X‐yne click polymerization

Alkyne‐based click polymerizations have been nurtured into a powerful synthetic technique for the preparation of new polymers with advanced structures and versatile properties. Among them, the emerging thiol‐yne, hydroxyl‐yne, and amino‐yne click polymerizations have made remarkable progress from reactions to applications. These polymerizations avoid the usage of inherently dangerous monomers and are safer to operate than the classical azide‐alkyne click polymerization (AACP), making them more prospective for diverse applications. To greatly promote the new alkyne‐based click polymerizations beyond AACP, a new concept of “X‐yne click polymerization” is proposed to unify them, where “X” denotes the monomers that can react with alkynes under mild reaction conditions, including thiols, alcohols, amines, and other promising ones. In this review, we mainly present a brief account of the progress of X‐yne click polymerization and discuss in detail the challenges and opportunities in this field.


C H A R T 1 Main contents of this review.
which limits large-scale preparation and further applications.Therefore, the development of new click polymerizations without using azide monomers is highly desired.
][24][25][26] Compared with azides, these thiol, alcohol, and amine-based monomers are safer during usage and storage, and mostly easy to be synthesized or commercially available.Moreover, most of these polymerizations can proceed smoothly under mild reaction conditions, even spontaneously under ambient conditions.
In 1920, Staudinger put forward the concept of "macromolecule" and then opened the door of polymer science.In 2001, Sharpless and coworkers came up with the concept of "click chemistry" and then fueled a boom in the rapid synthesis of functional molecules, and he was awarded the Nobel Prize in Chemistry 2022 for his outstanding contribution in this field.The proposal of new concepts that are easy to understand and accept is crucial for science development, which will spur the uncovering of novel scientific results.To promote and unify these new efficient click polymerizations, we propose a new concept of "X-yne click polymerization" in this review (Chart 1), where "X" denotes the monomers that can react with alkynes by free-radical addition, nucleophilic addition or other mechanisms under mild reaction conditions, including thiols, alcohols, amines, and other promising ones.Although the terms "yne" and "alkyne" used in AACP mean the same substance, the former is more concise.X-yne click polymerization is a further refinement for click polymerization and has the same click characteristics as AACP but is safer than it because no explosive azide monomers are involved.
As an emerging and efficient polymerization methodology, X-yne click polymerization has become systematic and can serve as a powerful tool for the synthesis of versatile polymeric materials.The current progress is that new building blocks have been explored, new catalyst systems have been invented, new reaction routes have been established, and new functional polymers have been created.X-yne click polymerization has received much attention from other scientific communities and has been applied in many fields, including synthesis of polymer networks, hyperbranched polymers, sequence-controlled/defined polymers, unconventional elastomer materials and fluorescent polymers, surface modification and immobilization, bioconjugation and therapy, drug release, and so on.
In this review, we briefly summarize the current progress in X-yne click polymerizations from reactions to applications and look forward to the future development (Chart 1).We also provide our perspective on how to tackle and grasp the challenges and opportunities that may lie ahead.It is hoped that this review will contribute to the further development of click polymerizations.

PROGRESSES IN X-YNE CLICK POLYMERIZATION
Herein, we mainly focus on the advances of thiol-yne, hydroxyl-yne, and amino-yne click polymerizations.The influences of monomer design, catalyst selection, reaction condition optimization, and other factors on polymerization results will be discussed in detail and their representative applications will be elaborated.Moreover, the polymerization reactions that temporarily cannot meet the requirements of click polymerization owing to harsh reaction conditions or unstable polymer structures but hold the potential are also listed.

Thiol-yne click polymerization
Thiol-yne click polymerization is a well-studied alkynebased click polymerization besides AACP.In general, it can be classified into four categories based on the catalytic systems, namely, photo/thermo-initiated, base-mediated, transition-metal catalyzed, and catalyst-free (including spontaneous) ones. [5]Similar to the analogous thiol-ene polymerization, the photo/thermo-initiated thiol-yne polymerization usually proceeds via a free-radical mechanism involving the addition of a thiyl radical to an ethynyl group, and the resulting carbon-centered radical subsequently attracts a hydrogen from another thiol, generating a vinyl sulfide moiety and a new thiyl radical. [27]However, unlike the thiol-ene polymerization, thiol-yne click polymerization possesses a unique bis-addition feature; that is, the generated vinyl sulfide is capable of undergoing further addition with a second thiyl radical, making it suitable for the preparation of highly crosslinked polymer networks and hyperbranched polymers with high sulfur contents. [28]For example, after Bowman and coworkers firstly used the photo-initiated thiol-yne click polymerization to synthesize highly crosslinked networks in 2009, [27] Chiappone and coworkers utilized this method to synthesize new-type 3D printable materials (Figure 1A). [29]he 3D objects with controllable components could be obtained by adjusting the relative ratios of ethynyl and thiol groups in printing formulation process.The excess unreacted ethynyl groups could continue to react with azide-terminated squaraine dye by an azide-alkyne click reaction so as to realize further functionalization of 3D objects.

