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DOI: 10.1055/a-2564-4826
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Emerging Trends in Organic Chemistry: A Focus on India

Regioselective Synthesis of 1,4-Disubstituted 1,2,3-Triazoles: Advances in Click Chemistry and Multicomponent Reaction Engineering

Priyanka Gogoi 
,
Kalyanjyoti Deori  ∗
,
Diganta Sarma  ∗

D.S. and K.D. are thankful to Council of Scientific and Industrial Research (CSIR), New Delhi, India for the research grant [Grant No. 02(0399)/21/EMR-II]. P.G. thanks CSIR, New Delhi for research fellowship. We sincerely thank DST for financial support under Department of Science and Technology PURSE (DST-PURSE) project (SR/PURSE/2022/143 (C)) and Department of Science and Technology FIST (DST-FIST) project (SR/FST/CS-I/2020/152).
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Abstract

The regioselective synthesis of 1,2,3-triazoles has emerged as a cornerstone of modern synthetic chemistry, offering immense potential in pharmaceuticals, materials science, and functional applications. This account focuses on advancing the click reaction with an emphasis on the innovations stemming from the contributions from our group. Highlights include the development of novel catalytic systems, both homogeneous and heterogeneous, and the exploration of copper-free and photocatalytic methodologies. This account bridges traditional and modern approaches, offering mechanistic insights and engineering strategies to improve regioselectivity and efficiency. This work envisions a transformative feature for azide–alkyne cycloaddition, advancing from copper-based or copper-free catalysis to light-driven innovations.

1 Introduction

2 Fundamentals and Mechanistic Insights of the CuAAC

3 Homogeneous Catalysts for Regioselective AAC

3.1 Copper-Catalyzed Homogeneous Catalytic Systems

3.2 Copper-Free Homogeneous Catalytic Systems

4 AAC Reactions Using Heterogeneous Catalysts

4.1 Copper-Based Catalysts on Solid Supports

4.2 Copper-Free Heterogeneous Catalytic Systems

5 AAC Using Non-conventional Sources of Energy

5.1 Microwave-Assisted Synthesis

5.2 Ultrasound-Assisted Synthesis

5.3 Photocatalytic AAC (PcAAC) Reactions

6 Some Applications of 1,2,3-Triazoles

7 Concluding Remarks and Future Scope


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Key words

click reaction - regioselectivity - azide–alkyne cycloaddition - multicomponent reaction - triazoles - light-mediated

Biographical Sketches

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Priyanka Gogoi is currently pursuing her Ph.D. at Dibrugarh University under the supervision of Prof. Diganta Sarma. She is a CSIR-SRF (NET) fellow, and her research focuses on developing novel nanostructured materials for the sustainable synthesis of carbon–nitrogen bond containing heterocycles. She completed her undergraduate studies at Miranda House, University of Delhi, and earned her master’s degree from IIT Delhi. Throughout her academic journey, she has received several prestigious fellowships, including the DST-INSPIRE Fellowship (2015), the Ishan Uday Scholarship (2016), and the DST Travel Award (2023). Additionally, she qualified for CSIR NET with JRF (2018 and 2019), GATE (2020), and IIT-JAM (2018).

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Dr. Kalyanjyoti Deori, Assistant Professor at Dibrugarh University, holds his M.Sc. and Ph.D. degrees in chemistry from the University of Delhi, India and before joining this University in 2018, he was an Assistant Professor at Kirori Mal College, University of Delhi. He has an extensive publication record in high-impact journals and book chapters and he is a co-inventor on multiple patent applications. His research focuses on the development of advanced functional nanomaterials for catalytic processes, including sustainable photocatalysis, electrocatalysis, and energy conversions. Dr. Deori has received numerous awards including research fellowships, University Teacher Award-2023 and multiple best poster and paper awards. His work continues to inspire and advance the field of sustainable chemistry and environmental applications.

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Dr. Diganta Sarma, Professor, Department of Chemistry, Dibrugarh University received his Ph.D. from CSIR-NCL (Pune) and M.Sc. from Guwahati University. He pursued postdoctoral research as a JSPS Fellow at Kyoto Pharmaceutical University, Japan (2007–2009), followed by another postdoctoral tenure at the University of Kansas, USA (2009–2012). His research focuses on sustainable organic transformations, catalysis, and the synthesis of novel medicinally active biomolecules. To date, he has published 117 research papers in esteemed international journals. He has received multiple prestigious awards, including the Japanese Peptide Society Award (2009), the JSPS Bridge Fellowship Award (2018), and the DST Travel Award (2006, 2013, and 2017). Most recently, he was honored with the ACT Prof. Lallan­ Singh Award for Best PG Chemistry Teacher (2024). He also serves as the Convener of the CRSI local chapter, North-East region. His contributions to research and innovation serve as a foundation for future advancements, inspiring the next generation of scientists in the field of organic and medicinal chemistry.

1

Introduction

The use of azide–alkyne cycloaddition (AAC) to synthesize 1,2,3-triazoles represents one of the most impactful transformations in modern organic chemistry, with applications spanning pharmaceuticals, materials science, and bioorthogonal chemistry.[1] Its origins trace back to the late 19th century when Arthur Michael first synthesized 1,2,3-triazole by reacting diethyl acetylenedicarboxylate with phenyl azide.[2] This pioneering discovery laid the foundation for what would later be extensively studied by Rolf Huisgen and co-workers in their exploration of 1,3-dipolar cycloaddition reactions.[3] Huisgen’s seminal work in the 1960s brought critical mechanistic insights to this reaction; however, it was hindered by slow kinetics and limited product yields with unactivated azides and alkynes, necessitating high reaction temperatures. Despite these limitations, the reaction became the most important foundation for synthesizing 1,2,3-triazoles due to its structural and functional diversity.

The paradigm shifts in this field occurred in 2001 when the Sharpless group in the US and the Medal group in Denmark first independently reported the copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction.[4] [5] [6] With the enhancement of the reaction rate by an astonishing factor of 107 compared to the uncatalyzed thermal AAC, CuAAC emerged as a highly efficient, regioselective, and versatile reaction. It consistently delivers 1,4-disubstituted 1,2,3-triazoles under mild reaction conditions with remarkable yields. This simplicity and efficacy have transformed CuAAC into a pillar of modern synthetic chemistry, earning it the title of the ‘click’ reaction. The impact of CuAAC extends far beyond organic synthesis, finding applications across an array of scientific disciplines. For example, its utility in microcontact printing, polymer modifications, and three-dimensional cell microenvironments exemplifies the adaptability in advanced material design.[7–10] In the pharmaceutical sector, CuAAC has become indispensable for the synthesis of bioactive molecules, drug candidates, and bioconjugates.[11] [12] [13] [14] Furthermore, its role in chemical modifications, such as functionalization of various organic moieties and biomolecules, significantly shows its versatility. However, the use of copper poses challenges related to biocompatibility and environmental concerns, motivating the development of copper-free and alternative catalytic systems without compromising the sustainability and efficiency of AAC reactions.[15] [16] [17]

