A Chinese chemist accidentally discovered that an extremely simple reaction could actually solve a century-old problem.

On October 28th, the research team led by Zhang Xiaheng from the Hangzhou Institute for Advanced Study, UCAS, published a significant article titled "Direct deaminative functionalization with N-nitroamines" in Nature.

The fewer the words, the bigger the event. In a nutshell, their research achievement has optimized the traditional circuitous process into a simple, safe, and elegant new technology.

Many industry insiders believe that it may not only rewrite university textbooks but also have the opportunity to compete for the Nobel Prize in the future. One of the reviewers of the article, Scott Bagley, the senior R & D director of pharmaceutical giant Pfizer, called it a "true masterpiece."

What kind of research can receive such high praise? How will this new achievement change our lives?

What's the research about?

It all starts with aromatic amines.

Aromatic amines are a large class of organic compounds. They have a wide range of sources and diverse uses, permeating almost every aspect of our lives - from the synthesis of pharmaceutical molecules to dyes, pesticides, rubber additives, and then to functional materials and the electronics industry. They are the cornerstone of agriculture, medicine, and even the entire chemical industry.

In the late 19th century, aromatic amines had industrial applications. However, until recently, there has been little progress in the processing technology of aromatic amines - it is dangerous, expensive, cumbersome, and inefficient, and it also produces intermediate products with explosion risks and a large amount of heavy - metal - containing waste liquid.

German chemist Peter Griess, who laid the foundation for the aromatic amine industry

In the past 140 years, organic chemists have been trying to tame this wild horse, hoping to find a safe and efficient way. Now, Zhang Xiaheng's team has finally found the right reins and tamed it in a gentle and precise way.

The reason why the amino group is difficult to handle is that it is very "lazy" and likes to stay on the aromatic ring, not being replaced by the target molecule as scientists expect. To get rid of this lazy guy, you have to give it a hard kick to activate the amino group.

For 140 years, the commonly used method has been to activate the amine group into diazonium salts, which is a very unstable state, like a hissing gas tank.

When decomposing, diazonium salts release nitrogen and a large amount of energy. Once the reaction speed is too fast, an explosion will occur. In the past, every time the amino group was converted into other groups in the development of new drugs or materials, it was like running a race with a gas tank on your back.

Zhang Xiaheng's team took another approach. They activated the amine group into N - nitroamines. Compared with diazonium salts, this activated state is much milder, significantly improving safety. At the same time, it also has sufficient activity and is easy to undergo subsequent reactions.

Reaction mechanism of direct deaminative functionalization mediated by N - nitroamines

The reaction starts with the most common amines. Pyridinamine is heated and dehydrated under the action of nitric acid, and the amino group (–NH₂) is converted into a special intermediate - N - nitroamine. The significance of this step is to initially activate the inert aromatic amine.

Step two: In an appropriate system, N - nitroamine will undergo proton migration and several tautomerizations, which is a process in which the number and type of atoms remain unchanged but their positions change. This intramolecular transposition makes the structural energy more favorable for subsequent reactions and prepares for deamination.

Step three is activation and further dehydration. Under the action of protons (H⁺) or promoters (such as DMAP, SOCl₂), the intermediate further loses water molecules and reaches a highly activated aromatic ring state. At this time, a fragment with a leaving group N = O = O is formed on the molecule, which is the source of nitrous oxide (N₂O) that will be discharged later.

Step four is deamination and the formation of new chemical bonds. When chloride ions (Cl⁻) attack the aromatic ring, the N = O = O fragment detaches and releases N₂O. At the same time, the chlorine atom enters the aromatic ring and forms a direct bond with the carbon atom. Finally, the target product - chloropyridine is obtained.

Compared with the traditional method in university textbooks for hundreds of years, this method is elegant and efficient.

How does this achievement change industrial production?

Just improving safety is not enough to make this research result stand out. In fact, this method is not only safe but also compatible with more reactants, and even pushes the reaction efficiency to a new height.

The problem still lies with diazonium salts. Because of the unstable nature of diazonium salts, if the thermal decomposition method is used directly to release nitrogen, the reaction is likely to get out of control. Therefore, copper ions have become the pressure valve of the pressure cooker, playing an important role in moderating the reaction.

In the reaction system, copper ions will stabilize the reaction process through ingenious electron transfer. First, cuprous ions will give an electron to the diazonium salt to stabilize it, release nitrogen in a milder way, and enter a stable intermediate state. Then, copper ions transfer the target atom they carry to the aromatic ring to complete the replacement of the amino group.

In contrast, N - nitroamines do not require additional metal reagents. A simple reaction can complete the functional group replacement. It is not only safer but also cleaner and more efficient.

The well - known controllable deamination involving copper ions

Moreover, Zhang Xiaheng's team also found that this method is hardly affected by the position of the amino group on the aromatic ring, which expands the selection range of reactants. In the traditional method, the situation is far from ideal.

