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Strain-Promoted Azide-Alkyne Cycloaddition

Liao Yiming , Wu Baoqi , Tang Rongzhi , Lin Feng , Tan Yu

Progress in Chemistry ›› 2022, Vol. 34 ›› Issue (10) : 2134 -2145.

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Progress in Chemistry ›› 2022, Vol. 34 ›› Issue (10) : 2134-2145 DOI: 10.7536/PC220103
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Strain-Promoted Azide-Alkyne Cycloaddition
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Abstract

In recent years, strain-promoted azide-alkyne cycloaddition (SPAAC) reaction has been widely used in many fields such as biomedicine and materials science due to its high efficiency, rapidity, high selectivity, and bioorthogonality. SPAAC reaction does not require additional stimuli such as light, heat, ultrasound or catalysts. The driving force of the reaction comes from the active cyclic alkynes with high strain. Therefore, the rational design of the cycloalkynes is the key to the SPAAC reaction. In this review, the stability and reactivity of cycloalkynes with different ring numbers are discussed, and the stable cycloalkynes participating in SPAAC smoothly as well as their second-order reaction rate constants in the SPAAC reaction are summarized. The research progress in the preparation methods of representative cyclic alkynes that are currently widely used is also introduced. Moreover, the application, challenge and future outlook of SPAAC without copper catalysis are discussed and prospected.

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click chemistry / cycloalkynes / azide-alkyne cycloaddition / biorthogonality / strain

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Liao Yiming, Wu Baoqi, Tang Rongzhi, Lin Feng, Tan Yu. Strain-Promoted Azide-Alkyne Cycloaddition. Progress in Chemistry, 2022, 34(10): 2134-2145 DOI:10.7536/PC220103

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Contents

1 Introduction
1.1 Click chemistry
1.2 Azide-alkyne cycloaddition reaction
2 Cyclic alkynes substrates involved in SPAAC reaction
2.1 Discussion on the number of rings
2.2 Stable cycloalkynes participating in SPAAC
3 Scale-up preparation of DIBAC
4 Applications of SPAAC
4.1 SPAAC in the field of medicine
4.2 SPAAC in the field of life science
4.3 SPAAC in the field of material science
5 Conclusion and outlook

1 Introduction

1.1 Click Response Overview

The concept of click chemistry was first proposed by Sharpless et al., a famous American chemist, in 2001. It refers to a class of simple and efficient chemical reactions[1]. Under mild reaction conditions, the chemical reaction of reactants is as direct and precise as a snap, and as rapid as a "click"[2].
The common types of click reactions are nucleophilic substitution/addition reactions (such as nucleophilic ring-opening reactions involving strained rings and thiol-ene addition reactions), condensation reactions of carbonyl compounds (such as the reaction of aldehydes with hydrazine to produce hydrazones), and cycloaddition reactions of unsaturated compounds (such as Diels-Alder reactions and cycloaddition reactions of azides and alkynes)[1]. These reactions are not only easy to operate, but also have high specificity, little or no by-products, and can produce the target product in high yield. The click reaction proceeds well under many conditions (generally insensitive to water and oxygen) and is not affected by the presence of other functional groups attached[3]. Since its discovery, click chemistry has developed rapidly and has been widely used in many fields, such as medicine, life science and material science, and has broad application prospects.

