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So, Fisher The high-end organic chemistry in the dream of uncovering the mystery of Protein , is actually no longer needed, because Molecular Biology took over the baton. But he didn't have the chance to see this day with his own eyes.
Some readers complain that this year's Chemistry Award is a bit of a joke, and even if you read the award-winning questions alone, you can't appreciate the charm of the second one. You see, Royal Swedish Academy of Sciences announced that it will award the 2021 Nobel Prize in Chemistry to Benjamin List and David MacMillan for their contributions to " in the development of asymmetric organic catalysis ". How much does this asymmetry mean in chemical terms?
Although I am not an organic chemist, this year's award reminds me of a lesson that I was impressed by in college chemistry classes many years ago.
Before talking about this lesson, let’s talk about a concept closely related to this “symmetry/asymmetry” in organic chemistry: chirality, Chirality.
As the name suggests, chiral molecules refer to chemical molecules having the properties of "hand". The human left and right hands are symmetrical, just like the real object and its image in the mirror. The left and right hands of a human are mirrored, but they cannot overlap. Maybe someone would ask, if they match their hands together, wouldn’t they overlap?
If the human hand is a symmetrical object, and the palm of the hand and the back of the hand are exactly the same, then the left and right hands can indeed overlap, and it is indistinguishable. But the problem is that the human hand has three-dimensional shapes of length, width and height. Even if the hands are opposite each other, the shape is in line with each other, but the palm of the left hand and the back of the right hand will never match. A pair of chiral molecules are like human left and right hands.
Knowing that human hands have three-dimensional asymmetric shapes is common knowledge, but realizing that the spatial three-dimensional structure of the atomic structure and the chemical bond is an amazing scientific theory for humans. In 1875, the Dutch , published a classic paper on Space Chemistry , proposing the most basic element of the organism carbon atom , and the four chemical bonds that extend around it form a tetrahedral configuration. It is precisely because of such a three-dimensional spatial structure that diamond , composed of pure carbon atoms, has become the hardest substance in the world with its absolute compressive-resistant chemical bond layout that is interlocking and three-dimensionally unfolded.
The asymmetric shape of the human hand and its three-dimensional structure make the left and right hands mirror each other and never overlap; similarly, according to the principle of Jacobs Henrix Vantov, if the four chemical bonds of the carbon atom link different components, then there must be a pair of chiral molecules corresponding to this carbon atom and mirror each other in terms of physical structure and chemical properties. They are independent individuals .
The above sentence is still difficult to understand. So let’s look at a specific example, such as the following pair of molecular structures:
This is a schematic diagram of a three-dimensional structure being projected on a plane. In these two structures, the intersection point of each line segment represents a carbon atom, which is not marked separately in order to make the icon less crowded. Compared with these two structures, it is interesting that except for the pair of carbon atoms marked in the red box, the other line segment intersection points (carbon atoms) are the same. For example, the carbon atom below the red box, the hydroxyl (OH) it links to are on the left, and the hydrogen atom (H) is on the right.But the pair circled in the red box is different. Their hydroxyl group (OH) is on the left and the other is on the right. That is to say, are mirrored and cannot overlap. This is a pair of chiral carbon atoms .
It should be said that the two molecules on the left and right have the same molecular formulas, both C6H12O6, and the chemical bonds are exactly the same. The only difference is that the carbon atom produced by the red coil, the hydroxyl group (OH) it links to is different from the other atoms of this molecule, and the relative position distribution of .
