Three-Component Asymmetric Polymerization toward Chiral Polymer

Open AccessCCS ChemistryRESEARCH ARTICLE3 Oct 2022Three-Component Asymmetric Polymerization toward Chiral Polymer Ming Li, Xuelun Duan, Yu Jiang, Xinhao Sun, Xiang Xu, Junnan He, Yubin Zheng, Wangze Song and Nan Zheng Ming Li State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024 Google Scholar More articles by this author , Xuelun Duan State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024 Google Scholar More articles by this author , Yu Jiang State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024 Google Scholar More articles by this author , Xinhao Sun State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024 Google Scholar More articles by this author , Xiang Xu State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024 Google Scholar More articles by this author , Junnan He State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024 Google Scholar More articles by this author , Yubin Zheng State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024 Google Scholar More articles by this author , Wangze Song *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024 Google Scholar More articles by this author and Nan Zheng *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.021.202101655 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Chiral-polymers with metal-coordination ability show great potential for mediating asymmetric reactions. However, the synthesis of structurally diverse chiral polymers remains a great challenge, especially doing so efficiently. Herein, four types of Cu-catalyzed multicomponent asymmetric polymerizations were developed using a flexible combination of OBoc-alkyne, amine and azide to facilely afford 30 chiral poly-triazolyl-methanamines with the desired molecular weights (Mn up to 46,700 g/mol) and well-defined chiral structures. As excellent ligands for coppers, such poly-triazolyl-methanamines exhibit unique catalytic performance: (1) Amphiphilic poly-triazolyl-methanamines prepared from water-soluble azides can self-assemble into nanoparticles in water, exhibiting excellent catalytic efficiency for aqueous click reaction at a low Cu loading of 10 ppm. (2) Poly-triazolyl-methanamines obtained from aromatic amines possessed the capability to sustainably stabilize cuprous upon exposure to water and air for up to 42 days. (3) Chiral poly-triazolyl-methanamines also outperformed commercially available chiral ligands, such as Py-box, in mediating the asymmetric propargylic substitution reaction. Download figure Download PowerPoint Introduction Chirality exists extensively in natural biomacromolecules, such as DNA, RNA, and proteins, due to the asymmetric centers located in sugars and amino acids.1,2 Chiral polymers are widely explored in various fields, such as chiral recognition, kinetic resolution, and asymmetric catalysis.3–6 Inspired by the unique functions of chiral polymers in the life sciences, artificial synthesis of chiral polymers has attracted considerable interest in recent decades. Triazole is a typical functional group with strong ability to coordinate with metals, which has been widely used to form metal complexes, such as tris(benzyltriazolylmethyl)amine (TBTA).7,8 Most triazoles can be straightforwardly prepared through the copper-catalyzed alkyne-azide cycloaddition reaction (CuAAC).9,10 However, synthesis of enantioenriched triazole remains challenging because (1) both alkynes and azides are linear molecules, and the resulting triazole is a sp2-hybridized heterocycle; and (2) no new sp3 center is generated to provide stereogenicity during the formation of triazoles.11,12 Even though several examples have been reported that afford enantioenriched triazoles via desymmetrization or kinetic resolution methods,13,14 few of them have been utilized in constructing chiral poly-triazoles, especially for chiral poly-triazoles functionalized by tertiary amines (chiral