1.2 Azide-alkyne cycloaddition reaction

Click reaction is an exothermic reaction, the reactants generally have high energy, the reaction is regioselective, and finally a stable product is obtained.
Azide-alkyne cycloaddition reaction is one of the most efficient, typical and practical reactions in click chemistry. The reaction can be efficiently carried out, on the one hand, because the chemical potential energy of the azide and the alkyne substrate as reactants is very high, the cycloaddition reaction can release more than 188 kJ/mol of heat when generating stable triazole, which meets the condition that the reaction needs to have high energy[3]; On the other hand, azides and alkynes are difficult to react with biomolecules under reaction conditions, and are inert to most other reagents and solvents. In addition, the alkynyl group and the azide group have small molecular weight and weak polarity, have little influence on the chemical properties of the connected structure, and meet the selectivity required in many applications such as biology and materials.
The traditional uncatalyzed Azide-Alkyne Cycloaddition reaction (Huisgen cycloaddition reaction) has the disadvantages of high temperature and time consumption. In 2002, Meldal et al. Of Denmark and Sharpless et al. Of the United States independently discovered the Copper (I) -catalyzed Azide Alkyne Cycloaddition (CuAAC) (Figure 1), which can be carried out rapidly under mild conditions[4][5]. This classical click reaction does not use cyclic alkyne, but terminal alkyne 2. In fact, this reaction can also occur at 90 ~ 100 ℃ without copper ion catalysis[6⇓~8]. Thermally promoted azide-alkyne cycloaddition can also be carried out efficiently in application scenarios that are not sensitive to high temperatures, but it is not suitable for many scenarios that require room temperature or physiological temperature.
Copper-catalyzed azide-alkyne cycloaddition can be carried out efficiently and rapidly under physiological conditions, but there is a problem of copper residue. The cytotoxicity of copper, especially its effects on the nervous system, has limited the development of this reaction in biochemistry and other fields[9][10]. Therefore, the development of copper-free azide-alkyne cycloaddition reactions will promote the wider application of azide-alkyne cycloaddition reactions.
With the continuous exploration of scholars, cyclic alkynes with high reactivity have been used in copper-free catalyzed azide-alkyne cycloaddition. Bertozzi et al., a famous American female organic chemist and molecular cell biologist, reported the Strain-Promoted Azide-Alkyne Cycloaddition (SPAAC) reaction without copper catalysis in 2004 (Scheme 2)[11]. This kind of bioorthogonal reaction takes advantage of the high ring tension of cyclic alkyne 4 itself, and can occur chemoregioselective click reaction without the participation of copper catalyst, which is a new type of efficient azide-alkyne cycloaddition reaction.
In the SPAAC reaction, the effect of azide on the reactivity of SPAAC depends on whether the part linked to azide is conjugated (such as benzene azide) and the steric effect, which has been thoroughly studied and is relatively easy to control. The rational design of cyclic alkynes, which is the driving force of SPAAC reaction, is the key to the success of the reaction and the core of the development of efficient SPAAC reaction. Therefore, in this paper, we focus on the substrates of cyclic alkynes, and also summarize the preparation of important cyclic alkynes, the application of SPAAC and the challenges faced, so as to provide a comprehensive understanding of SPAAC and promote the application of SPAAC reaction in more fields.