S C H E M E 1 (A-M)
The categories of thiol-yne click polymerization based on different initiator/catalyst systems.
[32][33] The AB 2 -type monomer could be easily synthesized by sequential thiol-ene or thiolhalogen together with thiol-yne click reactions. [34,35]When the ratio of thiol and π bonds of ethynyl group was 1:1, linear bis-addition polymers with side chains could be F I G U R E 1 (A) Chemical structures of the formulation used for 3D printing, together with the images of the 3D printed objects under bright field and fluorescence field, respectively.Reproduced with permission: Copyright 2019, Royal Society of Chemistry. [29](B) Stereo-controlled synthesis of the resorbable elastomers, and subcutaneous in vivo degradation of poly(L-lactic acid) (PLLA) and samples with different stoichiometries of succinate incorporation and different cis% over 4 months.Reproduced with permission: Copyright 2021, Springer Nature. [50](C) Synthetic route to highly refractive polyimides.Reproduced with permission: Copyright 2021, American Chemical Society. [63](D) Synthetic strategy for polymeric two-photon photosensitizers and schematic illustration of two-photon excited photoablation toward cancer cells.Reproduced with permission: Copyright 2022, John Wiley and Sons. [64]quired (Scheme 1B).Through the introduction of large hindrance substituent groups and rational condition control, mono-additive products can also be obtained solely.For instance, Voit and coworkers reported a series of linear and hyperbranched poly(vinyl sulfide)s (PVSs) constructed by thermo-initiated thiol-yne click polymerizations of arylsubstituted internal alkynes with dithiols (Scheme 1C,D). [36]espite thiols were greatly excessive, all the PVSs were predominantly or even only mono-addition units because of the large hindrance of aryl substituents.Moreover, the conjugation of the aromatic rings and the formed vinyl groups will also deactivate the bis-addition of the latter.The incorporation of high sulfur content, conjugated C=C bonds, and aromatic groups endowed the polymers with high refractive indices and moderate Abbe numbers, making them prospective for optical applications.
In addition to the photo/thermo-initiated process, basemediated thiol-yne click polymerization is another feasible tool for the preparation of PVSs.It avoids the disadvantage of forming reactive intermediates during the radical process, which might lead to unexpected side reactions. [27]In general, it undergoes a nucleophilic addition process involving the hydrogen abstraction from thiol, nucleophilic addition of a thiolate anion to an ethynyl group, and subsequent intermolecular proton transfer to generate the final product.The bis-addition of thiols and terminal alkynes could also be realized in this nucleophilic addition reaction.However, different from the photo/thermo-initiated process where bis-addition occurred on the two neighbor carbon atoms of ethynyl group, a bis-addition reaction occurring on the same carbon atom was reported by Truong and Dove. [37]They found that in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD), a highly basic catalyst, two equivalents of thiols could be successively attached to the same carbon atom of the esteractivated terminal ethynyl group, generating a bis-thioether product.This bis-addition reaction was further developed into polymerization of propiolates and dithiols for the synthesis of polythioethers by Durmaz and coworkers (Scheme 1E). [38]ributylphosphine (n-Bu 3 P) with high nucleophilicity could also catalyze this reaction, but the sequence of nucleophilic attacks might be slightly different. [39]More interestingly, there existed a dynamic thiol exchange process between the mono-addition and bis-addition products under the catalysis of TBD and elevated temperature, and Du Prez and coworkers implemented this feature in the construction of covalent adaptable networks (CANs). [40,41]When the terminal alkyne was replaced by the internal one activated by two ester groups, the bis-addition site would change again.In 2018, when Durmaz and coworkers studied the post-modification of the polyester containing electron-deficient triple bonds in the backbone, they occasionally found that a ultrafast thiol-yne addition occurred simultaneously on the two adjacent carbon atoms of an ethynyl group in only 2 min in the presence of TBD, which might be due to the high catalytic activity of the base, and the existence of two ester groups making the two carbon atoms with both high reaction activity. [42]Then, they developed the TBD-catalyzed polymerization of dithiols and disubstituted acetylenedicarboxylates in chloroform, quantitatively producing various linear polythioethers with high molecular weights in 1 min (Scheme 1F). [38,43,44]ono-addition polymerization could be realized by using the less basic catalyst.In 2010, Tang and coworkers reported an organobase-catalyzed thiol-yne click polymerization of ester-activated terminal alkynes and 4,4′-thiodibenzenethiol (Scheme 1G). [45]With diphenylamine as catalyst, sole anti-Markovnikov adducts of PVSs with high Z-stereoregularities (Z contents up to 81.4%), satisfactory molecular weights (M w up to 32,300) and polydispersity indices (Ð) in the range of 1.70-3.20 were successfully generated in high yields (up to 98.2%) under ambient conditions.In addition, the as-prepared polymers containing tetraphenylethylene (TPE) moiety exhibited aggregation-induced emission (AIE) characteristics. [46][49][50][51][52][53][54][55][56] In 2016, they found that by judicious choice of organobase catalyst and solvent polarity, the stereochemistry of the formed vinyl group could be precisely controlled so as to remarkably impact on polymer properties, such as crystallization behaviors and mechanical and thermal properties.Thanks to the abundant alkyl chains in polymer skeletons and moderate crystallization, the resultant polymers could serve as thermally processable elastomer-like materials with tunable mechanical properties. [48][51][52][53][54][55] For example, they used a degradable succinate-based monomer for the polymerization and prepared a new type of resorbable elastomer-like material for bionic soft tissue regeneration (Figure 1B). [50]hrough altering the stoichiometry of succinate incorporation, the degradation rate of the materials could be tuned precisely while retaining control over the mechanical properties by maintaining the E/Z ratios of the vinyl groups.After being implanted in a subcutaneous rat model, the variant containing 100% succinate incorporation was capable of degradation in vivo after 4 months and was gradually replaced by mature and developing tissues with limited inflammation, which showed huge potential for biomaterial applications.
Inorganic base could also catalyze this polymerization coupled with higher Z-stereoselectivities.In 2019, Qin, Tang and coworkers found that in the presence of K 3 PO 4 , aromatic diynes and aromatic dithiols could be facilely polymerized in N-methyl-2-pyrrolidinone at 100 • C, producing 100% Zstereoregular PVSs (M w up to 18,500, Ð: 1.61-1.84) in high yields (up to 95%) after 24 h (Scheme 1I). [57]However, 100% E-stereoregular adducts (M w up to 31,500, Ð: 2.60-3.30)could be obtained by the polymerization of aromatic alkynes and dithiols in the presence of Rh(PPh 3 ) 3 Cl under ambient conditions (Scheme 1J). [58]In addition, Markovnikov addition of thiols to ethynyl groups was realized by the promotion of Rh I (NHC)-based catalyst, and the vinylidene content was up to 80% (Scheme 1K). [59]The adjacent vinylidene groups and sulfur atoms in products could be selectively hydrogenated and oxidized, respectively, offering the possibility to prepare functional materials.The Rh-catalyzed thiol-yne click polymerizations might proceed in a migratory insertion pathway including the oxidative addition of the thiol, 1,2-insertion of ethynyl group into the Rh-H bond for Rh(PPh 3 ) 3 Cl-catalyzed process or Rh-S bond for Rh I (NHC)-catalyzed one, and subsequent reductive elimination to generate corresponding products. [60,61]However, the Rh residue is hard to be removed completely, which may adversely affect the optical properties of polymers.
All the works mentioned above needed the help of ultraviolet (UV) light, heat, base, or transition-metal catalyst, which complicated the experimental operations so as to limit their further applications to some extent.In 2014, Qin, Tang and coworkers successfully established a catalyst-free and spontaneous thiol-yne click polymerization of aromatic alkynes and dithiols, by which functional PVSs with linear and hyperbranched structures were prepared (Scheme 1L). [62]imply mixing the monomers in equivalent molar ratio in tetrahydrofuran (THF) at 30 • C readily produced soluble and regioregular PVSs with high molecular weights (M w up to 85,200, Ð: 1.49-3.11) in excellent yields (up to 97%) after as short as 2 h.The polymer with a low M w of 9300 was yielded when the polymerization was performed in chloroform, which is known as a chain transfer reagent in radical polymerization, implying the free-radical addition mechanism of such polymerization.The addition of radical trapper, γ-terpinene, made the M w of product decrease distinctly, further confirming the mechanism.The spontaneity and ease of operation of this polymerization makes it a powerful tool for the preparation of versatile materials.For instance, unlike conventional two-step polycondensation, Zhang and coworkers synthesized functional polyimides (PIs) with good optical properties and robust mechanical properties by spontaneous thiol-yne click polymerization (Figure 1C). [63]he resultant PIs showed good tensile strengths as high as 114.9 MPa and high glass transition temperatures and thermal decomposition temperatures (up to 238 • C and 381 • C, respectively).Notably, one of the prepared polymer films, PI BPADA-TBT, demonstrated a comparable or even preferable refractive index and much lower birefringence than most of the previously reported PIs.This film possessed a refractive index exceeding 1.70 at 633 nm and transmittance above 81% at 450 nm, making it a potential candidate in advanced optical applications.Recently, Tang and coworkers proposed a new strategy for the preparation of sulfur-containing polymeric photosensitizers (PSs) by this spontaneous thiol-yne click polymerization (Figure 1D). [64]The introduction of sulfur atoms induced a "heavy atom effect" so as to enhance the intersystem crossing (ISC) process of PSs, thereby further promoting the generation of reactive oxygen species (ROS).More importantly, this effect could be significantly amplified by the polymerization itself.The introduction of AIE unit of tetraphenylpyrazine (TPP) also benefited the ISC by suppressing the non-radiative decay in the aggregate state.Moreover, the D-π-A structure consisting of weak electron donor of sulfur atom, electron acceptor of TPP and π bridge of vinyl group, endowed the PSs with two-photon excited photosensitization.The excellent two-photon excited properties of PSs combined with the high ROS generation efficiency enabled them to perform well in the in vitro twophoton excited photodynamic therapy (PDT) toward cancer cells, and have great potential in the treatment of deep-tissue diseases.In addition, Li and coworkers also developed a catalyst-free thiol-yne click polymerization based on esteractivated internal alkynes and 4,4′-thiodibenzenethiol in 2020 (Scheme 1M). [65]The activation ability of ester groups increased the difference in the electrophilicity of the two ethynyl carbon atoms, thus improving the regioselectivity of polymerizations.Although this reaction was carried out at 60 • C, the experimental results showed that the addition of γ-terpinene had little effect on the polymerization, indicating that this polymerization tended to be a nucleophilic addition process rather than a radical addition.

