In 2001, Professor Sharpless proposed that nature prefers carbon heteroatoms to carbon-carbon bonds (C-C). Nucleic acids, proteins, and polysaccharides are condensation polymers linked together by carbon-heterogeneous atom bonds. Professor Sharpless was inspired by this and proposed the concept of click chemistry. Prior to this, chemical synthesis methods were complex, difficult, and had low yields. Until the first generation of click chemistry (the monovalent copper-catalyzed azide-alkyne cycloaddition reaction, i.e. CuAAC reaction) was proposed, functional molecules were constructed through a patterned reaction method, and complex reactions began to be simplified. However, the cytotoxicity of copper catalysts limits the in vivo and in vitro applications of CuAAC reactions.
Chemists have since discovered strain-promoted alkyne-azide cycloaddition (SPAAC), allowing the azide-alkyne reaction to occur without the need for a cytotoxic copper catalyst. However, some chemists were not satisfied with the second-order reaction rate constant of SPAAC, and the inverse electron demand Diels-Alder reaction (iEDDA) came into being. Click chemistry has always been a popular research topic in the field of chemistry due to its simple reaction, high yield, no by-products, and fast reaction rate.
Fig.1 Schematic diagram of click chemistry (Li X., Xiong Y. 2022).
Classification of Click Chemistry
There are four main types of click chemistry reactions: cycloaddition reaction, nucleophilic ring-opening reaction, nucleophilic addition reaction, and carbon-carbon multiple bond addition reaction.
Cycloaddition Reaction
Following the introduction of the concept of click chemistry, the monovalent copper-catalyzed azide-alkyne cycloaddition reaction (CuAAC reaction) was independently reported by Sharpless and Medal groups in 2002. Azides and terminal alkynes remain stable under most chemical conditions but can be efficiently and specifically converted to 1,3-substituted triazole under monovalent copper catalysis. It has the advantages of mild conditions, high yield, high chemical selectivity, and no interference from water and oxygen. Due to the advantages of the CuAAC reaction, it is an efficient method for hydrogel preparation and is often used to design hydrogel networks. It has been used in many other polymer materials used in biochemistry and drug synthesis. In addition, the Hetero-Diels-Alder reaction is also a cycloaddition reaction, including a [4+2] cycloaddition reaction between a diene and a dienophile.
Nucleophilic Ring-Opening Reaction
This reaction belongs to the ring opening of strained heterocyclic electrophiles, such as epoxides, aziridines, aziridinium ions, cyclic sulfates, etc. Among these compounds, epoxides and aziridines are the most common substrates, and their regioselective ring-opening reactions form various bioactive compounds. This click reaction is usually carried out in an alcohol and water solvent mixture, and the final product can be isolated in high yield using a simple working procedure.
Nucleophilic Addition Reaction
It includes the reaction of carbonyl groups to form hydrazones, oxime ethers, amides, urease, aromatic heterocycles, etc. This type of reaction takes longer and has lower thermodynamic forces.
Carbon-Carbon Multiple Bond Addition Reaction
It involves epoxidation, dihydroxylation, aziridination, nitrosyl halide addition, thiohalide addition and certain Michael addition reactions.
Application of Click Chemistry in Biomedicine
Click chemistry is a promising field that allows the rapid synthesis of pharmacologically active 1,2,3-triazole molecules. Triazole compounds have high aromatic stability, are stable to both acidic and alkaline hydrolysis, exhibit a wide range of beneficial biological properties, and have been used as potential targets for developing anticancer, antibacterial, antiviral, and biomedical imaging agents. In addition, click chemistry also plays an important role in cell culture, drug delivery, tissue repair, and 3D bioprinting because of its ability to prepare hydrogels.
References
- Li X.; Xiong Y. Application of "Click" Chemistry in Biomedical Hydrogels. ACS Omega. 2022, 7(42): 36918-36928.
- Sethiya, A.; et al. Role of click chemistry in organic synthesis. Current Topics in Chirality-From Chemistry to Biology. IntechOpen. 2021.
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