So the physicochemical properties of these two substances are very similar, both are white crystalline powders with similar melting point boiling points. However, their biological characteristics are very different. The molecule on the left is the well-known glucose , which is the product of photosynthesis . If metabolic disorders in the human body, it will cause diabetes ; while the molecule on the right is mannose, which has very little distribution in nature. In contrast to glucose, which is the main energy source of the human body, most of it cannot be absorbed after entering the human body but is excreted through the kidneys. A few years ago, authoritative research showed that even a small amount of mannose intake has a function of preventing cancer. The spatial arrangement of
Jacobus Henricus van 't Hoff
However, Jacobs Henrix Vantov's theory is still on paper. For example, based on the chemical composition and properties of glucose at that time, he inferred that there are four chiral asymmetric structures among the six carbon atoms of this sugar molecule. Then if there is a pair of mirror structures in each, the , six-carbon sugar molecule, which is exactly the same as the component of the glucose element, should have 4 to the power of 2, and 16 stereoisomers. According to the number of carbon atoms and the arrangement and combination of hydroxyl and hydrogen atoms on each carbon, it should be easier to draw the structural imaginary diagram of the following 16 types of six-carbon sugar molecules (the head and tail of the molecule and the focus of each line segment represent a carbon atom):
The six-carbon sugars that had been discovered from nature or happened to be artificially synthesized were: glucose, galactose and mannose. It is widely known that glucose is the richest in nature and is biologically most important. But how to match these 16 hypothetical structures with the sugar substances present in reality? Which of these molecular structures is glucose?
In that era when organic analysis technology was extremely rough, it was basically only possible to quantitatively analyze elements by combustion and analyze physical properties of measuring the boiling point of the melting point. This was no different than climbing to the sky.
Fortunately, in addition to these low-level technologies, the field of organic chemistry benefited from the emergence of a strange man at the end of the 19th century.
This strange man is called Emil Fischer.
Fisher's first pot of gold in his scientific research career was when he was in his early 20s. He accidentally discovered and synthesized an important compound called phenylhydrazine . This molecule contains an extremely active amine group and is very easy to attack the carbon atoms carrying hydroxyl groups on the sugar chain. This material was crucial to Fisher's later work. Because, if you want to identify the three-dimensional structure of sugar, in addition to the contradiction of too much theoretical prediction and too little practical knowledge, you also face a problem of experimental operation: sugar substances are viscous and easy to coalesce into slurry, and it is extremely difficult to study their physical and chemical properties by crystallization.
If we look at the sugar structure bond diagram in the figure above, we will find that each molecule has a red hat on its head, which represents aldehyde . The carbon atom below it is very easy to react with phenylhydrazine, causing the loss of its chirality (that is, its own asymmetry), turning the carbon atom with a four-sided three-dimensional structure into a plane. Fisher carefully allowed glucose, mannose and phenylhydrazine to interact, and found that the two final products formed were glucose and mannose, which were easier to separate, crystallize and identify, and then found that they were the same thing. Fisher's reasoning result is that the disappearance of a chiral carbon atom causes the convergence of two originally different substances, glucose and mannose, to be different, so the only difference between them is the conformation of this carbon atom.
This magical compound phenylhydrazine and Fisher's reasoning on the similarities and differences in the structure of glucose mannose have become the first key to understanding the maze of sugar structure. The second key of
involves a concept of photophysics, that is, " optical rotation ". In 1844, the ancestor of microbiology , Pasteur, discovered that when the polarized light passing through a prism passes through a solution of a substance with a molecular structure asymmetric , the refraction of light will deflect. If you look carefully, the 16 structures of the sugar molecules in the picture above are all autologously asymmetric, which means they are all optically active. The primary reason for this is that all sugar structures are a "head-heavy" asymmetric structure. The "head" of the molecule, which is the red hat, represents the aldehyde group, and the tail of the molecule is a carbon atom that connects the hydroxyl group.
Fisher's second genius flashed his light was . He imagined using strong acid to oxidize both upper and lower ends of the sugar molecule into exactly the same appearance (that is, a structure similar to vinegar). For example, the two pairs of molecules 1/9 and 7/15 will become autosymmetric, which means that they will no longer have optical activity in theory.
Then he actually oxidized glucose and mannose, and as a result, the final product of sugar acid is still optically active. Then the above two pairs of four configurations (1/9, 7/15) will automatically exit the candidate structure of glucose.
At this time, glucose and mannose are only different from the cognition of the first carbon atom under the Red Hat. Because 2/10 and 8/16 are only one carbon atom different from the two pairs of eliminated structures. If they are glucose, then 1/9 and 7/15 must be mannose, which is inconsistent with the evidence that mannose remains optically active after oxidation, so 2/10 and 8/16 must also be excluded.