Hydroxyl-yne click polymerization
Although oxygen and sulfur atoms belong to the same main group in the periodic table of elements, alcohols possess weaker nucleophilicity and lower reaction activity than thiols, which requires extra catalyst (usually an organic base) to activate the hydroxyl group.The reports on the polymerization of hydroxyl monomers and alkynes are also relatively scarce after Endo and coworkers creatively reported the first example. [24,25]It mainly follows a nucleophilic addition mechanism involving the hydrogenabstraction reaction of hydroxyl group, nucleophilic addition of an alkoxyl/phenol anion to an ethynyl group, and intermolecular proton transfer.In 2017, Qin, Tang and coworkers reported a superbase t-BuP 4 catalyzed polyhydroalkoxylation of aromatic diynes (Scheme 2A), [66] from which soluble and thermostable anti-Markovnikov additive products with high molecular weights (M w up to 40,600, Ð: 1.75-4.10)were produced in high yields (up to 99%).The resultant poly(vinyl ether)s containing TPE moiety showed unique aggregationenhanced emission characteristics, and their aggregates could be used as fluorescence probes to detect explosives with a super-amplification quenching effect.In addition, the acidresponsiveness of vinyl ether bond made the polymers degradable under acidic conditions, and thus, they are capable of being used as drug carriers.In addition, Qin, Tang and coworkers also successfully established a polymerization of internal of bromoalkynes and phenols mediated by inorganic base of Cs 2 CO 3 , obtaining polymers with high molecular weights (M w up to 47,600, Ð: 1.25-3.08) in high yields (up to 95.2%).Thanks to their containing bromovinyl groups, the resultant polymers could be easily post-functionalized by thiophenols under ambient conditions (Scheme 2B). [67]owever, these two polymerizations both proceeded in high boiling point solvents at elevated temperatures, making them hard to be regarded as standard click polymerizations.
The reaction conditions could be greatly moderated by the introduction of electron-withdrawing groups directly connected with the ethynyl groups.As shown in Scheme 2C, carbonyl-activated ethynyl (i.e., aroylacetylene) groups could be polymerized with diphenols in the presence of 4-dimethylaminopyridine (DMAP) at room temperature, affording sole anti-Markovnikov adducts (M w up to 35,200, Ð: 1.44-2.05)with 100% E-isomers in excellent yields (up to 99%). [68]Density functional theory (DFT) calculations supported the proposed nucleophilic addition mechanism and unveiled the reason why only E-stereoregular products were favored.Notably, thanks to its high efficiency and mild reaction conditions, this organobase-catalyzed hydroxyl-yne click reaction has been used for the chemical modification of ethyl cellulose (EC) to prepare UV blocking and fluorescent materials (Figure 2A). [69]The residual aliphatic hydroxyl groups of EC could be reacted with the ethynyl groups of 1-phenyl-2-propargyl-1-ketone (PPK) at room temperature.The degree of substitution mainly depended on the OH/PPK molar ratio, and could reach up to 82% when the OH/PPK molar ratio was 1:5.Simply mixing and stirring the THF solution of EC and PPK with DMAP for 5 min could reach more than 80% substitution, further proving the high efficiency of this reaction.The introduction of PPK moieties extended the thermal processing temperature range of ECPPKs compared with pristine EC and endowed ECPPKs with strong UV absorption performance and visible light excited fluorescence properties.
Ester-activated alkyne is also an ideal candidate for hydroxyl-yne click polymerization.Compared with aroylacetylene groups, the alkyl or aryl propiolates can be easily synthesized by a one-step esterification reaction of propiolic acid with diols or diphenols, which greatly facilitates the development of propiolate-involved click polymerizations and their practical applications.Subsequently, Qin, Tang and coworkers succeeded in the development of a novel hydroxyl-yne click polymerization based on bipropiolates and diols or diphenols monomers in the presence of an organobase of bicyclo[2.2.2]-1,4-diazaoctane (DABCO)

S C H E M E 2 Examples of established polyhydroalkoxylations (A and B) and hydroxyl-yne click polymerizations (C and D).
F I G U R E 2 (A) Illustration of the modification of ethyl cellulose (EC) by hydroxyl-yne click reaction.Reproduced with permission: Copyright 2021, Royal Society of Chemistry. [69](B) Synthetic strategy for the sequence-defined polymers by sequential hydroxyl-yne and thiol-ene click reactions and molecular structure of the miktoarm star oligomer.Reproduced with permission: Copyright 2022, American Chemical Society. [75](C) Synthesis of the two-way shape memory polymer networks, together with schematic and photographic illustration of the reversible grasp-release process.Reproduced with permission: Copyright 2020, Royal Society of Chemistry. [76](D) Synthesis process of the amphiphilic hyperbranched polyprodrug RBP based on resveratrol (RSV) and the preparation procedure of RBP@DOX nanoparticles.Reproduced with permission: Copyright 2021, Elsevier. [79]DOX, doxorubicin.
under mild reaction conditions (Scheme 2D). [70]The resultant polymers possessed different crystallization behaviors, semicrystalline or amorphous states, depending on the different flexibilities of monomers.Interestingly, the polymers composed of aliphatic chains only showed an E-isomeric configuration, while the participation of aryl alkyne or phenol monomers would impair the stereoselectivity of polymers.
By taking the striking advantages of simple synthesis of propiolates and high reaction efficiency, this click polymerization or reaction has been applied in diverse areas.[73] For example, as shown in Figure 2B, thanks to the great functional group tolerance of click chemistry, the DABCO-catalyzed hydroxyl-yne and N-heterocyclic carbene (NHC)-catalyzed thiol-ene click reactions were combined for the efficient protecting-group-free preparation of sequence-defined oligomers, the sequences of which could be encoded and decoded by tandem electrospray ionization-mass spectrometry/mass spectrometry for high-density data storage. [74,75]In particular, besides linear and homoarm star oligomers, the unprecedented miktoarm star oligomer was also constructed through the combination of the convergent (from arms to core) and divergent (from core to arms) synthetic strategies in an overall 68% yield, which could serve as a new-type topological digital macromolecule to achieve 2D information matrix encoding for information encryption.Apart from linear and star polymers, this DABCO-catalyzed hydroxyl-yne click polymerization was also used to construct polymer networks [76] and hyperbranched polymers. [77]For example, Qin, Tang and coworkers successfully constructed a luminescent two-way shape memory polymer network by polymerization of dipropiolates and 4-arm poly(ε-caprolactone)s (PCLs) terminated with hydroxyl groups (Figure 2C). [76]The as-prepared network PCL 5800 -OH containing TPE moiety showed reversible shape transformation and remarkable blue emission, which could be fabricated into a micro-robotic gripper.The gripper could grasp the screw pre-coated with a red-emissive AIE luminogen (AIEgen) in cool water (0 • C) and release it in warm water (39 • C) automatically and reversibly.The weight of the screw is 148 times higher than that of the gripper.Thanks to the introduction of AIE moiety, the grasp and release process could be clearly observed under UV light irradiation.
Besides in synthetic chemicals, hydroxyl groups are widely found in natural products, such as polysaccharides, amino acids, and polyphenols.In view of the requirements of green chemistry, using natural products for polymer synthesis is the future development trend.Resveratrol (RSV) is a trifunctional polyphenol featured as excellent antioxidant and cardiovascular protective agent, as well as a synergistic drug with antitumor drug doxorubicin (DOX) for the cancer treatment. [78]Based on these findings, Meng and coworkers developed a pH-responsive and degradable hyperbranched polymer-based drug carrier via hydroxyl-yne click polymerization of trifunctional RSV and bifunctional propiolate. [79]he drug carrier could co-assembly with hydrophobic DOX into nanoparticles (NPs) in water and then breakdown under an acidic tumor microenvironment due to the pH-sensitive vinyl-ether and vinyl-amino bonds, releasing the covalently bonded RSV and encapsulated DOX for synergistic tumor chemotherapy (Figure 2D).

