Under heating conditions, conjugated dienes and compounds containing carbon carbon double bond or carbon carbon triple bond undergo 1,4-cycloaddition reaction to generate six membered cycloalkenes, and the reaction also goes through a ring transition state.The temperature required for ring forming reaction is lower than that for ring opening reaction.This reaction is calledDiene synthesis reactionIt was discovered by German chemists Diels and Alder, also known as the Diels Alder reaction.In 1928, German chemist Otto Diels and his student Kurt Alder first discovered and recorded this new reaction, and they also obtainedNobel Prize in Chemistry。
Diels Alder reaction is an organic reaction, in which conjugated dienes react with substituted alkenes (commonly referred to as dienophiles) to form substituted cyclohexenes.This reaction can synthesize six membered ring with little energy, which is one of the most important means of carbon carbon bond formation in organic chemical synthesis reaction, and also one of the commonly used reactions in modern organic synthesis.The reaction has rich stereochemical presentationStereoselectivity, stereo specificity andRegional selectivityEtc.The reaction is reversible. The reaction temperature of forward ring formation is lower, and the reverse ring opening reaction requires higher temperature.[1]
Diels Alder reaction formula
It can be seen from the reaction formula that this reaction is divided into two parts, one is to provide conjugated diene compound - diene, the other is to provide unsaturated bond compound - diene.
Types of diolefins
(1) Open chain cis conjugated dienes: such as cis 1,3-butadiene and its derivatives
(2) Intracyclic Dienes: such as cyclopentadiene and its derivatives
(3) Transcyclic Dienes.
Types of dienophiles
(1) Double bond dienophile: such as - C=C-Z or Z-C=C-Z '(Z or Z' CHO, COR, COtwoH，COtwoR，COCl，COAr，CN，NOtwo，Ar，CHtwoOH，CHtwoCl，CHtwoNHtwo， CHtwoCN，CHtwoCOtwoH. X or C=C)
(2) Three bond dienophiles: such as - C ∨ C-Z or Z-C ∨ C-Z (Z or Z ′ as above)
(3) Heterophilic diene containing other atoms: such as - CN, - C=N -, - N=N -, O=N and - C=O, etc.
catalyzer
The Diels Alder reaction is basically spontaneous. Generally, no catalyst is needed, but the reaction is difficult at room temperature or low temperature. Some catalysts can be added to accelerate the reaction.The catalyst used is generallyLewis acid, such as AlClthree，BFthree，SnClfourAnd TiClfourEtc.[2]
developing process
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The earliest research on Diels Alder reaction can be traced back to 1892.Zinke found and proposed tetrachloride, the product of Diels Alder reactionCyclopentadieneStructure of ketone dimer;Later, Lebedev pointed out that vinyl cyclohexene is the conversion relationship of butadiene dimer.But neither of them realized the deeper things behind these facts.
1906
University of Munich, GermanyPostgraduate Albrecht did the experiment of synthesizing a dye by condensation of cyclopentadiene and ketones under alkali catalysis according to the requirements of Tutil.At that time, they tried to use benzoquinone to replace other ketones for experiments, but benzoquinone was easy to decompose under alkaline conditions.The experiment was unsuccessful.Albrecht found that the reaction could be carried out without alkali, but a colorless compound was obtained.Albrecht proposed a wrong structure to interpret the experimental results.
1920
Study by German von Euler and student JosephisopreneStructure of reaction product with benzoquinone.They correctly proposed the structure of the Diels Alder product and the possible mechanism of the reaction.In fact, they are very close to the discovery of Diels Alder reaction.However, Von Euler did not go deep into his research, because his main business was biochemistry (he later won the Nobel Prize for his research on fermentation), and his research on the Diels Alder reaction was purely recreational, so the Diels Alder reaction sank again.