poly-triazolyl-methanamines) since amine can provide synergistic coordination functions in mediating various asymmetric transformations. Direct polymerization of enantioenriched monomers and asymmetric kinetic resolution polymerization of racemic monomers are two commonly used methods for constructing chiral polymers.15–23 However, neither of them can efficiently afford chiral poly-triazolyl-methanamines due to the above-mentioned issues. Asymmetric polymerization of achiral or racemic monomers is the most straightforward method for efficiently introducing chiral centers on the backbones of the polymers via repeated asymmetric reactions assisted by chiral catalysts or ligands.24–27 Inspired by some asymmetric transformations reported to successfully construct chiral alkynes,28,29 we wondered whether chiral poly-triazolyl-methanamines could be prepared by a similar approach. In 2008, the Nishibayashi and van Maarseveen’s group,28–31 respectively, reported a Cu-catalyzed asymmetric propargylic substitution reaction using propargylic acetates and amines, obtaining chiral propargylic amines in excellent enantioselectivities (Schemes 1a and 1b). Taking advantage of the terminal alkynyl moieties on side chains, this offered the potential for tandem functionalization toward chiral polymers bearing triazoles. Recently, our group has been engaged in the transition metal-catalyzed AAC reaction32,33 as well as the Cu-catalyzed alkyne-based multicomponent polymerization (MCP).34,35 MCP is a highly efficient polymerization method involving at least three monomers which can easily accomplish the modification during polymerization to provide abundant structures. Herein, we first disclose a Cu-catalyzed multicomponent asymmetric polymerization (MCAP) toward chiral poly-triazolyl-methanamines using p-phenylene-di-tert-butyl propargyl carbonate (p-PDBPC, di-OBoc-alkynes, AK), di-functional amine (primary amine/di-secondary amine, AM), and azide ( AZ) (Scheme 1c). Both primary and di-secondary amines mediated the asymmetric polymerization to afford high molecular weight (Mn) polymers (Mn up to 46,700 g/mol) with controlled chirality. Azide as the third component allowed the formation of polymers bearing triazoles and did not alter the polymers’ chirality. Moreover, the monomer scope of such MCP could be further extended in flexible combinations. Two other successful MCAPs were also developed using p-PDBPC, di-azides and secondary amines, as well as a combination including di-azides, di-secondary amines, and various racemic monofunctionalized OBoc-alkynes. All the MCP proceeded smoothly, giving the polymers with Mn up to 46,700 g/mol. Interestingly, amphiphilic poly-triazolyl-methanamines obtained from water-soluble poly(ethylene glycol) (PEG)-azide served as macromolecular ligands for Cu(I), which formed the nanoparticles (NPs) upon self-assembly in water. Due to their ability to increase the local concentration of substrates, such NPs worked as a nanocatalyst and efficiently catalyzed the CuAAC reaction in aqueous solutions at a Cu(I) loading ratio as low as 10 ppm. Taking advantage of the strong coordination with triazoles and aromatic amines, as well as the protection of the macromolecular formation of NPs, this system efficiently stabilized cuprous compound in the core and prevented undesirable oxidation in air and water. The NPs stored for up to 42 days remained highly efficient and powerful catalysts to promote various transformations at an extremely low Cu(I) loading ratio in trace amounts. More importantly, these novel chiral poly-triazolyl-methanamines could catalyze asymmetric transformations with higher enantioselectivies and better performance than commercially available Py-box ligands. Scheme 1 | Cu-catalyzed asymmetric propargylic substitution reaction (a and b) and four types of Cu-catalyzed MCAP in this work (c). Download figure Download PowerPoint Experimental Methods General procedure of 3-CAP All the