2 Cyclic alkyne substrates involved in the SPAAC reaction

2.1 Discussion on the Number of Rings

The hybridization mode of carbon-carbon triple bond in alkyne is sp hybridization. In the case of open chain, the bond angle of C — C ≡ C — C is 180 °, the bond length of C ≡ C triple bond is 1.2121 Å, and the configuration is linear without ring strain[12]. For cyclic alkynes, although the bond length of the C ≡ C triple bond does not change, the C — C bond is forced to deform under the action of ring strain, resulting in a bond angle of less than 180 °. The size of the deformation is closely related to the size of the ring, and with the increase of the ring, the bond angle gradually increases and approaches 180 ° again. Krebs used the term "angle-strained cyclic alkyne" to describe this group of substances, which is defined as a cyclic alkyne with a C — C ≡ C — C structure and a bond angle deformation of more than 10 °[13]. High energy angle-strained cyclic alkynes are thermodynamically unstable and highly reactive.
The stability of cyclic alkynes and the reactivity brought by ring strain together determine whether they can effectively participate in the SPAAC reaction, and the differences between different sizes of cyclic alkynes in this respect will be discussed in detail next.
Three-ring alkynes are hydrocarbons with high content in interstellar space, but they can not exist stably in normal environment because of their excessive ring tension, and can only form instantaneous reaction intermediates in situ and participate in the reaction immediately[14]. In the current report, there are only theoretical studies, and the 3-membered cyclic alkyne can not be used as a separable independent intermediate[15].
Four-membered cyclic alkynes, which are very similar to three-membered cyclic alkynes, are more stable, but the current synthetic storage technology still fails to meet the requirements of their stability, and they can only be studied as transient reaction intermediates, but can not be used as stable reaction intermediates[16].
Five-membered cyclic alkynes, whose C ≡ C — C bond angle has been restored to nearly 116 °, are stable enough to support their existence as independent reaction products, although they are still far from linear molecules[17]. As early as 2014, Medina et al. Reported that cyclopentyne 7 was used as an independent reaction intermediate to participate in the reaction, and different capture agents were used to add to it to produce different corresponding products (Scheme 3)[18].
Six-membered alkynes, which have a similar ring structure to the benzene ring, have attracted much attention for a long time, and the earliest research record of them can be traced back to 1957[19]. Structurally, the C — C ≡ C — C bond angle of cyclohexyne has been relaxed to 132 °, which makes it more stable than smaller cycloalkynes while still having extremely high reactivity, and it can exist independently below -100 ℃ for characterization[16]. The synthesis process is also relatively simple, and cyclohexyne 10 can be obtained independently by debromination of 1,2-dibromocyclohexene 9 or dehydrogenation of 1-chlorocyclohexene 11 (see Scheme 4), but a large amount of by-product 1,2-cyclohexadiene is produced[20][21]. To avoid this problem, similar to the synthesis of 5-membered cyclic alkynes, stable complexes are formed by reaction with suitable capture agents under strong alkaline conditions and under the catalysis of cesium fluoride[22].
The C — C ≡ C — C bond angle of the seven-membered cycloalkyne has been relaxed to 146.0 °. Although cycloheptyne still needs to be stably characterized independently under strict environments such as low temperature, the structure of cycloalkyne can be stabilized by introducing heteroatoms such as substituents or sulfur atoms[12]. Therefore, through rational design, 7-membered cyclic alkynes synthesized and stored under conventional conditions can be obtained, which can stably participate in click reactions in experiments and applications.
The eight-membered cyclic alkyne, with a C — C ≡ C — C bond angle of 158.1 °, has the best balance of stability and reactivity among all the cyclic alkynes involved in the SPAAC reaction[12]. Cyclooctyne can obtain a stable structure through structural modification and has high reactivity to participate in the azide-alkyne cycloaddition reaction promoted by ring strain. In addition, substituents can be introduced to improve the reactivity of the 8-membered ring without reducing its stability. Therefore, cyclooctyne is the most used class of cyclic alkyne in SPAAC.
Nine-membered and more than nine-membered cyclic alkynes, although having a stable structure, have less ring strain, so their reactivity is low[23]. Even if it has the ability to participate in the azide-alkyne cycloaddition reaction, the reaction rate will be relatively slow.
It is worth mentioning that 7-9-membered cyclic alkynes can be separated separately under conventional organic experimental conditions, and can be analyzed by means of infrared, nuclear magnetic resonance and X-ray diffraction, which is conducive to the study of the reaction by experimenters, and the efficiency and conversion rate of the click reaction can be improved by structural modification, which has obvious advantages in practicality[24].
To sum up, 8-membered cycloalkynes, namely cyclooctyne and its derivatives, as well as structurally stabilized 7-membered cycloalkynes, are more widely used in practice and are the cycloalkyne substrates used in most SPAAC reactions.
After nearly two decades of continuous development, many cycloalkynes that can stably and efficiently participate in the SPAAC reaction have been synthesized, which are discussed below.

2.2 Reported stable cyclic alkynes involved in SPAAC

2.2.1 7-membered alkyne

The first 7-membered cyclic alkyne reported to be involved in the SPAAC reaction was TMTH (Fig. 1)[25]. The TMTH structure stabilizes the high-energy 7-membered ring by introducing a sulfur atom, which balances its activity and stability, thus enabling it to participate in the SPAAC reaction smoothly. The 7-membered alkynes TMTI and TMTHSI, which were subsequently reported to participate in the SPAAC reaction, are based on TMTH[26][27]. Klan, reported in 2016, achieved similar results by introducing silicon atoms[28]. Due to the high reactivity of the 7-membered ring, Klan is the cyclic alkyne substrate with the highest second-order reaction constant among all the SPAAC reactions reported so far. The second-order reaction constant of TMTH is second only to that of Klan, and is still much higher than that of most cyclooctyne or larger cycloalkyne substrates.

