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Why are scientists so obsessed with the 1,4 addition of the Michael reaction? Impossible compounds can be created so easily!
In organic chemistry, the Michael reaction or 1,4-addition is an important chemical reaction. This reaction usually involves the interaction between a Michael donor (usually the enol anion of a ketone or aldehyde) and a Michael acceptor (usually an α,β-unsaturated carbonyl compound). The efficiency of this reaction allows chemists to create carbon-carbon bonds under milder conditions, which is a revolutionary technology for the synthesis of new compounds.
Michael addition is an atom-economic method that can efficiently form C-C bonds without producing excessive by-products.
The Michael reaction is particularly suitable for stereoselective and enantioselective reactions. In this reaction, the structure of the Michael donor may contain various electron-attracting substituents. These groups make the adjacent methylene hydrogen atoms quite acidic, thus forming negatively charged carbonyl compounds. This not only allows scientists to obtain more diverse products during the synthesis process, but also more effectively controls the stereochemistry of the reaction.
The mechanism of Michael’s reaction
The mechanism of the Michael reaction begins with the deprotonation of the Michael donor by a basic substance to form a stable negatively charged enol anion. Next, this negative ion acts as a nucleophile and reacts with the positively charged alkene, ultimately forming a new carbon-carbon bond. This process depends largely on the orbital properties of the molecule rather than on electrostatic interactions; this makes the reaction extremely selective in the formation of specific compounds.
The reaction mainly depends on the polarity of the electron cloud. The frontier orbits of these polarizations are energetically close to each other, so the reaction efficiency is extremely high.
The history of Michael’s reaction
The Michael reaction was proposed by Arthur Michael in 1887. The earliest research inspiration for this reaction came from the literature on substitution reactions published by Conrad and Kuster in 1984. Michael noticed that when he used ethyl 2-bromoacrylate to react with diethylmaleic acid, he observed the formation of a reaction product, which directly motivated him to further explore the potential of this reaction.
As time goes by, scientists have continued to study the Michael reaction in depth, gradually covering a variety of new nuclear affinity agents and receptors. This expands the application scope of Michael reaction to many fields such as pharmaceuticals and materials science.
Application of Michael reaction
In the field of medicine, the Michael reaction is widely used in the synthesis of a variety of therapeutic drugs. Many anticancer drugs, such as ibrutinib, osimertinib, and rociletinib, utilize specific compounds with Michael acceptor groups, which allow them to interact efficiently with their targets. The active sites of enzymes interact, thereby inhibiting enzyme activity.
Scientifically, the Michael reaction provides a highly efficient way to design novel drugs, especially those that are powerful covalent inhibitors.
In addition, significant progress has been made in the application of Michael reaction in polymerization reactions. It can not only be used to synthesize various high-performance polymers, but is also widely used in the biomedical field. Some of the polymers are designed for drug release and high-performance composite materials.
Today, scientists’ love for the Michael reaction not only stems from its convenience, but also from the infinite potential displayed by this technology. Future research will bring us more surprising discoveries and applications. Against this background, can the scientific community create more new synthetic methods based on the Michael reaction?