polymerizations were performed in the glovebox as mentioned below using AK1, AM1, and AZ1 as a typical example. To a 4 mL-sized vial with a magnetic bar, Cu(CH3CN)4PF6 (1.9 mg, 5 mol %), 2,6-bis((S)-4-phenyl-4,5-dihydrooxazol-2-yl)pyridine ( S-L1, 3.7 mg, 10 mol %), and anhydrous CHCl3 (0.5 mL) were added. The mixture was stirred for 1 h at room temperature (rt), then p-PDBPC AK1 (38.6 mg, 0.1 mmol), di-secondary amine AM1 (21.2 mg, 0.1 mmol), benzyl azide AZ1 (25 μL, 0.2 mmol), and N,N-diisopropylethylamine (DIPEA) (40 μL, 0.24 mmol) in anhydrous CHCl3 (0.5 mL) were added. Then the reaction was kept at rt for 24 h. The product was precipitated using Et2O, then washed with ethylene diamine tetraacetic acid (EDTA) and pure water, and finally collected by centrifugation. The obtained polymer P1 was dried under vacuum and characterized by 1H NMR, 13C NMR, matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF), gel permeation chromatography (GPC), and circular dichroism (CD). Results and Discussion AK1, commercially available N,N′-diphenylethane-1,2-diamine ( AM1), and benzyl azide ( AZ1) were chosen as model monomers to initially optimize the polymerization conditions. AK1 was synthesized from terephthalaldehyde via the Grignard reaction and protection ( Supporting Information Figure S1).36 The model three-component asymmetric polymerization (3-CAP) of AK1, AM1, and AZ1 occurred smoothly to afford the targeting polymer with Mn around 4600 g/mol. The effect of copper (I) catalyst, solvent [CHCl3, tetrahydrofuran (THF), MeOH], polymerization temperature (0–60 °C), and polymerization time (0.5–48 h) were systemically investigated. On the basis of the yields and Mn, all six Cu(I) catalysts, including the organic and inorganic ones, efficiently promoted the polymerization. Cu(CH3CN)4PF6 exhibited the highest Mn of 5400 g/mol ( Supporting Information Table S1, entries 1–6), which was possibly due to the favorable coordination between Cu(I) and ligand 2,6-bis[(S)-4-phenyl-4,5-dihydrooxazol-2-yl]-pyridine ( S -L1). Encouragingly, 2,6-bis[(R)-4-phenyl-4,5-dihydrooxazol-2-yl]-pyridine ( R -L1) with the ligand as the additive also obtained the polymers with similar yields and Mn ( Supporting Information Table S1, entry 7). Bases as the additives were necessary for such polymerization ( Supporting Information Table S1, entry 9). Solvent played an important role, and the results shown in Supporting Information Table S2 indicate that polymerization in THF and MeOH led to lower yields and Mn compared with that in CHCl3. Although polymerization in MeOH resulted in a similar yield with that in THF, the Mn was dramatically decreased, which was due to the precipitation of the oligomers in MeOH when Mn was increased to a certain extent ( Supporting Information Table S2, entry 3). We then evaluated the temperature effect on the polymerization. As shown in Supporting Information Table S3, the yield and Mn of the polymer peaked at rt. Polymerization under low temperature (0 °C) led to an unsatisfactory result, which was mainly caused by the low reactivity. Further increase of the temperature to 40 °C did not improve the yields and Mn. Polymerization under 60 °C resulted in the formation of insoluble products, which was probably due to the undesired side reactions. To monitor the polymerization process, samples were taken from the reaction mixture at the predetermined time intervals, and the Mns were recorded. The Mn quickly increased to 9000 g/mol (absolute Mn was 21,700 g/mol) after the first 24 h and remained almost unchanged with further elongations of the reaction time. Continuously elongating polymerization time obviously did not contribute to the increase of Mn ( Supporting Information Table S4). Ultimately, the polymerization was optimized when processed in CHCl3 at rt for 24 h with Cu(CH3CN)4PF6/ S -L1 as the catalyst and ligand. To demonstrate whether all the monomers contributed to the 3-CAP, P1 was prepared by