Click chemistry as a connection tool: Grand opportunities and challenges

doi:10.1016/S1872-2067(23)64434-1

Chinese Journal of Catalysis ›› 2023, Vol. 49: 8-15.DOI: 10.1016/S1872-2067(23)64434-1

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Click chemistry as a connection tool: Grand opportunities and challenges

Chen Wang^,¹, Junzhu Yang^,¹, Yuan Lu^*()

Key Laboratory of Industrial Biocatalysis, Ministry of Education, Department of Chemical Engineering, Tsinghua University, Beijing 100084, China

Received:2023-03-01 Accepted:2023-03-21 Online:2023-06-18 Published:2023-06-05
Contact: E-mail: yuanlu@tsinghua.edu.cn (Y. Lu).
About author:Yuan Lu is an Associate Professor at Tsinghua University. After receiving B.S. (2004) and Ph.D. (2009) in chemical engineering from Tsinghua University, China, Yuan Lu received postdoctoral training from Johns Hopkins University (2009-2010) and Stanford University (2010-2014), USA. He was a project researcher from 2014 to 2016 at the University of Tokyo, Japan. Dr. Lu joined the faculty of Chemical Engineering at Tsinghua University in 2016. The central paradigm of his research is using interdisciplinary approaches in engineering, biology, chemistry, physics, and computer science to manipulate biomolecules and complex biological systems. The main focus lies on developing and applying synthetic biology and other cutting-edge technologies to engineer nucleic acids, proteins, pathways, and networks for addressing the most daunting challenges in human health.
First author contact:¹ Contributed equally to this work.
Supported by:
National Key R&D Program of China(2018YFA0901700);National Natural Science Foundation of China(22278241);Institute Guo Qiang, Tsinghua University(2021GQG1016);Department of Chemical Engineering‐iBHE Joint Cooperation Fund

Abstract

Abstract:

Although the concept of click chemistry was proposed more than twenty years ago, the research progress of click chemistry has emerged with great vitality, and this year's Nobel Prize in chemistry has once again highlighted the importance of the field of click chemistry. Click chemistry is a reaction in which a variety of molecules are quickly and reliably synthesized by piecing together small units. In particular, it emphasizes the development of new combinatorial chemistry methods based on the synthesis of carbon-heteroatomic bonds and the simple and efficient acquisition of molecular diversity through these reactions. Based on the superior reaction characteristics of click chemistry, click chemistry methods for production are advancing toward precision, simplicity, and high returns, especially in producing polymer materials and some bright biomedical applications. Here, we describe the development logic of typical click reactions with different substrates and catalysts. The latest technologies of click chemistry in the structure control and functional properties of polymers, as well as in the field of biomedicine and its expanding applications, are discussed. Finally, we identify the challenges of click chemistry in reaction mechanisms and engineering applications, and suggest potential future development directions in the future.

Key words: Click chemistry, Bioorthogonal chemistry, Combinatorial chemistry, Polymer material, Biomedical science

Chen Wang, Junzhu Yang, Yuan Lu. Click chemistry as a connection tool: Grand opportunities and challenges[J]. Chinese Journal of Catalysis, 2023, 49: 8-15.

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Figures/Tables 4

Fig. 1. Available reaction types in click chemistry and their development to meet the needs of the application. Click chemistry aims to synthesize molecules through the simple linkage of functional modules, just like a strap connector. The criteria of click chemistry have instructed us to find several available reaction types. These reactions are not perfect at the beginning and still need improvement. Since the application fields have been broadly enlarged, click reactions should be further developed in two main directions, meaning they should be more condition-relaxed and more intelligent. In this case, strain-activated substrates have been proven to accelerate reactions in the physiological environment. Light-triggered and dissociative click reactions have provided new breakthroughs to make this field smarter and more controllable.

Table 1 Common click reaction types and their conditions. Most click reactions happen under mild conditions, but they could still need proper catalysts.

Reaction category	Catalyst	Substrate	Temperature	Solvent
Nucleophilic opening of spring-loaded rings	—	spring-loaded cyclic electrophile (epoxides, aziridines, cyclic sulfates, etc.), nucleophile	ambient or slightly higher than 100 °C	no solvents, water; alcohol
Huisgen 1,3-dipolar cycloaddition	Cu(I), Cu(II), strain-promoted	dipoles (propargyl, allyl, mesoionics), dipolarophiles (alkynes, allenes, etc.)	ambient	water, polar organic solvents
Diels-Alder reactions	lewis acid, strain-promoted	conjugated diene, dienophile (substituted olefin)	< 200 °C	water, organic solvent
“Protecting Group” reactions	acid	idol, hydroxysulfonamides, aldehydes/ketones	ambient	without water
Michael addition	acid, base, noble metal	activated alkynes, soft nucleophiles	ambient or slightly higher than 100 °C	solvent tolerant, high-polar solvent preferred
Staudinger reactions	—	triarylphosphines, azides	ambient	water

Fig. 2. The potential application of click chemistry in the field of polymer science and biomedical. Click chemistry could facilitate the accurate structure control and flexible function modification in polymer synthesis. It also brings new breakthroughs in bioconjugation, further applied to biomarker/imaging, drug delivery, and drug target screening fields.

Fig. 3. Challenges and possible solutions in click chemistry. The various application fields have proposed new challenges to click chemistry. Summarily, click reactions should be more biocompatible and easily happen in physiological conditions. They should also be more extensible to facilitate the construction of a molecule library. Smart click chemistry is also encouraged to bring intelligent control to this process. To face these challenges, we propose to further explore the detailed mechanism of click reactions, especially in complicated application scenarios. Computer science might provide solutions for constructing a large-scale molecule library and high-throughput screening based on click reactions. Additionally, physical factors, such as light and magnetism, could be introduced as controllable elements, which might promote smart click chemistry.

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Click chemistry as a connection tool: Grand opportunities and challenges

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