Diversity-Oriented Synthesis of Functional Polymers with Multisubstituted Small Heterocycles by Facile Stereoselective Multicomponent Polymerizations

Multicomponent polymerization (MCP) has received world-wide attention as a powerful synthetic strategy toward various polymers with complex structures. However, few studies have been reported to fully utilize the monomer combination diversity of MCPs to facilitate the synthesis of diversified polymers with novel structures and advanced functionalities. Herein, we reported a facile multicomponent polymerization route based on the diversity-oriented synthesis. Using varying combinations of difunctionalizable alkynes, sulfonyl azides and Schiff bases, diverse functional polymers with multisubstituted small heterocycles were successfully produced. High stereoselectivity was observed on specific polymeric products. The obtained azetidine-derivative heterocycles exhibit high stability even after treatment with extra HCl and KOH for 48 h. Additionally, polymers with tetraphenylethylene moieties show strong aggregationinduced emission and can function as promising chemosensors for detecting Pd and Cr2O7 . The facile MCP routes present could bring new inspiration to polymer chemistry, and the fascinating functionalities of the obtained polymers with stable four-membered heterocycles could promote further research on the design, modification, and applications of diversified functional polymer materials.


Introduction
It is well-known that subtle difference in microscopic structure can result in dramatically different macroscopic performance. 1 For example, it is the different composition and sequence of base pairs in DNA molecules that contribute to such a complex and diverse biosphere. 2 In materials science, it is of vital importance to design and finely tune the structures at the molecular level to obtain materials with specific functions, and the development of novel polymerization routes is a significant means to achieve such fine tuning of the polymer structures. 3 For example, living free radical polymerization can effectively control the molecular weight of the polymer by adjusting the connection site to obtain the target product with corresponding performance. 4 In the meantime, multicomponent polymerization: with multiple chemical bonds formed in a highly concise fashion, has emerged as a powerful structure tuning strategy. 5 Multicomponent polymerization (MCP), in which three or more monomers are involved in a one-pot polymeric procedure can be classified as one-step MCP and multi-step MCP. 6 The onestep polymerization enjoys great synthetic simplicity, in which all the monomers and catalysts are added in one-step and reacted within the same period. Representative examples include the onestep Passerini polymerization of aldehyde, carboxylic and isonitrile; 7,8 the A 3 -coupling polymerization of alkynes, aldehydes, and amines; 9 the Biginelli polymerization of aryl aldehyde, β-keto ester, and urea (thiourea); 10,11 and the Cu-catalyzed MCP of alkynes, sulfonyl azides with various nucleophiles. [12][13][14][15][16] On the other hand, the multi-step MCP is also known as multicomponent tandem (or cascade) polymerization, in which different monomers and catalysts are added in multisteps and reacted in a sequential period. 17 Representative examples are Sonogashira polycouplings of alkynes and carbonyl chlorides, followed by a subsequent reaction with nucleophiles such as thiols, 18,19 amines 20,21 , amino ester salts 22 and indoline derivatives. 23 Multicomponent 4 polymerization integrates numerous advantages such as high efficiency, mild conditions, atom economy and facile construction of complex structure in-situ. A unique and outstanding characteristic of MCP is the product diversity. 24 Firstly, diverse monomers with different structures contribute to versatile products. For example, Choi et al. reported a diversity-oriented polymerization towards 54 samples of graft and dendronized products by polymerizing diverse mono-alkynes, bis-sulfonyl azides and diamines. 12 Secondly, multiple combinations of monofunctional and bifunctional monomers produce polymers with totally different backbone structures. For instance, a three-component polymerization can be theoretically combined in three different ways, namely "A2 + B2 + C1", "A2 + B1 + C2" and "A1 + B2 + C2" (Scheme 1b), potentially affording diverse products with novel structures and functionalities. Few studies have been reported to fully utilize this combination diversity advantage of MCP.