AK1, AM1, and AZ1 under the optimized conditions. As the control, P1′ was also synthesized by AK1 and AM1 under similar conditions for comparison, and the chemical structures of AK1, AM1, AZ1, P1′ (AK1–AM1), and P1 were characterized by both 1H NMR and 13C NMR. Comparing the 1H NMR spectra of P1′, P1, and AK1, the peak of the tert-butyl group at δ 1.49 ppm corresponding to AK1 completely vanished in the spectra of both P1′ and P1, demonstrating the complete consumption of monomer AK1 and the high conversion rate (Figure 1a). In the 13C NMR spectrum of AK1, the peaks at δ 152.34 ppm, δ 83.32 ppm, and δ 27.75 ppm corresponding to Boc vanished in the spectra of both P1′ and P1, which also supplementarily verified the elimination of the OBoc group (Figure 1b). The appearance of the typical peak at δ 5.48 ppm representing the methylene protons of the benzyl group demonstrated that AZ1 participated in the 3-CAP (Figure 1a). In addition, the peak at δ 6.24 ppm representing the propargyl protons in AK1 slightly shifted downfield in P1 while it shifted upfield in P1′, indicating the successful transformation of alkyne (Figure 1a). Moreover, the integral of aromatic protons increased quantitatively compared with the 2-CAP product, which also proved that azide as the third component had been successfully modified onto the side chains of the polymers (Figure 1a). In 13C NMR of P1, the appearance of the peak at δ 123.36 ppm responded to the carbon from triazole, and the peak at δ 53.96 ppm represented the carbon from the benzyl group (Figure 1b). To further verify the repeating unit of the resulting polymer, the MALDI-TOF spectrum of P1 was obtained, as shown in Figure 1c. The MALDI-TOF analysis also revealed that azide as the third component quantitatively participated in the 3-CAP (Figure 1c). The molecular weight of the repeating unit for P1 was clearly observed as 628 g/mol, which was in accordance with the calculated value. Three different end-groups for P1 were also observed in the MALDI-TOF spectrum. All the evidence confirmed that we have successfully achieved 3-CAP. Figure 1 | (a) 1H NMR spectra of polymer P1 in CDCl3. (b) 13C NMR spectra of polymer P1 in CDCl3. (c) MALDI-TOF spectrum of polymer P1. The peaks of related solvent and water are marked with asterisks. Download figure Download PowerPoint The substrate scope of the 3-CAP was further expanded, and a library of 3-CAP products (20 polymers with diverse structures) were successfully prepared using such strategy (Scheme 2). Seven di-secondary AMs and six primary AMs were selected in combination with seven AZs. Four di-secondary amines, including AM2, AM3, AM4, and AM6, were synthesized and fully characterized with the exception of the commercially available monomers37–39 (Scheme 2 and Supporting Information Figures S2–S5). All the chemical structures of the polymers in the library were characterized by both 1H NMR and 13C NMR ( Supporting Information Figures S6–S44).a Both relative molecular weight and absolute molecular weight information, including the Mn and Đ, are summarized in Table 1. The absolute molecular weights of all the polymers in the library were characterized by GPC using multiangle laser light scattering (MALLS) detectors except for several polymers which cannot be fully dissolved in dimethylformamide (DMF). Scheme 2 | 3-CAP of AK1, various di-functional AMs including di-secondary amines (AM1–AM7) and primary amines (AM8–AM13), and azides (AZ1–AZ7). Download figure Download PowerPoint Table 1 | 3-CAP Results of AK1, Di-functional AMs, and AZsa Entry Polymers Monomers Yield (%) Mnb (MALLS)c Đb (MALLS)c 1 P1d AK1 + AM1 + AZ1 74 9000 (21,700) 1.90 (1.34) 2 P2 AK1 + AM2 + AZ1 60 10,600 (10,400) 1.34 (1.76) 3 P3 AK1 + AM3 + AZ1 68 9000 (21,200) 1.22 (1.57) 4 P4 AK1 + AM4 + AZ1 65 9800 (12,800) 1.38 (1.81) 5 P5f AK1 + AM5 + AZ1 62 8000 1.20 (1.36) 6 P6d AK1 + AM6 + AZ1 68 7400 (15,500) 1.21 (1.73) 7 P7e,d AK1 + AM8 + AZ1 60 8200 1.16 8 P8e,d