At the dawn of novel aromatics: “On the Synthesis of Hinokitiol” by Tetsuo Nozoe et al.

Abstract

A paper titled “On the Synthesis of Hinokitiol” appeared in this journal in 1950 and marked the beginning of a new research field of novel aromatics.

Introduction

The Proceedings of the Japan Academy and its predecessor, the Proceedings of the Imperial Academy, had an important place in the early-stage career of eminent chemist, Professor Tetsuo Nozoe. This “man of boundless energy”¹⁾ started his long, 70-year path in organic chemistry at this journal in 1926.^2)–4),¶ Unusually, this 1926 paper had one name, Tetsuo Nozoe, as a single author to describe his undergraduate research,^5),# and Nozoe’s supervisor, Rikō Majima,⁶⁾ only appeared as an academician who communicated this study to the Academy, with acknowledgment received from Nozoe for his courteous advice.^‡,§ This paper starts with the following introductory paragraph (Fig. 1): “In connection with other studies, it seemed very desirable to investigate the behavior of some quinoline derivatives against reducing agents. First, the easily accessible quinoline-2,4-dicarboxylic acid was subjected to this experiment. This experiment has not yet been fully completed, but because of personal reasons the experiment had to be discontinued. I therefore take the liberty of reporting here at least the results obtained so far”. This “personal reason” unexpectedly led this 24-year-old chemist to his life in Formosa (Taiwan) for 22 years and to his lifelong explorations of novel aromatics.

Fig. 1.

Nozoe’s first paper. Published at this journal in 1926 (reproduced from Ref. 2).

After 14 years from his first paper,²⁾ Nozoe contributed three consecutive papers to the seventh issue of this journal in 1950: “On the Synthesis of Tropolone (Cycloheptatrienolone)”,⁷⁾ “On the Synthesis of Hinokitiol (m-Isopropyltropolone)”,⁸⁾ and “On the Synthesis of α-Thujaplicin (o-Isopropyltropolone)”.⁹⁾ These contributions were immediately followed by a large number of papers published in this journal within 6 years until 1956, which reflected Nozoe’s keen interest in a specific subject that was ignited by his discovery of “hinokitiol”.^10),11) His interest paved his straight path toward troponoid chemistry until 1996 over a span of 70 years from the first paper.^12),13) As there are many excellent papers and books about Nozoe’s works and life,^4),14),15) including his (must-read) autobiography,¹⁾ this commentary shall briefly describe his and relevant works by centering on one of his first monumental papers in this journal, i.e., “On the Synthesis of Hinokitiol”.⁸⁾

Encounter

The “personal reason” described in Nozoe’s first paper²⁾ originated from a job offer from Kinzo Kafuku at the Monopoly Bureau of Formosa. After Nozoe’s undergraduate research in 1926, Majima strongly urged Nozoe to go to Formosa and take this job by saying, “You know, Taihoku Imperial University will soon be established there, and it would be nice for you to be there now”, with a return telegram ready in his hand with a message of “Job offer accepted”.^16),17) At the Monopoly Bureau, Nozoe started working on taiwanhinoki (hinoki cypress; Chamaecyparis taiwanensis) essential oils, which was his first encounter with natural products from this tree.^18),19) After 3 years of his arrival in Formosa, Nozoe became an assistant professor in 1929 at the newly established Taihoku Imperial University and, along with his main studies of saponins and wool wax, started a small research project to reexamine other natural products from taiwanhinoki.^1),16) Among many specimens, a dark-red pigment, known as hinokitin, caught Nozoe’s attention. Embarking on preliminary studies of the red pigment, Nozoe found that its proposed chemical composition,²⁰⁾ C₃₀H₃₄O₁₀, was incorrect and determined it to be C₃₀H₃₃O₆Fe. With this preliminary discovery of an unusual iron complex, Nozoe received a research grant from the Imperial Academy (1935–1937, Suzuki Saburosuke fund) with the aid of Majima¹⁶⁾ and set out for further studies.

