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Young researchers' inquiring minds and ambition, to produce newborn benzene molecules

  • Read in Japanese
  • 2015/05/26
  • WPI-ITbM
  • Graduate School of Science
  • JST-ERATO Itami Project
  • Mr. Shin Suzuki (a graduate student)
  • Associate Prof. Junichiro Yamaguchi
  • Prof. Kenichiro Itami

Prof. Kenichiro Itami, Associate Prof. Junichiro Yamaguchi, Mr. Shin Suzuki (a graduate student), and Designated Associate Prof. Yasutomo Segawa at the Institute of Transformative Bio-Molecules (WPI-ITbM), Graduate School of Science at Nagoya University, and JST-ERATO Itami Molecular Nanocarbon Project have developed a new approach to synthesize multisubstituted benzenes "at will." The programmed synthesis enables the formation of substituted benzenes selectively; therefore, it provides an answer to one of the most important issues in chemistry development, i.e., "the multisubstituted benzene problem," for which an answer has thus far remained elusive.
This research was published online in Nature Chemistry on January 26, 2015. → Nagoya University Press Release

In 2015 this year—190 years have passed since Faraday’s discovery of benzene, and 150 years since Kekulé reported the structure of benzene—, researchers found the answer to “the multisubstituted benzene problem.”

"I would like to make every single molecule we can conceive."

Prof. Kenichiro Itami at the Graduate School of Science is also a director of the Institute of Transformative Bio-Molecules (WPI-ITbM) and a project leader of the JST-ERATO Itami Molecular Nanocarbon Project. He is an advocate for programmed synthesis, which can be considered the ultimate solution in synthetic chemistry.

Programmed synthesis is an approach for making structurally diverse molecules selectively and “at will,” based on one synthetic scheme. Molecules form regioisomers from the combination of various substituents. Through programmed synthesis, not one but all regioisomers can be developed selectively using a synthetic method.

Figure 1. Programmed synthetic methods for multisubstituted organic molecules. (FigureSuzuki et al. Nature Chemistry (2015) 7: 227-33. Copyright © 2015, Rights Managed by Nature Publishing Group)

Prof. Itami and his research group have developed the programmed syntheses of multisubstituted organic molecules such as alkenes, thiophenes, and thiazoles (Figure 1).

However, because the number of possible substitution patterns N is extremely high (cf. Burnside's counting theorem) and because of a deficiency of methods in synthetic chemistry, the programmed synthesis of multisubstituted benzenes has remained elusive.

ーーー Burnside's counting theorem ーーー

The number of substituted benzenes (N) from n different substituents is as follows:

The number of multisubstituted benzenes stands out when compared with that of all other organic molecules. In theory, > 80,000 multisubstituted benzenes can be generated from the combination of 10 different substituents and > 1.3 billion substituted benzenes from 50 different substituents.


Mr. Shin Suzuki, who was a second year master’s student (currently, a first year Ph.D. student) at the Graduate School of Science at Nagoya University, addressed such a challenge: the multisubstituted benzene problem.

While Mr. Suzuki learned under the supervision of Prof. Itami and Associate Prof. Junichiro Yamaguchi in the same research group, as a researcher, he successfully characterized the world’s first hexaarylbenzenes (HAB) with five or six different substituents.

By finding unprecedented molecules developed by a new programmed synthesis, thus, Prof. Itami and his research group have obtained a new understanding of the physical properties of these new molecules.


The structure of benzene, which can be called a “turtle shell” because of its resemble shape, is symbolic in organic chemistry.

Besides the beauty of the structure, benzene is the most utilized molecule for medical and agricultural compounds, aroma chemicals, dye compounds, plastics, liquid crystals, and electronic materials. It is also interesting that benzenes change the chemical and physical properties of these products, depending on the type of substituents and the position of substitution (cf. hexabenzocoronene).


Although an attractive molecule, benzene is difficult to synthesize and characterize “at will” because a large number of multi-substitutions can exist. This has long been known as an issue in the field of chemistry.

Even though Prof. Itami and his colleagues repeatedly attempted to introduce substituents to the precursor of benzene, it did not go well, and after many attempts, it still remained impossible.


At the end of March, 2012

“However, it is relatively easy to perform C–H arylation of thiophenes (a five-membered ring).”

Associate Prof. Yamaguchi, originally having an expertise in the field of natural product synthesis and pharmaceutical short-step synthesis, was inspired by a synthetic technology that transforms a five-membered ring into a six-membered ring. Then, he suggested that the synthesis should be initiated from the programmed synthesis of multisubstituted thiophenes (as originally reported by Prof. Itami et al.), followed by reaction with alkynes, to produce five and six different substituted benzenes (Figure 2). In this way, he addressed the multisubstituted benzene problem.