AK1 + AM9 + AZ1 60 2500 (7700) 1.58 (2.15) 9 P9e,d AK1 + AM10 + AZ1 54 3200 (12,800) 1.77 (2.84) 10 P10e,d AK1 + AM11 + AZ1 32 2900 (17,800) 1.48 (2.13) 11 P11e,d AK1 + AM12 + AZ1 40 3400 (9800) 1.67 (2.47) 12 P12e,d,f AK1 + AM13 + AZ1 23 4100 1.24 13 P13 AK1 + AM3 + AZ2 56 9700 (17,300) 1.29 (1.86) 14 P14f AK1 + AM3 + AZ3 46 13,300 1.77 (1.94) 15 P15 AK1 + AM3 + AZ4 80 9800 (12,200) 1.24 (1.39) 16 P16 AK1 + AM3 + AZ5 79 9500 (12,000) 1.32 (1.63) 17 P17 AK1 + AM3 + AZ6 77 8200 (20,600) 1.19 (1.39) 18 P18 AK1 + AM1 + AZ7 80 17,000 (46,700) 1.63 (1.97) 19 P19 AK1 + AM4 + AZ7 73 13,900 1.40 20 P20 AK1 + AM7 + AZ7 76 14,600 1.57 aConditions: experiments carried out at rt in the glove box for 24 h in the CHCl3 catalyzed by Cu(CH3CN)4PF6. [AK1] = [AM] = 0.1 M, [AZ] = 0.1 M, DIPEA = 0.24 M, Cu(CH3CN)4PF6 = 0.005 M, S-L1 = 0.01 M. bMn and Đ were determined by GPC in DMF with polymethylmethacrylate (PMMA) standards. cAbsolute molecular weights were determined by GPC in DMF using a MALLS detector. d[AK1] = [AM] = 0.1 M, [AZ] = 0.2 M. eReaction in MeOH:CHCl3 = 1:1. fAbsolute molecular weights cannot be accurately calculated due to the limited solubility in DMF. The 3-CAP proceeded smoothly and the polymers could be obtained with suitable yields (up to 80%) and Mn (up to 46,700 g/mol). Both di-secondary AMs and primary AMs efficiently achieved polymerization. And all the polymers had the absolute Mn ranging from 7700 to 46,700 g/mol. Increasing the σ-bond length of aromatic amines did not notably affect the Mn (Table 1, entries 1–4). Aliphatic di-secondary AMs (AM5 and AM7) were also well tolerated, and gave polymers with Mn up to 46,700 g/mol in good yields (Table 1, entry 5 and 20). AM6 with cleavable ketal group responsive to acidic conditions was also tolerated, which obtained the polymer with Mn of 7400 g/mol (Table 1, entry 6). Such polymer ( P6) could be degraded to a small chiral molecule for further quantitative evaluation of the ee value using high-performance liquid chromatography (HPLC). Unfortunately, insoluble products were formed when di-secondary AMs were replaced by primary AMs using the previous polymerization conditions. Such phenomenon was possibly due to the formation of the polymers with higher Mn. Since it has been observed that the solubility was significantly improved by extending the linker of di-secondary AMs, the reduced solubility for the polymers prepared from primary AMs was also attributed to the limited distance between the repeating units. Therefore, MeOH/CHCl3 was selected as the solvent instead of CHCl3 to acquire the polymers with lower Mn. To our delight, the low Mn products afforded in MeOH/CHCl3 were well dissolved in CHCl3, DMSO, and DMF, which allowed them to be further characterized. The results indicated that polymers prepared by primary AMs showed lower Mn compared with those prepared by di-secondary AMs (Table 1, entries 7–12). Then, we investigated a series of azides containing various substituted groups including the electron-donating group (–Me), electron-withdrawing group (–Cl), different σ-bond lengths, and carboxylic groups for postmodification (Table 1, entries 13–17). The results indicated that 3-CAP could tolerate both aromatic and aliphatic azides although the polymers obtained from the aromatic azides exhibited lower Mn due to the steric issues. It was encouraging to find that PEGylated azide also participated in 3-CAP, affording water-soluble polymers ( P18– P20) with absolute Mn up to 46,700 g/mol (Table 1, entries 18–20). Such polymers self-d into NPs in aqueous solutions, which acted as macromolecular ligands for further applications. To evaluate the stereochemistry and the chirality of the resulting polymers, R -P4′, S -P4′, and TBTA-P4′ were prepared as the model polymers using AK1 and AM4 catalyzed by chiral or achiral ligands ( S -L1, R -L1, and TBTA), respectively (Figure 2a). As shown in Figure 2b, R -P4′ exhibited an obvious positive peak in the