oxide nanowires (acceptors) present in its pores, then synthesizing polythiophene chains (donors) in the 1D channels, a perfectly alternating array structure was achieved (Figure 5)32. Investigations showed that this array creates long-lived charge separation states, with the half-life of the charged species exceeding 1 millisecond – about 1,000 times longer than that of any other reported titanium oxide system. Results like this provide a useful guide to building new materials to raise the efficiency of photoelectric devices, and draw attention to their possible applications in solar cells. The above methods all focus on the post-synthetic introduction of polymers to form host–guest complexes. In contrast, if we instead use polymers which incorporate ligands that can make up a MOF, we may create hybrids where these materials are connected directly by covalent bonds. Cohen and co-workers are researching what they call a ‘polyMOF’ – a complex where polymers with repeating units containing terephthalate (a common MOF ligand) are incorporated directly into the MOF structure by mixing them in during the MOF synthesis process33. Building complexes like this enhances properties such as the stability and hydrophobicity of the MOF, and there are even cases where the MOF crystals form structures resembling thin films. Recently, the Johnson group has been carrying out the synthesis of polyMOF nanoparticles using block copolymers34. In this system, MOF crystals are formed around blocks of ligand moieties in the polymer while the remaining blocks encircle the outside, resulting in nanoparticles with decorated surfaces. In short, the use of block copolymers as precursors enables simultaneous control over both the MOF nanoparticles and their surfaces. Practicality issues arise in many cases when MOFs in particle form are considered for use in real-world implementations. As such, there are times when MOFs are simply mixed with

Figure 5: Fabrication of a perfectly alternating donor–acceptor architecture at the molecular level. 52 | December 2021

www.facs.website

various polymers to form mixed-matrix membranes. Compared to the conventional inorganic fillers, MOFs’ hybrid organic-inorganic structures display high compatibility with polymers. Complex membranes constructed using this method have already shown excellent functionality as gas separation membranes, nanofiltration membranes, and solid electrolytes35.

Separating desired polymer chains

Polymers are made up of chains containing countless monomer units, and can thus have any number of diverse and distinct structures. While sequence disorder is of course present in the case where a mixture of several monomers is used, a statistical distribution of molecular weights is observed even if only one monomer type is used. Stereo- and regiochemical control are often difficult to achieve, and thus the polymeric materials we use in our daily lives consist of mixtures of various types of polymer chain. It goes without saying that the polymers’ structures determine their physical properties, and so the isolation of specific desired polymers from mixtures is extremely important both academically and industrially. This is no simple task, however, due to the complete ineffectiveness of standard chemical separations (distillation, recrystallization, solvent extraction, etc.) with respect to polymer-polymer mixtures. Essentially, even if there were a different moiety present at some point in a polymer chain, we could not usually single that moiety out and isolate only the polymer chains that possess it in a designated location on the chain. On top of that, polymers undergo self-entanglement unique to the chain-like nature of their structures, so even in solution they exist in states which constantly bend and knot themselves together, leaving us no option but to process them as ‘clumps’. For this reason, one could discriminate between polymers based on ‘clump’ size (which is proportional to chain length) using size-exclusion chromatography, but recognition and separation according to some minute change of structure within a long chain (large ‘clump’) was impossible. Recently, our group has sought a resolution to this problem by methods utilizing the adsorption of polymers into the nanospaces of MOFs 29,36,37. While such a description makes it sound simple, at the time it was considered common sense that the very idea of polymers adsorbing into channels on the sub-nanometer scale would be impossible, due to the great loss of entropy it would entail. In fact, there were no reported examples of their adsorption into conventional microporous materials – zeolites – either. Nevertheless, by shunning ‘common sense’ we were able to find that many polymers do, in fact, spontaneously penetrate into MOF www.asiachem.news

Figure 6: Time-evolved snapshots from MD simulations of PEG (Mw = 600 g/mol) intercalated in [Zn2(terephthalate)2(triethylenediamine)]n.

Figure 7: Well-defined nanopores of MOFs serve as a universal workspace for highprecision polymer recognition and separation, which is not possible with conventional methods. December 2021 | 53

nanospaces, even into those whose radii number in the angstroms (Figure 6). T his phe nome non ope ns door s to the previously non-existent concept of ‘precision polymer separation’ 7,8 . For example, polymers which differ only by terminal structure experience less and less influence from the terminals as their chains become longer (i.e. as the terminal becomes a smaller component relative to the whole chain) and so existing methods have proven incapable of recognizing and separating them based on this difference. Using MOFs, our group has succeeded in discriminating between polymer chains which possess molecular weights in the tens of thousands of Daltons, and differ only by their terminal structure 38. Further, we have carried out liquid chromatographic separation using prototype columns loaded with MOF particles 37,39 . The result was a shocking level of recognition, with retention times differing enough to discriminate in response to changes as small as one atom on a long polymer chain. As this method disentangles polymer chains into linear arrays along the MOF pores, it enables structural recognition without neglecting any features within the chain, some of which might otherwise be shrouded by the outer layers of an aggregate structure. Various types of polymer separation have been realized based not only on molecular weight37, but topological differences such

as cyclic-versus-linear40, or even monomer composition within a copolymer, making this a macromolecular recognition-separation system of unparalleled precision (Figure 7).

Developing “urban oil wells”

Our new approach of polymer separation can provide structurally controlled polymers without the use of tedious synthetic techniques. These could then be used as enhanced plastics in applications such as electrical devices and medicine, bringing prosperity to our everyday lives. However, looking at the results of a survey by the Japan Plastics Industry Federation (JPIF)41, we find that for 20 years consumers’ impressions of plastics’ “usefulness” has remained consistently high, and that most are already satisfied with the ‘work’ plastic does for us (Figure 8). A point that’s cause for concern, however, is the “Environmental friendliness” and “Resource efficiency” categories, where public opinion has abruptly fallen in recent years (Figure 8) 41. One major reason for this is a raised awareness of the pollution problems plastic litter causes, and people continue to celebrate switches toward bioplastics and biodegradable materials in response to this. Such materials do not actually solve the problem in marine environments, however, and the United Nations Environment Programme (UNEP) has stated

Usefulness

2003 2007 2012 2016 2020

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2003 2007 2012 2016 2020

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2003 2007 2012 2016 2020 0%

20% positive

40%

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negative

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Figure 8: Impression of plastics surveyed by the Japan Plastics Industry Federation (JPIF).41 54 | December 2021

as much – biodegradation occurs in conditions that rarely ever occur in our oceans, and concern has been raised that hiding such a fundamental problem behind an ‘eco-friendly’ image may actually worsen the situation42. Returning to the survey (Figure 8), and the fact that nearly 100% of respondents were satisfied with plastics’ performance41 – one way to read this would be that what we have already is completely sufficient as-is. From that standpoint, it would be best to let a perfectly satisfactory plastic do its job again and again, so our society must consider having plastics which fulfilled their role once do so multiple times by way of recycling. The current reality, however, is that in Japan roughly 60% of waste plastic resources end up undergoing combustion (in solid fuel, electricity generation, and other applications) by a process called ‘thermal recycling’, with the range of products reused as actual plastics (‘material recycling’) restricted mainly to those made of PET43. The reason renewal of other plastics remains stagnant is that they form various mixtures, complexes, and composites from which pure polymers cannot be effectively separated43. So here too, we see that current technology’s inability to separate desired polymers out of a mixture is connected directly to a societal problem. We are confident our MOF method can perform this separation, having witnessed its capabilities in lab-scale separations of simple polymer mixtures. However, realworld application will bring new technological challenges in both the processing of unpredictable mixtures and the upscaling of this process, and even if it proves to be possible in principle, there would be no meaning in doing so if the process takes an excessive amount of energy or creates an extreme environmental burden of its own. Complex socioeconomic factors will also have to be accounted for. But at the end of the line, could we not consider the plastics welling up in the streets a high-quality “urban oil well”? We dream of a future for society where plastic no longer piles up, but is used in cycles just as water and air are. ◆ www.facs.website

Reference

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Metal Sites in Coordination Nanochannels. ACS Macro Lett. 4, 788-791. 18. Mochizuki, S., Ogiwara, N., Takayanagi, M., Nagaoka, M., Kitagawa, S., Uemura, T. (2018). Sequence-Regulated Copolymerization Based on Periodic Covalent Positioning of Monomers along One-Dimensional Nanochannels. Nat. Commun. 9, 329. 19. Anan, S., Mochizuki, Y., Kokado, K., Sada, K. (2019). Step-Growth Copolymerization between an Immobilized Monomer and a Mobile Monomer in Metal–Organic Frameworks. Angew. Chem. Int. Ed. 58, 8018-8023. 20. Kitao, T., MacLean, M.W.A., Le Ouay, B., Sasaki, Y., Tsujimoto, M., Kitagawa, S., Uemura, T. (2017). Preparation of Polythiophene Microrods with Ordered Chain Alignment Using Nanoporous Coordination Template. Polym. Chem. 8, 5077-5081. 21. Kitao, T., Nagasaka, Y., Karasawa, M., Eguchi, T., Kimizuka, N., Ishii, K., Yamada, T., Uemura, T. (2019). Transcription of Chirality from Metal-Organic Framework to Polythiophene. J. Am. Chem. Soc. 141, 19565-19569. 22. Distefano, G., Suzuki, H., Tsujimoto, M., Isoda, S., Bracco, S., Comotti, A., Sozzani, P., Uemura, T., Kitagawa, S. (2013). Highly Ordered Alignment of a Vinyl Polymer by Host–guest Cross-Polymerization. Nat. Chem. 5, 335-341. 23. Hosono, N., Mochizuki, S., Hayashi, Y., Uemura, T. (2020). Unimolecularly Thick Monosheets of Vinyl Polymers Fabricated in Metal–Organic Frameworks. Nat. Commun. 11. 3573. 24. Kobayashi, Y., Honjo, K., Kitagawa, S., Uemura, T. (2016). Preparation of Porous Polysaccharides Templated by Coordination Polymer with ThreeDimensional Nanochannels. ACS Appl. Mater. Interface 9, 11373-11379.

11. Hwang, J., Lee, H.-C., Antonietti, M., Schmidt, B.V.K.J. (2017). Free Radical and RAFT Polymerization of Vinyl Esters in Metal-Organic Frameworks. Polym. Chem. 8, 6204-6208.

25. Ishiwata, T., Furukawa, Y., Sugikawa, K., Kokado, K., Sada, K. (2013). Transformation of Metal– Organic Framework to Polymer Gel by CrossLinking the Organic Ligands Preorganized in Metal–Organic Framework. J. Am. Chem. Soc. 135, 5427-5432.

12. Lee, H.-C., Antonietti, M., Schmidt, B.V.K.J. (2016). A Cu(II) Metal-Organic Frameworks as a Recyclable Catalyst for ARGET ATRP. Polym. Chem. 7, 71997203.

26. Ishiwata, T., Kokado, K., Sada, K. (2017). Anisotropically Swelling Gels Attained through AxisDependent Crosslinking of MOF Crystals. Angew. Chem. Int. Ed. 56, 2608-2612.

13. Uemura, T., Ono, Y., Hijikata, Y., Kitagawa, S. (2010). Functionalization of Coordination Nanochannels for Controlling Tacticity in Radical Vinyl Polymerization. J. Am. Chem. Soc. 132, 4917-4924.

27. Uemura, T., Kaseda, T., Sasaki, Y., Inukai, M., Toriyama, T., Takahara, A., Jinnai, H., Kitagawa, S. (2015). Mixing of Immiscible Polymers Using Nanoporous Coordination Templates. Nat. Commun. 6, 7473.

14. Uemura, T., Uchida, N., Higuchi, M., Kitagawa, S. (2011). Effects of Unsaturated Metal Sites on Radical Vinyl Polymerization in Coordination Nanochannels. Macromolecules 44, 2693-2697. 15. Dubey, R.J.C., Comito, R.J., Wu, Z., Zhang, G., Rieth, A.J., Hendon, C.H., Miller, J.T., Dinca, M. (2017). Highly Stereoselective Heterogeneous Diene Polymerization by Co-MFU-4l: A Single-Site Catalyst Prepared by Cation Exchange. J. Am. Chem. Soc. 139, 12664-12669. 16. Lee, H.-C., Hwang, J., Schilde, U., Antonietti, M., Matyjaszewski, K., Schmidt, B.V.K.J. (2018). Toward Ultimate Control of Radical Polymerization: Functionalized Metal–Organic Frameworks as a Robust Environment for Metal-Catalyzed Polymerizations. Chem. Mater. 30, 2983-2994.

28. Uemura, T., Horike, S., Kitagawa, K., Mizuno, M., Endo, K., Bracco, S., Comotti, A., Sozzani, P., Nagaoka, M., Kitagawa, S. (2008). Conformation and Molecular Dynamics of Single Polystyrene Chain Confined in Coordination Nanospace. J. Am. Chem. Soc.130, 6781-6788. 29. Uemura, T., Yanai, N., Watanabe, S., Tanaka, H., Numaguchi, R., Miyahara, M.T., Ohta, Y., Nagaoka, M., Kitagawa, S. (2010). Unveiling Thermal Transitions of Polymers in Subnanometre Pores. Nat. Commun. 1, 83.

30. MacLean, M.W.A., Kitao, T., Suga, T., Mizuno, M., Seki, S., Uemura, T., Kitagawa, S. (2016). Unraveling Inter- and Intra-chain Electronics in Polythiophene Assemblies Mediated by Coordination Nanospaces. Angew. Chem. Int. Ed. 55, 708-713. 31. Le Ouay, B., Boudot, M., Kitao, T., Yanagida, T., Kitagawa, S., Uemura, T. (2016). Nanostructuration of PEDOT in Porous Coordination Polymers for Tunable Porosity and Conductivity. J. Am. Chem. Soc. 138, 10088-10091. 32. Wang, S., Kitao, T., Guillou, N., Wahiduzzaman, M., Martineau-Corcos, C., Nouar, F., Tissot, A., Binet, L., Ramsahye, N., Devautour-Vinot, S., Kitagawa, S., Seki, S., Tsutsui, Y., Briois, V., Steunou, N., Maurin, G., Uemura, T., Serre, C. (2018). A Phase Transformable Ultrastable Titanium-Carboxylate Framework for Photoconduction. Nature Commun. 9, 1660. 33. Zhang, Z., Nguyen, H.T., Miller, S.A., Cohen, S.M. (2015). PolyMOFs: A Class of Interconvertible Polymer-Metal-Organic-Framework Hybrid Materials. Angew. Chem., Int. Ed. 54, 6152-6157. 34. Gu, Y., Huang, M., Zhang, W., Pearson, M.A., Johnson, J.A. (2019). PolyMOF Nanoparticles: Dual Roles of a Multivalent polyMOF Ligand in Size Control and Surface Functionalization. Angew. Chem. Int. Ed. 58, 16676-16681. 35. Bachman, J.E., Smith, Z.P., Li, T., Xu, T., Long, J.R. (2016). Enhanced Ethylene Separation and Plasticization Resistance in Polymer Membranes Incorporating Metal–Organic Framework Nanocrystals. Nat. Mater. 15, 845-849. 36. Uemura, T., Washino, G., Kitagawa, S., Takahashi, H., Yoshida, A., Takeyasu, K., Takayanagi, M., Nagaoka, M. (2015). Molecule-Level Studies on Dynamic Behavior of Oligomeric Chain Molecules in Porous Coordination Polymers. J. Phys. Chem. C 119, 21504-21514. 37. Oe, N., Hosono, N., Uemura, T. (2021). Revisiting Molecular Adsorption: Unconventional Uptake of Polymer Chains from Solution into Sub-Nanoporous Media. Chem. Sci. 12, 12576-12586. 38. Le Ouay, B., Watanabe, C., Mochizuki, S., Takayanagi, M., Nagaoka, M., Kitao, T., Uemura, T. (2018). Selective Sorting of Polymers with Different Terminal Groups Using Metal-Organic Frameworks. Nat. Commun. 9, 3635. 39. Mizutani, N., Hosono, N., Le Ouay, B., Kitao, T., Matsuura, R., Kubo, T., Uemura, T. (2020). Recognition of Polymer Terminus by Metal–Organic Frameworks Enabling Chromatographic Separation of Polymers. J. Am. Chem. Soc. 142, 3701-3705. 40. Sawayama, T., Wang, Y., Watanabe, T., Takayanagi, M., Yamamoto, T., Hosono, N., Uemura, T. (2021). Metal–Organic Frameworks for Practical Separation of Cyclic and Linear Polymers. Angew. Chem. Int. Ed. 60, 11830-11834. 41. The Japan Plastics Industry Federation (JPIF). (2021). Results of Survey: Questionnire for Plastics. 42. United Nations Environment Programme (UNEP). (2015). Biodegradable Plastics and Marine Litter: Misconceptions, Concerns and Impacts on Marine Environments. 43. Plastic Waste Management Institute (PWMI). (2021). An Introduction to Plastic Recycling in Japan.

17. Uemura, T., Mochizuki, S., Kitagawa, S. (2015). Radical Copolymerization Mediated by Unsaturated

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Reactivity Prediction Through Quantum Chemical Calculations

By Satoshi Maeda, Yu Harabuchi, Taisuke Hasegawa, Kimichi Suzuki, and Tsuyoshi Mita https://doi.org/10.51167/acm00024

Satoshi Maeda

Satoshi Maeda received his Ph.D. from Tohoku University in 2007. He was a JSPS research fellow in 2007–2010 and was an assistant professor of the Hakubi project at Kyoto University in 2010–2012. In 2012–2017, he served as an assistant professor and an associate professor at Hokkaido University. He is now a full professor at Hokkaido University and the director of WPI-ICReDD. He is also the research director of JST-ERATO “MAEDA Artificial Intelligence in Chemical Reaction Design and Discovery Project.” His research interest is the development of automated reaction path search methods for accelerating chemical reaction discovery.

56 | December 2021

Yu Harabuchi

Yu Harabuchi received his Ph.D. from Hokkaido University, in 2013. In 2013–2016, he was a postdoc at Iowa State University and Hokkaido University. In 2016, he became a JST-PRESTO researcher. Since 2017, he has worked as an Assistant Professor at Hokkaido University. In 2019, he joined WPI-ICReDD, and he joined JST-ERATO, “MAEDA Artificial Intelligence in Chemical Reaction Design and Discovery Project” as a group leader of quantum chemistry group. His research interests focus on theoretical investigations of photoreactions based on a systematic search for non-radiative decay paths, and he works on theoretical analyses and predictions of chemical reactions.

Kimichi Suzuki

Kimichi Suzuki received Ph.D. from YokohamaCity University in 2010. After joining the NEDO project as a postdoctoral fellow at AIST, he worked at SUMITOMO Chemical. Co., LTD. Afterwards, he worked at Kyoto University and Hokkaido University. Since 2019, he is a specially appointed associate professor at the Institute for Chemical Reaction Design and Discovery at Hokkaido University. His research interest is development of efficient reaction path search algorithm for large molecular systems and its applications.

Tsuyoshi Mita

Taisuke Hasegawa

Taisuke Hasegawa received his bachelor degree in Chemistry at Nagoya University, master degree (2009) and Ph.D. in Chemistry (2011) at Kyoto University. He then worked at Hamburg University, Max Planck Institute for the Structure and Dynamics of Matter (MPSD), Kyoto University, Max Planck Institute for Polymer Research (MPIP), and National Institute for Materials Science (NIMS) as a postdoc. He is currently a specially appointed associate professor at faculty of science, Hokkaido University. His research interests are application of reaction path networks for functional materials and surface chemistry.

Tsuyoshi Mita obtained his Ph.D. from the University of Tokyo and was a JSPS Postdoctoral Fellow (SPD) at Harvard University. After 10 years as an Assistant Professor at Faculty of Pharmaceutical Sciences, Hokkaido University. In 2019, he joined WPI-ICReDD, Hokkaido University as a Specially Appointed Associate Professor. He is also a group leader in organic chemistry group of JST, ERATO “MAEDA Artificial Intelligence in Chemical Reaction Design and Discovery Project” His current research interests are in the areas of synthetic organic chemistry, organometallic chemistry, medicinal chemistry, and computational chemistry.

The main challenge in chemistry is understanding and controlling the movement of atoms, which play a leading role in chemical reactions. In principle, one could predict the movement of atoms by solving the Schrödinger equation, however, which for many-particle systems is too complicated to solve with high accuracy. Thanks to advances in quantum chemical calculation methods, the Schrödinger equation for the motion of electrons is solvable with reasonable accuracy under various approximations.1 Among the approximation algorithms, the density functional theory (DFT) based on the Kohn-Sham equation is routinely used in calculations of the potential energy surface (PES) for a system of several hundred atoms. www.facs.website

DFT-BASED REACTION mechanism study is currently popular. By performing DFT calculations for each ever-changing nuclear configuration, molecular dynamics (MD) calculations simulate the motion of atoms while solving Newton’s eqation of motion based on the gradient of the PES.2 Nevertheless, MD calculations require DFT calculations every 10-15 seconds in the simulation step width, and as many as 10 6 DFT calculations are necessary to run a simulation of 10-9 seconds. Many reaction mechanism studies discuss energy profiles.3-5 After geometry optimization obtains the transition state (TS) of each elementary reaction process,6 the movement of atoms during the reaction is visualized by the intrinsic reaction coordinate (IRC) calculated from the TS.7,8 Then, an energy profile can be drawn using the energy levels of the TS and the two end-points along the IRC path. Since several tens to several hundreds of DFT calculations are needed for one geometry optimization and one IRC calculation each, the calculation cost is much lower than MD calculations. On the other hand, the TS obtained by geometry optimization depends on the initial structure, which is generally created based on the computators’ own experience and intuition. Therefore, it is www.asiachem.news

necessary to repeat DFT-based geometry optimization calculations for the mechanism assumed by the computators until the energy profile becomes consistent with the experimental result. Recently, several automated reaction path search methods that do not require the initial structure of TS have been developed.9 -11 The methods enable systematic analysis of reaction mechanisms without relying on the computators’ experience or intuition. In addition, the automated reaction path search methods are opening the way to ab initio prediction of new chemical reactions passing through unknown reaction paths. This article outlines the artificial force induced reaction (AFIR) method, which has been developed by the authors.12-15 Further, by applying the rate constant matrix contraction (RCMC) method, a kinetic analysis method developed by the authors, to the reaction path network obtained by the AFIR method, the products and their formation paths can be elucidated.16,17 Combined usage of the AFIR and RCMC methods also facilitates on-thefly kinetic simulation to explore elementary reaction processes while solving the chemical kinetics.18 Finally, this article introduces quantum chemistry aided retrosynthetic analysis

(QCaRA), which searches reaction paths backward from a product to possible reactants, and its application to chemical reaction discovery.19

Artificial Force Induced Reaction (AFIR) Method

The basic idea behind the AFIR method is quite simple, as explained below. The fragments in a molecule or complex are repeatedly pushed against each other or pulled apart by an artificial force. Fig. 1(a) shows the AFIR function FAFIR applying an artificial force between fragments A and B, where Q is a set of variables describing the molecular structure, E is PES, α is a parameter defining the strength of the artificial force, R i is the covalent radius of the i-th atom, rij is the distance between the i-th and j-th atoms, and p is a parameter (after adjustment, it is set p = 6). This procedure for minimizing FAFIR corresponds to the application of an artificial force between substructures A and B. The three examples in Fig. 1(b) indicate that different molecules can be obtained by specifying various fragments, A and B, in each case and minimizing FAFIR. In other words, by systematically generating combinations of A and B and minimizing FAFIR for each instance, new December 2021 | 57

one can obtain the population after thermal equilibration for tMAX seconds. The magnitude of the population of each stable structure is comparable to the reaction yield of the stable structure; therefore, one can identify the stable structures corresponding to the major and minor products. From the propagation of the initial population, one can also identify the path that contributes the most to the reaction. Most importantly, the RCMC method can be used as kinetic navigation for automated reaction path search. Starting from a single stable structure, the AFIR method searches and obtains another stable structure. The AFIR method, then, is applied to the obtained stable structures successively to construct a reaction path network. However, applying the AFIR method to all the obtained stable structures is extravagant. Kinetic navigation solves this problem by applying the RCMC method periodically to the reaction path network during the search, where stable structures that cannot be accessed kinetically from the input structure are excluded from the search target. This process reduces the number of stable structures to which the AFIR method is applied, and hence dramatically cuts down the cost. This can be referred to as on-thefly kinetic simulation, which performs kinetic simulation without any prior information. In the backward search from a product to various reactant candidates, the kinetic navigation for backward search is also available, where the search target is narrowed down based on the yield of products from each reactant candidate.20

Strecker Synthesis

Figure 1 (a) AFIR function applying an artificial force between fragments A and B, (b) reactions induced by the artificial force between different fragment pairs. molecules can be assembled on a computer as if building up Lego brocks. Moreover, it is possible to efficiently calculate and automatically search for the actual reaction path based on the path followed by the system in the process of minimizing FAFIR. The AFIR method has made it possible to automatically search for stable structures that the system can adapt in its chemical composition, isomerization paths among them, and their decomposition and formation paths, by starting from a set of input molecules. The connections between stable structures via reaction paths can be visualized as a reaction path network, where each node in the reaction path network represents a stable structure, and the edges between them represent the connections between stable structures. In the reaction path network, an enormous number of paths exist between the node of the reactant and that of the product, so are energy profiles. Among them, the path that gives the most favorable 58 | December 2021

energy profile is the one for the actual chemical reaction. The reaction path network obtained by the AFIR method often contains over 1000 stable structures. Kinetic analysis is necessary to identify the product among those structures, considering the experimental conditions. To easily analyze a huge reaction path network, the RCMC method was devised. The RCMC method, which is a kinetic analysis method, forms superstates by clustering stable structures that the system moves back and forth within below or equal to a time constant tMAX given by a user. Each superstate is represented as a linear combination of stable structures as if each stable structure was distributed into multiple superstates. While the stable structure is distributed into superstates, by distributing the initial population given to a specific stable structure in the same way, one can simulate how the population propagates during the thermal equilibration process for tMAX seconds. Thus,

First, we discuss the application to the Strecker synthesis, which is one of the classical organic reactions and is still used in the chemical synthesis of α-amino acids. The typical Strecker synthesis employs a carbonyl compound, ammonium chloride, and cyanide to yield aminonitrile. In this calculation, acetone as a carbonyl compound, ammonium chloride, and sodium cyanide were mixed in water at three different reaction temperatures, 250 K, 300 K, and 350 K, and reacted for one day. The initial structure of the search was generated by the random arrangement of acetone, ammonium cation, cyanoanion, sodium cation, and chloroanion. The initial search was performed by DFT calculations using the ωB97X-D functional, where SV basis functions were used for H, C, N, and O atoms, and Def2-SVP basis functions for Na and Cl atoms. Subsequently, single-point calculations at the ωB97X-D/Def2-SVP level were performed for all discrete points on all paths obtained in the search, where the solvent effect of water was considered by the SMD method. Fig. 2(a) shows the obtained reaction path network. The above procedure yielded 8042 stable structures and 19543 reaction paths www.facs.website

connecting them. The stable structures were categorized based on the bonding pattern, and the nodes and the edges in the network represent the groups and the reaction path connecting them, respectively. When the RCMC method was applied to the reaction path network, we predicted cyanohydrin (Me2C(OH)CN) would be produced in 97.49 % yield at 250K, while at 300 K and 350 K, the targeted aminonitrile (Me2C(NH2)CN) would be produced in 97.96 % and 93.28 % yield, respectively. In addition, the examination of the most feasible reaction path revealed that first cyanohydrin was formed even at 300K and 350K, then it returned to the reactant by the retro-cyanation, and finally, aminonitrile was formed. The white arrows on the reaction path network in Fig. 2(a) illustrate the path from the reactant to aminonitrile, while Fig. 2(b) shows the structural changes along this path. The reactant is a complex consisting of acetone, ammonium cation, cyanoanion, sodium cation, and chloroanion. The reactant undergoes the following steps on the reaction path: (1) the addition of cyanoanion to the carbonyl carbon followed by the proton transfer from the ammonium cation to the carbonyl oxygen generates cyanohydrin, (2) a retro reaction of the step (1) regenerates the reactant complex, (3) the proton transfers from the ammonium cation to the cyanoanion generates ammonia and hydrogen cyanide, (4) ammonia is added to acetone, (5) the proton transfers from hydrogen cyanide to the carbonyl oxygen, (6) the proton elimination by the chloroanion generates a hemiaminal intermediate, (7) the dissociation of water from the hemiaminal intermediate generates an iminium cation, and (8) the addition of cyanoanion to the iminium cation generates aminonitrile.

The results of this simulation reproduce the known features of the Strecker synthesis very well, including the detailed reaction mechanism. It is interesting to note that this simulation was performed without any known information. In other words, based on a priori DFT calculations, we have succeeded in reproducing the reaction mechanism of the Strecker synthesis hitherto proposed.

Thermal Structural Transition of Amorphous Carbon

The AFIR method can be applied to periodic systems using periodic boundary conditions. Here, we present the results of calculating the structural changes of the interfacial amorphous carbon induced by the annealing of carbon nanotube (CNT) yarns.21 In this application, the structure of the interfacial amorphous carbon was represented by 96 carbon atoms sandwiched between two parallel CNTs, as illustrated in Fig. 3(a). We assumed a one-dimensional periodicity along the two CNTs. As a reference, the same calculations were performed for the system without CNTs. For these systems, the reaction path network consisting of more than 10000 stable structures was obtained by the AFIR search using the DFTB3 method with pbc-0-3 parameters. Fig. 3(b) illustrates the reaction path network for the structural transition of the interfacial amorphous carbon structure sandwiched between two CNTs. Among the various reaction paths predicted on the network, we

found the most kinetically favorable path, passing through the region highlighted by the arrow in Fig. 3(c), was the one for the transition to a structure with more sp2-bonds. The results of the kinetic simulation using this reaction network shown in Fig. 3(d) also indicate that the transition to the sp2-bond-rich structure occurs during annealing at 1500 K or higher. On the other hand, in the results of the kinetic simulation for the system without CNTs shown in Fig. 3(e), which was performed as a reference calculation, we found that the transitions to the sp 2-bond-rich structure were suppressed. Amorphous carbon (without CNTs) is known to transform into the sp2-bond-rich structure only when annealed at 2500 K or

Figure 2(a) Reaction path network of the Strecker synthesis. Each node is colored based on the free energy value of each stable structure. White arrows indicate the path from the reactant to the product. (b) Reaction mechanism of the Strecker synthesis found in the reaction path network as the path highlighted by white arrows. www.asiachem.news

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Figure 3(a) Model system used in the simulation viewed from three different directions. Only 3 unit cells are shown for the clarity. (b) Reaction path network for the structural transition of the interfacial amorphous carbon at the interface of the CNTs. The map on the left is colored by the structural energies, while that on the right is colored by the bonding type. (c) The structural transition path from the initial structure 1 to the sp2-bond-rich structure 3 through the transient structure 2. The sp2-type-bonds are colored in cyan. (d) The number of sp2-bonds with respect to the annealing time. The initial number of sp2-bonds is shown with black dashed line. (e) Those of in vacuum simulation.

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higher; Fig. 3(e) did exhibit this fact. In other words, Fig. 3(d) suggests that the amorphous carbon sandwiched between two CNTs can transform into the sp2-bond-rich structure by annealing even at relatively low temperatures below 2000K. This prediction was verified experimentally, leading to the discovery of new carbon material with high thermoelectric properties.21

In the QM/MM method,the reaction center is treated by the accurate and high-cost QM calculation and the rest by the low-cost MM calculation. Lactate Dehydrogenase

The hybrid quantum mechanics/molecular mechanics (QM/MM) and microiteration methods are often used together to optimize the structure of macromolecules like enzymes. In the QM/MM method, 22-24 the reaction center is treated by the accurate and high-cost QM calculation and the rest by the low-cost MM calculation. In the case of enzymatic reactions, the QM calculation is often used for regions involving chemical bond rearrangements, while the MM calculation is used for the surrounding proteins. The microiteration method is a technique to reduce the number of QM calculations in geometry optimization using the QM/MM method, where the coordinates of the MM atoms are optimized as the coordinates of the QM atoms change.25,26 In general, the geometry optimization using the MM calculation is less expensive than a single QM calculation. Thus, the total calculation time can be significantly reduced compared to the geometry optimization when all atoms are treated equivalently. In the microiteration method, the position of the MM atom changes according to the structural change of the QM part. Therefore, it is not applicable to the case where the structural change of the MM part promotes the reaction. To solve this problem, the multistructural microiteration (MSM) method was proposed, in which the entire molecule is represented by a single QM structure and a weighted sum of multiple MM structures, as schematically illustrated in Fig. 4(a).27 The weight of each MM structure is determined by a Boltzmann distribution and varies according to the QM structure. Recently, by combining the MSM and AFIR methods, a reaction path was calculated www.asiachem.news

in which L-lactate dehydrogenase (LDH) in rabbit muscle catalyzes the transformation of pyruvate to L-lactate. Fig 4(b) illustrates an experimentally proposed mechanism,28 where (1) the open LDH binds the substrate, (2) the LDH changes from the open form to the closed one, (3) the chemical transformation of pyruvate to L-lactate occurs in the closed LDH, (4) the LDH changes from the closed form to the open one, and (5) the product is released from the open LDH. Before the calculations, we performed replica exchange molecular dynamics simulations and prepared six open-form and six closedform structures. The MSM method was used to represent the MM structure as a weighted sum of these six open and six closed structures. The QM/MM-ONIOM method was used as the QM/MM method. The QM part was calculated at the B3LYP/6-31+G(d,p) level, and the MM part was calculated using the AMBER force field. Fig. 4(c) shows the obtained energy profile. Among the three peaks, the middle peak corresponds to the TS for the pyruvate to L-lactate chemical transformation. At this TS, the closed-form structure was dominant as shown in Fig. 4(d), which is consistent with the mechanism in Fig. 4(b). Moreover, the transition from the open-form to the closedform structure occurred around the first peak, and the transition from the closed-form to the open-form structure occurred around the third peak. These are again consistent with the mechanism in Fig. 4(b). Because the first and third peaks describe changes in the surrounding protein structure, these peaks are

termed as surrounding structural TS (SSTS) in Fig. 4(c). The combination of the MSM and AFIR methods could be a powerful computational tool for elucidating the mechanism of enzyme reactions.

Difluoroglycine Synthesis

Finally, we introduce an attempt to propose a new synthetic method by the AFIR method. To achieve this, we adopt a new concept called Quantum Chemistry-aided Retrosynthetic Analysis (QCaRA), which systematically explores decomposition and isomerization paths of a target molecule using automated reaction path search methods like the AFIR method and proposes a synthetic method for the target molecule as a reverse reaction of the obtained path. QCaRA requires the backward search of the reaction path from the product to the reactant; hence, searching for the path through the high barrier must be considered as well. This is because a pathway that proceeds with a low barrier from the reactant may have a high barrier when traced from the product to the reactant. The AFIR method can be used as a reaction path search engine in QCaRA since its capability of exhaustive search, including high barrier paths, has been proved.15 QCaRA was proposed in 2013, 9 and the results of its hypothetical application to search for the formation path of glycine molecule was presented. However, over the next seven years, QCaRA was not used in actual organic synthesis. In 2020,19 the first successful discovery of organic reaction by QCaRA was reported in the development

Figure 4(a) Schematic illustration of the MSM method, (b) experimentally proposed reaction mechanism of LDH, (c) energy profile along the minimum energy path for the pyruvate to L-lactate chemical transformation obtained by combining the AFIR and MSM methods, (d) variation of the weights of the MM structures along the path in (c). December 2021 | 61

Figure 5(a) Flow of α,α-difluoroglycine derivatives synthesized from a reaction path network by (1) QCaRA/AFIR and (2) subsequent AFIR calculations, (b) scheme for the synthesis of experimentally discovered α,α-difluoroglycine derivatives, (c) examination of the substrate scope by the newly discovered synthetic method. 62 | December 2021

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of a synthetic method for α,α-difluoroglycine derivatives, which are considered to be bioisosteres of natural glycine and good candidates as drug discovery resources. The flow of this discovery is illustrated in Fig. 5(a). First, the application of QCaRA/AFIR to α,α-difluoroglycine gave a reaction path network, where over 30 reactant candidates were found. Among these candidates, a set of reactants consisting of CF2+NH3+CO2 was selected in consideration of the availability of the species involved. Then, assuming CF3− and CF2Br− as sources of CF2 formation in situ, the reaction path networks for CF3−+NH3+CO2 and CF2Br−+NH3+CO2 were computed by the AFIR method. The results showed that while CF 3 − +NH 3 +CO 2 gave CF3CO2−, CF2Br−+NH3+CO2 gave a mixture of the target product and by-products. It was also found that the protons of NH3 promoted the formation of by-products. Then, the reaction path network for CF2Br−+NMe3+CO2 with the replacement of the proton with the methyl group was obtained by the AFIR method. It was predicted that the desired α,α-difluoroglycine derivatives could be obtained from CF2Br−+NMe3+CO2 in >99% yield.

generated in situ by mixing Me3SiCF2Br and Ph 3SiF2·NBu4. The synthetic experiments afforded α,α-difluoroglycine derivatives from CF2Br−+NMe3+CO2 in 96% yield. Lastly, we succeeded in isolating the resulting α,α-difluoroglycine derivative as a stable solid after methyl esterification by the treatment with Meerwein reagent. Its three-dimensional structure was confirmed by X-ray crystallography. Furthermore, this three-component reaction proceeded well with various tertiary amines and nitrogen-containing heteroaromatics; hence, it became feasible to synthesize various α,α-difluoroglycine derivatives shown in Fig. 5(c).29

Conclusions

This article described the reactivity prediction by the AFIR method, which has been developed by the authors, including the latest application results. By applying virtual forces between fragments in a system and inducing chemical changes, the AFIR method gives the reaction paths based on the resulting structural changes. By systematically testing combinations of various fragment pairs, a systematic automated search for reaction paths is possible. The resulting reaction path network is valuable for elucidating the mechanisms of complicated chemical reactions. The complex reaction path network obtained by the AFIR method can be easily analyzed by the RCMC method based on the kinetics, which is also used to limit the scope of the AFIR search to kinetically accessible paths and to suppress combinatorial explosions.