Official discovery
Research on Dills and his graduate student BackDiethyl azodicarboxylate(A reagent that shines brightly in organic synthesis due to photoextension reaction half a century later) The esterification of amine with amine occurs when they use2-NaphthylamineWhen doing the reaction, according to the element analysis, the product obtained is an adduct rather than the expected substitute.Diels was acutely aware of the similarities between this reaction and the strange reaction Albrecht had made more than ten years ago.This led him to think that the product was similar to Albrecht's double bond addition product.Diels naturally imitated Albrecht to replace naphthylamine with cyclopentadieneAzodicarboxylic acidThe third adduct was obtained by the action of ethyl ester.Through the stoichiometric hydrogenation experiment, Diels found that there was only one double bond in the adduct.If the structure of the product is as proposed by Albrecht, then the potential must have two double bonds.This phenomenon deeply attracted Diels, who together with another graduate student Alder proposed the correct structure of diene adducts.In 1928, they published the results, which marked the official discovery of the Diels Adel reaction.
1950
Woodward pioneered the application of Diels Alder reaction in total synthesis.Since then, the synthesis masters have used their wise brains to bring the application of Diels Alder reaction to the acme of perfection.It is worth pointing out that before Woodward, the Chinese chemist Zhuang Changgong once tried to use the Diels Alder reaction to synthesizeSteroidHowever, it failed due to the lack of knowledge of controlling the regioselectivity of the Diels Alder reaction at that time.
reaction mechanism
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Diels Alder reaction is a typical [4+2] type cycloaddition reaction. Its reaction mechanism is generally believed that the two reactants are close to each other and interact to form a ring filter state during the reaction.Then it is gradually transformed into product molecules, that is, the breaking of old bonds and the formation of new bonds are mutually coordinated and completed in the same step - cooperative reaction, no intermediate is generated.The reaction diagram is as follows:
Diels Alder reaction principle
It is proved that the reaction of 1,3-butadiene and ethylene is a simple and typical orbital controlled Diels Alder reaction. At first, the frontier orbital principle was used, as shown in Figure 1 below. This is a cooperative reaction of old bond breaking and new bond forming. Initially, the Diels Alder reaction was explained by symmetry matching.[3]
Fig. 1 Explanation of D-A reaction by frontier orbital theory
Stereochemistry
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1、Regional selectivityThe reaction products are often pseudoortho para products.That is, if the six membered ring product is compared to the benzene ring, then the mutual position between the functional groups on the ring (assuming there are two functional groups) is mainly ortho (such as 1) or para (such as 3)
Domain Selectivity Diagram
2. Stereoselectivity: the reaction product is mainly endomorphic (i.e. 5), that is, the main reaction product is obtained through the transition state of endomorphic.
Stereoselectivity diagram
3. Stereospecificity: the only product of the reaction is the cis spin product under heating conditions, and the only product is the counter spin product under light conditions.
Application extension
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Since the reaction generates two carbon carbon bonds and up to four adjacent chiral centers at a time, it has attracted much attention in synthesis.If a synthesis design uses the Diels Alder reaction, it can greatly reduce the reaction steps and improve the efficiency of synthesis.Diels Alder reaction plays an important role in organic synthesis, which is to synthesize six elementsCyclic compoundImportant methods.A similar reaction can be carried out by replacing the carbon atom in the reaction with a heteroatom to obtain a six membered ring compound containing heteroatoms.
Azadiene
Synthesis of tetrahydropyridines from imines and dienesCycloaddition reaction。This organic chemical reaction is a variation of the Diels Alder reaction. The nitrogen atom replaces the methylene or methylene in the diene or diene affinity in the original reaction.The imine in this reaction reactant is often produced in situ by amine and formaldehyde, such asCyclopentadieneFormation of aza with benzylamineNorborneneThe reaction process is shown in Figure 2 below:[4]
Fig. 2 Synthesis of azanorbornene
Lewis acid catalysis
Curry also made great contributions to the Diels Alder reaction, inventing an asymmetric Diels Alder reaction catalyzed by Lewis acid.In its synthesisprostaglandinIn the process, Cory tried to useCyclopentadieneDo the Diels Alder reaction to construct the parent ring of prostaglandins, thus inventing instabilityKeteneSubstitute reagents for.Dani Shefsky invented“Danichevsky diene”It is most famous for its use in the Diels Alder reaction. In its total synthesis practice, the Diels Alder reaction can also be seen everywhere.
Lewis acid catalyzed asymmetric Diels Alder reaction
