NOZOE, TETSUO

(b. Sendai, Japan, 16 May 1902, d. Tokyo, Japan, 4 April 1996)

organic chemistry, chemistry of nonbenzenoid aromatic compounds.

A leading Japanese organic chemist, Nozoe discovered hinokitiol, a seven-membered aromatic compound, and based on this discovery developed a new area of chemistry known as nonbenzenoid aromatic compounds.

Early Life and Education Tetsuo Nozoe was born in Sendai, one of Japan’ s largest cities, located in northern Honshu, on 16 May 1902. His father, Ju-ichi, was born in Nagasaki prefecture in Kyushu, as the third son of Sukeuchi Kinoshita, in 1865, just three years before the Meiji Restoration, which marked the beginning of the modernization of Japan. When he was seventeen, Ju-ichi was adopted by a Nagasaki family, Yasouzaemon Nozoe, and sent to Tokyo to study at the Law College of the Imperial University, then the only university in Japan. In 1890, while still a student, he married twenty-year-old Toyo, the sixth daughter of his adopted family. When Ju-ichi graduated from the Imperial University in 1893, he became a lawyer and moved to Sendai, a central city in northern Honshu, the largest island in Japan, with his family. There, he became involved in politics, serving as chairman of the Municipal Assembly, and as a member of the House of Representatives for one term.

Tetsuo was the sixth of eleven children; he had seven brothers and three sisters. He first became interested in chemistry while in his early teens in junior high school thanks to a chemistry teacher, who inspired him to begin to do some experiments at home. In 1920 he entered Dai Ni Koto-gakko at Sendai (which literally means the second high school), one of the elite national all-male liberal arts colleges; most graduates went on to one of the imperial universities. Even though his parents wanted him to be a medical doctor and he initially took a premedical class, Tetsuo soon decided to study chemistry and entered the Department of Chemistry of the College of Science at Tohoku Imperial University in 1923.

Tohoku Imperial University was founded in 1907 as the third imperial university, after Tokyo (1886) and Kyoto (1897). With a research-oriented mission and liberal admission policy, the university opened its doors not only to graduates of elite all-male liberal arts colleges, from which Tetsuo graduated, but also to those who graduated from technical colleges as well as teachers colleges, including women’s teachers colleges.

The first professors in the Department of Chemistry included the distinguished chemists Masataka Ogawa, Masao Katayama, and Toshiyuki (Riko) Majima. Ogawa discovered a new chemical element, which he called “nipponium” (which was first incorrectly designated as the 43rd element but only recently shown to be rhenium). Katayama, a professor of physical chemistry, was a close acquaintance of Tetsuo’s mother; they were members of the same Christian church. Although Katayama transferred to Tokyo Imperial University before Nozoe entered Tohoku Imperial University, it was perhaps upon Katayama’s advice that Tetsuo decided on this university. There, Majima, a well-regarded professor of organic chemistry, became Nozoe’s mentor and was to play a decisive role in his life.

Nozoe’s Mentor: Riko Majima Born in 1874 in Kyoto, Riko Majima graduated from the Department of Chemistry of the College of Science at Tokyo Imperial University in 1899. After a four-year stay in Europe, from early 1907 to early 1911, he became a professor of organic chemistry at the newly established Tohoku Imperial University in March 1911. He was especially famous for the study of urushiol (a catechol [o-dihydrobenzene] derivative), the main component of the sap of the Japanese lacquer tree (Rhus verniciflua Stokes, urushi-no-ki in Japanese). The sap produced a black glossy varnish known as “japan” and japan ware was an important export product. From the very beginning of research on organic chemistry in Japan in the late 1870s, Japanese chemists often studied local natural products using methods newly developed in Europe. Majima, as well as Nozoe, followed this line of research. After discovering urushiol, Majima devised a new synthesis of the indole ring and started to study indole derivatives. As a leader of the first generation of research organic chemists, he contributed greatly to the establishment of organic chemistry laboratories in higher education and research institutes in Japan. Nozoe first studied the synthesis of indole derivatives under Majima.