Heterocyclic polymers were first introduced in 1960s to fulfill the requirement of high thermal stability of aerospace materials. They have gradually received consistent academic and industrial interest for their outstanding thermomechanical, dielectric and optical properties. 25 Among various functional polymers, those with small heterocycles such as three-or four-membered heterocyclic polymers are indispensable in organic synthetic chemistry, due to their unique ring-strained structures and distinguished properties such as clusteroluminescence and special stimuliresponsiveness. 26 While our group has widely reported that the preparation of five-membered or six-membered heterocyclic polymers, 19,[27][28][29][30] those with small heterocycles are rarely studied in our previous work. Firstly, the costly reactants and the difficulty in incorporation of multi-substituents lead to large synthetic challenges. Secondly, the small rings often show low stability where their ring-opening reactions will result in polymer decomposition. 31 Tang et al. reported an in-situ synthesis of 4-membered heterocyclic polymers via multicomponent polymerization. 24 However, the polymer backbones are vulnerable and easily experience acid hydrolysis. Meanwhile, one of the monomer components in this polymerization cannot be developed into bifunctional molecule, which fails to fully utilize the combination diversity of MCP.
Attracted by the unique properties of polymers with small heterocycles and inspired by the advantages of MCP, we aim to utilize MCP for facile construction of diverse 4-membered heterocyclic polymers. With this purpose, a three-component reaction of alkynes, sulfonyl azides and Schiff bases towards azetidine derivatives has drawn our attention (Scheme 1a). 32 The reaction proceeds efficiently at room temperature with high atom economy in high yields. It is also worth noting that all the third components can be developed into a variety of bifunctional monomers.
Based on this reaction, we successfully developed a facile access to functional polymers with multisubstituted four-membered heterocycles. Distinct from the previous work, all the monomers including alkynes, sulfonyl azides and Schiff bases are respectively bifunctionalized, with which all the possible monomer combination ways ("A2 + B2 + C1", "A2 + B1 + C2" and "A1 + B2 + C2") are successfully realized (Scheme 1b). This enables the polymer chain to extend in all possible directions which greatly enhances the product diversity. All polymerizations perform efficiently under mild conditions with good tolerance to different functional groups. The resulting polymers exhibit distinguished properties such as high chemical stability after acid and base treatment, and stereoselectivity was observed on specific polymeric products. Furthermore, they show typical aggregation-induced emission characteristics and can function as a promising fluorescent chemosensor in response to Pd 2+ and Cr2O7 2-. The feasible and diverse MCP strategy used in this work will provide useful guidance to future research constructing and expanding functionalized small-membered heterocyclic polymers.

Polymerization
All the monomers used in this work are easily accessible. The diyne 1a, disulfonyl azide 2a-d and Schiff base 3b-e were respectively prepared following the literature procedures. 33,34 All the polymerizations proceeded in one-pot in the presence of triethylamine (Et3N) and copper iodide (CuI) at ambient temperature under nitrogen atmosphere. The impacts of reaction parameters including the solvent, catalyst, base, and monomer concentration were systematically investigated, which aimed at generating soluble polymers with high molecular weights in high yields.
Taking the polymerization of 1a, 2a and 3a as an example (Scheme 1), the effect of solvent was first examined (Table S1, entry 1-5). Among all the tested organic solvents, the polymerization in dichloromethane (DCM) afforded the polymer with the highest molecular weight (Mw = 11500) in a relatively high yield of 62%. Regarding the catalyst loading (Table S1, entry 5-6), the use of the copper oxide (Cu2O) led to a dramatic decrease in both yield and molecular weight, thus CuI was chosen as the preferred catalyst. Next, the base effect on the polymerization ( Table 1, entry 1-7) was examined, which plays a crucial part as the small molecule synthesis reported in the literature. 