Amino-yne click polymerization
In addition to thiol-yne and hydroxyl-yne click polymerizations, amino-yne click polymerization has been developed rapidly and has become a promising tool for the preparation of nitrogen-containing polymers.In 2016, Qin, Tang and coworkers reported a Cu(I)-catalyzed polyhydroamination of ester-activated internal alkynes and aromatic primary diamines (Scheme 3A).This polymerization could proceed smoothly in bulk with 100% atom economy at 140 • C, producing sole anti-Markovnikov adducts with moderate molecular weights (M w up to 13,470, Ð: 1.32-1.66) in high yields (up to 97%). [80]Although elevated temperature is needed, which cannot fully meet the requirements of ideal click reaction, this polymerization gave regioregular products and thus was coined as "amino-yne click polymerization" in publication.To endow the reaction with ideal click features, they subsequently replaced the internal alkynes with more active terminal ones and found that the polymerization readily occurred when diynes and aliphatic secondary diamines were simply mixed in dichloromethane (DCM) at room temperature without any external catalyst (Scheme 3B). [81]hrough the systematic optimization of reaction conditions, solely anti-Markovnikov adducts with 100% E-isomer and high molecular weights (M w up to 64,400, Ð: 1.40-2.53)were obtained in high yields (up to 99%).This spontaneous amino-yne click polymerization was also successfully used for the preparation of hyperbranched polymers. [82]FT calculations confirmed that there existed two elementary processes of nucleophilic addition and proton transfer.The spontaneity might result from both electronic effect and steric effect.On the one hand, it has been demonstrated that electron-withdrawing groups can effectively activate the ethynyl groups and increase their electrophilicity.And terminal alkynes may possess higher reactivity than internal ones because of the absence of π-electron conjugation with benzene rings and reduced steric hindrance.On the other hand, the electron-donating inductive effect of alkyl substituents makes secondary amine monomers more nucleophilic than primary ones, and the steric hindrance of the substituents makes it more inclined to generate trans structures.Aliphatic primary amines could also be polymerized with alkynes under the optimized conditions but with a lower stereoselectivity (Z/E = 60/40) because the Z-isomers could be stabilized by the intramolecular hydrogen bonds.Aromatic amines could not react with alkynes, probably owing to the conjugation of amines with aromatic rings, which reduced their nucleophilicity.
To further enhance the universality of amine monomers, carbonyl group with stronger electron-withdrawing ability was used to replace the ester one for the amino-yne click polymerization, from which polymers with high molecular weights (M w up to 49,400, Ð: 1.30-2.28)were produced in high yields (up to 99%) (Scheme 3C). [83]Subsequent studies showed that different stereoregularities could be obtained by varying amine monomers.Similar to esteractivated alkynes, the polymerizations of carbonyl-activated alkynes with aliphatic secondary amines furnished products with sole E-isomers, whereas the ones with only Z-isomers were produced when primary amines were used.DFT calculations unveiled that the Z configuration product was favorable because of its lower Gibbs energy value with a small energy difference, which was benefited from the formation of intramolecular hydrogen bonds.When the carbonyl group was changed to sulfonyl one, which has the strongest electron-withdrawing ability compared with carbonyl and ester groups, the resultant activated terminal diynes could be polymerized with all kinds of amines, including aromatic and aliphatic primary and secondary ones, producing almost only E-isomers (up to 100%) with high molecular weights (M w up to 160,000, Ð: 1.61-2.72) in high yields (up to 99%) under very mild conditions (Scheme 3D). [84]otably, the enaminone moieties formed by this click polymerization were verified as a new type of dynamic bond and amine exchange occurred when another amine was added at elevated temperature.Taking advantage of the dynamic characteristics, the resultant polymers could be depolymerized upon the addition of primary amines.Similarly, the formed βaminovinylsulfone moiety also possesses a dynamic feature, which endows polymers with degradability through amine exchange process.In particular, Lewis acid was not needed in this process because of the stronger electron-withdrawing activity of sulfonyl group.
Thanks to the simple operation, no need of catalyst and excellent polymerization results, spontaneous amino-yne click polymerizations, especially those involving esteractivated alkynes, have been widely applied in biological field, and in the preparation of polymer networks, sequencecontrolled polymers, and non-traditional intrinsic luminescent materials, etc.As typical crosslinked polymer networks, hydrogels have unique swelling behaviors in water and have been served as a kind of biomaterial. [85,86]Langer and coworkers successfully designed and prepared polyethylene glycol (PEG)-based hydrogels via spontaneous click polymerization of PEG tetra-alkynoates and amines in aqueous media without using any initiator or catalyst (Figure 3A). [87]he gelation kinetics and rheological properties could be regulated by adjusting the weight percentage of PEG tetraalkynoates and amines relative to the total mass of water.Moreover, 3D cell culture experiments indicated that these hydrogels had good cytocompatibility, making them promising in biomaterial applications.Similarly, Zhang and coworkers successfully prepared reversible metallacycle-crosslinked supramolecular polymer networks by combination of metal coordination and spontaneous amino-yne click polymerization (Figure 3B). [88]The introduction of rigid metallacyclic structures not only offers the formed polymeric network with good emission and self-healing properties but also increases its adhesion strength and glass transition temperature, enabling it to serve as a new type of supramolecular adhesive material.
Meanwhile, the spontaneous amino-yne click polymerization was also applied in preparation of sequence-controlled polymers.Such polymers with ordered compositions have become a hot research topic in recent years on account of their great potential in data storage and biological applications. [89,90]However, existing synthetic approaches mostly require time-consuming reactions, and multi-pot processes or the use of DNA or RNA as templates, [91] which severely limit their further development.From this point of view, click reactions are well suited for the preparation of sequence-controlled polymers owing to their high efficiency and simple purification procedures.For example, Hong and coworkers combined the catalyst-free thiol-ene click reaction and amino-yne click reaction/polymerization to prepare sequence-controlled polymers in one pot under very mild conditions (Figure 3C). [92]The sequence structures of polymers could be definitely and easily controlled by adjusting the feeding sequence according to the different reaction preferences between thiol/amino and vinyl/alkynyl groups.This work provides an easy but efficient method for the preparation of functional polymers with controlled sequences.Moreover, thanks to its good compatibility with other reactions, amino-yne click polymerization has also been applied in multicomponent tandem polymerization together with ring-closing reaction for the preparation of poly(aminomaleimide)s (PAMs) with non-traditional intrinsic luminescence characteristics (Figure 3D). [93]The resultant PAMs exhibited low cytotoxicity and were used as fluorescent probes for bioimaging.
Besides the dynamic feature of the β-aminoacrylate formed by the click polymerization of ester-activated diynes and diamines, this bond is cleavable under external stimuli of F I G U R E 3 (A) Illustration of the preparation of β-(aminoacrylate) hydrogels.Reproduced with permission: Copyright 2018, John Wiley and Sons. [87]B) Construction of the metallacycle-crosslinked polymer networks.Reproduced with permission: Copyright 2020, Elsevier. [88](C) Synthetic strategy for the sequence-controlled polymers via the combination of thiol-ene click reaction and amino-yne click reaction/polymerization in one pot.Reproduced with permission: Copyright 2018, Elsevier. [92](D) Synthesis of the non-traditional intrinsic luminescent poly(aminomaleimide)s (PAMs), fluorescent images of PAMs in solution state and aggregate state, together with the merged confocal colocalization images of HeLa cells stained with PAMs.Reproduced with permission: Copyright 2020, American Chemical Society. [93][96][97] As shown in Figure 4A, the β-aminoacrylate moieties could be degraded into aldehyde and amine in an acidic environment, while N-formyl derivative and alcohol/phenol will be generated when 1 O 2 exists.][98][99] For example, Ni and coworkers synthesized an ethynyl group-terminated amphiphilic copolymer via amino-yne click polymerization, and the terminal ethynyl groups could react with the amino groups of anticancer drug DOX through amino-yne click reaction to yield the drug-loading polymeric prodrug DOX-ena-PPEG-ena-DOX (Figure 4B). [94]The prodrug was able to self-assemble into NPs in aqueous solution, and disassociate into amine and aldehyde derivatives under an acidic environment (pH value below 6.5) on account of the acid-responsive cleavability of enamine bond, releasing the encapsulated DOX.In vitro drug release study showed that 85% of original DOX could be released at pH 5.0.Cell test further demonstrated that the prodrug NPs could be internalized into HeLa cells through endocytosis and then release DOX owing to the acidic environment of cells, suggesting the huge potential of this pH-responsive polymeric prodrug for cancer chemotherapy.Afterward, the 1 O 2 -responsive drug carriers were also reported.To overcome the cisplatin resistance of tumors, Wu and coworkers designed a dual-responsive Pt(IV)/Ru(II) bimetallic polymer (PolyPt/Ru) constructed by amino-yne click polymerization, [99] which could self-assemble into NPs and accumulate in tumor site and then be taken up by cisplatin-resistant cancer cells (Figure 4C).Under the irradiation of red light, the Ru(II) moieties could generate 1 O 2 and escape from polymer skeleton through ligand substitution.The generated 1 O 2 not only had the PDT effect for cancer cells but also further stimulated the cleavage of enamine bonds, inducing the disassociation of polymer chains.Meanwhile, the released Pt(IV) was reduced into the anticancer drug cisplatin in the reductive microenvironments.Overall, the combination of the released Ru(II) anticancer agent and cisplatin as well as the generated 1 O 2 realized a synergistic effect against cisplatin-resistant tumors.
Apart from being used as a building tool for drug carriers in biological applications, spontaneous amino-yne click polymerization itself could be served as an effective technique for bioimaging and therapy.As shown in Figure 4D, a lab-in-cell was successfully constructed by Qin, Tang and coworkers. [100]The polymerization of carbonyl-activated diyne and a TPE-containing diamine could proceed smoothly in cells by sequential feeding and incubation, producing poly(β-aminoacrylate) with a M w of 7300.Thanks to the AIE feature of TPE moiety, the resultant polymers showed bright green fluorescence in cells, thus enabling a "turnon" cell imaging.Meanwhile, in situ killing was realized by destroying the structures of actin and tubulin of cells, which could not be achieved by polymers pre-prepared outside the cell.This intracellular polymerization expands the biological application of click polymerization and holds great potential in bioimaging and therapy applications.
It is well known that most novel polymerizations derive from and depend heavily on the development of highly F I G U R E 4 (A) Breakage of enamine bond in the presence of weak acid or 1 O 2 .(B) Chemical structure of DOX-ena-PPEG-ena-DOX and schematic illustration of self-assembly, endocytosis and acid-responsive drug release processes.Reproduced with permission: Copyright 2019, American Chemical Society. [94](C) Chemical structure of the amphiphilic triblock copolymer PolyPt/Ru and its disassociation process under red light irradiation, and schematic illustration of self-assembly, extracellular and intracellular processes for anticancer therapy using PolyPt/Ru.Reproduced with permission: Copyright 2020, John Wiley and Sons. [99](D) Schematic illustration of the lab-in-cell constructed by sequential incubation, and synthetic route to poly(β-aminoacrylate).Reproduced with permission: Copyright 2019, Springer Nature. [100]DOX, doxorubicin.efficient organic reactions.However, since spontaneous amino-yne click polymerization based on ester-activated alkynes was reported in 2017, this polymerization in turn has facilitated a wide range of applications of its homologous chemical reaction, that is, amino-yne click reaction.][103] For example, Qin, Tang and coworkers realized the site-selective, multi-step functionalization of CO 2 -based hyperbranched poly(alkynoate)s (hb-PAs) with nearly 100% conversion in each step via an amino-yne click reaction and threecomponent polymerization/reaction of CO 2 , alkynes, and alkyl dihalides (Figure 5A). [102]Because these two reactions did not interfere with each other during the synthesis process, one-pot, multi-step tandem polymerization with successive feeding and simplified purification procedures was realized.By introducing the hydrophilic oligo(ethylene glycol) chains and DOX into the branched chains and/or periphery of polymers, hyperbranched polyprodrug amphiphiles with high drug-loading content (44.3 wt%) were generated.Moreover, 78% loaded DOX at a pH value of 5.0 in vitro could be released owing to the acid-responsive enamine bonds.This work provides a powerful strategy for the post-modification of hyperbranched polymers into versatile functional materials.In addition, amino-yne click reaction has also been utilized for preparing multicolor fluorescent N,N-dimethyl-substituted boron ketoiminates (NBKI) with dimethylamino group as electron-donating unit, phenyl ring as π bridge and asymmetric OBF 2 N as electronaccepting unit (Figure 5B). [104]The D-π-A conjugated system endowed NBKI with efficient fluorescent emission in solution.NBKI with varied optical properties could be obtained by adjusting the substituent in N-position via aminoyne click reaction.Moreover, multicolor fluorescent initiators based on NBKI were further prepared and used to initiate atom transfer radical polymerization and reversible additionfragmentation chain transfer polymerization, producing a series of fluorescent polymers.
Bioconjugation plays an important role in the development of biomedicine and material science. [105]However, there are many problems in traditional biological coupling methods, such as metal residues, complicated pre-modification and limited reaction efficiency.In 2018, Tang and coworkers put forward a metal-free bioconjugation strategy that was achieved by click reactions of activated alkynes and abundant native amino, thiol, and hydroxyl groups in biomolecules (Figure 5C). [106]Thanks to the high efficiency of spontaneous amino-yne click reaction, pre-functionalization of biotargets and the use of metal catalysts are not required, which help largely to simplify the conjugation procedures but still maintain the normal activity of biomolecules.Thus, this strategy enabled the highly efficient modification and F I G U R E 5 (A) Schematic illustration of post-modification of hyperbranched polymers by tandem multi-component polymerization/reaction together with amino-yne click reaction.Reproduced with permission: Copyright 2020, John Wiley and Sons. [102](B) Synthetic routes of N,N-dimethyl-substituted boron ketoiminates (NBKI), CIE coordinate and fluorescence photos of NBKI derivates and related polymers.Reproduced with permission: Copyright 2020, American Chemical Society. [104](C) Schematic illustration of the metal-free bioconjugation strategy based on activated alkynes and native groups in biology.Reproduced with permission: Copyright 2018, American Association for the Advancement of Science. [106](D) Schematic illustration of the fast and facile surface mobilization method.Reproduced with permission: Copyright 2020, Royal Society of Chemistry. [107](E) Preparation of white light-emitting (WLE) silk and its fluorescence spectrum and Commission International del'Eclairage (CIE) coordinate, together with fluorescence photos of flexible WLE fabrics fabricated from the AIE luminogen (AIEgen)-silk fibers.Reproduced with permission: Copyright 2021, John Wiley and Sons. [108](F) Graphical illustration of the bioconjugation of TPAP-C5-yne with mitochondria in neurons, confocal microscopy image of neurons stained with TPAP-C5-yne, and recorded single mitochondrion trajectory in the 3D diagram.Reproduced with permission: Copyright 2022, Royal Society of Chemistry. [110]unctionalization of natural polysaccharides, biocompatible PEG, synthetic polymers, cell-penetrating peptides and proteins, fast whole-cell mapping, quick differentiation and staining of gram-positive bacteria, etc.This work not only provided a general platform for facile biocompatible labeling of biotargets but also provided a general approach for efficient modification of both organic and inorganic materials, exhibiting broad prospects in the fields of biology, chemistry, and material science.For example, Qin, Tang and coworkers successfully expanded this metal-free bioconjugation method to fabricate the activated ethynyl-functionalized surfaces for rapid immobilization of native proteins and cells (Figure 5D). [107]Biomolecules such as bovine serum albumin, human immunoglobulin G, and a peptide of C(RGDfK) could be covalently fixed on the surfaces within 30 min while retaining their biological activity.In addition, Tang and coworkers applied this amino-yne click reaction in functionalization of silk. [108]Silk is an important natural biopolymer in textile industry and biological applications, which is mainly composed of animal proteins and has abundant residue amino groups that are capable of reacting with activated alkynes. [109]By chemical conjugation with activated alkynes bearing different AIEgens, fluorescent silks with full-color emission and high stability were facilely prepared.Compared with other fluorescent silks functionalized by physical absorption or non-covalent combination, AIEgen-silks constructed by bioconjugation showed the higher retention rates of fluorescence due to the stable covalent bonding.And white light-emitting silk was also realized by simultaneous conjugation with blue-, green-, and redemissive AIEgens (Figure 5E).Moreover, the red-emissive AIEgen-functionalized silks could be applied in long-term cell tracking and two-photon bioimaging.Furthermore, Tang and coworkers realized the accurate and long-term tracking of mitochondrial movement in neurons by bioconjugation (Figure 5F). [110]By elaborate structural design, TPAP-C5-yne with AIE features could target mitochondria and conjugate with amino groups on them.Then, under a confocal fluorescence microscope, an apparent change in the mitochondrial location was captured.Even after a week, the neurons stained by TPAP-C5-yne remained intact with bright fluorescence signal.This work provides more possibilities for neuroscience applications.

