Chemistry: a Bridge Between Molecular World and Real World

J. Synth. Org. Chem., Japan, 76, 1232-1246 (2018) : doi.org/10.5059/yukigoseikyokaishi.76.1232

Chemistry: A Bridge between Molecular World and Real World

Eiichi Nakamura

Department of Chemistry, The University of Tokyo, Bunkyo-ku, Tokyo, Japan E-mail: [email protected]

Abstract: This essay summarizes a personal history of studies on fluoride-mediated reactions of enol silyl ethers, metal homoenolate, cytochalasin and cortisone synthesis, cycloaddition chemistry of cyclopropenone acetals and dipolar trimethylenemethanes, biological activity of organofullerenes and DNA and siRNA delivery, organocuprate(I) reaction mechanisms, iron-catalyzed cross coupling and C–H activation reactions, 15O labeling for positron emission tomography (PET), functional fullerene molecules including bucky ferrocene, shuttlecock molecules and [10]cyclophenacene, fullerene bilayer vesicles, new design materials for organic and lead perovskite solar-cell fabrication, carbon-bridged oligophenylene vinylenes and single- molecule atomic-resolution real-time transmission electron microscopy (SMART-TEM) for structural and kinetic studies of molecules and molecular clusters. It also describes how the encounters with key people may change the course of your scientific research as well as of your personal life. These examples suggest that life is a stochastic process, and, moreover, science in the future would be something that we do not even imagine now as a subject of research.

1. My Interest learned only a few words of Hebrew, including “slihah,” My interest in exploring the unknown was probably (excuse me) a word of absolute necessity in a crowded bus in fostered through the quest of model building. Building wooden Tel Aviv, this extended trip, generously supported by my 1/1000-scale model battleships of the Japanese Navy was my parents and grandparents, via London–Rheine–Köln– serious undertaking in the primary school period. During the Nürnberg–München–Graz–Rome–Athens–Istanbul–Israel– high school to college years, I made 1/80 brass models of Japan Ulm–Paris for three months became the most valuable treasure Railways trains and steam locomotives, such as Series 1550 in my life. and 1810, using drills, saws and a lathe, day and night. The year 1969 was the year of student movements all over Retrospectively, scratch building from brass sheets and rods the world, and the entrance exam of the University of Tokyo was indeed a very creative activity; I made model locomotives was canceled at short notice of 44 days. This changed my following 2-D plans in the catalog of the Imperial Japanese destination to Tokyo Institute of Technology (TIT), in which I Railways, which gave me the length and height of the engine had never thought of becoming a faculty member. I asked a (8,928 mm and 3,658 mm, respectively, in the case of Series question to Prof. Aoyagi, an applied chemistry professor, 1550), and 3-D plans reconstructed from several old “Who is the best chemist in TIT?” and he said, “Mukaiyama,” photographs. who was only 42 years old at that time. The year 1972 was the time when the Mukaiyama aldol reaction was being developed by Dr. Koichi Narasaka, an assistant professor in the lab, and when I started my undergraduate work. I worked on the hydrolysis of 1,3-dithiane mediated by CuCl2/AuClO4, and a formidable explosion put me out of action through injury for nearly half a year. So I did not do too much in the Mukaiyama lab, but still learned much about his philosophy—“Don’t imitate others.”

Figure 1. Engine 1550 Series on iPhone 5.

2. My First Research Paper: “The Israel Railway–Past and Present,” 1972 My interest in formal research started in 1971 when I was 20 years old, working as a summer trainee in the Derech Petah Tikva dairy factory of Tnuva in Tel Aviv. An encounter with excavated 1050-mm gauge rail/crosstie composites at the location of the old Tel Aviv Railway Station stirred my interest in this peculiar gauge. After a half-year investigation during Figure 2. Prof. Mukaiyama at an alumni party around 1980. the stay in Israel and also back in Japan, I published a research paper in Railway Pictorial, 1 describing how the Hejaz 3. My First Chemistry Paper: “Fluoride Ion Activation Railways started in the Near East, and how the railroads thrived of Enol Silyl Ether,” 1975–1983 after the establishment of Israel in 1948. The Hejaz Railways may be best known through the film Lawrence of Arabia, in When Prof. Mukaiyama moved to the University of which a steam train is blown up by Lawrence. Although I Tokyo in April 1973, he asked me to work with a newly

1 J. Synth. Org. Chem., Japan, 76, 1232-1246 (2018) appointed associate professor, Dr. Isao Kuwajima. He had studied with Prof. E. J. Corey and asked me to test many of his ideas on a variety of research projects—different subjects every few months. Watching how chemistry research was done in the top laboratories, I thought that being a player in the Chemistry World Series was more interesting than being an amateur historian studying British colonial railways in his spare time—it was my planned life’s work when I was a sophomore student. Two lectures during the master studies left a great impression on me. Prof. Akio Yamamoto hosted Prof. Melvin Calvin, who talked about the importance of sunlight harvesting—a subject of our research now. I remember that I asked a question about the connection between light harvesting and the molybdenum chemistry that he mentioned in his lecture. Another lecture, also hosted by Prof. Yamamoto, literally changed my life. It was a lecture by Prof. Iwao Tabushi on quaternary ammonium phase transfer catalysis in water, and I became curious about the possibility of generating an ammonium enolate–a naked enolate. My idea was to push up energetically a neutral enol silyl ether into an enolate anion through compensation of the energetic penalty by forming a strong Si–F bond. Enol silyl ether was an intermediate developed earlier by Prof. Gilbert Stork and used for the Mukaiyama aldol reaction. I was struck then by the realization that the best substrate I chose based on conventional wisdom was, in fact, the worst substrate, and the worst was the best. Chance favors the prepared mind. Figure 4. The Kuwajima Group around 1980 with Hirokazu Urabe (now TIT) and Byeang Hyean Kim (POSTECH) in the front row.

During the Ph.D. study, I noted a fundamental limitation of enolate chemistry in that the enolate anions do not add to simple olefins because of the large exothermicity of such reactions. It was 20 years later that I solved this problem by using zinc enamide, which allowed me to add a ketone enamine to an olefin and even to a vinyl Grignard reagent to obtain an a-alkylated ketone. 4 Interestingly, I could add a zincio Figure 3. My first successful research idea: Generation of an enamide to gaseous isobutylene to achieve even t-butylation of anion from neutral precursors through energy gain by the a ketone. formation of a stable Si-F bond. 4. Metal Homoenolate and Cyclopropanone Acetal, 1977–1987 My mother passed away on February 4, 1975, as a result Homoenolate ion is a b-anion of a carbonyl compound, of metastatic cancer. I wrote a one-page article for the and is an intermediate proposed in the 1960s as a putative Communication section of J. Am. Chem. Soc. (JACS) during transient species in carbanionic rearrangements. During a study the time I was away from the lab for her funeral. The paper was on the reactivity of 1,2-siloxycyclobutene, I noticed that a received by the JACS office on February 24, my 24th birthday, silylated hemiacetal of cyclopropanone is available on a large and appeared in print in May–my first chemistry publication.2 scale by reductive cyclization of a 3-chloropropionate ester. I Prof. Kuwajima then received a letter from Prof. Noyori, a thought that the fluoride ion could induce ring opening to rising star at that time. The letter said that he was working on generate a homoenolate anion, but this idea failed. Instead, I the same chemistry as applied to the aldol reaction. found that the Mukaiyama conditions worked perfectly— Collaboration including Mr. Makoto Shimizu, who served as a “electrophilic activation of an aldehyde partner with TiCl .”5 Dean until this March at Mie University, started and continued, 4 Sounds wonderful! However, very deep coloration of the to produce our first joint paper in JACS in 1977, followed by reaction mixture made me suspicious about the Mukaiyama- another one after I came back from Columbia.3 Through this type mechanisms … I asked Prof. Akio Yamamoto about the collaboration, I learned Prof. Noyori’s tenacity to seek for the possible involvement of titanium homoenolate, but the ultimate truth. organometallic background of mine at that time was too weak During the Ph.D. period, Prof. Tabushi brought me to study such a brand new organometallic species in a another life event -- a one-on-one dialogue with Prof. Don professional manner. Cram in his office in Kyushu University. It was just the beginning of Prof. Cram's Nobel-prize-winning work, and I followed his work carefully after my personal acquaintance with him.

