Showing papers on "Click chemistry published in 2020"

The Huisgen Reaction: Milestones of the 1,3-Dipolar Cycloaddition.

Abstract: The concept of 1,3-dipolar cycloadditions was presented by Rolf Huisgen 60 years ago. Previously unknown reactive intermediates, for example azomethine ylides, were introduced to organic chemistry and the (3+2) cycloadditions of 1,3-dipoles to multiple-bond systems (Huisgen reaction) developed into one of the most versatile synthetic methods in heterocyclic chemistry. In this Review, we present the history of this research area, highlight important older reports, and describe the evolution and further development of the concept. The most important mechanistic and synthetic results are discussed. Quantum-mechanical calculations support the concerted mechanism always favored by R. Huisgen; however, in extreme cases intermediates may be involved. The impact of 1,3-dipolar cycloadditions on the click chemistry concept of K. B. Sharpless will also be discussed.

Recent Fascinating Aspects of the CuAAC Click Reaction

Abstract: CuAAC chemistry is used to compose incredible synthetic molecular architectures and acts as a true click chemistry reaction allowing densely functional molecular fragments to be joined in a highly controlled manner. Using supercatalysts based on our mechanistic understanding and in the absence of oxygen, CuAAC reactions are superior even in bioligation chemistry. The catalytic cycle provides an organometallic intermediate reacting through electrophilic or oxidative escape valves resulting in trisubstituted 1,2,3-triazoles and allowing CuAAC-multicomponent reactions. The ease of CuAAC provides new pathways in the development of exquisitely selective macrocyclic protein–protein interaction inhibitors (PPIs) and enzyme inhibitors as putative novel classes of pharmaceuticals.

A General Strategy for Macrotheranostic Prodrug Activation: Synergy between the Acidic Tumor Microenvironment and Bioorthogonal Chemistry

Abstract: Prodrugs activated by endogenous stimuli face the problem of tumor heterogeneity. Bioorthogonal prodrug activation that utilizes an exogenous click reaction has the potential to solve this problem, but most of the strategies currently used rely on the presence of endogenous receptors or overexpressed enzymes. We herein integrate the acidic, extracellular microenvironment of a tumor and a click reaction as a general strategy for prodrug activation. This was achieved by using a tumor pH-responsive polymer containing tetrazine groups, which formed unreactive micelles in the blood but disassembled in response to tumor pH. The vinyl ether group on the macrotheranostic prodrug (CyPVE) is activated by the tetrazine groups, which was confirmed by tumor-specific fluorescence activation and phototoxicity restoration. Therefore, the bioorthogonal reactions in the context of the ubiquitous acidic tumor microenvironment can provide a general strategy for bioorthogonal prodrug activation.

Large-scale preparation for efficient polymer-based room-temperature phosphorescence via click chemistry

Abstract: To achieve efficient polymer-based room-temperature phosphorescence (RTP) materials, covalently embedding phosphors into the polymer matrix appeared as the most appealing approach. However, it is still highly challenging to fabricate RTP materials on a large scale because of the inefficient binding engineering and time-consuming covalent reactions. Here, we have proposed a scalable preparation approach for RTP materials by the facile B─O click reaction between boronic acid-modified phosphors and polyhydroxy polymer matrix. The ab initio molecular dynamics simulations demonstrated that the phosphors were effectively immobilized, resulting in the suppressed nonradiative transitions and activated RTP emission. In comparison to the reported covalent binding time of several hours, such a B─O click reaction can be accomplished within 20 s under ambient environment. The developed strategy simplified the construction of polymer-based RTP polymeric materials by the introduction of facile click chemistry. Our success provides inspirations and possibilities for the scale-up production of RTP materials.

Diversity Oriented Clicking (DOC): Divergent Synthesis of SuFExable Pharmacophores from 2‐Substituted‐Alkynyl‐1‐Sulfonyl Fluoride (SASF) Hubs