Recent years have witnessed the emergence of copper-free alternatives, heterogeneous catalysts, and photocatalytic systems to address challenges like residual metal toxicity, scalability, and energy efficiency. The exploration of heterogeneous catalysts, particularly nanostructured materials, has provided robust platforms for sustainable and scalable AAC reactions.[18] [19] [20] [21] [22] [23] [24] [25] These catalysts include copper and copper-free nanoparticles, hybrid nanocomposites, ruthenium-based systems, silver-based systems, transition-metal-free alternatives, and metal-organic frameworks (MOFs). They offer enhanced recyclability, operational simplicity, and tunable catalytic properties, addressing the limitations of homogeneous systems. Parallel to these developments, the integration of photocatalysis has revolutionized click chemistry by introducing light-driven pathways for azide–alkyne cycloaddition. Photocatalytic systems harness the power of light to activate substrates under mild conditions, enabling regioselective triazole formation with high precision.[26] Notably, the emergence of single-electron transfer (SET) pathways in photocatalytic AAC has introduced a unique mechanistic route that facilitates regioselective transformations under visible light, reducing reliance on traditional thermal or metal-catalyzed methods.[27] This account highlights advances in regioselective 1,2,3-triazole synthesis, with a particular emphasis on the contributions of our group. Our innovations span from novel homogeneous and heterogeneous catalytic systems to multicomponent reaction strategies and photocatalytic methodologies. By addressing key challenges in click chemistry and multicomponent reaction engineering, this work contributes to the growing legacy of AAC as a transformative tool in modern chemistry. The field transitions from copper-based to copper-free to light-driven methodologies, showcasing a bright future for regioselective click chemistry at the nexus of catalysis and innovation.


# 2

Fundamentals and Mechanistic Insights of the CuAAC

The synthesis of 1,2,3-triazoles has garnered immense importance due to the diverse biological and pharmaceutical applications of these heterocycles. Many triazole derivatives exhibit potent medicinal properties, including antiviral, antifungal, anticancer, and antimicrobial activities. Their structural versatility makes them indispensable in the development of drugs and functional materials.[28] [29] [30] [31] A few examples of biologically active triazole-based compounds are illustrated in Figure [1]. As discussed in the previous section the azide–alkyne cycloaddition was first explored through the Huisgen 1,3-dipolar cycloaddition reaction, where the reaction proceeds thermally without a catalyst, resulting in a mixture of regioisomers, both 1,4- and 1,5-disubstituted 1,2,3-triazoles (Scheme [1a]). While both regioisomers have utility, the 1,4-disubstituted triazoles are particularly significant due to their superior biological activity and functional properties. However, the thermal approach suffers from slow reaction rates and poor regioselectivity; the introduction of copper-catalyst suppressed this limitation by specifically facilitating the formation of the 1,4-disubstituted triazole in near-quantitative yields under mild conditions, as shown in Scheme [1a]. The regioselectivity in CuAAC is governed by the coordination of the copper catalyst to both the alkyne and azide, which orients the substrates to favor 1,4-regioisomer formation.

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Figure 1 Some medicinally active 1,2,3-triazoles
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Scheme 1 (a) Huisgen 1,3-dipolar cycloaddition reaction and copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction and the proposed mechanisms for CuAAC by (b) mononuclear pathway, and (c) binuclear pathway

Mechanistic insights into CuAAC reveal two proposed pathways: (a) the mononuclear pathway and (b) the binuclear pathway, as illustrated in Schemes 1b and 1c. In the mononuclear mechanism, a single copper center activates the alkyne, forming a copper acetylide intermediate that undergoes cycloaddition with the azide.[32] [33] In contrast, the binuclear mechanism involves two copper centers, one coordinating with the azide and the other with the alkyne, which facilitates a more concerted reaction process. Both pathways underline the critical role of copper in enhancing regioselectivity and reaction efficiency. The major factors influencing regioselectivity in AAC include electronic effects of substituents on the azide and alkyne, steric hindrance, and the choice of catalyst.[34,35]


# 3

Homogeneous Catalysts for Regioselective AAC

3.1

Copper-Catalyzed Homogeneous Catalytic Systems

Although copper in the +1 oxidation state (Cu(I)) is thermodynamically unstable, it serves as the active site for CuAAC reactions. However, there are challenges with using Cu(I) salts directly. To overcome this, Cu(II) salts are often employed in combination with a reducing agent.[36] [37] Among the commonly used combinations, CuSO4 with sodium ascorbate is one of the most popular. However, this method requires an excess of the reducing agent to prevent the reoxidation of Cu(I) and protect the catalyst from hydration or atmospheric oxygen. Unfortunately, using excess reducing agent can lead to oxidative byproducts, especially in open-air conditions (Scheme [2]).[38]

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Scheme 2 Formation of potential products while performing CuAAC under oxidative conditions

To address this, coordinating ligands or support materials have been introduced to prevent side reactions by stabilizing the Cu(I) species within the catalytic system. Ligands like Pericas ligand, Hünig’s base, and benzimidazole-pyridine have been found to stabilize Cu(I) salts effectively while also reducing side product formation.[39] [40] Some of these ligands not only stabilize Cu(I) but also significantly enhance the reaction rate. However, challenges such as high catalyst loading, complex synthesis, and lengthy reaction times remain. To simplify this process, we utilized a nitrogen-containing ligand, hydroquinidine-1,4-phthalazinediyl diether ((DHQD)2PHAL), to facilitate the synthesis of 1,4-disubstituted 1,2,3-triazoles at room temperature in water (Scheme [3a]).[41] By combining CuI and the ligand in equimolar amounts, triazoles were synthesized in just five minutes, producing 12 different products under mild conditions.

Ionic liquids (ILs), another class of stabilizing agents, have also proven effective as stabilizing agents for these purposes. Our group utilized 1-butyl-3-methylimidazolium hydroxide ([Bmim]OH), an ionic liquid that acts as both a stabilizer and solvent, to enable the synthesis of triazoles at room temperature without requiring additional bases, reducing agents, bulky ligands, or harmful organic solvents.[42] This dual-function ionic liquid streamlines the process and eliminates the need for extra reagents (Scheme [3b] and 3c).