In this way, all eight structures have been eliminated, and half of the 16 candidate structures are left. They are 3/11, 4/12, 5/13, 6/14, 7/15, and one of them must be glucose and its mirror body. Relying on hard perseverance, precise determination and logical exclusion, Fisher's marathon halfway through .
There are four pairs of molecules excluded (a red cross), and half of the candidates are left
However, those who travel a hundred miles are half ninety, and the rest are hard to crack.At this time, Fisher discovered that neither phenylhydrazine nor optical rotation method can go further, , so his next step can only simplify the problem : Since the sugar structure containing six carbons cannot be solved, then let’s try a simpler five-carbon sugar?
At this time, Fisher was standing on the giant's shoulder. Another German chemist at the same time, Heinrich Kiliani, discovered that sodium cyanide, a highly toxic substance, has very active carbon atoms (or how toxic it is), which can increase the sugar chain by attacking the aldehyde group on the head of the short-chain sugar.
Fisher spent several years studying Kiliani's technology. He could extend the shortest tricarbon glycerol to nine-carbon sugar, so later generations called this method Kiliani-Fischer synthesis. With such strong and solid accumulation, Fisher can achieve the ultimate transformation research between 5-carbon sugar and 6-carbon sugar.
He found that a five-carbon sugar called arabinose can be extended to a mixture of glucose and mannose oxides with cyanide. The magic of cyanide in this chemical reaction is that it only attacks the head of the sugar molecule, and the three-dimensional conformation of the carbon atoms below the head of the sugar molecule remains intact. Therefore, the understanding of the known sugar structure can be used to reversely deduce the structure of Arabia, the five-carbon sugar.
As I wrote this, I had to go to the question and leave Fisher's work for a short time. At the same time, it is actually a return to the topic, because this article was about this year's Nobel Prize in Chemistry, "Asymmetric Synthesis Catalysis".
In Fisher's sugar chain extension experiment, Why does arabinose form a mixture of gluconic acid and mannonic acid under the attack of cyanide, rather than a single product? This is because most of the organic chemical reactions of are symmetric . In this example, the carbon atom of the sugar head is a planar structure, and the attack of cyanide on it can come from above or below, and the final product is also a mixture of two chiral carbon symmetric products: gluconic acid and mannonic acid.
This is a disadvantage in the pharmaceutical industry. As mentioned at the beginning of the article, glucose and mannose only have slight differences in spatial conformation, but their biological functions are very different. Similarly, the organic molecules used as medicine are likely to be only effective for specific steric isomers. If the chemically synthesized product is a mixture of active and inactive substances, a lot of subsequent work is required for separation and purification to increase costs.
pharmaceutical industry requires asymmetric organic synthesis of .
The work of previous people found that many biological enzymes and rare metal can also catalyze asymmetric reactions, that is, let attack group launch asymmetric invasion of from the single side of the plane structure of carbon atoms to generate simple space isomers. This work has won the Nobel Prize 20 years ago, and the winners are William S. Knowles, Ryoji Noyori and K. Barry Sharpless. However, these catalysts are not suitable for large-scale industrial production. And this year's Chemistry winners Benjamin List and David MacMillan, their contribution is to discover that specific simple and cheap organic matter can also catalyze asymmetric stereochemical reactions.
This achievement is of great significance and has great significance for the chemical and pharmaceutical industries, but I think even the two of them today will convince and admit that the work of Fisher, the ancestor, is far more difficult and meaningful than that of himself.
Back to Fisher.
As mentioned earlier, the structure of glucose and mannose containing 6 carbons has been limited to 4 pairs, that is, among the 8 possible molecules. As their predecessors, arabinose has one less carbon than them, while other chiral carbon atoms are the same, so its possible structure is reduced to 8/2 = 4, and the complex problem is simplified in this way.