Other potential X-yne click polymerizations
In addition to aforementioned three types of X-yne click polymerizations, there are actually other polymerizations being developed at the same time.However, some issues, including product stability, reaction selectivity, complicated catalysts, and additional energy input, currently limit the acceptance of these polymerizations as click polymerizations.
Organoboron compounds are widely used in organic transformations for their high reactivities and effective deborylation reactions.The hydroboration process is the most important method for the synthesis of boranes.As shown in Scheme 4A, polyhydroboration of diynes can proceed smoothly in THF at room temperature, producing regioand stereoregular polymers in moderate yields.It seems to meet the requirements of click polymerization.However, decomposition experiments indicated that the polymers were unstable and underwent continuous degradation in air or upon UV irradiation, which may be attributed to the oxidation of vinylborane moieties to form the corresponding ketones. [111]his inherent defect complicates the synthetic procedure and makes it hard to store the products for a long time, therefore influencing the further applications.The air-and photo-stability are affected largely by the electronic effect and hindrance effect of substituents and can be improved by proper monomer design, [112] such as replacing thexylborane with mesitylborane. [113]If the stability problem could be settled out completely, this polymerization holds potential to become a new type of click polymerization.
Similar to hydroboration process, hydrosilylation reaction has also been developed.The operational simplicity of the hydrosilylation process, high tolerance toward various functional groups in the reagent structures, and the diversity of selectivities that can be tuned by appropriate catalysts, have rendered this transformation the preferred choice for synthesis of organosilicon compounds.For instance, Tang and coworkers utilized the polyhydrosilylation to prepare a series of E-stereoregular poly(silylenevinylene)s with high molecular weights (M w up to 95,300, Ð: 1.80-4.60) in moderate to high yields (up to 92%) (Scheme 4B). [114]Thanks to the high functional group tolerance, typical AIEgens, such as silole or TPE moieties, can be easily introduced into polymer backbones and endow the resultant polymers with AIE features.However, this polymerization depends heavily on the usage of expensive transition-metal catalysts, such as ruthenium, platinum, palladium, and nickel catalysts, [115][116][117][118][119][120][121] which makes it not "click" enough.
The development of new building blocks for polymerization is of great importance for the preparation of functional materials.Vinyl iodide groups are commonly enlisted for selective chemical transformations of small molecules but are rarely used in polymer science due to the limited methods for installing vinyl iodide groups into polymers.Jaye and Sletten put forward a novel iodo-yne polymerization assisted by sonication. [122]In this work, perfluorodiiodide in which iodide atoms were activated by electron-withdrawing fluorine groups could react with alkynes under the initiation of Na 2 S 2 O 4 , generating polymers with vinyl iodide groups (Scheme 4C).Compared with other relative reports, this work could proceed in aqueous conditions using mild initiator and realized the direct installation of vinyl iodide groups into polymer backbone instead of the indirect post-modification of polymers that involved the pre-installation of activated functional groups such as vinylstannanes and then replacement by elemental iodine.However, this process requires external energy input through ultrasound, which is energy consuming.
If the reaction conditions can be milder, avoiding the assistance of metal catalyst or sonication, hydrosilyl-yne and iodo-yne polymerizations, etc., may be regarded as new types of X-yne click polymerizations.