Work in Formosa After graduating in March 1926, Nozoe stayed on as Majima’s assistant. However, at the end of June, Nozoe left Sendai for Formosa (now Taiwan) to become a researcher at the Monopoly Bureau in Taipei, the capital of Formosa, helped by Majima’s strong recommendation. As one of Majima’s most talented students, Nozoe was certainly a well-qualified candidate for a professorship at a planned new imperial university in Formosa. However, there may have been other reasons behind Majima’s help and recommendation. In 1920 Tetsuo’s father was elected a member of the Parliament (House of Representatives) after a heated general election against a local political leader, Ikunosuke Fujisawa, who later became the minister of Commerce and Industry and served as speaker of the House of Representatives. However, Tetsuo’s father lost his seat in the following election in 1924 to Fujisawa. The defeat was a terrible blow to Ju-ichi Nozoe, who died in 1927 at the age of sixty-one, and his family began to experience financial difficulties. This may partly explain why all five surviving brothers (the other three having died young), including Tetsuo himself, worked overseas: two elder brothers as engineers for overseas trading companies, one as a principal of an agricultural college in Manchuria, and the other as a banker in Manchuria.

Nozoe arrived in Taipei on 2 June 1926. After the Sino-Japanese War in 1895, Formosa had become a Japanese colony. In 1930 the population of the island was 4.6 million, of which 229,000 were Japanese. Japanese was the official language. Nozoe was employed at the Camphor Research Laboratories of the Monopoly Bureau for the first year and for the next two years at the Department of Chemical Industry of the Central Research Institute, both of which were institutes of the Formosan Government-General in Taipei. He worked under Kinzo Kafuku, a graduate of the Chemistry Department of Tokyo Imperial University and a leading chemist in Formosa since 1912. In 1927, a year after his arrival, Nozoe married Kyoko Horiuchi, Kafuku’s niece and a daughter of a director of an agricultural experimental station of the Formosan Government-General. The couple had one son and three daughters, all born in Formosa. Their son, Shigeo, born in 1931, followed his father’s path by studying chemistry at Tohoku University, where he later became a professor at the College of Pharmacy.

In 1928 Taihoku Imperial University (Taihoku is the Japanese name for Taipei) was established, and Kafuku became a professor of chemistry in the College of Science and Agriculture. Nozoe was appointed as Kafuku’s associate professor the following year. Taihoku Imperial University was the second Japanese imperial university in its colonies after Keijo Imperial University at Keijo (now Seoul), founded in 1925. Nozoe’s main research interest was the study of natural products, especially those found in Formosa. Nozoe started actively studying the structures of saponins, glycosides with a distinctive foaming characteristic, and sapogenins, derivatives of the triterpenoid groups and nonsugar components of sapogins, isolated from local fruits (Barringtonia asiatica and B. racemosa). In 1936 he submitted a dissertation to the newly established Osaka Imperial University, where Professor Majima had become dean of the College of Science, and received a doctor of science degree. The following year, Nozoe predicted the correct structures for oleanolic acid and hederagenin, well-known sapogenins, using ultraviolet absorption spectroscopy. In 1937, upon Kafuku’s return to Japan, Nozoe replaced him as a full professor at the university.

Nozoe also studied constituents of wool wax and those of other animal skin waxes and discovered a series of unusual branched chain fatty acids, lanolinic acids, and agnolinic acids (1939). However, World War II interrupted his studies. Aware of the profound advancements in these areas during and soon after the war, Nozoe did not resume these studies.

Discovery of Hinokitiol Nozoe’s most widely known research in Formosa was that on the chemical constituents of taiwanhinoki (Chamaecyparis obtusa var. formosana, now C. taiwanensis), a native conifer found in high mountainous areas. Some researchers in Japan were interested in the tree’s acidic components because of the tree’s resistance to wood-decaying fungi. Nenokichi Hirao, a chemist at a pharmaceutical company in Kobe, had reported the formation of a dark-red pigment from these components and had named it hinokitin in 1926. Nozoe obtained a phenolic compound, C₁₀ H₁₂ O₂, as the alkaline salt by shaking an ethereal solution of hinokitin with an aqueous alkaline solution (see Figure 1). The new compound was named hinokitiol and was first reported in 1936 in a special issue of the Journal of the Chemical Society of Japan to celebrate Professor Majima’s sixtieth birthday. Nozoe also proved that hinokitin, which was sublimable in vacuo and soluble in organic solvents, was an iron complex of hinokitiol, (C₁₀ H₁₁ O₂)₃ Fe, some of the earliest evidence for the presence of an iron complex in a natural compound.