In another approach, we generated Cu(I) in situ using a mild reducing agent and stabilization with a small amount of base. Diisopropylethylamine (DIPEA), a non-nucleophilic tertiary amine, served as both an acetylene proton extractor and a Cu(I) stabilizer, facilitating cycloaddition to produce the desired triazole (Scheme [3d]). Fehling’s solution was used as the copper source, generating Cu2O in situ.[43]

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Scheme 3 CuAAC by: (a) Cu(Ι) halide salt with N-containing ligand, (b and c) Cu(Ι) halide salt with ionic liquid, and (d) Fehling solution as Cu source

To further simplify the process, our group introduced cetyltrimethylammonium bromide (CTAB) as an easily available, ready-to-use stabilizing agent. This additive enabled the synthesis of triazoles at room temperature, using water as the solvent, which produced 18 regioselective triazole products with 100% regioselectivity (Scheme [4]).[44] In another method, we eliminated the need for stabilizing additives by using Benedict’s solution and ascorbic acid as a cost-effective copper source and reducing agent, respectively (Scheme [4]). In this method, a Cu-ascorbate complex forms in situ, followed by the generation of Cu(I) oxide, which acts as the active site for CuAAC reactions.[45]

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Scheme 4 CuAAC by: (a) Cu(Ι) halide salt with CTAB as capping agent and (b) Benedict solution as Cu source

This versatile protocol was extended to a one-pot, three-component reaction by directly adding organic bromides, sodium azide, and alkynes, enabling the azides to form in situ and eliminating the need for their separate synthesis. Many methodologies have been developed to achieve simpler, more efficient pathways. However, studies focusing on their synthesis using different starting materials remain limited. Our group has proposed a novel and emerging pathway for synthesizing 1,4-disubstituted 1,2,3-triazoles from arylboronic acids through a one-pot, three-component approach. In this method, for the first time, an aqueous bio-surfactant was employed as a micellar medium to stabilize the Cu(Ι) formed during the reaction. Sodium azide served as both the azide source and reducing agent, allowing for efficient triazole formation.[46] Mechanistically, arylboronic acids undergo oxidation in the presence of Cu(Ι) to generate aryl radicals, which subsequently react with in situ formed organic azides derived from sodium azide. The resulting intermediates undergo a 1,3-dipolar cycloaddition with terminal alkynes to furnish the 1,4-disubstituted 1,2,3-triazoles with high regioselectivity. A plausible mechanism is depicted in Figure [2].

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Figure 2 Mechanism of CuAAC from arylboronic acid through in situ azide formation

Moreover, the CuAAC reaction could also be realized using calcium carbide (CaC2) as an alkyne source in triethylamine, which acted as both the base and solvent at 55 °C, offering another efficient route to triazoles as reported by Novák and co-workers (Scheme [5]).[47] Various other methodologies have also been developed, but efforts continue to simplify the process further while using readily available starting materials.[48] [49] [50] [51] [52]

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Scheme 5 (a) NaDC accelerated CuAAC from arylboronic acids and (b) CuI-catalyzed AAC in presence of triethylamine

# 3.2

Copper-Free Homogeneous Catalytic Systems

As discussed in the Section 3.1, the cytotoxicity and thermal instability of Cu(I) systems hinder their application in biological environments, limiting the use of CuAAC reactions in bioorthogonal chemistry. To address this challenge, copper-free azide–alkyne cycloaddition (AAC) protocols were developed. Initially, metals other than copper showed lower efficiency. In 2010, Chen and co-workers introduced the first copper-free AAC protocol using zinc on charcoal as a catalyst.[53] This method produced the triazole products in dimethylformamide at 50 °C without requiring additional ligands or additives. However, its prolonged reaction time made it less efficient compared to CuAAC (Scheme [6a]).

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Scheme 6 Copper-exempted homogeneous catalytic protocols using Zn- and Ag-based catalysts

In 2011, McNulty and co-workers advanced the field by employing silver for AAC reactions, motivated by silver’s chemical similarities to copper.[54] [55] They developed a stable and homogeneous silver(I) complex with P,N-type ligands, enabling the reaction at room temperature. This system minimized side reactions like Glaser–Hay coupling observed with Cu catalyst. However, the tedious ligand synthesis and extended reaction times were the significant limitations. To overcome all these challenges, in 2015, we introduced an efficient Ag-based catalytic system utilizing dicyanamide as a coordination polymer with infinite –Ag–NC–N–CN–Ag– spiral chains (Scheme [7a]).[56] In this method, DIPEA was employed as a base to ensure regioselectivity through steric hindrance provided by the isopropyl groups. This catalytic system allowed the synthesis of 18 different triazoles within 2–5 hours at room temperature.

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Scheme 7 Copper-exempted homogeneous catalytic protocols

Building on this work in 2019, we developed a cationic surfactant-capped Ag2CO3 catalyst, which formed spherical micelles in water (Scheme [7b]).[57] The micelles facilitated the incorporation of reactants, eliminating the need for ligands or bases. In 2024, we introduced a novel PCy3-ligand-assisted silver(I) catalytic system for the regioselective synthesis of 1,2,3-triazoles at room temperature (Scheme [7c]).[58] The in situ formed Ag-PCy3 complex, generated using diethylamine as a base, delivered high regioselectivity, as confirmed by single-crystal XRD analysis. This method was applicable to phenyl azides and internal alkynes, broadening its scope. As shown in Figure [3], the mechanism of the PCy3 ligand assisted AgAAC reaction involves the initial coordination of the phosphine ligand (PCy3) to Ag(I), forming a highly reactive Ag-PCy3 complex. This complex activates the terminal or internal alkyne by π-coordination, facilitating the nucleophilic attack of the azide to form a metalacyclic intermediate. The subsequent ring contraction leads to the formation of a triazole product with excellent regioselectivity. The steric hindrance and electron-donating properties of the PCy3 ligand play a crucial role in maintaining regioselectivity throughout the reaction.

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Figure 3 Plausible reaction mechanism for AgAAC reaction

Apart from Ag, other metals have also been explored for AAC reactions at the later stage of time. In 2014, Rao and Chakibanda demonstrated the use of Raney nickel in toluene for 1,4-disubstituted 1,2,3-triazoles at 45 °C (Scheme [8]).[59] This approach allowed easy product recovery through centrifugation and solvent evaporation. However, most metal-based AAC methods, including those with Ni, Au, and Ru, were effective only with terminal alkynes, limiting the synthesis to disubstituted triazoles.[23] [60] [61] In 2017, Morozova and co-workers introduced a zinc-catalyzed AAC (ZnAAC) system capable of synthesizing both 1,4-disubstituted and 1,4,5-trisubstituted triazoles using terminal and internal alkynes, respectively. Their work provided mechanistic insights into ZnAAC, identifying a crucial zinc-containing intermediate.[62] This protocol employed Zn(OAc)2 in neat water, offering an inexpensive and environmentally friendly method for triazole synthesis (Scheme [8]). These advancements reflect the evolution of copper-free AAC methodologies, paving the way for more efficient and sustainable catalytic systems suitable for bioorthogonal and industrial applications.