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+ TiCl4 H Me3SiO O CHO EtO H R NHBoc OTHP Me3SiO O HN R OMe EtO EtO (MeO) PO OTHP O 2 O • H O TiCl4 OH H Li H R COOMe O EtO

OH Figure 5. Homoenolate: Lewis acid mechanism or H organometallic intermediate? OH OH HN O HN O 5. Westbound Trip to New York City, March 20–April 20, O O O O 1978 cytochalasin B After consultation with Profs. Mukaiyama, Kuwajima, Figure 7. Cytochalasin B synthesis. Noyori, the late Tabushi, Hisashi Yamamoto, and Takashi Takahashi in 1976, I decided to work with Prof. Gilbert Stork Organic chemistry at Columbia was extremely strong in for the postdoctoral study. Yoko and I, newlyweds, left Tokyo research and education. Every Thursday evening after dinner, westbound for New York City on March 20, 1978. We traveled we had an organic seminar/problem session where all organic through Istanbul, Athens, Crete, Florence and Zürich. Prof. professors, Stork, Breslow, Nakanishi, Katz, Turro and Still, Dieter Seebach was kind enough to provide me an opportunity sat in the front row of a classroom in the Havemeyer Hall and to give a seminar at ETH Zürich, then in the city center, and gave insightful comments for students and postdocs. I met Prof. put us up in the Hotel Poly nearby. We put away the Amos Smith in a graduate classroom one day. Amos was on honorarium of 40 Swiss francs in an ETH envelope so carefully his sabbatical. The weekly Thursday Departmental Seminar in that we could not find it again. It was my second research the main lecture theater invited eminent speakers such as Prof. seminar, after the first one during my Ph.D. study kindly Wilkinson, a colleague of Gilbert at Harvard. I was therefore organized by Dr. Iwao Ojima, then at the Sagami Chemistry greatly thrilled when I was later invited to give a Gilbert Stork Research Center. We left Europe from Milano Malpensa Lecture there in 2006. I was nominated by Gilbert to the Airport to arrive at NYC on April 20. American Academy of Arts and Sciences, and inducted in 2008. Gilbert sent me an e-mail on July 29, 2008:

Dear Eiichi, getting together with Yoko and you for dinner Thursday, October 9 sounds great! But, there is a condition: we will take you out–after all, how often does one of my former associates get inducted as a Foreign Honorary Member of the American Academy of Arts and Sciences? All the best to you and Yoko, Gilbert

Figure 6. With Prof. Seebach at ETH, April 12, 1978.

6. Total Synthesis of Cytochalasins, 1978–1980 The project in Prof. Stork’s laboratory was the total synthesis of cytochalasin families via a macrocyclic Diels– Alder reaction. On the first day at Columbia, Gilbert took me to the library, quickly looked through many issues of Chemical Abstracts and suggested a few synthetic routes and synthetic Figure 8. With Prof. Stork at Columbia in 1988. intermediates to me. I wished to contribute to the Stork lab with my expertise in synthetic methodology, and incorporated two The Xmas party was another entertainment at Columbia 6 new reagents in the total synthesis of cytochalasin B and F. I Chemistry, which always featured Koji Nakanishi’s famous recall that I did 750 experiments/year then, the most productive magic and, in 1979, a rare B-class movie “The Big Drop” period as a bench chemist. I met Gilbert for the last time on produced by Carl Djerassi. Gilbert tried in vain to sell this April 11, 2018, when he had just submitted his last movie in NYC. I later benefited very much from being a 7,8 publication. member of the Stork Mafia, a Columbia alumnus and a member of the natural product chemistry family in the US and in Japan, where people from chemical, pharmaceutical and biological communities gather. From Gilbert, I learned mentorship, different from the Mukaiyama/Kuwajima style. It helped me greatly in my career development. I also learned that “A research seminar must be entertaining for the audience. Details can be learned from publications.”

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7. Metal Homoenolates via C-C Bond Activation, 1980– cyclopropenones. 15 With these cyclopropenones in hand, I 1988 imagined intercalating them among DNA base pairs. During a When I came back to the Kuwajima lab as Assistant discussion with Dr. Ryoichi Ando of Mitsubishi Chemicals, Professor, I managed to identify the putative titanium however, this idea underwent complete metamorphosis into the homoenolate involved in the TiCl4-mediated reaction after design of enzyme inhibitors. Ron passed away last year considerable detours. 9 I then synthesized a number of 3- following Gilbert. metallated propionate esters 10 and transient palladium homoenolates from 1-alkoxy-1-siloxycyclopropane, 11 and applied this chemistry to the synthesis of adrenal hormone12 and marine sterols originally isolated in the Red Sea near OO OO OO Israel. 13 This cyclopropane ring-opening reaction is, M R R' retrospectively, remarkable in two respects: as a demonstration of the utility of functionalized organometallics, and as a rare, O R2 O H N OR3 and perhaps too early, example of efficient catalytic C–C bond R1 N OO + OO H cleavage. OH O ± R - During the study of zinc homoenolate, I found that R' vinyl carbene trimethylenemethane Me3SiCl vastly accelerates the conjugate addition of calpain inhibitor organocopper reagents. 14 Circumstantial evidence suggested intermediacy of a triorganocopper(III), which led me later to Figure 10. From metallated cyclopropenone acetal to enzyme perform systematic theoretical studies on the mechanism of organocuprate(I) reactions. inhibitors and singlet biradical reactive species. Through the coupling of a metallated cyclopropenone acetal and an amino aldehyde, we synthesized a variety of OSi(CH ) 3 3 peptidyl cyclopropenones, some of which inhibited cysteine COOR COOR OR 16 R1COCl/cat. Pd proteases very well, and were further developed by the R1 O O OSi(CH3)3 ZnCl 2 (CH3)3SiCl/cat. Cu Mitsubishi Chemicals people, but died during an animal 1 2 COOR R CHO/R COCl R1 X cat. Cu COOR OR toxicity test. This work on cyclopropenones provided me the R1 OCOR2 R1 1 2 1 X R C(OR )2 2 R first opportunity to learn about the connection between my own cat. Cu Zn O cat. Ni COOR COOR molecular world and the real world of business. From this 1 X 1 R CHO/(CH3)3SiCl ArX R R1 OR2 cat. Pd cat. Pd R1 experience, I formulated my view about the role of a university COOR COOR COOR professor in society. “Scientists should provide solutions to 1 Ar R OSi(CH3)3 R1 social problems and dreams for people.” This statement at the 43rd ACS National Organic Chemistry Symposium (June 23 Applications to OH OH OH to 27, 2013) was cited by Chemical & Engineering News steroid syntheses O O OH OH among “Quotes of the Year 2013.” OR