2.2.2 8-membered alkyne

Since the SPAAC reaction was reported in 2004, more than ten kinds of 8-membered cycloalkynes that can stably participate in the SPAAC reaction have been synthesized, which can be roughly divided into aliphatic cyclooctyne and benzocyclooctyne or dibenzocyclooctyne (Figure 2). OCT, ALO and DIMAC improve the reactivity of 8-membered alkyne ring by introducing electron-donating oxygen functional groups at the ortho position, and MOFO, DIFO, DIFO2, DIFO3, DIFBO and thiaDIFBO improve the reactivity of 8-membered alkyne ring by introducing electron-withdrawing fluorine functional groups at the ortho position[1][29][30][29][29][31][32][28]. In addition, rings with different sizes can be introduced to the para-position of the cyclooctyne triple bond to maintain the relative stability of the 8-membered ring and improve the reaction activity, such as BCN, PYRROC and TRIPCO, and COMBO, which are introduced to the 3-membered ring, the 5-membered ring and the benzene ring[33][34][35][36]. Researchers have also developed benzocyclooctyne DIFBO, which can efficiently participate in the SPAAC reaction, and a series of dibenzocyclooctyne, which are currently the most studied and widely used, including DIBO, DIBC, DIBAC, BARAC, Sondheimer Diyne, TMDIBO, DIBONE, S-DIBO, ODIBOS, FMDIBO and DINO[37][28][28][29][38][39][32][28][40][28][41][41]. High-strain 8-membered cyclic alkynes are the most representative and practical substrates for the SPAAC reaction.

2.2.3 9-membered cyclic alkynes and above

Most of the 9-membered and above cycloalkynes are not active enough to participate in the SPAAC reaction efficiently. It was not until 2012 that researchers first reported the 9-membered cycloalkyne TMBN, which can be used in the SPAAC reaction. Its second-order reaction constant is only 0.2×10-3L·mol-1·s-1, which is lower than that of the first discovered cyclooctyne OCT, which can be used in SPAAC reaction[42]. Due to the low reactivity, only a few 9- and 10-membered cycloalkynes have been demonstrated for the SPAAC reaction to date (Fig. 3). Among them, ABSACN with aminobenzenesulfonamide structure is worth mentioning. Because of the unique properties of benzenesulfonamide structure in pharmaceutical chemistry, its participation in SPAAC reaction has certain potential applications[43].
Table 1 lists the rate constants for the participation of different cyclic alkynes in the SPAAC reaction. It is not difficult to find that cyclooctyne with ortho-electron-withdrawing functional group (MOFO, DIFO, DIFO2 and DIFO3) has a higher rate constant than cyclooctyne with ortho-electron-donating functional group (OCT and DIMAC), that is, the ortho-electron-withdrawing functional group improves the reactivity of cyclooctyne. In general, benzocyclooctyne and dibenzocyclooctyne (DIBO, DIBAC, BARAC, TMDIBO, S-DIBO, ODIBO and FMDIBO) are significantly more reactive than aliphatic cyclooctynes with electron-donating or electron-withdrawing functional groups introduced at the ortho position. However, when a five-membered heterocyclic ring with large steric hindrance was introduced to the para-position of the triple bond of cyclooctyne, the reaction rate constant was small (PYRROC), and when a cyclopropane or benzene ring with small volume was introduced (BCN and COMBO), the reaction rate constant was large, which was equivalent to that of some dibenzocyclooctyne. It is worth mentioning that although many cyclooctynes have been developed to participate in the SPAAC reaction, the reaction rate constant of 7-membered cycloalkyne TMTH is still much higher than that of cyclooctyne.This indicates that the subsequent modification of cyclic alkynes can not compensate for the reduction of cyclic alkyne tension caused by ring enlargement, which is also the reason why 9-membered cyclic alkynes with low ring tension are difficult to be modified to participate in SPAAC reaction. In biomedical applications, SPAAC reaction is often carried out in aqueous phase. In order to alleviate the high lipophilic hydrophobicity caused by the introduction of benzene ring, researchers introduced polar functional groups such as methoxy group[30]. It can be seen that the introduction of four methoxy groups leads to a decrease in the reaction rate constant (TMDIBO compared to DIBO), and surprisingly, the reaction rate constant is increased by an order of magnitude (FMDIBO compared to TMDIBO and DIBO) by replacing two of the methoxy groups with strong electron-withdrawing fluorine substituents. These results indicate that the substituents on the benzene ring of dibenzocyclooctyne have a significant impact on the reactivity, and the rational design and synthesis of dibenzocyclooctyne with specific substituents on the benzene ring is an important strategy for exploring new substrates for SPAAC reaction.