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Scheme 8 Homogeneous Ni- and Zn-catalyzed AAC reactions

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# 4

AAC Reactions Using Heterogeneous Catalysts

The use of homogeneous catalysts in azide–alkyne cycloaddition (AAC) reactions while effective, often suffers from a critical limitation of non-recoverability. Once used, these catalysts are challenging to separate from the reaction mixture, leading to waste generation and raising significant environmental concerns. In the current era of sustainable chemistry, simply achieving high product yields is not enough. The focus has shifted towards developing catalytic systems that enable efficient product synthesis while minimizing environmental impact. Heterogeneous catalysts present a promising solution to these challenges. Unlike their homogeneous counterparts, heterogeneous catalysts can be easily separated from the reaction mixture, allowing for their recovery and reuse in subsequent reactions. They often exhibit enhanced stability, enabling their application under a wide range of reaction conditions, including those required for bioorthogonal and green chemistry applications. Also, in recent years single atom catalysts are also emerging as potential materials which can provide the combined benefits of homogeneous and heterogeneous catalysts.[63]

Several research groups have reported innovative heterogeneous catalytic systems for AAC reactions. For instance, supported copper nanoparticles on various solid supports, such as polymers, silica, and carbon, have demonstrated remarkable efficiency for the synthesis of 1,4-disubstituted 1,2,3-triazoles.[64] [65] [66] These catalysts combine the activity of Cu(I) with the robustness of the solid support, ensuring high efficiency and recyclability. In addition, magnetic nanoparticles functionalized with catalytic sites have been employed, enabling easy separation of the catalyst using an external magnet. Our group has also explored heterogeneous systems for AAC reactions, developing novel surfactant-stabilized silver nanoparticles and other solid-supported catalytic systems. These systems demonstrated not only excellent reactivity but also recyclability for multiple cycles without significant loss of activity.

4.1

Copper-Based Catalysts on Solid Supports

Among many efforts to develop click-compatible heterogeneous systems, polymer-supported catalytic systems are gaining popularity due to their stability in the reaction system. For instance, nitrogen ligand based copper complexes grafted onto polymers were among the first heterogeneous systems developed for CuAAC reactions. A notable example is CuI@A-21, a catalyst created by immobilizing Cu(I) on the diaminomethyl-functionalized polymer Amberlyst A-21, using CuI in acetonitrile as the copper source.[67] This system successfully synthesized 61 triazole products with excellent yields. Although the activity of the catalyst was initially lower than the homogeneous catalysts, its reusability for up to six cycles highlighted its practical advantages. In later advancements, zeolite-immobilized Cu(I), Cu(0) on charcoal, and various nanoparticulate copper catalysts were developed, further improving the scope of CuAAC reactions.[68] [69]

Transitioning to inorganic supports, copper catalysts supported on metal oxides such as Fe3O4 have garnered attention. Our group introduced a chitosan-supported copper-iron oxide nanocomposite (CS-Fe3O4-Cu, represented as Cu@Fe3O4) as a heterogeneous catalyst (Scheme [9]).[70] This system, prepared via co-precipitation, provided excellent yields of triazole products and retained activity up to four catalytic cycles. However, the use of chlorinated solvents like dichloromethane pose environmental and health risks, prompting the adoption of greener alternatives such as ethylene glycol (EG). While EG is safer and less toxic than chlorinated solvents, it has its own drawbacks, including prolonged environmental persistence and potential health issues if ingested.[71] [72] To address these concerns, we developed a solvent system combining water and a minimal amount of EG (H2O/EG, 10:1), achieving 99% yield of 1-benzyl-4-phenyl-1,2,3-triazole in just 30 minutes at 60 °C.[73] The synergistic effect of the high dielectric constant of water and the ability of EG to stabilize copper intermediates improved reaction efficiency while reducing EG usage.[73]

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Scheme 9 Heterogeneous CuAAC reactions

A novel silica-supported Cu-N-heterocyclic carbene (Cu-NHC) catalyst demonstrated high efficiency for CuAAC and multicomponent click reactions (Scheme [10]).[73] The strong σ-donating properties of the NHC ligands stabilized the active Cu(I) center, ensuring high activity and recyclability for up to five cycles.

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Scheme 10 Silica-coated CuNHC-catalyzed AAC reaction

Expanding the versatility of solid-supported catalysts, our group introduced a hydrotalcite (HT, Ca6Al2(CO3)(OH)16·4H2O)-supported copper nanoparticle catalyst (Cu@HT) for CuAAC reactions (Scheme [9]).[74] This catalyst achieved a remarkable 97% yield within 1 hour and maintained its catalytic activity over five cycles. Hydrotalcite’s layered structure provided excellent dispersion of copper nanoparticles, contributing to its efficiency.

Copper nanoparticles immobilized on other solid supports have also been extensively studied. For example, Cu(0) nanoparticles supported on charcoal exhibit high surface activity due to the porous structure of the support, enhancing the availability of catalytic sites for azide and alkyne activation.[69] Similarly, Cu nanoparticles immobilized on zeolites have shown promise due to the uniform pore sizes of zeolites, which facilitate substrate access and improve reaction kinetics.[68] Further innovation involved using starch-capped copper nanoparticles (SCuNPs) to catalyze a solvent-free azide–alkene cycloaddition reaction, where alkynes were replaced by alkenes (Scheme [11]).[75] This oxidative [3+2] cycloaddition employed atmospheric O2/DMSO as oxidants, producing both di- and trisubstituted triazoles. Figure [4] shows its mechanistic pathway to produce regioselective triazole product via [3+2] cycloaddition. The absence of a solvent and the recyclability of the catalyst for up to five cycles made this approach sustainable and efficient.

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Scheme 11 Copper-catalyzed azide–alkene cycloaddition reaction for the synthesis of 1,2,3-triazoles
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Figure 4 Mechanism for [3+2] azide–alkene cycloaddition reaction

Other innovations involving supported systems include carbon-based supports and metal-organic frameworks (MOFs). Graphene oxide (GO) and reduced graphene oxide (rGO) have been used to anchor Cu nanoparticles. The large surface area and functional groups of GO improve Cu dispersion, enhancing catalytic activity. On the other hand, Cu-based MOFs provide a unique platform for CuAAC due to their tunable porosity and active sites. For instance, CuBTC (Cu3(BTC)2, where BTC = benzene-1,3,5-tricarboxylate), CuBTC–PyDC, and MOF-Cu (BTC)-[Pd] etc. have been reported as efficient CuAAC catalysts with excellent recyclability.[76] [77] These systems exemplify how innovative design and materials science can address the limitations of homogeneous catalysis while achieving high efficiency and minimal environmental impact.


