Chinese name: Diels-Alder reaction mbth: Diels-Alder reaction alias: D-A synthesis reaction, diene synthesis type: definition of organic reaction, discovery, Nobel Prize in chemistry, 1892, 1906, adduct structure, subversion, application in total synthesis, reaction mechanism, stereochemistry. The reaction of conjugated dienes with alkenes or alkynes to form six-membered rings is one of the most important means to form carbon-carbon bonds in organic chemical synthesis, and it is also one of the commonly used reactions in modern organic synthesis. The reaction is rich in stereochemistry and has stereoselectivity, stereospecificity and regioselectivity. The discovery of Diels-Alder reaction in the Nobel Prize in Chemistry was discovered by German chemist Otto Paul Diels and his student Kurt Alder in 1928, so they won the Nobel Prize in Chemistry in 1950. 1892 The earliest research on Diels-Alder reaction can be traced back to 1892. Zink discovered and put forward the structure of tetrachlorocyclopentadiene dimer, which is the product of Diels-Alder reaction. Later, lebedev pointed out that vinyl cyclohexene was the conversion relationship of butadiene dimer. But neither of them realized the deeper things behind these facts. 1906 1906 Albrecht, a graduate student at the University of Munich, Germany, did an experiment to synthesize a dye by condensation of cyclopentadiene with ketone under the catalysis of alkali according to Thiele's requirements. At that time, they tried to replace other ketones with benzoquinone, but benzoquinone was easy to decompose under alkaline conditions, and the experiment was unsuccessful. Albrecht found that the reaction could be carried out without adding alkali, but colorless compounds were obtained. Albrecht proposed a wrong structure to explain the experimental results. From 65438 to 0920, German Von Euler and student Joseph studied the structure of the reaction product of isoprene and benzoquinone. They correctly put forward the product structure of Diels-Alder and the possible mechanism of the reaction. In fact, they were very close to discovering the Diels-Alder reaction. But Von Euler didn't go any further, because his main business was biochemistry (later he won the Nobel Prize for his research on fermentation), and the research on Diels-Alder reaction was purely a pastime, so Diels-Alder reaction was silent again. The structure of the adduct is 192 1 year. Diers and his graduate student Back studied the ester-amine reaction between ethyl azodicarboxylate (a reagent that shines brightly in organic synthesis after half a century) and amine. When they react with 2- naphthylamine, according to elemental analysis, the products obtained are addition products, not expected substitution products. Dills was keenly aware of the similarities between this reaction and Albright's strange reaction more than ten years ago. This makes him think that the product is similar to the double bond addition product proposed by Albrecht. Diers naturally imitated Albrecht's reaction and used cyclopentadiene instead of naphthylamine to react with ethyl azodicarboxylate. As a result, the third addition product was obtained. Diers found that the adduct contained only one double bond through the metering hydrogenation experiment. If the structure of the product is as proposed by Albrecht, there must be two double bonds. This phenomenon attracted Diels deeply. Together with another graduate student, Alder, he proposed the correct structure of diene adducts. They published the results on 1928. This marks the formal discovery of Diels-Adel reaction. From then on, the names Diers and Adel began to shine in the history of chemistry. Subversion In their papers, the two authors deeply saw the subversive effect of this reaction on the concept of organic synthesis, and they predicted the great significance of this reaction in the future field of natural product synthesis. Of course, the two also reveal the style of landlords and bullies in their articles. At the beginning of the article, Albrecht criticized the wrong structure in very vicious language. At the end of the article, they declared that they had exclusive rights to the reaction and did not allow others to use it. Of course, the scientific community does not take these words seriously. Dills and Alder were later involved in the dispute over the discovery right of the reaction, which distracted them and failed to realize their prediction of "application in the total synthesis of natural products". Woodward took the lead in applying Diels-Alder reaction to total synthesis in 1950. Since then, the synthesis masters have used their intelligent brains to apply this reaction to the extreme. It is worth pointing out that before Woodward, Zhang Gong, a chemical scientist in China, tried to synthesize steroid compounds through this reaction, but failed because of the lack of understanding of selective control of reaction areas at that time. Reaction mechanism Diels-Alder reaction is a cycloaddition reaction between conjugated diene system and olefin or alkyne bond to obtain cyclohexene or 1, 4- cyclohexadiene ring system. 