CHALLENGES AND OPPORTUNITIES
Although X-yne click polymerizations and their applications have made great progress in the past decade, there is still a large room for further improvement.Future challenges and opportunities lying ahead are urgent to be tackled and grasped.In the following section, we will discuss them in detail from four aspects, including monomer scope expansion, polymerization development, structure regulation, and function exploration.

Monomer scope expansion
Monomer is the cornerstone of polymerization.Accompanying the expansion in monomer scope, the territory of click polymerization is also anticipated to be widened accordingly.Monomers used in X-yne click polymerizations mainly consist of alkynes inactivated or activated by electronwithdrawing groups and commercially available or easily synthesized "X" ones.Previous experiments have shown that electron-withdrawing groups can efficiently enhance the electrophilicity and reactivity of alkynes compared with inactivated ones.Common electron-withdrawing groups include ester, carbonyl, sulfonyl, amide groups, and halogen elements.It is reasonable to speculate that other groups, such as imide and sulfoxide, may have the same effect.Despite these groups look slightly similar, tiny differences in structures and reactivity may lead to huge distinctions in polymerization results and product properties.For example, very recently, Jiang and coworkers found that self-catalyzed hydroxyl-yne click polymerization could be realized in the presence of tertiary amine-containing alcohols, which could serve as both monomers and internal bases during the polymerization process. [123,124]The introduction of nitrogen atoms into alcohol monomers allows this polymerization to occur without an external base catalyst.Furthermore, activated alkynes mentioned above generally result in the partially conjugated polymers by X-yne click polymerizations.The design and preparation of conjugated activated alkynes for the synthesis of fully conjugated polymers is another promising direction.In addition, compared with terminal alkynes, internal alkynes were less reported in X-yne click polymerization, which should be of greater concern.At present, polymeric raw materials are mainly derived from the petrochemical industry.There are abundant functional groups, especially hydroxyl groups, in natural products such as monosaccharide (glucose), polysaccharide (chitosan), polyphenol (RSV), and amino acid (cysteine) (Scheme 5A). [125]Using these natural products as monomers is not only in line with the concept of green chemistry but can also lower production costs.] However, these works focused more on biological purposes, and natural monomers were not the research priority.Systematic studies of polymerization itself using these monomers are scarce.Solubility may be a major challenge in using natural monomers as building blocks because they are mostly water soluble, while alkynes are mostly dissolved in organic solvents, which may have a great impact on polymerization results.How to improve the compatibility through reasonable structural design and monomer choice is a problem that needs to be considered seriously.Moreover, other from traditional monomers, some natural monomers containing various groups with different reactivities simultaneously, such as amino acids, which have been applied in some multicomponent polymerizations, [128,129] can be regarded as a new kind of asymmetrical monomer.How to adjust the reaction conditions to make some groups reactive while others remain intact or make all groups reactive is challenging.
Carboxylic acid is also a potential candidate for X-yne click polymerization, but works on it have not yet been reported.Resembling the hydroxyl group, the carboxyl group can lose a proton in a basic environment, generate the nucleophilic carboxyl anion, and then attack the activated ethynyl groups.Similarly, amides and imides are less nucleophilic than amines owing to the existence of conjugated carbonyl groups unless they are converted into their more reactive anions when using base catalysts.Vilarrasa and coworkers found that a series of amides, imides, and their derivatives could react with tosylacetylene to furnish enamine adducts with Z configuration in the presence of catalyst of Et 3 N or NaH, while E configuration products were generated when DMAP was used as catalyst (Scheme 5B). [130]The adjustable and high stereo-selectivity together with excellent yields of this reaction indicated that amides, imides, and their derivatives have great potential as new nucleophilic monomers for X-yne click polymerizations.In addition, amidine is also a promising candidate for the cyclic addition polymerization with ester-activated internal alkynes. [131]