Discovery

In 1936, Nozoe published the first report on his discovery of “hinokitiol” in the Bulletin of the Chemical Society of Japan (Fig. 2).^21),22) This paper was written in German and appeared with a subtitle of “preliminary communication” in the third issue of 1936 that celebrated the 60th birthday (Kan-reki) of Rikō Majima.²³⁾ Some important descriptions are translated here: “Even in a very dilute solution, it is quite intensely red in color and has two absorption maxima at 584 and 540 mµ in the visible region of the spectrum. According to the analysis, its formula is not C₃₀H₃₄O₁₀ but C₃₀H₃₃O₆Fe; i.e., it contains iron contrary to all assumptions. If the iron is removed from hinokitin, a volatile oil of the formula C₁₀H₁₂O₂ is obtained, whose physical and other properties correspond fairly well to those of the original phenolic substance. When this oil is treated with ferric chloride, the hinokitin is quantitatively obtained again. The oil related to hinokitin in this way is now designated hinokitiol …. The relationship between hinokitiol and hinokitin is thus assumed to be as follows: 3C₁₀H₁₂O₂ + FeX₃ $ \rightleftarrows $ C₃₀H₃₃O₆Fe + 3 HX …. Thus, in summary, hinokitin and metal–hinokitiol complex salts generally have the following formula I and II, respectively, and, accordingly, the compounds of the complex salts with organic bases have formula III” (cf. Fig. 2). In this paper, Nozoe also reported complexes of hinokitiol with various metal ions (Cr, Fe, Co, Cu, Ni, Mn, Cd, Zn, and Mg).

Fig. 2.

A figure from Nozoe’s paper on the discovery of hinokitiol (1936; reproduced with permission from Ref. 21).

Entr’acte

Nozoe’s first “preliminary communication” on hinokitiol in 1936 did not have follow-up papers in an internationally accessible form until 1950. Even in Japan, only one oral presentation was conducted by his coworker in 1942 with its abstract being published later in a Japanese journal in 1944.¹¹⁾ It was a difficult time, as can be seen from a chapter titled “The War Years (1939–1945)” in Nozoe’s autobiography.^1),‡‡ In this section, some representative facts before his second paper on hinokitiol shall be described. For this purpose, his autobiography undoubtedly provided the best resource,¹⁾ and this author tried to add some more objective facts by referring to other resources. During this period, Nozoe became a full professor at the Taihoku Imperial University in 1937 and came back to Japan in 1948 to be a full professor at Tohoku University.

The first molecular structure of hinokitiol appeared in an oral presentation of Nozoe’s coworker (S. Katsura) at the annual meeting of the Pharmaceutical Society of Japan in April 1942.^11),24),25) According to Nozoe,^{26),27),††} “as a result of preliminary studies, Nozoe and Katsura in 1942 were forced to put out a tentative formula (A₁ or A₂) for hinokitiol as C₁₀H₁₄O₂” instead of the original composition of “C₁₀H₁₂O₂” that was determined and reported in 1936 (Fig. 3).²¹⁾ After this proposal, however, Nozoe went back to Formosa and reconfirmed that the original composition of C₁₀H₁₂O₂ was indeed correct by performing additional experiments. Unfortunately, he had no chance to present the corrected structures until 1949/1950.

Fig. 3.

The first hinokitiol structure with a seven-membered ring by Nozoe and Katsura (1942; reproduced with permission from Ref. 26).¹¹⁾ The finalized structure of hinokitiol appeared in this journal in 1950.⁸⁾

Although no report could be published, Nozoe must have recognized a correct molecular structure of hinokitiol during the war years. He must also have been confident about its anomalous, novel aromaticity by 1946 with evidence accumulated in his and coworkers’ experiments. This fact can be seen from his student’s (Tung-Bin Lo) recollections then in Taiwan.²⁸⁾ “In the fall of 1946, I took the ‘Organic Chemistry and Laboratory’ course taught by Professor Nozoe …. We did have weekly lectures, and Professor Nozoe showed us every detail in the structural elucidation of seven-membered conjugated hinokitiol. I recalled that Professor Nozoe taught resonance theory based on Linus Pauling’s ‘The Nature of the Chemical Bond’. He was so excited to apply this new theory to the structure of hinokitiol”.