The AFIR method can predict chemical reactions in a system consisting of 30 atoms or less with no previous knowledge. The application to the Strecker synthesis was shown as an example. Even for the system with more than 30 atoms, the reaction mechanism can be analyzed systematically by combining with calculation methods for macromolecular systems such as the semi-empirical quantum chemical calculation method and the QM/ MM method. As examples, this article presented the structural transition of interfacial amorphous carbon and the conversion of pyruvate to L-lactate by LDH. Lastly, this article introduced the discovery of a synthetic method of difluoroglycine derivatives by QCaRA using the AFIR method as a reaction path search engine. The AFIR method is now widely used in reaction mechanism analysis. This method is implemented in the GRRM20 program and is used by many users.30 The new reaction prediction method combined with QCaRA suggests even more exciting possibilities of the AFIR method. We hope that the new AFIR features in GRRM20 will contribute to many chemical studies in the future. ◆

Acknowledgement

This work was partly supported by a grant from JST-CREST (No. JPMJCR14L5), JSTERATO (No. JPMJER1903), and JSPS-WPI. We thank to Ms. Takako Homma for editing a draft of this manuscript.

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F. Jensen, Introduction to Computational Chemistry, 3rd ed.; Wiley, Chichester, U.K., 2017. M. Paranjothy, R. Sun, Y. Zhuang, W. L. Hase, WIREs Comput. Mol. Sci. 3, 296 (2013). N. Koga, K. Morokuma, Chem. Rev. 91, 823 (1991). K. N. Houk, P. H.-Y. Cheong, Nature 455, 309 (2008). K. N. Houk, F. Liu, Acc. Chem. Res. 50, 539 (2017). H. B. Schlegel, WIREs Comput. Mol. Sci. 1, 790 (2011). K. Fukui, Acc. Chem. Res. 14, 363 (1981). S. Maeda, Y. Harabuchi, Y. Ono, T. Taketsugu, K. Morokuma, Int. J. Quant. Chem. 115, 258 (2015). S. Maeda, K. Ohno, K. Morokuma, Phys. Chem. Chem. Phys. 15, 3683 (2013). A. L. Dewyer, A. J. Argüelles, P. M. Zimmerman, WIREs Comput. Mol. Sci. 8, e1354 (2018). G. N. Simm, A. C. Vaucher, M. Reiher, J. Phys. Chem. A 123, 385 (2019). S. Maeda, K. Morokuma, J. Chem. Phys. 132, 241102 (2010). S. Maeda, Y. Harabuchi, M. Takagi, T. Taketsugu, K. Morokuma, Chem. Rec. 16, 2232 (2016). M. Hatanaka, T. Yoshimura, S. Maeda, Top. Organomet. Chem. 67, 57 (2020). S. Maeda, Y. Harabuchi, WIREs Comput. Mol. Sci. 11, e1538 (2021). Y. Sumiya, Y. Nagahata, T. Komatsuzaki, T. Taketsugu, S. Maeda, J. Phys. Chem. A 119, 11641 (2015). Y. Sumiya, S. Maeda, Chem. Lett. 49, 553 (2020). Y. Sumiya, S. Maeda, Chem. Lett. 48, 47 (2019). T. Mita, Y. Harabuchi, S. Maeda, Chem. Sci. 11, 7569 (2020). Y. Sumiya, Y. Harabuchi, Y. Nagata, and S. Maeda, ChemRxiv (2021) [DOI: 10.33774/chemrxiv-2021-3xfds]. M. Hada, T. Hasegawa, H. Inoue, M. Takagi, K. Omoto, D. Chujo, S. Iemoto, T. Kuroda, T. Morimoto, T. Hayashi, T. Iijima, T. Tokunaga, N. Ikeda, K. Hujimori, C. Itoh, T. Nishikawa, Y. Yamashita, T. kiwa, S. Koshihara, S. Maeda, Y. Hayashi, ACS Appl. Energy Mater. 2, 7700 (2019). A. Warshel, M. Levitt, J. Mol. Biol. 103, 227 (1976). H. M. Senn, W. Thiel, Angew. Chem. Int. Ed. 48, 1198 (2009). L. W. Chung, W. M. C. Sameera, R. Ramozzi, A. J. Page, M. Hatanaka, G. P. Petrova, T. V. Harris, X. Li, Z. Ke, F. Liu, H. B. Li, L. Ding, K. Morokuma, Chem. Rev. 115, 5678 (2015). T. Vreven, K. Morokuma, Ö. Farkas, H. B. Schlegel, M. J. Frisch, J. Comput. Chem. 24, 760 (2003). T. Vreven, M. J. Frisch, K. N. Kudin, H. B. Schlegel, K. Morokuma, Mol. Phys. 104, 701 (2006). K. Suzuki, K. Morokuma, S. Maeda, J. Comput. Chem. 38, 2213 (2017). K. Suzuki, S. Maeda, K. Morokuma, ACS Omega 4, 1178 (2019). H. Hayashi, H.Takano, H.Katsuyama, Y. Harabuchi, S. Maeda, T. Mita, Chem. Eur. J. 27, 10040 (2021). AFIR-web, see https://afir.sci.hokudai.ac.jp (accessed date: November 16, 2021).

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Therapeutic in vivo synthetic chemistry by glycosylated artificial metalloenzymes for innovative biomedical modality By Katsunori Tanaka and Tsung-Che Chang https://doi.org/10.51167/acm00025

Katsunori Tanaka

Katsunori Tanaka received his B.S degree (1996) and Ph.D. degree (2002) in chemistry from Kwansei Gakuin University under the guidance of Prof. Shigeo Katsumura. Following a postdoctoral stint with Prof. Koji Nakanishi at Columbia University, he worked as an assistant professor in the group of Prof. Koichi Fukase at Osaka University. At present, he holds concurrent roles as a professor at the Tokyo Institute of Technology and as a Chief Scientist at the RIKEN institute. In addition, he also holds various adjunct positions; one being as a Professor at Kazan Federal University. His research interests include organic synthesis, molecular imaging, in vivo synthesis, and natural products.

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Tsung-Che Chang

Tsung-Che Chang received his Ph.D. degree (2012) in chemistry from National Tsing-Hua University under the direction of Prof. Chun-Cheng Lin. Following a JSPS postdoctoral fellowship with Prof. Koichi Fukase at Osaka University, he worked as a postdoctoral researcher in the group of Katsunori Tanaka at the RIKEN institute. His research interests are in the field of carbohydrate chemistry and biocatalysis.

This article is to depict the steps taken by our team for the development of glycosylated artificial metalloenzymes (GArMs) that we have used to develop therapeutic in vivo synthetic chemistry. To achieve this goal, we have had to combine technologies developed over the course of a decade that range from protein conjugation methodologies, identification of glycan-dependent targeting, development of functional biocatalysis and the biocompatible reactions. As a result, we have begun to reveal the framework for GArM complexes and their potential towards creating novel biotechnological tools and therapeutic applications. Therapeutic In Vivo Synthetic Chemistry

In the past century, synthetic chemistry, which is the artificial execution of various chemical reactions to obtain the desired products, has greatly enabled the development of pharmaceutical research, leading to an improvement in the health of patients worldwide. Recently, innovations in new synthetic methods, biocatalysis, reaction miniaturization, and chemoinformatics have powerfully improved the quality of products in pharmaceutical research. One of the most influential research trends within the last few decades was the race to discover anticancer drugs. However, the adverse health effects of current

anticancer drugs have sparked a new research trend centered on localized drug delivery to avoid unwanted side effects against untargeted normal cells.1 Currently, numerous research groups are developing vastly different approaches to overcome this issue. Some notable approaches (Fig. 1A-D) include the use of external stimuli (ex/ MRI, ultrasound, and light)2, and bioorthogonal click-to-release chemistry3 to convert prodrugs into their active form. In addition, pH-sensing liposomes and nanoparticles have extensively explored to release encapsulated drugs under the acidic conditions of cancers4. Recently, abiotic www.facs.website

metal-catalyzed uncaging reactions to release drugs have also utilized to cancer treatments due to bioorthogonal character and the outstanding catalytic activity of metals5. These approaches, however, still have some drawbacks. For example, the use of external stimuli requires expensive machinery, while click-to-release strategies use abiotic small molecules that need to be directly injected at tumors sites. Since only fully developed tumors are acidic, pH triggered drug release is not as effective for early-stage cancers. Encapsulation of metal nanoparticles can reduce toxicity of abiotic metals in vivo and are accumulated in cancer tissues by enhanced permeability and retention (EPR) effect, however, thousands of research papers gave a critical verdict, that is, the EPR effect works in rodents but not in humans6. And, the studies revealed that after treatment, nanomaterials were found to accumulate in the spleen, liver, brain, and lungs to cause oxidative stress via the production of reactive oxygen species (ROS), leading to significant toxicity7. Our group offers a vastly different approach by in vivo synthetic chemistry to achieve localized drug synthesis/release on cancers. By definition, in vivo synthetic chemistry is a term used by our group to describe the ability to perform non-natural chemical reactions within living biological systems. Because of the complexity of biological environments, however, a multitude of challenges need to be overcome to achieve the feat. Practically speaking, there are three main areas to address. The first area of focus is related to the targeting methodology. Without proper localization of in vivo synthetic chemistry, this system would be incapable of applicability for biomedical research. The second is the need to develop an effective and biocompatible catalyst for the implementation of in vivo synthetic chemistry. Our group felt that the advantages afforded by abiotic transition metal catalysis, such as the potential for in vivo natural product synthesis, made it an attractive strategy. Lastly, development of biocompatible chemical reactions is also indispensable to the system. In vivo synthetic chemistry does not only require mild and aqueous conditions, but also specific chemoselectively without interfering with biological metabolism. Although our group has only begun to challenge the immense feat, we have identified a path forward using a system that integrates different aspects of our past interesting research (Fig 1E). The article is to highlight the steps taken at each stage, and how they all ultimately fit together for therapeutic in vivo synthetic chemistry.

RIKEN Click Reaction

As shown in Fig. 2A, the thermal cyclization of 1-azatrienes to 1,2-dihydropyridines via 6p-azaelectrocyclization could be an attractive tool to be utilized for the modification of the lysine amino group on proteins through Schiff-base (imine) formation. However, the requirement for high temperatures and long reaction times for the strategy limited the application of the method in biological systems. Incorporating the interesting chemistry, we found that modification at the www.asiachem.news

Figure 1. In vivo cancer therapeutic modalities based on strategies of localized drug delivery mediated by (A) external-stimuli responsive systems, (B) click-to-release chemistry, (C) the cancer microenvironment, or (D) the abiotic metal-mediated reactions. (E) Therapeutic in vivo synthetic chemistry via glycosylated artificial metalloenzymes. C4-carbonyl and C6-alkenyl or phenyl groups in 1-azatrienes enables reducing the energy gap between HOMO and LUMO to significantly accelerate the azaelectrocyclization and occur in a matter of a few minutes at room temperature.8 Then, We began to shift our interest to developing 6p-azaelectrocyclization for protein labeling. Although many lysine conjugation methodologies were developed at the time, most of them were too slow or not reactive enough. As a result, azaelectrocyclization for lysine-selective conjugation (later coined as the RIKEN click reaction9 -11) has become a standard technique heavily utilized in our research today. As shown in Figure 2B, we first began to prepare the aldehyde probe directly linked with molecules of interest via amide linkage.12-18 To simplify the operation of the RIKEN click reaction, we transitioned to using another reaction to link the molecules. This has led to the preparation of RIKEN click reagents modified with groups such as a azide (for Staudinger ligation)19, dibenzocyclooctyne (for strain-promoted azidealkyne cycloaddition)20,21, and trans-cyclooctene (for tetrazine ligation)22-35. Numerous successfully applied molecules for protein modification clearly prove the versatility of the RIKEN click reaction. For instance, molecular imaging and radiotherapeutic applications have seen the usage of metal chelating agents, such as DOTA12,13,18,20,30, NOTA20,30, and closo-decaborate21. Moreover, the fluorescent imaging studies have utilized various fluorophores like coumarin12,14,15, NBD14,18, TAMRA12,13,17,23,30, Cy513,18,19 , Hilyte Fluor 75016, fluorescein23, and FRET pairs24. Other molecules that have also found significant usage in our research include the conjugation of biotin17,19,22, and numerous types of complex N-glycans19,22-34. In terms of conjugates done using the RIKEN click reagent, our studies have shown applicability to various amine-containing scaffolds. A number

of peptides and proteins have been conjugated under in vitro conditions; such as the cRGDyK peptide22,24,30, somatostatin12,14,22, albumin, orosomucoid12, and asialoorosomucoid12. This has also been extended to dendrimer complexes18, as well as a number of antibodies that include anti-GFP mAb12, anti-IGSF4 mAb20, and trastuzumab21. For example, the rapid rate of the RIKEN click reaction has also been beneficial for the preparation of radiotherapeutic agents20,21. To approach it, a onepot reaction can be performed the RIKEN click reagent, a tetrazine-linked metal chelator, and a targeting antibody (Fig. 2C). These radiolabeled antibodies have been shown in mouse models to effectively accumulate to targeted tumors and suppress their growth. Intriguing, the RIKEN click reagent has also been shown to be applicable in labeling the surface proteins of live cells. For instance, to investigate and identify glycan-dependent mechanisms that could potentially influence in vivo lymphocyte trafficking in living animals, we labeled the lymphocyte that were extracted from nude mice with a(2,6)-sialic acid terminated complex N-glycan19. The glycosylated lymphocytes were then administered into DLD-1 tumor bearing mice. In the case of glycosylated lymphocytes, observations revealed that besides lymphocyte accumulation in spleen/lymph nodes, detection was also found in implanted tumor regions (Figure 2D). In a control setting, lymphocytes without glycan modifications naturally accumulated to the spleen and intestinal lymph nodes, while no detection was found in the tumor. Current literature has strongly implicated cancer cell glycosylation to be vital for mediating tumor metastasis and invasion35. On the basis of the concept, we first established four kinds of human cancer cells (two cancer cell December 2021 | 65

Figure 2. (A) 6p-azaelectrocyclization reaction mechanism from the cyclization of 1-azatrienes to 1,2-dihydropyridine. (B) Applications of the RIKEN click reagent for protein labeling in a number of targeted scaffolds. (C) Preparation of 67Cu-, or 211At-labled radiotherapeutics via a one-pot reaction using the RIKEN click reagent, tetrazine-linked metal chelator, and targeting antibody. In vivo data reveals effective accumulation and suppression of tumor growth. (D) Artificial glycosylated lymphocytes used to study glycandependent changes to lymphocyte trafficking. Organs of interest are the spleen (SP), lymph node of the epidermal intestinal tract (LN), and implanted DLD-1 tumor (TN). (E) Artificial glycosylated cancer cells used to study glycan-dependent changes to metastasis. I) Effects of polylactosamine in MKN45-related metastasis. II) Effects of fucosylation in HCT116-related metastasis. 66 | December 2021

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lines, MKN45 and HCT116, and their transfected versions expressing surface glycan-related genes, MKN-GnT-V and HCT116-GMDS). These cancer cells were labeled by RIKEN click reagent linked with Hilyte Fluor 75016. Following injection into mice, the in vivo imaging clearly showed that tumor metastasis was dependent upon the cell surface glycans. Namely, polylactosamine structure (Fig. 2E-(I)) or the loss of fucosylation (Fig. 2E-(II)) on the cancer cell surfaces, respectively, enhanced the metastatic potential of the tumor cells. The other tested cells line also include cultures of MDCK17, HeLa17,22, HUVEC23, and RAW264.7 cells24. Overall, we have found the RIKEN click reagent to be quite robust and versatile, with its value especially evident when used for labeling large macromolecules.

Glycan Targeting

In nature, one of the major components that drives cell-to-cell interactions is glycan recognition with lecitns. This is due to the fact that many different types of cell surfaces are composed of complex assemblies of glycoproteins, glycolipids, and proteoglycans to regulate their physiological functions (Fig. 3A). Since most types of malignant and diseased cells compared to healthy cells have altered their glycan patterns, this represents a potential targeting mechanism. Individually, lectin-glycan interactions are poor (Kd in the mM range), such that their one-to-one interactions have little biological selectivity. However, due to the enormous presence of lectin isoforms, especially in cancer cells, the combined interactions of clustered sugars (i.e., homogeneous vs. heterogeneous) allows for strong and selective cell binding in

nature; we refer to the phenomena here as glycan pattern recognition (Fig. 3B). As mentioned above, one issue with conjugating large biomolecules is that conventional protein ligation techniques often suffer from low yields. Therefore, the ability of our RIKEN click reagent to handle the conjugation of complex N-glycans makes it a principle approach for the preparation of artificial glycoproteins by decorating various glycan assemblies. In one of our earlier investigations, homogeneous artificial glycoproteins (1a-h) were prepared by using human serum albumin (HSA) as the protein scaffold and injected into mice27. As depicted in Figure 3C, a number of observations were made based on the following changes in accumulation and excretion. For instance, glycoproteins 1a-c were found with prolonged and selective liver accumulation. In contrast, the use

Figure 3. (A) Various type of glycans that exist on cell surfaces. (B) Concept of glycan pattern recognition. In the presence of matching glycan patterns and lectin expression, glycoclusters can exhibit strong and selective cell binding. (C) Imaging studies showing the biodistribution of artificial glycoproteins 1a-h following injection into mice. (D) Imaging studies showing the tumor targeting properties of glycoproteins 1f, 2a, and 3a-b for accumulation to different tumors implanted into mice. www.asiachem.news

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Figure 4. (A) Development of albumin-based artificial metalloenzymes (ArMs) by incubation of metal catalysis into hydrophobic binding pocket (drug site I), and mechanism of glutathione resistance is based on the combined effects of the hydrophobic pocket and surface charge repulsion. (B) The two kinds of ArM-Au can catalyze amide bond formation and hydroamination, and the other two kinds of ArM-Ru can catalyze ring-closing metathesis and alkylation. (C) ArM-Ru-1 was found to be catalytically active even in the presence of up to 1000 x equivalents of glutathione. (D) The mechanistic basis behind the ArM ethylene probe (AEP) relies on the ethylene-triggered release of a quencher. (E) Fluorescent images of ripe kiwifruit slices to highlight the capabilities of AEP to detect endogenously induced ethylene. (F) The ArM-Au-2 successfully triggers drug synthesis to achieve cancer therapy in cell-based assays. 68 | December 2021

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of non-glycosylated protein (HSA) was found to spread out the whole body. Since these are known substrates of receptors normally expressed on nonparenchymal liver cells, our histological studies could indeed confirm that mannose-terminated 1b was captured by Kupper

cells and/or macrophages through the interaction with C-type lectins. Meanwhile, glucosamine-terminated 1a and hybrid-type 1c mainly interacted with liver stellate cells and sinusoidal endothelial cells. As for galactose-terminated 1d, liver accumulation is consistent with being rapidly captured

by certain receptors (asialoglycoprtein receptors, ASGPR) expressed on parenchymal hepatocytes. Intriguingly, dissection studies revealed an excretion pathway where 1d was found to be shuttled to the gall bladder and intestines from liver. On the other hand, sialylated-terminated 1f-g were

Figure 5. (A) In vivo labeling of organ by the organ-targeting GArM-Au-1. I) Illustration of protein labeling on the surface of targeted cell by the GArM-Au-1 mediated reaction. II) Imaging data displayed that labeling of organs in mice were dependent on the identify of the linked N-glycan. (B) In vivo prevention of tumor onset and progression via SeCT therapy. I) Illustration of labeling target tumor cells with cRGD moieties in vivo to block integrin-based cell adhesion via the GArM-Au-1. II) A representative set of the tumor progression in mice after 4 weeks through IVIS imaging results. (C) In vivo inhibition of tumor growth using a therapeutic peptide via SeCT therapy. I) Illustration of labeling target tumor cells with a therapeutic peptide via (cRGD)ArM-Ru-2. II) Measurement of tumor size in mice over time. Comparison of mice survival rates under various treatment. (D) In vivo synthetic prodrug therapy against HeLa tumour growth in mice. I) Schematic depiction of HeLa targeted activation of prodrug using the GArM-Ru-1. II) Measurements of tumor size (mm3) in mice over time. Tumours were initially implanted in mice and developed over 4 days before therapy. www.asiachem.news

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shuttled towards the kidneys and urinary bladder from liver. To further increase glycan complexity, the biodistribution in mice based on the usage of heterogeneous glycoproteins 1e and 1h, containing additional branching, was also studied25. Although glycoprotein 1e followed a pathway similar to 1d, it showed higher accumulation in intestines compared to 1d. The glycoprotein 1h accumulation compared glycoproteins 1f-g was rather directed to the kidneys and then excreted via urinary bladder. Moving away from biodistribution, we next focused on the investigation of the tumor targeting capacity of artificial glycoproteins. According to the in vivo imaging data (Fig. 3D)28, homogeneous a(2,3)-sialic acid terminated glycoprotein 1f was the most promising, as it accumulated at a significantly higher level in the A431 tumor than the other tested glycoproteins 1a, c, d, and g. With the aim of improving upon this modest target, the focus of a later study was on artificial glycoproteins composed of heterogeneous glycan assemblies. To test differential tumor selectivity, several heterogeneous glycoproteins were injected into mice implanted with 3 different tumors (HeLa, DLD-1, and U87MG).29 In this study, the most significant observation was that the a(2,3)-sialo and a(2,6)sialo terminated glycoprotein 2a showed selective accumulation to HeLa tumors, while it showed no targeting to the DLD-1and U87MG tumors. A possible explanation for this result is that HeLa cells are known to express both galectin-1 and siglec-3 lectins, which are receptors for a(2,3)-sialic acid and a(2,6)-sialic acid, respectively. In contrast, DLD-1 and U87MG only express galectin-1 lectin. Given this promising result, to multiply technique to more selectively target tumors, we developed another approach using higher-order heterogeneous glycoalbumins that were conjugated with four kinds of complex N-glycans.33 As depicted in Figure 3D-(III), the in vivo data revealed that the higher-order glycoalbumin 3b displayed the strongest targeting towards SW620 tumors than lower-order glycoalbumin 3a. Overall, the use of glycan pattern recognition for organs or cancer cells targeting represents a novel and promising strategy for the development of diagnostic, prophylactic, and therapeutic agents for various diseases. Moreover, the use of glycan targeting would have significant advantages over current techniques (i.e. antibody targeting), such as shorter accumulation times and lower immunogenicity.

Biocatalysis and Mild Biocompatible Reactions

Translating abiotic metal catalysts into in vivo synthetic chemistry could encounter numerous challenges regarding their biocompatibility, stability, and reactivity in the complicated biological environment. To solve these issues, we have been actively involved in research related to artificial metalloenzymes (ArMs). ArMs are created by incorporating synthetic metal complexes into protein scaffolds, thereby combining the advantageous features of organometallic and 70 | December 2021

enzymatic catalysts and facilitating the design of novel biocatalysts to perform new-to-nature reactions. To combine with glycan targeting, we were mainly interested in developing ArMs from human serum albumin. Owing to previous direction from the late Prof. Koiji Nakanishi, we decided to utilize coumarin derivatives as an anchor for the hydrophobic binding pocket of albumin (Fig. 4A). With the use of a varying series of coumarin-metal complexes, we developed four kinds of ArMs (mainly ArM-Au and ArM-Ru) (Fig. 4B)32,36-41. An important observation from these studies was the discovery that a combination between the deep hydrophobic binding site of albumin and the negatively charged surface of albumin naturally repels entry to hydrophilic metabolites (i.e., glutathione (GSH)). As a result, using a 1,6-heptadiene-based substrate, metastasis activity was shown to proceed even in the presence of up to 1000 x equivalents of GSH additive.36 As depicted in Figure 4B-I, we also have developed several biocompatible organic reactions that are applicable to these ArMs. In a preliminary screen to identify amide bond formation, we were surprised to see that the Au(III) complexes coordinated with 2-benzoylpyridine could generate amide via propargyl esters.32,39,41 Forming an activated ester intermediate (via Au binding) likely leads to amide bond formation via a nucleophile amine. Using this chemistry, we have shown that fluorescent labeling of proteins is possible using propargyl ester-based probes and the ArM-Au-1. On the other hand, the ArM-Au-2 containing Au(I) complexes coordinated with an N-heterocyclic carbene ligand can perform hydroamination to synthesize phenanthridinium derivatives with an excellent turnover number (Fig. 4B-II).38 In particular, the phenanthridinium moiety has attracted a great deal of attention because of its presence in the scaffolds of several DNA-intercalating agents with antitumor properties. Importantly, hydroamination is not catalyzed by any known naturally occurring enzymes, highlighting the significance of the ArM-Au-2 catalyzed hydroamination under physiological conditions. In addition to that, ring-closing metathesis (RCM) for olefins and ene-ynes can be catalyzed smoothly by the ArM-Ru-1, which incorporates the 2nd generation Hoveyda catalyst.36,37,41 RCM is widely recognized as a powerful method for creating heterocycles and phenyl moieties that are most significant structural components of pharmaceuticals. Lastly, ArM-Ru-2 can effectively catalyze alkylation with nucleophilic moieties such as thiol, hydroxyl, and amino groups in biomolecules using a benzyl fluoride substrate via a quinone imine intermediate.40 Overall, the ArM-Au-2 and the ArM-Ru-1 could be utilized as powerful biocatalysts for application in therapeutic in vivo drug synthesis. As for in vivo imaging and drug conjugation, the ArM-Au-1 and the ArM-Ru-2 are competent for these tasks, respectively. With these new developed biocatalysts and biocompatible reactions, we would like to adapt and apply these technologies for innovative applications. In one of our endeavors, we looked

specifically at development of ArM-based biosensors, which would offer a unique path for tailoring against difficult-to-detect metabolites. Ethylene gas is an essential plant hormone that plays a major role in regulating aspects of growth, immunity, and senescence. With this in mind, our group has investigated the creation of an ethylene-sensing ArM biosensor.37 As depicted in Figure 4D, the basis of this approach is to use the albumin scaffold to solubilize and protect a quenched ruthenium catalyst complex. In the presence of ethylene, cross metathesis is then occurred, leading to the removal of the quencher and the emission of a fluorescent signal. Using the ArM ethylene probe (AEP), the AEP was used to detect changes in ethylene biosynthesis specifically in the outer pericarp of kiwifruit. Since this process is typically unregulated during the ripening process, comparative studies showed an increase in pericarp fluorescence for ripening kiwifruits (Fig. 4E). Since chemotherapy is not perfectly specific for cancer cells, it has significant side effects on healthy cells. Therefore, another practical application is to employ the ArM-Au-2 as a trigger to control the release of bioactive drugs to improve the defect of chemotherapy.38 As shown in Figure 4F, the ArM-Au-2 successfully implemented drug synthesis from a non-active prodrug to achieve cancer therapy in a cell-based assay, suggesting the potential of the gold ArM to be a therapeutic ArM for in vivo anticancer application.

Therapeutic in vivo Synthetic Chemistry by GArMs

Given our interest in both glycan targeting and biocatalysis, a natural course of action eventually led to combining both aspects of targeting glycoproteins and ArMs to establish the concept of glycosylated artificial metalloenzymes (GArMs). The ultimate goal of this endeavor will be to eventually establish effective and biocompatible therapeutic ArMs, which can then be conferred with organ/tumor targeting properties by simply decorating the protein scaffold with an appropriate glycan assembly. Our first attempt at developing GArMs came during a study to determine whether specific tissues of mice could be targeted for in vivo labeling (Fig. 5A-I).32 In this work, glycosylated ArM-Au-1 with the intent to label targeted cells in vivo with propargyl ester-based probes. As depicted in Figure 5A-II, mice were first intravenously injected through the tail vein with a GArM. Then, a near infrared fluorescent propargyl ester (Cy7.5-PE) was injected. As shown in the imaging results, preferential organ labeling could be achieved depending on the identity of the attached glycans; α(2,6)-sialic acid terminated glycans targeted the liver, while Gal terminated glycans targeted the intestines. In the controls, localization of fluorescence labeling was not exhibited in targeted organs. Given the promising results, more recently, we represented research on selective cell tagging (SeCT) therapy in vivo via the GArM-Au-1 (Fig. www.facs.website

5B).39 The concept of SeCT therapy is based on a strategy of preferentially tagging specific cells with a biological small molecule. In contrast to traditional chemotherapy that directly eliminates cancer cells using highly cytotoxic drugs, the principal benefit of SeCT therapy allows cancer cells to be tagged using non-toxic chemical moieties that can either disrupt cellular function (ex/ inhibitors of adhesion) or elicit immunological responses (ex/ antigens). Subsequent functional impairment or related biological responses can indirectly lead to cancer cell death without significantly harming surrounding tissue. As depicted in Figure 5B-I, it showed that individual HeLa cancer cells in living mice can be tagged in vivo with cyclic-Arg-GlyAsp (cRGD) moieties for integrin-blocking, leading to disrupted cell adhesion and compromised successful seeding onto the extracellular matrix (ECM). The mice populations that received just one dosage of the SeCT labeling reagents via intrapenetrial injection showed a significant delay in tumor onset by 4 weeks (Fig. 5B-II), resulting in an improvement in overall survival rates over a period of 81 days. Following the same concept of the SeCT therapy, we report a cancer therapy based on targeted cell surface tagging with proapoptotic peptide 1 (Ac-GGKLFG-X; X = a benzyl fluoride moiety) that induce apoptosis when

attached to the cell surface (Fig. 5C-I).40 Using the Ru-catalyzed alkylation, the proapoptotic peptide 1 showed excellent therapeutic effects in vivo. In particular, co-treatment with the proapoptotic peptide and the cRGD-coated ArM-Ru-2 significantly and synergistically inhibited tumor growth and prolonged survival rate of tumor-bearing mice after only a single injection (Fig. 5C-II). This is the first report of Ru catalyst application in vivo. Except of the above samples of therapeutic in vivo synthetic chemistry, we also successfully carried out cancer treatment through localized in vivo drug synthesis. As depicted in Figure 5D, we investigated the design and optimization of synthetic prodrugs that can be robustly transformed in vivo to reach therapeutically relevant levels. To do this, retrosynthetic prodrug design led to the identification of naphthylcombretastatin-based prodrugs, which form highly active cytostatic agents via sequential ring-closing metathesis and aromatization (Fig. 5D-I). Structural adjustments were then made to improve aspects related to catalytic reactivity, intrinsic bioactivity, and hydrolytic stability. Furthermore, in vivo activation by intravenously administered the GArM-Ru-1 was also found to induce significant reduction of implanted tumour growth in mice (Fig. 5D-II).

References

1. E. Petru, D. Schmahl, Neoplasma 1991, 38, 147. 2. J. Yao, J. Feng, J. Chen, Asain J. Pharm. Sci. 2016, 11, 585. 3. X. Ji, Z. Pan, B. Yu, L. K. De La Cruz, Y. Zheng, B. Ke, B. Wang, Chem. Soc. Rev. 2019, 48, 1077. 4. S. J. Sonawane, R. S. Kalhapure, T. Gocender, Eur. J. Pharm. Sci. 2017, 99, 45. 5. D. C. Luther, R. Huang, T. Jeon, X. Zhang, Y.W. Lee, H. Nagaraj, V. M. Rotello, Adv. Drug. Delivery Rev. 2020, 156, 188. 6. F. Danhier, J. Control. Release 2016, 244, 108121. 7. A. B. Sengul, E. Asmatulu, Environ. Chem. Lett. 2020, 18, 1659. 8. K. Tanaka, H. Mori, M. Yamamoto, S. Katsumura, J. Org. Chem. 2001, 66, 3099. 9. K. Tanaka, K. Fukase, S. Katsumura, Chem. Rec. 2010, 10, 119. 10. K. Tanaka, K. Fukase, S. Katsumura, Synlett 2011, 2115. 11. K. Fujiki, K. Tanaka, in Encyclopedia of Reagents for Organic Synthesis, John Wiley & Sons, Ltd., 2020, doi: 10.1002/047084289X.rn02050 12. K. Tanaka, T. Masuyama, K. Hasegawa, T. Tahara, H. Mizuma, Y. Wada, Y. Watanabe, K. Fukase, Angew. Chem. Int. Ed. 2008, 47, 102. 13. K. Tanaka, K. Minmi, T. Tahara, Y. Fujii, E. R. O. Siwu, S.Nozaki, H. Onoe, S. Yokoi, K. Koyama, Y. Watanabe, K. Fukase, ChemMedChem 2010, 5, 841. 14. K. Tanaka, Y. Fujii, K. Fukase, ChemBioChem 2008, 9, 2392. 15. K. Tanaka, M. Kitadani, K. Fukase, Org. Biomol. Chem. 2011, 9, 5346. 16. K. Tanaka, K. Moriwaki, S. Yokoi, K. Koyama, E. Miyoshi, K. Fukase, Bioorg. Med. Chem. 2013, 21, 1074. 17. K. Tanaka, S. Yokoi, K. Morimoto, T. Iwata, Y. Nakamoto, K. Nakayama, K. Koyama, T. Fujiwara, K. Fukase, Bioorg. Med. Chem. 2012, 20, 1865. 18. K. Tanaka, E. R. O. Siwu, K. Minami, K. Hasegawa, S.Nozaki, Y. Kanayama, K. Koyama,

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W. C. Chen, J. C. Paulson, Y. Watanabe, K. Fukase, Angew. Chem. Int. Ed. 2010, 49, 8195. K. Tanaka, K. Minami, T. Tahara, E. R. O. Siwu, K. Koyama, S. Nozaki, H. Onoe, Y. Watanabe, K. Fukase, J. Carbohydr. Chem. 2010, 29, 118. K. Fujiki, S. Yano, T. Ito, Y. Kumagai, Y. Murakami, O. Kamigaito, H. Haba, K. Tanaka, Sci. Rep. 2017, 7, 1912. K. Fujiki, Y. Kanayama, S. Yano, N. Sato, T. Yokokita, P. Ahmadi, Y. Watanabe, H. Haba, K. Tanaka, Chem. Sci. 2019, 10,1936. K. Tanaka, Y. Nakamoto, E. R. O. Siwu, A. R. Pradipta, K. Morimoto, T. Fujiwara, S. Yoshida, T. Hosoya, Y. Tamura, G. Hirai, M. Sodeoka, K. Fukase, Org. Biomol. Chem. 2013, 11, 7326. A. Ogura, K. Tanaka, Tetrahedron 2015, 71, 4518. K. Tanaka, M. Kitadani, A. Tsutsui, A. R. Pradipta, R. Imamaki, S. Kitazume, N. Taniguchi, K. Fukase, Org. Biomol. Chem. 2014, 12, 1412. L. Latypova, R. Sibgatullina, A. Ogura, K. Fujiki, A. Khabibrakhmanova, T. Tahara, S. Nozaki, S. Urano, K. Tsubokura, H. Onoe, Y. Watanabe, A. Kurbangalieva, K. Tanaka, Adv. Sci. 2017, 4, 1600394. R. Sibgatullina, K. Fujiki, T. Murase, T. Yamamoto, T. Shimoda, A. Kurbangalieva, K. Tanaka, Tetrahedron Lett. 2017, 58, 1929. A. Ogura, T. Tahara, S. Nozaki, K. Morimoto, Y. Kizuka, S. Kitazume, M. Hara, S. Kojima, H. Onoe, A. Kurbangalieva, N. Taniguchi, Y. Watanabe, K. Tanaka, Sci. Rep. 2016, 6, 21797. A. Ogura, T. Tahara, S. Nozaki, H. Onoe, A. Kurbangalieva, Y. Watanabe, K. Tanaka, Bioorg. Med. Chem. Lett. 2016, 26, 2251. A. Ogura, S. Urano, T. Tahara, S. Nozaki, R. Sibgatullina, K. Vong, T. Suzuki, N. Dohmae, A. Kurbangalieva, Y. Watanabe, K. Tanaka, Chem. Comm. 2018, 54, 8693. Y. Nakamoto, A. R. Pradipta, H. Mukai, M. Zouda, Y. Watanabe, A. Kurbangalieva, P. Ahmadi, Y. Manabe, K. Fukase, K. Tanaka, ChemBioChem 2018, 19, 2055.

Conclusions

In an ideal world, one could simply perform reactions developed in a lab setting directly in a living system without any significant loss of reactivity. Unfortunately, for most transition metal catalyzed reactions, the key issues pertaining to biocompatibility are the ease of metal quenching and the intrinsic toxicities of metals. To the credit of many former and current researchers worldwide, numerous ways have been elegantly devised to successfully perform metal-catalyzed reactions in biological settings. Following the success of our works, our group is continuing to research how we can adapt GArMs for biomedical research, as well as to find ways to address the challenges needed for their improvement. Our final ambition is to cure diseases, especially cancer, without any side effects using our technology. Since our technology is targeting, non-invasive, without risk of immunogenicity, non-toxicity, and high efficiency of in vivo drug synthesis, we must point out that our technology, compared to other methods, could be the only possible method to apply to patients for disease treatment in a hospital. We anticipate that our technology will make a substantial contribution to biomedical fields in the future. ◆

31. K. Nakamura, K. Tsubokura, A. Kurbangalieva, Y. Nakao, T. Murase, T. Shimoda, K. Tanaka, J. Carbohydr. Chem. 2019, 38, 127. 32. K. Tsubokura, K. K. H. Vong, A. R. Pradipta, A. Ogura, S. Urano, T. Tahara, S. Nozaki, H. Onoe, Y. Nakao, R. Sibgatullina, A. Kurbangalieva, Y. Watanabe, K. Tanaka, Angew. Chem., Int. Ed. 2017, 56, 3579. 33. I. Smirnov, R. Sibgatullina, S. Urano, T. tahara, P. Ahmadi, Y. Watanabe, A. R. Pradipta, A. Kurbangalieva, K. Tanaka, Small, 2020, 16, 2004831. 34. I. Smirnov, I. Nasibullin, A. Kurbangalieva, K. Tanaka, Tetrahedron Lett., 2021, 72, 153089. 35. S. Ihara, E. Miyoshi, J. H. Ko, K. Murata, S. Nakahara, K. Honke, R. B. Dickson, C. Y. Lin, N. Taniguchi, J. Biol. Chem. 2002, 277, 16960. 36. S. Eda, I. Nasibullin, K. Vong, N. Kudo, M. Yoshida, A. Kurbangalieva, K. Tanaka, Nat. Catal. 2019, 2, 780. 37. K. Vong, S. Eda, Y. Kadota, I. Nasibullin, T. Wakatake, S. Yokoshima, K. Shirasu, K. Tanaka, Nature Commun. 2019, 10, 5746. 38. T.-C. Chang, K. Vong, T. Yamamoto, K. Tanaka, Angew. Chem. Int. Ed. 2021, 60, 12446. 39. K. Vong, T. Tahara, S. Urano, I. Nasibullin, K. Tsubokura, Y. Nakao, A. Kurbangalieva, H. Onoe, Y. Watanabe, K. Tanaka, Sci. Adv. 2021, 7, eabg4038. 40. P. Ahmadi, K. Muguruma, T.-C. Chang, S. Tamura, K. Tsubokura, Y. Egawa, T. Suzuki, N. Dohmae, Y. Nakao, K. Tanaka, Chem. Sci. 2021, 12, 12266-12273. 41. Y. Lin, K. Vong, K. Matsuoka, K. Tanaka, Chem. Eur. J. 2018, 24, 10595. 42. Nasibullin, I. Smirnov, P. Ahmadi, K. Vong, A. Kurbangalieva, K. Tanaka, Nature Commun. DOI : 10.1038/s41467-021-27804-5.