Since the content of hinokitiol in taiwanhinoki is very low (0.1–0.2%), and even though he had found that hiba(Thujopsis dolabrata var. hondae), grown in northern Japan, also contained hinokitiol and became an important source of hinokitiol after the war, the source of hinokitiol remained a problem then. Shigehiro Katsura, a newly appointed professor of medicine transferred from Tohoku Imperial University, began in about 1938 to investigate the chemotherapy of tuberculosis and showed significant antibacterial activity in hinokitiol and l-rhodinic

acid, both of which were extracted from taiwanhinoki. At Nozoe’s request, the Taipei factory of the Takasago Perfumery Company (renamed the Takasago Chemical Company in 1939) collected stumps of taiwanhinoki left in the mountains and obtained the hinoki oil. The Takasago Perfumery Company was founded in 1920 in Tokyo by Tadaka Kainosho, a graduate of the Chemistry Department of Kyoto Imperial University. The company built a factory in Taipei to extract the by-products of manufactured camphor, which was indigenous to Formosa. Masayasu Kainosho, the second son of the founder of the company, had studied under Nozoe at Taihoku Imperial University and worked for the company in Taipei after graduating in 1940. Masayasu separated hinokitiol and l- rhodinic acid from hinoki oil. Nozoe obtained about 10 grams of hinokitiol, sufficient for a structural study that demonstrated that the compound was a seven-membered cyclic α-enolone with an isopropyl group. When Nozoe visited mainland Japan for the last time before the war, in 1940, he proposed an erroneous formula for hinokitiol, C₁₀ H₁₄ O₂, which contained two hydrogen atoms more than required by the correct structure. However, after his return to Formosa, unusual stability toward both acid (concentrated sulfuric acid) and alkaline solution (50% aqueous potassium hydroxide) that he found, along with a reconfirmation of the elemental analyses of hinokitiol, its acetate, and its methyl ether showed the correct molecular formula to be C₁₀ H₁₂ O₂. After the war hinokitiol, extracted from hiba in Japan, was used commercially as antibacterial for cosmetics, wood preservative, termite disinfestant, paint, wax and coatings.

Because of the war, European chemical journals became unavailable in Formosa around 1937, and by 1941 the American chemical journals could not be obtained. Fortunately, Nozoe managed to obtain a copy of Linus Pauling’s The Nature of the Chemical Bond (1939), probably one of the last academic publications imported into Formosa before the war with the United States began. After reading the book, Nozoe arrived at the idea that hinokitiol could be a new type of aromatic compound stabilized by resonance, involving an intramolecular hydrogen bond. Even though it turned out later that hinokitiol existed not as a resonance hybrid but as a pair of tautomers that interconverted through intramolecular hydrogen bonding, this idea was the first step that opened the new research area of nonbenzoniod aromatic compounds. Nozoe presented his ideas at the local Formosan branch of the Society of the Chemical Industry in 1941 for the first time, but the audience remained skeptical about his seven-membered structure.

Japan’s plunge into World War II with the attack on Pearl Harbor on 7 December (8 December in Japan time) 1941 forced Nozoe to abandon fundamental research and pursue wartime practical research instead. Because of the continuous heavy bombing in Taipei, especially after 1943, the university had to evacuate the campus, and Nozoe decided to move his laboratory to a mountainside about 20 kilometers (12 miles) from the city. However, on the very day they completed the evacuation and were ready to resume research, the war ended (15 August 1945). It then took a year to move the laboratory back to its original location.

Research in Taiwan after the War After World War II, Formosa was returned to the Republic of China, and Taihoku Imperial University was renamed Taiwan National University. When the war ended, about 488,000 Japanese, including 166,000 military personnel, were living in Formosa. The last governor-general, Rikichi Ando, organized their return to Japan shortly before the Japanese colonial government in Formosa was officially abolished on 31 May 1946, with the exception of approximately 26,000 specialists, whom China kept. Nozoe had his son Shigeo return to Japan first. Nozoe hoped to follow Shigeo, but had to stay on with his wife and daughters, and he worked as a professor of chemistry at Taiwan National University under the orders of the Chinese government.