M O O HO 9. Methylenecyclopropane and Trimethylenemethane, cortisone depressosterol 1989–1995 Shigeru Yamago, who was my first student, isomerized a Figure 9. Zinc homoenolate and steroid syntheses. methylcyclopropenone acetal (R = Me) into a methylenecyclopropane (MCP, R¢ = H) as a stable distillable The work on the metal homoenolate brought me the compound. We then discovered a thermal [3 + 2] cycloaddition Young Chemists Award from the Chemical Society of Japan reaction with electron-deficient olefins and C=X bonds—a (CSJ) in March 1984, and, on December 16, promotion to Associate Professor at TIT, where I started my independent thermal endo-selective 6-p cycloaddition of a trimethylenemethane biradical to form five-membered rings career. I did not then expect that so many from my research 17,18 group, now counting 13, would later receive the same prize. even at room temperature, albeit slowly. Profs. Mukaiyama and Noyori kindly wrote recommendation I have kept my eyes on buckminsterfullerene (C60) as a letters for me for this position. A memorable event then was a strained olefin since 1985, when my high-school classmate, face-to-face discussion with Prof. Roald Hoffmann of Cornell Prof. Hideo Aoki, then in the Physics Department in Tsukuba for 30 min on the occasion of his TIT visit just after his Nobel University, challenged me about its total synthesis. Therefore, Prize. I owe very much to Prof. Hiroshi Kobayashi, who kindly when C60 became commercially available in 1992, I was eager to examine C60 as a cycloaddition partner of MCP. To our arranged this discussion. Friendship with Prof. Jerry Meinwald 19 of Cornell and his wife Charlotte through music also started at pleasant surprise, the reaction went very well. The product this time. I owe a great deal to Jerry and Roald who provided was a ketene acetal that gave an ester upon hydrolysis. My me much help on a variety of occasions in my professional life. interest in DNA reared its head again: Can we bind this 1-nm- Last year, Yoko and I had occasions to have dinner with Jerry sized molecule to the major groove of DNA? My interests and and Charlotte, in Paris and in Tokyo, without realizing that it research focus were changing rapidly then. would be the last time to see Jerry.

8. Cyclopropenone Acetal and Enzyme Inhibitor, 1985– 1995 During the study of the homoenolate chemistry, I became fascinated by cyclopropenone, for which Prof. Ron Breslow had published an Org. Synth. preparation. Extending Ron’s methodology, I developed a new synthesis of substituted

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had just returned from Yale. At dinner at Yale with Prof. Fred OO OO Ziegler, a dozen fried oysters came as a starter, which made me OO CH CN 3 O CN completely full! At Cornell, I gave a seminar on Friday and a OO concert on Sunday in the A.D. White House for Friends of Ph NC CN O n-Bu CO2Et O O Music with Jerry and Charlotte, and professors of the Cornell Ph O O O2 Music School. Bu CO2Et

Ts OO N OO (CH3)3Si SOCH3 Ph Ph N Ts OO+ Ph (CH ) Si SOCH MeO C Ph 3 3 3 2 N C60 - Ph O R R' O OO OO O O NCO2Me R' Ph R + (1) H3O , (2) succinic anhydride

O O 14 C OH OO O

Figure 11. From trimethylenemethane to water-soluble 14C- labeled C60.

10. Discovery of Biological Activity of Fullerenes, 1989– Figure 12. With Prof. Danheiser at MIT with JACS and 2015 Prof. Yukio Sugiura came from Kyoto to lecture at TIT Tetrahedron Letters in the back in 1988. hosted by Prof. Takashi Takahashi. In the evening drinking By the time I turned 40, I was receiving some recognition session, I talked about my idea of the DNA binding of C60, and his response was, “I tried the same idea without success from the chemistry community. I was invited by Prof. Scott Denmark as the inaugural R. C. Fuson Visiting Scholar at the because C60 doesn’t dissolve in water at all.” Shigeru Yamago and Hidetoshi Tokuyama prepared a succinate derivative of our Chemistry Department of the University of Illinois (1990). Scott and his colleagues thought that Yoko and I would do C60 derivative, and it was immediately tested in Kyoto. After two weeks, they found that our water-soluble fullerene cuts pretty well at Illinois. Thus, on my second visit to Illinois, I DNA, and, as studied at Mitsubishi Chemicals, it also inhibits paid a visit to Prof. E. J. Corey, who was at Illinois before enzyme activities. Our paper was first submitted to Nature, moving to Harvard. EJ gave me strong encouragement, and where it was rejected with an appalling reviewer comment, escorted me from his office to the Harvard Square Station! I “too weak activity to be useful as an anticancer drug,” and then continued to stay at TIT, however. published as a JACS Communication.20 Alas, while our work was in press, a paper by Prof. Fred Wudl reporting on AIDS 12. Visiting Taiwan and China: Profs. Luh and Dai protease inhibition also appeared in print in JACS and received Sometime in 1991, a former student Masahiko Isaka, now worldwide publicity. We studied the metabolism of a 14C- in Thailand, visited Prof. Tien-Yau Luh in Taipei and this was labeled derivative in mice showing that this compact and my first connection with TY. Since then, we have worked hydrophobic compound passes through the blood–brain together on a variety of occasions, including a Pacifichem 2000 barrier.21 Regioselective DNA cleavage was made possible by symposium that we coorganized with Rick Danheiser, and the triple-helix formation by tailor-designed fullerene–DNA Tateshina Conference started in 2000. Then, sometime in 1993, conjugate molecules made through collaboration with the late on the occasion of a symposium in Nagoya, Prof. Noyori Prof. Claude Helene in Paris.22 introduced me to Prof. Li-Xin Dai, who kindly arranged my The work on the biradical chemistry and some early first visit to China in May 1994—the beginning of my close works on fullerene science brought me the Japan IBM Science connection to China. This visit has had a big impact on my Prize, as supported by Prof. Hisashi Yamamoto, whom I met academic and personal life. I visited Shanghai Institute of in the summer of 1993 in a Gordon Conference in New Organic Chemistry, Fudan University and the Institute of Hampshire. Chemistry at the Chinese Academy of Sciences in Beijing. Through the connection established by this first tour, I later 11. My First Lecture Tour in the USA, 1988 became very close to Prof. Li-Jun Wan—the former Director At the 1987 Taniguchi Conference on catalysis held in of the Institute of Chemistry and the President of The Kobe, I shared a room with Prof. Peter Vollhardt of Berkeley University of Science and Technology of China, where a in a Japanese inn at Kurashiki, and he strongly recommended number of my former associates are now working as faculty, me to do a US lecture tour. Prof. Rick Danheiser of MIT, including Prof. Yutaka Matsuo. Li-Jun has ascended the career another member of the Stork Mafia, kindly arranged a terrific ladder to the rank of the 19th Central Committee of the two-week tour through MIT–Harvard–Yale–Columbia– Communist Party of China. Merck–Cornell–UCLA–Caltech–Stanford–Berkeley and the ACS LA meeting. At Harvard, I had dinner with Profs. E. J. Corey, Yoshito Kishi, David Evans and Stuart Schreiber, who

