Elaborating On Photo-on-Demand Synthesis

In nature, some animals make elastic and strong fibers such as the silk spiders produce for their webs. Such fibers consist of a polypeptide structure and inspire study into the growth of functional materials.

Alpha (α)-amino acid N-Carboxyanhydrides (NCAs) are precursors for artificial polypeptides, but this compound decomposes simply, thereby making it hard to obtain commercially.

Thus, it is essential to synthesize the correct quantity of α-amino acid NCAs at the location and time that they are needed. Generally, NCAs are synthesized from plant-derived amino phosgene and acids.

Phosgene, however, appears to be exceedingly deadly and hazardous to use, resulting in an increasing demand for new chemical compounds and reactions that could replace it.

Utilizing the photo-on-demand phosgenation technique, Associate Professor TSUDA Akihiko’s research group at Kobe University’s Graduate School of Science has successfully synthesized NCA in a secure, low-cost, and easy way from amino acid and chloroform, a common organic solvent.

Patents corresponding to this study were filed in November 2018 and November 2019. The academic paper was reported online in ACS Omega on October 19^th, 2022.

The main points were:

• Safe, on-site, and on-demand synthesis of polypeptide precursors (NCAs) using light.
• The research group has been successful in synthesizing 11 kinds of NCA from chloroform commercial amino acid and (a common organic solvent).
• In the lab, they synthesized these substances on a scale of up to ten grams (this could be generalized to production on a kilogram scale).
• Compared to the traditional synthesis technique (utilizing phosgene) and phosgene substitution techniques, the raw materials are cheaper, the work involved is simpler and less waste is produced. This could decrease cost and environmental damage.
• The reaction has been encouraged by visible light, and it is theoretically possible to execute this synthesis reaction with the help of sunlight.
• Such research outcomes will expedite industry or academia’s development of bio-derived functional polypeptides.
• It is anticipated that such methods will become established techniques that will greatly contribute towards the SDGs and efforts to become carbon neutral.

Phosgene (COCl₂) is utilized as a precursor for polymers and also as a pharmaceutical intermediate. The worldwide phosgene market remains to grow by several percent annually, with around 8 to 9 million tons produced yearly.

Phosgene is, however, exceedingly poisonous. For safety reasons, research and development is being performed to determine alternatives. In a world-first discovery, Associate Professor Tsuda’s research group irradiated chloroform with the help of ultraviolet light, which made it react with oxygen and produce high yields of phosgene (patent no. 5900920).

To do this in an even safer and simpler way, the research group discovered a method by which the phosgene-generating reactions could be executed instantly. Initially, they dissolved the catalysts and reactants in chloroform and produced phosgene by irradiating the solution with light (patent no. 6057449). This method could perform phosgene-based organic synthesis as if phosgene was not utilized.

The research team has named their breakthrough the “photo on demand organic synthesis method” and has favorably used it to synthesize several useful polymers and organic chemicals.

For instance, the researchers successfully synthesized huge quantities of carbonate and chloroformate in a harmless, low-cost, and easy manner solely by irradiating a combination solution of chloroform and alcohol (with a base added as required) with light.

Such highly original reactions developed at Kobe University have been enhanced via partnerships with domestic chemical companies, and the ultimate goal of this study is practical implementation.

With the increase of funding from JST A-STEP, an additional applied study is being performed, as well as the growth of functional polyurethane, utilizing this synthesis technique.

The photo-on-demand organic synthesis technique is highly secure and economical, besides having a low effect on the surrounding. As a result, it has grabbed the attention of both industry and academia as a sustainable chemical synthesis technique.

In this study, α-amino acid N-Carboxyanhydrides (NCAs) successfully synthesized the raw materials chloroform and α-amino acid utilizing the photo-on-demand technique.

NCA is known as a polypeptide precursor. Even though α-amino acid melts easily in water, it does not melt in chloroform. This means that the research group has not been able to combine NCA by using the earlier photo-on-demand technique.

The team discovered that by adding acetonitrile (CH₃CN), which could be mixed with water and chloroform as a solvent, a high yield (around 91%) of NCA could be created. The reaction was not anticipated to proceed as normal since acetonitrile tends to absorb the light, impeding the chloroform's photooxidation.

Unexpectedly, the scientists found out that the reaction happened despite this obstacle, resulting in the successful outcomes of the study.

Separately from the raw material (amino acid) dissipated by the light, this photoreaction could also be utilized to generate NCAs synthesized normally with the help of the phosgene technique. Until now, the research group has successfully synthesized 11 kinds of NCA by using this photoreaction.

An elaborate breakdown of the synthesis technique is as follows. Initially, α-amino acid was suspended in a mixed solution of acetonitrile and chloroform.

This solution was then photo-irradiated for two to three hours at 70 °C. After the lamp was switched off, NCA was produced by heating and stirring the solution for nearly one hour. This product could be extracted and refined to achieve highly pure NCA.

The photooxidation of the chloroform was encouraged by a radical chain reaction that was initiated by the light-cleaving C-Cl bonds. Therefore, synthesis could be achieved on a scale of up to 10 grams solely by increasing the size of the reaction container and retaining the same light source.

It is believed that, by scaling up this technique, it could be employed in an extensive range of fields varying from academia to chemical industries.

The latest Photo-on-Demand NCA synthesis technique developed through this research allows vast quantities of NCAs (known as polypeptide precursors) to be synthesized securely, inexpensively, and simply.

This simple obtainment of NCAs will urge the study and development of artificial polypeptides, resulting in the production of new materials, such as novel functional polypeptide fibers that surpass natural fibers produced by animals.

It is also anticipated that synthesizing new polypeptide fibers with the help of plant-derived amino acids as a starter will allow the growth of next-generation biomaterials that fulfill the requirements of the times.

The Tsuda group intends for the photo-on-demand NCA Synthesis Method to be used industrially. As a result, they are providing patent licenses and guidance on how to use these methods to interested companies besides continuing their study and development measures. They intend to develop this study even further by collaborating with industries.

This study was financially supported by the Adaptable and Seamless Technology Transfer Program through Target-driven R&D (A-STEP) (seeds development type) from the Japan Science and Technology Agency (JST).

Journal Reference

Sugimoto, T., et al. (2022) Photo-On-Demand Synthesis of α-Amino Acid N-Carboxyanhydrides with Chloroform. ACS Omega. doi.org/10.1021/acsomega.2c05299.