# 4.2

Copper-Free Heterogeneous Catalytic Systems

Catalysts based on Cu(I) face limitations due to their susceptibility to oxidation and disproportionation, which can arise from their thermal instability. These challenges often necessitate the use of an inert atmosphere or anhydrous solvents, neither of which are practical or environmentally friendly. Additionally, the use of volatile organic solvents possess ecological concerns, prompting significant interest in developing copper-free heterogeneous catalytic systems. In 2013, Muthusubramanian and co-workers introduced a catalyst system where gold nanoparticles supported on nanoporous TiO2 efficiently facilitated AAC reactions to synthesize 1,4-disubstituted 1,2,3-triazoles under heating conditions (Scheme [12a]).[78] Remarkably, water served as the sole solvent in this process, showcasing a sustainable approach to triazole synthesis. However, the high cost of gold as a catalyst motivated researchers to explore alternative metals. In 2015, Molteni and co-workers developed a copper-free AAC reaction using Ag2O nanoparticles as the catalyst. Silver(I) oxide was selected for its chemical similarity to Cu2O.[18] Oleic acid coated Ag2O proved effective, although azides containing electron-withdrawing groups exhibited notable substituent effects, and the regioselectivity was inconsistent. The reaction utilized toluene (both anhydrous and non-anhydrous), which could benefit from being replaced with greener solvents (Scheme [12b]).

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Scheme 12 Heterogeneous copper-free azide–alkyne cycloaddition reaction

Building on this work, our group developed a silica-supported Ag catalyst for AAC reactions in water. This system utilized a minimal silver loading (0.006 mol%) and offered advantages such as catalyst stability, reusability, broad substrate compatibility, and mild reaction conditions at 60 °C with quinine as the base (Scheme [13]).[79]

A significant advance in this field was reported by Jana, Islam, and co-workers, who introduced the first multicomponent copper-free heterogeneous system for in situ azide formation from anilines. Their method employed graphene-supported Ag nanoparticles. The conductive properties of graphene enhanced electron migration across the catalyst surface, improving the overall efficiency of the reaction.[80]

Apart from silver, zinc has emerged as a cost-effective alternative for copper-free AAC reactions. Our group developed a reusable zinc-chitosan complex (Zn@CS) for the synthesis of 1,4-disubstituted 1,2,3-triazoles from azides and mono- or disubstituted acetylenes in water or 4-substituted NH-1,2,3-triazoles from benzaldehydes, sodium azide, and nitromethane or nitroethane in a deep eutectic solvent (DES, ChCl/PEG-400/glycerol) (Scheme [14]).[81] Chitosan, a non-toxic, biodegradable, and biocompatible biopolymer, provided excellent coordination sites for zinc due to its -NH2 and -OH groups. The catalyst delivered excellent yields (97%) in just 4 hours at 100 °C.

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Scheme 13 Heterogeneous AgAAC reaction by silica supported Ag catalyst
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Scheme 14 Heterogeneous Zn in chitosan (Zn@CS) catalysts for the synthesis of 1,2,3-triazoles

To further improve reaction conditions, nanostructured ZnC2O4 was synthesized by our group using a hydrothermal method. This catalyst, with its irregular sheet-like morphology, demonstrated high stability and recyclability (up to five cycles) without losing its crystallinity. The newly developed materials emerged as a promising material in non-copper category for the diverse synthesis of 1,2,3-triazole molecules (Scheme [15]).[82] The plausible mechanism suggests the coordination of the Zn to the acetylene molecule to form π-complex Ι which further generates the six-membered Zn-containing metallacycle ΙΙ and finally affords the desired 1,4-disubstituted 1,2,3-triazoles. Some ZnAAC based reports also suggests the formation of a zinc-alkylidene intermediate.[81] The method enabled gram-scale synthesis and was suitable for one-pot multicomponent approaches.

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Scheme 15 Heterogeneous ZnAAC reaction and its plausible reaction mechanism

Seeking milder conditions, we developed ZnO nanomaterials coated with cetyltrimethylammonium bromide (CTAB) via a sonochemical route. These ZnO-CTAB nanocrystals, featuring rod-like morphology, offered superior regioselectivity compared to bulk or unsupported ZnO (Scheme [16]).[83] The process also enabled the synthesis of N-unsubstituted triazoles in water through a one-pot multicomponent reaction. This protocol could also be extended to synthesize medicinally active triazole molecules.

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Scheme 16 ZnO-CTAB-catalyzed AAC reaction

Additionally, to achieve room temperature copper-free AAC reactions, we synthesized bimetallic nano-heterostructures combining Ag and ZnO. The catalysts, Ag-ZnO and Ag2O-ZnO, were prepared through simple thermal and solution phase methods. Among these, Ag2O-ZnO exhibited the highest catalytic efficiency, attributable to the oxidation state of silver (Scheme [17]).[84] This one-pot system efficiently synthesized a wide variety of triazoles, including those with medicinal relevance, and demonstrated exceptional stability, with reusability up to eight cycles.

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Scheme 17 Ag-Zn bimetallic azide–alkyne cycloaddition reaction

The application of copper-free heterogeneous catalysts in one-pot multicomponent reactions therefore offers significant advantages, including enhanced sustainability through reduced waste, toxicity and solvent use, high atom economy, and streamlined reaction processes that ensure regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles with excellent yields and minimal byproduct formation. These catalysts are ecofriendly, often reusable, and scalable for industrial applications. To further advance this approach, strategies such as designing multifunctional catalysts with tunable active sites, copper-free systems using alternative metals like silver and zinc and optimizing reaction conditions under ambient or green solvent systems for improved activity and selectivity should be adopted. Additionally, integrating continuous flow systems and mechanistic studies can enhance scalability and provide deeper insight into reaction pathways, paving the way for more efficient and sustainable multicomponent reaction engineering.


#
# 5

AAC Using Non-conventional Sources of Energy

AAC reactions using non-conventional energy sources, such as microwave irradiation, ultrasound, and photocatalytic (visible light) methods, have emerged as sustainable and efficient alternatives to traditional thermal approaches. These methods significantly reduce reaction times, improve energy efficiency, and often eliminate the need for harsh conditions or toxic solvents. Microwave-assisted AAC accelerates reaction kinetics through uniform heating, while ultrasound enhances mass transfer and facilitates catalyst-substrate interaction. Photocatalytic AAC utilizes visible light to activate catalysts, enabling reactions under mild conditions while reducing energy consumption. These techniques, combined with copper-free heterogeneous catalysts, present a promising route for ecofriendly, rapid, and regioselective synthesis of 1,2,3-triazoles.