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Figure 13. With Prof. Dai with The Bund in the back in 1994. Figure 14. The 41st Group Seminar at Tateshina in 2013. 13. Group Management: Lab Manual and Tateshina Group Seminar On the basis of my experience in Israel during my college By the end of the 90s, I was rarely working in the lab years, I have almost all of my Ph.D. students do research in myself after my Grignard experiment blew up, and I realized foreign universities and companies. I recall, however, that until that management of people was the single most important key the mid-1990s, our government did not allow us to use research issue for running a productive and self-motivated research money for overseas travel expenses of graduate students, and group. As I realized that some excellent knowledge and know- we needed to raise money from companies for their travel and how cannot be transmitted through generations, I wrote “The living expenses for the summer research activities. I thank here Nakamura Laboratory Manual,” where I summarized our best all of my overseas friends who have willingly accepted my laboratory techniques so that good traditions could be students in the past 30 years. maintained. We read through the entirety of this 130-page manual every April 1. The front page reads as follows: 14. Moving to the University of Tokyo, 1995 One day in the November of 1994, I received a phone call Actual Planning of the Experiment (a daily, weekly and monthly plan is essential) to take up the Physical Organic Chemistry Chair of the University of Tokyo, to succeed Prof. Hiizu Iwamura, famous In planning the experiments for a day or week, consider such for his organic magnets. Being then a synthetic organic chemist, combinations as the following: I was a little hesitant to take up this important position. After Difficult experiment vs. Simple experiment 25 years, though, I am more of a physical organic chemist than Experiment likely to succeed vs. Experiment likely to fail a synthetic organic chemist. Your work environment creates Time-consuming experiment vs. Quick experiment your career. Two facts astonished me when I moved to the Hongo *Prioritize all issues and then address the important ones first. campus. First, I found that eight professors, including the late Often, the issues you are willing to address are typically not the Prof. Kazuo Tachibana, out of some 50 faculty members in the important ones. Chemistry Department had graduated from the same high *Learn not only the knowledge and information but also the school, which produces only 160 graduates per year. methods to acquire such knowledge and information. Undoubtedly, science teaching there was enlightening and *Protect yourself. Wearing protective goggles is mandatory. Awareness as a researcher is demonstrated by assuming fruitful. I owe the most to my teachers, Messrs. Hisao Fukuoka, responsibility for personal health and the wearing of protective Hiroya Shiroki and Ichiro Tada, who inspired me in a variety clothing. of subjects, chemistry, art, and music. Second, I found that my My long-standing interest in research management office on the fifth floor of the Chemistry West Building continued into my 40s. To cultivate a culture of cooperation in overlooks the old part of the University Hospital campus, my group, I started the “Tateshina Group Seminar Series” at where I was born on February 24, 1951. Even more astonishing the Harmony-no-Ie (the house with harmony), held twice a is that our new office and lab since April 2016 are located year since the fall of 1993. We have just finished the 50th exactly in this old campus of the pediatrics division (the seminar this May. We leave Hongo on Friday morning to arrive maternity ward had long been demolished). I have returned to at Tateshina by noon to start the group seminar at 1 pm, the birthplace of mine! followed by an onsen (hot bath) nearby and BBQ from 5 pm. After recessing to the house around 8 pm, we spend a relaxing time till well after midnight. On Saturday morning, we have breakfast at 8 am on the terrace, resume the seminar, have lunch, clean up the rooms and leave Tateshina at 3 pm to come back to the university by 6 pm. This short retreat in the woods has become a part of our lab life, leaving a fond memory for us all.

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Figure 16. A new reaction mechanism of conjugate addition of

(Me2CuLi)2 of methyl vinyl ketone. The fastest computer then was slower than the PC now. As Moore’s law predicted, by 1994, I could study systems as complex as the conjugate addition of solvated Me2CuLi dimers with methyl vinyl ketone. The first communication on a new mechanism of conjugate addition was submitted to JACS and rejected essentially by one reviewer. It was sent then to Angew. Chem. and rejected again by the same reviewer. We prepared two full papers back to back on the new mechanisms of conjugate addition and carbocation, and they were finally published after one year in 1997.23 The reviewer was silent and the mechanisms are now widely accepted.24 We also studied a variety of bimetallic systems, such as Li–Li, Zn–Li, Zn–Zn and Mg–Zn, as well as Co–Co, Rh–Rh, Ru–Rh and Co–Rh.25 The mechanism of Cu- and Rh-catalyzed C–H activation of diazoacetate that I studied with Naohiko Yoshikai stimulated 26 Figure 15. Born in the University Hospital of U Tokyo on my interest in C–H bond activation. February 24, 1951. 16. Iron Catalysis for Organic Synthesis and the “Element Strategy Initiative,” 1997–present 15. Mechanism of Organocuprate Reactions, 1990–2012 For reasons unclear to myself, I have been trying to do As soon as I became an Associate Professor in 1984, I something different from others since my childhood. Therefore, started an effort, albeit fruitlessly, to work on computational I have always stayed away from popular palladium catalysis. chemistry, in which I had had a long-standing interest. I Instead, I worked on zinc, titanium, copper, nickel and iron. obtained a magnetic tape copy of the MNDO/C program from Because 56Fe is the final product of element synthesis in the Prof. Eiji Osawa and compiled the program on the university universe, it is abundant and nontoxic. However, it took me a mainframe computer. After playing around for six months, I long time to decide to study iron because reactive iron species found it useless to study the subject of my interest. This attempt are often too active, and die quickly before doing anything in 1985 produced fruit later. Upon my appointment in 1989 as good in a flask. Adjunct Associate Professor at the Institute of Molecular We started to focus on iron catalysis in the late 1990s with Science (IMS), Prof. Keiji Morokuma offered me the Masaharu Nakamura, my fourth assistant professor and now opportunity to work with his postdoc Andrea Dorigo on a Kyoto Professor. It took us a few years to publish our first subject of my choice. I have published 10 JACS papers with paper on a new iron-catalyzed reaction, asymmetric Keiji. Sadly, he died last year when he was almost back to work carbometallation reaction—the first example of organoiron- after a heart attack two years ago. catalyzed asymmetric synthesis. 27 After working on iron- The IMS Hitachi computer system was the same as the catalyzed substitution reactions for some time,28 we made a TIT system, and therefore I could immediately start my work. serendipitous discovery of C–H functionalization in 2006 I first taught Masaharu Nakamura how to input data and to together with Naohiko Yoshikai, my seventh junior faculty analyze the output, and the theory tradition in the group member and now at Nanyang Technological University. 29 continued through Seiji Mori, Masahiro Yamanaka and Since then, a large part of the work was developed together Naohiko Yoshikai. I spent the next 25 years on computational with Dr. Laurean Ilies, the 13th staff member in our group, now research and answered many of my own questions on the at Riken.30 mechanism of organocuprate reactions and other metal- catalyzed reactions. Although organic chemists in those days 2004 cat. were somewhat skeptical about my efforts, now after 30 years, Fe(III) + none of them would have any objection to acknowledging the X BrMg importance of computation/theoretical chemistry for organic 25 °C X = I, Br, Cl 99% chemists.