At the dawn

The correct molecular structure of hinokitiol finally appeared in a paper titled “On the Synthesis of Hinokitiol”,⁸⁾ i.e., the second paper of Nozoe’s three consecutive papers published in the seventh issue of this journal in 1950. As Nozoe’s original paper will be reprinted in this journal along with this commentary, this author should not redraw the correct chemical structure of hinoitiol here and hope that the readers can enjoy examining Nozoe’s first, handwritten drawing of hinokitiol. By completing the synthesis of hinokitiol from a derivative of suberic acid, Nozoe concluded the paper with the following sentence: “From above mentioned synthesis there can be no doubt that hinokitiol is identical with m-isopropyltropolone (I)”. This statement was not only a conclusion of his work of hinokitiol but also one of declarations of a dawn of the chemistry of troponoids and the chemistry of novel aromatics.

When you examine the first paper of this series by Nozoe (“On the Synthesis of Tropolone (Cycloheptatrienolone)”),⁷⁾ you should immediately notice the presence of severe competitions that rapidly emerged during this period. Starting from Dewar’s proposal of a molecular structure for stipitatic acid, several papers were cited in the introduction.^29)–39) A new research field was emerging. For dramatic and exciting tales at the dawn of this field, the readers should enjoy reading every detail in Nozoe’s autobiography,¹⁾ and this commentary should describe some representative facts related to his publications in this journal.

In any competitive field that is internationally emerging, rapid disclosure of results by publishing papers in accessible forms is surely crucial. However, “in those days, there was no way of rapid publication of an article written in English in Japan (Nozoe)”.^1),¶¶ Consequently, Nozoe’s pioneering work on the structure elucidation of hinokitiol and tropolones was almost certainly unknown to Dewar and the other chemists who entered this field through another route in the 1940s, halfway around the world. In 1948, after obtaining his position at Tohoku University, Nozoe visited Majima in Takarazuka and explained his research on hinokitiol. Encouraging Nozoe for further studies, Majima told Nozoe: “the Japan Academy will soon resume the publication of the Proceedings in English, and I would be happy to communicate your results to the Academy”.¹⁶⁾ This eventually resulted in the publication of Nozoe’s 75 papers at this journal to cover 333 pages in total until 1956 (see Supplementary materials).^‡‡‡ To publish a paper in the Proceedings then, the handling academician was asked to deliver a lecture at the Academy by using brief flyers. Nozoe’s reminiscences about these processes for his papers would be suitable to close this section, which clarifies the role of the Academy and its journal for his early-stage research.¹⁶⁾

“Whenever Professor Majima came to Tokyo from Takarazuka, he would ask me about my research in the lobby of the YMCA, where he stayed. Professor Majima even wrote a flyer for his lectures about my research and introduced it at the meeting of the Japan Academy. When I told him that I would write a flyer for his lectures, he said, ‘I should write at least a flyer myself in order to talk about other people’s work’, and continued to do so indefinitely. I recall that I sometimes had to repeat the explanation of the reaction mechanism to Professor Majima many times for his lectures. Every month he wrote to me and asked me, ‘Aren’t you going to submit a paper to the Academy this month? I would be happy to introduce it anytime, so please feel free to contact me’. I sometimes felt that it was impossible for me to keep up with his expectations. In any case, thanks to his enthusiasm and encouragement, I was able to make up for the delay in my publications and gradually overtake the overseas researchers, even if only by a small margin …. In 1952, I received the Asahi Prize. Professor Majima was very pleased and made a joke during his speech for introduction at the ceremony: ‘Until Nozoe’s work, the chemical composition has been given as C₃₀H₃₆O₁₀ for hinokitin. However, this iron man, Tetsuo,^§§ successfully discovered that it indeed contains iron and gave it the correct chemical composition of C₃₀H₃₃O₆Fe …’ ”. In 1958, Majima wrote to the alumni association of Tohoku University, saying “From around 1956 at the turn of my 81 years old, I become old and have some problems with my leg. Since then, I cannot go out as much as I used to do”. Nozoe’s last papers at this journal appeared in its seventh issue in 1956.^{40),†††}

Never-ending story

Nozoe’s first paper on hinokitiol has been one of the first few drops of a stream, which, as the time flows, eventually forms a great river. With its bank located over the horizon, picturing countless drops of modern novel aromatics running there is beyond the reach of this author and this commentary. Nonetheless, to share some feelings about this never-ending story about hinokitiol, a rough sketch within sight of this author shall be given here.