Polymerization development
Generally, most polymerizations are originated from organic reactions.The exploration of new organic reactions also promotes the polymerization development.[141] Current Xyne click polymerizations are primarily proceeded based on symmetric monomers that contain two or more identical functional groups.However, asymmetric monomers that possess two or more different reactive sites, such as amino acids mentioned earlier, have rarely been studied in X-yne click polymerization.This kind of uncommon monomer accompanied by unique reaction mechanisms will help to construct novel polymeric materials and thus induce new properties and applications.
The examples of two pseudo-three-component reactions based on difunctional reactants of imidazoline or oxime are shown in Scheme 6.In Scheme 6A, 1,2-disubstituted 2-imidazoline first underwent a Michael addition with an electron-deficient alkyne, thereby attaching the vinylpropargylamine fragment at the N-position.Then, the second ethynyl group further attacked the α-position of nitrogen atom, leading to the disubstituted imidazoline. [142]Notably, this reaction could proceed smoothly at room temperature in commonly used aprotic solvents with moderate to high yields.In Scheme 6B, oxime and two molecules of ester-activated alkyne underwent a diastereoselective (up to >99:1) annulation, generating polysubstituted β-lactams. [143]he two reactions feature excellent substrate flexibility and benign functional group tolerance and the products are rich in nitrogen-containing heterocyclic rings, unsaturated bonds and carbonyl groups, which might bring some unique properties, such as nonconventional luminescence [144,145] and self-assembly behaviors. [146,147]In addition, the unsaturated bonds provide the possibility for further post-modification.If they are developed into polymerization reactions, the scope of X-yne click polymerization as well as polymer structures and properties will be greatly broadened.Theoretically, similar to thiol-yne click reaction, two hydroxyl groups can also be added to the same reaction site of triple bond to produce a bis-addition product (Scheme 6C). [148]This reaction is interesting and promising for the preparation of metastable polymer networks or linear polymers with pendant groups.
In addition to developing new polymerization reactions, the characteristics of the reactions themselves must also be considered.One of the most attractive characteristics is the orthogonality of the reaction, which means that when several reactants (or functional groups) coexist, the click reaction can proceed independently while keeping others intact (Scheme 6D).The combination of orthogonality and rapid reaction rate has made X-yne click polymerization be applied in the formation of interpenetrating dual network hydrogels, [47] preparation of sequence-defined/controlled polymers, [75,92] and so on.Orthogonal reactions can be achieved by proper monomer design, catalyst selection, and reaction condition adjustment according to the differences in reactive activity, catalytic system, and reaction conditions.

Structural regulation
One of the unique features of X-yne click polymerization is that it generates regio-and stereoregular products.As shown in Scheme 7A, mono-addition reactions can proceed through a Markovnikov addition route to produce polymers with saturated main-chains and vinyl side groups or undergo anti-Markovnikov addition to furnish the unsaturated linear adducts with E and/or Z configurations.At present, polymerizations based on Markovnikov addition are much less explored than those based on anti-Markovnikov addition due to the limitations of catalytic system.In general, the stereochemistry of vinyl groups is mainly affected by the catalyst choice, substrate design, and solvent polarity.For example, configuration modulation of thiol-yne click polymerization has been successfully realized by adjusting the catalyst.E-and Z-stereoregular and stereo-random PVSs were obtained under the catalysis of Rh(PPh 3 ) 3 , [58] K 3 PO 4 , [57] and in a catalyst-free way, [62] respectively.The influence of substrates mainly includes both the electronic and steric hindrance effects of substituent groups.For the systems involving intramolecular or/and intermolecular interactions, solvent polarity has a great impact on the Z/E configurations.Taking the catalyst-free model reaction of carbonyl-activated alkynes and amines as an example, when the reaction was carried out in a low polarity solvent such as DCM, sole Z-isomer was obtained when using a primary amine (e.g., butylamine) because of the formation of intramolecular hydrogen bonds, while large steric hindrance of substituents on secondary amines (e.g., diethylamine) and absence of intramolecular hydrogen bonds resulted in the sole E-isomeric product. [83]The Z/E-isomer ratio could readily be determined by 1 H nuclear magnetic resonance (NMR) spectra in CDCl 3 .However, an intriguing conversion of Eisomer to Z-isomer was observed in other deuterated solvents, including acetone-d 6 , toluene-d 8 , MeCN-d 3 , methanol-d 4 , and DMSO-d 6 . [149]First, the 1 H NMR spectra of E-isomer were recorded as quickly as possible after preparation.After 5 min, the E-isomer was predominated in all solvents.After 15 min, a significant shift from E toward Z-isomer was found in acetone-d 6 , toluene-d 8 , and MeCN-d 3 , eventually reaching an equilibrium of more than 84% Z-isomer in all cases, but exhibiting a 1:1 ratio in methanol-d 4 and a predominance of E-isomer (70%) in DMSO-d 6 .This may be due to the competition between the intramolecular hydrogen bonds of products and the intermolecular interactions between the products and deuterated solvents.The highly polar solvents such as MeOH and DMSO disrupted the intramolecular hydrogen bonds required for stabilization of Z configuration, leading to the dominance of E-isomers.Recently, we find that reaction concentration can also influence the E/Z-isomerization; that is, high concentration favors Z-isomer, while low concentration favors E-isomer.This might involve a competition between kinetic and thermodynamic control of the reaction process.
For the bis-addition reaction, to simplify the structures, we use terminal mono-alkyne as an example for discussion.In this case, there exist two possible linear saturated structures with side chains, depending on the addition sites (Scheme 7B).If the mono-alkyne is replaced by diyne or multifunctional alkyne, corresponding polymer networks or hyperbranched polymers will be produced.Different structures may cause variation in the chain stacking of linear polymers or the pore size of the polymer networks.It needs to be emphasized that we are not proposing a universal guideline for stereochemical control here.There are other examples that are not in full accordance with the trends mentioned above.All the factors act together, rather than independently, on the resultant configuration of products, the respective contribution of which remains unclear.Actually, a detailed understanding of the effects of catalyst system, substrate design, reaction solvent, and other factors on the selectivity of X-yne click polymerization has not been fully investigated.Thus, more systematic studies on the influencing factors of regio-/stereocontrol during the polymerization are urgently needed.