Figure 2. The proposed programmed synthesis for HAB. (Figure : by courtesy of Associate Prof. Yamaguchi)

“Shall we make stunning molecules?”

Associate Prof. Yamaguchi explained to Mr. Suzuki, who was then in his senior year at the School of Science at Nagoya University, the research on synthesizing multisubstituted benzenes, or “unprecedented compounds.” He described the beauty of the three-dimensional propeller structure of the multisubstituents when substituents attach to a flat benzene. In fact, Mr. Suzuki was attracted to the “stunning” molecules.

“It is like something awesome.”

Mr. Suzuki undertook the research with curiosity. Based on the programmed synthesis of tetraarylthiophene that was developed by Prof. Itami et al., the commercial product 3-methoxythiophene was used as the starting material. Then, C—H coupling and Suzuki—Miyaura coupling selectively introduced four aryl groups (Figure 3).

Although Mr. Suzuki had difficulties at the beginning, he managed to increase yield by 50 times by finding the appropriate parameters for the synthesis.

Figure 3. Programmed synthesis for tetraarylthiophene. (Figure : by courtesy of Associate Prof. Yamaguchi)

At the end of his senior undergraduate year, Mr. Suzuki succeeded in producing HAB with five different substituents by applying symmetric diarylacetylenes through the oxidation of tetraarylthiophene (Figure 4). That is, when the cycloaddition reaction of multisubstituted thiophene oxides and diarylacetylenes progresses and is followed by desulfurization of thiophene oxide, a benzene ring is formed.

Figure 4. HABs with five different substituents were successfully synthesized. (Figure : by courtesy of Associate Prof. Yamaguchi)

After this, Mr. Suzuki started preparing for the synthesis of HAB with six different substituents using unsymmetrical diarylacetylenes.

However, the six different substituted benzenes obtained were the mixture of two compounds (Figure 5). An additional difficulty was that no methodology such as thin-layer chromatography (TLC) could be used to identify these mixed compounds.

Figure 5. Two HABs with six different substituents were produced at a time; however, they were mixed and their identification was remained difficulty. (Figure : Suzuki et al. Nature Chemistry (2015) 7: 227-33. Copyright © 2015, Rights Managed by Nature Publishing Group)

Although Mr. Suzuki kept making efforts through trial and error, it was not going well. “To be honest, I could not find an interest in my research at that time,” he mentions. Meanwhile, he was also looking for employment, and during this time he started noticing his focus on his research: “job hunting was an opportunity to look back and analyze myself.”

“Mr. Suzuki has really been changing since then.”

Associate Prof. Yamaguchi, who supervises Mr. Suzuki, is impressed with his attitude, not only as a student but also as a researcher.

Mr. Suzuki, thinking by himself, applied a recrystallization method for the mixed six differently substituted benzenes. By controlling the time lag of the crystallization speeds, one of the two compounds was crystallized, and consequently, he successfully separated and identified the two mixed compounds.

“I was amazed when I saw the crystal structures by X-ray crystal structure analysis.”

Mr. Suzuki also asked Designated Associate Prof. Yasutomo Segawa, who is in the same research group, for his advice regarding the clear confirmation of molecular structure by X-ray crystal structure analysis. His recrystallization idea was then further applied to the characterization of HAB with six different substituents, by replacing one of the six substituents with a large molecule (Figure 6).

Figure 6. (Left) By replacing one of the six substituents with a large molecule, the two mixed compounds were successfully separated and identified. (Right) Mr. Suzuki and the crystal structure obtained by X-ray crsytal structure analysis @ Laboratory. (FigureSuzuki et al. Nature Chemistry (2015) 7: 227-33. Copyright © 2015, Rights Managed by Nature Publishing Group)

Because of this new development of the molecules, Mr. Suzuki has not only obtained new knowledge of their physical properties, but also applied this knowledge to the syntheses of tetraarylnaphthalenes and pentaarylpyridines, based on programmed synthesis (Figure 7).

Figure 7. The syntheses of tetraarylnaphthalenes and pentaarylpyridines are also possible to apply to the programmed synthesis. (FigureSuzuki et al. Nature Chemistry (2015) 7: 227-33. Copyright © 2015, Rights Managed by Nature Publishing Group)


“I do not know how these molecules are useful in the future at the moment;

They may turn out to be just rubbish,” Associate Prof. Yamaguchi adds. However, as we know, a green fluorescent protein (GFP) molecule, which has been usefully applied in the field of life-sciences (the great achievement accomplished by Dr. Shimomura, a 2008 Nobel laureate in chemistry), was also developed from basic research on understanding the relevant mechanisms.

In this new study, we could also expect transformative development of the new molecules.