Abstract: Diversity Oriented Clicking (DOC) is a unified click-approach for the modular synthesis of lead-like structures through application of the wide family of click transformations. DOC evolved from the concept of achieving "diversity with ease", by combining classic C-C π-bond click chemistry with recent developments in connective SuFEx-technologies. We showcase 2-Substituted-Alkynyl-1-Sulfonyl Fluorides (SASFs) as a new class of connective hub in concert with a diverse selection of click-cycloaddition processes. Through the selective DOC of SASFs with a range of dipoles and cyclic dienes, we report a diverse click-library of 173 unique functional molecules in minimal synthetic steps. The SuFExable library comprises 10 discrete heterocyclic core structures derived from 1,3- and 1,5-dipoles; while reaction with cyclic dienes yields several three-dimensional bicyclic Diels-Alder adducts. Growing the library to 278 discrete compounds through late-stage modification was made possible through SuFEx click derivatization of the pendant sulfonyl fluoride group in 96 well-plates-demonstrating the versatility of the DOC approach for the rapid synthesis of diverse functional structures. Screening for function against MRSA (USA300) revealed several lead hits with improved activity over methicillin.

Ionic‐Liquid‐Modified Click‐Based Porous Organic Polymers for Controlling Capture and Catalytic Conversion of CO2

Abstract: Capture and catalytic conversion of CO2 into value-added chemicals is a promising and sustainable approach to relieve global warming and the energy crisis. Nitrogen-rich porous organic polymers (POPs) are promising materials for CO2 capture and separation, but their application in the additive-free catalytic conversion of CO2 into cyclic carbonates is still a challenge. Herein, a nitrogen-rich click-based POP (CPP) was developed for the cycloaddition reaction of CO2 with epoxides in the absence of metal, solvents, and additives. The introduction of imidazolium-based ionic liquids on the CPP host backbone could modulate the porosity, CO2 adsorption/desorption, CO2 selectivity over N2 , and catalytic activity in the chemical transformation. A tentative catalytic pathway was proposed to account for the superior catalytic activity of the catalytic systems, in which the incorporated ionic liquid and porous properties of CPP synergistically contributed to the catalytic reaction. This study provides a platform to understand the cooperative effects of porous properties and nucleophilic anions on the cycloaddition reaction of CO2 with epoxides.

Adaptable Strategy to Fabricate Self-Healable and Reprocessable Poly(thiourethane-urethane) Elastomers via Reversible Thiol–Isocyanate Click Chemistry

Abstract: Currently, a variety of elastomers with a self-healing capacity and reprocessability have been developed by dynamic chemistry to extend the service life, increase the reliability of polymeric mater...

Click chemistry reaction-triggered DNA walker amplification coupled with hyperbranched DNA nanostructure for versatile fluorescence detection and drug delivery to cancer cells

Abstract: A new DNA hyperbranched hybridization chain reaction (HB-HCR)-amplified fluorescence platform combined with DNA walker was developed for versatile detection of Cu2+, adenosine triphosphate (ATP), and drug delivery to cancer cells. A novel click chemistry reaction-triggered DNA walking machine on magnetic beads (MBs) is introduced for the first time to convert target Cu2+ to lots of DNA S3 products. With the help of DNA S3 and H1 on the amino functionalized SiO2 microsphere, HB-HCR between super hairpin DNA (SH DNA), H3-DNA, and LT-DNA was initiated to assemble a novel dendritic DNA structure with numerous fluorescent Cy5, achieving enormously amplified signal for ultrasensitive detection of Cu2+. Furthermore, this contains large amounts of double-stranded DNA with plentiful GC bases, which can provide many loading sites for chemotherapeutic drug doxorubicin (Dox). The specific binding of ATP to aptamer in the dendritic DNA structure allows for release of Dox, leading to activation of Dox fluorescence for ATP assay. More importantly, this dendritic DNA nanostructure-loaded Dox enters into tumor cells by endocytosis, and then interacts with endogenous ATP, releasing Dox for efficient treatment of cancer cells. Taking advantages of these multiple amplification of HB-HCR on SiO2 microsphere, click chemistry reaction, DNA walking, and release of Dox, this method enables ultrasensitive detection of Cu2+ and ATP as low as 0.1 fM and 1.0 aM, respectively, which can be widely used for accurate detection of biomolecules in clinical diagnosis and biomedical applications. This dendritic DNA nanostructure provided an effective tool for designing smart nanodevices.