Function exploration
To make full use of the potential of X-yne click polymerization for the practical applications, functional exploration of resultant polymers is essential, which could be carried out based on the polymer structures.The examples are discussed below.The introduction of sulfur atoms effectively raised the refractive indices of polymers, making thiol-yne click polymerization promising for optical applications. [63]It is found that both vinyl ether bond and enamine bond are labile under weak acidic conditions, [79,94] and in addition, the enamine bond has an exceptional 1 O 2 -responsiveness. [96]hese unique characteristics make the corresponding polymers inherently degradable in the presence of acid or 1 O 2 conditions and have led to the widespread applications of hydroxyl/amino-yne click polymerizations in the construction of controlled release drug carriers.Moreover, the dynamic exchange processes were widely found in X-yne click polymerizations (Scheme 8).In 2012, Joshi and Anslyn reported the dynamic thiol exchange of thiol-yne adducts, especially between the mono-addition and bis-addition products (Scheme 8A). [41]Du Prez and coworkers conducted detailed kinetic studies of this process and revealed that the steric and electronic effects of alkyne monomers were the main factors influencing the exchange rates.The introduction of electron-withdrawing substituents favored the faster thiol exchange.Subsequently, they utilized the dynamic feature to prepare a series of thiol-yne-based CANs with excellent reprocessability, network integrity, and tunable exchange rates. [40]Eelkema and coworkers also realized the construction of self-healing injectable polymer hydrogels via this reversible thiol-yne bisaddition reaction. [150]Thanks to the dynamic thiol exchange feature, these hydrogels showed both self-healing and shear thinning properties.As shown in Figure 6A, two gels containing different dyes were cut into equal halves.Then, after pressing the two pieces together for 15 min, they could adhere to each other and hold their own weight.After 2 days, the dyes diffused into the opposite piece and the crack visually disappeared.Furthermore, the hydrogels could be injected through a 20 G syringe needle and instantly recovered after extrusion.
The enamine bonds connected with sulfonyl or carbonyl groups were also successively verified as new types of dynamic bonds in recent years. [83,84]An efficient amine exchange process will happen when an amino-yne adduct is reacted with another excessive amine (Scheme 8B).Polymer degradation was realized by taking advantages of the dynamic characteristics of enamine bonds.The polymer chains were disassociated gradually after the addition of excess monoamine, the M w of which decreased from nearly 48,000 to 1000 at 60 • C within 48 h. [84][153][154] However, it was reported that the former has less steric hindrance due to the absence of methyl substituent, leading to the faster dynamic exchange process than the latter. [155]By taking F I G U R E 6 (A) Graphical illustrations of the self-healing and injectable behaviors of thiol-yne bis-addition-based hydrogels.Reproduced with permission: Copyright 2020, American Chemical Society. [150](B) The Arrhenius analysis of the BPAE-PTH vitrimer compared with BPAE-ATH, and graphical illustration of hot-press reprocessing process.Reproduced with permission: Copyright 2021, American Chemical Society. [155](C) Schematic illustration of the preparation of porous film based on dynamic phenol exchange of hydroxyl-yne click reaction.Reproduced with permission: Copyright 2022, American Chemical Society. [158]vantage of this fascinating dynamic nature of enamine bonds, Lin and coworkers designed and prepared a vitrimer by amino-yne click polymerization. [155]Compared with the referenced vitrimer BPAE-ATH produced by amineacetoacetate condensation, the resultant vitrimer network BPAE-PTH showed a faster dynamic exchange as verified by Arrhenius analysis, and possessed superior mechanical properties, which was attributed to the absence of byproducts such as water molecules, thus reducing the network defects.As a result, a uniform transparent polymer film was recovered by pressing the BPAE-PTH sheet at 130 • C for 60 min (Figure 6B).In addition, they found that secondary amines could also serve as effective substrates for the construction of vitrimers, and the network dynamics and corresponding reprocessability could be modulated by adjusting the steric hindrance of substituents. [156]ecently, Carrillo and coworkers reported the dynamic phenol exchange of hydroxyl-yne reaction (Scheme 8C), further expanding the scope of dynamic chemistry in X-yne click polymerization. [157]Almost at the same time, Lin and coworkers also found this new dynamic exchange reaction and integrated it into the construction of reprocessable dynamic covalent network of BPA-TH. [158]By further introducing a degradable network of VPV-TH containing diacetal motifs into BPA-TH by hot press and utilizing the selective hydrolysis of acetal motifs under acidic conditions, functional porous polymer film with a porosity of 46% was fabricated (Figure 6C).These works demonstrate the great potential of X-yne click polymerization in the field of functional dynamic materials.
The vinyl moiety produced by the X-yne click reaction is not just a structural linker for connecting the repeat units together but also an important functional unit, which generally has both cis-and trans-configurations.Although our groups and others have endeavored on stereochemistry control of vinyl bond for many years, some stereoselective polymerizations have been successfully established, and Dove and coworkers have studied a lot on the effect of stereoselectivity on polymer properties of thiol-yne click polymerization, the impact of stereoselectivity needs to be considered more when studying polymer functionalities.Actually, the E/Z-isomerization can affect the packing mode of polymer chains so as to affect the mechanical and thermal properties of polymers. [159]For example, PVS with high content of cis-isomer (80%) was verified to be semicrystalline according to the wide-angle X-ray diffraction analysis and differential scanning calorimetry tests.The degree of crystallinity decreased with decrease in content of cis-isomers.However, when the value was below 53%, the samples were completely amorphous together with significantly reduced mechanical properties. [48]Furthermore, an intriguing configuration interconversion of the adduct of 3-butyn-2-one and aniline was observed in various solvents with different polarities. [149]The relationships between stereoregularity of polymers and their functionalities have not been sufficiently studied.Figuring it out and making it helpful for practical applications are of great importance.

CONCLUSIONS AND PROSPECTS
In this review, we put forward a new concept of "X-yne click polymerization" to unify newly developed alkyne-based click polymerizations, in which the "X" refers to a new kind of monomer that can react with alkynes by free-radical addition, nucleophilic addition, etc., in a "click" manner.By rational monomer design, catalyst selection, and reaction condition optimization, the scope of X-yne click polymerization has been greatly expanded.The progress in X-yne click polymerizations, especially thiol-yne, hydroxyl-yne, and amino-yne click polymerizations, is accounted for, and their applications in preparation of functional polymeric materials are briefly summarized.Thiol-yne click polymerization with abundant catalytic systems, diverse structures, and controllable configurations has been established.The weak nucleophilicity of hydroxyl monomers is overcome by the promotion of base catalysts and hydroxyl-yne click polymerization has also been realized.Notably, spontaneous amino-yne click polymerization with excellent polymerization results, sole regio-and stereoselectivity, and simple operability has been successfully developed.Thanks to the fascinating "click" characteristics, X-yne click polymerization has become an emerging tool for the synthesis of polymers with unique structures and advanced functionalities and is widely applied in the preparation of polymer networks and hyperbranched polymers, sequence-controlled/defined polymers, construction of drug delivery carriers, functional modification, etc.Meanwhile, although encouraging progress has been made, this field is still in a developing stage, with many challenges and opportunities awaiting to be addressed and grasped.At present, X-yne click polymerization mainly involves the nucleophilic monomers of thiols, alcohols, and amines.Other substrates, such as carboxylic acid, imide, and asymmetric monomer, have the potential to polymerize with alkynes as well.Other organic reactions can also be introduced into X-yne click polymerization.Despite several stereoselective polymerizations have been developed, there are few systematic studies on the influencing factors of stereoselectivity.In addition, studies on Markovnikov addition and bis-addition are also relatively less.The functional exploration of the resultant polymers of X-yne click polymerization still has great development space.Therefore, subsequent research directions should focus on the expansion of monomer scope beyond existing building blocks and substituents, development of novel polymerization methodologies based on other highly efficient organic reactions, precise regulation of the structures and configurations of polymers, and further clarification of the structure-property relationship.Furthermore, we cannot stop at the development of the reaction itself but should actively explore its function so as to broaden the application prospects.It is hoped that this review can draw more attention to X-yne click polymerization, making its advantages to be fully utilized and applied in more research fields.

S C H E M E 3
Examples of established polyhydroamination (A) and amino-yne click polymerizations (B-D).

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C H E M E 4 (A-C) Potential X-yne click polymerizations.

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C H E M E 5 (A and B) Expanding of the monomer scope of X-yne click polymerization.S C H E M E 6 Organic reactions (A-C) promising to be developed into X-yne click polymerizations and (D) schematic illustration of orthogonal reaction.

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C H E M E 7 (A and B) Several addition routes to X-yne click polymerization.

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C H E M E 8 (A-C) Dynamic exchange processes in X-yne click polymerization.

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C K N O W L E D G M E N T S This work was financially supported by the National Natural Science Foundation of China (21788102 and 21525417), the Natural Science Foundation of Guangdong Province (2019B030301003 and 2016A030312002), and the Innovation and Technology Commission of Hong Kong (ITC-CNERC14SC01).C O N F L I C T O F I N T E R E S T S TAT E M E N TThe authors declare no conflicts of interest.P R E P R I N T A C K N O W L E D G M E N T SThis article was posted on a preprint server Chemrxiv prior to publication in Aggregate.The corresponding preprint article can be found here: 10.26434/chemrxiv-2022-1hlv5.O R C I DAnjun Qin https://orcid.org/0000-0001-7158-1808R E F E R E N C E S Ben Zhong Tang received his BS and PhD degrees from SCUT and Kyoto University in 1982 and 1988, respectively.He conducted his postdoctoral work at the University of Toronto in 1989−1994.He joined HKUST in 1994 and was promoted to chair professor in 2008 and Stephen K.C. Cheong Professor of Science in 2013.His research interests include the exploration of new polymerization reactions, synthesis of new functional (macro) molecules, understanding of new luminescence processes, creation of new advanced materials, and development of new fluorescent biosensors.