Furthermore, this research result influenced an inquiring and ambitious mind of the young researcher:

“I want to make more of my molecules.”

Although Mr. Suzuki later got a job opportunity after looking for job employment, he could not forget his happiness during the research, and decided to continue the research in a doctorate course. Recently, he has been striving to establish his research theme.

Young researchers’ inquiring and ambitious minds can be the energy.

—They enable the novelty and originality of their achievements.

(Ayako Umemura)

Researchers featured in this article

From the left、Associate Prof. Junichiro Yamaguchi, Mr. Shin Suzuki, and Prof. Kenichiro Itami

Dr. Kenichiro ItamiProfessor, Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University

Dr. Itami graduated from the Department of Synthetic Chemistry, School of Engineering, Kyoto University in 1994 and achieved a doctorate degree in engineering at Kyoto University in 1998. Then, he worked as an assistant at the Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University. Dr. Itami moved to the Research Center for Materials Science (RCMS), Nagoya University, in 2005 to work as an assistant professor and became a researcher in the area of structure control and function for Precursory Research for Embryonic Science and Technology, Japan Science Technology Agency (JST). He became an associate professor at RCMS, Nagoya University, in 2007 and then a professor in the Department of Chemistry, Graduate School of Science at Nagoya University, in 2008. In addition, since 2013, Dr. Itami is a director of the Institute of Transformative Bio-Molecules (WPI-ITbM) and a project leader of the JST-ERATO Itami Molecular Nanocarbon Project.

Prof. Itami has received many awards during his career:

Fellow of the Royal Society of Chemistry, UK (2012);
Mukaiyama award (2013);
Novartis Chemistry Lectureship Award (2013);
The JSPS Prize (2014);
Arthur C. Cope Scholar Award (2015); and many more.


“Benzene is my most favorite molecule,” said Dr. Itami. Actually, I noticed his professor room was decorated with fashionable hexagonally shaped objects.
In such an artistic surrounding, Dr. Itami cheerfully conveyed to me his interests in the research, which caused my mind to open: I was truly inspired by him. I expect he will accomplish furhter great achievements (by AU)

Dr. Junichiro Yamaguchi 【Associate Professor, Graduate School of Science, Nagoya University】

Dr. Yamaguchi graduated from the Department of Industrial Chemistry in the Faculty of Engineering, Tokyo University of Science, in 2002. During his doctorate course, he became a fellow of the Japan Society for the Promotion of Science (JSPS) in 2004, and through studying abroad in the Department of Chemistry in the Scripps Research Institute (TSRI) in 2005, obtained his doctorate degree in engineering from the Tokyo University of Science in 2007. Dr. Yamaguchi then moved to TSRI to work as a JSPS postdoctoral fellow, and in 2008, started working as an assistant professor, and then as an associate professor in 2012 in the Department of Chemistry, School of Science, Nagoya University. Between August and September 2012, Dr. Yamaguchi concurrently researched as a visiting associate professor at Münster University. In addition, since 2013, he has been advancing his research as a cooperating researcher at ITbM, Nagoya University.

Associate Prof. Yamaguchi has received many awards during his career:

ITbM Research Award (2013);
Banyu Chemist Award (BCA) (2013);
Thieme Chemistry Journal Award (2014);
Asian Core Lectureship Award, China (2014);
Asian Core Lectureship Award, Thailand (2014); and many more.


“I like the word ‘unprecedented’,” Dr. Yamaguchi mentions. In fact, Dr. Yamaguchi is a person who does his utmost for unprecedented achievements, and he motivates and encourages young researchers.
The research group led by Dr. Yamaguchi, working in a positive and active environment, will keep producing brilliant research results. I look forward to their future success (by AU)

Mr. Shin Suzuki【at that time: Master’s Student, Graduate School of Science, Nagoya University】

Mr. Suzuki graduated from the Department of Chemistry at the School of Science, Nagoya University, in 2013. He completed his master’s degree in the Department of Chemistry, Graduate School of Science, Nagoya University, in 2015. Since 2015, Mr. Suzuki has worked as a Ph.D. student in the same research group at Nagoya University.


“Because of the unsuccessful times during my research, I realized that research is attractive, and it is now my passion,” Mr. Suzuki says. He describes himself as a lucky person, and I actually think that his ability is due to his positive way of thinking and his hard work.
“I’ve found my rhythm for the research,” Mr. Suzuki adds. I expect him to keep achieving much more in the future (by AU)


Shin Suzuki,Yasutomo Segawa, Kenichiro Itami & Junichiro Yamaguchi.

Synthesis and characterization of hexaarylbenzenes with five or six different substituents enabled by programmed synthesis.

Nature Chemistry 7: 227 (2015).
(First published on January 26, 2015; doi:10.1038/nchem.2174)


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