CD spectrum ranging from 275 to 335 nm while S -P4′ showed approximate amplitude with the opposite signal compared with R -P4′, demonstrating that the chirality of the ligand played a crucial role in mediating the asymmetric polymerization. There was no CD signal for TBTA-P4′ synthesized using the achiral ligand, which also complementarily verified the decisive effect of chiral ligands. The obviously positive CD signal of R -P4′ in the region of 275–335 nm was found in all concentrations tested, and the amplitude was concentration-dependent ( Supporting Information Figure S89). The CD spectra of R -P4′ synthesized under various solvents were also collected, and the results in Supporting Information Figure S90 clearly prove that both THF and MeOH decrease the chirality of the polymer. To investigate whether the positive CD signal originated from the chiral propargylic amine or the potential secondary structure (for example, the helical structure), R -P4′ with different Mns were prepared for CD analysis. The results in Supporting Information Figure S91 reveal that there was no dramatic difference for the CD signal of R -P4′ with different Mns, indicating that the positive signal was mainly derived from the chiral centers on the polymers. Moreover, significant differences in propargylic carbon signals and aromatic carbon signals between chiral and racemic polymers were also observed clearly via 13C NMR spectra. Double-equal-peaks for both the aromatic carbons (116.5 ppm) and propargylic carbons (56.5 ppm) were detected for TBTA-P4′ prepared using TBTA ligands, whereas the chiral R -P4′ prepared using S -L1 exhibited obvious integration variation for the double-peak (Figure 2c). To demonstrate the universality in developing chiral polymers, all the polymers in Table 1 were characterized using CD, and the results indicate that all the polymers prepared using S -L1 exhibited similar positive signals ranging from 275 to 335 nm ( Supporting Information Figures S92 and S93) except P5 and P20. To quantitatively evaluate the enantioselectivities of polymers and investigate whether the introduction of the third component alters the chirality of the polymers, an acid-labile di-secondary AM was used to prepare two degradable polymers, P6′ and P6 (Figures 2d and 2e). Consistent with previous results, CD signals of P6′ (Figure 2f) and P6 (Figure 2g), as well as the 13C NMR spectra of P6′ (Figure 2h) convinced us of their chiral structures. Then both P6′ and P6 were degraded into small molecules, 1 and 2, respectively. Their chemical structures were fully characterized by 1H NMR ( Supporting Information Figures S66 and S68). To evaluate their ee values, their racemic small molecules were also synthesized and characterized ( Supporting Information Figures S65 and S67), and the ee values of the degraded products were determined to be 71% and 77% by HPLC, indicating that this method definitely afforded chiral polymers and that azide does not influence the enantioselectivity of the polymers ( Supporting Information Figures S96–S101). Figure 2 | (a) Structure of P4′ obtained by two-component asymmetric polymerization of AK1 and AM4. (b) CD and UV–vis absorption spectra of P4′ with different ligands. (c) 13C NMR spectra of P4′ prepared using S-L1 and TBTA as the ligands. (d) Synthetic route of acid-labile P6′ and the ee value of the degradation product upon acid treatment. (e) Synthetic route of acid-labile P6 and the ee value of the degradation product upon acid treatment. (f) CD and UV–vis absorption spectra of P6′. (g) CD and UV–vis absorption spectra of P6. (h) 13C NMR spectra of P6′ prepared using S-L1 and TBTA as the ligand. Download figure Download PowerPoint In consideration of the 3-CAP involved in both the asymmetric propargylic amination of propargylic esters and the AAC reaction, it was important to explore the relationship of the two reactions and the possible underlying mechanism since both were catalyzed by