Liganding Functional Tyrosine Sites on Proteins Using Sulfur–Triazole Exchange Chemistry

Abstract: Tuning reactivity of sulfur electrophiles is key for advancing click chemistry and chemical probe discovery. To date, activation of the sulfur electrophile for protein modification has been ascribed principally to stabilization of a fluoride leaving group (LG) in covalent reactions of sulfonyl fluorides and arylfluorosulfates. We recently introduced sulfur-triazole exchange (SuTEx) chemistry to demonstrate the triazole as an effective LG for activating nucleophilic substitution reactions on tyrosine sites of proteins. Here, we probed tunability of SuTEx for fragment-based ligand discovery by modifying the adduct group (AG) and LG with functional groups of differing electron-donating and -withdrawing properties. We discovered the sulfur electrophile is highly sensitive to the position of modification (AG versus LG), which enabled both coarse and fine adjustments in solution and proteome activity. We applied these reactivity principles to identify a large fraction of tyrosine sites (∼30%) on proteins (∼44%) that can be liganded across >1500 probe-modified sites quantified by chemical proteomics. Our proteomic studies identified noncatalytic tyrosine and phosphotyrosine sites that can be liganded by SuTEx fragments with site specificity in lysates and live cells to disrupt protein function. Collectively, we describe SuTEx as a versatile covalent chemistry with broad applications for chemical proteomics and protein ligand discovery.

Metal‐Free Synthesis of Functional 1‐Substituted‐1,2,3‐Triazoles from Ethenesulfonyl Fluoride and Organic Azides

Abstract: The boom in growth of 1,4-disubstituted triazole products, in particular, since the early 2000's, can be largely attributed to the birth of click chemistry and the discovery of the CuI -catalyzed azide-alkyne cycloaddition (CuAAC). Yet the synthesis of relatively simple, albeit important, 1-substituted-1,2,3-triazoles has been surprisingly more challenging. Reported here is a straightforward and scalable click-inspired protocol for the synthesis of 1-substituted-1,2,3-triazoles from organic azides and the bench stable acetylene surrogate ethenesulfonyl fluoride (ESF). The new transformation tolerates a wide selection of substrates and proceeds smoothly under metal-free conditions to give the products in excellent yield. Under controlled acidic conditions, the 1-substituted-1,2,3-triazole products undergo a Michael addition reaction with a second equivalent of ESF to give the unprecedented 1-substituted triazolium sulfonyl fluoride salts.

Optimization of Cu catalysts for nitrophenol reduction, click reaction and alkyne coupling

Abstract: Earth-abundant nanocatalysts are actively searched to replace expensive noble metal catalysts for a number of essential processes. Here, Cu catalysts have been designed based on manganese oxide octahedral molecular sieve (OMS-2) supports to optimize the catalytic activity in nitrophenol reduction, CuAAC click reaction and terminal alkyne homocoupling. A correlation has been established between the different synthetic strategies and catalytic activities. CuOx/OMS-2 has also been found an efficient catalyst for the homocoupling of terminal alkynes, click reaction and the reduction of 4-nitrophenol, 2,4-dinitrophenol and 4-nitrobenzene diazo tetrafluoroborate with high activity, whereas Cu-OMS-2 only shows poor catalytic activity for reduction and click reaction, and no catalytic activity for homocoupling.

Living Supramolecular Polymerization of an Aza‐BODIPY Dye Controlled by a Hydrogen‐Bond Accepting Triazole Unit Introduced by Click Chemistry

Abstract: An aza-BODIPY dye 1 bearing two hydrophobic fan-shaped tridodecyloxybenzamide pendants through 1,2,3-triazole linkages was synthesized by a click reaction and characterized. 1 H NMR studies indicated that dye 1 exhibited variable conformations through intramolecular H-bonding interaction, which is beneficial for the polymorphism of aggregation. The thermodynamic, structural, and kinetic aspect of the supramolecular polymerization of dye 1 was investigated by UV/Vis absorption spectroscopy, IR spectroscopy, AFM, TEM, and SEM. Biphasic aggregation pathways of dye 1, leads to the formation of off-pathway, metastable Agg. I and thermodynamically stable Agg. II with distinct H-aggregation spectra and nanoscale morphology. The living manner of the supramolecular polymerization of dye 1 was demonstrated in seeded polymerization experiments with temperature-modulated successive cooling-heating cycles.