December 2021 | 71

Pillar-Shaped Ma Pillar[n]arenes: From Simple Receptors to

Tomoki Ogoshi

Prof. Ogoshi is a Professor in the Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering at Kyoto University and Specially Appointed Professor, WPI Nano Life Science Institute, Kanazawa University. He received his Ph.D. degree (2005) under Prof. Yoshiki Chujo at Kyoto University. He worked as a JSPS postdoctoral research fellow (2005–2006) at Osaka University (Prof. Akira Harada). He joined Kanazawa University, where he was promoted to assistant professor in 2006, associate professor in 2010, and full professor in 2015. In 2019, he moved to Kyoto University. He has received the Chemical Society of Japan Award for Young Chemists (2012), the Cram Lehn Pedersen Prize in Supramolecular Chemistry; Royal Society of Chemistry (2013), a Commendation for Science and Technology by the Ministry of Education, Culture, Sports, Science and Technology (2014), the Nozoe Memorial Award for Young Organic Chemists (2016), Lectureship Award MBLA 2016 (2017), Kao Academic Award (2019), and JSPS Prize (2020). He is the inventor of pillar[n] arenes and his current research interests focus on developing novel functional materials and systems based on pillar[n]arenes.

What are pillar[n]arenes?

Macrocyclic host molecules have an angstrom-level space because of their cyclic structures. Guest molecules that fit the space can be selectively bound by physical interactions such as hydrogen bonding, ionic, and aromatic interactions. This cavity-size-dependent guest binding is a lock-and-key relationship. Such selective guest binding enables their use in medical and material applications. The production of macrocyclic host molecules with new structures and properties has opened up new fields of chemistry with global participation. The history of macrocyclic host molecules is long and started in the 1880s.1 Figure 1 shows some widely used macrocyclic host molecules.

Figure 1 Structures of macrocyclic hosts of (a) pillar[n] arene, (b) calix[n]arene, (c) cyclodextrin, (d) crown ether, (e) cucurbit[n]uril and (f) number of reports concerning pillar[n]arenes from 2008 to 2020. During their long history, the development of macrocyclic host molecules, which are now used by many chemists,

72 | December 2021

was limited until recently. To enable their widespread use, macrocyclic host molecules must be easy-to-synthesize or commercially available, have unique host–guest properties, highly symmetric structures, and versatile functionalities, and endow the host–guest products with original properties that come from the structures and chemical compositions of the macrocyclic hosts. Cyclodextrins (Figure 1c), which are composed of sugar units, are typically obtained from natural products and have the longest history among macrocyclic host molecules. Their structures were first discovered by Villiers in 1891.2 Despite their long history, cyclodextrins have been mainly used by chemists until now. Crown ethers were first synthesized by Pedersen in 1967 (Figure 1d).3 They were the first macrocyclic compounds to be synthesized by chemists, therefore synthetic macrocyclic chemistry began with Pedersen’s work. To honor the greatness of his achievement, Pedersen received the Novel Prize for Chemistry at 1987. In the 1980s, calix[n] arenes were popularized by Gutsche (Figure 1b). In these compounds, phenol units are connected by a methylene bridge at the meta-position, therefore they have calixshaped structures, and this is the origin of their name.4 Other calix-shaped meta-bridged phenolic macrocyclic compounds, namely calix[n]resorcinarenes, have also been developed.5 Bowl-shaped macrocyclic hosts, which are formed from ortho-methylene-bridged phenolic units, i.e., cyclotriveratrylenes, have also been produced.6 Cucurbit[n] urils are unique pumpkin-shaped macrocyclic host molecules (Figure 1e).7-9 In 1981, Mock and coworkers identified a hexamer, i.e., cucurbit[6]uril, by X-ray crystallographic analysis.7 However, the chemistry of cucurbit[6]uril was not expanded after this first discovery because of its low solubilities in common solvents. In 2000, 19 years after this first www.facs.website

acrocyclic Hosts Supramolecular Assemblies By Tomoki Ogoshi https://doi.org/10.51167/acm00026

report, Kim and coworkers discovered other cucurbit[n]uril homologs, i.e., cucurbit[5-8]urils.8 These were obtained by tuning the reaction conditions. Their development triggered the expansion of cucurbit[n]uril chemistry because, apart from cucurbit[6]uril, cucurbit[n]uril homologs have relatively high solubilities in common solvents. However, these host molecules were reported until 2000, which suggests that the discovery of new classes of macrocyclic hosts that can be used widely by chemists is challenging. In 2008, we unexpectedly discovered new type of pillar-shaped macrocyclic host molecules, i.e., pillar[n]arenes (Figure 1a).10,11 Figure 1f lists a number of publications that report pillar[n]arenes. Until 2011, only a limited number of researchers, including ourselves, worked in this field. However, from 2012, global interest in pillar[n]arenes began to grow, and this triggered further expansion of pillar[n]arene chemistry. Since 2018, which is the tenth anniversary of pillar[n]arene chemistry, the number of publications per year has exceeded 200. This shows that pillar[n]arene chemistry is expanding. The success of pillar[n]arene chemistry has been recognized by chemists as a new route to novel fields of chemistry and this has instigated the development of new macrocyclic host molecules. Pillar[n]arenes are therefore recognized as game-changing molecules in supramolecular chemistry in the early 21st century.

obtained phenolic polymers with high molecular weights by changing the reaction conditions such as the types of Lewis acids and solvents. Unexpectedly, when 1,2-dichloroethane was used as the solvent, the product was not a polymer but a particular oligomer (Figure 2a).

How were pillar[n]arenes discovered?

The discovery of pillar[n]arenes was accidental as were the discoveries of other famous macrocyclic hosts. Pillar[n]arenes were first obtained as an unexpected product when we synthesized phenolic polymers. When I started my academic career as an assistant professor at Kanazawa University, one of the projects in the laboratory was the synthesis of new types of phenolic polymers. I started my research on the synthesis of new phenolic polymers by designing phenolic monomers with my students. We tried to synthesize new phenolic polymers by reacting 1,4-dimethoxybenzene with paraformaldehylde in the presence of a Lewis acid. We screened the polymerization conditions and www.asiachem.news

Figure 2 Solvent effect on macrocyclic formation. (a) 1,2-dichloethane and (c) chlorocylohexane acted as templates for pillar[5]arenes and pillar[6]arenes synthesis, respectively. (b) Chloroform did not act as a template for the particular pillar[n] arene formation. X-ray crystallographic analysis showed that the obtained product was a cyclic pentamer composed of five 1,4-dimethoxybenzene units connected by methylene bridges at the 2,5-position (Figure 1a, December 2021 | 73

para-position). Because of the para-bridge linkage, the macrocycle had a highly symmetric pillar-shaped architecture, which was quite different from that of calix[n]arenes. Typical calix[n]arenes have vaseshaped structures because of the meta-bridge linkage (Figure 1b). We called this new type of macrocycle as pillar[5]arene because of its shape.10

What is the key to pillar[n]arene formation?

The difficult part of macrocycle synthesis is formation of cyclic structures. The synthesis of macrocyclic structures requires connection of the ends of linear compounds. We obtained pillar[5]arene in high yield in one simple step under reaction conditions similar to those used for phenolic resin synthesis. The question is: why can we prepare pillar[5]arene in such a high yield? Generally, a template works well for macrocyclic compound synthesis in high yields. Macrocyclic compounds are formed by complexation with a template (guest). A single macrocyclic compound that reflects the template size can therefore be obtained in high yield in the presence of the template. In other words, the obtained macrocyclic compounds are thermodynamically stable products in the presence of the template. Without the template, a mixture of macrocyclic compounds with various cavity sizes is produced. The macrocyclic formation efficiency depends on the strain energies of the macrocyclic compounds. In the absence of a template, macrocyclic compounds formed in a kinetically controlled system. Careful tuning of the reaction temperature and time is therefore necessary to obtain macrocyclic compounds. In the synthesis of pillar[5]arene, we selectively obtained the product in high yield without careful reaction condition tuning, which indicates that some reagents work as a template for pillar[5]arene formation. We therefore investigated various reaction conditions to identify the template for selective production of pillar[5]arene. We realized that solvents for the cyclization acted as the templates for the selective formation of pillar[5]arene. When we used 1,2-dichloroethane, a cyclic pentamer, i.e., pillar[5]arene, was selectively obtained in high yield (>70%, Figure 2a).12 In contrast, with chloroform as the solvent, the obtained products were a mixture of linear oligomers and pillar[5–10]arenes (Figure 2b).13 These results are related to the host–guest properties of pillar[5] arenes. The cavity size of a pillar[5]arene is ca. 4.7 Å, which fits linear molecules. 1,2-Dichloroethane is a linear molecule, and therefore acts as a template for selective pillar[5]arene synthesis. In contrast, chloroform is a branched molecule, and therefore does not act as a template for a pillar[n]arene with a particular size. In chloroform, the reaction proceeds under kinetic control. Precise tuning of the reaction time therefore resulted in the synthesis of larger pillar[n]arene homologs (n= 6, 7, 8, 9 and 10), but their yields were low because of the kinetic control system.13 Based on these results, we tried to synthesize pillar[6] arene by using the template method. When we used chlorocyclohexane as a solvent, pillar[6]arene was obtained in 87% yield (Figure 2c). Chlorocyclohexane is a suitable size for the pillar[6]arene cavity, and therefore acts as a template for selective pillar[6]arene synthesis.14

How can pillar[n]arenes be functionalized?

Simple pillar[n]arenes have alkoxy groups on both rims. The alkoxy groups can be converted to phenolic groups by deprotection. Pillar[n]arenes with phenolic groups are useful key compounds for producing functionalized pillar[n]arenes because phenolic groups show high functionality. The easiest way to functionalize pillar[n] arenes by using the reactivity of the phenolic groups is etherification between the phenolic groups and compounds with a halogen group.15-17 The introduction of triflate groups enables the use of cross-coupling reactions such as the Suzuki, Sonogashira coupling to directly connect aryl groups. Pillar[n]arenes with phenolic groups are therefore useful key compounds for preparing various functionalized pillar[n]arenes. Pillar[n]arenes with 2n phenolic groups can be produced by deprotection of alkoxy groups with BBr3 (Figure 3a).10 74 | December 2021

Figure 3 Procedures for (a) per-, (b) mono-, and (c) di-functional pillar[5]arenes, and (d) rim-differentiated pillar[5]arenes. By tuning the deprotection conditions (Figure 3b), we prepared pillar[n]arenes with one phenolic group in moderate yields.15 In the case of pillar[n]arenes with two or more phenolic groups, a major problem is that these pillar[n]arenes have isomers. For example, difunctionalized pillar[5]arenes and pillar[6]arenes have five and seven possible isomers, respectively. These phenolic pillar[5,6]arenes cannot be obtained by direct deprotection of alkoxy groups because many constitutional isomers are generated by direct deprotection. We reported a new route for synthesizing pillar[5]arenes and pillar[6]arenes with two or more phenolic groups via oxidation–reduction of the pillar[n] arene units (Figure 3c). Pillar[5]arenes with one and two benzoquinone units, and pillar[6]arenes with one, two, three, and four benzoquinone units were obtained by direct oxidation of the units.16,17 Subsequent reduction of the benzoquinone units, gave pillar[5,6]arenes with phenolic groups at the same units. Rim-differentiated pillar[5]arenes, which have the same five substituents on one rim, can be produced by a “pre-orientation” strategy, which was developed by Ma et al., and Zuilhof and Sue et al in 2018.18-20 In this strategy, hydroxymethyl groups were first installed into monomers (Figure 3d). The pre-orientation enabled successful synthesis of rim-differentiated pillar[5]arenes in moderate yields (ca. 15%–20%). A pillar[5]arene with five phenolic groups on one rim was obtained by using an oriented monomer with a benzyl group because deprotection of the benzyl group affords phenolic groups.20

What are good guests for pillar[n]arenes?

Pillar[n]arenes are composed of electron-donating 1,4-dialkoxybezene units, therefore the interior cavity is an electron-rich space (Figure 4a).21-27 www.facs.website

Figure 4 (a) Electrostatic potential profile of permethylated pillar[5] arene. (b) Guest molecules for pillar[5–7]arenes. (c) Chemical structures of anionic pillar[5,6]arenes and guests, and summary of the association constants for each host–guest complex. Reproduced with permission from reference.27 Pillar[n]arenes capture electron acceptors that fit the pillar[n]arene cavity size. Pillar[n]arenes also form host–guest complexes with neutral guest molecules. Pillar[5]arenes can capture linear hydrocarbons such as n-hexane because of multiple efficient CH-π interactions between the C-H groups of hydrocarbons and electron-rich benzene groups in the 1,4-dialkoxybenzene units (Figure 4b).21 Linear molecules fit the pillar[5] arene cavity (ca. 4.7 Å). However, the host–guest interactions are less strong for n-alkanes (association constants: K = ca. 20–50 M-1). Linear alkanes with electron-withdrawing groups such as cyano, triazole, and halogens at both ends are better guest molecules than non-substituted linear alkanes. In particular, n-butylenes with these terminal substituents are good guest molecules (K > 103 M-1) because the pillar[5]arene height is suitable for the length of n-butylenes, and because of the high acidity of the C-H groups neighboring the electron-withdrawing groups. In pillar[6]arenes, the cavity size is ca. 6.7 Å, which is a suitable size for branched and cyclic compounds such as cyclohexane, ferrocenium and tropylium cations.22,23 An adamantane derivative is good guest molecules for pillar[7]arenes because the pillar[7]arene cavity size (ca. 8.7 Å) is suitable for the derivative.24 Substituents on the rims of pillar[n]arenes are important not only for enhancing the stability of the host–guest complex but also for changing the pillar[n]arene solubility. Normally, simple pillar[n]arenes with alkoxy groups are soluble in organic solvents such as halogenated and aromatic solvents. Host–guest complexation events are therefore mainly investigated in these organic solvents when simple pillar[n]arenes are used as the hosts. However, the solubilities of pillar[n]arenes depend on the types of the substituents. Cationic, anionic, and nonionic pillar[n]arenes are soluble in water, therefore water can be used as the host–guest complexation medium. In water, in addition to CH-π and charge-transfer interactions, hydrophobic–hydrophilic interactions stabilize host–guest complexes. In the case of cationic pillar[n]arenes, cationic–anionic interactions between the pillar[n]arenes and anionic guests also stabilize complexation.25 In the converse combination, anionic pillar[n]arenes can capture cationic guests by cationic–anionic interactions.26 Our group discovered that one application of the host–guest properties of pillar[n]arenes is the use of pillar[6]arene with carboxylic anions as a biosensor for the vitamin metabolite 1-methylnicotinamide (1-MNA, Figure 4c).27 1-MNA is produced from nicotinamide by the enzymatic reaction of cancer-associated nicotinamide N-methyltransferase (NNMT). In aggressive cancer cells, high levels of 1-MNA are observed because NNMT activity increases in cancer cells. In the detection of www.asiachem.news

the cancer-related molecule, 1-MNA is therefore an important research target. 1-MNA is cationic and water-soluble, therefore we hypothesized that a pillar[n]arene with carboxylate anions could be used as a biosensor for 1-MNA in aqueous media. An anionic pillar[5]arene formed a 1:1 complex with 1-MNA in water. The association constant (K) of the host–guest complex was 1.14 ± 0.13 × 103 M-1. The size of 1-MNA (ca. 0.58 nm × 0.68 nm) is larger than that of the pillar[5]arene cavity (ca. 0.47 nm), therefore the K value is not so high. Another weak point is that the anionic pillar[5]arene also formed relatively stable host–guest complex with nicotinamide (K = 1.28 ± 0.19 × 102 M-1), which is metabolized to 1-MNA by NNMT and in present in normal cells. To overcome the problem, our next choice for increasing the association constant was use of an anionic pillar[6]arene. The association constant (K) of the pillar[6]arene–1-MNA complex is 8.05 ± 0.96 × 103 M-1, which is eight times higher than that of the complex with pillar[5]arene. The cavity size of pillar[6]arene is ca. 0.67 nm, which should be suitable size for 1-MNA. Furthermore, the anionic pillar[6]arene hardly formed a host–guest complex with nicotinamide. The anionic pillar[6]arene therefore acted as a biosensor for 1-MNA.

How can planar chiral pillar[n]arenes be separated?

Simple pillar[n]arenes do not have stereogenic carbons, but show planar chirality because of the position of the alkoxy substituents (Figure 5a).28-31

Figure 5 (a) Planar chirality of pillar[5]arene. Separation of enantiomers by (b) introducing bulky substituents and (c) formation of [2]rotaxane. (d) A schematic representation of the planar chiral inversion triggered by achiral guest. Reproduced with permission from reference.31 In their single crystal structures, we found enantiomers in pS and pR forms in a 1:1 ratio. However, in most cases, we could not separate the enantiomers by chiral column chromatography because racemization occurred via rotation of the units. This means that separation of the enantiomers is possible if we can stop the unit rotation. One useful way to stop the unit rotation is introduction of bulky substituents on the rim because the steric hindrance inhibits the unit rotation (Figure 5b).29 When we installed cyclohexylmethyl groups on the rims, the unit rotation was inhibited, and the enantiomers were successfully separated by chiral column chromatography. This is the first example of the separation of pillar[n]arene enantiomers. Another method for enantiomer separation is formation of rotaxane structures in which a cyclic molecule is threaded onto an axle molecule and end-capped with bulky groups at the terminal of the axle molecule. Formation of a rotaxane structure also inhibits the unit rotation because of the presence of the axle in the cavity (Figure 5c).30 December 2021 | 75

In contrast to point chirality, one of the interesting aspects of planar chirality is the dynamic chirality changes caused by the unit rotation. By controlling the unit rotation, the pS and pR forms can be switched. To control the chirality, we designed a new catenane-like structure (Figure 5d).31 Catenanes are compounds in which two or more macrocycles are mechanically interlocked. In this molecule, the guest is an alkyl chain connected to one pillar[5]arene unit. Rotation of the unit connecting the alkyl chain therefore switches inclusion and dethreading of the alkyl chain. In the inclusion form, the structure is similar to that of [2]catenane. In the dethreaded form, two rings are connected covalently, but are not interlocked with each other. The molecule can therefore be described as a pseudo[1]catenane. The pS and pR enantiomers of the inclusion form were successfully separated by chiral column chromatography because of inhibition of the unit rotation in the inclusion form. On addition of a competitive guest, the planar chirality was converted from pS to pR or pR to pS because the unit rotation occurred via structural changes from the inclusion form to the dethreading form.

part of C8, which results in 1D channel formation. The length of the n-alkane guest determines the supramolecular assembly of pillar[5] arenes in the crystalline state. Complexation with a linear polymer also triggers 1D channel formation because polymer chains are much longer than the height of pillar[5] arene.34 Poly(ethylene oxide) (PEO) has been used as the linear polymeric chain. The melting point of PEO is approximately 60ºC, therefore PEO is in the molten state at 80ºC. Immersion of pillar[5]arene crystals in molten PEO affords 1D channel structures via complexation of PEO with pillar[5]arene. Pillar[5]arene crystals selectively took up high-molecular-weight PEO from a mixture of PEOs of various molecular weights (Figure 6c). This high mass fractionation resulted from the increasing number of attractive CH-π interactions between PEO C-H groups and the π-electron-rich 1D channel of pillar[5]arene with increasing PEO chain length. This was determined by molecular mechanics simulations. Length-controlled 1D tubes can be produced by layer-by-layer assembly of cationic and anionic pillar[5]arenes (Figure 7).35

How can pillar[n]arenes be assembled?

Formation of one-dimensional (1D) tubes: Pillar[n]arenes are highly symmetric polygonal structures. The pillar-shaped structures differ from those of other macrocyclic hosts and should be suitable for the construction of 1D tubes. The versatile functionality of pillar[n]arenes enables 1D tube formation from inter-molecular assemblies of pillar[n] arenes. Pillar[n]arenes have two faces of the same size, and this introduces sites for interactions such as hydrogen-bonding and ionic interactions on both rims, which leads to the formation of continuous 1D tubes. For example, pillar[5]arene with 10 hydroxy groups can form 1D tubes via inter-molecular hydrogen bonds, and this assembly can form bundle structures eventually (Figure 6a).32 The formation of 1D tubular structures has also been induced by host–guest complexation of pillar[5]arene crystals with long, linear n-alkane guests (Figure 6b).33 A pillar[5]arene with 10 ethoxy groups formed herringbone assemblies by complexation with short n-alkane guests such as n-hexane C6 (Cn, CnH2n+2), and C7 because C6 and C7 are shorter than the height of pillar[5]arene. The formation of 1D channels was achieved by complexation with long n-alkanes with chains containing more than eight carbon atoms (>C8). This is because the pillar[5]arene height is less than the length of C8. The C8 molecule is not completely covered by a single molecule of pillar[5]arene, therefore a neighboring pillar[5]arene needs to cooperatively cover the protruding

Figure 7 Layer-by-layer assembly by consecutive adsorption of cationic and anionic pillar[5]arenes. Reproduced with permission from reference.35 Normally, cationic and anionic polymers are used for layer-by-layer assembly because there are multiple cationic–anionic interactions between cationic and anionic polymeric chains. Pillar[n]arenes have two faces, and the two faces have multiple interaction sites. The formation of 1D channels on the surface via layer-by-layer assembly is therefore possible. Immersion of an inorganic substrate with anionic charges on the surface in a cationic pillar[5]arene solution leads to cationic pillar[5] arene assembly on the surface. An important point regarding this system is that pillar[5]arene has two cationic rims; one cationic rim is used

Figure 6 (a) 1D tube formation by inter-molecular hydrogen bonding between pillar[5]arenes with 10 hydroxy groups. (b) Guest length selective supramolecular assemblies of crystalline pillar[5]arenes. (c) High mass fractionation by 1D pillar[5]arene channels. Liquid chromatography traces of an equal-weight mixture of PEOs (upper) and host–guest complex crystals after the immersion in the mixture (lower). Reproduced with permission from reference.34

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for adsorption on the inorganic surface by cationic–anionic interactions, but the other rim still has positive charges. Dimeric tubular structures can therefore be formed on the surface by immersing the cationic pillar[5]arene film in an anionic pillar[5]arene solution. At this stage, the surface is anionic, therefore immersing the resulting film into a cationic pillar[5]arene solution results in formation of trimeric tubular structures. Eventually, by alternating immersions of the film, length-controlled 1D tubes can be obtained. Pillar[n]arenes have two interaction faces, and therefore form continuous 1D channel structures. Pillar[n]arenes with one interactive face and one face with no interaction sites can be used as the ends of 1D tubes to obtain length-controlled discrete 1D tubes (Figure 8a).36

Figure 8 Rational design of discrete tubes by dimerization and trimerization of pillar[5]arenes. Reproduced with permission from reference.36 Use of an improved procedure for synthesizing rim-differentiated pillar[5]arenes, enabled the synthesis of new rim-differentiated pillar[5] arenes bearing benzoic acid groups on one rim and alkyl chains on the other rim. Benzoic acids form dimeric structures at high concentrations, therefore the rim-differentiated pillar[5]arenes form dimeric structure at high concentrations. The formation of dimeric structures was confirmed by single-crystal analysis of the rim-differentiated pillar[5]arene. Two molecules of the rim-differentiated pillar[5]arene interact with each other headto-head via hydrogen bonds, which results in a dimeric tubular structure.

Discrete dimers can act as transportation channels for water molecules, but not for larger cations such as sodium or potassium cations (Figure 8b).37 The normal pillar[5]arene cavity size is ca. 4.7 Å, but a discrete dimer has a narrow cavity on the benzoic acid group rim. The inter-molecular hydrogen bonds between the benzoic acid groups on the rim narrow the cavity size to ca. 2.8 Å; this can act as a water channel but blocks the passage of sodium or potassium cations. Another interesting feature is a rapid water transportation ability. These dimers can transport ca. 107 water molecules s-1/channel, which is only one order of magnitude lower than the value for the natural membrane protein aquaporin (ca. 108-9 water molecules s-1/channel). The dimer can be converted to a discrete trimer (Figure 8c).36 Mixing a rim-differentiated pillar[5]arene and peralkylamino-substituted pillar[5] arene in a 2:1 feed ratio resulted in formation of a discrete tubular trimer via multiple ionic interactions. Formation of two-dimensional (2D) sheets: Pillar[5]arenes and pillar[6] arenes are regular pentagonal and hexagonal molecules, respectively. Hexagonal molecules are good building blocks for obtaining well-defined 2D supramolecular assemblies because the structures are more highly symmetric than pentagonal molecules, this is known as molecular tiling. We therefore decided to use hexagonal pillar[6]arene as a building block for 2D sheet synthesis (Figure 9).38 As the driving force for assembling pillar[6]arenes, we used formation of the intermolecular supramolecular charge-transfer complex between hydroquinone and benzoquinone, which is generated by oxidation of hydroquinone. Chemical or electrochemical oxidation of pillar[6]arene resulted in formation of 2D hexagonal sheets. The 2D hexagonal sheets have pores (4.04 Å) that arise from the pillar[6]arene assembly (4.10 Å). We speculated that the 2D porous sheets could potentially be used as a source for synthesizing carbon materials by carbonization at 900ºC because they have many phenolic groups similarly to good carbon sources such as phenolic resins. Carbonization of the 2D sheet gave carbon material in relatively high yield (54%). The carbon material had pores of size 4.09 Å, which was similar to those of the 2D sheet (4.04 Å) and the pillar[6]arene assembly (4.10 Å). A porous carbon material with pores of the same size as those of the organic building block can therefore be produced by the assembly and subsequent carbonization. Angstrom-level pore control of carbon materials has been investigated by using porous coordination polymers or metal–organic frameworks and covalent organic frameworks. However, their original porous structures were destroyed during the carbonization process in most cases. Porous material synthesis from the pillar[6]arene assembly is therefore a new strategy for creating carbon materials with pores controlled at the angstrom level from organic building blocks.

Figure 9 2D supramolecular polymerization by oxidation OH[6] and porous carbon (PC[6]) by carbonization of CT[6]. www.asiachem.news

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Formation of three-dimensional (3D) spheres: Fullerene (C60), which is constructed from 12 pentagons and 20 hexagons, has a 3D soccer-ball spherical structure. In this structure, the pentagons provide curvature for 3D sphere formation. We successfully obtained a 2D sheet by assembly of pillar[6]arenes (Figure 9), therefore our next challenge was construction of 3D spherical structures by incorporation of pentagonal pillar[5]arenes into the 2D sheet (Figure 10).39

Figure 10 SEM images and schematic representation of 1D tube formation by pillar[5]quinone, 2D hexagonal sheet formation by pillar[6]arene and the vesicle formation by co-assembly of pentagon pillar[5]quinones with hexagon pillar[6]arenes.

How can bulk pillar[n]arene assemblies be used?

Host–guest complexation events are generally performed in the solution state because the host molecules are solids in most cases. However, when we synthesized a pillar[5]arene with 10 tri(ethylene oxide) chains, the obtained macrocyclic compound was liquid at room temperature (Figure 11a).40 We therefore used the liquid pillar[5]arene not only as a macrocyclic compound but also as a solvent for synthesis of the interlocked molecule [2]rotaxane. An axle with azide groups at both ends and a stopper with an alkyne group were directly dissolved in bulk liquid pillar[5]arene (Figure 11b). The end-capping reaction was achieved by a Husigentype copper(I)-catalyzed alkyne–azide cycloaddition “click” reaction. Surprisingly, [2]rotaxane was obtained in high yield (>88%) in the bulk system, whereas the yield of [2]rotaxane was quite low when a normal solvent system was used. In a normal solvent system, at the molecular level, the macrocyclic host and guest molecules are dispersed in a good solvent, therefore host–guest complexation takes place when the guest molecules meet the host molecules. However, host and guest solvation decrease the chance of these molecules meeting each other and decrease the stability of the host–guest complex. The yield of [2]rotaxane is therefore low in normal solvent systems. In contrast, in a bulk system, the guest molecules are directly surrounded by an excess of liquid pillar[5]arene. Inclusion of the guest molecules into the pillar[5]arene cavity is therefore maintained, which results in high-yield synthesis of [2]rotaxane. We realized that a host–guest complexation system that uses bulk liquid pillar[5]arene is more efficient than a normal solvent system. We therefore next investigated host–guest complexation of crystalline pillar[n]arenes (Figure 12).41,42

However, a 2D sheet constructed from pillar[6]arenes was formed by simply mixing pillar[5]arene and pillar[6]arene because the more highly symmetric pillar[6]arene is easier to assemble than pillar[5] arene. Mixing of pillar[5]arene and pillar[6]arene at the molecular level was achieved by using the inter-molecular charge-transfer complex between hydroquinone and benzoquinone. Pillar[5]quinone, which was prepared by oxidation of pillar[5]arene, was mixed with pillar[6]arene. In this case, pillar[5]quinone was completely mixed with pillar[6]arene via the inter-molecular charge-transfer complex. The assembled structures were tubular that consisted of pillar[5]quinone alone, and co-assembled samples containing excess pillar[5]quinone. Disk-shaped hexagonal assemblies of pillar[6]arene alone were observed along with co-assembled samples with excess pillar[6]arene. At a 12:20 pillar[5]quinone:pillar[6]arene molar ratio, which is the magic ratio for C60, 3D spheres were formed by co-assembly of pillar[5]quinone with pillar[6]arene. Figure 12 Alkane-shape selective vapor uptake by crystalline (a) pillar[5]arenes and (b) pillar[6]arenes.

Figure 11 (a) Solid to liquid transition by modification of tri(ethylene oxide) chains on the rims of pillar[5]arene. (b) High yield synthesis of [2]rotaxane by Huisgen reaction in the liquid pillar[5]arene. 78 | December 2021

When pillar[5]arene crystals were exposed to linear alkane vapors such as n-hexane vapor, the crystals took up the linear alkane vapor (Figure 12a). However, no uptake of cyclic alkanes including cyclohexane and branched alkane vapors was observed. The converse results were obtained when pillar[6]arene crystals were used (Figure 12b). Pillar[6]arene crystals took up cyclic and branched alkane vapors, but did not take up linear alkane vapors. The selectivity is the same as that for the host–guest complexation in normal solvent systems. We therefore discovered that host–guest complexation events occur even in crystalline pillar[n]arenes. Furthermore, pillar[n]arene crystals quantitatively took up alkane vapors into the crystals, whereas the association constants for host–guest complexes between pillar[n] arene and alkane guests are quite low in normal solvent systems, as a result of solvation. Crystal-state complexation is therefore superior for host–guest complex formation even in the low association constants in solvent systems. www.facs.website

We used the alkane-shape selective complexation to separate linear and breached alkanes (Figure 13).42

isooctane (>99%) was achieved by heating the host–guest complex crystals at 110°C for 12 h. The crystals did not contain isooctane after heating, and could therefore be reused for gasoline quality improvement.

Conclusions

Figure 13 Representation of the method to obtain highly pure isooctane from a mixture of isooctane and n-heptane using crystalline pillar[6]arene as the adsorbent. Reproduced with permission from reference.42 Separation of linear and branched alkanes is an important technique because gasoline is mainly a mixture of the branched alkane—isooctane and linear alkane—n-heptane. Gasoline with a high isooctane ratio gives a good performance, therefore separation of isooctane and n-heptane is an important target. However, the boiling point of isooctane (99°C) is almost the same as that of n-heptane (98°C), therefore the separation of these alkanes by distillation is difficult, and new separation techniques are needed. We investigated the use of pillar[6]arene crystals for the isolation of isooctane from a mixture of isooctane and n-heptane. When pillar[6] arene crystals were exposed to vapor mixtures containing 5% isooctane, the ratio of isooctane in the crystals was 95%. Exposure of the crystals to vapor mixtures containing >17% isooctane increased the ratio of isooctane in the crystals to >99%. The included isooctane could be stored in air at 25°C for 1 month, therefore the crystals can be used for storage of volatile isooctane. The release of high-purity

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Research in the field of pillar[n]arene chemistry started in 2008 from our accidental discovery during phenolic polymer synthesis. The fundamental properties of pillar[n]arenes, e.g., their host–guest properties and planar chirality, were then discovered. In addition, position-selective functionalizations such as mono-, di- and per-functionalization procedures were developed. Uncovering these fundamental properties and the development of functionalization procedures triggered construction of various functional molecules at the single molecule level. Functional materials can be produced by installing functional groups on both rims of pillar[n]arenes. On the basis of their host–guest properties, pillar[n] arene-based interlocked molecules such as rotaxanes, catenanes, and polyrotaxanes were prepared. The direction of research into pillar[n] arene chemistry then turned from the single molecule level to supramolecular architectures and to supramolecular assemblies. Pillar[n]arenes have simple regular polygonal structures, therefore pillar[n]arenes are useful building blocks for creating various supramolecular assemblies with ordered structures. The pillar[n]arene structure is simple, therefore we believe that pillar[n]arenes have unlimited potential, and look forward to new directions in pillar[n]arene research, which might extend the present concept of supramolecular chemistry. ◆

Acknowledgments

We acknowledge support from a Grant-in-Aid for Scientific Research on Innovative Areas: π-System Figuration (JP15H00990 and JP17H05148), Soft Crystals (JP18H04510 and JP20H04670), and Kiban A (JP19H00909) from MEXT Japan, JST CREST (JPMJCR18R3, T.O.), and the World Premier International Research Center Initiative (WPI), MEXT, Japan.

25. Y. Yao, M. Xue, X. Chi, Y. Ma, J. He, Z. Abliz, F. Huang, Chem. Commun. 2012, 48, 6505–6507. 26. T. Ogoshi, M. Hashizume, T. Yamagishi, Y. Nakamoto, Chem. Commun. 2010, 46, 3708–3710. 27. M. Ueno, T. Tomita, H. Arakawa, T. Kakuta, T. Yamagishi, J. Terakawa, T. Daikoku, S. Horike, S. Si, K. Kurayoshi, C. Ito, A. Kasahara, Y. Tadokoro, M. Kobayashi, T. Fukuwatari, I. Tamai, A. Hirao, T. Ogoshi, Commun. Chem. 2020, 3, 183. 28. S. Fa, T. Kakuta, T. Yamagishi, T. Ogoshi, Chem. Lett. 2019, 48, 1278–1287. 29. T. Ogoshi, K. Masaki, R. Shiga, K. Kitajima, T. Yamagishi, Org. Lett. 2021, 13, 1264–1266. 30. T. Ogoshi, D. Yamafuji, T. Aoki, K. Kitajima, T. Yamagishi, Y. Hayashi, S. Kawauchi, Chem. Eur. J. 2012, 18, 7493–7500. 31. T. Ogoshi, T. Akutsu, D. Yamafuji, T. Aoki, T. Yamagishi, Angew. Chem. Int. Ed. 2013, 52, 8111–8115. 32. T. Aoki, T. Ogoshi, T. Yamagishi, Chem. Lett. 2011, 40, 795–797. 33. T. Ogoshi, R. Sueto, Y. Hamada, K. Doitomi, H. Hirao, Y. Sakata, S. Akine, T. Yamagishi, Chem. Commun. 2017, 53, 8577—8580. 34. T. Ogoshi, R. Sueto, M. Yagyu, R. Kojima, T. Kakuta, T. Yamagishi, K. Doitomi, A. K. Tummanapelli, H. Hirao, Y. Sakata, S. Akine. M. Mizuno, Nat. Commun. 2019, 10, 479. 35. T. Ogoshi, S. Takashima, T. Yamagishi, J. Am. Chem. Soc. 2015, 137, 10962–10964. 36. S. Fa, Y. Sakata, S. Akine, T. Ogoshi, Angew. Chem. Int. Ed. 2000, 59, 9309–9313. 37. D. Strilets, S. Fa, A. Hardiagon, M. Baaden, T. Ogoshi, M. Barboiu, Angew. Chem. Int. Ed. 2020, 59, 23213–23219. 38. T. Ogoshi, K. Yoshikoshi, R. Sueto, H. Nishihara, T. Yamagishi, Angew. Chem. Int. Ed. 2015, 54, 6466–6469. 39. T. Ogoshi, R. Sueto, K. Yoshikoshi, K. Yasuhara, T. Yamagishi, J. Am. Chem. Soc. 2016, 138, 8064−8067. 40. T. Ogoshi, T. Aoki, R. Shiga, R. Iizuka, S. Ueda, K. Demachi, D. Yamafuji, H. Kayama, T. Yamagishi, J. Am. Chem. Soc. 2012, 134, 20322−20325. 41. T. Ogoshi, R. Sueto, K. Yoshikoshi, Y. Sakata, S. Akine, T. Yamagishi, Angew. Chem. Int. Ed. 2015, 54, 9849–9852. 42. T. Ogoshi, K. Saito, R. Sueto, R. Kojima, Y. Hamada, S. Akine, A. M. P. Moeljadi, H. Hirao, T. Kakuta, T. Yamagishi, Angew. Chem. Int. Ed. 2018, 57, 1592–1595.