2.2.4 Second-order reaction constants of SPAAC with different substrates

In cyclic alkyne substrates, too low reaction activity leads to too slow reaction rate, while too large reaction rate constant leads to the instability of the substrate itself, resulting in limited application. Aliphatic cyclooctyne (BCN) and azadibenzocyclooctyne (DIBAC, also known as DBCO), which have high reactivity and stability, are the most widely used substrates in SPAAC reactions at present. The former is a substrate with small volume and short synthetic route developed by Dommerholt et al., and can stably participate in SPAAC reactions, so it has high utilization value[46][47]. Azadibenzocyclooctyne, which has higher reactivity and stability, has become the darling of the click chemistry reagent industry and has attracted more and more attention because of its easy modification and connection with other functional groups. Therefore, its synthesis has been studied more and more, and its synthesis research is introduced below.

3 Large scale preparation of dibenzocyclooctyne (DIBAC, DBCO)

Azadibenzocyclooctyne is the most commonly used cyclooctyne in the click reaction at present, and the traditional synthesis methods include the van Delft method (see Figures 4 and 6) and the Popik method (see Figures 5 and 6)[48][45][49]. The last step of both methods is the bromination and elimination of azadibenzocyclooctene 18 to give azadibenzocyclooctyne 24 as the final product, and the difference lies in the synthetic method of azadibenzocyclooctene 18. The van der Velt method requires more expensive raw materials and more complex steps, and has the advantages that the conversion rate of each step is higher, and the total yield is close to 70%; Popik's method only requires relatively cheap raw materials and simple steps, but the total yield is only about 40%, so the two methods have their own merits[50].
In recent years, researchers have actively improved and developed new synthesis methods on the basis of these two methods. In 2019, Adronov et al. Reported an optimized process method for the efficient and convenient synthesis of DBCO — COOH (17) (Figure 7)[46]. The method is obtain by an improved Popik method, that reaction process is similar to that of the Popik method, the chromatographic method and other separation and purification operation which are not favorable for industrial production are avoided, and on the premise that the yield is kept at 42%, not only is the cost greatly reduced,The preparation scale can also reach the level of 10 G, which provides a good reference for the industrial synthesis of azadibenzocyclooctyne, and also provides a valuable exploration to solve the problem of high preparation cost of thermodynamically unstable cyclooctyne, and is expected to further promote the application of SPAAC in many fields.

4 Application of SPAAC

SPAAC reaction has been widely used in many fields, such as biomedicine and chemical materials, and has shown strong application prospects because of its mild conditions, simplicity, efficiency and bioorthogonal.

4.1 Medical and pharmaceutical field

The SPAAC reaction has good regioselectivity. In addition to the absence of impurities introduced during the directional binding process, the introduction of low molecular weight azides and cycloalkynes into the macromolecule does not affect the expression of the desired potency of the macromolecule after binding. In addition, the SPAAC reaction has the advantage of being able to occur spontaneously under physiological conditions[51]. Therefore, the copper-free SPAAC reaction can play a role in guiding specific binding in the field of medicine, and has become an important tool in the field of medicine[52]. In addition to the most important synthetic targeted anticancer drugs (Fig. 4), which play a tracer role in pathological studies, they can also be used in the synthesis and administration of conventional drugs, and can even help to prepare highly active radiopharmaceuticals[53⇓~55][56][57][58⇓~60][61].

4.2 Life Science Field

SPAAC has good bioorthogonality in the biomolecular field[62]. The introduction of azides and cycloalkynes alone, without the use of copper catalysts, does not cause biological toxicity or affect the performance of biomolecules, thus helping to achieve many previously difficult syntheses or specific binding. Its good biological orthogonal reactivity makes it react in living cells or tissues without interfering with the biochemical process of the organism itself[63]. In 2004, Bertozzi et al. Successfully used OCT as an alkyne substrate to achieve SPAAC reaction in cells[11]. Up to now, SPAAC reaction has been widely used in the field of life science, including bio-orthogonal labeling, including fluorescent probe labeling, bio-specific protein labeling and bio-radioactive labeling[64⇓~66][67⇓⇓~70][71⇓~73]. Modification of biological macromolecules, including modification of protein molecules and modification of nucleotide molecules[74⇓⇓~77][78⇓~80]; And facilitating protein coupling, including accelerating coupling between proteins to prepare special carriers and accelerating polyethylene glycol coupling to peptides or proteins, i.e., accelerating PEGylation, and the like[81][45]. These areas can also be used in combination, such as visualization of metabolically labeled glycoconjugates in living cells for research, specific reaction with alkyne RNA for analysis of nicotinamide adenine diphosphate (NAD (+)) -capped transcripts, and pulse labeling of nascent proteins to assess their stability[82][83][84]. The authors have reported that a series of hydrogels with controllable viscoelasticity, stiffness and degradation properties were precisely constructed by SPAAC reaction, and further investigated the effects of these properties on the growth of chondrocytes in young rats and chondrocytes in arthritis patients and the deposition of cartilage characteristic proteins when the hydrogels were used as three-dimensional growth scaffolds. (Fig. 5)[85]. In this work, the effects of viscoelastic hydrogel properties on the growth of encapsulated chondrocytes were comprehensively examined through a single variable. This is the first report that the reversible physical crosslinking of DBCO-DBCO has a significant effect on the viscoelasticity, stiffness, and degradation rate of hydrogels. By adjusting the degradation rate of the hydrogel, the hydrogel can be used for three-dimensional cell culture and cell controlled release. On this basis, the authors introduced neutral, negative and amphoteric polymer molecular brushes into the hydrogel through SPAAC reaction to achieve controllable regulation of stiffness and viscoelasticity, and further studied the sensing effect of rat stem cell transcription factor YAP/TAZ on the mechanical signal of extracellular matrix[86].