Bioorthogonal Tetrazine Carbamate Cleavage by Highly Reactive trans-Cyclooctene

Abstract: The high rate of the 'click-to-release' reaction between an allylic substituted trans-cyclooctene linker and a tetrazine activator has enabled exceptional control over chemical and biological processes. Here we report the development of a new bioorthogonal cleavage reaction based on trans-cyclooctene and tetrazine, which allows the use of highly reactive trans-cyclooctenes, leading to 3 orders of magnitude higher click rates compared to the parent reaction, and 4 to 6 orders higher than other cleavage reactions. In this new pyridazine elimination mechanism, wherein the roles are reversed, a trans-cyclooctene activator reacts with a tetrazine linker that is substituted with a methylene-linked carbamate, leading to a 1,4-elimination of the carbamate and liberation of a secondary amine. Through a series of mechanistic studies, we identified the 2,5-dihydropyridazine tautomer as the releasing species and found factors that govern its formation and subsequent fragmentation. The bioorthogonal utility was demonstrated by the selective cleavage of a tetrazine-linked antibody-drug conjugate by trans-cyclooctenes, affording efficient drug liberation in plasma and cell culture. Finally, the parent and the new reaction were compared at low concentration, showing that the use of a highly reactive trans-cyclooctene as the activator leads to a complete cycloaddition reaction with the antibody-drug conjugate in seconds vs hours for the parent system. Although the subsequent release from the IEDDA adduct is slower, we believe that this new reaction may allow markedly reduced click-to-release reagent doses in vitro and in vivo and could expand the application scope to conditions wherein the trans-cyclooctene has limited stability.

Recent advances in bio-orthogonal and dynamic crosslinking of biomimetic hydrogels

Abstract: In recent years, dynamic, ‘click’ hydrogels have been applied in numerous biomedical applications. Owing to the mild, cytocompatible, and highly specific reaction kinetics, a multitude of orthogonal handles have been developed for fabricating dynamic hydrogels to facilitate ‘4D’ cell culture. The high degree of tunability in crosslinking reactions of orthogonal ‘click’ chemistry has enabled a bottom-up approach to install specific biomimicry in an artificial extracellular matrix. In addition to click chemistry, highly specific enzymatic reactions are also increasingly used for network crosslinking and for spatiotemporal control of hydrogel properties. On the other hand, covalent adaptable chemistry has been used to recapitulate the viscoelastic component of biological tissues and for formulating self-healing and shear-thinning hydrogels. The common feature of these three classes of chemistry (i.e., orthogonal click chemistry, enzymatic reactions, and covalent adaptable chemistry) is that they can be carried out under ambient and aqueous conditions, a prerequisite for maintaining cell viability for in situ cell encapsulation and post-gelation modification of network properties. Due to their orthogonality, different chemistries can also be applied sequentially to provide additional biochemical and mechanical control to guide cell behavior. Herein, we review recent advances in the use of orthogonal click chemistry, enzymatic reactions, and covalent adaptable chemistry for the development of dynamically tunable and biomimetic hydrogels.

A versatile biomaterial ink platform for the melt electrowriting of chemically-crosslinked hydrogels

Abstract: In this study, we designed a novel biomaterial ink platform based on hydrophilic poly(2-ethyl-2-oxazine) (PEtOzi) specifically for melt electrowriting (MEW). This material crosslinks spontaneously after processing via dynamic Diels–Alder click chemistry. These direct-written microperiodic structures rapidly swell in water to yield thermoreversible hydrogels. These hydrogels are robust enough for repeated aspiration and ejection through a cannula without structural damage, despite their high water content of 84%. Moreover, the scaffolds retain functional groups for modification using click chemistry and therefore can be readily functionalized as demonstrated using fluorophores and peptides to facilitate visualization and cell attachment. The PEtOzi hydrogel developed here is compatible with confocal imaging and staining protocols for cells. In summary, an advanced material platform based on PEtOzi is reported that is compatible with MEW and results in functionalizable chemically crosslinked microperiodic hydrogels.

Click by Click Microporous Annealed Particle (MAP) Scaffolds.

Abstract: Macroporous scaffolds are being increasingly used in regenerative medicine and tissue repair. While the recently developed microporous annealed particle (MAP) scaffolds have overcome issues with injectability and in situ hydrogel formation, limitations with respect to tunability to be able to manipulate hydrogel strength and rigidity for broad applications still exist. To address these key issues, here hydrogel microparticles (HMPs) of hyaluronic acid (HA) are synthesized using the thiol-norbornene click reaction and then HMPs are subsequently annealed into a porous scaffold using the tetrazine-norbornene click reaction. This assembly method allows for straightforward tuning of bulk scaffold rigidity by varying the tetrazine to norbornene ratio, with increasing tetrazine resulting in increasing scaffold storage modulus, Young's modulus, and maximum stress. These changes are independent of void fraction. Further incorporation of human dermal fibroblasts throughout the porous scaffold reveals the biocompatibility of this annealing strategy as well as differences in proliferation and cell-occupied volume. Finally, injection of porous HA-Tet MAP scaffolds into an ischemic stroke model shows this chemistry is biocompatible in vivo with reduced levels of inflammation and astrogliosis as previously demonstrated for other crosslinking chemistries.