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Hironobu Ozawa

Hironobu Ozawa received his Ph.D. from Kyushu University in 2007, working under the supervisiory of Prof. Ken Sakai. He carried out his Postdoctoral research in Prof. Koji Tanaka’s group at Institute for Molecular Science, Prof. Garry S. Hanan’s group at University of Montreal, and Prof. Ken Sakai’s group at Kyushu University. In 2010, he became an Assistant Professor at Tokyo University of Science (Prof. Hironori Arakawa’s group). In 2015, he moved to Kyushu University as an Assistant Professor (Prof. Ken Sakai’s group), and in 2018 he was promoted to an Associate Professor at the Department of Chemistry, Faculty of Science, Kyushu University. His current research interests are focused on the development of solar energy conversion systems based on coordination compounds.

Two-Electrode Solar Water Splitting

Permitting H2 Separation at a Dark Cathode By Hironobu Ozawa and Ken Sakai https://doi.org/10.51167/acm00027

Ken Sakai

Ken Sakai received his Ph.D. from Waseda University in 1993 where he initiated his ongoing study on the hydrogen evolution reaction catalyzed by platinum(II) complexes. He extended his study in the related areas at both Seikei University (1991-1999) and Tokyo University of Science (1999-2004), and was finally promoted to be a full professor at the Department of Chemistry of Kyushu University in 2004. His interests involve the development of hybrid materials for artificial photosynthesis together with the detailed mechanic studies on the dark and photochemical catalysis relevant to the energy conversion processes, such as water splitting and CO2 reduction. He has also been proving his volunteer services to the IUPAC activity as one of the elected members of Bureau (2018-2025).

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We want to develop an artificial photosynthetic water splitting device enabling separate evolution of H2 and O2 in two different aqueous phases. This approach avoids the evolution of a potentially explosive H2/O2 gas mixture together with development of a gas separation facility required to capture H2 from the mixture. We are thus attempting to develop a two-electrode system for solar-light water splitting with the anode only subjected for photo-driven water oxidation to uptake electrons and protons, as the nature does. Our target device converts the electrons transferred to the cathode directly to H2 without light illumination, as is the case for the Calvin cycle where CO2 is converted into glucose as a dark reaction. An outstanding feature also lies in the high specific surface areas of both electrodes due to the mesoporous nature of the TiO2 films adopted as the electrode materials. Why hydrogen and other fuel cells rather than battery?

Among various approaches attempting to develop renewable energy sources, solar hydrogen production via water splitting has received an increasing attention in recent years.1 It actually has a great relevance to the recent advancement in the hydrogen fuel cell technology. The fuel cell electric vehicles (FCEVs) possess several

important characteristics superior to the battery electric vehicles (BEVs),1 even though the FCEVs still suffer from the drawbacks arising from their high costs together with the lack of sufficient numbers of refueling stations. However, the pressurized hydrogen fuel (over 35 MPa)2 has a higher energy density than lithium-ion batteries, featuring the FCEVs superior to any other zero-emission vehicles for long-distance transportation. Especially, transportation of www.facs.website

heavy materials or a larger number of people by trucks or buses is not a realistic target for the BEVs but is considered achievable by the FCEVs. Moreover, the time required to refuel the FCEVs is short enough and comparable to the gasoline-powered vehicles, representing their high advantages in comparison with the BEVs. In addition, the fuel-to-electricity conversion efficiency over 60% already achieved by the hydrogen fuel cells3 makes them promising technologies towards the development of a hydrogen energy society.

How we separate the fuels yielded in artificial photosynthesis?

Currently, the mid-term direction rather concentrates on the hydrogen production based on natural gas reforming (i.e., steam methane reforming) together with the innovative technologies permitting the higher energy conversion efficiency as well as the capture, utilization and storage of the CO2 evolved in the reforming process.4,5 However, the long-term direction must be focused on the truly renewable energy cycles based on the storable fuels given by reduction of either water or CO2. For some simplest renewable fuels, the combustion energy averaged for storing two reductive equivalents (i.e., via 2-electron reduction) decreases in the order of H2 (he) > CO (0.99he), HCHO (0.99he) > HCOOH (0.89he) > CH3OH (0.85he) > CH4 (0.78he), where he denotes the combustion energy of H2 (286 kcal/mol). Only formic acid and methanol are liquid and possess superior characteristics from a viewpoint of energy density together with the feasibility in refueling and transportation in ambient conditions. Furthermore, formic acid has a remarkable potential as a source of H2 because of its reversible conversion capability: HCOOH ↔ H2 + CO2 (DG = -11.6 kcal/mol).6 There are several ways of converting solar energy into H2, CO, and HCOOH based on the simple 2-electron reduction (Figure 1, a-c). For all cases, the source of electrons and protons can be produced in the artificial photosynthetic water oxidation process (2H2O  O2 + 4H+ + 4e-). Without saying, it is important to separately develop some highly efficient water oxidation catalysts (WOCs).7 What are the forms of products in each case? In the gaseous fuel production, flammable or explosive gaseous mixture, {2H2+O2} or {2CO+O2}, is yielded, inevitably requiring the extra costs and energy in the gas separation processes.8 In this context, a two-phase gas evolution system, discussed below, has a great advantage. The photosynthetic production of the {O2+2HCOOH} mixture (Figure 1c) is also advantageous owing to the spontaneous separation of the two products into the gas and aqueous phases. Moreover, substantial efforts have been made to produce high pressure hydrogen based on the catalytic conversion of HCOOH into the {high-pressure H2 + supercritical CO2} mixture within a pressure-resistant vessel having a limited volume www.asiachem.news

(Figure 1d).9,10 This is a promising way to avoid the use of a mechanical compressor which consumes electrical energy during its operation (Figure 1f). In addition, desirable methods of handling the reverse process, i.e., the catalytic hydrogenation of CO2 into HCOOH (Figure 1e), must be advanced in order to facilitate the large-scale transportation of hydrogen energy in a liquid form. The above fuel generation processes combined with water oxidation catalysis may be driven using sustainable energy sources, such as solar, hydroelectric, oceanic, geothermal, wind and so forth. If we limit our discussion on the solar-driven artificial photosynthesis, oxidative and reductive equivalents required to drive the two catalytic processes must be generated via the light-harvesting of molecular and/or semiconductor systems.11-16

Molecular platinum(II)-based complexes as catalysts for hydrogen evolution reaction.

One of our interests over the last two decades has concentrated on the basic and applied chemistry of molecular hydrogen evolution reaction (HER) catalyzed by various platinum(II) complexes.17 The study was originally evoked in the late 1980s by finding the HER catalyzed by several cis-diammineplatinum(II) dimers doubly bridged by amidate ligands, [Pt(II)2(NH3)4(a-amidate)2]2+ (amidate = a-pyrrolidonate, a-pyridonate, acetamidate, 2-fluoroacetamidate, etc.) (Figure 2).18-20 In the earlier studies, their catalytic activity was scrutinized using a multi-component system comprising of [Ru(bpy)3]2+ (bpy = 2,2’-bipyridine) as a

photosensitizer (PS), methylviologen (N,N’dimethyl-4,4’-bipyridinium; MV2+) as an electron relay (Accepter), a platinum(II) complex as a water reduction catalyst (WRC), and EDTA·2Na (ethylenediaminetetraaceticacid disodium salt) as a sacrificial electron donor (Donor) (Figure 2). For many years, we insisted in studying all catalysts under a common aqueous acetate buffer condition (pH=5.0) in which the driving force for the HER driven by MV+• is only 150 meV. One of the most highly active catalysts (i.e., colloidal platinum) indeed works well so that the exploration of molecular catalysts active with this condition was believed to be the ideal target. The environmentally friendly aqueous conditions free on organic solvents were also considered to be the most suitable conditions when it happens to transfer the technology to the practical applications. Consequently, the Pt(II)-based catalysts had been for a long time the sole family of catalysts active under this condition until we reported on the second and third family of catalysts in 2010s, i.e., carboxylate-bridged dirhodium(II) catalysts21 and a cobalt-NHC catalyst.22 The specific features of the Pt(II)2 dimers are represented by the short bridged Pt(II)-Pt(II) distance (ca. 2.8-3.0 Å) together with the air-oxidizable metal centers displaying a quasi-reversible two-electron one-step Pt(II)2/Pt(III)2 redox couple at ca. 0.4-0.6 V vs. SCE,23 which can also be correlated with the blue and red chromophores in the mixed-valence tetranuclear Pt(2.25+)4 and Pt(2.5+)4 systems given by the stack of dimers. The subsequent studies on various mono- and dinuclear complexes suggested that the metal-metal interaction plays a

Figure 1. Handling the 2-electron-reduced fuels towards applications in renewable energy cycles. December 2021 | 81

none-negligible role in the catalytic enhancement.24-27 These studies provided various experimental and theoretical evidences supporting our conclusion that the Pt(II)-catalyzed H2 evolution is often accelerated via formation of a hydridodiplatinum(II,III) intermediate: 2Pt(II) + H+ + e- —> Pt(II)-Pt(III)-H. The stabilization of this intermediate has been interpreted in terms of the enhanced basicity of the electron pair in the filled Pt(II) dz2 orbital because of destabilization at the s*(dz2-dz2) antibonding orbital by the stack of two square-planar Pt(II) units. The high HER activity initially found for the amidate-bridged Pt(II)2 dimers may be similarly explained. As noted earlier,17 the hydride formation accompanies the formal oxidation at the metal center (i.e., Pt(II)2  Pt(2.5+)2 + e-) and therefore the strongly donating property of ligands together with the filled-filled dz2-dz2 interaction greatly contributes to the thermodynamic stability of the Pt(II)-Pt(III)-H intermediate. Several other groups have so far reported on the results consistent with our conclusion.28 On the other hand, we also attempted to develop the dyads and triads constructed by the covalent linkage of components selected from WRC, PS, Acceptor, and Donor.29-32 The first successful model was a PS-WRC dyad given by the amide coupling of [Ru(bpy)2(5amino-phen)]2+ (phen = 1,10-phenanthroline) and PtCl2(dcbpy) (dcbpy = 4,4’-dicarboxy-bpy) (Figure 2),24 which was turned out to be the

first example of a photo-hydrogen-evolving molecular device promoting the water reduction to H2 in the presence of Donor (EDTA) without any additional components. Based on the photocatalysis experiments combined with the in-situ dynamic light scattering (DLS) measurements, the lack of colloidal platinum formation was clearly evidenced for many of such molecular devices developed in our group.25,30,31,33

Developing PECs with a dark cathode rather than Tandem PECs

As mentioned above, the two-phase gas evolution technique adopted in our molecular-based photoelectrochemical cells (PECs) has a great advantage (Figure 3c). The original concept was developed by Fujishima and Honda in 1972 (Figure 3a).11 In their report, a TiO2 electrode, corresponding to an n-type semiconductor (SC), was irradiated by visible light to evolve O2 and H2 at the photoanode (TiO2) and the dark cathode (Pt), respectively, without applying external bias with the two compartments separated by a glass frit (Figure 3a). They also pointed out that the photoirradiation at the cathode by replacing Pt by a p-type SC should result in more efficient water splitting. By following this concept, the molecular-based PECs with both electrodes subjected for light illumination are intensively studied for overall water splitting in recent

years.34-37 Typically, such PECs consist of a photoanode modified with PS and WOC and a photocathode similarly modified with PS and WRC (Fig. 3b). These PECs are thus classified as Tandem PECs, where TiO2, SnO2, WO3 or BiVO4 (n-type SC) is adopted in the photoanode, while NiO, p-Si or p-GaP (p-type SC) is used in the photocathode. The word “tandem” denotes that two photosensitizers are connected in a tandem fashion in order to successively transfer a single electron based on twice of one-photon pumping. It means that two photons are required for the overall one-electron transfer. Theoretically, at least 8 photons must be absorbed to split water: 2H2O + 8hn  2H2 + O2, leading to the value of 50% in the highest attainable quantum efficiency for the overall photoreaction with this Tandem PECs. Some researchers misleadingly define that “Tandem” is equivalent to the “Z-scheme in oxygenic photosynthesis by green plants (PS-II and PS-I drive water oxidation and NADPH production, respectively)”. However, this is not the case because NADPH is not the only photoproduct. More importantly, the electron transport chain connecting the PS-II and PS-I generates the proton gradient energy across the Thylakoid membrane which is used to mechanically drive the ATP synthase. To keep the value of 100% regarded as the standard theoretical maximum for the quantum efficiency of photoreactions, our

Figure 2. Schematic representation of multi-component system for photochemical HER, and molecular structures of the Pt(II)2 dimers (WRC) together with the dinuclear Ru-Pt photocatalyst (PS-WRC dyad). 82 | December 2021

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PECs (Figure 3c) intend to drive the cathode reaction (HER) in the dark because of the much faster rate generally achieved for the HER compared to the OER (oxygen evolution reaction). In other words, the OER must be considered as a bottleneck in water splitting so that the overpotential required for the OER must be drastically controlled by finely tuning the redox properties of the PS together with the catalytic performance of WOCs in our photoanodes.

in aqueous media by monitoring the sustained evolution of H2 from the dark cathode. This behavior was also compared with the rapid deactivation of the PEC prepared by using a similar polypyridyl ruthenium dye possessing either carboxylate or phosphonate anchors instead of pyridyl anchors.42 Importantly, the H2 evolution was found to proceed even without applying any external bias, in line with our direction to avoid the Tandem type PECs (Figure 5).

Platinum(II)-based HER catalyst anchored to the cathode.

In spite of the superior zero-overpotential characteristics of the HER catalyzed by the platinum electrode, there has been a continued demand to develop comparably efficient non-precious metal HER catalysts for the sake of improving the cost effectiveness. However, as noted above, molecular catalysts capable of promoting the HER under the low driving-force conditions (150 meV by MV+•/MV2+) are quite

Why mesoporous TiO2 films? Why pyridyl anchors for stable adsorption?

The advancement of our projects on the molecular-based PECs largely relies on the knowledge and experimental techniques gained from the studies on dye-sensitized solar cells (DSSCs). 38 We assume that mesoporous TiO2 films possess extremely high specific surface area (ca. 80 m2/g),39 extremely larger than the apparent film area, and thereby permit the development of practically effective molecular-based PECs exhibiting relatively high hydrogen production capacity. Our initial effort was devoted to invent a new technique to produce tightly anchored molecular PECs which do not easily desorb the molecular components upon soakage into aqueous photolysis solutions. Both carboxylate and phosphonate anchors (Figure 4a,b) are widely adopted in making adsorption of polypyridyl ruthenium dyes and subcomponents in DSSCs, for they are relatively stable anchors in acetonitrile solvent adopted. However, these anchors rather easily dissociate from the TiO2 surfaces due to the hydrolysis in aqueous media when adopted for the artificial photosynthetic purposes, as described elsewhere.40 In general, such dyes are highly soluble in water, which also contributes to the rapid desorption of dyes from the TiO2 surfaces. To substantially suppress desorption of molecular components, we decided to utilize pyridyl anchors (Figure 4c). This pyridyl anchoring technique was evoked by a report on DSSCs which revealed improvement in cell performance based on the enhanced co-adsorption of two components using both carboxylate and pyridyl anchors.41 To test our idea, we initially developed a PEC consisting of a dye-anchored photoanode and a dark platinum cathode (Figure 5).42 The TiO2based photoanode was modified with [Ru(dmbpy)2(qpy)]2+ (Ru-dmqpy; dmbpy = 4,4′-dimethyl-2,2′-bipyridine, qpy = 4,4′:2′,2″:4″,4′′′-quarterpyridine) having two pyridyl anchors. By illuminating the photoanode by visible light in the presence of sacrificial Donor (EDTA), we could successfully demonstrate the stable adsorption of Ru-dmqpy over the TiO2 surfaces www.asiachem.news

Figure 3. Schematic representation of the PEC reported by Honda and Fujishima (a), tandem PECs (b), and PECs developed by the authors’ group (c).

December 2021 | 83

limited. Stability of molecular catalysts tends to become lower under the strong light illumination so that attention should also be paid to the stable ligand frameworks. In addition, molecular motifs having pyridyl anchor(s) showing relatively low solubility in water must be explored as a desirable target to be tightly anchored over the mesoporous TiO2 cathode surfaces. After our efforts, a platinum porphyrin having a single pyridyl anchor (PtP-py) was found to fulfill all these requirements (Figure 6).43 In the study, [Ru(dpbpy)2(qpy)]2+ (Ru-dpqpy; dpbpy = 4,4′-diphenyl-2,2′-bipyridine), possessing a higher hydrophobicity with stabler adsorption characteristics, was also used to improve the photoanode performance. The TiO2-based photoanode (FTO/TiO2/Ru-dpqpy) and the TiO2-based cathode (FTO/TiO2/PtP-py) were prepared by submersing the pristine FTO/TiO2 electrodes into the solutions of Ru-dpqpy and PtP-py, respectively. Based on the absorbance change in each solution, the amounts of Ru-dpqpy and PtP-py adsorbed over the individual FTO/TiO2 electrode were estimated to be 0.12 and 0.10 μmol/cm2, respectively.44 The detailed studies using the FTO/TiO2 / PtP-py cathode unveiled its extremely small onset overpotential for HER, which is even smaller than 50 meV. Although it still adopts a precious element, the single-atom nature per catalyst clearly achieves drastically higher cost effectiveness. Thus, at the PtP-py-modified

TiO2 electrode, H2 production proceeds spontaneously without the need for any additional external bias, in the same manner as observed when platinum was adopted at the cathode.42 It must be noted here that the conduction band (CB) edge potential (i.e., flatband potential; EFB = -0.40 -0.059pH V vs. SCE45) possesses a driving force for H2 production larger than 50 meV (ca. 160 meV), which is somehow closely correlated with the driving force for the MV+•driven HER at pH=5.0 (see above). We now postulate that the PtP-py anchored over the TiO2 surfaces cannot take the advantage of the above-mentioned dimerization pathway in order to lower the activation barrier for the often rate-limiting hydride formation process. Actually, the ideal p-p stacking distances of aromatic systems are ca. 3.4 Å, which clearly causes steric blockage to have a sufficiently strong Pt-Pt association (e.g., 2.8-3.2 Å) between the PtP-py units. An important insight gained in our recent study on the photocatalytic CO2 reduction by water-soluble cobalt porphyrins 46 seems relevant to the reason why the filled Pt dz2 electron pair in PtP-py can raise its basicity without the aid of metal-metal association. Our DFT-based mechanistic study on the cobalt porphyrins unveiled that the filled dz2 orbital gradually increases its basicity upon successive porphyrin-based reduction processes.46 The injection of electrons into the vacant p* orbitals causes

Figure 4. Schematic representations of possible binding modes for carboxylate (a), phosphonate (b), and pyridyl (c) anchors over the TiO2 surfaces.

Figure 5. The FTO/TiO2/Ru-dmqpy photoanode and a platinum electrode connected with a simple conductive wire, exhibiting its high stability and effectiveness in H2 evolution at the dark cathode.42 84 | December 2021

substantial congestion in the electron density surrounding the metal d orbitals, leading to cause the destabilization in some of the filled d orbitals. We thus speculate that the relatively low overpotential achieved by PtP-py is induced by the porphyrin-based reduction processes. The detailed study is now in progress.

Why electrons flow between the two electrodes with bias-free conditions?

To clarify the operation mechanism of our molecular-based PECs, linear potential sweep was made using a two-electrode configuration PEC made up of the FTO/ TiO2/Ru-dpqpy photoanode and FTO/TiO2/ PtP-py cathode.44 Using this setup, the photoanode potential was scanned versus the cathode potential with the reference terminal short connected to the cathode. The measurement was also combined with the light-on and -off switching cycles (Figure 7a). Thus, the potential axis has a description of V vs. cathode. The measurements were carried out using an acetate buffer solution (0.1 M, pH 5.0) containing Donor (EDTA). Control experiments were also carried out by suppressing either Ru-dpqpy or PtP-py in electrodes. One of the most remarkable results is that the photocurrent density reaches ca. 0.4 mA/cm2 even at 0 V vs. cathode, indicating that a sufficient current flows even with this bias-free condition (Figure 7a).44 In addition, upon holding the anode potential at 0 V for 1 h with the light-on condition, ca. 4.2 μmol of H2 evolved at the dark cathode with a near quantitative Faradaic efficiency. The results clearly indicated that electrons injected into the CB of TiO2 at the photoanode flow over to the cathode even without applying any external bias. Indeed, even by the lack of PtP-py in the cathode, the FTO/TiO2 cathode shows a color change into blue due to the substantial charge accumulation at the CB (Figure 7b,c). It was also confirmed that the electrons reaching the cathode can effectively drive the HER catalyzed by PtP-py with vigorous evolution of bubbles (Figure 7d,e). By disconnecting the electrochemical analyzer from the PEC, we further ascertained that a relatively small photoinduced potential shift is given between the two electrodes. The observed shift is rather small (ca. 20 μV) but certainly caused the electromotive force (EMF) required to transfer electrons from the photoanode to the cathode. The origin of EMF was further investigated by observing the charge accumulation into the CB at the photoanode by simply illuminating the FTO/ TiO 2 /Ru-dpqpy electrode soaked in the solution containing Donor (EDTA) (Figure 7f). The in-situ absorption spectroscopy clearly evidenced the growth of a broad visible to NIR band ascribable to the charge accumulation at the CB of TiO2 (Figure 7f). The electron www.facs.website

filling into the CB causes a negative shift in the Fermi level of TiO2, which is known as a Burstein-Moss shift. We thus concluded that the origin of EMF in our PEC arises from the upward shift in the Fermi level of TiO2 at the photoanode, leading to promote the transfer of electrons to the cathode. This interpretation was further supported by the rational correlation between the H2 evolution and the EMF (Figure 7g), for the rise in EMF (ca. 20 μV) and the H2 production both concomitantly take place only within the light-on period (Figure 7g). These observations well rationalized the fact that the solar H2 production occurs at the cathode even under bias-free conditions.

Splitting water by two TiO2 electrodes anchored with molecular catalysts.

In spired by our previous finding in the water oxidation activity of cobalt porphyrins,47 the anode photochemically driving water oxidation was initially designed to be given by co-adsorption of Ru-dpqpy (PS) and a cobalt porphyrin WOC possessing a pyridyl anchor (CoP-py; see Figure 8a). However, our study revealed that the FTO/TiO2/Ru-dpqpy/ CoP-py electrode does not show any desirable photocatalytic performance, which we assumed to be due to the lack of sufficient driving force for water oxidation when driven by the Ru(III)/Ru(II) couple of Ru-dpqpy. We thus postulated that the idealized PEC (Figure 3c) is only achievable with an appropriate choice of the PS having a sufficiently higher driving force for the water oxidation catalyzed by CoP-py, which is now in progress. In order to precisely understand the driving force required to promote the water oxidation by CoP-py, we decided to examine the electrolysis performance by the set of the FTO/TiO2/ CoP-py and FTO/TiO2/PtP-py electrodes when adopted in water splitting in the dark (Figure 8).48 As a result, this molecular-catalyst-anchored water electrolyzer was found to promote simultaneous generation of H2 and O2 in a 2:1 molar ratio with a nearly quantitative Faradaic efficiency. The electrocatalytic performances of the anode and cathode were separately examined as a function of pH using the standard three-electrode configuration electrochemical cell (Figure 8b). The cathode exhibited its pH-independent characteristics, consistent with the pH-dependent shift of the flatband potential (see above) which exactly coincides with that of the equilibrium potential for water reduction: E(H2/2H+) = -0.059pH. On the other hand, the anode showed a decrease in the onset overpotential with increasing pH, consistent with the shift in water oxidation potential: E(H 2 /2H+) = 1.23-0.059pH. The smallest onset potential was observed to be minimized at pH=9.0 with the value of ca. 1.00 V vs. SCE (i.e., 1.77 V vs. RHE), indicative of the onset overpotential of 540 meV for water oxidation with the CoP-py-anchored anode. www.asiachem.news

As for the PtP-py-anchored cathode, the onset potential for HER was observed to be located more positive than 0.83 V vs. SCE (i.e., -0.06 V vs. RHE) at pH=9.0, revealing that the onset overpotential is even smaller than 60 meV. We finally adopted a two-electrode configuration electrochemical cell by sweeping the anode potential versus the cathode potential which is shorted connected to the reference terminal. This setup allowed us to more clearly evaluate the water electrolysis performance of our TiO2-electrodebased electrolyzer. The large current derived from overall water splitting was thus observed with the applied potential of 1.8 V (Figure 8c). The minimum overall potential required to trigger the water decomposition was determined as ca. 1.75 V by conducting the in-situ quantification of the H2 and O2 evolved under various applied potentials. The result indicated that our molecular-catalyst-anchored water electrolyzer start splitting water with addition of 520 meV or more to the theoretical potential (1230 meV). This overall required overpotential (520 meV) corresponds to the sum of

driving forces required to drive the HER and OER. Interestingly, this value is even less than the sum of the values independently determined for the anode and cathode using the three-electrode system (600 meV; see above). During 1 h of controlled potential electrolysis (CPE) using the applied potential of 2.2 V vs. cathode, corresponding to ca. 1.0 V of applied overall overpotential, this water electrolyzer produced H2 and O2 in a 2:1 molar ratio (5.9 ± 0.8 and 3.1 ± 0.3 μmol, respectively) with a nearly quantitative Faradaic efficiency (90 ± 6% and 94 ± 4%, respectively) (Figure 8d). The TONs based on the amounts of PtP-py and CoP-py adsorbed over the individual FTO/ TiO2 electrode were estimated to be 59 ± 8 and 31 ± 3, respectively. An interesting observation for this water electrolyzer is that H2 production continues to occur until satisfying the quantitative Faradaic efficiency even after stopping the 1 h of CPE, while such a delay response is not observed for O2 production (Figure 8d). The delayed action in the cathode was rationally interpreted by the fact that the electrons transferred from the anode are once

Figure 6. (a) Schematic representation of molecular-based PEC cell for solar H2 production reported by authors′ group.43,44 (b) Schematic diagram and photograph of the molecular-based PEC consisting of the FTO/TiO2/Ru-dpqpy photoanode and the FTO/ TiO2/PtP-py cathode. December 2021 | 85

charged into the CB in the cathode followed by their delayed consumption in the PtPpy-catalyzed HER. This behavior is clearly attributable to the uncontrollable nature of

the driving force for the HER using the CB of TiO2. We also confirmed that both PtP-py and CoP-py are intact for at least an hour under the above water electrolysis conditions. Thus,

our study, for the first time, demonstrated that a molecular-catalyst-based water electrolyzer is achievable by employing the mesoporous TiO2 films as the electrode materials on both anode and cathode. The band engineering enabling the fine tuning of the CB levels in both electrodes is considered as one of the important strategies towards the development of advanced technology for the solar hydrogen generation.

Summary and Outlook

Figure 7. (a) Linear sweep voltammograms (LSV) for our PECs under intermittent irradiation (λ > 400 nm). Photographs of the FTO/TiO2 and the FTO/TiO2/PtP-py cathodes before (b,d) and after (c,e) the LSV measurements under irradiation condition. (f) Spectral changes during the visible light irradiation to the FTO/TiO2/Ru-dpqpy electrode submerged into an acetate buffer solution containing 30 mM EDTA under Ar. (g) Time course of the EMF and the amount of H2 evolved under intermittent irradiation.44

Figure 8. (a) Schematic representation of molecular-catalyst-anchored water electrolyzer consisting of the FTO/TiO2/CoP-py anode and the FTO/TiO2/PtP-py cathode (coverage of catalyst, 0.10 μmol/cm2 for each). (b) The pH dependences in the LSVs measured for either the anode or cathode (100 mV/s). (c) LSVs with the cathode short connected to the reference terminal (0.1 M borate buffer, pH=9.0). (d) The H2 and O2 evolved over time during 1 h of electrolysis with the anode potential held at 2.2 V vs. cathode (pH=9.0), where the dashed line corresponds to the amount of each gas expected for the 100% Faradaic efficiency.48 86 | December 2021

We have emphasized the importance of keep tackling to innovate the solar-driven hydrogen generation technology by appreciating rather highly advanced technology in the hydrogen fuel cells which are likely to offer a significant contribution to our future society because of their sufficiently high fuel-to-electricity conversion efficiency together with the high capacity enabling the large scale energy supply based on the storable high energy density fuels. In sharp contrast with the artificial fuel generation methods recently explored by other researchers, our fuel generation method is designed to avoid the gas separation facility together with the double photon pumping route to transfer one electron. These strategies intend to make our target photosynthetic devices amenable to produce the highest achievable energy on the basis of the solar light energy absorbed. Nature has somehow achieved such photosynthetic systems after repeating a few billion years of evolution processes. Nature does not evolve flammable fuels mixed with dioxygen by smartly converting their fuels into water-soluble as well as recognizable forms. The side product, that is, dioxygen is simply ejected from the organism. The chemical engineering features are thus well advanced in natural organisms. We notify that such chemical engineering part of research has not been well advanced in the field of artificial photosynthesis. The advanced studies on such issues are thus likely to open up a new avenue of research. In this review, we also discussed some of our successful advancement in getting deeper insights into the mechanisms of molecular catalysis related to energy conversion processes. Development of molecular-anchored photosynthetic systems largely relies on the knowledge gained from the basics studies on the small molecular systems. Since our ability to control the molecular catalytic properties is still quite limited, we should further advance our knowledge and artificial skills to finely control all the photochemical and electrochemical actions of the molecular systems in our hand. ◆

Acknowledgment

This work was suppor ted by JSPS KAKENHI Grant Numbers JP16K05726, JP18H01996, JP18H05171, JP19K05502 and JP21H01952. www.facs.website

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34. Ashford, D.L.; Gish, M.K.; Vannucci, A.K.; Brennaman, M.K.; Templeton, J.L.; Papanikolas, J.M.; Meyer, T.J. (2015). Molecular ChromophoreCatalyst Assemblies for Solar Fuel Applications. Chem. Rev. 115, 13006-13049. 35. Wang, M.; Yang, Y.; Shen, J.; Jiang, J.; Sun, L. (2017). Visible-Light-Absorbing Semiconductor/ Molecular Catalyst Hybrid Photoelectrodes for H2 or O2 Evolution: Recent Advances and Challenges. Sustainable Energy Fuels 1, 1641-1663. 36. Shan, B.; Brennaman, M.K.; Troian-Gautier, L.; Liu, Y.; Nayak, A.; Klug, C.M.; Li, T.T.; Bullock, R.M.; Meyer, T.J. (2019). A Silicon-Based Heterojunction Integrated with a Molecular Excited State in a Water-Splitting Tandem Cell. J. Am. Chem. Soc. 141, 10390-10398. 37. Gong, L.; Zhang, P.; Liu, G.; Shan, Y.; Wang, M. (2021). A Silicon-Based Hybrid Photocathode Modified with an N5-Chelated Nickel Catalyst in a Noble-Metal-Free Biomimetic Photoelectrochemical Cell for Solar-Driven Unbiased Overall Water Splitting J. Mater. Chem. A 9, 12140-12151. 38. Ozawa, H.; Sugiura, T.; Kuroda, T.; Nozawa, K.; Arakawa, H. (2016). Highly Efficient Dye-Sensitized Solar Cell Based on a Ruthenium Sensitizer Bearing a Hexylthiophene Modified Terpyridine Ligand. J. Mater. Chem. A 4, 1762-1770. 39. Ito, S.; Liska, P.; Comte, P.; Charvet, R.; Péchy, P.; Bach, U.; Schmidt-Mende, R.; Zakeeruddin, S.M.; Kay, A.; Nazeeruddina, M.K.; Grätzel, M. (2005). Control of Dark Current in Photoelectrochemical (TiO2/I−-I3−) and Dye-Sensitized Solar Cells. Chem. Commun. 2005, 4351-4353. 40. Brewster, T.P.; Konezny, S.J.; Sheehan, S.W.; Martini, L.A.; Schmuttenmaer, C.A.; Batista, V.S.; Crabtree, R.H. (2013). Hydroxamate Anchors for Improved Photoconversion in Dye-Sensitized Solar Cells. Inorg. Chem. 52, 6752−6764. 41. Shibayama, N.; Ozawa, H.; Abe, M.; Ooyama, Y.; Arakawa, H. (2014). A New Cosensitization Method Using the Lewis Acid Sites of a TiO2 Photoelectrode for Dye-Sensitized Solar Cells. Chem. Commun. 50, 6398-6401. 42. Takijiri, K.; Morita, K.; Nakazono, T.; Sakai, K.; Ozawa, H. (2017). Highly Stable Chemisorption of Dyes with Pyridyl Anchors Over TiO2: Application in Dye-Sensitized Photoelectrochemical Water Reduction in Aqueous Media. Chem. Commun. 53, 3042-3045. 43. Morita, K.; Takijiri, K.; Sakai, K.; Ozawa, H. (2017). A Platinum Porphyrin Modified TiO2 Electrode for Photoelectrochemical Hydrogen Production from Neutral Water Driven by the Conduction Band Edge Potential of TiO2. Dalton Trans. 46, 1518115185. 44. Morita, K.; Sakai, K.; Ozawa, H. (2019). A New Class of Molecular-Based Photoelectrochemical Cell for Solar Hydrogen Production Consisting of Two Mesoporous TiO2 Electrodes. ACS Appl. Energy Mater. 2, 987-992. 45. Boschloo, G.; Fitzmaurice, D. (2000). Electron Accumulation in Nanostructured TiO2 (Anatase) Electrodes. J. Electrochem. Soc. 147, 1117-1123. 46. Zhang, X.; Yamauchi, K.; Sakai, K. (2021). Earth-Abundant Photocatalytic CO2 Reduction by Multielectron Chargeable Cobalt Porphyrin Catalysts: High CO/H2 Selectivity in Water Based on Phase Mismatch in Frontier MO Association. ACS Catal. 11, 10436-10449. 47. Nakazono, T.; Sakai, K. (2016). Improving the Robustness of Cobalt Porphyrin Water Oxidation Catalysts by Chlorination of Aryl Groups. Dalton Trans. 45, 12649-12652. 48. Akamine, K.; Morita, K.; Sakai, K.; Ozawa, H. (2020). A Molecular-Based Water Electrolyzer Consisting of Two Mesoporous TiO2 Electrodes Modified with Metalloporphyrin Molecular Catalysts Showing a Quantitative Faradaic Efficiency. ACS Appl. Energy Mater. 3, 4860-4866.

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Think Globally, Act Locally An interview with Prof. Ryōji Noyori

By Ehud Keinan https://doi.org/10.51167/acm00028

Ehud Keinan

Professor Keinan of the Technion is President of the Israel Chemical Society, Editor-in-Chief of AsiaChem and the Israel Journal of Chemistry, Council Member of the Wolf Foundation, and past Board Member of EuChemS. He was Dean of Chemistry at the Technion, Head of the Institute of Catalysis, and Adjunct Professor at The Scripps Research Institute in California. His research program includes biocatalysis, organic synthesis, molecular computing, supramolecular chemistry, and drug discovery. He received the New England Award, the Herschel-Rich Award, the Henri Taub Prize, the Schulich Prize, the Asia-Pacific Triple E Award, AAAS Fellowship, the ACS Fellowship, and the EuChemS Award of Service. Since 2022 he is IUPAC VP and President-elect.

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Ryōji Noyori was born on September 3, 1938, in Kobe, Japan. He obtained his B.Sc. and M.Sc. in Industrial Chemistry from Kyoto University. In 1967 he obtained a Doctor of Engineering degree from Kyoto University under Prof. Hitosi Nozaki, and in 1968 became an associate professor at Nagoya University. After postdoctoral work with Elias J. Corey at Harvard University, he returned to Nagoya, becoming a full professor in 1972. He served as president of RIKEN (2003-2015), and since 2015 he has been Director-General of CRDS (Center of Research and Development Strategy) of the Japan Science and Technology Agency. Noyori shared the 2001 Nobel Prize in Chemistry with William S. Knowles and K. Barry Sharpless. Noyori’s other prominent recognitions include the 1992 Asahi Prize, the 1993 Tetrahedron Prize, the 1995 Japan Academy Prize, the 1997 Arthur C. Cope Award, the 1999 King Faisal International Prize, the 2001 Wolf Prize in Chemistry, the 2001 Roger Adams Award, and the 2009 Lomonosov Gold Medal. Our Zoom interview took place on September 27, 2021, about three weeks after his 83rd birthday. It was early morning in Israel and afternoon in Japan. How early in your childhood has science triggered your curiosity? Louis Pasteur once said, “Science has no borders, but scientists have their homeland.” Every scientist has a different social background. My life path is much different from that of Americans, Europeans, or even other Asians in many ways. Ehud, you live in the western end of Asia, while I live at the eastern end of Asia. Although we share

the same values in science, we grew up in different social and cultural environments. My career as a scientist has been full of challenges, excitement, and joy, but at the same time, I had to overcome many obstacles. My own experience makes me think: what is behind the talent and intuition of a Japanese scientist? My generation had a challenging time after the devastation of WWII. Yet, we survived and even contributed a bit to the progress of science. How were we able www.facs.website

1. Ryōji Noyori was a naughty schoolboy. In 1949 at age 11. 2. Ryōji Noyori was a black-belt “judo” expert. At a high school in Kobe, Japan in 1956. 3. Nozaki group of Kyoto University in 1964. From left, students R. Urakabe, M. Yamabe and N. Kozaki, Professor H. Nozaki, and Instructors R. Noyori and K. Kondo. to do this? We were patient, diligent, and hardworking. Also, we enjoyed complete academic freedom without any outside pressure or restriction. That freedom was a key factor for promoting academic research. We learned much from America and Europe and later enjoyed partnerships with colleagues from all over the world, including the Asian region. I would also acknowledge industrial collaboration here, for the industry eventually transforms our basic knowledge into social benefits. I was born in 1938 in a suburb of Kobe and grew up into the experience of World War II. At the very end of the war, in April of 1945, I was to enter elementary school. However, before the horrible atomic bombing on Hiroshima and Nagasaki in August 1945, American B29 bombers devastated Kobe, reducing the central city to ashes. My mother and her three sons (our younger sister was not born later) took refuge earlier in the nearby countryside, while my father remained working in Kobe and commuted www.asiachem.news

at weekends to take care of his family. What was waiting for us there was a life of self-sufficiency. That farming village was a world with no cars, telephones, electricity, no market for daily supplies, no running water, not even cooking gas. We used to pump water from a local well, firewood for heating, and candles for lighting. Our neighbors helped us with basic food, such as rice, vegetables, eggs, and river fish. We learned how to grow our vegetables, breed hens, and collect wild nuts and plants. As a 6-year-old boy, I learned from older friends how to make traps to snare sparrows and catch fish at the pond and river. I even made straw sandals because we had no shoes for school. I constructed a study desk from wood containers, and crude lumbers using a saw and nails. Even boiling water for the bath was a non-trivial task. These activities provided me with tacit wisdom rather than explicit knowledge taught at school and prepared me for my science career. Though very poor, the farmland, with its peaceful and beautiful natural

surroundings, triggered my curiosity in science. In addition, our stay in the countryside made me physically strong. Although my mother gave me many books to read, I preferred outdoor activities and sports. My interest in indoor learning came much later. My personal experience, learning to supply all my needs through exposure to Nature, also worked on the national scale. We learned to secure our lives and livelihood by ourselves. In a more general sense, Humanity can meet significant challenges, such as natural disasters and infectious diseases, through science and technology. When and why did you consider becoming a scientist? When WWII ended, we returned to Kobe, and I, a 7-year-old boy, continued my elementary school. Our country was devastated, we suffered food shortages and a lack of basic supplies, and my childhood remained difficult. My mother wisely managed to feed a family of six under these December 2021 | 89

conditions. Our clothes, including underwear and socks, were all hand-made. I remember her busy repairing our clothes late at night, and we helped with cooking and gardening. My mother was clever, patient, and devoted her entire life to our family. I was happy to pay her back by taking her to Stockholm for the Centennial ceremony of the Nobel Prize in 2001. At that time, she was 87 and looked happy. My wife Hiroko learned much from her, mainly how to handle a complex person like myself. In my view, although Japan was in ruins at the end of WWII, the Japanese scientific intellect remained unaffected. I have aspired to become a scientist ever since I was a small child, strongly influenced by my father, a gifted research director at the Kanegafuchi chemical company. In 1949 when I was 11 years old at the 5th grade, Professor Hideki Yukawa of Kyoto won the Nobel Prize in Physics. He was the first Japanese to receive

a Nobel Prize, and I was especially delighted with this event because my parents knew him personally. Understandably, Yukawa has become my hero and a role model. Another momentous event occurred in 1951 when I entered junior high school in Kobe. My father took me to a symposium on a newly discovered fiber called Nylon, and I was the only child in the audience. The lecturer, President of the Toray Company, proudly explained, “This new fiber can be synthesized from coal, water, and air, and it is thinner than a spider’s thread, yet stronger than a steel wire.” I was overwhelmed. Here was a new material created by chemistry from almost nothing. From that moment, I began dreaming of becoming an industrial chemist. I wanted to invent new materials to benefit society and Japan’s economic recovery. At that time, Japan’s industry was still underdeveloped, far behind the Western

Noyori was engaged in prostaglandin synthesis in E. J. Corey’s lab at Harvard in 1969–1970.