Then the old trick of sugar head and tail oxidation and measuring optical rotation was repeated on five-carbon sugar. Experiments show that the arabinose treated in this way is still optically active. And among its two candidate structures, one pair should theoretically lose its rotation, so it is excluded.
The only remaining pair of molecules is the structure of arabinose and its chiral molecules. This is only one step away from the unraveling of the glucose structure of the crown of organic chemistry back then, because the glucose structure is one of the two direct products of arabinose, the other is mannose. Therefore, the candidate structure of glucosaccharide and its chiral symmetric bodies has been reduced from 4 to 8 to 2 to 4.
Which of the remaining two pairs is glucose? Which pair is mannose? This is the final puzzle.
At this time, the last helper stepped on the stage. xylose was discovered. It has five carbons. After the head and tail oxidizes to acid, it loses its optical rotation. Then the chiral carbon structure of xylose must be internally symmetric, so two pairs of xylose candidate structural models were proposed. Fisher then extended the sugar chains it was performed with cyanide, and as a result, there was a property in the product that was very similar to natural gluconic acid in nature, but the optical activity was contrary to it, proving that this was a mirror symmetric body of active glucose, so that the structure of xylose was basically determined.
Finally, Fisher took the possible structure of the product after xylose extension and compared the candidate structures of the four (3/11, 4/12) that contained glucose and mannose. He found that only 3/11, the pair of structures, and the extension product of xylose, could become mirror symmetric bodies.
The structure of glucose and mannose has finally been separated, and the pair of 3/11 is glucose and its mirror body! A few years later, Fisher completed the positioning of all eight six-carbon sugars and their mirror structures.
Finally, Jacobs Henrix Vantov's genius theoretical framework was confirmed by Fisher's great organic synthesis practice. In 1902, Fisher won the second Nobel Prize in Chemistry after Jacobs Henrix Vantov.
The impressive organic chemistry class I took 30 years ago, and I have finished it now.
Bronze statue of Fisher
In order to commemorate this little-known great man, I found the original version of the German Chemistry Society in 1890 in which Fisher published a classic article in 1890. There are two classic articles in this magazine. This article reveals the difference between glucose and mannose in the two chiral carbons, and the second article is the synthesis of glucose.
Although this book spans three centuries, its quality is still very good. The paper has turned yellow, but it still cannot conceal the excellent texture. This reflects the respect for scientific heritage accumulated over hundreds of years of a Western power.
This magazine has two classic articles, this article reveals the difference between glucose and mannose in the two chiral carbons
This article is the synthesis of glucose
From today's perspective, it is still hard to believe that he spent 10 years alone, relying on such simple experimental techniques and thin background knowledge, constructing such a magnificent logical system from the vast theoretical predictions and messy empirical data, and thus predicting the structural relationship of all hexacarbon aldoses.
In the eyes of today's people, to complete the exploration of material structure at this level, he needs at least one or several of the mature chromatography technology (winning the Nobel Prize in 1952), biomolecular crystal diffraction technology (1962 Nobel Prize), nuclear magnetic resonance technology (1991 Nobel Prize), and mass spectrometry technology (2002 Nobel Prize). However, judging from the era of winning these technologies, Fisher was basically empty-handed 120 years ago. The only thing he had was repeated combustion, heating, cooling, oxidation, reduction, extraction, filtration, separation, and crystallization in test tubes or distillates, and thus repeating the details. What supports the monotonous and repetitive mechanical labor that has been like this decade is his incomparable confidence in the 16 theoretical prediction structures drawn on paper, and his logical analysis ability to lead the point to the surface like mercury, and to peel off the cocoon like a cook.
I think the achievements of every great scientist are unique, but if you have to make a popular analogy, the great Madame Curie 's feat of extracting a few milligrams of uranium from several tons of waste ore may be comparable to Fisher.
Unfortunately, Fisher's fate is similar to Madame Curie who died of radiation disease . The first pot of gold for his great scientific achievements was the discovery and synthesis of phenylhydrazine, which was Fisher's most important tool to overcome the six-carbon sugar structure, but this compound was chronic toxic. By 1919, Fisher, who was in his 60s, was deeply poisoned, but he did not know that the doctor misdiagnosed his illness as cancer, and the patient might have entered a state of loneliness. At this time, the war had ended and Germany was defeated. His two sons died or committed suicide in the war. How big is the contrast between the tragedy of his personal life and the success of his career!