The reactivity of diazonium salts is strongly affected by the substituents around the molecule: electron - donating groups (such as –OH, –OCH₃, etc.) will make the reaction too fast and difficult to control; while electron - withdrawing groups (such as –NO₂, –CF₃) will make the reaction difficult to proceed.

Zhang Xiaheng's team's method is also compatible with more target atoms. In addition to the chlorine atom shown above, they also tested other halogens such as fluorine and bromine; heteroatom bonds such as oxygen and sulfur; and various carbon - carbon bonds, which almost cover all types of chemical bonds in chemical applications.

Chemical reaction kettle | wikipedia

In terms of application, Zhang Xiaheng's team took another step forward: their reaction can be carried out in one pot - The traditional method introduces copper ions, which will interfere with subsequent reactions. Therefore, after obtaining the product, purification is required before the next reaction can continue. However, the system of Zhang Xiaheng's team is mild and clean enough. After the reaction is completed, there is no need for purification, and the next reaction can be carried out directly by adding materials to the reaction kettle. In the experiment, they successfully completed a kilogram - scale reaction experiment, which means that this method is approaching the scale of real industrial production.

With a more stable system, a wider range of substrates, and higher efficiency, this method is an exciting and comprehensive improvement of current industrial synthesis.

How will our lives change?

The deamination reaction is almost ubiquitous in current chemical production and is the basis of many core reactions. Improving the deamination process is not only beneficial to the country and the people.

In the agricultural field to ensure food security, the synthesis process of 2,4 - D (2,4 - dichlorophenoxyacetic acid), one of the most commonly used pesticide herbicides at present, requires a key deamination chlorination reaction of aromatic amines. Traditionally, this step relies on diazonium salts and copper salts for catalysis, which is not only dangerous but also produces a large amount of heavy - metal - containing waste liquid. If the new method is adopted to complete the reaction under mild conditions without copper ions, for this pesticide with an annual production of tens of thousands of tons, each reduction of one step of metal catalysis can reduce huge costs and significantly reduce pollution emissions.

A common commercial derivative of 2,4 - D

In the medical field, the impact of this achievement is even greater.

For anti - cancer drugs with complex structures and rich in aromatic amine structures, Zhang Xiaheng's team's deamination method is like a timely rain after a long drought. Imatinib Mesylate, an anti - cancer drug, is a patented drug produced by Novartis, a Swiss pharmaceutical company. It is also the life - saving drug that is so expensive in the movie "Dying to Survive" that it breaks people's hearts. Since it was introduced to China in 2001, its price has been 23,500 yuan per box, which is difficult for ordinary families to afford.

In the production process of Imatinib, multiple diazotization replacement reactions are required, which is the most labor - intensive part of the entire route. If the reaction is optimized, the production cost and efficiency can be significantly reduced, and the price of the drug may be lowered, saving countless families.

Moreover, the potential of this reaction is far from limited to this. In the R & D and iteration stage of drugs, relying on the characteristic of direct deamination not being picky about the type and position of reactants, pharmaceutical companies can directly perform rapid replacement on the drug parent and evaluate the drug efficacy, shortening the optimization cycle. It used to take months to synthesize a batch of candidate drugs, but now it may only take a few days. The pharmaceutical cycle that used to be iterated once every few years may now be greatly shortened. When the efficiency of drug synthesis is higher, more lives may be saved in time.

In the materials field, many directions will also benefit from this reaction. For example, the mobile phone you are looking at now may become cheaper and more useful because of this reaction. Almost all packaging resins for mobile phones, computer motherboards, and chips rely on aromatic amine curing agents. This new deamination reaction can not only significantly reduce production costs but also obtain more heat - resistant, more efficient, and lighter circuit materials. In the future, computers, mobile phones, cars, and even aerospace equipment may have a longer lifespan, better performance, and lower energy consumption because of this reaction.

Standing on the shoulders of giants again

Actually, N - nitroamines were not first discovered by Zhang Xiaheng's team. As early as 1893, this intermediate was discovered, but no one explored its reaction potential in the following hundred years. More intriguingly, the N - nitramine structure also appears in some well - known high - energy materials (such as cyclonite). Perhaps because of this dangerous association close to explosion, later researchers tended to avoid this route.

Zhang Xiaheng modestly pointed out: "Sometimes inspiration is not designed but 'bumped' into. We are very lucky to stand on the shoulders of our predecessors and see the direction they didn't see."

Some people say that what Zhang Xiaheng's team has done is too simple and not worth mentioning, but their contribution lies in truly showing the potential of this route.

Even if an important result really appears in front of us, we need to think carefully, prove it meticulously, and conduct subsequent persistent research. Otherwise, even if good luck comes, it will sink into the long river of history again.

References

[1] https://www.zhihu.com/question/1967282093101941035

Tu, G., Xiao, K., Chen, X. et al. Direct deaminative functionalization with N - nitro