Receiving the 1995 Japan Academy Prize, Noyori was congratulated by Member Kenichi Fukui (1981 Nobel laureate). 90 | December 2021

countries. Many significant corporates worked under a technological license from American or European companies, and my father strongly disagreed with that trend. Every evening at the dinner table, he preached to our family on the significance of self-sustainability, saying, “We have to develop powerful technology by ourselves. Otherwise, Japan’s stagnated economy cannot recover.” My home was full of chemistry journals and books and various samples of polymer powders, beakers, and flasks. Then, my two younger brothers and I were convinced to study engineering at universities. We decided that I’d take industrial chemistry, and they would take mechanical engineering and electrical engineering. Indeed, my two brothers pursued industrial careers. How supportive were your family and friends about your choice? My family was highly supportive. Perhaps, my father had expected me to become a chemical engineer in the industry rather than a university professor. In my middle and high school days in Kobe, my favorite subjects were mathematics and sciences. Interestingly, my first chemistry teacher was Kazuo Nakamoto, dispatched from Osaka University and later became an inorganic chemistry professor in the USA, first at the Illinois Institute of Technology and later at Marquette University. My mathematics teacher, Mr. Masanori Maino, taught us math and many other things, including Chinese poetry. Several other enthusiastic teachers triggered my appetite for chemistry even more. Another person I admired in connection with my future direction was Professor Ichiro Sakurada of Kyoto University, inventor of Vinylon, the first Japan-made synthetic fiber. He was one of the reasons I decided to study chemistry at Kyoto. The other reason was Professor Yukawa of the physics department at Kyoto University. In the mid-1950s, with the rapid development of the petrochemical industry, the chemistry departments within the engineering faculties attracted the best high school students. Did you receive appropriate formal education to become a scientist? If you ask about Japan’s public schools or university system, you may be surprised that my answer is probably NO. We grew up mainly by self-learning rather than formal, curriculum-based, Western-style education. Although I highly appreciate my mentors’ thoughtful guidance, giving me freedom, encouragement, and independence, I think that much of my background is self-education. I believe that systematic education, as done in the USA, is essential for nurturing www.facs.website

scientists. However, we should remember that some 30% of the American Nobel Prizes in science went to scientists born and educated in other countries, and many of them are ethnic Asians. That statistic suggests that Asian education, experience, and culture foster creativity and ambition. I believe that Israel’s success in science and technology also stems from the strong emphasis on mathematical thinking in schools, regardless of the field. A successful science career needs explicit and implicit knowledge, which is strongly affected by cultural background. English and American science, French la science, German Wissenschaft, and Japan’s Kagaku are all different. “Indigenous” knowledge or wisdom is essential for unique achievements. Asian scientists exposed to diverse social environments have thus great potential. Japan was in the hinterland during my youth, but we enjoyed rich nature and freedom. In contrast, today’s children who live in modern cities enjoy comfort life, but they live in a restricted, artificial space, and they like it. I feel that we are losing our blessed tradition. I started my undergraduate studies at Kyoto University in 1957, only 12 years after WWII. Thus, we came up from Ground Zero or, more precisely, Ground Minus Ten. Since Japan’s economic situation was far behind North America and Europe, the government intended to rapidly revive industrial productivity by nurturing a young workforce rather than promoting science that typically requires a much longer effort. This policy was not good, but quite understandable. Consequently, the size of Chemistry Depar tments within the Faculties of Engineering, like the one I attended, became much more significant than those in the Faculties of Science. In the Japanese system, we have different chemistry departments, some belong to the faculties of Engineering, Agriculture, or Pharmacy, and others belong to the Faculty of Science. In the third year of my undergraduate course, we studied organic chemistry using Fieser’s textbook, “Introduction to Organic Chemistry,” which changed my interest from polymer chemistry to organic chemistry. In the following year, in 1960, I joined Professor Keiiti Sisido’s laboratory at the Department of Industrial Chemistry for further experimental training. Associate Professor Hitosi Nozaki has become my guide and mentor from this starting point. The laboratory environment at that time was very hospitable. Although Japan’s economy improved, the academic research and education labs were lagging. At the organic chemistry laboratories, we determined the structures of organic compounds mainly by elemental analysis. The hand-operated Beckman UV–visible spectrometer was the sole reliable spectroscopic tool, and we had only one IR spectrometer on the www.asiachem.news

entire university. As neither silica gel nor active alumina was available for column chromatography, we obtained analytically pure substances by recrystallization or by making crystalline derivatives. We purified oily compounds by large-scale distillation or steam distillation. Since only a few solvents and reagents were commercially accessible, we synthesized common chemicals and solvents, including benzophenone, triphenylphosphine, diborane, and dimethoxyethane. We conducted reactions on a relatively large scale, which required high skill. We studied very hard in the department library. Chemical Abstracts was indispensable because access to original literature was limited. We read the literature more seriously

than students of our time because photocopying machines were unavailable. We had to generate an abstract or take full notes after reading the article from beginning to end. With such inefficiency, the research progress was extremely slow. Nevertheless, students were highly motivated and enjoyed free speculations despite the limited knowledge. The undergraduate course in all Japanese universities included practical research in the 4th year through an apprenticeship in various laboratories. In the 1960s, more than half of the B.Sc. graduates pursued industrial careers. Some students continued their graduate training under the same mentor, typically a two-year master’s and three-year doctor’s course. The science

Noyori group at Nagoya in 1991. Front row, left: Masato Kitamura, right: Ryōji Noyori.

From left to right: Ryōji Noyori, K. Barry Sharpless, and Robert H Grubbs (2005 Nobel laureate) watched “sumo” wrestling in the National Sports Hall in Tokyo. In September, 1996. December 2021 | 91

and engineering curriculum remained much less systematic than the US and Europe, so the Japanese graduates conducted their research in various styles. Fortunately, the research environment, and internationalization, improved in the mid-1960s thanks to coordinated efforts of the government and universities. I started speaking English only at age 30 upon my first trip to Harvard University. Thanks for appreciating the innovative Israeli economy. I think that the situation in Israel is very similar to that of Japan. Israel

does not have natural treasures and raw materials. But both Japan and Israel have outstanding human capital. In my view, the Japanese and Israeli cultures consider education and intellectual activities top priority. Do you agree with me? I agree that both Japan and Israel are eager to nurture the young generation towards science and technology. However, the main difference is the higher level of the human network in your country. Israel, and more generally, the Jewish people, appreciate human interactions very much. Young Japanese stay in Japan, reluctant to travel

The 2001 Wolf Prize recipients. Front row: from left K. Barry Sharpless, the third Ryōji Noyori, and the fourth Henri B. Kagan. Back row: the fourth from left, Avram Hershko (2004 Nobel laureate). At the Chagall Hall of Knesset, Jerusalem in May of 2001

In December, 2001, the Nobel Foundation celebrated the centennial anniversary and invited more than 130 former laureates to Stockholm. Noyori’s sharing a Chemistry Prize with W. S. Knowles and K. B. Sharpless was congratulated by his supervisor at Harvard. From left to right: Hiroko and Ryōji Noyori, Claire and E. J. Corey (1990 laureate). 92 | December 2021

and mix with other cultures. There is not much one person can do alone, so the human network is essential. I am a bit disappointed by the public attitude in Japan towards science. Unlike in Israel, many people in Japan consider scientists as slaves of the economy. Are you trying to influence the young generation to choose a career in science, and how? Yes, I enjoy encouraging the younger generation, and I see it as one of my most important duties. The curious minds and enthusiasm of young people inspire innovative scientific discoveries. Science is beautiful, exciting, and often beneficial for humankind. However, we should avoid pushing our yet naïve kids toward social matters too early. Children inherently love and enjoy nature simply because natural phenomena are exciting and marvelous. Our most important task is to maintain our kids’ “sense of wonder” until they reach their academic studies and much later. We know that intellectual curiosity rather than duty drives the progress of science. Unfortunately, this approach is difficult in Japan because of the fallacy of our school system. Our school pupils need to sacrifice their joyful endeavors because they are too busy gaining skills to pass the entrance examination of good high schools and universities. Regretfully, the university’s reputation is a major benchmark for achieving a promising career. So, parents consider that playing in wild nature or visiting science museums is a waste of time. This atmosphere misleads science teachers as well. Kids are not matric-regulated machines or robots but our living assets who will shape our future society. Education is not a tool for discrimination against children. I firmly believe healthy curiosity comes from the liberation of the spirit. Therefore, we must give our youths a well-balanced, proper STEAM (science, technology, engineering, arts, and mathematics) education. I prefer natural science “science brut” in French, like “art brut,” rather than modern computer-controlled scientific research. We should motivate high school or university students in a bit different way. The essence of science that we should transfer to our students must always be the pursual of truth and the Socratic ability to recognize that we know nothing (knowledge of ignorance). The creation of new knowledge opens new windows to the unknown, and the accumulation of scientific discoveries keeps transforming myths into reality. Your biography suggests that the way to attract the young generation to science is non-trivial. Your advice about education seems challenging to implement, even in your case. Your father was a successful www.facs.website

chemical engineer, and you have attended the best possible schools where you had excellent teachers, including primary school, the Nada Middle and High School. Yet, as a young pupil, you preferred having a good time with friends, playing baseball, practicing Judo, and going on trips rather than studying. You joined the rugby football club at Kyoto University and preferred social activities with friends and wine. You became serious about science only after joining the group of Hitosi Nozaki. So, perhaps the most effective way to attract the young generation to science is by singular events of personal experience, like the “Nylon Case” of your childhood. Such Eureka moments at a very early age can be more valuable than armies of teachers. I suspect that your father had this idea in mind, taking you to the event to create an unforgettable experience that could attract you to science. Do you agree with that approach? I agree that accidental encounters are very influential in motivating young people. In analogy to chemistry, such singular events serve as catalysts, and they are more effective than stoichiometric formal education. I remember another singular event when my father, on the occasion of the Nylon case,

took me to a small restaurant for dinner with his colleagues. We were very poor at that time, and I was impressed by the unfamiliar, though now casual, rich menu, the group of enthusiastic industrial chemists, and the frank conversation around the dinner table. That unforgettable event impressed me so much that I aspired to be like them. Only years later, Hitosi Nozaki convinced me to switch my aspiration from industrial to an academic career. Science has attracted me in multiple ways. One of them was the feeling that a scientist can do anything at will. Another essential factor is freedom and the sense that I can do anything by myself as a scientist. University professors should nurture their young students by pushing them to pursue an independent research career and provide them with maximal freedom. I was attracted to the academic mentality at the universities, which is quite different from the corporate or governmental institutions. Furthermore, academic research depends much on the mindset and personality of every scientist. To encourage young science students, I often cite the statement of Isaac Newton: “If I have seen further, it is by standing on the shoulders of giants.” At every age, the young students should explore new frontiers,

and we must be patient as they make their way. Youth are creating new science on the assets founded by their predecessors. The young generation should be proud that their perseverant study and research lie higher than Einstein, Watson and Click, Ziegler and Natta, or R. B. Woodward, as Max Weber noticed, “Science is destined to make progress.” Many young chemists grow to become researchers, shaping future science, and we should remember that science is a single entity because it stems from the common laws of nature. Therefore, research must be interdisciplinary, trans-disciplinary, or even anti-disciplinary to create new scientific fields. As all disciplines deal with materials, chemistry links all scientific domains since all materials consist of atoms and molecules. So, I am asking our younger generation to understand that chemistry is the central science. Schroedinger asked in 1944, “What is life?” and Jim Watson, who pioneered molecular biology, responded, “Life is simply a matter of chemistry.” And in this century, many Nobel Prizes in Chemistry recognized research in the interface between chemistry and physics or the life sciences.

2 1. Congratulating Satoshi Omura (right) who was just announced to receive the Nobel Prize in Physiology or Medicine. October, 2015 in Tokyo. 2. Yuan-Tseh Lee (1986 Nobel laureate, left) was conferred the title of RIKEN Honorary Fellow in March, 2011. Together with Mrs. Lee and Ryōji Noyori, President of RIKEN

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3. In his office of the Center for Research and Development Strategy, Japan Science and Technology Agency. In Tokyo, 2015 December 2021 | 93

Therefore, I am not satisfied with the current discipline-based academic system, which I see as a global problem of our time. Our young chemists should radically change their mindset through exposure to other scientific disciplines. In my view, the origin of creativity is highly complex, and discovery, by definition, is difficult to design. Historically, many discoveries came from serendipity and luck. As only a few researchers are outstanding geniuses, there is a need for systematic laboratory work applicable in most fields. Therefore, we must prepare a research environment or ecosystem that will encourage cooperation rather than harsh competition, thereby fostering collective knowledge. The current digital revolution is accelerating this trend. The key to promoting Asian science is to guide our youth toward enhanced collaboration. By nature, Japanese people are very collaborative, but we are affected by the competitiveness we imported from the Western culture. Did you try to promote science in your country and the world? Yes, I am trying to do so. Science is a universal endeavor, but scientists cannot walk alone. Individual knowledge is inseparable from the combined knowledge of all humanity. So, we must encourage multi-disciplinary collaboration to create a peaceful, pleasant world. Moreover, to promote science, we should convince the public that science is highly beneficial, particularly chemistry and its applications. We must explain what we are doing because the tax-payer money supports our endeavor. Also, we need to explain what we know and what we don’t know yet so that everybody has equal expectations. Our intellectual endeavor cannot be categorized. Science pursues the truth of Nature through exploring the unknown, leading to “discovery,” whereas “invention” occurs when technology tries to overcome seemingly impossible goals. Both scientific and technological activities take place within the context of society. Today, science-based technology enriches our lives, contributes to our nation’s security and peaceful sovereignty, and sustains human civilization. Consequently, we must recruit the best minds worldwide to foster scientific and technological development with diverse leadership. Governments of many countries promote science, technology, and innovation (STI) as a source of the nations’ competitiveness, public health, welfare, and the mitigation of natural and unnatural disasters. I would say that innovation is not a mere technological invention but is also the creation of economic or other societal values. Therefore, governments must consistently promote both basic and applied science. Most innovations originate from basic research and significant collaborative efforts. And meeting global and national challenges 94 | December 2021

requires trusted and fruitful conjunction between the research community and other sectors. Without ST-based innovations, we could not have realized the affluent, civilized societies we live in today. Thus, STI is strongly linked with social views and values and is affected by religion, ethics, historical and philosophical aspects, politics, economy, etc. So, to enhance STI, science cannot stand alone but must be adequately merged with national or regional cultural heritage. I would also like to acknowledge industrial collaboration, for it is the industry that eventually transforms our basic knowledge into the social benefit. In this regard, I respect Israel as a leading nation of innovation. The benefits of modern science-based technology are evident from the enhanced food security worldwide, increased life expectancy from 45 to 80 years in just one century, external expansion of human physical abilities, improved quality of Life, and high-speed communication, to name a few. Now we are fast-forwarding to an age of networked society that we have never experienced before, entering soon into an era of super-intelligence. We should be proud of being chemists because chemistry-based materials are everywhere in this modernized society. We have long contributed to, among others, the improvement of health care with the aid of pharmaceutical innovations based on synthetic chemical substances. The contribution of chemistry to STI has already been enormous, but our community must further develop toward creating a peaceful, pleasant world. For instance, synthetic chemists must pursue artificial photosynthesis and element strategy to overcome the resource problem. Here again, intensive interdisciplinary collaboration is needed. We must protect the environment. I have been walking on an avenue of chemical research for over six decades. I have educated chemistry in Kyoto since 1957 and later in Nagoya since 1968. In 2003, I was appointed President of RIKEN, the flagship research institution in Japan, before assuming, six years ago, the current position, Director-General of CRDS (Center of Research and Development Strategy) of JST (Japan Science and Technology Agency). Our institution aims to navigate science and technology policy in our country. Responding to your comments, did you try to make the world a better place? Obviously, “Making the world a better place” is a gigantic goal. However, as a tiny individual chemist, I could have contributed a little toward this direction. And I would ask the young readers of this interview, “Where are you now? Where are you going from here? Is your destiny Utopia or Dystopia?”

Seniors like me are afraid that the combined effects of various complicated social issues since the Industrial Revolution have brought modern civilization to a severe crisis. And it is our responsibility and partly that of the younger generation. motivated by such concerns, the United Nations general assembly in 2015 passed a resolution titled, “The 2030 Agenda for Sustainable Development.” The leading slogan is: “No one should be left behind.” They defined 17 Sustainable Development Goals (SDGs) that rely on the advancement of science and technology. All Asian countries, together with others, must play an active role in striving for these SDGs. We cannot remain passive but must consider this an opportunity for new development and progress. If we do not change our focus now, there can be no tomorrow. Every one of the SDGs represents a mammoth objective that is impossible for any individual researcher to attain alone. Frankly, we did not have the required foresight in our university days, and very few of us seriously considered these problems. I believe that our chemistry science goes beyond mere observation and understanding of Nature. Our science can generate very high values from almost nothing. Synthetic substances and materials determine the quality of our Life. And catalysis is fundamental because it is the only rational, general means to produce essential compounds in a cost-effective, energy-saving, and environmentally benign manner. More than 25 years ago, as a senior chemist, I took the initiative to promote Green Chemistry, which now corresponds to SDG 12 (responsible consumption and production). As an essential aspect of Green Chemistry, we sought catalysis in a safe and harmless medium. We pioneered supercritical CO2 as a medium for catalytic reactions with the beneficial effects of both liquid and gas phases. It is a non-toxic, non-flammable, and very cheap solvent. We can remove it from the reaction mixture without leaving harmful residue. Today, Green Chemistry is an essential component of chemical manufacturing, and it is our responsibility to reduce the amount of undesired waste. In a step-by-step synthesis of any target molecule, each step should proceed with high “atom economy” or “atom efficiency” without leaving hazardous waste. We have developed a clean oxidation reaction using aqueous H2O2 with a tungsten catalyst under organic solvent-free conditions, producing water as the only byproduct. Regarding reduction, catalytic hydrogenation is the ultimate Green Chemistry. We have successfully replaced the most environmentally unfriendly reduction methods with clean catalytic hydrogenation with 100% atom efficiency. Asymmetric hydrogenation is essential because our Life depends on enantiomerically pure chiral molecules. Our www.facs.website

methodology, which employs chiral BINAP/ transition metal catalysts, particularly Ru, represented a breakthrough in asymmetric hydrogenation. The reaction is rapid, very general, and highly productive. These achievements, together with W. S. Knowles and K. B. Sharpless were recognized by the 2001 Nobel Prize in Chemistry. Although the Nobel Prize is the highest honor of any scientist, we need to examine the impact of my achievements on society and the economy. In 19 92, th e US Fo o d a n d D r u g Administration set out guidelines for “racemic switches,” contributing to significant improvements in medicine. The new regulations strongly urged pharmaceutical companies to manufacture and commercialize enantiomerically pure pharmaceuticals. Our contribution to asymmetric catalysis was a crucial contributor to the policy change in the USA. Furthermore, our asymmetric hydrogenation technology with our fruitful cooperation with the industry also contributed to attaining SDG 12, SDG 3 (good health and well-being), SDG 9 (industry, innovation, and infrastructure), and SDG 17 (partnerships for the goals). At the beginning of the 21st century, Sumitomo Chemical has established the Olyset Net technology, acknowledging the SDGs as its corporate concept. Using our asymmetric catalysis concept, Sumitomo’s researchers synthesized permethrin, a new chiral insecticide containing a cyclopropane group, and incorporated it into high-density polyethylene fiber to manufacture Olyset Nets. The new material allows for a slow release of the pyrethroid over five years. Every year, malaria infects 300-500 million people by the Anopheles mosquito, and more than 1 million, mostly children, die of the disease. Sumitomo decided to join forces with the WHO’s “Roll Back Malaria” campaign in Tanzania and provided the Olyset Net technology to Tanzania free of charge, thus creating more than 7000 new jobs and significantly improving school facilities. Related to this is the story on the Sakura Girls Secondary School (SGSS), which opened in 2016, with the support of ODA (Official Development Assistance) and JICA (Japan International Corporation Agency). I highly respect Professor Sumiko Iwao (1935–2018), a central figure establishing this school in Tanzania, not far from Kilimanjaro. Tanzania is still a Male-dominated country, with minimal opportunities for girls. Thus, the school’s main objective is to train women to become teachers, scientists, and technocrats. And teachers from Japan lead the efforts to encourage Tanzanian girls to develop independent careers in science and mathematics and lead their country’s future development. I want to emphasize that I have not contributed personally to achieving the SDGs. The credit should go to the enthusiastic Sumitomo researchers and engineers and the www.asiachem.news

bold decision of its CEO, Hiromasa Yonekura (1937–2018), who was a good friend of mine. He was a visionary manager of the company who also promoted Japanese governmental initiatives worldwide. The hear-warming story of the SGSS has taught me something new and significant on how chemistry may benefit society. How and why did you start exploring asymmetric hydrogenation, which eventually brought you to Stockholm? In 1966 when I was still in Kyoto, we discovered an asymmetric carbene reaction through purely curiosity-driven research. We reacted styrene and ethyl diazoacetate in the presence of chiral Schiff base-Cu catalyst. That experiment represented the birth of asymmetric catalysis using chiral organometallic catalysts, which is quite common these days. Although we achieved less than 10% ee, which is meaningless for synthesis, that experiment was probably the most exciting event in my entire academic career. In 2001, when I received the Wolf Prize together with Henri Kagan and Barry Sharpless, I was delighted and honored that this small discovery was cited as one of the reasons for recognition by the most prestigious prize in Israel. That case teaches me that it is important to recognize the significant achievements of young researchers at their early stage, even if they seem premature or based on stupid ideas. I was 27 years old at the time of my discovery. Immediately after that, I moved to Nagoya and then to Harvard to work under E. J. Corey, so I put aside that exciting chemistry. During my stay at Harvard, Corey asked me to selectively hydrogenate one of the two olefinic bonds in a PGF2α derivative to produce the corresponding PGF1α. That experimental work encouraged me to initiate asymmetric hydrogenation as soon as I returned to Nagoya. Eventually, my 1966 discovery of a primitive asymmetric carbene reaction, which was described in a then overlooked publication, turned out to be a starting point of a long journey from Kyoto to Stockholm. Tadatoshi Aratani, one of the students who worked in the same laboratory in Kyoto in 1966, later joined the Sumitomo Chemical Company, where he developed an excellent chiral Cu catalyst. He established a largescale synthesis of chrysanthemic esters and a building block of cilastatin, an in vivo stabilizer of carbapenem antibiotic produced in the USA by Merck. Such technological development in the 1980s became a logical result of our initial work. Less apparent results are the links to societal implications beyond science and technology, as reflected by SDG 1 (no poverty), SDG 4 (quality education), and SDG 5 (gender equality), in addition to the previously mentioned SDGs 3, 9, 12, and the important SDG 17 (partnerships for the goals).

Noyori has been enchanted by the molecular beauty of chiral BINAPtransition metal catalysts over four decades. My initial discovery half a century ago in a poorly equipped laboratory in Kyoto has taught me that a tiny chemical seed could eventually lead to a significant contribution to the global welfare of all humanity. Consequently, the scientific community and industry, government, and many other sectors should always discuss the societal implications of science and technology and the mechanisms to catalyze these beneficial implications. How would you like to conclude our conversation? I have come to this interview to tell you my own story, and I am just one of many other Asian scientists. Although every one of us looks like a tiny dot on this planet, I can see fine red threads connecting us and all scientific knowledge. In today’s global society, and with the contributions of many countries and diverse social sectors, even small research outcomes may contribute to realizing the SDGs. Therefore, I would like to send a concise message to the young generation, “Think Globally, Act Locally.” Modern civilization appears to face challenging times. And the science community needs to reconfirm the significance of open-science policies to avoid catastrophic consequences. Because science is a longterm, limitless endeavor, we must ensure the solidarity of researchers. Moreover, inter-sector and international collaboration will be critical in accelerating research and development to combat the difficulties we face. Earlier I said, “Science is one.” But now, I would like to say, “The world is one.” The 20th century was an era of international competition, symbolized by war and economic rivalry. In the 21st century, however, we will have to cooperate globally to survive our species within the limits of this planet. Whatever we do, we must do our best to move in this direction. I believe that my views represent many other senior scientists of the Asian region, and I hope you share these values with me. Thank you for inviting me to this important arena of AsiaChem. ◆ December 2021 | 95

A Scientist and A Musician

Tête-à-tête with Eiichi Nakamura

By Ehud Keinan https://doi.org/10.51167/acm00029

Ehud Keinan

96 | December 2021

Eiichi Nakamura is an old friend. We first met in 1977 at Columbia University when he had just started his postdoctoral research with Gilbert Stork, and I was on my way to Madison, Wisconsin, to begin my postdoctoral research with Barry M. Trost. Over the following 44 years, we have had many opportunities to meet in various countries. I have always enjoyed Eiichi’s original science and Baroque flute music. He and his wife Yoko Nakamura visited my family at our home in Israel, and I had a chance to spend time in their beautiful home in Tokyo. Hence, I found it peculiar to conduct a friendly conversation over Zoom. But electronic communication has become an integral part of our life during the Covid19 pandemic. It was a relaxed weekend in late October 2021, early morning in Israel and afternoon in Tokyo. It was as close as possible to a face-to-face meeting, spending a couple of hours together while staying in our home offices. EK: As a science educator, I’ve always been looking for ways to attract the young generation to science. So, I am curious to know what had attracted you to science. I know that you came from a highly educated family, and your father was a mining engineer. Undoubtedly, you had a good start at home, and yet, much of the credit probably goes to your teachers who influenced you in elementary school, junior high, and high school. How early in your life did you decide to become a scientist, and why? EN: First, I’ll tell you the reason why I may not have become a chemist. When I was 20 years old, during my third year in college, I was so interested in studying

railways that I almost decided to study railway history, particularly the British colonial railways. I thought of taking that as a serious hobby while making my living working in a chemical company as an engineer. This plan would not have allowed me to become a university professor. The second reason was my severe injury when I was a fourth-year undergraduate student in Mukaiyama’s lab, just two months after joining him. I had a big explosion of silver perchlorate, and the whole flask exploded in my face. This unfortunate injury could be a good reason to abandon chemistry forever. Nevertheless, somehow these events worked in different ways. www.facs.website

Still, during my entire undergraduate years at the Tokyo Institute of Technology, I was not particularly attracted to chemistry, and I considered working at a chemical company, satisfying my intellectual curiosity by taking railway history as a serious hobby. And that idea was stimulated by my visit to Israel. When I was a first-year M.Sc. student, I was still interested in chemistry and railway history to the same extent. I have realized that the two fields were not orthogonal to one another. For example, fieldwork with railways looked like scientific experiments. So, it was not difficult to switch from railways to chemistry. After the big explosion and severe injury, I thought it would be stupid to give up my chemistry career after suffering so much. So, I decided to study chemistry even more. During the three months in hospital and three months at home, I started reading chemistry books thoroughly, such as Cram’s organic chemistry textbook. EK: I try to understand your early decision as a young person to focus on the history of the railway system, which is not motivated by practical considerations. I remember that you told me about your trip to Israel, working as a technician at the Tnuva company in Tel Aviv. I guess that employment at a food company was not the actual reason for that visit. Was your interest in the British railways the main reason for coming to Israel? EN: Not even that. I was interested in Roman and Greek architecture and art in my teens, and Israel has much of that. For example, there are old churches like the one in Bethlehem built around 300AD, and I wanted to look at these, although I am not Christian. Mr. Shiroki, an art teacher in my junior high school and high school triggered that interest. He fascinated me with stories about Chinese, Roman, Greek, European, Japanese arts, and architecture. I became particularly interested in Greek and Roman architecture and sculpture, which led me to Israel. I stayed in a small apartment next to the old bus station in South Tel Aviv, a walking distance from the ancient city of Jaffa. One day, close to my apartment, I found an old railway station on the Jaffa-Damascus

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line. I was astonished to discover that the distance between the rails was 1050 millimeters, whereas the Japanese railway’s gauge is 1067 millimeters (3 ft 6 in). Soon, I realized that the 1050 gauge is peculiar to the Hejaz Railway systems. I traveled to Israel railway headquarters in Haifa, asking them to show me historical records. I kept in touch with them after the visit, and they sent me copies of plans of steam engines and passenger cars. I published the first research paper in my life, “Israel Railways, History and Status Quo” in July 1972. EK: I see that your primary areas of interest as a young person were railway, ancient architecture, and probably Greek philosophy. But you became a chemist by pure chance. It reminds me of the Robert Frost famous poem “the road not taken.” how come you finally became a chemist? EN: Not by pure chance. There was a background for choosing chemistry, though. My father was a mining engineer, and he was involved with gold mining. There are not many gold mines to find pure, crystalline gold. The Nakaze mine, which is no longer active, about 50 kilometers away from Osaka, was fascinating. I remember the location in the mountains, where everything was covered by deep snow. My father specialized in mineralogy and kept beautiful crystals in many boxes at our home, repeatedly showing them to me. I remember the nice-looking blue crystals of copper sulfate. So, it became natural that I would be interested in chemistry. In those days, the regulations on chemicals were less stringent, and I could buy manganese oxide and hydrogen peroxide and generate oxygen by mixing them. When I did those experiments, I was 10-year-old. I still remember producing hydrogen gas by mixing zinc with acids, and I became very excited when the hydrogen flask exploded in front of me, fortunately with no injury. EK: Well, I remember conducting even more ambitious experiments when I was 14-year-old, preparing gun powder, various improvised explosives, Molotov cocktails,

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and even primitive rockets. Luckily, I didn’t kill myself when initiating these devices in our backyard. Fortunately, current regulations on chemicals forbid this kind of amateur laboratory practice. EN: Well, my primary school teacher even helped me buy chemicals at a local pharmacy. I joined the Komaba Junior and Senior High School attached to Tsukuba University. Komaba, blessed with outstanding teachers, is still considered the top school in Japan. I had an excellent chemistry teacher, Mr. Fukuoka, who formed a chemistry club and taught us chemistry and many other things. We used to go together to the mountains, 3000 meters high in the Japanese Alps. He told us about the clouds and the water cycle, the Alpine flowers, and many other things not included in formal textbooks, including practical skills. For example, since preserved food was not too common those days, he told us to bring thinly sliced pork meat placed between layers of miso, which is fermented soybeans, used as a preservative. Those days, there was no instant dry food, and canned food was too heavy to carry. He also taught us

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many enjoyable things, like singing in the mountains, so everybody wanted to join the chemistry club. Mr. Fukuoka later published a book on the Alpine flowers. EK: It sounds like a dream school. I can hardly think of a teacher in Israel who could have the liberty and talent to conduct such extraordinary programs. From your description, it sounds like the ideal chemistry teacher. EN: Yes, we had several other ideal teachers besides the art and chemistry teachers. We also had an exceptional music teacher featured in a recent movie, “A Scientist and a Musician.” Mr. Tada is the first-generation professional recorder and baroque flute player and the best throughout the 1960s and 70s. He regularly gave public concerts and invited his pupils to attend them. As a result, a few of my classmates eventually became musicians, including the professional harpsichord player Yoshio Watanabe, one of the movie’s heroes. Although I kept playing music in public for nearly 40 years, only now to commemorate our 70th birthday, Watanabe and I played together for the first time. It was recorded in the movie. In junior high school, we had two classes with 40 students in each, and when we continued in the senior high school, 160 students split into four parallel classes. The Komaba school still exists, affiliated with the President Office of Tsukuba University. EK: As a private school that selects its students, I assume it does not need to report to the Japanese Ministry of Education. EN: No, it is a National School under the control of Tsukuba University, which is a State University. The school is like an independent university department. It is not under the control of a municipal government or local educational committee, so the teachers had complete liberty to teach whatever they wanted. It is an autonomous operation, which gained a steady reputation over more than 50 years as the best school.

EK: So, how does the school attract such high-quality teachers? What is the incentive for new teachers? Does the school offer them high salaries or something equivalent? EN: The salaries are comparable with the teachers’ salaries in ordinary schools. The incentive for good teachers has never been money but outstanding students. The school carefully selects the incoming students, which is still the same today. The school is relatively small but has produced a number of leaders of society and academia. The teachers tell the junior high students and parents not to study hard the school subjects, but to find what they are good at. Yet, many of them end up at the University of Tokyo. EK: You have touched upon Japanese cultural issues, and I wish to follow up on that. On many occasions, I had opportunities to discuss Japanese culture and science. Western scientists tend to stereotype Japanese scientists as focused technocrats. Many perceive them as highly efficient but conservative professionals who prefer to narrow down their field of expertise rather than develop a broad perspective. They do not look at other fields or non-scientific disciplines, such as arts, literature, and music, and you don’t fit this stereotype. I remember someone at Columbia University referred to you as “banana,” which means yellow outside and white inside. Do you consider yourself a non-typical Japanese scientist or, perhaps, the stereotype outlined by many Western scientists is inaccurate? EN: My grandparents used to do business in the Japanese territory of Dalian and survived the anarchy in the city after the end of the war. They respected Eiichi Shibusawa, the father of Japan’s modern economy, whose name was given to me by Shibusawa’s grandson. In 1971 when I decided to visit Israel for the summer internship, no one opposed it. It was a year before the Lod Airport massacre. Visiting Britain,

Germany, Italy, France, Greece, Turkey, and Israel at the age of 20 changed my perception of the world. EK: This does not seem to fit the Japanese stereotype. EN: I agree. Professor Mukaiyama was not an average Japanese. When I joined his group as an undergraduate student, he always demanded in every group seminar to come up with a reasonable Arbeitshypothese and a new theory. He impressed me very much with that approach, and so did Prof. Kuwajima, a Mukaiyama student. I am pleased that most of the things I’ve done in my early career align with how Mukaiyama thought about chemistry. For example, during the second year of my graduate studies, I hypothesized that a fluoride anion might attack silyl enol ethers to generate a reactive enolate. I assumed that creating a bond between silicon and fluoride would release much energy to form a reactive enolate anion. I checked this idea, and we published it in JACS in 1975. When Prof. Noyori saw our paper, he was already working along the same line and proposed to Kuwajima to continue this research together. Noyori and Kuwajima have been good friends who worked together in Corey’s lab. So, the collaboration came naturally. I worked with Prof. Noyori for two years on fluoride activation of silicon compounds, reinforcing my conviction that a hypothesis-driven, rational approach is the way to do science. EK: What about modeling molecules and chemical reactions in those early days? EN: In those days, I was not satisfied with the available molecular models such as the Dreiding Model, always trying to find better ways to explain mechanisms. As a graduate student, I participated in several summer schools and had a chance to network with eminent chemists. For example, I spent a week with Hisashi Yamamoto when he was very young and met Donald Cram just at the beginning of his recognition chemistry. He extensively used CPK models to explain the chiral environment of binaphthol and other molecules. I wrote him a letter indicating that molecular models were not helpful in my chemistry studies. But Cram wrote back that CPK models represent reality, telling us exactly what’s happening, and they can predict the outcome of chemical reactions. I still remember his words: “I have considerable faith in CPK models for their predictive power.” EK: So, your frustration with the molecular models had eventually led you to pursue computational chemistry? Did you consider that time studying the complex mechanisms of organocopper and other organometallics reactions? www.facs.website

EN: In the mid-1970s, there were essentially no computers in chemistry. We were still using Bunsen burner to heat things, fractional distillation, and crystallization, and all that we had was a 60 MHz NMR machine in our department. For that reason, people were so impressed by the CPK models and used them to solve chemistry problems. And Cram said that CPK models are the reality. My interest in modeling continued until the late 1980s, when we got a mainframe computer. Although that colossal machine was much slower than today’s iPhone, I immediately jumped into computational chemistry because I was eager to see events that happen in solution. I started collaborating with the late Prof. Keiji Morokuma in 1989, and that work eventually led me to transmission electron microscopy (TEM) in 2004. EK: This story leads me to the next question. You have traveled to many territories in science, including organic synthesis, nanoscience, organic electronics, organometallics, theoretical chemistry, EM, dynamic EM, to name a few. I find it quite unusual for a Japanese scientist who usually focuses on one area of interest for the entire career. What was your motivation to switch from one field to many others? EN: I have not switched the field. I have always stayed in physical organic chemistry but tried to explore new opportunities ahead of people. I’m not interested in synthetic chemistry by itself but getting the desired product in 100% yield suggests that you understand the mechanism pretty well. My main interest in mechanisms has taken me to all territories you’ve mentioned. In the 1970s, I was interested in molecular models, and after the 1990s, I went to computational chemistry. I started it in the late 1980s since Moore’s law predicted that we could study realistic systems in the mid-1990s. Similarly, when I started working on TEM around 2002, collaborating with Prof. Sumio Iijima, I hoped to study molecules at atomic resolution within 10 years. In 2015, we acquired a millisecond camera and the excellent resolution machine that we use now, and the camera was replaced by an even faster one in 2020. When I identify an opportunity, I tend to start preparing the background about five years ahead of others and wait for improved instrumentation and computer science. This way, as soon as the instrumentation and software become available, I can immediately do what I planned to do.

the available knowledge to make something valuable and practical. For example, those who study methodology and reaction mechanisms in synthetic organic chemistry look at basic phenomena. In contrast, those who practice total synthesis exploit the available knowledge to make molecules for various purposes. Where do you place yourself on that spectrum?