NIR Scaffold Bearing Three Handles for Biocompatible Sequential Click Installation of Multiple Functional Arms

Abstract: Near-infrared (NIR) probes are ideal for fluorescence labeling and imaging of biological targets in living animals. However, the instability of common NIR dyes hampers the construction of NIR probes bearing multiple functional components such as biomolecules for specific targeting and imaging reagents for multimodality imaging. To overcome these limitations, we designed a novel NIR scaffold bearing two terminal alkynes as clickable handles and a chloride on the heptamethine backbone that allows nucleophilic substitution with an azide to generate the third clickable handle. This unique scaffold allows for facile installation of multiple functional arms for the construction of multifunctional NIR probes. Various biomacromolecules or imaging reagents can be introduced to the NIR scaffold by sequential one-pot click reactions under biocompatible conditions. The preclickable handle chloride on the NIR backbone does not interfere with the initial click reactions, and it can be easily transformed into an azide for a following click reaction. On the basis of this unique NIR scaffold, we developed a highly efficient method to construct diverse NIR probes containing multiple functional biomolecules including peptides, antibodies, nucleic acids, and NIR/PET (positron emission tomography) dual-modality imaging probes bearing tumor-targeting groups. NIR imaging or multimodality imaging using these probes was performed on live cells or tumor models on living mice.

Nonswelling, Ultralow Content Inverse Electron‐Demand Diels–Alder Hyaluronan Hydrogels with Tunable Gelation Time: Synthesis and In Vitro Evaluation

Abstract: Hyaluronan (HA) is a major component of the extracellular matrix and is particularly attractive for cell-based assays; yet, common crosslinking strategies of HA hydrogels are not fully tunable and bioorthogonal, and result in gels subject to swelling, which affects their physicochemical properties. To overcome these limitations, HA hydrogels based on the inverse electrondemand Diels–Alder (IEDDA) “click” reaction are designed. By crosslinking two modified HA components together, as opposed to using telechelic components, tunable gelation times as fast as 4.4 ± 0.4 min and as slow as 46.2 ± 1.8 min are achieved for facile use. By optimizing HA molar mass, ultralow polymer content hydrogels of 0.5% (w/v), resulting in minimal (<3–5% mass variation) to nonswelling (<1%), transparent and biodegradable hydrogels are synthesized. To demonstrate their versatility, the newly designed hydrogels are tested as matrices for 3D cell culture and retinal explant imaging where transparency is important. IEDDA hydrogels are cytocompatible with primary photoreceptors and enable multiphoton imaging of embedded retinal explants for double the time (>38 h) than agarose thermogels (<20 h). IEDDA HA hydrogels constitute a new hydrogel platform. They have low polymer content, tunable gelation time, and are stable, thereby making them suitable for a diversity of applications.

Electrophilic Azides for Materials Synthesis and Chemical Biology.