32 The common organic bases including pyridine, 2,6-lutidine and Et3N all gave the desired polymeric products with expected structures, among which Et3N afforded the polymer with the highest molecular weight (Mw) of 11500. The effect of Et3N concentration on the polymerization was then examined (Table 1,   Based on the optimized conditions, we then expanded the monomer scope of the polymerization in the combination mode of "A2 + B2 + C1" first to enrich the structural diversity (Scheme 3a). Various disulfonyl azides and Schiff bases were utilized in the polymerizations with the TPE-containing diyne to generate polymers in good yields of up to 93% and high Mws of up to 19100 (Scheme 3b). Sulfonyl azide 2b and 2c with a rigid structure were also applicable for the polymerization, generating products with Mws up to 15900 in good yields. When monomer 2d carrying a flexible alkyl chain was used, the resulting polymer P1a/2d/3a was generated in a high yield of 87% with high molecular weight of 19100. Regarding the monomer scope of Schiff bases, monomer 3b bearing terminal electro-donating groups was efficient for the polymerization affording the expected polymeric product in a high yield of 86%. Monomer 3c carrying a bulky tert-butyl group was also applicable and effective for the polymerization, yielding a product with a Mw of 30900 in a high yield of 93%. When Schiff base 3d carrying a halogen atom (Br) was employed, the desired polymer was obtained with a Mw of 19000 in a good yield. However, monomer 3e carrying an iodine atom generated a polymer P1a/2a/3e with a decreased Mw due to its poorer solubility. Inspired by the success in expanding the monomer scope in the combination mode of "A2 + B2 + C1", we then explored the expanding possibility of other two combinations modes, "A2 + B1 + C2" and "A1 + B2 + C2" (Scheme 4). Delightfully, all polymerizations generated the expected azetidine derivative rings along the polymer backbones. However, compared with the forementioned combination mode "A2 + B2 + C1", these two combination modes give polymers in lower yield and molecular weights. Some unidentified structures were also found in P1b/2a/3f and P1b/2a/3h. These results can be explained as follows: (1) the decreased solubility of bifunctional Schiff bases decreases the efficiency of the polymerization; (2) according to the mechanism reported by previous literature, 32 these reactions follow the pathway that the alkyne group first 13 reacts with sulfonyl azide to form an intermediate, which further reacts with the imine bonds of Schiff base to yield the 4-membered heterocycles. The two monomer combination modes ("A2 + B1 + C2" and "A1 + B2 + C2") shown in Scheme 4 suffer relatively higher steric hindrance that is detrimental to the chain propagation of the polymerizations. Yet they are still effective means to broaden the polymerization applicability. The results shown in Scheme 3 and 4 together demonstrate that this MCP tool has a great tolerance to different functional groups, and has fully utilized the monomer diversity and combination diversity to provide a facile access to diverse polymers with multisubstituted small heterocycles.

Structural Characterization
To get an insight into the structures of the obtained polymers, a model compound was synthesized from phenylacetylene, 4-methylbenzenesulfonyl azide and N-benzylideneaniline.
Consistent with the reported literature, 32 it was found that both cis (cis-M) and trans (trans-M) isomers were produced and their structures were fully characterized by high-resolution mass spectrometry ( Figure S1 and S2), IR specctroscopy ( Figure S3), NMR techniques (Figure 1 and 2) and single crystal X-ray diffraction (Figure 1d and Table S2). The structures of all the obtained polymers were also confirmed by the above-mentioned methods.
The characterization results of P1a/2a/3a were compared with the model compounds (trans-M and cis-M) and the corresponding monomers, which was discussed as an example. As shown in the IR spectrum provided in Figure S3, the ≡C-H and C≡C stretching vibration of 1a were observed at 3271 and 2104 cm -1 respectively, while the stretching vibration bands of N3 of monomer 2a were found at 2128 and 2160 cm -1 . All these characteristic peaks disappeared in both the model compounds and P1a/2a/3a, suggesting the complete consumption of C≡C and N3 groups during the polymerization. 1 H NMR analysis was conducted to obtain more detailed information of the polymer structure.
As shown in Figure 1, the acetylene proton of 1a resonated at δ 3.03, which disappeared in both model compounds and P1a/2a/3a. The resonance peak in "d" position of monomer 3a at δ 7.92 shifted to the broad peak in aromatic zone in the spectrum of P1a/2a/3a. The peak in "c" position at δ 8.47 shifted to δ 5.07 with the formation of a new peak at δ 4.58 in the spectrum of P1a/2a/3a.
Compared with trans-M, these two peaks can be respectively assigned as the protons of P1a/2a/3a in "e" and "f" position, suggesting the formation of the 4-membered heterocycle. 13   P1a/2d/3a in chloroform-d. The solvent peaks were marked with asterisks.