Fisher decided to break himself up and said goodbye to the bottles and jars that he loved all his life. But this is an organic chemist after all. He chose a highly toxic cyanide that he could use easily. This magical agent that can extend the sugar chain while faithfully maintaining the molecular structure, completing the final blow to terminate the life of a great chemist.
. Amid the praise of scientific historians throughout the ages, how did Fisher himself view his achievements in sugar chemistry? Interestingly, in his speech to receive the Nobel Prize, he said: "Compared with future protein research, sugar chemistry is as simple as a child's trick."
This is not the self-modestness of great scientists. In Fisher's era, scientists have learned that proteins are the main carriers carrying life traits. They consist of 20 different amino acids, ranging in length from tens to thousands, and fold into three-dimensional conformations. The organic chemistry technology required to study the structure and function of this substance is indeed one dimension higher than sugar chemistry.
So Fisher predicts that organic chemistry is facing another technological revolution , in response to the call of the new century and solve the mystery of protein.
He was wrong.
Over the past hundred years, especially after World War II , protein research has certainly made breakthroughs and progress, and its peak is the successful development of multiple new crown vaccines today, saving millions of lives. This is because humans already know how to accurately control human cells to produce spike proteins on the surface of the virus, thereby obtaining immune .
But organic chemistry is not the protagonist of this drama.
In fact, if we say a joke, the regret of missing the life science revolution over the past century can be "blame" on Fisher's other great achievement in addition to sugar chemistry, purine synthesis.
Because purines (and similar pyrimidine ) and five-carbon monosaccharides form nucleotide , which is the cornerstone of nucleic acids (DNA and RNA).Therefore, Fisher's research on monosaccharide and purines laid the foundation for the descendants to uncover the mystery of nucleic acid chemistry and DNA double helix . For example, 40 years after Fisher won the award, Aswald Avery of the Rockefeller Institute in the United States used logical reasoning and exclusion methods similar to Fisher but far inferior to Fisher, to prove that nucleic acids, rather than proteins, are the genetic material of living organisms. Another half century later, molecular biology has finally come into being. People can accurately and easily change the sequence and composition of proteins by changing the sequence of nucleic acids, and thus study their structure, function and applications.
Therefore, Fisher's dream of high-end organic chemistry that uncovers the mystery of protein is actually no longer needed, because molecular biology took over the baton.
just he didn't have the chance to see this day with his own eyes.
(Image from the Internet)
Reference:
Emil Fischer and the Structure of Grape Sugar and Its Isomers.
http://ursula.chem.yale.edu/~chem220/chem220js/STUDYAIDS/history/Fischer/fischer.html
Emil Fischer--unequaled classicist, master of organic chemistry research, and inspired trailblazer of biological chemistry.
https://pubmed.ncbi.nlm.nih.gov/12458504/
Nobel Lecture of Emil Fischer: Syntheses in the Purine and Sugar Group.
https://www.nobelprize.org/prizes/chemistry/1902/fischer/lecture/
extended reading:
talk about this "laboratory" that was suddenly hyped | Xiang Xixing
The halo of hope of people is no longer there, who is the next one who leads the way? | Xiang Xixing
The first oral anti-coronavirus drug surfaced! | Xiang Xixing
The average age of the deceased in the new crown is 78. Does it mean that the deceased only "shorts his lifespan for a few months"? | Xiang Xixing
Inspiration of the 2020 Nobel Prize in Chemistry: From 1 to 100, it is very important from 0 to 1 | Yuan Lanfeng
Background introduction: This article was published on the WeChat public account North American new drug science popularization history network (This year's Nobel Prize in Chemistry led to a legend in the history of chemistry a hundred years ago), The Voice of the Wind and Clouds was authorized to reprint.
Editor: Chen Xinyue
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