Abstract: Organic azides are involved in a variety of useful transformations, including nitrene chemistry, reactions with nucleophiles and electrophiles, and cycloadditions. The 1,3-dipolar cycloadditions of azides constitute a major class of highly reliable and versatile reactions, as shown by the development and rapid adoption of click chemistry and bioorthogonal chemistry. Metal-catalyzed azide-alkyne cycloaddition (Cu/RuAAC), the prototypical click reaction, has found wide utility in pharmaceutical, biomedical, and materials sciences. The strain-promoted, or distortion-accelerated, azide-alkyne cycloaddition eliminates the need for a metal catalyst.In the azide-mediated 1,3-dipolar cycloaddition reactions, azides are ambiphilic, i.e., HOMO-LUMO-controlled dipoles where both the HOMO and LUMO interact strongly with the dipolarophile. Azide-alkyne cycloaddition proceeds primarily through the HOMOazide-LUMOdipolarophile interaction, and electron-deficient dipolarophiles react more readily. The inverse-electron-demand reaction, involving the LUMOazide-HOMOdipolarophile interaction, is less common because of the low stability of electron-deficient azides such as acyl, sulfonyl, and phosphoryl azides. Nevertheless, there have been reports since the 1960s showing enhanced reaction kinetics between electron-poor azides and electron-rich dipolarophiles. Our laboratory has developed the use of perfluoroaryl azides (PFAAs), a class of stable electron-deficient azides, as nitrene precursors and for reactions with nucleophiles and electron-rich dipolarophiles. Perfluorination on the aryl ring also facilitates the synthesis of PFAAs and quantitative analysis of the products by 19F NMR spectroscopy.In this Account, we summarize key reactions involving electrophilic azides and applications of these reactions in materials synthesis and chemical biology. These electron-deficient azides exhibit unique reactivity toward nucleophiles and electron-rich or strained dipolarophiles, in some cases leading to new transformations that do not require any catalysts or products that are impossible to obtain from the nonelectrophilic azides. We highlight work from our laboratories on reactions of PFAAs with enamines, enolates, thioacids, and phosphines. In the reactions of PFAAs with enamines or enolates, the triazole or triazoline cycloaddition products undergo further rearrangement to give amidines or amides as the final products at rates of up to 105 times faster than their non-fluorinated anlogues. Computational investigations by the distortion/interaction activation strain model reveal that perfluorination lowers the LUMO of the aryl azide as well as the overall activation energy of the reaction by decreasing the distortion energies of the reactants to reach the transition states. The PFAA-enamine reaction can be carried out in a one-pot fashion using readily available starting materials of aldehyde and amine, making the reaction especially attractive, for example, in the functionalization of nanomaterials and derivatization of antibiotics for the preparation of theranostic nanodrugs. Similar fast kinetics was also observed for the PPAA-mediated Staudinger reaction, which proceeds at 104 times higher rate than the classic Staudinger ligation, giving stable phosphoimines in high yields. The reaction is biorthogonal, allowing cell-surface labeling with minimal background noise.

Synthesis of unsymmetrical sulfamides and polysulfamides via SuFEx click chemistry

Abstract: As hydrogen-bond donors and acceptors, N,N′-disubstituted sulfamides have been used in a range of applications from medicinal chemistry to anion-binding catalysis. However, compared to ureas or thioureas, the utilization of this unique moiety remains marginal, in part because of a lack of general synthetic methods to access unsymmetrical sulfamides. Specifically, polysulfamides are a virtually unknown type of polymer despite their potential utility in non-covalent dynamic networks, an intense area of research in materials science. We report herein a practical and efficient process to prepare unsymmetrical sulfamides via Sulfur(VI)-Fluoride Exchange (SuFEx) click chemistry. This process was then applied to synthesize polysulfamides. Thermal analysis showed that this family of polymers possess high thermal stability and tunable glass transition temperatures. Finally, hydrolysis studies indicated that aromatic polysulfamides could be recycled back to their constituting monomers at the end of their life cycle.

The Molecular and Macromolecular Level of Carbon Nanotube Modification Via Diazonium Chemistry: Emphasis on the 2010s Years

Abstract: The present review focusses on the recent progress in the reductive grafting of diazotized big molecules and polymers on carbon nanotubes (CNTs). We briefly summarize the essentials on diazonium synthesis and discuss the CNT physical properties. The different routes for CNT covalent functionalization through diazonium salt interface chemistry are reviewed. The main analytical and spectroscopic techniques used to track carbon nanotube surface modification were cited as well as their advantages and limitations in the light of the information they provide. In this review, the emphasis is on big molecules such as dyes, crown ether, calixarene, cyclodextrin, fullerene and Ru-complex, and biomolecules such as biotin, proteins, and antibodies. The attachment of synthetic polymers to CNT via diazonium chemistry, or by preparing CNT-Polymer nanocomposites through: (1) in situ polymerization (controlled radical polymerization and click chemistry). (2) Oxidative polymerization of conjugated monomers. (3) Grafting onto method by Huisgen 1,3-cycloaddition click reaction and epoxy ring-opening were summarized and discussed. Throughout this review, we reported the recent advances using diazonium salt chemistry in numerous research areas (biomedicine, environment, energy conversion, sensors and actuators, structural composites,…).