As previously described, stereoisomerisms were generated during the model reaction, which is consistent with the reported literature. 32 The configuration of the trans model compound (trans-M) was verified by the single crystal X-ray diffraction (Figure 1d and Table S2). Analysis by 1 (1) and (3) and are all repeatable. The stereoselectivity of all the polymers are labelled in Scheme 3b and Scheme 4. The factors contributing to stereoselectivity are complex and may work collectively, such as the steric hindrance, electron density and tension force of the small heterocycle. 36 As shown in Scheme 3b, all the stereoselective polymerization (P1a/2d/3a, P1a/2a/3b, P1a/2a/3d and P1a/2a/3e) in the monomer combination mode "A2 + B2 + C1" shared a common characteristic: all of them used sulfonyl azide with a flexible chain (2a or 2d). When this monomer was replaced with a rigid chain (2b or 2c), the regioselectivity in the resulting polymers P1a/2b/3a and P1a/2c/3a became poorer. Only one exception was observed in P1a/2a/3c, which used flexible azide as monomer however showed no regioselectivity. Also, the regioselectivity is not observed in polymers prepared by using monomer combination modes of "A2 + B1 + C2" and "A1 + B2 + C2". The exact reason for this phenomenon remains unclear at present and will be explored in the near future work.

Stability and Solubility
Thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) measurement were conducted to investigate the thermal and morphological stability of the obtained polymers. Figure S7 illustrates the thermal degradation process of the polymers after heating at a rate of 10 °C/min. All the polymers lost 5% of their weight at 181-268 ℃. No glass transition temperatures were detected in their DSC thermograms ( Figure S8), possibly ascribed to their rigid structures. 37 All the polymers possessed fairly good solubility, and can be dissolved in common organic solvents, such as dichloromethane, chloroform, dimethyl sulfoxide, and tetrahydrofuran.  20 We then tested the chemical stability of the polymers under acidic and basic conditions. It is well-known that the 4-membered heterocycles are vulnerable under extreme pH environment, undergoing ring-opening reactions. 38 To our surprise, both the model compounds and P1a/2a/3a showed no structure change after stirring in excess amount of HCl (25 equiv.) and KOH (25 equiv.) in water/THF mixture for 48 h. Notably, there is a distinctive reactivity difference of the heterocycle obtained in this work compared with the 4-membered azetidine structure we reported before, 24 which experienced a fast acid-mediated ring-opening reaction. To get an insight into this structure-reactivity relationship, DFT calculations on the model compounds of these two works were conducted following the reported literatures. [39][40][41][42][43][44] The results of the calculated condensed Fukui function and condensed dual descriptor (CDD) of M1 (stable ring, this work) and M2 (unstable ring, previous work) were summarized in Table 2. From the condensed Fukui function, the fof M2 (0.0855)was distinctively larger than that of M1 (0.0670), indicating the larger electron density of the 4-membered ring in M2 to experience acidic ring-opening reaction. The same conclusion can be drawn from the calculated condensed dual descriptor (CDD). The CDD of M2 (-0.0421) was smaller than that of M1 (-0.0332) which demonstrated the less nucleophilicity of the latter one. The cause of the electron density difference can be further understood by the analysis of the molecular structure. In M2, the nitrogen atom of the 4-membered ring is sp 3 hybridized. Thus, the lone pair electrons possessed higher electron density to give rise to stronger nucleophilicity. In M1, the nitrogen atom is conjugated with aromatic substituent and is sp 2 hybridized, thus with lower electron density in the heterocycle showing lower nucleophilicity.
Herein, the experimental data, theoretical calculation and structure analysis are in perfect agreement. To conclude, the stability difference is attributed to the electron density difference of the 4-membered heterocycle, resulting from the different substituents on the heterocycle. Such 21 investigation can serve as a useful strategy to optimize the small ring stability by adjusting the ring electron density.

Photophysical Properties
Aggregation formation is a well-known natural process causing fluorescence quenching in traditional fluorophores, which therefore became a stumbling block for their practical applications. 45 Our group firstly reported an opposite phenomenon in 2001 called aggregationinduced emission (AIE). AIE luminogens are faintly emissive in solutions but show intense emission enhancement upon aggregation formation. 46 Since TPE is a representative AIE-active moiety, 47 the polymers obtained in this work are anticipated to be AIE-active. Thus, their photophysical properties are systematically investigated.