1928, German chemists O. P.H Diers and K. Alder discovered this kind of reaction when studying the interaction between butadiene and maleic anhydride: in this kind of reaction, olefins and alkynes interacting with conjugated dienes are called dienophiles, and electrophilic substituents (such as carbonyl, cyano, nitro, carboxyl, etc. ) and dienophiles on * * *. This kind of reaction has strong localization and stereoselectivity. When both dienes and dienophiles have appropriate substituents, so that the reaction may take place at different positions to get two products, in fact, only one is the main one. For example, isoprene reacts with methyl vinyl ketone to obtain methyl -(4- methyl -3- cyclohexenyl) ketone. In stereochemistry, these reactions are all cis-addition. When the reactants may produce internal products and external products, there are generally only reactions of internal compounds, such as cyclopentadiene and maleic anhydride. These stereoselectivity not only accords with a large number of experimental facts, but also can be explained theoretically by the conservation of molecular orbital symmetry. Diels-Alder reaction is generally reversible, and this reversibility can sometimes be well applied in synthesis. For example, when a small amount of butadiene is needed in the laboratory, cyclohexene can be obtained by pyrolysis; The synthesis of methyl 2- cyclopropyl formate is also based on Diels-Alder reaction and its inverse reaction. This is a one-step synergistic reaction, there is no intermediate, only transition state. Generally speaking, the highest electron-containing orbitals (HOMO) of dienes interact with the lowest empty orbitals (LUMO) of dienophiles to form bonds. Because it does not involve the synergistic reaction of ions, ordinary acid and alkali have no effect on the reaction. However, Lewis acid can affect the energy level of the lowest empty orbital through complexation, so it can catalyze the reaction. Stereochemical Diels-Alder reaction has the following rules: Alder reaction 1, regioselectivity: the reaction products are often mainly "pseudo-ortho-para" products. That is to say, if the six-membered ring product is compared to benzene ring, the mutual position between functional groups on the ring (assuming there are two functional groups) is mainly ortho (such as 1) or para (such as 3). 2. Stereoselectivity: the main reaction product is endotype (i.e. 5), that is, the main reaction product is obtained through the transition state of endotype. 3. Stereospecificity: The diene synthesis reaction shows high stereospecificity for both dienes and dienophiles. The dienophile always carries out cis addition to diene, and the adduct maintains the relative orientation of the substituents of diene and dienophile. Only when two new σ bonds are formed at the same time, and they are interrelated and restricted each other in the process of formation, can the stereospecificity of the reaction be completely guaranteed. For example, in the following two thermal reactions, the relative steric configurations of products 7 and 8 are unique, and the cis-trans stereochemical relationships of the original functional groups A, B, C and D of the two olefin raw materials are faithfully translated in the products. The value in synthesis is highly valued, because the reaction produces two carbon-carbon bonds and at most four adjacent chiral centers at a time. If Diels-Alder reaction is used in the synthesis design, the reaction steps can be greatly reduced and the synthesis efficiency can be improved. Many famous synthetic masters are good at using Diels-Alder reaction to synthesize complex natural products, such as Robot Burns Woodward, elias james corey and Danishefsky. It is said that Woodward predicted the existence of Diels-Alder reaction in childhood according to the irrefutability of the two structures of benzene ring in Kekule. /kloc-at the age of 0/2, Woodward obtained some German chemical journals through German diplomats in Boston. In the first issue, he read an article published by Dills and Alder and witnessed the discovery of this reaction. Woodward used Diels-Alder reaction to construct six-membered rings in his life-long synthetic practice. Woodward started from the 1960' s, joined hands with rod hoffman, a theoretical chemist who just entered Harvard University for research, and combined with a large number of experimental facts, conducted in-depth theoretical research on the stereochemistry of Diels-Alder reaction and related pericyclic reactions, and finally gave birth to the "conservation of molecular orbital symmetry" that shocked the whole field of organic chemistry at that time. Woodward died in1979; 198 1 year, Hoffman won the Nobel Prize in chemistry for this theory (shared with Kenichi Fukui of Japan). In 2004, another famous figure in the field of organic synthesis, Cory, publicly claimed that Woodward had plagiarized his ideas and created the law of conservation of symmetry more than 20 years after Woodward's death. All these make the Diels-Alder reaction full of some fatalistic legend. Alder reaction division also made great contribution to Diels-Alder reaction, and invented asymmetric Diels-Alder reaction catalyzed by Lewis acid. In the process of prostaglandin synthesis, Corey tried to construct the mother ring of prostaglandin by Diels-Alder reaction with cyclopentadiene, thus inventing a substitute reagent for unstable ketene. Denishevsky is most famous for inventing "Denishevsky diene" which is very useful for Diels-Alder reaction, and Diels-Alder reaction can also be seen everywhere in his total synthesis practice. alder reaction