During the last years of the war, the Takasago Chemical Company mass-produced hinoki oil from taiwanhinoki as a gasoline substitute as well as a mineral processing oil. After the war, Nozoe found a large amount of hinokitin, the reddish brown mud iron complex compound of hinokitiol, discarded in the backyard of the factory. Suddenly, by chance, Nozoe had a very large amount of hinokitiol, several kilograms of crystals, soon after the war, when everything was in short supply. In the summer of 1946, Nozoe finally began his research on hinokitiol with all the members of his laboratory at the university.

Since he regarded hinokitiol as a compound with a novel aromatic system, he examined various substitution reactions: halogenation, nitration, azo coupling and so on. The results of his group’s research at National Taiwan University were published in 1951–1952 after Nozoe returned to Japan.

In 1947 a Taiwanese uprising (called the “228 Incident”) was forcibly put down by Chiang Kai-shek’s Kuomintang government, and many Taiwanese intellectuals lost their lives. This political chaos in Taiwan offered Nozoe an opportunity to leave the country. He thus managed to return to Japan at the end of May 1948. His alma mater, Tohoku University, offered him a position.

Research on Hinokitiol at Tohoku University At Tohoku University, Nozoe was first appointed temporary lecturer in July 1948. He was initially treated as a suspicious agent of some sort, which was not uncommon during the Cold War period for national officials, including teachers in national universities, but by December he was appointed professor of organic chemistry.

At the end of that year, Nozoe was invited to Osaka University to talk at a special seminar of the Department of Chemistry about his study on hinokitiol in Taiwan. In February of the following year, he was invited to give the same lecture at the University of Tokyo. This lecture was printed as “Studies on Hinokitiol” in Yakugaku, a pharmacy review journal in Japanese published by the Japanese Pharmaceutical Society. In the article, Nozoe gave an explanation, based on the variety of its reactions, of his 4-isopropltropolone structure for hinokitiol. He also suggested possible future directions for research on seven- and five-membered unsaturated cyclic systems. The article shows that he was able to follow the developments in this area of research in the West soon after his return from Taiwan.

In 1945 Michael J. S. Dewar, later a leading theoretical chemist, was a postdoctoral fellow at Oxford with Robert Robinson studying stipitatic acid, a mold product whose structure was in dispute. Dewar proposed a new kind of aromatic structure with a seven-membered ring for which he coined the term tropolone (cycloheptarienolone). At the end of 1948, Nozoe received, from Professor Shigehiko Sugasawa at the College of Pharmacy of the University of Tokyo, a copy of a letter from Holger Erdtman, professor of organic chemistry at the Royal Institute of Technology in Stockholm, together with a reprint of Erdtman’s paper on the structure of thujaplicins, published in Nature in 1948. Sugasawa had once worked under Robinson at Oxford along with Erdtman, and Erdtman had isolated three isomeric monoterpenoids (named the α-thujaplicin, β-thujaplicin, and γ-thujaplicin) from Thuja plicata (Western red cedar). After corresponding, Erdtman and Nozoe found hinokitiol to be identical to B-thujaplicin, and to have the tropolone structure. Erdtman was only twenty days older than Nozoe, and they became lifelong friends.

When a symposium, “Tropolone and Allied Compounds,” was organized by the Chemical Society of London in November 1950, Erdtman mentioned Nozoe’s work on hinokitiol as a pioneering contribution to tropolone chemistry, thus helping Nozoe’s research gain recognition in the West. Nozoe was able to publish his work on hinokitiol and its derivatives in Nature in 1951 thanks to J. W. Cook, chairman of the symposium.

At Tohoku University, Nozoe resumed his studies on the reactions of hinokitiol and its derivatives. He concentrated on electrophilic substitutions of the natural product. He succeeded in synthesizing tropolone as well as hinokitiol and its isomers in 1950 and 1951. The results were published in English in the Proceedings of the Japan Academy thanks to Professor Majima, a member of the Japan Academy since 1926. Majima’s support and understanding greatly helped early recognition of Nozoe’s work

in Japan. Nozoe received various awards, such as the Majima Award for Organic Chemistry of the Chemical Society of Japan (1944), the Japan Academy Award (1953), and the Order of Culture (1958), the most prestigious medal for one’ s contribution to culture in Japan. He was only the second chemist recipient of the Order of Culture in postwar Japan, after Majima, who himself received the award in 1947.