5.1

Microwave-Assisted Synthesis

To enhance reaction efficiency and promote sustainable protocols, researchers have explored non-conventional energy sources like microwave irradiation for the synthesis of triazoles. Microwave-assisted methods are widely recognized for their uniform and rapid dielectric heating, which significantly accelerates reaction kinetics, making them time-efficient and ecofriendly compared to traditional thermal approaches. The pioneering work of Fokin, Van Der Eycken, and co-workers first demonstrated the synthesis of 1,2,3-triazoles using microwave irradiation. This one-pot protocol, driven by the in situ generation of Cu(I) active sites through comproportionation of Cu(II) and Cu(0), yielded the desired products in just 15 minutes (Scheme [18a]).[85]

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Scheme 18 MW-assisted 1,4-disubstituted 1,2,3-triazole synthesis

Several other groups have developed innovative strategies for triazole synthesis under microwave conditions. Sedić, Raić-Malić, and co-workers reported a microwave-assisted protocol for synthesizing pyrimidine-2,4-dione-triazole hybrids with superior efficiency compared to conventional methods (Scheme [18b]).[86] Subhashini and co-workers introduced a rapid method for pyrazole-linked triazoles, reducing reaction times from 6 hours to just 4–6 minutes using CuSO4·5H2O and sodium ascorbate under microwave conditions (Scheme [19a]).[87] Another remarkable study employed alumina-supported CuI as a catalyst in water, enabling a wide substrate scope with catalytic recyclability for up to eight cycles (Scheme [19b]).[88]

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Scheme 19 Cu-catalyzed MW-assisted 1,4-disubstituted 1,2,3-triazole synthesis

Our group has also contributed to this field by developing a microwave-assisted, metal-free protocol for synthesizing N-unsubstituted triazoles via a one-pot reaction using aldehydes, nitroalkanes, and NaN3. Anthranilic acid served as an organocatalyst, and the protocol demonstrated scalability and therapeutic potential (Scheme [20a]).[89] As an extension of this work, a metal-free, microwave-derived approach was established for the synthesis of N-substituted 1,2,3-triazoles with an amino group at C5.

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Scheme 20 MW-assisted metal-free synthesis of NH-1,2,3-triazoles and 5-amino-1,2,3-triazoles

Furthermore, we designed a bifunctional ionic liquid (1,3-dihexadecylimidazolium hydroxide, [DHIM][OH]) as both a catalyst and solvent for the efficient microwave-assisted synthesis of 5-amino-1,2,3-triazoles under mild conditions, eliminating the need for external bases or solvents (Scheme [20b]).[90] In another study, we developed a metal-free, ionic liquid based approach for the rapid synthesis of 4-aryl-NH-1,2,3-triazoles in just two minutes. This method was further extended to synthesize indoleamine 2,3-dioxygenase inhibitors, showcasing its application in medicinal chemistry (Scheme [20c]).[91] These advancements highlight the potential of microwave irradiation in developing sustainable, rapid, and efficient methods for triazole synthesis, contributing significantly to green chemistry and scalable reaction protocols.


# 5.2

Ultrasound-Assisted Synthesis

Ultrasound-assisted methods have emerged as a sustainable and efficient approach for the synthesis of 1,2,3-triazoles. Ultrasonication accelerates reaction rates by generating acoustic cavitation, a phenomenon involving the rapid formation, growth, and collapse of bubbles in the liquid medium. This process produces localized high temperatures and pressures, which create an energy-rich microenvironment. These extreme conditions facilitate bond formation, enabling the synthesis of triazoles in significantly shorter reaction times compared to conventional methods. In one notable study, a hybrid catalytic system containing of two active metal centers, zinc (Zn) and copper (Cu), was introduced for ultrasound-mediated triazole synthesis. This method was conducted at room temperature using a 2:1 mixture of water and t BuOH as the solvent (Scheme [21a]).[92] The reaction afforded triazole derivatives within just 10 minutes, demonstrating the remarkable efficiency of this approach.

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Scheme 21 Ultrasound-assisted synthesis of 1,4-disubstituted 1,2,3-triazoles

Further advancements in ultrasound-assisted synthesis were made by Portilla and co-workers, who developed a protocol that exclusively used water as the reaction solvent. This ‘water-only’ method featured low catalyst loading, scalability to multigram quantities, and simplified purification processes, making it highly practical for green chemistry applications. While this approach required a mild reaction temperature, it represented a significant step forward in sustainable synthetic methodologies (Scheme [21b]).[93] In another innovative study, Khurana and co-workers proposed a room-temperature protocol using an ionic liquid as the catalyst for the ultrasound-assisted synthesis of triazoles. This method offered several advantages, including operational simplicity, short reaction times, easy workup, and excellent product yields (Scheme [21c]).[94]

These developments highlight the versatility and efficiency of ultrasound-assisted synthesis. Combined with the unique features of hybrid catalytic systems and ionic liquids, ultrasound-assisted methods offer a robust and sustainable platform for the rapid synthesis of 1,2,3-triazoles, paving the way for ecofriendly and scalable protocols.


# 5.3

Photocatalytic AAC (PcAAC) Reactions

Using light energy to drive chemical transformations has become a growing trend in recent years, inspired by natural processes like photosynthesis. Light is not only an abundant and cost-effective energy source, but also provides an alternative, efficient pathway for activating chemical reactions. The integration of light with click chemistry has led to the emergence of ‘photocatalytic click chemistry’ offering a more sustainable approach than traditional methods. This field facilitates the synthesis of complex molecular systems and functional conjugates. Photocatalytic azide–alkyne cycloaddition (PcAAC) reactions enhance reaction kinetics by utilizing light energy as an external stimulus making them valuable for synthesizing a wide range of medicinally and industrially significant compounds.[95] [96] The concept of photocatalytic AAC was introduced by Tasdelen and Yagci in 2010, who employed low-energy UV light (350 nm) for azide–alkyne cycloaddition (Scheme [22]).[97] They achieved high product conversions (93–99%) using a CuCl2-PMEDTA (pentamethyldiethylenetriamine) ligand system.

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Scheme 22 UV-light derived AAC reactions

In 2017, Zou, Huang, and co-workers developed a homogeneous photoinitiated AAC using carbon quantum dots complexed with Cu(I). This reaction was performed in a 1:1 water/ethanol solvent mixture under UV light.[98] In 2016, Mallick and co-workers advanced the field by creating a heterogeneous PcAAC system using quantum dot-sized Cu2S impregnated on polyaniline (PANI) (Scheme [22]).[99] This catalyst efficiently produced various triazoles within 2 hours under UV light. However, the use of methanol as a solvent raised environmental concerns. Also in 2016, two hybrid heterogeneous photocatalysts, CuxO@TiO2 and CuxO@Nb2O5 were developed (Scheme [22]).[100] These systems were air- and moisture-tolerant, recyclable for multiple catalytic cycles, and operated under UV light with triethylamine as a base. Despite their effectiveness, most UV-light-based photocatalytic AAC methods face compatibility issues with biological systems.

Efforts to develop visible or near-infrared (NIR)-light-driven AAC protocols have gained momentum. Jain and co-workers introduced a bipyrimidine-bridged Ru-Mn bimetallic complex as a photosensitizer (Scheme [23]).[101] This system facilitated the in situ reduction of Cu(ΙΙ) to Cu(Ι) under visible light, enabling the synthesis of 14 different triazole derivatives at room temperature in ethanol. A readily available 25-W visible light source was used; in the absence of light, only a 4% yield was obtained in 16 hours. However, the protocol requires a labor-intensive catalyst design and stoichiometric amounts of copper salts. In 2017, Duan and co-workers designed a Cu(II)-coordination polymer with a chromophore linker (TCTA) for triazole synthesis under household light irradiation (Scheme [23]).[102] Triethylamine was required as both a base and an electron donor to prevent Cu(Ι) oxidation. However, the complex catalyst preparation and precise control during polymerization posed significant challenges.