For those who work in the field of novel aromatics,⁴¹⁾ joining and/or being invited to the International Symposia on Novel Aromatic Compounds (ISNA) are one of the most important experiences for their career.⁴²⁾ This author remembers, together with anxiety and excitement at his first ISNA, his first encounter with Professor Shô Itô who was 84 years old at that time (Fig. 4a).⁴³⁾ Itô was invited by the organizers as “a delegate from ISNA-1, 1970”,^44),45) which may highlight one of the remarkable features of ISNA: a warm atmosphere of “family”.

Fig. 4.

(a) A scene from an ISNA-14 banquet (2011). From left at the table: Shô Itô, Yasujiro Murata, Hiroyuki Isobe, and Kenichiro Itami. The three young chemists in this picture are recipients of “Nozoe Memorial Award for Young Organic Chemists” (The Society of Physical Organic Chemistry, Japan, http://jpoc.ac). Photograph was taken by Akihiro Orita. (b) The logo of the Department of Chemistry, Tohoku University. A heptagon is decorated with urushi leaves, which surround a flask, i.e., a cradle for a crescent moon of “C”hemistry. (c) A crystal structure of hinokitin, i.e., a complex of hinokitiol and Fe(III). The structure was created using the cif data of CCDC1536565 from a paper published in 2017.⁵²⁾ The data can be obtained free of charge from The Cambridge Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.

The number 36 of the Chemical Heritage by the Chemical Society of Japan is given to Nozoe’s collections of nonbenzenoid compounds and his autograph books (https://www.chemistry.or.jp/know/heritage/).⁴⁶⁾ The colorful collections of (heptagonal) nonbenzenoids can be viewed at the Tohoku University Museum, located nearby a heptagonal monument of troponoid chemistry in the Aobayama campus (http://www.museum.tohoku.ac.jp/center/aobayama-002.html). The heptagon was also featured in a logo of Nozoe’s alma mater, the Department of Chemistry, Tohoku University, with decoration of urushi leaves (Fig. 4b; http://www.chem.tohoku.ac.jp/).^47),48) Beside the nonbenzenoid exhibit at the museum, you can also find an exhibit of ciguatoxin, a contribution including a grandson of Nozoe’s family tree in chemistry.⁴⁹⁾ The readers of this commentary should not fail to visit Nozoe’s autograph books that are accessible at a website (https://application.wiley-vch.de/util/nozoe/).^15),50) A title, “Bonding beyond Borders”, given to the website shows the contents, and readers can see the myriad of bonds stemming from hinokitiol on the website.

Remarkably, the chemistry of hinokitiol and hinokitin by itself is also still active. The dark-red pigment of hinokitin, a complex of hinokitiol with iron, that “somehow attracted Nozoe’s attention (Nozoe)”⁵¹⁾ has recently attracted a renewed interest to result in a few papers. One paper published in 2017 revealed an extremely high association constant of 5.8 × 10²⁵ for the reaction reported by Nozoe in 1936 (3C₁₀H₁₂O₂ + FeX₃ $ \rightleftarrows $ C₃₀H₃₃O₆Fe)¹⁰⁾ and disclosed protein-like functions of hinokitiol for iron transport.^52),53) This author wonders if, along with a concluding remark of the new paper to suggest “broader scientific and therapeutic implications”, Professor Tetsuo Nozoe was delighted and excited to finally see the crystal structure of hinokitin (Fig. 4c).⁵²⁾

Supplementary materials

Supplementary materials (a list of Nozoe’s papers in this journal) are available at https//doi.org/10.2183/pjab.99.020.

Acknowledgments

The author wishes to express his gratitude to Professors Toyonobu Asao, Masahiro Hirama, and Lawrence T. Scott for reading a draft of this commentary and for their warm comments and valuable suggestions. He also thanks Professor Keisuke Suzuki for his kind encouragement and for bringing an important reference to this author’s attention. Mr. M. Takeuchi (Japan Academy) is also acknowledged for providing information about Nozoe’s relationship with the Japan Academy at his early-stage career.