4.3 Field of materials science

The high efficiency and selectivity of SPAAC reaction also has a good application prospect in the field of material science. This excellent property can be used to prepare films, coatings, adhesives, functional polymers and dendrimers, or to modify the surface of materials[87,88][89][90][91⇓~93][94,95][96,97][98,99].
Gunawardene et al. Used azide-functionalized gold nanoclusters to undergo SPAAC reaction with cyclooctyne, which opened up a new platform for surface modification after functional assembly of nanoclusters (Fig. 6)[96]. They confirmed the involvement of all surface azides in the SPAAC reaction by single-crystal X-ray crystallography, mass spectrometry, UV-visible spectroscopy, infrared spectroscopy, and NMR spectroscopy. Because of the high efficiency and good selectivity of SPAAC reaction, small molecules and polymers can also be modified on the surface of nanomolecules to prepare functional nanomaterials[100][101⇓~103]. In addition, the SPAAC reaction can also be used to construct hydrogels with specific functions[104⇓~106].

5 Conclusion and prospect

SPAAC reaction has been continuously studied since it was discovered in 2004. Today, SPAAC is one of the most representative and practical bioorthogonal reactions in click chemistry, and has been widely used in many fields such as biomedicine and material science. As a copper-free azide-alkyne cycloaddition reaction, SPAAC is a green version of CuAAC reaction. As more and more highly active cyclic alkynes that are stable under conventional conditions are synthesized, SPAAC reaction will be more widely used in more fields, especially in applications where the adverse effects of copper accumulation need to be considered.
Although the SPAAC reaction does not require additional stimuli such as light, heat, ultrasound and catalysts, and has many advantages such as high efficiency, high selectivity and bioorthogonality, it has made great progress in recent years, but there are still many challenges. (1) Stable cyclic alkynes require not only high reactivity, but also the introduction of functional groups such as carboxylic acids or NHS esters, which are easy to modify subsequently, so as to be introduced into the connecting part. If the efficiency of this step is not enough, it will cause waste of raw materials. For different connecting parts and considering the stability of the connecting bond, the installation of different functional groups on cyclic alkynes still needs to be optimized. (2) The lipophilic hydrophobicity of the cyclic alkyne moiety leads to problems such as solubility and interference with cell membranes, which can be alleviated by the introduction of functional groups such as methoxy groups, which also leads to the complexity of the structure of the cyclic alkyne moiety. (3) The preparation of highly active cyclic alkynes has always been a difficult problem, which has also led to the high price of cyclic alkynes suitable for SPAAC, which is also an obvious disadvantage of SPAAC over CuAAC. Improving the large-scale production of cyclic alkynes will be an important factor in determining the breadth of SPAAC applications. (4) The safety of azide preparation has also been a problem faced by SPAAC and CuAAC. At present, other substrates for the reaction with highly active cyclic alkynes are also under study, which are expected to replace organic azides in some application scenarios. It is believed that the rational design and synthesis of stable cyclic alkynes with high activity based on the in-depth study of SPAAC reaction and overcoming the problem of mass production will greatly expand the application scope of SPAAC.

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Funding

Start-up Fund(76110-18841290)

Innovation and Entrepreneurship Training Program for College Students of Sun Yat-sen University(20211956)

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