Time may soon come that artificial intelligence tells us all what we need. Then we may need to accept it as the reality of chemistry in the years to come. EN: Well, you may correctly put me in the first group because I am interested in fundamental research and mechanisms. However, I feel that I belong to both groups because I want to test my mechanistic hypothesis on something tangible like solar cells and iron catalysis. In line with the UN Sustainable Development Goals (SDGs), we cannot rely forever on precious metals like palladium. In 2004 I coined the term “element strategy”, proposing a research initiative to the Japanese government. In the same year, I started our EM project. The generous funding of $15 million in our ERATO program led me to propose the teamwork of fundamental research and solar cells. We use functionalized carbon nanotubes as substrates to study chemical structures by TEM. But we also employ functionalized C60 for fabricating solar cells. Very recently, we have synthesized tiny blue quantum

dots by self-organization approach. We did TEM video imaging at atomic resolution to precisely identify the whole structure of a single quantum dot. EK: I feel that your fundamental research is much more rewarding and fruitful, even when aiming at practical research goals. I see that your hypothesis-driven study can lead to valuable results, probably more effectively than a trial-and-error search. EN: Correct. Most achievements in the science of quantum dots resulted from the trial-and-error approach. Following empirical observations, people mixed various components making large and small dots with various ligands. That research has never been rational because they didn’t know the actual structure. We can change this practice by using our atomic resolution EM technology. EK: As for the empirical strategy, I remember attending a seminar by a famous Japanese chemist many years ago. He spoke about many successful palladium-catalyzed reactions. At the end of his lecture, I asked him about his efforts to explore the mechanism of the new reaction. He seemed puzzled when he looked at me, as if I was asking a silly question, and responded: “This reaction is very successful, and we get the product in nearly quantitative yield, so why should we waste time studying the mechanism?” EN: I am not surprised by this story, which can fit a significant number of Asian scientists. Asian scientists may continue to be more opportunistic and risk-taking. On the other hand, I feel that the 19th-century European value of “rationality” is dying out these days. Perhaps, we have already stepped into a “post-causality era”, as classical causal reasoning is not functioning anymore in this world of complexity. Time may soon come that artificial intelligence tells us all what we need. Then we may need to accept it as the reality of chemistry in the years to come.

EK: I understand that what I saw as diverse fields are different manifestations of the same general interest in mechanisms. There are two different types of scientists or two extremes of a continuous spectrum: those who try to understand and decipher the clockwork of Nature and those who take advantage of www.asiachem.news

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EK: An interesting theory claims that the main difference between Western and Asian cultures goes back to the fundamental differences between wheat and paddy rice. Wheat-based agriculture involves low yields, is less nutritional, depends on rainfall irrigation and easy labor, and can support only a small population per square kilometer. As a result, Western culture people are more individualist, ideological, aggressive, and opportunistic. In contrast, paddy rice agriculture involves high yields, is more nutritional, intensive, and can support a dense population. It is also labor-intensive, requiring seasonal group efforts, planning, construction, and maintenance. As a result, people of the Asian culture are more socially responsible, pragmatic, tolerant, and flexible. I assume that you value social awareness and social responsibility in light of these ideas. Also, I guess you agree that it is essential to improve the community, promote science teaching, and attract the young generation to choose a career in science and technology. Although these are non-trivial tasks, nobody can do the job better than scientists, certainly better than administrators and politicians. Have you invested efforts in these directions? EN: I have been keen about this issue for a long time and have tried to influence society through research funding and undergraduate education. Together with my colleagues, we transformed our Department Chemistry at the University Tokyo into English teaching, first for graduate students and then undergraduate students. We invite international students to the third year of the undergraduate program to mix with the Japanese students, and we have recently hired Prof. Robert Campbell from the University of Alberta in Canada to be a regular faculty member. We have many non-Japanese junior faculty. Hopefully, what we have done in the past ten years could serve as a model for opening Japanese science education to the world. We are starting to utilize our “molecular movies” to make chemistry more familiar to school kids. EK: The public looks at scientists as people who could help solve problems at national and global levels. In Taiwan, for example, the President and many Ministers regularly consult with top scientists at the Academia Sinica and other universities, not only on scientific issues but almost everything. They trust those professors for their knowledgeable and objective opinions. Similar consultations with the local academy also happen in Isreal, although to a lesser extent. Is something like this happening in Japan? Did you and your colleagues try to help your country and the world with novel ideas and capabilities? EN: Unfortunately, the current Japanese government does not seem to respect scientists very much. In the past, the Prime Minister and cabinet members had communicated 100 | December 2021

much with various scientists when reorganizing the Japanese system. For example, about 20 years ago, Prof. Noyori worked very hard with the Prime Minister. But in the past decade, that tradition has almost gone. I think that the main reason for that is the financial problems of our government. Due to extraordinary social and national security expenditures, they are running out of money. People are aging, and tensions are increasing in the seas around our country.

Perhaps, I am opening up a new era of “cinematic chemistry” for studying and teaching chemistry by using motion pictures at atomic resolution. EK: It’s a global phenomenon that politicians think they are brilliant and know better than others, so they don’t need to consult with anybody. Regardless of their field, all scientists can serve as a think-tank, producing new ideas and participating in brainstorming sessions. And we know that global problems cannot be solved by politicians but by scientists and engineers through international collaboration. How open are the Japanese scientists to international cooperation? EN: I think Japanese scientists are very open to international collaboration. The question is how we define international? I don’t believe that collaboration among European countries is truly international. If we consider only trans-continental and trans-cultural cooperation, Japan is quite international. Of course, there’s a language barrier, and Japanese scientists are very close to each other historically and structurally. Still, we are ready to accept any talented professor and student, and I don’t think there are any barriers. The Japanese system is very open now, and you can see many Chinese professors as faculty in Japanese universities. So, nationality doesn’t matter in Japan. The situation is the same as in Germany, where you need to communicate in German for teaching at the undergraduate level. And research rapidly becomes more international with joint programs with many countries. EK: Let’s talk about your music. I know that music is essential for you, and it is a very significant part of your life. I watched the recent movie “A Scientist and a Musician” which focuses on you and your friend Watanabe and realized that you take music very seriously.

I know very few scientists worldwide who adopted such a “schizophrenic” lifestyle of science and music, and you have done it very successfully. How do you share your attention between the two worlds? EN: Unfortunately, I cannot afford to spend more than 5% of my time on music. Every day I spend at least ten hours on chemistry and only 15 minutes on music. Admittedly, I make many mistakes when playing music, and I’ve never thought I’d become a professional musician. In addition to music, I did oil painting, but this art is very different from music. One needs a story and logical thinking for painting, whereas music is more sensational. Painting requires logic and a plan to convert the 3-dimensional world into a limited 2-dimensional space. Probably because of this complexity, I cannot relax with painting or drawing, but I can relax by playing music. For me, music is like going to the mountains. I can liberate myself and forget about science. I focus only on music when I play my flute, totally forgetting about chemistry. EK: So, where do you place your interest in railroads on that landscape of various hobbies? EN: My interest in the history and technology of railroads has never been complementary to science. It has been an intellectual activity similar to scientific research, and this experience in my college years helped me a lot to do chemistry research later. Music, however, is entirely orthogonal to science unless you really go deep. EK: Although music and science use the emotional and analytical halves of the brain, I can think of several known scientists who were also musicians. Albert Einstein was a violinist. Alexander Borodin was an organic chemist, a cellist, and a composer. JeanMarie Lehn and Gerhard Ertl are talented pianists in our times, and I can add many more names to this list. EN: Many scientists who do intensive intellectual work need relaxation and temporary escape mechanisms, so they go to the arts. But the arts are not one homogeneous domain. There are types of art that are more emotional and others more analytical. Some even require physical capabilities, like playing the piano, which sometimes seems like a sport. EK: Let’s switch to your current science, where you focus all your energy now. The ability to watch molecules in action and see something that people have only imagined is fascinating. It opens new windows to inaccessible areas and may support or disprove many hypotheses on how molecules behave and look. Therefore, it is not too difficult to predict that your dynamic EM technology will result in global recognition. We know that www.facs.website

once a new technology became widely available, like the case of the CRISPR gene-editing, it became so common that many people joined, including practitioners of theoretical, basic, and applied science. Nevertheless, the dynamic EM may remain a scientific niche. You are the obvious pioneer and most active player in the field, but you don’t want to remain lonely there. This situation raises several questions. First, what are the most significant achievements of your EM technology? EN: What have I achieved? I am still wondering. Perhaps, I am opening up a new era of “cinematic chemistry” for studying and teaching chemistry by using motion pictures at atomic resolution. In this broad sense, we are among microscopists working on such instruments as environmental TEM and super-resolution optical microscopy–technologies, however yet to be suitable for molecular-level studies. We started our research in 2004 and reported the first result in 2007 in Science Magazine. We received a wonderful review comment, “The ability to image conformations of individual small molecules is “holy grail” of microscopy, and the authors present a convincing case that they have managed to do so.” Our discovery is an ultimate form of a long-lasting endeavor in seeing minute matters by our eye since Hooke’s Micrographia. EK: How do you encourage others to join the field? EN: This is a rather tricky question. Overall, our work initially created more skepticism than enthusiasm among chemists and electron microscopists. In addition, chemists at the beginning of the 21st century were still happy with cartoons and sculptures of molecules, not interested in “molecular cinemas”. Instead, enthusiastic support came from school kids, laypeople, and scientists in other disciplines. Our most recent videos showing the time-course of “molecular shuttling”, “flat molecule converting to fullerene”, and “emergence of a NaCl crystal” have become a popular subject on Twitter and YouTube. The NaCl paper in JACS was viewed over 20,000

times within a few weeks after publication and has recorded the highest Altmetric score of >900 among all JACS publications. Do you know the fifty-second film showing a steam train coming at some distance? “The Arrival of a Train at La Ciotat Station” by the Lumiere Brothers in 1895. This historic cinematograph opened up “the era of cinema”. When this film was first shown to the public, the legend says the audience was so excited that they jumped out of their seats. After a hundred years, the era of the cinema is just coming to the world of chemistry. EK: And how can you expand, popularize, and democratize your science? Your technology depends on prohibitively expensive infrastructure, which is not affordable to most people. EN: Let’s think about the cost. Take cryo-EM as precedence to our case. Thirty years ago, when cryo-EM was first introduced, EM was a complex instrument to operate, and it was costly. Now it is everywhere. Nowadays, the electron microscopes that we use are available in every major institution, and even an undergraduate can use them after a week of training. We still see some problematic relationships between chemistry and electron microscopy. Chemists are not yet interested in using EM, and electron microscopists believe organic molecules are too unstable. Microscopists are afraid of contamination by the vapor of organic molecules, which is not at all a problem in our 15-year experience. My group has essentially opened the door of EM-imaging to organic chemistry, particularly dynamic imaging of molecular motions and reactions. We demonstrated since 2007 that the observation of the dynamic behavior of single organic molecules in a carbon nanotube and studying it without decomposition is a norm rather than the exception. I say “without decomposition”, meaning that any organic molecules would be stably observed for one to tens of minutes until a carbon nanotube container decomposes. Here, pi-electron-rich molecules

may be slowly converted to something else. This phenomenon may seem like “decomposition” for physicists, but it is not. It is a perfectly rational behavior of such molecules reacting via excited state or radical cation. EM-imaging provides a new opportunity for a single molecule study of such species. You can draw a perfect analogy to a laser spectroscopic study of reactive species, except that we can see the reacting molecules one by one in real space and in real-time. Like any microscopic research, the choice of the substrate that holds the specimen in place is crucial. In scanning probe microscopy, you need to literally immobilize the molecule on a substrate. We have discovered the use of a carbon nanotube as a “test-tube” and a “fishing rod”. We used the tube as a test tube and put the specimen loosely in the interior. Or we installed a “chemical fishhook” on the pointed tip of the fishing rod to capture the specimen. In both cases, the molecules are half fixed, half free to move or to react. You can also use a thin graphene sheet as a “fishing net”. EK: It looks like comparing the motion of a free dog with that of a chained dog. EN: This is a good metaphor. Ideally, we would like to watch the free dog, but that is impossible as the molecules will fly away into the vacuum. Therefore, we chain the dog and watch its movement. There is an additional essential function of our nanotube “fishing rod”. This conductive rod connects the specimen molecule to the TEM instrument, which is grounded. The EM-imaging ionizes the organic specimens to form radical cations like in mass spectrometry experiments. The conductive nanotube supplies an electron to bring the radical cation back to the neutral molecules. The tube, therefore, protects the molecule from uncontrollable reactions, that is, decomposition. We have been working on this mechanism for six years and just finished the study’s first phase under variable temperature/ variable voltage conditions. EK: It is precisely like the grounding technology in electrical engineering.

EN: Yes, grounding sounds like a perfect analogy. Only now, 15 years after our initial discovery, have we come to understand our system and can answer many of the questions raised by the referees of our 2007 Science paper. The carbon nanotube is an active participant rather than an inert bystander. EK: It would be great if more people could join this line of research, which still depends on a $4 million EM machine. What can attract more chemists to join the club? EN: I have a question for you. Why don’t you study individual molecules like biologists studying individual animals and flowers? Chemists may be too accustomed to discuss their business using structural formulae and spectroscopic data. Why shouldn’t they be proud of discussing and teaching chemistry using the movies of molecules in action? Chemistry has been so successfully built on the images of molecules that chemists have probably lost their naive interest in molecular reality. Abstraction is the power of science, but I sense that there is still a lot to learn from molecular reality. Please remember the enthusiasm shown by people worldwide for the NaCl movie. The movie has successfully visualized the chemical reaction that everyone has known since their primary school period. Chemists should share this naive feeling of people because “Scientific breakthroughs often build upon the successful visualization of objects invisible to the human eye”–– citation of the 2017 Nobel Prize for cryo-EM technology. As to the instrument, most research universities already possess the necessary instrumentation in their analytical center. I know that you have excellent EMs at the Technion, so your colleagues can do similar experiments. It is up to you to approach electron microscopists and discuss your chemistry. Many people are already working in this field. The EM technology and infrastructure are rapidly becoming democratic, as once expensive NMR machines have become commonplace. EK: From my perspective as an organic chemist, the turning point will be when the video analysis of single-molecule atomic resolution time-resolved EM (SMART-EM)

Nakamura and Keinan floating on the Dead Sea together, October 2007. 102 | December 2021

crosses the barrier between organic chemistry and physical chemistry. Many will join once this technology becomes relevant to organic chemistry rather than just physical chemistry. I am sure this will happen one day, but how can you accelerate the process? Your work on the crystallization of sodium chloride inside a nanotube renders the technology highly attractive to experimental inorganic chemistry. But the key is the relevance to organic chemists. You know that organic chemists believe that they can do everything. If you show them something valuable that they cannot do, they will become highly interested. EN: Indeed, things are moving fast in that direction. With Dom Lungerich of Yonsei, we have already reported a time-resolved evolution of the conversion of a flat C60H30 molecule to a spherical C60 molecule, where we identified several transient intermediates that other methods could have never identified. We are now finishing work on the aggregation behavior of daptomycin, a cyclic peptide that is effective against many drug-resistant bacteria. Using our SMART-EM, we could determine the structure of the products of their calcium-mediated aggregates at atomic resolution. We installed a fishhook using Jeff Bode’s KAT ligation method. Our approach is the only way to obtain atomistic structural information on small and medium-size peptides or their aggregates, none of which is crystallize. Other people do in-silico studies of daptomycin aggregation, and we can provide them with the actual structure as a realistic reference point for their computations. We provide them with the reality for their molecular dynamics study. Altogether, we are getting closer to organic chemistry. We have started a collaboration project with Yoram Cohen of Tel Aviv University, studying the supramolecular chemistry of pillararenes. Another study focuses on the aggregation of amyloid-beta model compounds together with James Nowick of UC Irvine. With Tobin Marks of Nortwestern, we are uncovering new reaction intermediates in heterogeneous Mo catalysis, and, with Toray people, intermediates in the formation on carbon fibers. And for inorganic chemistry, we see various polymorphs of inorganic solids at a nanometer scale. We can see them as crystal nuclei and how they go from one polymorph to another. We can even study the relative stability of the polymorphs. Polymorphism has always been a fundamental phenomenon in science, but people could only study big crystals, averaged over many atoms. We can now see atom by atom in the initial stages of crystallization and start understanding polymorphs formation. EK: The new applications of the EM technology are indeed mind boggling, and I am sure we’ll see many people joining this technology soon. I wish to conclude our conversation by going back to the movie “A Scientist and A Musician.” In one episode, you offer advice to

the young generation: “Doing just what you like is wrong. It would be best if you did what you could. Find something that you like and can do and do it thoroughly.” Would you please explain what did you mean? EN: In the Japanese culture these days, and probably everywhere, most parents encourage their kids to do whatever they enjoy, and I find it wrong. I would better advise kids to find out what they can do best and then go for it. Kids may be very interested in something but cannot meet the requirements. For example, I may like baseball very much, but my body is too fragile to make a good baseball player. I wish I were Shohei Otani. EK: In many cases, kids like what works for them at best, so the two issues eventually merge. If kids do something right and gain much satisfaction and external appreciation, they ultimately like what they do. So, being driven by what one wants and can do becomes the same thing. EN: This is correct, and happy people succeed in doing what they like. But you need a certain level of human competence. Problems arise when people are interested in things they cannot accomplish. A temporary attraction to something unrealistic provides some short-living indulgence and transient satisfaction. But the following day, the kid may want something else. In contrast, if they try to find out what they can do best, they can develop a successful, enduring career. I like music, but I know my limitations and abilities. However, my music progresses still at this age, as chemistry does the same. ◆ Opposite Page: 1. “The whale club” welcomed Ehud Keinan, March 26, 2004. From front left: Toshikazu Hirao, Masaaki Suzuki, Ehud Keinan, Tsutomu Katsuki, Koichiro Oshima. From back left: Eiichi Nakamura, Hisao Nishiyama, Ilhyong Ryu, Tamio Hayashi, Takao Ikariya. 2. In the TEM room in December 2020. ©MONTAGE. INC. 2021 3. Eiichi and Yoko Nakamura with the Keinan family, Bethlehem of Galilee, Israel, January 4, 2003. 4. Watching a quantum dot. ©MONTAGE. INC. 2021 5. Playing the baroque flute in Keinan’s home, Timrat, Israel, January 2003. 6. Nakamura with Gilbert Stork, Tateshina Meeting, November 2003, 7. Nakamura with Keinan, Jiro Tsuji, Henry Kagan, and Keiji Yamamoto at the front gate of Tokyo Institute of Technology, July 1985. 8. Nakamura with John D. Roberts at the Tateshina Meeting, November 2003.

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A History of Chemistry in Japan 1820-1955 Yoshiyuki Kikuchi

Yoshiyuki Kikuchi is an associate professor at the Department of British and American Studies, School of Foreign Studies, Aichi Prefectural University in Nagakute, Japan. Kikuchi obtained his PhD in History of Science, Technology and Medicine (2006) from the Open University, Milton Keynes, UK and did postdoctoral research at the Chemical Heritage Foundation (today’s Science History Institute) (2008-9), Massachusetts Institute of Technology (2009-2011), Harvard University (20112012) and the International Institute for Asian Studies, Leiden (2012-2013). He taught at the Graduate University for Advanced Studies (Sokendai), Hayama (2013-2016) and Nagoya University of Economics, Inuyama (2017-2020) before taking up the current position. Kikuchi’s research focuses on the history of modern chemistry, especially physical chemistry, and AngloJapanese scholarly relations in scientific and technical fields. He is currently vicepresident of the Japanese Society for the History of Chemistry and vice-chair of the Commission on the History of Chemistry and Molecular Sciences, IUHPST/DHST.

104 | December 2021

Yona Siderer

Senior Researcher, Edelstein Center for the History and Philosophy of Science, Technology and Medicine, the Hebrew University of Jerusalem, Israel. sideryon@ netvision.net.il Dr. Siderer was a recipient of a fellowship in Chemistry and Chemical Engineering from UNESCO and the Japanese Government. Holding Japanese fellowships she returned to Tokyo Institute of Technology (2008), and to Nichibunken, International Research Center for Japanese Studies in Kyoto (2009-2010) to study the history of chemistry in Japan. Dr. Siderer holds B.Sc. and M.Sc. in physical chemistry from the Hebrew University of Jerusalem; Ph.D. from the Weizmann Institute of Science and MBA from Tel Aviv University. She was a researcher in Israel, Japan, USA, Italy and England; studied Japanese in Japan and in Israel. Dr. Siderer published poetry books in Hebrew and English and poems in Japanese; presented her paintings in exhibitions in 1993, 2003, 2019. Former Head of the Israel-Japan Friendship Society; a member of the Israeli and the European Associations for Japanese Studies, and the Japanese Society for the History of Chemistry.

THE HISTORY OF chemistry in Japan is a chronicle of how Japanese learned Western chemistry and contributed to its further development.2 The Meiji Restoration in 1868 is often credited as the starting point of Japan’s introduction to Western science. In fact, Japanese encounter with chemistry started earlier, in the early nineteenth century during the Tokugawa period (1603-1868). Medical doctors took the lead in the reception of chemistry because of their interest in the medicinal properties of chemicals. The development of manufacturing and military industries such as mining and smelting, pottery, brewing, dyeing, photography, and gunpowder manufacturing further stimulated Japanese interest in chemistry. Historical developments of chemistry in Japan thus reflected the process of Japanese modernization and industrialization that eventually led to its prosperity in the twentieth century.3

Translations and Chemistry in Tokugawa Japan

In most of the Tokugawa period, the only Western country with which Japan had trade relationships was the Netherlands.4 Foreign traders were required to live in Dejima, an artificial fan-shaped island on the Nagasaki Bay. Overseas travel of common Japanese was strictly forbidden. For those reasons, until the mid-nineteenth century Japanese intellectuals studied Western science through translating Dutch books, hence the term “Dutch learning” (rangaku) for Western scholarship practiced in Tokugawa Japan.5 Pioneers in Dutch learning were mainly medical doctors by profession. The two most famous of them, Maeno Ryōtaku 前野良澤

(1723-1803) and Sugita Genpaku 杉田玄白 (1733-1817), were both physicians serving daimyos (feudal lords). They translated a Dutch illustrated book of anatomy, itself a translation from German, and published it as the Kaitai shinsho (“New book on anatomy”) in 1774.6 Medical doctors practicing Dutch learning started to pay attention to chemistry in the 1820s, copying and translating textbooks of chemistry as well as chapters on chemistry in pharmacopoeia in Dutch into Japanese. The culmination of this trend was the publication between 1837 and 1847 of the massive 21-volume Seimi kaisō (“Introduction to chemistry”) by Udagawa Yōan 宇田川榕菴 (1798-1846).

Udagawa Yōan: The Creator of Chemical Nomenclature in Japanese

Udagawa was a talented scholar who touched many topics during his lifetime. His work might be divided into three main categories: 1. Botany, 2. Chemistry, 3. Variety of other topics. He was a medical doctor serving the daimyo of the Tsuyama Domain in today’s Okayama Prefecture.7 In his youth, Udagawa studied Chinese Classics in the house of his teacher and adoptive father, Genshin. In 1826 Udagawa joined the translation office of the Tokugawa Shogunate, Bansho Wage Goyō that was established in 1811. He could choose appropriate Chinese-Japanese characters to transfer the meaning of words from Dutch to Japanese. For the new ideas in chemistry, he tried to choose characters that would not have the connotation of, and would distinguish the terms from, Confucian thought on nature. Udagawa studied foreign languages, first www.facs.website

Courtesy of the National Diet Library, Tokyo, Japan

By Yoshiyuki Kikuchi and Yona Siderer1 https://doi.org/10.51167/acm00030

Dutch, to some level German, even Latin and Greek, English, Russian, and copied a list of Arabic letters.

constituents of plants. He studied the ingredients of water in hot springs in Japan and described chemical ingredients of hot springs in foreign countries.8 He cited fifty-eight elements, and five of them were found to be mistakes, among which are caloric and light.9 The chemistry studies that Udagawa started continued after him, and some of the chemistry terms that he coined are still in use today.10 Where did those foreign books come from? A thorough survey in archives was carried

Figure 1. Udagawa Yōan. Courtesy of the Kyō-U Library, Takeda Science Foundation

Published from 1837 to 1847, Udagawa Yōan’s Seimi kaisō is considered the first extensive book on chemistry in Japan. It includes seven books; each is divided into three volumes and numbered chapters. Six books are considered inner, main text; the seventh book is called an external book. Altogether it has more than 1100 pages, printed in kanji and katakana, including drawings of tools for chemical experiments (see the drawings above). In Seimi kaiso, Udagawa dealt with topics such as chemical affinity, solution, caloric, alkali, salts, phosphoric acid, ammonia, oxidation and reductions of metals, glass, and www.asiachem.news

Figure 2. Title Page of Seimi kaisō, Book 1, First volume. Courtesy of the National Diet Library

out by J. MacLean, searching for the years 1712-1854. He studied the records of the Dutch Factory in Japan, preserved in the Rijksarchief (State Archive) in The Hague. MacLean listed the year that a ship arrived in Japan, its name, its captain’s name, and the scientific instruments and books that were imported;11 Udagawa Yōan might have had access to some of those books and instruments. Seimi kaisō is based on more than 24 chemistry books from Europe of the late eighteenth and early nineteenth centuries, including William Henry (1774-1836), A. L. Lavoisier (1743-1794), and Adolph Ypey (1749-1822).12 A partial list of authors that Yōan mentions in the first book of Seimi kaisō includes: P. J. Kasteleyn, (1746-1794), J. F. Blumenbach, (1752-1840), J.J Plenck, (1735–1807) G. Niewenhuis, L. B. Guiton de Morveau (17371816), J.B. Trommsdorff, (1770-1837), O. Ségur (1779-1818), Dutch Pharmacopeaia 1826, and Catz Smallenburg. Udagawa studied other contemporary European authors who were cited in the books that he had, e.g., Berzelius (1779-1848), Davy (1778-1829), Dulong (17851838), Gay-Lussac (1778-1850) and others.13 He actually considered and chose which text and authors to cite. In 1975 Udagawa Yōan’s Seimi kaisō was translated into modern Japanese with translators’ commentaries. The translation is written in kanji, hiragana, and katakana. The editor who contributed a preface is Tanaka Minoru, and five Japanese scholars joined in this important project.14 In 2014 Endō Shōji and his colleagues published Studies on Udagawa Yōan’s Botanical Works housed in the Kyō-U Library, Takeda Science Foundation.15 These December 2021 | 105

two research books are excellent sources for further research of Udagawa Yōan. Udagawa’s successful pioneering of chemistry translation and terminology served as a milestone on the road towards Japanese modernization.

Seimi or kagaku? Chemistry in Tokugawa Japan after Udagawa

As discussed above, Udagawa Yōan coined a variety of chemical terms still used today, but arguably the most important of his coinage eventually became obsolete: seimi 舎密, meaning chemistry, included in the title of his opus magnum.16 It was the transliteration of a Dutch word for chemistry, chemie, and was widely used as such until the early Meiji period. Another term for chemistry, kagaku 化學 (“the study of change”) was first used in Japan by Kawamoto Kōmin 川本幸民 (1810-71). Being aware of the emergence of a Chinese term for chemistry, huaxue 化學, in the 1850s, Kawamoto adopted the Japanese reading of huaxue, kagaku, as part of the title of his chemistry books. The most well-known of Kawamoto’s works, Kagaku shinsho (“A new book of chemistry,” 1861) is a Japanese translation from the Dutch translation of Die Schule der Chemie (1846) by Julius Adolph Stöckhardt (1809-86). Through Kagaku shinsho he updated Japanese chemistry by transmitting Dalton’s chemical atomism with the stoichiometric concept of atomic weights and equivalents and the electrochemical dualism of Berzelius. The fact that Kawamoto worked at the Tokugawa Shogunate’s Bansho Shirabesho (“Institute for the Study of Barbarian Books”) from its establishment in 1856 was an important factor in kagaku becoming the current Japanese term for chemistry. That did not happen overnight. When a section of the Bansho Shirabesho devoted to chemistry was established in 1860, it was named the Seiren kata (“Department of Refining”). The Seiren kata assumed the new name Kagaku kata (“Department of Chemistry”) in 1865, indicating that kagaku established itself as the term for chemistry in this institution around this year. The Bansho Shirabesho (renamed the Yōsho Shirabesho in 1860 and Kaiseijo in 1865) was one of the antecedent schools of Tokyo University, established in 1877,17 and Tokyo Imperial University, established in 1886.18 Former professors and students at the Kaiseijo dominated Japanese education mostly as university administrators and education officials in the early Meiji period, ensuring that kagaku became a wide-spread translation for chemistry by the mid-Meiji period. Kawamoto was also a good example of how Western chemistry got related to Japanese industrialization in the 1850s and 1860s.19 His first chemical work, Heika sudoku seimi shingen (“A true foundation of chemistry that military officers should read”) in 1856, was translated from the Dutch translation of Moritz 106 | December 2021

Meyer’s Grundzüge der Militair-Chemie (1834) with a strong emphasis on combustion and gunpowder and was widely used in Japan as a textbook of chemistry for training in Westernstyle artillery. Kawamoto was also involved with the production of matches, beer, telegraphs, and photographs with his extensive knowledge of chemistry and physics. By the 1860s Western chemistry became an essential part of the Japanese endeavor for industrialization for both military and peaceful purposes.

Institutionalization of Higher Chemical Education in Meiji Japan

Western-style higher education in science and technology, chemistry not the least, was fully established in the Meiji period between 1868 and 1912. As we discussed above in the case of Kawamoto and kagaku, there were connections between the pre-Meiji Kaiseijo and Tokyo Imperial University, the pillar of early Meiji higher education. The same applies to the Igakusho (“The Medical Institute”), another antecedent school of Tokyo Imperial University. However, there were also discontinuities as the scientific and technical education and research at Tokyo University and other institutions created in the Meiji period were undertaken by foreign professors (who taught in Western languages, usually their mother tongues) and their Japanese students.20,21 Four institutions, all established in the 1870s, were particularly important for the development of Japanese chemistry and eventually converged into Tokyo Imperial University in the 1880s and early 1890s. 1) The Faculty of Medicine at Tokyo University (successor institution of the Igakusho and Tokyo Medical School) became the College of Medicine at Tokyo Imperial University in 1886, including a Department of Pharmacy and a chair in medical chemistry. Chemistry was taught there first by the German, Alexander Langgaard (1847-1917), and later by the Dutch Johan Frederik Eijkman (1851-1915).22 2) The Faculty of Science at Tokyo University (successor institution of the Kaiseijo and Tokyo Kaisei School) became the College of Science at Tokyo, including the Department of Chemistry. Chemistry was taught there by the British, Robert William Atkinson (1850-1929), the German Georg Hermann Ritter (1827-74), and Frank Fanning Jewett (1844-1926) from the United States. 3) The Imperial College of Engineering, Tokyo, became the core of the College of Engineering, including the Department of Applied Chemistry. Chemistry was taught by the British chemist Edward Divers (1837-1912) who later became professor at the College of Science, Tokyo Imperial University. 4) The Komaba Agricultural School (renamed the Tokyo Agricultural and Forestry School in 1886 by merger with the Tokyo Forestry School) became Tokyo’s College of Agriculture in 1890, including a Department of Agricultural

Chemistry. Chemistry was taught at Komaba first by the British chemist Edward Kinch (18481920) and later by the German, Oskar Kellner (1851-1911). These four institutions produced the first generation of Japanese chemists who established the first chemical society in Japan, the Tokyo Kagakukai or Tokyo Chemical Society in 1878.23 It was renamed the Chemical Society of Japan in 1921 and has become the national society for chemistry in Japan. The second imperial university, Kyoto Imperial University, was established in 1897, followed by Tohoku (est. 1907), Kyushu (est. 1911), Hokkaido (est. 1918), 24 Keijō (est. 1924 in today’s Seoul, Republic of Korea), Taihoku (est. 1928 in today’s Taipei, Republic of China), Osaka (est. 1931), and Nagoya (est. 1939). These nine imperial universities (seven inland and two colonial) and their successor institutions were major, if not the only, players in the history of science in Japan (and in Korea and Taiwan) in the pre-World-War-II and later periods.

Meiji Japan’s Practical Chemists in Pharmacy, Industry and Agriculture

Figure 3: Nagai Nagayoshi. Courtesy of the Ochanomizu University History Museum

As chemistry became an essential part of Japanese industrialization, it is unsurprising that a large number of young talents were drawn to the practical fields of chemistry such as pharmaceutical, industrial and agricultural chemistry. Nagai Nagayoshi 長井長義 (18441929), for example, was a pioneering Japanese organic chemist with strong interests in pharmacy. Originally from the Awa Domain in today’s Tokushima Prefecture, he was trained first with Dutch medical doctors in Nagasaki and then attended the Tokyo Medical School for a short period. Nagai was then sent to Germany for overseas study and studied organic chemistry at the University of Berlin www.facs.website

with August Wilhelm von Hofmann (1818-92) between 1870 and 1884. Back in Japan, Nagai taught at the Department of Pharmacy, College of Medicine, Tokyo Imperial University and made great contributions to pharmaceutical chemistry both by his research (the most important of which was the isolation of ephedrine, the active ingredient of drugs for asthma, from the Chinese herbal medicine Ephedra vulgaris) and his involvement with the Pharmaceutical Society of Japan (established in 1880) as its long-term president and a couple of pharmaceutical companies as a technical advisor. In his later life Nagai technically supported indigo dye manufacturers in his native Tokushima Prefecture.25 Takamine Jōkichi 高峰譲吉 (1854-1922) was an industrial chemist trained with Edward Divers at the Imperial College of Engineering, Tokyo. After working as an engineer at the Ministry of Agriculture and Commerce, Takamine established the Tokyo Artificial Fertilizer Company and then moved to the United States to establish an independent industrial laboratory. In the United States Takamine first undertook the project of applying Japanese brewing techniques to whiskey brewing and to the development of digestive enzyme marketed as “Taka Diastase.” He is best-known internationally for the crystallization with Uenaka Keizō 上中啓三 (1876-1960), a student of Nagai, and commercialization of adrenaline, a hormone used as a hemostatic and cardiotonic agent.26

Figure 4: Takamine Jōkichi Courtesy of the Science History Institute, Philadelphia

Takamatsu Toyokichi 高松豊吉 (1852-1937) and Nakazawa Iwata 中澤岩太(1858-1943), two alumni of Tokyo University and former students of Atkinson, contributed to the establishment of applied chemistry teaching at the College of Engineering, Tokyo Imperial University.27 After graduation from Tokyo University, Takamatsu studied with chemists Henry Enfield Roscoe www.asiachem.news

(1833-1915)28 and Carl Schorlemmer (183492), and chemical technologist Watson Smith (1845-1920) at Owens College Manchester (today’s University of Manchester) and with Hofmann at the University of Berlin. Nakazawa used his time abroad mainly inspecting various chemical factories in Germany to observe the actual working of the chemical industry. For Tokyo’s Department of Applied Chemistry, Takamatsu and Nakazawa blended chemical and practical machine-operating components to design a curriculum suited to the training of chemical technologists much needed in the Meiji period. They also gave technical advice to government and private chemical companies in their respective specialties of applied organic chemistry (especially dyeing and dye manufacturing) and inorganic chemistry (especially alkali-acid manufacture and pottery). Suzuki Umetarō 鈴木梅太郎 (1874-19 43) belonged to a later generation of Japanese chemists. He was trained at the College of Agriculture, Tokyo Imperial University with Kozai Yoshinao 古在由直 (1864-1934), Kellner’s student in agricultural chemistry. Kozai became well known for his analysis of soil from rice paddies contaminated by copper-containing streams from nearby Ashio copper mines in Tochigi Prefecture, which caused serious damage to agriculture and fishery.29 After overseas study with Emil Fischer (1852-1919) at the University of Berlin in 1903-1906, Suzuki was appointed full professor at his alma mater and published in 1911 his discovery of what he called oryzanin (today’s Vitamin B) from rice bran, the deficiency of which caused beriberi, a life-threatening disease that especially plagued the Imperial Japanese Army. Suzuki thereafter successfully undertook other practical research projects such as extracting vitamins and other nutrients from natural products and the synthesis of sake, a Japanese alcoholic beverage, mainly at RIKEN, the Institute of Physical and Chemical Research established in 1917 (cf. the next section on Sakurai).30 The above paragraphs described only part of many early Japanese contributions to applied chemistry broadly construed. That being said, Japanese chemistry is not all about applied chemistry, and there were also important developments in pure chemistry, or the ideal of chemical research for its own sake, in Japan. Together with Divers, Sakurai Jōji 櫻井錠二 (1858-1939) was responsible for nurturing the idea of pure chemistry in Japan as one of the founding professors of the Department of Chemistry at the College of Science, Tokyo Imperial University.