2016 O O OH OH PPh2 cat. + P N Fe(III) Me H PPh2 + AlMe3

O B Cl Cl O B O 70 °C O 89%

Figure 17. Iron-catalyzed cross coupling, and C–H activation.

Organized by Profs. Shinji Murai and Kohei Tamao, the Japan Science and Technology Agency (JST) held a workshop Transition state of C–C bond formation on “Dream Materials in the 21st Century,” where many interesting futuristic ideas were proposed. To fit all these ideas into one single scheme for policy makers, I summarized the discussion by coining the term “Element Strategy Initiative.” This project was implemented in 2007 as two government

7 J. Synth. Org. Chem., Japan, 76, 1232-1246 (2018) projects in MEXT and METI. This initiative provided a model for similar projects in the EU, USA and China. The concept of the Element Strategy Initiative is detailed in my Commentary in Nature Materials.31

17. DNA and siRNA Delivery with Aminofullerene, 1997– present Having the university medical school was an obvious asset of Hongo for me over TIT. When the chair of the Recombinant DNA Committee was assigned to me, I started to work together with Prof. Hiroto Okayama on the use of aminofullerenes for in vitro and in vivo delivery of DNA.32 A graduate student, Hiroyuki Isobe, pushed this new area forward. He was my fifth assistant professor, later a Tohoku Professor and now my successor in the Physical Organic Chemistry Chair at Hongo. We continue to work in this field (siRNA) with Prof. Eisei Noiri of the University Hospital and Dr. Koji Harano, a current associate professor in my group.33 Figure 19. Multiple addition of organic groups to C60. 18. PET Imaging with a 122-s Half-life 15O-Glucose, 1995– 2007 During our move to Hongo, Dr. Masaya Sawamura, my In my second collaboration with industry, I developed a third assistant professor, and a new student, Hitoshi Iikura, new positron emission tomographic (PET) imaging reagent, joined my group, both from Kyoto. They made a big discovery. 15O-labeled glucose. This short-lived PET imaging agent is I asked Iikura to control Grignard addition to fullerene with a 18 11 faint hope of creating a cyclopentadienyl anion out of a useful for multiple labeling studies using F- and C-labeled 37 drugs. The study was planned and executed together with Dr. pentagon in C60. Our lab was then studying organocopper Shintaro Nishimura of Fujisawa Pharmaceuticals (now chemistry; it was perhaps natural for him to add a pinch of a Astellas Co.) and Dr. Hideki Yorimitsu, an SPD JSPS postdoc copper salt to the reaction mixture of a phenyl Grignard reagent. from Kyoto, who also contributed to shifting my interest into He found, in his HPLC chart, a trace of a peak with a molecular electron-microscopic imaging. 34 The idea of this synthesis weight corresponding to C60(C6H5)H–the unexpected but originated from our own synthetic method for ultrasound- desired product. In a few months, he improved the yield from initiated oxygenation of organic radicals, and the challenge a few percent to over 90%. Further pursuit of this reaction later was how to combine rapidly and effectively a glucose molecule by Dr. Yutaka Matsuo, my sixth assistant professor, produced and a 15O atom that has a half-life of only 122 s. The whole over 800 multiaddition products of this kind that we published project took 10 years. In 2005, we published an ultrarapid in the literature. He has been extremely productive in my group 15 and published over 120 papers on the synthesis and solar synthesis and bioimaging of O-labeled 2-deoxy-D-glucose, synthesized in 1.5 min on an automated synthesis/purification applications of organofullerene compounds. flow system. 35 This compound is still the most complicated 15O-labeled compound ever made.

Figure 18. 15O-labeling of glucose for PET imaging. Adapted with permission from ref 35. Copyright 2005 John Wiley and [10]Cyclophenacene Sons [10]cyclophenacene 19. Bucky Ferrocene, Shuttlecock and Vesicles, 1998– present After some success in the biological research on Figure 20. Bucky ferrocene and double-decker bearing a organofullerenes, I decided to explore more seriously the [10]cyclophenacene part structure. potential of organofullerenes. The fruit of this decision was the discovery of an efficient, scalable synthesis—regioselective With Yutaka Matsuo’s expertise in inorganic chemistry, and high-yield penta-addition of organocopper reagent to we could make numerous organometallic complexes [60]fullerene. This was the most intriguing and productive highlighted by bucky ferrocenes–a hybrid of fullerene and subject of my research, which illustrates how science starts ferrocene.38 [10]Cyclophenacene in a “double-decker” bucky from a seemingly minor detail and self-propagates into ferrocene is another intriguing system that we reported in something unexpected—in this case, atomic-resolution 2003.39 It is a fully conjugated hoop-shaped aromatic system electron-microscopic imaging of organic molecules and their that had defied synthetic efforts for half a century since the 36 reactions. theoretical prediction by Heilbronner in the 1950s. The double- decker is an aesthetically pleasing organometallic compound. The compound caught the eye of Roald, who made the following remark and invited me to Cornell as a Blomquist

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Lecturer in 2006. Yoko and I enjoyed playing for the School of Figure 22. Watertight bilayer vesicle of fullerene anion. Music Lunch Concert with Jerry and Charlotte again. Adapted with permission from ref 42b. Copyright 2001 The American Association for the Advancement of Science. “Beauty does not reside in simplicity. Nor in complexity, per se. For a molecule or a song, for a ceramic vase or a play, beauty is created out of the labor of human hands and minds. 20. Contribution to the Academic Society It is to be found, precarious, at some tense edge where Tateshina Conference on Organic Chemistry, 2000– symmetry and asymmetry, simplicity and complexity, order and 2010 chaos, contend.”40 The Tateshina Conference on Organic Chemistry is an offshoot of my social “Fava-Bean (Sora-mame) Group,” organized with Mr. and Mrs. Shigeyuki Koide. Through this fava-bean scheme, I conceived a new type of chemistry conference in the woods away from towns. I consulted Profs. Noyori, Murahashi and Otera as well as Profs. Li-Xin Dai, Yong Hae Kim, Tien-Yao Luh and Henry Wang of Hong Kong, and held a test conference in 2000. The first official conference started in 2001; it was run together with Prof. Keisuke Suzuki until 2010, and now by Prof. Shū Kobayashi. It is designed as a Far East version of the Bürgenstock Conference and Gordon Conference to foster friendship among industry and academic researchers in this area of the world. In 2003, Prof. Jack Roberts of Caltech came with his wife, Edith, and introduced Prof. Gilbert Stork for 30 min with many stories on adventures from the early days, such as Gilbert’s waving Edith’s red coat at a bull.