Notes

Edited by Keisuke SUZUKI, M.J.A.

Correspondence should be addressed to: H. Isobe, Department of Chemistry, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan (e-mail: [e-mail]).

Footnotes

This paper commemorates the 100th anniversary of this journal and introduces the following paper previously published in this journal. Nozoe, T., Seto, S., Kikuchi, K., Mukai, T., Matsumoto, S. and Murase, M. (1950) On the Synthesis of Hinokitiol (m-Isopropyltropolone). Proc. Jpn. Acad. 26 (7) 43–46 (https://doi.org/10.2183/pjab1945.26.7_43).

¶ Some modern databases may not have entries of Nozoe’s early works. For instance, the Web of Science database does not have entries of Proc. Jpn. Acad. before 1960.

# Nozoe gave his undergraduate research presentation in the Majima group on March 22, 1926.

‡ This paper was the first paper that was communicated by Rikō Majima who became an academician in this year (1926).

§ The original manuscript was written in Japanese by Tetsuo Nozoe and was translated into German by Rikō Majima (see Ref. 1).

‡‡ As described by Nozoe (Ref. 27), even communications between Japan and Formosa (Taiwan) were intercepted since the middle of 1942.

†† The paper in Ref. 27 was a translated version of Ref. 26, containing some additional supplements.

¶¶ Nozoe’s manuscripts that were submitted to J. Am. Chem. Soc. were rejected, because “some references were in Japanese and were not available in the United States” (Ref. 1). One of the rejected papers was eventually published in Nature (https://doi.org/10.1038/167688b0), but it took almost 1 year from the initial submission to the publication.

‡‡‡ There are 11, 27, 13, 8, 8, 1, and 6 papers in 1950, 1951, 1952, 1953, 1954, 1955, and 1956, respectively. One of his students wrote in his reminiscence: “I vividly recall the sound of Professor Nozoe’s typewriter echoing like a machine gun” (see page 255 of Ref. 4). In this journal, there also appeared some papers on troponoid chemistry by other researchers.

§§ In Japanese, “Tetsu” means “iron” and “o” means “man”.

††† In recollection, one of Nozoe’s students wrote: “My presentation at a conference was coming closer. One night, right before the conference, Professor Nozoe dropped by the laboratory on his way back home with a bag in his hand. He looked at me and said, ‘Give me your draft for the flyer’. Taking off his jacket, rolling up his sleeves, he started writing the flyer on the desk next to me and urged me to continue my experiments” (page 229 of Ref. 4).

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Appendices

[From Proc. Jpn. Acad., Vol. 26 No. 7, pp. 43–46 (1950)]

Profile

Hiroyuki Isobe was born in Tokyo in 1970. He received his bachelor and master degrees from Tokyo Institute of Technology in 1994 and 1996 with Professors Eiichi Nakamura and Katsumi Kakinuma as actual and formal supervisors, respectively. He entered the Department of Chemistry of the University of Tokyo in 1996, and in the same year, stayed at Princeton University to work on oligosaccharides with Professor Daniel Kahne for three months. He started his academic career as Assistant Professor at the University of Tokyo in 1998 before receiving his Ph.D. degree (1999) and was promoted to Associate Professor in 2004. His early works on amphiphilic/gene-delivery fullerenes were recognized by several awards, including IUPAC Prize for Young Chemists (2000), Young Scientists Research Award in Natural Product Chemistry (2001), Chemical Society of Japan Award for Young Chemists (2004), Osawa Award (2005), Young Scientists Prize from MEXT (2008) and Nozoe Memorial Award for Young Organic Chemists (2009). In 2007, he was appointed as Professor at Department of Chemistry in Tohoku University where he was concurrently assigned as Principal Investigator of AIMR in 2013. He served as a research director of ERATO Isobe Degenerate π-Integration project from 2013 to 2019. In 2016, he moved back to the University of Tokyo. Since 2007, he renovated his lab space seven times, which involved two award-winning labs (Good Design Award, 2014 and 2017). His scientific works on nanocarbon molecules in these labs were recognized by Honorary International Chair Professorship of Taipei Tech (2015), Chemical Society of Japan Award for Creative Work (2016) and Inoue Prize for Science (2017).