Sakurai Jōji: Pioneer in Pure Chemistry, Scientific Diplomat, and Institution Builder

Sakurai studied at the Tokyo Kaisei School and its antecedents between 1871 and 1876.31 As one of his chemistry teachers was Atkinson, a student of Alexander William Williamson

(1824-1904) at University College London (UCL), it is natural that Sakurai chose to do overseas study at UCL with Williamson. This choice had a tremendous impact on Sakurai’s character formation as a scholar. First, under the influence of Williamson, Sakurai came to believe that pure science should be at the core of university curricula. According to Williamson, education in pure science would discipline students’ minds and hands through the systematic learning of theoretical principles and by laboratory training. He further argued that these trainings in pure science would provide a sound basis for subsequent employment in a wide variety of science-related fields such as pharmacy, medicine, agriculture, metallurgy, manufacturing and teaching.32 It is important to note that Williamson and Sakurai’s idea of “pure” science was not detached from the concern of their colleagues in “practical” chemistry outlined in the previous section. It was more about the role of university education and what should be taught there.

Figure 5. Sakurai Jōji. Courtesy of the Ishikawa Prefectural Museum of History

Second, in starting his career as a “pure” chemist as the founding professor of the Department of Chemistry at the College of Science, Tokyo Imperial University, he chose organic chemistry and the emerging field of physical chemistry as his specialties and promoted physics and mathematics in departmental teaching. Williamson’s own penchant for chemical theories and physical chemistry such as the three-dimensional imaging of molecules, reaction mechanism and thermochemistry revealed itself in his research on Williamson ether synthesis and was reflected in Sakurai’s research interests as well.33 Sakurai’s research outputs include the modification of Beckmann’s method of measuring molecular weights by the rise in boiling points of solutions and the structural investigation of glycine December 2021 | 107

(glycocol) by means of measuring its electric conductivity, both falling within the realms of organic and physical chemistry.34 Amid his busy student life at UCL, Sakurai also enjoyed a cultural life in London, visiting his friends there, reading Victorian novels and poetry, watching Shakespeare’s plays, and visiting parliamentary debates. He thereby gained near-native fluency in English and a strong command of French and German and underwent a process of indoctrination into British and more general Western culture, thereby laying the foundation of his later career as a “scientific diplomat.” Sakurai frequently became a Japanese representative attending international conferences and participating in the management of international organizations in the twentieth century. For example, he served the International Union of Pure and Applied Chemistry (IUPAC), established in 1919, as a vice-president twice, first in 1923-25 and again in 1928-30.35 It signifies Japan’s surprisingly early entry to international chemistry, and his “diplomacy” played a crucial role in it. The discussion of Sakurai’s life would not be complete without mentioning his outstanding roles as an “institution builder.” Scarcity of research opportunities for his students had been a major issue for him since he was appointed professor at Tokyo in the 1880s, and the outbreak of World War I gave him a once-in-a-lifetime opportunity (“a blessing from heaven” according to him) to realize his long-cherished wish to promote scientific research in Japan. Building on Takamine’s pioneering activities toward the establishment of a “Nation’s Scientific Research Institute” in 1913, Sakurai collaborated with Takamine, Takamatsu and entrepreneur Shibusawa Eiichi 澁澤榮一(1840-1931) to tirelessly advance this cause and became the foremost institution builder for Japanese science between the 1910s and 1930s, creating scientific research organizations such as RIKEN (Rikagaku Kenkyūsho, the Institute of Physical and Chemical Research established in 1917) and GAKUSHIN (Nihon Gakujutsu Shinkōkai, Japan Society for the Promotion of Science established in 1932).36 These research institutes and funding bodies immensely benefited the following generations of Japanese chemists, including his own students.

Pure Chemists from Tokyo’s Department of Chemistry and their Students

Tokyo’s Department of Chemistry under the leadership of Divers and Sakurai produced a sizeable number of pure chemists. Here we introduce only some of the most important students from there, namely: Ikeda Kikunae 池田菊苗 (1864-1936), Katayama Masao 片山正夫 (1877-1961), Ogawa Masataka 小川正孝 (1865-1930), and Majima Rikō 眞島利行 (1874-1962).37 108 | December 2021

Ikeda started his career as a physical chemist. He first studied with Sakurai at Tokyo’s Department’s Chemistry and later did an overseas study under Wilhelm Ostwald (18531932) at the University of Leipzig between 1899 and 1901. Upon returning to Japan, he became full professor at his alma mater and held this position until 1923. Ikeda was also appointed head of the chemistry section of RIKEN when it was established in 1917 and was one of its chief researchers in 1923-1932.

Figure 6: Ikeda Kikunae. In: Ikeda Kikunae hakushi tsuiokuroku (Tokyo, 1956)

Ikeda’s research topics in physical chemistry would be broadly categorized into chemical kinetics (including catalysts) and the theory of solutions,38 and he was also an active proselytizer for Ostwald’s energetics, especially in the educational and philosophical circles in Japan.39 Today, however, Ikeda is well known internationally first and foremost as the inventor of the flavor enhancer, l-monosodium glutamate marketed as Ajinomoto and the originator of the umami concept in the science of taste.40 Just like his mentor Ostwald, who invented his namesake process to turn ammonia into nitric acid, Ikeda is the kind of chemists moving flexibly between pure and applied chemistry. The most important student of Ikeda in physical chemistry was Sameshima Jitsusaburō 鮫島實三郎 (1890-1973).41 Graduated from Tokyo’s Department of Chemistry in 1914, he originally tackled the research topic of the vapor pressure of binary mixture of solutions under Ikeda’s guidance. During overseas study in 1917-21, Sameshima worked with Theodore W. Richards (1868-1928) at Harvard University, Frederick G. Donnan (1870-1956) at UCL, and Heike Kamerlingh-Onnes (1853-1926) at Leiden University. He was then appointed assistant professor at the Department of Chemistry, Faculty of Science, Tohoku Imperial University in 1922. He succeeded Ikeda as

professor of physical chemistry at Tokyo’s Department of Chemistry in 1925 and stayed in this office until his retirement in 1951. Publishing the well-received textbook, Butsuri kagaku jikken hō (“Experimental Methods in Physical Chemistry”) in 1927, Sameshima was a superb experimentalist and worked broadly on the study of physical properties of materials (called bussei kenkyū in Japanese), especially in colloid and surface chemistry. His research was centered on gas absorption by porous materials such as charcoal and dehydrated zeolite, which impacted colloid chemist James William McBain (18821953) in formulating the concept of “molecular sieve,” and the dynamic phenomena of colloids such as the formation of monomolecular film, viscosity, lubricity, and foamability which made him a Japanese pioneer in rheology. Sameshima was succeeded by one of his students, Akamatsu Hideo 赤松秀雄 (191088) who published an important research in Nature on the electric conductivities of polycyclic aromatic hydrocarbons with his student, Inokuchi Hiroo 井口洋夫 (1927-2014) in 1954 that led to the concept of “organic semiconductor.”42 Katayama was another chemistry student at Tokyo who chose physical chemistry as his specialty under Sakurai’s influence.43 Graduated from the Department of Chemistry at Tokyo in 1900, Katayama studied overseas at the University of Zurich with Richard Lorenz (1863-1929) and at the University of Berlin, Germany, with Walter Nernst (1864-1941) and Max Bodenstein (1871-1942) between 1905 and 1909. He was appointed the first professor of physical chemistry at the newly established Tohoku Imperial University in Sendai in 1911, succeeded Sakurai as the professor of physical chemistry at Tokyo in 1919 and stayed in this office until his retirement in 1938 with an extra position as chief researcher at RIKEN. Following Sakurai’s pro-atomistic view, Katayama positively adopted atomism as a working hypothesis and published an influential textbook of physical chemistry based on chemical thermodynamics in Japanese, Kagaku honron (“Fundamentals of Chemistry”) in 1914. Like Sameshima, Katayama specialized in surface and colloid chemistry but chose to do theoretical investigations based on his molecular interpretation of thermodynamics and the quantum theory. His most important research outcome was “Katayama’s equation” published in 1916, an equation describing the relationship between the surface tension and temperature of liquids. Katayama trained quite a few Japanese physical chemists who became internationally known in a variety of fields like colloids, catalysts, and molecular structures. Mizushima San-ichirō 水島三一郎 (1899-1983), for example, first undertook research, while working with Katayama at Tokyo as a student, on the dispersion of radio waves by glycerin www.facs.website

and monovalent alcohols to give experimental proofs to the polar molecular theory of organic substances postulated by Dutch physicist Peter Debye (1884-1966).44 With his student-day research recognized, Mizushima was appointed assistant professor at Tokyo’s Department of Chemistry in 1927 and then traveled to Europe to work at the University of Leipzig with Debye himself in 1929-31. While in Germany he learned quantum mechanics firsthand from Debye and became one of the first Japanese chemists who introduced quantum mechanics to Japan in the 1930s.45 Upon returning to Tokyo Imperial University, Mizushima started with his student, Morino Yonezō 森野米三 (1908-95), a path-breaking research in conformational analysis, coining around 1940 the “gauche” form for a conformation where two vicinal groups are separated by a 60-degree torsion angle. This research was made possible by Mizushima’s additional post from 1934 as chief researcher at RIKEN and his promotion to full professorship in 1938 as the successor of Katayama. His “gauche” research garnered him an international reputation and brought him a scholarly network with first-class colleagues in physical chemistry such as the two-time Nobel laureate Linus Pauling (1901-1994). Mizushima’s work as a bureau member of the IUPAC in 195567 would not have been possible without his growing reputation and international network. One of Mizushima’s students, Nagakura Saburō 長倉三郎 (1920-2020) developed the intermolecular charge-transfer theory of chemical reactions postulated by his American teacher, Robert S. Mulliken (1896-1986), starting with the publication of two papers in the Journal of Chemical Physics and the Journal of the American Chemical Society in 1955. Nagakura became a leading figure in postwar Japanese physical chemistry together with Akamatsu, Inokuchi, Morino, and Fukui Kenichi (cf. the section on the Kyoto school and the first Japanese Nobel Laureate in Chemistry below).46 Ogawa Masataka was first trained as an inorganic chemist and honed his analytical skills with Divers at Tokyo.47 Ogawa then studied overseas in 1904-1906 with William Ramsay (1852-1916) at UCL and encountered his life-long research project on a new element by means of analyzing the newfound mineral, thorianite. After getting back to Japan, he continued the same project with another mineral, molybdenite, and announced the discovery of element 43, naming “Nipponium” (Np) in 1908 after the name of his country, Nippon 日本. Ogawa was appointed professor at the Tohoku Imperial University in 1911, and his assistants and students there worked on the Nipponium project, though without success in reproducing Ogawa’s result. The discovery of element 43, later named technetium (Tc), in 1937 meant that Ogawa’s research was in the wrong. Recent reassessments of Ogawa’s www.asiachem.news

work by chemist historian Yoshihara Kenji, however, claimed that Ogawa did discover a new element but that it was not the 43rd element as he had claimed but the 75th element, today’s rhenium (Rh). He is now considered in Japan as a great pioneer in searching new elements in his country, especially in the wake of the successful synthesis of the transuranium element of atomic number 113 in 2004 by RIKEN researchers. Their proposed name, nihonium (Nh) (after another reading of the country name, Nihon 日本), was approved by the IUPAC in November 2016.

other universities such as Osaka Imperial University (est. 1931). In so doing, Majima paid great attention to equipping laboratories with adequate facilities to support experiments with the technique he brought back from Europe. For example, he carefully designed water supply facilities on the Tohoku Imperial University campus in Sendai, where there was no running water yet, to provide enough water pressure to be used for vacuum (reduced pressure) distillation.49

Figure 8: Majima Rikō. Figure 7: Ogawa Masataka. Courtesy of the Tohoku University Archives.

Majima Rikō (born Toshiyuki but generally referred to as “Rikō” by himself and his colleagues) majored in organic chemistry at Tokyo and worked with Sakurai, who was originally trained as organic chemist by Williamson.48 Majima however received little advice from Sakurai and taught largely himself the craft of organic chemical research. He started his first structural research of urushiol, the main component of raw lacquer juice, based on his research strategy to compete with Western chemists by studying Japanese local products with analytical techniques of Western chemistry, taking advantage of the proximity to the localities of these products. During his overseas study in 1907-1911, Majima worked with Carl Harries (1866-1923) at the University of Kiel and Richard Willstätter (1872-1942) at the Zurich Polytechnic to learn the cutting-edge techniques of organic chemistry such as vacuum distillation, ozonolysis, and catalytic reduction that could be applied to his urushiol project. He was appointed professor (as Ogawa) at Tohoku Imperial University in 1911, completed the urushiol project and established influential research schools in organic and natural product chemistry first at Tohoku and later at RIKEN and

Courtesy of the Tohoku University Archives

Nozoe Tetsuo 野副鐵男 (1902-96), arguably the most important student of Majima, was graduated in 1926 from the Department of Chemistry at Tohoku Imperial University with Majima as his thesis advisor.50,51 Nozoe moved to the then Japanese colony of Formosa (Taiwan) to take up a research appointment at the Laboratory attached to the Government of the Governor-general of Taiwan in Taipei (“Taihoku” in Japanese) in 1926. He was appointed assistant professor at the newly founded Taihoku Imperial University in 1929 and promoted to a full professorship in 1937. Following in the footstep of his mentor, Nozoe started his research on the structure of hinokitiol, the oil extracted from Chamaecyparis taiwanensis, a species of cypress native to Taiwanese mountains in 1935. He confirmed by 1940 that hinokitiol has a seven-member ring structure and yet exhibits aromaticity. After the end of World War II and Taiwan’s retrocession to Chinese sovereignty, Nozoe stayed in Taipei until 1948 as the chemistry professor at the National Taiwan University (reorganized from Taihoku Imperial University in 1945). Appointed a chemistry professor of his alma mater, the Department of Chemistry at Tohoku University, in 1948, Nozoe’s hinokitiol research gradually became internationally known and made him one of the pioneers of December 2021 | 109

nonbenzenoid aromatic chemistry. Nozoe was a prime example of Majima’s research style of tackling local products contributing to the creation of a universal scientific discipline.

Kuroda Chika: Pioneer Woman Chemist in Twentieth Century Japan

An early student of Majima in organic and natural product chemistry at Tohoku, Kuroda Chika 黑田チカ (1884-1968) became a pioneer woman chemist in early Twentieth Century Japan. Kuroda Chika was born in Saga, Kyushu Island in 1884. Her father, Heihachi, made sure that his children, including his daughters, were well educated. In 1902, aged 18, she entered the Division of Science, Women’s Higher Normal School (Joshi Kōtō Shihan Gakkō or Jokōshi), where she graduated in 1906. She was invited as a teacher to Fukui Normal School where she spent one year, training teachers. In 1907-1909 she completed the graduate course at the Women’s Higher Normal School and became assistant professor at Tokyo Women’s Higher Normal School.52 Kuroda was one of the first two women who studied at the recently established Tohoku Imperial University in Sendai, north of Tokyo. In 1913 she passed the entrance examination after Nagai, who was a champion of women’s education in Japan, recommended that she apply. A director at the Ministry of Education sent a critical letter to the president of Tohoku Imperial University against letting women start their education there, pointing out that it had not happened previously. However, Kuroda Chika was allowed to continue her studies and graduated in 1916.53 It is important to note here that the issue of hindrance of women participation in science was not unique to Japan.54 Studies on women in science in Japan and the global context of this issue were published by Otsubo Sumiko,55 Kodate Kashiko and Kodate Naonori,56 and Ogawa Mariko.57 An introductory Japanese book on the history of chemistry includes a chapter on gender and the history of chemistry featuring Marie-Anne Lavoisier (17581936), Marie Curie (1867-1934), and Kuroda.58 Kuroda’s case is therefore a part of the longterm and worldwide phenomenon awaiting full scrutiny. The study of natural dyes had a long history in Japan.59 Majima Rikō, who started modern organic chemistry studies in Japan, focused on plants; Kuroda Chika, his student, continued and deepened the chemical studies of plant dyes.60 In 1918 she was the first woman to publish the results of her research “On the Pigment of Purple Root,” an important fabric-dyeing material, and presented her findings in front of the assembly of Tokyo Chemical Society.61 In 1918 she became a full professor at Tokyo Women’s Higher Normal School. 110 | December 2021

Figure 9. Kuroda Chika at RIKEN, 1924. Kindly provided and permitted to use by Ochanomizu University History Museum.

During 1921-1923 Kuroda was at Oxford University in England, sent there by the Ministry of Education, and continued research work in the laboratory of William Henry Perkin Jr. (1860-1929), with a letter of recommendation from Sakurai who had been acquainted with Perkin.62 In her memories she tells how she enjoyed her time in Oxford and the Perkin family’s hospitality. During summer vacation she traveled to Switzerland, climbed the Jungfrau Mountain, and visited Italy. After returning to Japan Kuroda reentered Tokyo Women’s Higher Normal School. However, the earthquake of September 1923 destroyed the buildings of that school. Majima offered her a commissioned position in the recently established RIKEN, the Institute of Physical and Chemical Research founded in 1917. There Kuroda continued her research and published her research results titled “About the structure of safflower pigment” (1929) that was her doctoral thesis. In 1929, at 45 years old Kuroda Chika received the title Doctor of Science (D.Sc.) from Tohoku Imperial University. She received the first Majima Award from the Chemical Society of Japan in 1936. In 1949 Kuroda Chika became professor of the newly established Ochanomizu University, formerly Jokōshi. In dozens of articles, she described detailed processes for isolation, crystallization, as well as synthesis, and determination of the structure of the dyes extracted from plants and a sea animal that were traditionally used in Japan. In 1936 she concluded that many of those substances were derivatives of anthocyanin. Robert Robinson (1886-1975), Nobel chemistry laureate in 1947, cited her research in 1955.63 In her memoirs written in 1957 Kuroda acknowledged and included photos of those scientists

from whom she learned: Majima, W. H. Perkin Jr., Arthur George Perkin (1861-1937, Perkin Jr.’s younger brother) and Robinson. It should be realized that Kuroda Chika’s research and achievements were on topics similar to those of the leading organic chemists in England, though there was far less support for laboratory facilities in Japan, and less recognition of her work. She continued part time research and teaching as a professor emeritus after her retirement in 1952. Kuroda Chika started her memoirs by writing “Since I’ve learned about the endless world of academic study and the joy of walking that path, I was just drawn to the joy of discovering something I hadn’t seen yet; and before I knew it, I had reached the age of 72. I am grateful that I still have enough energy to continue my research. At the end of last year, the research on substances in onion skin that act against high blood pressure which I had been working on for a long time, finally came to fruition, and it was made the blood pressure medicine ‘Keltin C’; I am incredibly happy that it will be useful to many people, it will be my honor.”64 In 1959 (aged 75) Kuroda Chika received the Medal with Purple Ribbon and in 1965 she received the Order of the Precious Crown. Together with her friend the first woman biologist Yasui Kono 保井コノ (1880 –1971) they established a prize for young students that is awarded annually. Kuroda Chika died in Fukuoka City in Kyushu on 8 November 1968 at 84 years of age. Her memory is cherished in Japan as a pioneering woman chemist.

The “Kyoto School” and the First Japanese Nobel Laureate in Chemistry

This short article on the history of chemistry in Japan ends with Fukui Kenichi 福井謙一 (1918-98), who became the first Japanese Nobel Laureate in Chemistry in 1981 for his pathbreaking quantum mechanical theory on the course of chemical reactions, the frontier orbital theory. An interesting point about his career and work is that, despite the highly theoretical character of his research, Fukui was trained at and affiliated to the Faculty of Engineering, not Science, of Kyoto (Imperial)65 University. This is best understood by considering the fact that Fukui was a member of the “Kyoto school” of chemistry, established by industrial chemist Kita Gen-itsu 喜多源逸 (1883-1952) and thoroughly studied by historian of chemistry Furukawa Yasu, on whose works this section is based.66 The Kyoto school epitomized how the traditions of pure and applied chemistry in Japan, outlined above, converged in the twentieth century. Kita was born in Nara Prefecture and graduated from the Department of Applied Chemistry, College of Engineering, Tokyo Imperial University in 1906.67 His original research field was fermentation, especially www.facs.website

the chemistry of enzymes, and was appointed assistant professor in 1908 at his alma mater. In spite of his seemingly smooth career development, Kita was not happy at Tokyo because of the discrepancy between his own philosophy and the teaching policy of Tokyo’s Department of Applied Chemistry. Whereas Kita believed that industrial chemists should thoroughly understand the basics of pure chemistry and have the ability to do basic research, the chemical component in applied chemistry teaching at Tokyo was diluted, so to speak, as Takamatsu and Nakazawa blended chemical and practical machine-operating aspects of the chemical industry to design a curriculum suited to the training of chemical technologists (cf. the previous section on Meiji Japan’s practical chemists). Kita’s move in 1916 to the Department of Industrial Chemistry, Faculty of Engineering, Kyoto Imperial University, together with his research appointment at the RIKEN in 1917 (most probably based on a recommendation from Sakurai), opened the way to realize his ideal. His experience of working at the Massachusetts Institute of Technology (MIT) with Arthur Amos Noyes (1866-1936) during his overseas study in 1918-1921 reaffirmed his conviction and arguably taught him the relevance of physics and mathematics to chemistry, for Noyes was a physical chemist and a vocal advocate of the importance of basic scientific education and research in an engineering school.68 Kita also probably learned from what Noyes’ rival at MIT, industrial chemist William H. Walker (1869-1964), was doing to establish a Department of Chemical Engineering in 1922: Kita brought teaching materials about the unit operation, the key concept of chemical engineering, from MIT to Kyoto.69 Once he resumed his teaching at Kyoto and was promoted to full professor in 1921, Kita moved quickly to realize his vision of “To aim at the application, study the basic.” The first is the curricular reform to lay more emphasis on basic scientific subjects like inorganic, organic and physical chemistry, mathematics, and theoretical physics. In so doing, Kita enabled students of the Department of Industrial Chemistry to enroll in scientific courses of Kyoto’s Faculty of Science,70 including the Department of Chemistry, by working closely with professors there. One of the chemistry professors of Kyoto’s Department of Chemistry then was physical chemist Horiba Shinkichi 堀場信吉 (1886-1968). A graduate from the Department of Chemistry at Kyoto in 1910 taught by Ōsaka Yūkichi 大幸勇吉 (1867-1950), another student of Sakurai and Ostwald, Horiba was appointed assistant professor in 1913 and full professor in 1924 at Kyoto’s Department of Chemistry. Horiba pursued research on the rates of a variety of reactions using the thermal analysis method and built a research tradition in chemical kinetics at Kyoto and indeed the www.asiachem.news

whole field of physical chemistry. His leading position in physical chemistry in Japan is exemplified by Horiba’s editorship (co-editorship with Sameshima at Tokyo from 1939) of Butsuri kagaku no shimpo (“Review of Physical Chemistry of Japan”) launched in 1926 by the Horiba laboratory at Kyoto.71 From the Horiba school emerged quite a few kineticists of international standing. Ree Taikyue 李泰圭 (Ri Taikei in Japanese reading, 1902-92), of the “Ree-Eyring theory” (1955) fame, played a pioneering role in Japan, as well as in his native Korea after World War II, in introducing quantum chemistry into chemical kinetics.72 Satō Shin 佐藤伸 (b. 1928), a student of Horiba’s student Shida Shōji 志田正二 (1912-2001) who taught at the Tokyo Institute of Technology, published in 1955 a substantial modification of the London-Eyring-Polanyi (LEP) method73 of calculating the potential energy reaction surface of bimolecular systems based on a simplified quantum mechanical equation (the London equation), which is now recognized as the LEPS method.74 Simultaneously with departmental curricular reforms, Kita established a research school encompassing fermentation (his original research field), textile, fuel, and rubber. This broadening of his research horizon reflected Kita’s growing sense of mission to contribute to Japan’s “autarky” in the 1930s and 1940s in the context of Japan’s worsening international relations leading to the outbreak of the Second Sino-Japanese War in 1937 and the Pacific War in 1941. In this process Kita attracted various talents. Sakurada Ichirō 櫻田一郎 (1904-86), for example, was sent by Kita to Germany and spent two years in 19291931 with Kurt Hess (1888-1961), who was a cellulose chemist and the main opponent of the macromolecular theory of polymers postulated by Hermann Staudinger (1881-65).75 Sakurada first joined the polymer controversy in his mentor’s favor but later converted to the macromolecular theory and became a pioneer in polymer and textile chemistry in Japan. Sakurada invented Japan’s first synthetic fiber, vinylon, with Korean chemist Ri Sung-gi 李升基 (Ri Shōki in Japanese reading, 190596) and many other collaborators in 1939.76 Kodama Shinjirō 兒玉信次郎 (1906-96), the most loyal supporter of Kita’s vision, was an industrial chemist with working experiences in chemical factories. He was sent by Kita to Germany and worked with Michael Polanyi (1891-1976) on research in chemical kinetics and learned quantum mechanics in 19301932. Through these experiences Kodama turned his mentor’s vision into a concrete research methodology, i.e. solving technical problems “first by theories as much as possible and then by experimental measuring if no theory is available for them.”77 Kita and Kodama were also aware of the needs to turn their laboratory findings into factory products. They put a considerable effort to solving the

chemical engineering problem of scaling-up in the pilot study of synthetic petroleum production by the Fischer-Tropsch process before moving to the factory scale during World War II.78 These developments were recognized with the establishment of the Department of Fuel Chemistry in 1939 and the Department of Textile Chemistry in 1941, both at Kyoto’s Faculty of Engineering. Fukui Kenichi was another talent attracted to Kita’s vision of “To aim at the application, study the basic” and quite literally a product of the Kyoto school without any experience in overseas study.79 A distant relative of Kita coming from the same Nara Prefecture, Fukui chose chemistry as his major and entered the Department of Industrial Chemistry, Faculty of Engineering at Kyoto in 1938 following Kita’s advice that “if you are good at mathematics, study chemistry.” Considering quantum mechanics as the basis of chemistry and the best tool to “mathematize” it, he spent much time in his undergraduate days teaching himself quantum mechanics by reading library holdings at Kyoto’s Department of Physics. Fukui later deepened his knowledge of quantum mechanics with Kodama, Fukui’s supervisor at the graduate school, who had brought many up-to-date reading materials on quantum mechanics and statistical thermodynamics from Germany.

Figure 10. Fukui Kenichi In: Yamabe, Tokio (ed.) (1982). Nōberu shō kagakusha Fukui Ken-ichi: Kagaku to watashi (Kyoto: Kagaku Dōjin). Courtesy of the publisher, Kagaku Dōjin

Another key to Fukui’s success as quantum chemist was his familiarity with the reactions of hydrocarbons, both theoretically and experimentally. That he gained from his undergraduate thesis advisor and later colleague at the Department of Fuel Chemistry, synthetic organic chemist Shingū Haruo 新宮春男 (1913-88) and from his wartime research experience at the Army’s Fuel Research Institute in 1941-45. Fukui was appointed lecturer in 1943 December 2021 | 111

and assistant professor in 1945 at Kyoto’s Department of Fuel Chemistry while retaining his military affiliation and got back to his fulltime teaching position at Kyoto after the end of World War II. In spite of its strong military connotations, the Department of Fuel Chemistry at Kyoto was allowed to keep this name after the war due to the strenuous effort of Kodama, who redefined the mission of the department as the postwar economic reconstruction of the country by means of science-based technology (it was renamed the Department of Petroleum Chemistry in 1966).80 Fukui’s first postwar research project was for his doctorate, awarded in 1948, and supervised by Kodama. Titled “the theoretical investigation of temperature distribution within industrial research apparatuses,” his thesis was a highly mathematical treatment of the chemical engineering problem that Kodama had encountered while he was working at a chemical factory. Now with a doctorate, his own laboratory, and students, and being promoted to full professorship in 1951, Fukui was in a good position to start something new. It is much owing to the intense discussion with Shingū, and Shingū’s vocal critique of the then influential electronic theory of organic chemistry postulated by Robinson and Christopher Kelk Ingold (1893-1970), that Fukui formulated the “Frontier Orbital Theory” of organic reactions in 1951. He published its first paper in 1952 with his student Yonezawa Teijirō 米澤貞次郎 (1923-2008), and with Shingū as its authors in the Journal of Chemical Physics, followed by the second paper published in the same journal in 1954. Electrons occupying the highest occupied molecular orbital (HOMO), which play the essential role in Fukui’s theory together with the lowest unoccupied molecular orbital (LUMO) to explain the course of substitution reactions of hydrocarbons, was originally named “frontier electrons” at Shingū’s suggestion. Fukui’s frontier orbital theory was thus born at the intersection of pure science, quantum chemistry, on the one hand, and applied science, fuel chemistry, on the other. This is in

References 1.

To clarify each co-author’s responsibilities: Siderer contributed the sections “Udagawa Yōan: The Creator of Cchemical Nomenclature in Japanese” and “Kuroda Chika: Pioneer Woman Chemist in Twentieth Century Japan,” and Kikuchi contributed the other sections of the article. The two co-authors collaborated with each other in editing and proofreading the whole article. In what follows (except in “Acknowledgments”), Japanese names are rendered in the original order, i.e., family names followed by persons’ names. It should also be noted that, from their second appearance, Japanese persons are referred to by their family names such as Udagawa, Kawamoto, and Sakurai (instead of Yōan, Kōmin and Jōji) unless full names are given. Macrons are used in Japanese long vowels except in some geographical names such as Tokyo (Tōkyō), Kyoto (Kyōto), Osaka (Ōsaka), Tohoku (Tōhoku), and Hokkaido (Hokkaidō). The history of chemistry in Japan has also been briefly discussed in: Furukawa, Y. (2021). Exploring the History of Chemistry in Japan. Ambix, 68, 302-317, on 11-16. N. Koertge (ed.), New Dictionary of Scientific Biography (NDSB), 8 vols. (Detroit, Mich.: Charles Scribner’s Sons/ Thomas Gale, 2008) is an essential reference tool for anyone interested in the history of twentieth-century science. The NDSB includes the entries of the following four Japanese

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stark contrast with the research trajectories of another pioneer in quantum chemistry in Japan, Mizushima San-ichirō (cf. the previous section on pure chemists from Tokyo’s Department of Chemistry), which were focused on molecular structures, not reactions. Fukui’s interests in chemical reactions likely came partly from Kyoto’s research traditions in chemical kinetics but mainly from industrial needs to elucidate and control reactions, which mattered less to Mizushima. Fukui succeeded because of, not in spite of, his training at and affiliation to an engineering faculty, albeit of a peculiar kind.

Towards Postwar Japanese Chemistry

The aim of this article was to outline the history of chemistry in Japan in the context of its modernization, industrialization, and other historical events such as two world wars. Our choice of historical actors and cases inevitably depended on our expertise as historians, meaning that we could only cover part of the postwar period of the twentieth century. That being said, it does suggest that many of the Japanese chemists we have discussed contributed to the development of Japanese chemistry whose level was approaching the international standard in the 1950s. A couple of indicators point to the coming-of-age of Japanese chemistry by the mid-1960s.81 One such indicator is the international conferences, symposia and seminars held in Japan: The IUPAC International Symposium on Molecular Structure and Spectroscopy held in Tokyo in 1962, in which Mizushima, Nagakura and the successor of Mizushima at Tokyo, Shimanouchi Takehiko 島内武彦 (1816-1980), were involved;82 The Third IUPAC Symposium on the Chemistry of Natural Products held in Kyoto in 1964;83,84 and the First Japan-US Science Seminar in physical organic chemistry co-organized by Nozoe and the American physical organic chemist, John D. Roberts (1918-2016) and held in 1965 in Kyoto.85 As chemists: Fukui Ken-ichi (by James R Bartholomew, vol. 2, pp. 85-89), Mizushima San-ichirō (by Yoshiyuki Kikuchi, vol. 5, pp. 207-211), Nozoe Tetsuo (by Masanori Kaji, vol. 5, pp. 287-293), and Sakurada Ichirō (by Yasu Furukawa, vol. 6, pp. 330-335). This article discusses all of them in later sections. 4. The most up-to-date reference work for the history of chemistry (especially its Japanese component) is: Kagakushi Gakkai (ed.) (2017). Kagakushi jiten [Encyclopedic Dictionary of the History of Chemistry] (Kyoto: Kagaku Dōjin). Its entry on chemistry in Tokugawa Japan written by Yatsumimi Toshifumi (pp. 492-493), is an excellent guide to this topic. 5. Goodman, G. K. (1986). Japan: The Dutch Experience (London and Dover, N.H.: The Athlone Press). 6. Sugita, G. (1969). Dawn of Western Science in Japan: Rangaku kotohajime (Tokyo: Hokuseido Press). 7. Dōke, T. (1973). Yōan Udagawa—a pioneer scientist of early 19th century feudalistic Japan. Japanese Studies in the History of Science, 12, 99–120. 8. Osawa, M. (2019). The Evolution of the Research on Hot Springs in Japan from Siebold and Burger to Udagawa Yōan (in Japanese). Onsen, 87 (1), 35. 9. Siderer, Y. (2017). Udagawa Yōan ‘s (1798-1846) translation of light and heat reactions in his book Kouso Seimika. Foundations of Chemistry, 19, 224-240. 10. Siderer, Y. (2021). Udagawa Yōan (1798-1846), Pioneer of Chemistry Studies in Japan from Western Sources and his Successors. Substantia, 5, 99-117.

we hope to have shown here, the dynamic balance between pure and applied chemistry and internal and external forces affected the historical development of chemistry in Japan that led to its prosperity in the latter half of the twentieth century, producing seven more Nobel laureates in chemistry following Fukui to this date, overcoming difficulties of scientists from East Asia in receiving this prize.86 ◆

Acknowledgments (Kikuchi)

It is our pleasure to extend our gratitude to Prof. Yasu Furukawa (The Graduate University for Advanced Studies [Sokendai], Japan) for reading an entire earlier draft, removing mistakes there and giving advice to improve it. I was trained by Prof. Furukawa as a historian and am grateful to him for generously sharing his wisdoms and a vast range of expert knowledge for more than three decades. We are also grateful to our colleagues at the Japanese Society for the History of Chemistry for invaluable advice and suggestions, especially Ms. Mari Yamaguchi (Nihon University) who kindly shared her expertise in the history of physico-chemical instrumentation in Japan and gave us insight into postwar chemistry.

Acknowledgments (Siderer)

I cannot fully express my deep gratitude, appreciation and friendship to each of my teachers in Japan: Prof. Shin Sato, my first chemistry teacher at Tokyo Institute of Technology and since then advisor on Japanese chemistry and language; Prof. Masanori Kaji who has left us too early, for broadening my view on the hisory of science in Japan; and Prof. Frederik Cryns at Nichibunken, The International Research Center for Japanese Studies, Kyoto, for sharing his knowledge of Japanese thought and advising me on my writing. Prof. Kuroda Kotaro is acknowledged for discussion on Kuroda Chika. During my short and long visits to Japan, I was lucky to be acquainted with colleagues and friends who helped me in many ways, I am very thankul to all of them. 11. MacLean, J. (1974). The Introduction of Books and Scientific Instruments into Japan, 1712-1854. Japanese Studies in the History of Science, 3, 9-68. 12. Azuma, T. (2013). Udagawa Yōan ‘s Acceptance of Western Chemistry as seen through Kyō-U Library Collection in Osaka. Part 1: An Analysis of his manuscripts translated from Adolphus Ypey’s Chemical Books in Dutch (in Japanese). Kagakushi, 40, 189-209. 13. Tsukahara, Togo. (1993). Affinity and Shinwa Ryoku, Introduction of Western Chemical Concepts in Early Nineteenth-Century Japan (Amsterdam: J.C. Gieben). 14. Tanaka, M (1975). Seimi kaisō ni okeru Yōan no kagaku ninshiki [Yōan’s understanding of chemistry as shown in Seimi kaisō]. In Udagawa Yōan, Seimi kaisō fukkoku to gendai goyaku・chū [Reprint of Seimi kaisō and its translation into modern Japanese, with Explanatory notes] (Tokyo: Kōdansha), 99–114. 15. Endō, S., Kato, N, Kōda, M, and Matsuda, K. (2014). Studies on Udagawa Yōan ‘s Botanical works housed in the Kyō-U Library, Takeda Science Foundation (in Japanese) (Osaka, Takeda Science Foundation). 16. Yatsumimi, T. (2019). “Kagaku” no hajimari [The beginning of kagaku in Japan]. In Kagakushi Gakkai (ed.), Kagakushi eno shōtai [Introduction to the History of Chemistry] (Tokyo: Ohmsha), 232-239. 17. Historically and in current usage, the official translation of Tokyo Daigaku has been “The University of Tokyo,” even

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25.

26. 27.

28.

29.

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34. 35. 36. 37.

38. 39.