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Scheme 23 Visible-light-derived AAC reactions

To address these issues, efforts have shifted toward developing copper-free or low-copper-loading photocatalytic systems. Recently, our group introduced an ultra-low copper-loaded graphitic carbon nitride (Cu1.8S/GCN) catalyst for visible-light-driven AAC reactions (Scheme [24]).[103] This system achieved 99% product yield with 100% regioselectivity under mild conditions. The protocol features wide substrate compatibility, high atom economy, and adherence to green chemistry principles. A 250-W visible light source drives the reaction by ejecting an electron from the photocatalyst, facilitating bond formation. While, stirring the reaction under dark gave minimal product yield (Figure [5]). In this reaction, power of light plays a crucial role. More intense 450-W visible light afforded lower yield of the product as it generates more electron-hole pair which results greater number of acetylide molecules. The increased collision among the acetylide molecules leads to lower yields of the product. As described in the Figure [5], the ejection of an electron from the valance band to conduction band under visible light irradiation plays a crucial role. The electron transferred to the conduction band of Cu1.8S that acts as a proton scavenger of the terminal alkyne and forms the Cu-acetylide intermediate. In some other reports, the ejected electron helps in the formation of Cu(Ι) from Cu(ΙΙ), which act as an active site for AAC reaction.

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Scheme 24 Visible-light-assisted synthesis of 1,4-disubstituted 1,2,3-triazoles
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Figure 5 Plausible reaction mechanism of visible-light-assisted synthesis of 1,4-disubstituted 1,2,3-triazoles

Additional advancements include visible-light-driven AAC protocols developed by Jiang and co-workers[104] and Manjupriya and Roopan.[105] The work of Jiang and co-workers involved a confined copper iodide supramolecular cluster that exhibited exceptional photocatalytic activity in acetonitrile (Scheme [24]).[104] Manjupriya and Roopan developed a heterojunction catalyst comprising CuO, carbon quantum dots, and GCN, which operated under a 12-W blue LED in a nitrogen atmosphere (Scheme [24]).[105] Both systems demonstrated robustness, recoverability, and high turnover numbers (TON) and frequencies (TOF).

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Scheme 25 Copper-free visible-light-assisted synthesis of 1,4-disubstituted 1,2,3-triazoles

Considering the toxicity and thermal instability of copper, Zheng and co-workers developed a copper-free PcAAC protocol using an iridium-based photoredox catalyst.[106] The catalyst facilitated single-electron oxidation of alkynes, enabling their cyclization with azides. However, the use of dichloromethane as a solvent, the high cost of iridium complexes, and limited recyclability due to photo-corrosion remain drawbacks. To address these limitations, our group recently designed a novel copper-free photocatalyst comprising nanoparticulate silver on graphitic carbon nitride (Ag-gCN) for visible-light-triggered AAC reactions (Scheme [25]).[107] This system follows a single-electron transfer (SET) mechanism, which is different from the traditional metal-based AAC approach, offering stable and recyclable catalysis, wide substrate scope, and excellent sustainability metrics. The mechanism was well-validated by radical experiments (Figure [6]). The presence of silver acted like an electron reservoir which decreases the electron-hole pair recombination rate of gCN. This electron involves in the single electron oxidation of the intermediate C to form the desired product which was replenished by another electron from the acetylene to the hole of valance band of gCN. Thus, the flow of electrons continues throughout the progress of the reaction. There are several metrices to measure the greenness of a protocol, which can be calculated from the experimental data. Atom economy measures the utilization of atoms into the product, environmental factor (E-factor) measures the waste generated by a protocol, eco-scale score measures the economical as well as energy efficiency, and reaction mass efficiency determines the mass of the product relative to the total mass of the reactants. High atom economy, reaction mass efficiency (RME), low E-factor, and superior eco-scale scores highlight the protocol’s environmental compatibility. As photochemical methodologies continue to advance, the combination of light and click chemistry is expected to revolutionize synthetic strategies, opening new avenues in materials science and chemical biology.

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Figure 6 Single electron transfer (SET) mechanism for PcAAC reaction

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# 6

Some Applications of 1,2,3-Triazoles

Apart from the synthesis of triazoles, its versatile applications in various fields portray their importance. In the growing field of medicinal chemistry, click chemistry has been strengthening the core in the synthesis of many novel drug molecules.[108] [109] Click chemistry could be used in situ in target-directed synthesis within the human body. These in situ click reactions are thermodynamically favorable and do not produce any byproduct which could affect the ternary structures of protein molecules.[110] [111] Both azide and alkyne functionalities are also bioorthogonal, meaning they can remain stable under biological conditions. This in situ click chemistry could achieve extended applications in microfluidic chip devices also. The concept of click chemistry is being used to create innovative bioconjugation products; e.g., modifying proteins and nucleic acids with fluorophores, ligands, and chelates.[112] [113] Modifications include the use of radioisotopes and affinity tags, as well as the fusion of several proteins or the joining of complicated carbohydrates with peptides. Bioconjugation can label biomolecules in vivo. Click chemistry has been effective in ligating and decorating peptides. DNA could be successfully labeled with the ‘click reaction’.[114] Azido-sugar is a versatile semi-protected aldehyde with numerous applications. Using the click reaction for the simple derivatization of biomolecules and pseudo-biomolecules has shown a way for more complex bioconjugation processes.

Not only in medicinal chemistry but also in the field of materials science, the synthesis of polymers has been made easy by the introduction of click chemistry. For example, synthesis of dendrimers faces many difficulties in separation and purification, which was successfully addressed by CuAAC reactions. One dendrimer could be ‘clicked’ onto another alkyne-containing dendrimer by introducing click chemistry there.[8] [115] Also, click chemistry’s high efficiency, accuracy and ease of work up has made it a potential candidate for the synthesis of polymers. Synthesis of long chain as well as branched polymers could be easily achieved by CuAAC. Moreover, click chemistry could be successfully applied in the field of nanomaterials. Single walled carbon nanotubes (SWNT), having numerous applications find difficulties in solubility when it comes to the solution phase. To improve the solubility, its outer surface could be modified introducing polymers synthesized using CuAAC.[116] Synthesis of rotaxanes or other interlocked macrocycles could be easily tailored using click chemistry.[117] The click reaction does have enormous applications in catalysis too.[118,119] Click-based ligands have been used in different transition metal catalysis for synthesizing different medicinally important organic molecules. For example, a ‘clickphos’ ligand containing a Pd complex was applied as a potential candidate for Suzuki–Miyaura cross-coupling reactions of unactivated aryl chlorides.[120] Triazole-based organic molecules have gained recent popularity as good sensors for heavy metal cations as well as anions.[121] CuAAC facilitated the synthesis of these sensor molecules as well. It is a growing field of research with limitless possibilities which makes click chemistry shine brighter than any other discoveries in organic chemistry.