Figure 21. With Profs. Hoffmann and Meinwald, Charlotte, and Hsu.

Our research activity toward material science was driven by collaboration between Prof. Takashi Kato in the School of Engineering and Masaya Sawamura, and later Dr. Matsuo in my group, who conceived the possibility of 1-D stacking of pentaorganofullerenes like badminton shuttles. 41 This molecular packing attracted a great deal of attention from the general public throughout the world. When Masaya was entertaining freshmen of the university – at a summer school, he discovered that the (C6H5)5C60 anion forms a homogeneous aqueous solution,42 and I happened to have a chance to discuss this puzzling phenomenon with Prof. Ben Chu. Being the world expert on the analysis of Figure 23. Gilbert, Jack, Minoru Isobe, and Edith (from right) polyelectrolytes in water, Ben found out what was going on. In at the Tateshina Conference in Harmony-no-ie 2001, we published a paper together in Science reporting that this anion forms a bilayer vesicle in water. This story also Academic Journal Publication, 1992–present greatly entertained the general public and was cited in an My appointment as Associate Editor of Chemistry Letters annual encyclopedia published in Spain! in 1992 was the beginning of my association with journal We are continuing to work on the fundamental studies on publishing. I helped Prof. Shunichi Murahashi remodel and the unique behavior of the fullerene amphiphiles with Koji reform Chem. Lett. operations. One day in 1999, I received a 43 Harano, and with Prof. Motomu Tanaka of Heidelberg. phone call from Scott Denmark, who delivered a message from Amos Smith soliciting me to work for Organic Letters. Org. Lett. was one of the first electronic-communication-based ACS journals; the data on a host computer located in my office were updated every night via a telephone line! During my travels abroad, I received, every morning at the hotel, tens of pages of manuscripts by fax. By the time I started to serve as Associate Editor of J. Am. Chem. Soc. in 2009 upon request by Prof. Peter Stang, all was done quickly through the Internet.

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about the governmental research support system. I commuted every Thursday and Friday to my office at the JSPS for three and a half years, and we set up new rules and protocols for funding for basic research in Japan. Working together with people including the JSPS General Manager, Ms. Maki Kubo, Profs. Hideo Utsumi and Hiroaki Aihara, a KAKENHI reform committee that I chaired proposed a future plan for funding reform, which has been mostly implemented in the funding system in the past 10 years.45 Subsequently, I was recruited by JST as Chair of the Board of Program Directors for their funding (ERATO/CREST/PESTO) and worked together with the JST staff members and the MEXT officers to draft future plans for needs-oriented research in Japan.

Pacifichem 2010, 2015, and 2020 In 2005, I joined an international team for Pacifichem Figure 24. Inauguration of CAJ with Profs. Noyori, Tatsumi, 2010 and 2015 headed by Profs. Howard Alper and Peter Stang, respectively. The Japanese committee included Profs. Mitsuo Murai, Drs. Gölitz and Wille in Palace Hotel (2005). Sawamoto, Kazu Tatsumi, Kaoru Yamanouchi, Hiroshi Kitagawa and Atsushi Takahara—a wonderful team working Chemistry—An Asian Journal together and roaming around the Pacific Rim countries. The Between Org. Lett. and JACS, from 2006 to 2009, I Pacifichem 2015 meeting hosted a record-breaking 16,000 worked for Chemistry—An Asian Journal (CAJ), an outcome participants from all over the world. Pacifichem Inc. was of the Tateshina Conference on Organic Chemistry, which Drs. founded in 2016 as a nonprofit organization in Washington Peter Gölitz and Eva Wille visited in 2003. In 2005, Profs. D.C. to take care of the organization of the Pacifichem Noyori, Murai and Tatsumi, and Drs. Gölitz and Wille and I meetings, and I just succeeded Prof. Shinji Murai as the finalized the details of the organization of the journal over President of Pacifichem. Inc. heading toward Pacifichem 2020. dinner in the Palace Hotel in Tokyo. Peter was kind enough to publish a special issue in February 2011 celebrating my 60th 21. Nakamura Functional Carbon Cluster ERATO birthday (kanreki), for which my old friend, Shuzaburo Shibi, Project, 2004–2010 designed a cover page.44 This issue contained an editorial by A five-year ERATO project literally changed my research Roald and as many as 56 papers by the authors listed below, life in a way I had never dreamed of. A chance of a lifetime for which I thank all of my friends. came to realize my motto: “Scientists should provide solutions to social problems and dreams for people.” The pioneering Contributors: Professors and Drs. Roald Hoffmann, Seiji entrepreneurial spirit of Prof. Kikunae Ikeda, the discoverer of Shinkai, Terunori Fujita, T. S. Andy Hor, Valentine P. the umami taste in our department, helped me to ponder on this Ananikov, Irina P. Beletskaya, Jin-Ho Choy, Martin Pumera, issue.46 With this grant, I switched my research toward the Tsukasa Matsuo, Kohei Tamao, Keisuke Suzuki, Takashi nano and mesoscopic boundary between the molecular world Matsumoto, Naohiko Yoshikai, Insung S. Choi, Klaus Müllen, and the real world—what I believed to be the research subject Varinder K. Aggarwal, Younan Xia, Hisashi Yamamoto, Teck- of the 21st century. During the ERATO period, I had the Peng Loh, Jun Okuda, Zhenfeng Xi, François Diederich, Guy immense honor of receiving the Medal of Purple Ribbon from Bertrand, Alakananda Hajra, Masaya Sawamura, Takeshi his Majesty. Several other eminent prizes from CSJ, the Akasaka, Shigeru Nagase, Jian Pei, Li-Jun Wan, American Chemical Society, the Royal Society of Chemistry, Ayyappanpillai Ajayaghosh, Andreas Hirsch, Hiroshi and the Fujiwara Foundation followed. Watanabe, Shigeru Yamago, Kimoon Kim, Yong-beom Lim, It was a top-down project, and one day in the summer of Myongsoo Lee, Ian Paterson, Gernot Frenking, Eric Meggers, 2004, I had 1.8 billion yen (US$1.5 million) at my disposal. Diego J. Cárdenas, Antonio M. Echavarren, Won Jong Kim, The aim of the project was to extend my synthetic expertise to Byeang Hyean Kim, Wonwoo Nam, Erhard Kemnitz, Sergey I. a new world of organofullerenes and nanotubes (with Yutaka Troyanov, Masahiro Yamanaka, Paul Knochel, Tien-Yau Luh, Matsuo as group leader), to printable organic electronics (Dr. Hiroyuki Arai, Makoto Arita, Masayuki Inoue, Chi-Ming Che, Yoshiharu Sato), and to molecular imaging at atomic Waka Nakanishi, Hiroyuki Isobe, Hidetoshi Tokuyama, Tohru resolution with transmission electron microscopy (TEM) (Dr. Fukuyama, Dawei Ma, Wei-Zheng Weng, Hui-Lin Wan, Kazu Suenaga and later Dr. Masanori Koshino). An Atsushi Wakamiya, Kenichiro Itami, Andreas Pfaltz, Keiji administration team headed by Dr. Takao Kaneko and Ms. Maruoka, Jeffrey W. Bode, Shū Kobayashi, Zuowei Xie, Chul- Akemi Maruyama was truly instrumental for the success of this Ho Jun, Hee-Yoon Lee, Young Ho Ko, Mikiko Sodeoka, project that changed my research field afterward. In fact, I must Hideki Yorimitsu, Koichiro Oshima, Iwao Ojima, Stefan admit that I was a complete amateur in these areas when we Matile, Shingo Ito and Kyoko Nozaki. started. No results were obtained in the first 18 months, but significant progress was made by 2006 in both organic solar JSPS Program Officer and JST Program Director, cells and microscopic imaging. I was much relieved. 2003–2015 A sudden intrusion in 2003 into my calm academic life was the new job as Senior Program Officer of a newly established KAKENHI funding center at the Japan Society for the Promotion of Science (JSPS), where Profs. Ryoji Noyori, Tasuku Honjo and the late Yoji Totsuka served as directors. Although it was an entirely unwanted job, I did it with my characteristic perseverance and eventually learned thoroughly