40.

though the early Meiji Tokyo Daigaku (mentioned here) and today’s Tokyo Daigaku are different institutions: the former is just one of the antecedent schools of the latter, the successor institution of Tokyo Imperial University. For this reason, the early Meiji Tokyo Daigaku is translated as “Tokyo University” in this article to distinguish it from the current University of Tokyo. The official English name of this institution was “The Imperial University” until 1897, when “of Tokyo” was added to it to distinguish it from Kyoto Imperial University established in this year. Throughout this article, we adopt “Tokyo Imperial University” for the sake of consistency. Yatsumimi, T. (2011). Nihon Gakushi-in zō Kawamoto Kōmin kankei shiryō [The Kawamoto Kōmin Collections in the Japan Academy]. Kagaku to kōgyo [Chemistry & Chemical Industry], 64, 611-613. Ozawa, T. (2020). Meiji shoki no oyatoi Doitsu jin kagaku kyōshi tachi [German Chemistry Teachers in early Meiji Japan]. Kagaku to kyōiku [Chemistry&Education], 68, 466-469. Kikuchi, Y. (2020). Meiji shoki no igirisu jin kagaku kyōshi tachi [British Chemistry Teachers in early Meiji Japan]. Kagaku to kyōiku, 68, 470-473. He was the older brother of a 1929 Nobel Laureate in physiology or medicine, Christiaan Eijkman (1858-1930). Tsukahara, Tokumichi (1978). Meiji kagaku no kaitakusha [Pioneer chemists in Meiji Japan] (Tokyo: Sanseidō), 10-20. Hokkaido Imperial University has its origin as the Sapporo Agricultural School (est. 1876), where Canadian botanist and agriculturist David Pearce Penhallow (1854-1910) taught chemistry. Yongue, J. (2021). Kagaku ga unda shin sangyō; Nagai Nagayoshi no katsudō to Keizai kōken [New industries from Chemistry: Nagai Nagayoshi’s activities and contributions to economy]. Kagaku to kyōiku, 69, 42-45. Arai, K. (2021). Sekai o mezashita kagaku kigyōka Takamine Jōkichi [Takamine Jōkichi who aspired to be a global chemical entrepreneur]. Kagaku to kyōiku, 69, 46-49. Kikuchi, Y. (2008). Analysis, Fieldwork and Engineering: Accumulated Practices and the Formation of applied Chemistry Teaching at Tokyo University, 1874-1900. Historia Scientiarum, 18, 100-120. On the impact of Roscoe’s books on Japan, see: Siderer, Y. (2021). Translation of Roscoe’s Chemistry Books into Japanese and Hebrew: Historical, Cultural and Linguistic Aspects. Substantia, 5, 39-52. Dehn, U. (1995). TANAKA Shôzô: ein Vorkämpfer für Menschenrechte und Umweltschutz (Tokyo: Deutsche Gesellschaft für Natur- und Völkerkunde Ostasisens [OAG Tokyo]). Wakabayashi, F. (2021). Suzuki Umetarō: Nōgaku to kagaku no yūgō [Suzuki Umetaro: fusing agriculture and chemistry], Kagaku to kyōiku, 69, 54-57. Kikuchi, Y. (2013). Anglo-Japanese Connections in Japanese Chemistry: The Lab as Contact Zone (New York: Palgrave Macmillan). Kikuchi, Y. (2009). Samurai Chemists, Charles Graham and Alexander William Williamson at University College London, 1863-1872. Ambix, 56, 115-137; on 121. On Willamson’ s ether synthesis and its historical significance: Rocke, A. J. (2010). Image & Reality: Kekulé, Kopp, and the Scientific Imagination (Chicago: The University of Chicago Press), chapter 1 “Ether/Or” (pp. 1-37). Kikuchi, Y. (2013) (note. 31), 142-145. Kikuchi, Y. (2011). World War I, International Participation and Reorganisation of the Japanese Chemical Community. Ambix, 58, 136-49; on 146. Yamanaka, C (2021). Joji Sakurai’s Thoughts and Activities on the Promotion of Science in the Modern Era in Japan (in Japanese). Kagakusi kenkyū, ser. 2, 51, 138-147. Shibata Yūji 柴田雄次 (1882-1980) was another graduate from Tokyo’s Department of Chemistry who played an important role in chemistry in Japan. Trained first as an organic chemist and then converted to inorganic chemistry, Shibata was appointed assistant professor in 1913 and promoted to full professorship in 1919 at his alma mater, and undertook research projects and trained chemists in coordination chemistry and a variety of other fields: biochemistry; geochemistry; and conservation science. See: Tanaka, M. (1975). Nihon no kagaku to Shibata Yūji [Japanese Chemistry and Shibata Yūji] (Tokyo: Dai Nihon Tosho). Saitō, S. (1978). Ikeda Kikunae to hannō sokudo ron [Ikeda Kikunae and chemical kinetics]. Kagakusi kenkyū, ser. 2, 17, 165-173. Kikuchi, Y. (2018a). Ikeda Kikunae and Reactions to Energetics in Japan. Historia Scientiarum, 28, 54-68. “Energetics” is the scientific and intellectual movement in the late nineteenth century that attempted at explaining natural as well as social and cultural phenomena only with reference to the concept of energy, of which Ostwald as the main advocate. See: Deltete, R. J. (2007). Wilhelm Ostwald’s Energetics 1: Origins and Motivations. Foundations of Chemistry, 9, 3-56. The antonym of “energetics” is “atomistics” advocated by Austrian physicist Ludwig Boltzmann (1844-1906). Hirota, K. (1994). Kagakusha Ikeda Kikunae: Sōseki, Umami, Doitsu [The Chemist Ikeda Kikunae: Natsume Sōseki, Umami, Germany] (Tokyo: Tokyo Kagaku Dōjin).

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41. Tachibana, T. (1979). Sameshima Jitsusaburō no gyōseki mokuroku to sono kaisetsu [List of publications by Sameshima Jitsusaburō with commentaries]. Kagakushi, (9), 23-36; (10), 39-47. 42. Pope, M. (1994). Professor Hiroo Inokuchi: A pioneer and major contributor to the field of electronic processes in organic materials. Synthetic Metals, 64, 109-113. We owe this information to Ms. Mari Yamaguchi. 43. Tamamushi, B. (1978). Kaimen Kagaku eno Michi: Katayama Masao Kyōju Seitan 100- shūnen ni chinande [The Way to Surface Chemistry: In Memory of Centennial birth of Prof. Masao Katayama]. Kagakushi, (8), 1-6. 44. Kikuchi, Y. (2008). Mizushima, San-ichirō. In NDSB (note 3), vol. 5, pp. 207-211. See also: Kikuchi, Y. (2016). San-ichiro Mizushima and the Realignment of the International Relations of Japanese Chemistry. In Kaji, M, Furukawa, Y., Tanaka, H, and Kikuchi, Y. (eds.). The International Workshop on the History of Chemistry 2015 Tokyo (IWHC 2015 Tokyo) “Transformation of Chemistry from the 1920s to the 1960s): Proceedings (Tokyo: Japanese Society for the History of Chemistry), 50-55; and Kikuchi, Y. (2018b). International Relations of the Japanese Chemical Community. In Rasmussen, S. C. (ed.). Igniting the Chemical Ring of Fire: Historical Evolution of the Chemical Communities of the Pacific Rim (Singapore: World Scientific), 139-155. 45. Furukawa, Y. (2017). Kagakusha tachi no Kyoto gakuha: Kita Gen-itsu to Nihon no kagaku [The Kyoto School for Chemists: Kita Gen-itsu and Japanese Chemisttry] (Kyoto: Kyoto Daigaku Gakujutsu Shuppankai), p. 186. 46. Hirota, N. (2016). Robert Mulliken and His Influence on Japanese Physical Chemistry. In Kaji, M, Furukawa, Y., Tanaka, H, and Kikuchi, Y. (eds.) (note 44), 192-199. Nagakura served the IUPAC as the first ever Japanese president in 1981-83. See: Kikuchi, Y. (2019). Pioneers of Japanese Participation in the IUPAC. Chemistry International, 41, 16-19. 47. Yoshihara, K. (1997a). Glory and Collapse of the Work on Nipponium by Masataka OGAWA (in Japanese). Kagakushi, 24, 295-305. English article: Yoshihara, H. K. (1997b). Nipponium, the Element Ascribable to Rhenium from the Modern Chemical Viewpoint. Radiochimica Acta, 77, 9-13. Outcomes of Yoshihara’s subsequent investigations are summarized in: Yoshihara, K. (2019). Sai hakken: Nipponiumu no shinjitsu [Truth about Nipponium rediscovered]. In Kagakushi Gakkai (ed.), Kagakushi eno shōtai (note 16), 26-34. Oppositions to Yoshihara’s reassessments are also expressed. See, for example: Nicholson, J. (2021). Who Discovered Rhenium? RSC Historical Group Newsletter, (79), 38-43. 48. Kaji, M. (2011). Majima Rikō to Nihon no yūki kagaku kenkyū dentō no keisei [Majima Rikō and the formation of research traditions in organic chemistry in Japan]. In Kanamori, O. (ed.), Shōwa zenki no kagaku shisōshi [History of Scientific thoughts in early Showa Japan] (Tokyo: Keisō Shobō), 185-241. 49. Majima, R. (1954). Waga shōgai no kaiko (II) [Reminiscences of my life, part II]. Kagaku no ryōiki, 8, 137-146, on 137-138. 50. Kaji, M. (2016). The Transformation of Organic Chemistry in Japan: From Majima Riko to the Third International Symposium on the Chemistry of Natural Products. In Kaji, Furukawa, Tanaka, and Kikuchi (eds.) (2016) (note 44), 14-19, on 15-16. 51. Kaji, M. (2018). Development of the Natural Products Chemistry by Tetsuo Nozoe in Taiwan. In Rasmussen (ed.) (note 44), pp. 357-368. 52. Kuroda, K. (2017). Kuroda Chika (1884-1968) (in Japanese). In Kagakushi jiten (note 4), 216-217. “Tokyo” was added to the name of Kuroda’s alma mater in 1908 when the second women’s higher normal school was established in Nara. “Jokōshi” kept widely used for the Tokyo Women’s Higher Normal School. 53. Maeda, K. (2000). Chika Kuroda: Research on the Constitution of Natural coloring Matters and Her Life as a Pioneering Woman Chemist. In Kuroda Chika shiryō mokuroku [Catalogue of the Kuroda Chika Papers] (Tokyo: Ochanomizu University Gender Research Center), 8-10. Online version: http://www.igs.ocha.ac.jp/igs/ IGS_publication/pdf/kuroda_archive_en.pdf (last accessed 23 June 2021). 54. Historical studies on women in science are numerous. See, for example: Schiebinger, L. (ed.) (2014). Women and Gender in Science and Technology, 4 vols. (London: Routledge). 55. Otsubo, S. (2008). Women Scientists and Gender Ideology. In Robertson, J. (ed.), A Companion to the Anthropology of Japan (Malden, Mass.: Blackwell Publishing), 467-482. 56. Kodate, N, and Kodate, K. (2016). Japanese Women in Science and Engineering: History and Policy Change (London and New York: Routledge). We owe this information to Prof. Yasu Furukawa. 57. Ogawa, M. (2017). History of Women’s Participation in STEM Fields in Japan. Asian Women, 33, 65-85. We owe this information to Prof. Yasu Furukawa. 58. Kagakushi Gakkai, ed. (2019). Kagakushi eno shōtai (note. 16), Chapter 5 (pp. 165-189). 59. Vande Walle, W. F., and Kasaya, K. (eds.) (2001). Dodonaeus in Japan: Translation and the Scientific Mind in the Tokugawa Period (Leuven: Leuven University Press). See especially the introduction written by Vande Walle on pp. 9-29. 60. Kuroda, C., and Majima, R. (1922). On the Colouring Matter of Lithospermum Erythrorhizon. Acta Phytochimica, 1, 43-65.

61. Kuroda, C. (1918). Shikon no shikiso ni tsukite [On the Pigment of Purple Root]. Tokyo kagaku kaishi, 39, 1051-1115. 62. Kuroda, C., and Perkin, Jr., W. H. (1923). Derivatives of Phthalonic Acid, 4:5-Dimethoxy-phthalonic Acid, and 4:5-Dimethoxy-o-tolylglyoxylic Acid. J. Chem. Soc. Transactions, 123, 2094-2111. 63. Robinson, R. (1955). The Structural Relations of Natural Products, Being the First Weizmann Memorial Lectures, December 1953 (Oxford: The Clarendon Press), p. 42 and Ref. no. 87 on p. 39 and p. 130: Kuroda C. Proc. Imp. Acad. Tokyo 1929 5,32,82,86. 64. Kuroda, C. (1953). Kagaku no michi ni ikite [The Road of Chemistry in which I lived], Fujin no tomo, 51 (3), 28-33; 51 (4), 44-51. Reproduced in: Kuroda Chika shiryō mokuroku (note. 53), 77-64. Online version: https://teapot.lib.ocha. ac.jp/record/4093/files/catalogKurodaChika63-80.pdf (last accessed 23 June 2021). 65. The adjective “imperial” in Japanese imperial universities was removed in 1947 as part of the postwar educational reform. 66. Furukawa, Y. (2017). Kagakusha tachi no Kyoto gakuha: Kita Gen-itsu to Nihon no kagaku (note 45). For an English article on this topic by the same author, see: Furukawa, Y. (2018). Gen-itsu Kita and the Kyoto School’s Formation. In Rasmussen (ed.) (note 44), 157-168. The Kyoto school is also mentioned in: Furukawa, Y. (2021) (note 3), p. 5. Discussions not from Furukawa’s works are notified by endnotes. 67. Furukawa, Y. (2017), pp. 13-24. 68. Furukawa, Y. (2017), pp. 25-30. 69. On Noyes: Servos, J. W. (1990). Physical Chemistry from Ostwald to Pauling: The Making of a Science in America (Princeton, NJ: Princeton University Press), Chapter 3. 70. “Colleges (bunka daigaku)” as the constituent entities of imperial universities was renamed “Faculty (gakubu)” in 1919. 71. Suito, E. (1983). Academic Achievement and Career of Dr. Shinkichi Horiba (in Japanese). Kagakushi, (22), 19-32. Horiba was the father of entrepreneur Horiba Masao 堀場雅夫 (1924-2015), founder of the analytical instrument company HORIBA. 72. Kim, D (2005). Two Chemists in Two Koreas. Ambix, 52, 67-84, on 68-71. 73. On the LEP method, see: Laidler, K. J. (1987). Chemical Kinetics, Third Edition (New York: Harper Collins), 68-70; and Nye, M. J. (2007). Working Tools for Theoretical Chemistry: Polanyi, Eyring, and Debates Over the “Semiempirical Method.” Journal of Computational Chemistry, 28, 98-108. In formulating the LEP method, Henry Eyring (1901-81) and Polanyi used the calculations of the Coulombic and exchange integrals in the London equation by Japanese physicist Sugiura Yoshikatsu 杉浦義勝 (1895-1960). Sugiura is now recognized as a Japanese pioneer in quantum physics and chemistry. See: Nakane, M. (2019). Yoshikatsu Sugiura’s Contribution to the Development of Quantum Physics in Japan. Berichte zur Wissenschaftsgeschichte, 42, 338-356. 74. Sato, S. (1955a). On a New Method of Drawing the Potential Energy Surface. Journal of Chemical Physics, 23, 592-3. Sato, S. (1955b). On a New Method of Drawing Potential Energy Surface. Ibid., 2465-6. Laidler, K. J. (1996). A Glossary of Terms used in Chemical Kinetics, including Reaction Dynamics (IUPAC Recommendations 1996). Pure and Applied Chemistry, 68, 149-192, on 171. See also a recent appraisal of Satō’s work in terms of its impact on computational chemist Martin Karplus (b. 1930), a 2013 Nobel laureate in chemistry: Macuglia, D., Roux, B., and Ciccotti, G. (2021). The breakthrough of a quantum chemist by classical dynamics: Martin Karplus and the birth of computer simulations of chemical reactions. The European Physical Journal H, 46, article 12, p. 6. 75. On the history of polymer chemistry, see: Furukawa, Y. (1998). Inventing Polymer Science: Staudinger, Carothers, and the Emergence of Macromolecular Chemistry (Philadelphia: University of Pennsylvania Press). 76. Furukawa, Y. (2017), Chapter 3 (pp. 93-164). See also Kim (2005) (note 72), 72-73. 77. Furukawa, Y. (2017), p. 39. 78. Furukawa, Y. (2017), Chapter 2 (pp. 57-92) and pp. 192-202. 79. Furukawa, Y. (2017), Chapter 4 (pp. 165-251), 80. Furukawa, Y. (2017), p. 205. 81. Kaji, Furukawa, Tanaka, and Kikuchi, (eds.) (2016). The International Workshop on the History of Chemistry 2015 Tokyo (IWHC 2015 Tokyo) “Transformation of Chemistry from the 1920s to the 1960s)” (note 44). 82. http://pac.iupac.org/publications/pac/conferences/ Tokyo_1962-09-10r/ (last accessed 6 September 2021). 83. Kaji, M. (2016) (note 50), pp. 17-18. 84. Seeman, J. I. (2015). Taking IUPAC Literally: An International Union of Pure and Applied Chemistry. Chemistry International, 37, 4-9. 85. Nozoe, T. (1991). Seventy Years in Organic Chemistry (Washington, D.C.: American Chemical Society), 103. This page is a reproduction from the Nozoe Autograph Books, published in The Chemical Records in 15 segments: https://application.wiley-vch.de/util/nozoe/online.php (last accessed 7 September 2021). We owe this information to Ms. Mari Yamaguchi. 86. Bartholomew, J. R (2010). How to Join the Scientific Mainstream: East Asian Scientists and Nobel Prizes. East Asian Science, Technology, and Medicine, 31, 25-43.

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Science Diplomacy

Where Chemistry is Crucial

John M Webb John Webb is a graduate in chemistry from the University of Sydney (B.Sc.) and from the California Institute of Technology (Ph.D.). He coordinated chemistry networks in Asia for many years for UNESCO, for the FACS and for the Australian government aid program. His subsequent diplomatic roles included UNESCO Paris and as Counsellor (Education, Science and Training) at the Australian High Commission in New Delhi with responsibilities that included Nepal and Pakistan. He now is Adjunct Professor at Swinburne University of Technology. In 1996 he was awarded the Medal of the Order of Australia for establishing collaborative research networks in Asia

114 | December 2021

Thomas H Spurling Tom Spurling received his PhD in Physical Chemistry from the University of Western Australia in 1966. He joined CSIRO in 1969 and led its Chemistry research from 1989 to 1998. In 1999 he led the World Bank ‘Management and Systems Strengthening-LIPI’ project in Jakarta. He is now Professor of Innovation Studies at Swinburne University of Technology. Tom was President of the FACS from 1989 to 1991. He was made a Member of the Order of Australia in 2008 ‘For service to chemical science through contributions to national innovation policies, strategies and research, and to the development of professional scientific relationships within the Asian region.’

Gregory W Simpson Greg Simpson received his PhD in organic chemistry from the University of Sydney in 1979 and an MBA from UNSW. After periods at Imperial College London and the University of Canterbury NZ be joined CSIRO in 1983. At CSIRO he developed strong linkages between research and industry with a focus on sustainable development, receiving several awards for business excellence. He contributed to UNEP Montreal Protocol committees on Ozone Depleting Substances and to Australia’s assessment of Counter Terrorism technologies. He is a former President of the RACI. Recently a Professor of Practice at Monash University he is now an Adjunct Professor at Swinburne University of Technology.

The interactions between the worlds of science and of diplomacy have increased in scope and significance over recent decades, leading to a focus on understanding the emerging field of science diplomacy1-4. Just over ten years ago, the United Kingdom’s Royal Society and the American Association for the Advancement of Science met to clarify what is meant by this term, science diplomacy, and to stimulate further study and analysis. They proposed a schema identifying three aspects of science diplomacy. Despite being criticised by scholars in Europe through the recent European Union project on science diplomacy4, the taxonomy proposed by the Royal Society and AAAS is widely used1-3. The three aspects are science in diplomacy, science for diplomacy and diplomacy for science. This classification into three separate types of science diplomacy is inevitably imperfect since many activities in science diplomacy are complex and stretch across these three classifications. www.facs.website

by John M Webb, Thomas H Spurling and Gregory W Simpson https://doi.org/10.51167/acm00031

IN THIS PAPER we consider examples of international multilateral treaties that have needed the science of chemistry to reach agreements involving many governments. For the most part, they fall into the classification of science in diplomacy activities, that is, activities where science is crucial to achieve identified international objectives. In addition to the six international agreements discussed in this paper (Table 1), we can mention the Antarctic Treaty, signed in 1959 by twelve nations to ensure that the continent of Antarctica would be used exclusively for peaceful purposes with freedom of scientific cooperation, articulating a clear link between collaborative scientific research and the pursuit of peace. When US President Eisenhower called the 1959 conference he declared the American aim to have Antarctica ‘open to all nations to conduct scientific or other peaceful activities there’ even though the State Department had been trying to find ‘a way through the labyrinth of competing interests and fierce rivals’ created through decades of competition and competing claims of sovereignty 5. Science was caught up in this rivalry, with the State Department noting in 1962, that scientific knowledge had become the primary resource to be exploited in the www.asiachem.news

Antarctic 5. A focus on science enabled the territorial issues to be put aside and the Treaty to be signed and, eventually, ratified by the various governments involved. Since 1959, another 42 countries have acceded to the Treaty and a Secretariat has been established, in 2004, in Buenos Aires6. Thus, the Antarctic Treaty can be seen as an instance of science for diplomacy, science helping to resolve differences among nations. This is not an exclusive label in the context of science diplomacy, for aspects of the Treaty’s creation also reflect intense diplomatic efforts to ensure scientific research in Antarctica, that is, diplomacy for science. This second mentioned type of science diplomacy activities, those labelled science for diplomacy refers to the creation of international science cooperation that helps international relations. In addition to a multinational context, striking examples of this form of science diplomacy can be seen most readily in bilateral relations between States. Thus, the establishment of diplomatic relations between Israel and Germany in 1965, barely 20 years after the end of the second world war, was built on a range of links within civil society in both countries. As noted in an editorial7 in the Israel Journal

of Chemistry in 2015, ‘Scientific, technological and cultural links between Germany and Israel preceded and catalysed the establishment of formal diplomatic relations’. The third aspect of science diplomacy, diplomacy for science, concerns diplomatic efforts to gain access to international science facilities such as telescopes, synchrotrons and the like. An example of the need for diplomacy to develop an international science facility is the synchrotron established in Allan, Jordan, known as Sesame8. It is an international facility, established through the auspices of UNESCO that brought together as member countries Cyprus, Egypt, Iran, Israel, Jordan, Palestine and Turkey. One can imagine the diplomatic challenges in reaching agreement. Sesame’s ambition is not limited to just scientific research: the web site states that one of its goals is to build scientific and cultural bridges between diverse societies, that is, to contribute to a culture of peace. From this perspective, Sesame is an example, as is the above case of German-Israel science cooperation, of science for diplomacy. The ubiquitous nature of chemistry means that chemists are involved in myriad international diplomatic matters. Chemistry is an December 2021 | 115

Agreement

Web site (accessed 21 April 2021)

Montreal Protocol

https://ozone.unep.org/treaties/montreal-protocol

Basel Convention

http://www.basel.int/

Rotterdam Convention

http://www.pic.int/

Stockholm Convention

http://chm.pops.int/TheConvention/Overview/tabid/3351/Default.aspx

Minamata Convention

https://www.mercuryconvention.org/

Chemical Weapons Convention

https://www.opcw.org/chemical-weapons-convention/download-convention

Table 1: Internet addresses for the international Agreements discussed important component of many trade issues, environmental issues and even security issues. Countries become involved in such international issues to resolve matters of concern or dispute, often requiring the specialised knowledge and expertise of chemists. Thus, chemistry and diplomacy professionals have to work together to resolve diverse contentious issues of international significance. In this paper we provide several examples of international agreements where chemists and their expertise make crucial contributions. Many of these agreements emerge from international discussions, often under the auspices of the United Nations and its various specialized agencies. Such discussions can lead to the creation of an international treaty, often called a Convention, whereby countries agree to behave in certain ways. Sometimes these discussions extend over many years and, when the treaty is eventually signed, it is often referred to after the city in which it was finalised. The six international Agreements considered in this paper are listed in Table 1 together with the relevant internet address. The Agreements we have chosen to highlight here are ones where chemistry and chemists have been, and continue to be, closely involved.

Antarctic Treaty meeting Beijing 2017 116 | December 2021

They are the Montreal Protocol that emerged from the Vienna Convention (for protection of the ozone layer), the Basel, Rotterdam and Stockholm (often referred to as the BRS) Conventions, the Minamata Convention and the Chemical Weapons Convention. The Montreal Protocol’s genesis began with the science research data collected initially in the Antarctic, on measurements of ozone in the upper atmosphere., confirming the significance of the Antarctic Treaty 6 The Montreal Protocol on substances that deplete the ozone layer was opened for signature by States and regional economic integration organisations (such as the EU) in Montreal in September 1987 and later at the UN Headquarters in New York. The authentic texts, in Arabic, Chinese, English, French, Russian and Spanish are held by the Secretary-General of the UN. The text of the treaty is accompanied by several Annexes listing the chemical compounds, mostly chlorofluorocarbons but also their brominated analogues as well as hydrochlorofluorocarbons and their brominated analogues, that are the controlled substances. One Annex lists the products that contain such substances and which are therefore covered by the Protocol: air

conditioners in trucks and automobiles, refrigeration units, aerosols (except medical aerosols), portable fire extinguishers, insulations boards and pre-polymers. This list emphasises that the Protocol had considerable impact on many industries, globally, and could only have been successfully implemented with the cooperation between the chemical industry and their partner industries. By 2006, twenty years since its creation, the Handbook of the Montreal Protocol, prepared by its administrative secretariat within the UN Environment Programme, ran to 482 pages. The Montreal Protocol has been described as the world’s most successful environmental agreement. An analysis 9 by a long-serving adviser to the Protocol, a chemistry professor together with a colleague from the Australian government’s environment department, has highlighted the factors that contributed to its success, based on the cooperation and commitment by the international community, including chemistry and chemical industry. It has been accepted by all members of the United Nations, and the ozone layer is expected to return to 1980 levels by 2045-2060. The Basel Rotterdam and Stockholm Conventions are often grouped together and today, share a web site: http://www.pic.int/. The first one negotiated was the Basel Convention on the Control of transboundary movements of hazardous wastes and their disposal. It was agreed in Basel in 1989 under the auspices of the UN Environmental Programme. The Rotterdam Convention is also concerned with trade in chemical substances, creating a prior informed consent procedure for certain hazardous chemicals and pesticides in international trade, and was signed in Rotterdam in 1998, also supported by the UNEP. The third Convention in this group, signed in Stockholm in 2001 concerns persistent organic pollutants. These three Conventions have much in common, particularly involving organic and industrial chemists in their development and implementation. The Minamata Convention on Mercury is also a Convention driven by environmental concerns, specifically the protection of human health and the environment from anthropogenic emissions and releases of mercury and mercury compounds. The concern for mercury was highlighted in the recognition www.facs.website

Ozone concentrations in 2065 with and without the Montreal Protocol. Dobson Units measure the concentration of ozone in the atmosphere. Higher measurements of Dobson Units = more protection for the earth. Source: NASA Visualization Studio of the teratogenic effects of organic mercury compounds formed in the waters of the Japanese town of Minamata and taken up the food chain to be present in fish eaten by residents. The severe birth defects in children born from mothers who had consumed fish contaminated with these organo-mercury compounds were powerful incentives to develop the Convention. The text of the Convention was opened for signature in 2013. The Convention seeks to stop the manufacture and trade of mercury-added products, listing them specifically in an Annex. Certain types of batteries, lamps, switches and cosmetics are also to be phased out. The major manufacturing processes using mercury are also to be phased out or modified to control any use or release of mercury. The goal is to remove mercury from its current uses, including dental amalgam, and so this Convention has a considerable impact on chemical industry. It also leads to stockpiles of elemental mercury whose future requires careful consideration. The Chemical Weapons Convention (CWC), that is, the Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on their Destruction, has a different history from those of the Agreements outlined above. The CWC emerged from a lengthy historical process beginning in the 19th century with the Hague Conventions of 1899 and 1907, the first international treaties that addressed the conduct of warfare and explicitly forbade the use of poisons. The use of chemical weapons during the first World War (1914-1918) and elsewhere kept the issue on international disarmament agendas leading to the 1925 Geneva Protocol. Progress after 1925 was limited, as described in detail by Mathews 10. Negotiations for the CWC commenced in Geneva in 1972 but concluded only in 1992 at the UN Conference on Disarmament. The CWC opened for signature in Paris in January 1993 and came into force in www.asiachem.news

April 1997.The Organisation for the Prohibition of Chemical Weapons (OPCW) is the implementing authority for the CWC. A significant feature of the CWC is its verification provisions. Since entry into force of the CWC, over 70,000 tonnes (98.5%) of declared CW stockpiles have been destroyed and 9000 relevant chemical industry, production and research facilities have been inspected. Chemists of many countries were closely involved with their diplomatic colleagues in the negotiations to establish the treaty and to determine the scope of the chemicals and facilities to be subject to routine verification measures. The OPCW established a Scientific Advisory Board (SAB), consisting mostly of chemists, experts in their field relevant to the CWC. The 2019 list of members of the SAB includes chemists from five FACS member countries: Bangladesh, China, Japan, Pakistan, Philippines. More recently, a series of seminars and workshops (referred to as Science for Diplomats program) have been established within the OPCW to assist diplomats in their understanding of

scientific and chemical concepts relevant to the CWC 11,12. The then Director-General of the OPCW, Ambassador Ahmet Üzümcü, spoke at the FACS’ Asian Chemical Congress in Melbourne in 2017 on the challenges and achievements of the OPCW. The OPCW SAB has worked closely with IUPAC in preparing for the report of the SAB on developments in science and technology for the Special Sessions of the Conference of States Parties to review the Convention which have typically convened every five years. This and other SAB reports provide an up-to-date briefing for diplomats on the scientific and technological developments relevant to the CWC. As of April 2021, the FACS has 31 chemical societies as members, with Timor Leste the most recent member, being accepted at the Taipei FACS meeting in December 2019. The geographic spread of member societies ranges across Asia, involving 28 member States of the United Nations. For Table 2, the maximum number of FACS countries having signed up to the several Conventions is thus 28. The data of Table 2 indicate that, within the geographic scope of the FACS, these chemistry-related Conventions have received widespread support, a compliment to the chemistry community of FACS. Two of them, the Montreal Protocol and the Chemical Weapons Convention have universal coverage across the FACS geographic spread. Several of the Agreements concern environmental issues where chemistry is crucial in understanding and ameliorating dangerous pollution matters. The role of the chlorofluorocarbons in depletion of the ozone layer was an intense issue of public debate and controversy for many years before consensus was reached across industry, environmental chemists, political actors and the broader community that could lead to the Montreal Protocol. The 1995 Nobel Prize in chemistry was awarded to three chemists ‘for their work in atmospheric chemistry, particularly concerning the formation and

Date text agreed

No. FACS countries signed, ratified or acceded

Montreal Protocol

1987

Basel Convention

1989

Rotterdam Convention

1998

Stockholm Convention

2001

Minamata Convention

2013

Chemical Weapons Convention

1992

Agreement

Table 2: FACS countries and the several Agreements Note that while the Hong Kong Chemical Society and the Chemical Society located in Taipei are members of FACS their governments do not sign or ratify international agreements.

December 2021 | 117

Johnston Atoll Chemical Agent Disposal System during “Operation Steel Box”. “Operation Steel Box”, also known as “Operation Golden Python”, was a 1990 joint U.S.-West German operation which moved 100,000 U.S. chemical weapons from Germany to Johnston Atoll. decomposition of ozone’ 13 . The trade issues behind the BRS Conventions had less global publicity but environmental concerns eventually led to these Conventions. The Minamata Convention will see the disappearance of mercury from the industrialised world. The Chemical Weapons Convention emerged from concern for disarmament within the political and legal worlds concerning the law of armed conflict and international humanitarian law. In all these discussions, the knowledge and skills of chemists engaged with legal and diplomatic colleagues to resolve what needed to be done to negotiate the CWC and establish the implementation organisation, the Organisation for the Prohibition of Chemical Weapons (OPCW). The OPCW’s achievements were recognised with the Award of the 2013 Nobel Prize for Peace ‘for its extensive efforts to eliminate chemical weapons’ 14. It is impossible to count the number of chemists who have been involved in the development and the maintenance of these Conventions and Protocols, but they must surely number in the thousands Many of these would have come from our region across Asia and the south Pacific. On a more formal level, the international union for chemistry, IUPAC, has continuing cooperation with the OPCW, which also has a link to the Federation of European Chemical Societies (FECS). When the CWC was opened for signature in the January 1993, the FACS passed a motion of strong support for the Convention. The OPCW has been very active in developing guidelines for chemists faced with ethical issues in their 118 | December 2021

professional life 15. These Hague Guidelines have received broad support within the international chemistry community. Considerable progress has been made on ridding the world of chemical weapons, but more work on disarmament still needs to be done. The Conference on Disarmament meets three times a year in Geneva and thirteen FACS countries are members of the Conference (Australia, Israel, Japan, New Zealand, Korea, Turkey, Iraq, Malaysia, Mongolia, Pakistan, Sri Lanka, Vietnam and China). Two other FACS countries regularly send observers (Philippines and Singapore). There is no doubt that FACS chemists are relevant to the efforts of their diplomats! Additional challenges remain for science diplomacy involving chemists. The convergence of chemistry and biology poses particular challenges for controlling the emergence of new chemical-biological weapons 11 . Another issue where chemists will be needed is responding to the current concern with controlling marine plastics pollution, a topic attracting global media attention 16. It is clear, as noted in the 2015 editorial already cited 7, that scientists, particularly chemists, can advance humanity in multiple ways, well beyond their obvious contribution to science and technology. ◆

Acknowledgements

The authors wish to thank their colleagues Veronica Borrett, Robert (Bob) Mathews and Ian Rae for helpful discussions in the preparation of this paper and the Editor for constructive comments.

References

1. A short version of this paper was published in

2. 3. 4. 5. 6. 7. 8. 9.

10.

11. 12.

13. 14. 15. 16.

Chemistry in Australia. John M Webb, Thomas H Spurling and Gregory W Simpson, Chemistry in Australia, December 2020 – February 2021, p.33 Davis, L S and Patman RG, Science diplomacy: new day or false dawn? World Scientific 2015 Krasnyak O and Ruffini P-B, Science diplomacy, Oxford Bibliographies 2020 Flink, T. The Sensationalist Discourse on Science Diplomacy: A Critical Reflection. The Hague Journal of Diplomacy 15, 359-370 (2020) Day, D, Antarctica. A Biography. Random House Australia 2012 614pp https://www.ats.aq/e/secretariat.html Keinan E, Diesendruck C and Reetz M https:// onlinelibrary.wiley.com/doi/full/10.1002/ ijch.201510013. https://www.sesame.org.jo/about-us/historicalhighlights I Rae and A Gabriel, Saving the ozone layer: Why the Montreal Protocol worked, The Conversation 2012 https://theconversation.com/saving-the-ozone-layerwhy-the-montreal-protocol-worked-9249. Accessed 21 April 2021 Robert J Mathews, ‘Chemical and Biological Weapons’, Chapter 12 in ‘Routledge Handbook 0f the Law of Armed Conflict’, Eds (Rain Liivoja and Tim McCormack), (Routledge London, 2016), pp. 212-232. JE Forman, CM Timperley, S Sun and D van Eerten, Chemistry and Diplomacy, Pure Appl Chem 90(10), 1507-1525 (2018) CW Timperley et al. (29 authors) Advice from the Scientific Advisory Board of OPCW on isotopically labelled chemicals and stereoisomers in relation to the CWC, Pure Appl Chem 90(10), 1647-1670 (2018) https://www.nobelprize.org/prizes/chemistry/1995/ summary/. Accessed 10 May 2021 https://www.nobelprize.org/prizes/peace/2013/pressrelease/. Accessed 10 May 2021 https://www.opcw.org/hague-ethical-guidelines. Accessed 28 April 2021. K McVeigh, https://www.theguardian.com/ environment/2020/nov/16/us-and-uk-yet-to-showsupport-for-global-treaty-to-tackle-plastic-pollution The Guardian 16 Nov 2020, accessed 6 May 2021

www.facs.website

19 TH

19ACC

Asian Chemical Congress

8–14 June 2023 (Tentative)

Istanbul University Congress and Culture Center

We, as the Turkish Chemical Society, are excited to be the host for the 19th Asian Chemical Congress (ACC) and the 21st General Assembly of the Federation of Asian Chemical Societies (FACS), taking place 8–14 June 2023 (tentative) in Istanbul, Turkey. The ACC is a biennial event is organized by members of the FACS to promote the advancement of chemistry and related disciplines, offering the opportunity to learn from experts, share experiences and debate challenging topics. We are looking forward to seeing you in Istanbul. Prof. Mustafa Culha On behalf of the organizing committee

Organization Secretariat Lorem ipsum

Bilge Yuksel bilge.yuksel@brosgroup.net

www.acc2023.org

The Bowei Research Conference (BRC) series was created by the LCY Education Foundation. The third BRC will include plenary lectures, short lectures, poster sessions, and social events. The three-day event will take place on January 3-5, 2023 in Southern Taiwan in an informal environment. The scientific program, which will focus on functional materials, was prepared by the Scientific Advisory Board. Attendance, by invitation only, is limited to 120 participants. LCY Education Foundation, the event’s sponsor, was founded by entrepreneur Bowei Lee, a chemical engineering graduate from MIT with an MBA from Stanford University and the chairman of LCY Group, which is headquartered in Taiwan. The Foundation aims to empower young talent and upgrade chemical academic research for the chemical industry. In addition to the BRC series, the Foundation has developed several programs, such as the Student Scholarship Award and Young Professors of Excellence Award.

SPEAKERS

Takuzo Aida

Harry Anderson

Zhenan Bao

Luisa De Cola

Ben Feringa

Alon A. Gorodetsky

Bartosz Grzybowski

Stefan Hecht

K. Barry Sharpless

Samuel Stupp

Omar Yaghi

Jackie Y. Ying

University of Tokyo Japan

University of Groningen, Netherlands Nobel Prize 2016

The Scripps Research Institute USA Nobel Prize 2001

University of Oxford UK

UC Irvine USA

Northwestern University USA

Stanford University USA

UNIST South Korea

UC Berkeley USA

University of Strasbourg France

Aachen University Germany

A*STAR NanoBio Lab Singapore

International Scientific Advisory Board: Ehud Keinan (Chairman), Technion, Israel; Jacqueline K. Barton, California lnstitute of Technology, USA; Ilan Marek, Technion, Israel; Scott Miller, Yale University, USA; Eiichi Nakamura, The University of Tokyo, Japan; Helma Wennemers, ETH-Zurich, Switzertand; Chi-Huey Wong, The Scripps Research Institute, USA Taiwan Local Scientific Advisory Board: Ying-Chih Chang, AcademiaSinica; Ito Chao, AcademiaSinica; Chia-Chun Jay Chen , National Normal University; Jiun-Tai Chen, National Chiao Tung University; Jeng-Shiung Jan, National Cheng Kung University; Hsiu-Po Kuo, National Taiwan University; Shiao·Wei Kuo, National Sun Yat-sen University

BRC CONTACTS: Dr. Andrew Chen andrew.chen@lcygroup.com Ms. YJ Jii Yuehjin.jii@lcygroup.com

BRC WEBSITE: https://sites.google.com/view/brc-portal/home

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