Cu(I). On the basis of the possible mechanism proposed by Nishibayashi,28,30,31 the propargylic amination initially underwent through the Cu-allenylidene intermediate, which was important for constructing the chiral center. However, CuAAC could also occur rapidly under similar conditions. To investigate the specific sequence of asymmetric propargylic amination and the AAC reaction, a series of control experiments were performed. First, monofunctional tert-butyl (1-phenylprop-2-yn-1-yl) carbonate AK2 was prepared and reacted with N-ethylaniline AM15 under standard conditions for 12 h, followed by the addition of AZ1 for stirring another 12 h. Product 3 was successfully isolated in 85% yield (Figure 3a and Supporting Information Figures S63 and S64). Next, AK2, AM15, and AZ1 were simultaneously added to the reaction system, and product 3 was also acquired with 82% yield. However, if AK2 initially reacted with AZ1 for 12 h, it was surprising to observe trace targeting product. It seemed unusual because CuAAC as an important reaction for click chemistry has the advantage of a high reaction rate. Such phenomenon could possibly be attributed to the different coordination abilities of OBoc-alkyne and N-alkyne with Cu(I) caused by the electronic and steric hindrance effect ( Supporting Information Figure S110). Therefore, the sequence of the reaction seemed clear, that propargylic amination occurred before CuAAC in this 3-CAP system. It was accidentally beneficial to the 3-CAP that the monomer AK1 was unfavorable for the CuAAC reaction. This was due to the fact that the OBoc-alkyne was efficiently involved in asymmetric polymerization and generated a new chiral substrate N-alkyne bearing propargylic amine, which became favorable for the further CuAAC modification. As revealed in the analysis of the polymer composition using 1H NMR spectra, the main chain polymerization and side chain modification almost simultaneously occurred owing to the high reactivity of the CuAAC reaction . As shown in Figure 3b, the composition of the polymers kept unchanged and quantitative to the feeding ratio at all the time intervals, indicating that all three components successfully participated in the reaction simultaneously. Even in the sample taken at 0.1 h, there was no peak between δ 2.00 ppm and δ 3.00 ppm on the 1H NMR spectrum, proving that all the alkynyl groups had already been rapidly converted to triazoles. Moreover, the low Mn obtained from the aromatic azides further verified it. If the chain polymerization occurred first, such low Mn polymer would be impossible to obtain. The influence of AZ1’s feeding ratio was also investigated ( Supporting Information Figure S70), and the results indicated that azide as the third component was quantitatively attached onto the side chains. The proposed polymerization mechanism and sequence are shown in Figure 3c and Supporting Information Figure S111. Figure 3 | (a) Sequential study of small molecule reactions. (b) 1H NMR spectra of P1 at different time intervals. (c) Schematic diagram of polymerization sequence. Download figure Download PowerPoint MCP is advantageous to the structural diversity of polymers. To construct versatile polymer libraries, another two types of MCP were also developed based on the above-mentioned discovery. First, 3-CAP of AK1, di-azides ( AZ8), and various secondary amines ( AM14–AM17) was performed to afford P21–P24 with excellent yields and Mns (Mn up to 37,700 g/mol) (Scheme 3a, Table 2, entries 1–4). Considering the solubility issues, di-azides bearing ether groups were selected as the monomers. As it has been demonstrated that OBoc-alkyne in AK1, does not react with azide due to the inactivated coordination ability with Cu(I) under standard conditions, it was understandable that no polymerization occurred without the addition of amines as the third component. Upon the addition of secondary amines, the propargylic amination with AK1 was quickly achieved to