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started to work then on lead perovskite solar cells, and we are continuing with Drs. Yunlong Guo, my seventh associate professor, and Rui Shang, the eighth, on the inorganic and crystallographic mechanistic studies on lead perovskite,49 and development of a new concept of hole-transporting materials.50

23. New p-Systems, a Solid-state Laser and Molecular Wire, 2006–present Dr. Masaharu Nakamura left our group to succeed Prof. Tamao in Kyoto in 2006. I then hired as my fourth associate professor Dr. Hayato Tsuji from the Tamao Group, and later also Dr. Shunsuke Furukawa, my 15th staff member, to explore the potential of new heteroaromatics for organic electronic research. We first synthesized a variety of benzodifurans and their nitrogen, phosphorus and silicon congeners,51 and finally came up with a carbon version, carbon-bridged Figure 25. The future of chemistry in the 21st century lies in oligo(phenylenevinylene)s (COPVs) with Dr. Xiaozhang Zhu, 52 the nano–mesoscopic boundary. now a professor in Beijing. This last class of compounds features an entirely flat and rigid conjugated system, exhibiting 22. Organofullerenes and Printable Solar Cells, 2009– 100% quantum yield of fluorescence and hosting highly stable present negative and positive polarons as well as excited states as Prof. Katsumi Yoshino of Osaka University is a pioneer shown by studies with Profs. Juan Casado and Shinichi of photon-induced charge separation using fullerene as an Ohkoshi. Thus, they show excellent photostability and serve as acceptor. A casual conversation with him in the late 1990s led a highly efficient dye for a solid-state laser, as studied with Prof. 53 us to work together to use my organofullerene repertoire for María A. Díaz-García. An electron tunnels through the solar-cell applications. By the time Dr. Sato joined the ERATO COPV framework, rendering these compounds effective project, I was quite confident that our repertoire of single-molecule molecular wires as studied with Prof. Dirk 54 organofullerenes, then well over 200 in number, gave us a Guldi. chance to be a winner in this competitive field of solar-cell research. Serendipitously, we found in 2006 a method to induce phase separation between tetrabenzoporphyrin (BP) and silylmethylfullerene (SIMEF), which formed a nm-scale “column–canyon structure.” 47 This work turned out to be widely cited because of its uniqueness in the use of small molecules for efficient photovoltaic conversion. It took us the following 10 years to understand why such columns of BP molecules form so readily.48

Figure 27. COPV molecules—flat, rigid and robust p-system for molecular transistors and solid-state lasers.

24. SMART-TEM Movie of Individual Molecular Events, Figure 26. Column–canyon device made of BP and SIMEF. 2004–present The world-first filming of the motions and reactions of single organic molecules was the most memorable discovery This nanostructure was ideally suited for charge in my research life. A dream of watching individual chemical separation at the donor–acceptor interface, and the device reactions with my eyes came to my mind during the theoretical recorded 7% in our lab. The technology was immediately studies where I saw everyday virtual images of molecules on a transferred to Mitsubishi Chemicals, who heavily modified the computer screen. I really wished to see how real molecules device structure and recorded the world’s highest efficiency of react with each other. After 15 years of endeavor, we recently >11% for their single-cell solar cells in 2011. The long succeeded in determining the kinetic parameters of a chemical collaboration with Dr. Hiroaki Yamaoka of Mitsubishi Chemicals on the R&D of the solar-cell business has been a reaction to discuss the reaction mechanism by just watching individual reaction events with variable-temperature atomic- very rewarding experience for me. resolution TEM. The work on our side was pushed forward by a device My dream, originally very vague, was materialized with specialist, Dr. Hideyuki Tanaka, my 14th staff member. I an unanticipated encounter with Prof. Sumio Iijima at a hot

11 J. Synth. Org. Chem., Japan, 76, 1232-1246 (2018) spring resort in Nagano in 1999. The whole story started to evolve with the ERATO project with Drs. Kazu Suenaga, Hiroyuki Isobe and later Masanori Koshino as Group Leaders, and we have developed a protocol for atomic-resolution imaging of single organic molecules in action,55 which we named “single-molecule atomic-resolution real-time TEM movie imaging technology” (SMART-TEM).56

25. Capturing of Transient Species in Solution: Crystallization Mechanism, 2010–present The SMART-TEM fishing strategy provides a unique Figure 28. The first movie of the conformational change of an experimental method for capturing otherwise undetectable organic molecule. Adapted with permission from ref 55a. transient species in a variety of chemical systems. We first tested this potential on crystallization. Phase separation, of Copyright 2007 The American Association for the which crystallization is an important member, is one of the Advancement of Science. most ubiquitous yet least understood phenomena in chemistry. During our study on the imaging of C–C bond rotation, I One referee of our Science paper called our work the serendipitously found a TEM movie image of a termolecular “Holy Grail of microscopy,” while the other two were skeptical, aggregate of Y-shaped tribromide molecules, and I thought that saying “The TEM data are heroic and very new. However, the it may well be a “prenucleation molecular cluster” that people interpretation of those incredible images is not convincing at have long tried in vain to identify.58 With Koji Harano, my best and dead wrong at worst.” It took 10 years for people to sixth associate professor, working together with our TEM change their opinion of our work: “Professor Nakamura’s staffs and Prof. Ludwik Leibler of Paris Tech, we redesigned campaign … has been a hard-fought uphill battle for more than the experimental system and succeeded in capturing and a decade, but he has achieved a level of success that many identifying the structures of long-sought molecular clusters thought would be impossible” (a review comment for my that precede the formation of crystals. We are currently trying 57 recent Account published in 2017). to identify intermediates of metal–organic frames (MOFs), and also working on the control of the crystal nucleation processing, targeting drug formulation. A future target would be the mechanism of protein aggregation and folding by taking advantage of our ability to capture molecular clusters from solution. Dr. Takayuki Nakamuro, my 18th junior faculty member, has just joined our group from Kyoto/Nagoya to explore new directions of TEM research.