In 1953 Nozoe was invited to lecture on troponoid chemistry at the 14th International Union of Pure and Applied Chemistry Congress in Stockholm. This was the first time he had been abroad. Before the war, it had been common practice for Japanese intellectuals to study in Europe or the United States for a few years before becoming a professor at an imperial university, but Nozoe had not had such a chance. Taking this opportunity, he visited various leading organic chemists in Europe and the United States during his five months of leave. After this, he took every opportunity to visit or invite chemists from all over the world to discuss topics of mutual interest. From his first trip abroad, he started to collect autographs, comments, tributes, and good wishes from famous chemists he encountered. He recorded them in his nine-volume notebook diaries; the surviving volumes are now kept in the Tohoku University Archives.

Nozoe’s articles on the synthesis of tropolone appeared at almost the same time as those of William Von Eggers Doering in the United States and J. W. Cook and R. D. Haworth in the United Kingdom on the same subject. The synthesis of tropone, the parent ketone compound, was accomplished by William G. Dauben (1951), Doering (1951), and Nozoe (1952). In 1954 Doering synthesized the positively charged tropylium ion by the bromination of tropilidene, confirming the theory of aromatic character proposed in 1931 by Erich Hückel.

After the syntheses of tropone and tropolone, Nozoe concentrated his efforts on clarifying their chemical reactivity. He extended his research by cooperating with physical chemists in Japan to study various physical properties to gain a firm footing in aromatic chemistry. It must be noted that Nozoe was one of the first organic chemists in Japan to actively employ those physical approaches, such as electronic theory and physical instrumentation, that transformed organic chemistry after World War II elsewhere but were uncommon for organic chemistry in Japan at that time.

Since the azulene system contains the seven-membered ring system of troponoids, Nozoe started to study the conversion of troponoids to azulenoids soon after he returned to Sendai in 1948. He developed efficient syntheses of heteroazulenes and variously functionalized azulenes.

During the 1960s, Japan experienced unprecedented growth and expansion of its economy, as well as its institutions of higher education, especially the faculties and departments of science and technology. Thanks to Nozoe’s efforts, a second chemistry department was established at Tohoku University in 1962. When Nozoe retired in 1965 at the age of sixty-three, the mandatory retirement age at the time, he made a financial donation for the establishment of a professorship for troponoid chemistry at the university and worked as the first professor on the post he created for two more years at Sendai until March 1968.

Work in the International Community After his complete retirement from Tohoku University, Nozoe moved to Tokyo and continued laboratory work with a young research assistant and a secretary, offered by the Research Institute of the Kao Soap Company in Tokyo. He did his research in cooperation with small groups of professors all over Japan. Nozoe studied the reaction mechanism of azulenoids synthesis from troponoids and the design of new azulene syntheses. In the last years of his life, he was interested in the structural elucidation of the oxidation products of azulenes. The results were summarized in a thirty-page article, published posthumously. On 4 April 1996, just one month before his ninety-fourth birthday, Nozoe died of cancer in a hospital, a day after finishing proofreading his last paper.

During the second half of his life, Nozoe had contributed immensely to international meetings and congresses on organic chemistry, especially on nonbenzenoid aromatic chemistry. These activities helped greatly with the construction of international networks for the postwar generation of Japanese chemists.

Nozoe participated in the organizing committee of the 4th International Union of Pure and Applied Chemistry Symposium on the Chemistry of Natural Products, held in Kyoto in 1964 and coinciding with the Tokyo Olympics. It was the first large-scale international congress on chemistry in Japan and symbolized the postwar recovery of Japan in the academic world. In 1965 Nozoe cochaired, with John D. Roberts of the California Institute of Technology, the first Japan-U.S. Cooperative Seminar on Physical Organic Chemistry in Kyoto, where five U.S. chemists and fourteen Japanese chemists discussed their research for an entire week.

In 1970 the first International Symposium on the Chemistry of Nonbenzenoid Aromatic Compounds was held in Sendai. This meeting had been initially proposed by Ronald Breslow, a professor of chemistry at Columbia University, nine years earlier to commemorate Nozoe’s retirement. The symposium was so successful that it was decided to hold such an international meeting every three to four years. Nozoe participated through 1995.

