Click chemistry

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Azide Alkyne cycloaddition

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CuAAC Catalytic Cycle

Strain-promoted Azide-Alkyne Cycloaddition

SpAAC vs SpANC

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Tetrazine-Alkene Reaction

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Unnatural Amino Acids

Click Chemistry is a term that refers to a group of chemical reactions that are modular, wide in scope, give very high yields, and generate only byproducts that can be removed without chromatography. The concept was introduced by K. Barry Sharpless in 2001 and has since become a valuable tool in various areas of chemistry including bioconjugation, material science, and drug discovery.

Overview

Click chemistry is based on the idea that chemical synthesis can be accelerated and made more efficient by using reactions that are highly reliable, selective, and simple to perform. The most widely recognized click reaction is the Copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC), often referred to as the quintessential click reaction. This reaction involves the cycloaddition of an azide and a terminal alkyne to form a 1,2,3-triazole, facilitated by a copper(I) catalyst.

Principles

The principles of click chemistry are centered around the use of reactions that:

• Are highly efficient and yield high product purity
• Use readily available starting materials and reagents
• Proceed under mild and benign conditions
• Generate minimal byproducts that are non-toxic and can be easily removed

Applications

Click chemistry has found applications in a wide range of fields due to its efficiency and versatility:

• In bioconjugation, it is used to attach biomolecules to one another or to solid supports without affecting their biological activity.
• In material science, it enables the creation of novel polymers and nanomaterials with tailored properties.
• In drug discovery, it facilitates the rapid synthesis of libraries of compounds for screening as potential new therapeutics.

Key Reactions

• Copper(I)-catalyzed Azide-Alkyne Cycloaddition (CuAAC): The most emblematic click reaction, used extensively in the synthesis of triazoles.
• Strain-promoted Azide-Alkyne Cycloaddition (SPAAC): A copper-free version of the azide-alkyne cycloaddition, useful in sensitive biological contexts where copper might be deleterious.
• Thiol-ene Reaction: A reaction between a thiol and an alkene to form a thioether, used in polymer chemistry and bioconjugation.

Challenges and Future Directions

While click chemistry has revolutionized many aspects of chemical synthesis, challenges remain, such as the development of more reactions that fulfill the criteria of click chemistry and the expansion of its applicability in more complex biological systems. Future research is likely to focus on discovering new click reactions, improving the efficiency and selectivity of existing reactions, and expanding the range of applications in science and technology.