O Br HN

Br + Br Br Figure 29. Chemical fishhook strategy that we developed. 2 Adapted with permission from ref 57. Copyright 2017 Br American Chemical Society. Figure 31. Capturing of a transient, termolecular, van der The development of “chemical hooks” was the key for the Waals cluster preceding crystal growth. Adapted with successful imaging of single molecules. To visualize single permission from ref 58. Copyright 2012 Nature Publishing organic molecules by TEM, the specimen molecules are put in Group. the nm-scale imaging field of the TEM by use of a functionalized single-walled carbon nanotube (CNT). To 26. Chemical Kinetics by Watching Individual Reaction capture molecules on the surface of a carbon nanotube, we Events One by One, 2015–present developed a method to synthesize aminated carbon nanotubes A big recent technology progress since 2005 is the and then formed an amide bond with the specimen molecules. introduction of complementary metal oxide semiconductor

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(CMOS) camera. This camera allows us now to continuously 103–203 K, and the apparently slow “rate” of the dimerization monitor molecular motions and reactions with a frame rate as originates from the extremely low frequency of the reaction. fast as sub millisecond, while the conventional charge coupled Thus, the first path with an activation energy of 33.5 kJ/mol device (CCD) worked only intermittently because of one- occurs with PEF of 3.9 ´ 10–4, while the second with an second long data retrieval time, during which we may miss extremely small activation energy of 1.9 kJ/mol occurs 3000 some important molecular event taking place. times less frequently. We surmised that this frequency General skepticism about the SMART-TEM movie difference originates primarily from the faster frequency of the imaging continued for several years after our 2007 Science vertical S0-to-S1 excitation than that of radical cation formation, paper, as I learned from the reviewers’ comments in many of which requires geometry changes of both CNT and C60. our publications. Such skepticism was expected because the The examples given above amply illustrate the difference molecular motions and chemical reactions that we saw were so between the SMART-TEM imaging and the cryo-EM method unusual. The basic premise that escaped the notice of the honored with the 2017 Nobel Prize in Chemistry. Our method reviewers was that what we are observing is a quantum is unique in that we can see and study, at atomic resolution, the mechanical phenomenon occurring probabilistically rather static and time-dependent structural features of individual than a classical mechanical one that occurs statistically. This single molecules and their assemblies attached to a CNT, while was initially pointed out by our chemical physics colleague, the latter provides the image of molecules frozen in ice Prof. Kaoru Yamanouchi. averaged over molecules and time, that is, a quality similar to The caveat was that no one has ever imagined it possible that of crystallography. The method also differs from scanning to observe in situ individual molecular events one by one, as probe microscopy, which can study essentially static molecules we do with the SMART-TEM technology. Since 2014, we fixed on a flat substrate. quantitatively examined this problem of the “rate” of the observed molecular events for [2 + 2] dimerization of C60 under I often cite in my SMART-TEM lectures the following 1-D conditions. We succeeded for the first time in determining remarks by Robert Hooke, the predecessor of Isaac Newton in the “frequency” of chemical reaction events, and determined the Royal Society, and known for Hooke’s law of elasticity. the kinetic parameters, by observing individual reaction events one by one. We found that seemingly random reaction events “The truth is, the Science of Nature has been already too long follow the rule of quantum mechanical transition state theory made only a work of the Brain and the Fancy: It is now high when the integrated sum of events are considered. The concept time that it should return to the plainness and soundness of of “reaction rate” that we are so familiar with gives way to Observations on material and obvious things.” (Robert Hooke, “frequency” (e.g., pre-exponential factor, PEF) of seemingly Micrographia, 1665) random individual events.59 The Science of Nature he is referring to is biology and time astronomy, which then developed quickly thanks to optical 8 sec 1 2 3 4 5– 6 7 8 9 10 11 12 13 14 15 16 17 microscopy and the optical telescope. After all the progress of chemistry since the 19th century, chemistry may have too long relied on a work of the Brain and Fancy, and it may be high time to return to the plainness and soundness of Observations 197 sec 1 2– 3 4 5– 6 7 8 9 10 11––12 13 14 15 16 17 of molecular matters with the aid of atomic resolution TEM movie imaging.

402 sec 1 2 3 4 5 6 7 8 9 10 11 12 13 14

2 nm

1 Total 39 events found 60 Integration 0.8 of events rate const 6 443 K 0.6 0.0445 4 0.4 x 10–6 e–1 nm2 2 0.2 Remaining C Remaining 0 0 0 20 4060 80 100 0 2040 60 80 100

Reaction events 6 – –2 Total elect dose [106 e– nm–2] Total elect dose [10 e nm ]

activation PEF energy mechanism (e–1 nm2) (kJ/mol) Figure 33. "Micrographia 350" Symposium in Christ Church, singlet path (493–593 K) 33.5 ± 6.8 3.9 x 10–4 Oxford, 2015, with one of the 17 original prints of –7 radical cation path (103–203 K) 1.9 ± 0.7 1.4 x 10 Micrographia.60 Figure 32. From random events of the dimerization reaction of 27. “Molecular Technology Innovation” Endowed Chair, C60 to activation energy and frequency of reaction events. 2015–present Adapted with permission from ref 59. Copyright 2017 In this rapidly changing world, things have started to American Chemical Society. change even in this most ancient country. A party commemorating the inauguration of "Molecular Technology The quantitative data showed that the reaction occurs Innovation" Endowed Chair started at 5 pm on July 3, 2016 either via S1 excited state at 393–493 K or a radical cation at

13 J. Synth. Org. Chem., Japan, 76, 1232-1246 (2018) with a speech of Prof. Makoto Gonokami, the President of the he or she knows how it should have been started and University of Tokyo, preceded by a symposium featuring conducted.”61 I might add then, “Science in the future would lectures by Profs. Takuzo Aida, Rick Danheiser, Ludwik be something that we do not imagine now as a subject of Leibler, Tien-yau Luh, Klaus Müllen, Ian Paterson, and Li-jun research.” The future of chemistry rests on the shoulders of the Wan. Establishment of this Chair Professor position was an young generations reading this essay. indication of the forthcoming changes put forward by Prof. Gonokami, and I am still carrying out my research and Acknowledgements education activities just as before as a member of the The research, educational and social activities Department of Chemistry in a new building – "Molecular and summarized above were possible only through collaboration Life Innovation Building" completed on February, 2016 in the with the dedicated members of my research group, who University Hospital Campus next to the Chemistry Building. A number roughly 300, many from foreign countries. The group state-of-the-art JEOL TEM with the world fastest camera activities from 1984 until today have been maintained together designed for use in the SMART-TEM study is in the basement by 18 junior faculty members. I express my sincere with a 5-m thick concrete foundation, and synthetic and device appreciation to the alumni of the Nakamura Group for their laboratories on the 7th floor. This way, I continue to explore contributions and cooperation and hope they develop their own the chemistry that connects the molecular world and the real interest to promote science and technology for sustainable world. development of our society. I also thank the JSPS and JST for continuous and generous financial support, and Towa 28. Conclusion Pharmaceutical, JEOL Ltd., Mitsubishi Chemicals and the Donald and Jane Cram once said, “An investigator starts Kaiteki Institute for the establishment of the endowed chair. research in a new field with faith, a foggy idea, and a few wild experiments. Eventually, the interplay of negative and positive References results guides the work. By the time the research is completed,

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