In 1961 Nozoe had published a 700-page reference book in Japanese, titled Nonbenzenoid Aromatic Compounds, one of twenty-five volumes in the Comprehensive Organic Chemistry series. He also published a textbook on organic chemistry in two volumes with some of his former students. In his last days, he planned to publish a comprehensive book in English, which covered the development of research on seven-membered aromatic compounds. He had collected more than 6,000 references on the subject and had drawn up a voluminous table of contents, but his plan was not realized in his lifetime; all of his students had already retired, and the new generation of chemists was too busy with their own research to compile such a comprehensive book on a research area that was no longer as active. Tetsuo Nozoe was nevertheless one of the fortunate chemists who helped to create a new field of chemistry and who lived long enough to see its full growth, during a period when chemistry research in Japan had finally achieved international recognition.

BIBLIOGRAPHY

Nozoe Tetsuo Kyoju Ronbun Mokuroku-shu (Collection of Papers of Professor Tetsuo Nozoe)[in Japanese], published by Nozoe Tetsuo Kyoju Go-taikan Kinen-kai (Commemoration Committee for Professor Nozoe’s retirement), 1966.

WORKS BY NOZOE

“Studies on Hinokitiol.” Yakugaku[Science of drugs] (in Japanese) 3 (1949): 174–198.

With S. Seto, Y. Kitahara, M. Kunori, and Y. Nakayama. “On the Synthesis of Tropolone (Cycloheptatrienolone).” Proceedings of the Japan Academy 26, no. 7 (1950): 38–42.

With S. Seto, K. Kikuchi, T. Mukai, S. Matsumoto, and M. Murase. “On the Synthesis of Hinokitiol (m-Isopropyltropolone).” Proceedings of the Japan Academy26, no. 7 (1950): 43–46.

“On the Substitution Products of Tropolone and Allied Compounds.” Nature 27 (1951): 1055–1060.“Chemistry of Natural Tropolone and Allied Compounds (Main Lecture at XVIth Int. Congr. Pure and Applied Chemistry, Paris, 1957).” Experientia (Basel), Supp. VII (1957): 306–327.

“Tropones and Tropolones.” In Non-benzenoid Aromatic Compounds, edited by D. Ginsburg. New York: Interscience, 1959.

With K. Takase, H. Matsumura, T. Asao, K. Kikuchi, and S. Ito. “Non-benzenoid Aromatic Compounds.” In Dai-YukiKagaku [Comprehensive organic chemistry] (in Japanese), vol. 13, edited by M. Kotake. Tokyo: Asakura-Shoten, 1960.

“Tropylium and Related Compounds.” In Progress in Organic Chemistry, vol. 5, edited by J. W. Cook. London: Butterworths, 1961.

“Recent Advance in the Chemistry of Troponoids and Related Compounds in Japan.” Pure and Applied Chemistry 28 (1971): 239–280.

“Cyclohepta[b][1,4]benzoxazine and Related Compounds: Some Novel Aspects in Heterocyclic Chemistry (A Review).” Heterocycles 30 (1990): 1263–1306.

“Seventy Years in Organic Chemistry.” In Profiles, Pathways, and Dreams: Autobiographies of Eminent Chemists, edited by J. I. Seeman. Washington, DC: American Chemical Society, 1991.

With H. Takeshita. “Chemistry of Azulenoquinones and Their Analogues.” Bulletin of the Chemical Society of Japan 69 (1996): 1149–1178.

Nozoe, Tetsuo, ed. Organic Chemistry [in Japanese], 2 vols. Tokyo: Hirokawa Shoten, 1970–1972.

OTHER SOURCES

Asao, Toyonobu, Sho Ito, and Ichiro Murata. “Tesuo Nozoe (1902–1996).” European Journal of Organic Chemistry(2004): 899–928.

Hitosuji no Michi: Tsuioku Nozoe Tetsuo Sensei[One way: For the memory of professor Tetsuo Nozoe] (in Japanese). Nozoe Tetsuo Sensei Tsuito Jigyo-kai [Commemoration committee for passing away of Professor Nozoe], Tokyo, 1997.

Takashima, Shinji, and Public Relations Department of Hinoki Shinyaku, Ltd. Hinokitiol Monogatari [The story of hinokitiol] (in Japanese). Tokyo: Hinoki Shinyaku, 1996.

Masanori Kaji