Types of Click Chemistry Reagents

Click chemistry has emerged as a powerful tool in modern chemical research, enabling precise and efficient reactions between molecular components. At the heart of this groundbreaking methodology are click chemistry reagents, which are essential for facilitating highly selective and reliable reactions. 

Creative PEGWorks specializes in advanced polymer products, with years of experience in the innovation, production, and distribution of some of these click chemistry reagents. Here, we’ll delve into various types of click chemistry reagents, each tailored to specific applications across a wide range of scientific disciplines.

What is Click Chemistry?

First coined by K. Barry Sharpless in 2001, “click chemistry” refers to a set of highly reliable, selective, and versatile reactions used for the rapid and efficient assembly of molecular structures. The hallmark of click chemistry is its simplicity and efficiency, allowing chemists to join molecules together with ease and precision, often under mild reaction conditions.

“for the development of click chemistry & bioorthogonal chemistry.”

The 2022 Nobel Prize in Chemistry is about making complex processes easier. Sharpless and Meldal laid the foundation for a functional form of chemistry in which molecular building blocks snap together quickly and efficiently – known as click chemistry. Bertozzi then took this to a new dimension and started utilizing click chemistry in living organisms.

They get their name for their ability to “click” together, often with the formation of a covalent bond. Click chemistry reactions are widely used in various scientific disciplines and have practical applications in fields such as drug development, materials science, bioconjugation, and chemical biology.

There are a few signature characteristics of click chemistry:

High Yield and Speed 

Click reactions typically yield a high percentage of the desired product, minimizing the generation of byproducts.

As Nwe and Brechbiel state: “Drug discovery based on natural products can be hampered by slow, complex synthesis. Click chemistry, on the other hand, simplifies and optimizes syntheses, providing faster, efficient reactions. Click chemistry was employed by Zhang et al. to produce the peroxisome proliferator-activated receptor γ (PPAR-γ) agonists for the treatment of type II diabetes.” ^[1]

High Selectivity

Click reactions are highly specific, ensuring that they occur between the intended reactants while avoiding unwanted side reactions.

Orthogonal

Click reactions can be conducted under mild conditions that are compatible with a wide range of functional groups and biological systems. This orthogonality allows for the selective modification of complex molecules.

Modularity

Click chemistry reactions are often modular, allowing researchers to design and synthesize compounds with specific properties by combining building blocks.

Bioorthogonal

Some click reactions are bioorthogonal, meaning they can be performed in biological systems without interfering with native biological processes. This property is particularly valuable for labeling biomolecules, tracking cellular processes, and conducting research in living organisms.

Classifications of Click Chemistry Reactions

Hein, Liu, and Wang, summarize the four classifications of click chemistry reactions:

• “Cycloadditions – these primarily refer to 1,3-dipolar cycloadditions, but also include hetero-Diels-Alder cycloadditions.”^[2]
• “Nucleophilic ring-openings – these refer to the openings of strained heterocyclic electrophiles, such as aziridines, epoxides, cyclic sulfates, aziridinium ions, episulfonium ions, etc.”^[2]
• “Carbonyl chemistry of the non-aldol type- examples include the formations of ureas, thioureas, hydrazones, oxime ethers, amides, aromatic heterocycles, etc.Carbonyl reactions of the aldol type generally have low thermodynamic driving forces, hence they have longer reaction times and give side products, and therefore cannot be considered click reactions.”^[2]
• “Additions to carbon-carbon multiple bonds – examples include epoxidations, aziridinations, dihydroxylations, sulfenyl halide additions, nitrosyl halide additions, and certain Michael additions.”^[2]

Click Chemistry Reagents

Reagents are the essential ingredients that make chemical reactions possible. In the realm of click chemistry the choice of reagents are particularly important. These specialized compounds play a pivotal role in enabling the precise and selective assembly of molecules, turning the theory of click chemistry into tangible scientific and technological advancements. 

Azides

Azides are a class of organic compounds containing the azide functional group (-N3). They are a cornerstone of click chemistry reactions, particularly in copper-catalyzed azide-alkyne cycloaddition (CuAAC). Azides readily react with alkynes to form stable triazole linkages, making them invaluable in bioconjugation, drug development, and materials science.

Alkynes

Alkynes are hydrocarbons containing at least one carbon-carbon triple bond (C≡C). They are crucial counterparts to azides in CuAAC reactions. Alkynes form triazole linkages with azides under the influence of a copper catalyst, contributing to the success of click chemistry in various applications, including biomolecule labeling and surface modification.

Cyclooctynes

Cyclooctynes are strained cycloalkynes that participate in strain-promoted azide-alkyne cycloaddition (SPAAC) reactions, a copper-free alternative to CuAAC. Their strained structure enables them to react efficiently with azides without the need for a copper catalyst. SPAAC reactions are popular in bioorthogonal chemistry due to their low cytotoxicity and compatibility with biological systems.

Thiols

Thiols are sulfur-containing compounds (R-SH) that react with alkenes in thiol-ene reactions. These reactions are valuable for bioconjugation and materials science, allowing the creation of thioether linkages between molecules. Thiols are also used in Staudinger ligation, where they react with azides to form amide bonds.

Dienes

Dienes are hydrocarbons containing two carbon-carbon double bonds (C=C=C). They are essential in Diels-Alder reactions, a type of click chemistry involving the formation of cyclohexene rings. Diels-Alder reactions are employed in the synthesis of complex organic compounds and functional materials.

Phosphines

Phosphines are compounds containing phosphorus atoms and are often used in Staudinger ligation reactions. In these reactions, phosphines react with azides to form amide bonds. Staudinger ligation is valuable for labeling biomolecules and conducting bioconjugation.

Diazides

Diazides are compounds with two azide functional groups. They are employed in Huisgen 1,3-dipolar cycloaddition reactions, where they react with alkynes to form triazole rings. This type of click chemistry reaction is integral to CuAAC reactions.

Clickable Handles

Clickable handles are specific functional groups or moieties introduced into molecules to enable click chemistry reactions. Examples include azide- and alkyne-containing handles that facilitate bioconjugation, allowing researchers to label and modify biomolecules with precision.

Final Word: Types of Click Chemistry Reagents

Click chemistry reagents have revolutionized the way scientists approach chemical reactions and have become indispensable tools in various scientific fields. From bioconjugation and drug development to materials science and chemical biology, these reagents offer versatility, selectivity, and efficiency. 

For more on Creative PEGWorks work with click chemistry reagents and their potential applications, contact us today. Or buy PEG products online from the leading PEGylation Reagent supplier!

References 

1. Nwe K, Brechbiel MW. Growing applications of “click chemistry” for bioconjugation in contemporary biomedical research. Cancer Biother Radiopharm. 2009;24(3):289-302. doi:10.1089/cbr.2008.0626
2. Hein CD, Liu XM, Wang D. Click chemistry, a powerful tool for pharmaceutical sciences. Pharm Res. 2008;25(10):2216-2230. doi:10.1007/s11095-008-9616-1