# 7

Concluding Remarks and Future Scope

The rapid evolution of click chemistry, especially in conjunction with photocatalytic and other unconventional methodologies, has opened new frontiers in sustainable synthesis. These advanced approaches, including metal-free, low-metal, and heterogeneous catalytic systems, offer efficient and ecofriendly pathways for the construction of 1,2,3-triazoles and related compounds. By adhering to green chemistry principles, such as high atom economy, minimal waste generation, and the use of renewable energy sources like light, these methodologies have significantly reduced the environmental footprint of traditional synthetic protocols. However, the field still has numerous opportunities for refinement and innovation.

One of the primary goals for future research is the development of universally sustainable methods that are metal-free and solvent-free, which would eliminate toxic byproducts and align fully with the principles of green chemistry. Goal for zero-waste production in ‘click chemistry’ should be a primary objective in future research. While significant strides have been made in regioselective synthesis of 1,4-disubstituted 1,2,3-triazoles, there is still a need to address the efficient and scalable synthesis of 1,4,5-trisubstituted triazoles. Internal alkynes, long-chain aliphatic azides, and sterically hindered azides remain challenging substrates, and efforts to expand the substrate scope will increase the versatility and application of these protocols. Developing more efficient catalyst as well as optimizing the reaction conditions could be important assets for achieving greater versatility in the protocols. In the context of photoclick reactions, fine-tuning the reaction conditions, such as light intensity, wavelength, and irradiation time, is crucial to improving reaction efficiency and energy utilization. The exploration of solar-light-driven reactions could further enhance sustainability and reduce costs, making these methodologies accessible for industrial applications. Additionally, designing catalysts with improved surface modifications and optimized electronic structures could unlock broader catalytic utility and address the limitations of existing systems. The challenge of long-term stability and scalability for industrial applications must also be addressed. Scalable synthesis of maximum substrates of a protocol should be highly focused. The loss of catalytic activity in heterogeneous catalysts during recyclability is another critical issue to focus. Thermal stability (in heat-driven synthesis), photocorrosion (in light-driven synthesis), leaching and physical loss during handling are the primary causes of declining catalytic performance. Therefore, developing heat and moisture resistant catalysts, and using stable photocatalysts instead of photosensitizers would help minimize yield loss over multiple catalytic cycles. Robust heterogeneous catalysts that maintain high turnover numbers (TON) and turnover frequencies (TOF) under diverse reaction conditions are particularly desirable. Efforts should also be made to incorporate computational chemistry and machine learning into the field. Predictive models can be employed to optimize reaction parameters, design catalysts with higher efficiencies, and predict outcomes for new substrates, thereby reducing experimental efforts and accelerating progress. The synthesis of bioactive molecules, functional polymers, and smart materials through these sustainable approaches could transform industries ranging from pharmaceuticals to renewable energy.


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Conflict of Interest

The authors state that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.


Corresponding Authors

Kalyanjyoti Deori
Department of Chemistry, Dibrugarh University
Dibrugarh 786004 Assam
India   

Diganta Sarma
Department of Chemistry, Dibrugarh University
Dibrugarh 786004 Assam
India   

Publication History

Received: 31 January 2025

Accepted after revision: 21 March 2025

Accepted Manuscript online:
21 March 2025

Article published online:
21 May 2025

© 2025. Thieme. All rights reserved

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Figure 1 Some medicinally active 1,2,3-triazoles
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Scheme 1 (a) Huisgen 1,3-dipolar cycloaddition reaction and copper-catalyzed azide–alkyne cycloaddition (CuAAC) reaction and the proposed mechanisms for CuAAC by (b) mononuclear pathway, and (c) binuclear pathway
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Scheme 2 Formation of potential products while performing CuAAC under oxidative conditions
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Scheme 3 CuAAC by: (a) Cu(Ι) halide salt with N-containing ligand, (b and c) Cu(Ι) halide salt with ionic liquid, and (d) Fehling solution as Cu source
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Scheme 4 CuAAC by: (a) Cu(Ι) halide salt with CTAB as capping agent and (b) Benedict solution as Cu source
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Figure 2 Mechanism of CuAAC from arylboronic acid through in situ azide formation
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Scheme 5 (a) NaDC accelerated CuAAC from arylboronic acids and (b) CuI-catalyzed AAC in presence of triethylamine
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Scheme 6 Copper-exempted homogeneous catalytic protocols using Zn- and Ag-based catalysts
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Scheme 7 Copper-exempted homogeneous catalytic protocols
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Figure 3 Plausible reaction mechanism for AgAAC reaction
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Scheme 8 Homogeneous Ni- and Zn-catalyzed AAC reactions
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Scheme 9 Heterogeneous CuAAC reactions
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Scheme 10 Silica-coated CuNHC-catalyzed AAC reaction
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Scheme 11 Copper-catalyzed azide–alkene cycloaddition reaction for the synthesis of 1,2,3-triazoles
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Figure 4 Mechanism for [3+2] azide–alkene cycloaddition reaction
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Scheme 12 Heterogeneous copper-free azide–alkyne cycloaddition reaction
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Scheme 13 Heterogeneous AgAAC reaction by silica supported Ag catalyst
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Scheme 14 Heterogeneous Zn in chitosan (Zn@CS) catalysts for the synthesis of 1,2,3-triazoles
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Scheme 15 Heterogeneous ZnAAC reaction and its plausible reaction mechanism
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Scheme 16 ZnO-CTAB-catalyzed AAC reaction
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Scheme 17 Ag-Zn bimetallic azide–alkyne cycloaddition reaction
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Scheme 18 MW-assisted 1,4-disubstituted 1,2,3-triazole synthesis
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Scheme 19 Cu-catalyzed MW-assisted 1,4-disubstituted 1,2,3-triazole synthesis
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Scheme 20 MW-assisted metal-free synthesis of NH-1,2,3-triazoles and 5-amino-1,2,3-triazoles
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Scheme 21 Ultrasound-assisted synthesis of 1,4-disubstituted 1,2,3-triazoles
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Scheme 22 UV-light derived AAC reactions
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Scheme 23 Visible-light-derived AAC reactions
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Scheme 24 Visible-light-assisted synthesis of 1,4-disubstituted 1,2,3-triazoles
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Figure 5 Plausible reaction mechanism of visible-light-assisted synthesis of 1,4-disubstituted 1,2,3-triazoles
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Scheme 25 Copper-free visible-light-assisted synthesis of 1,4-disubstituted 1,2,3-triazoles
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Figure 6 Single electron transfer (SET) mechanism for PcAAC reaction