The absorption spectra of the polymers in dilute (10 -5 M) THF solutions were shown in Figure   S9. All the spectra were peaked at similar wavelengths (~330 nm). Then their photoluminescence (PL) in THF/water mixtures with different water fractions (fw) was studied. The PL spectra of P1a/2a/3a are given in Figure 4 as an example. When fw was lower than 40%, no obvious emission was observed. Afterwards, a noticeable signal was detected due to the aggregate formation. The PL intensity kept rising upon addition of more water and reached its maximum at the fw of 80% at 475 nm, which was 22-fold higher than that in pure THF solution ( Figure 4B). The PL intensity then slightly decreased with the further addition of water. This is commonly observed in PL spectra of AIE polymers due to the formation of large-sized aggregate at high water content, which decrease the effective concentration of polymer mixtures. 48 The PL behavior of P1a/2a/3a in THF/water mixtures with different fw could be directly visualized. Together with the PL spectra of other TPE-bearing polymers ( Figure S10), it clearly demonstrated the AIE feature of the obtained polymers. The active intramolecular motions of the TPE unit is restricted in the aggregate state, which blocks the nonradiative decay pathway of the excited state to enable the polymers to show intense emission. 49

Ion Detection
Palladium and chromium are common heavy metal elements with potential health hazards.
Palladium, which is widely used as the catalyst in organic synthesis, its divalent residue in low dose is sufficient to cause deterioration in optoelectronic devices or allergic reactions in susceptible individuals. 17,50 Chromium, especially in its hexavalent state (Cr (VI)), is carcinogen with strong oxidizing ability, exposure to which leads to not only potential irritation, but the risk of severe mutagenic and cell damage. 51 To make matters even worse, these heavy metals can move up the food chain in progressively greater concentrations by biological magnification. 52 The detection of divalent palladium and hexavalent chromium are therefore of vital importance. As P1a/2a/3a is an AIE macromolecule with merits of high reliability, sensitivity, and selectivity, 53 we investigated its potential application in ion detection. To our surprise, it exhibits good response as a bifunctional probe towards the detection of these two ions.
The PL spectra of P1a/2a/3a (10 μM) in 80% aqueous mixtures (fw = 80%) with different concentrations of palladium ion (Pd 2+ ) were shown in Figure 5a. By increasing the Pd 2+ concentration from 0 to 0.84 mM, the spectra profile remained unchanged, but a distinct and progressive PL intensity decrease was observed. More details on the quenching process were provided in the Stern-Volmer plot shown in Figure 5b. 54 The quenching constants calculated from the linear region increased sequentially from 8330 M -1 to 24150 M -1 and then 107140 M -1 , showing a super amplification quenching effect. 55 The limit of detection (LOD) was calculated according to the equation LOD = 3SB/m (SB = the standard deviation of the repeated 8 blank measurements, and m = the slope of the relative intensity over Pd 2+ concentration), and was equal to 8.5×10 -6 M, indicative of good sensitivity. 56 Then the selectivity of P1a/2a/3a as Pd 2+ sensor was investigated.
P1a/2a/3a also served as a potential bifunctional anion probe. As shown in Figure 5d, a PL quenching response was observed upon addition of potassium dichromate to its 80% aqueous mixture. A similar quenching amplification effect was found, where the quenching constants raised Considering applications in daily life, the in-situ detection working on the solid support requires no sophisticated equipment, with higher efficiency and lower cost than the "wet" detection. 57,58 In view of this, we tested whether this bifunctional ion probe can be applied in the solid state. By can be clearly visualized by naked eyes to identify the tested ion. Another "solid" measurement was performed by adsorbing P1a/2a/3a onto a filter paper. Cr2O7 2solution was then used as "ink" to draw on the filter paper by a glass tube. A "Swan" graph could be clearly identified under UV light owing to the quenching effect (Figure 5j). The same operation worked successfully when replacing "Cr2O7 2-" with Pd 2+ . Both experiments demonstrated the high feasibility of using AIEactive P1a/2a/3a as bifunctional probe for daily detection.

25
We then investigated the quenching mechanism for this AIE ion probe. Due to the absorption similarity of the Cr2O7 2and Pd 2+ , we compared their electronic transitions with other common metal ion, especially chromogenic ions such as Fe 3+ , Co 2+ , Cr 3+ and Cu 2+ . As shown in Figure S11, the molar absorptivity of Pd 2+ , Cr2O7 2and Fe 3+ ions were higher than other tested ions. Meanwhile the absorption of Cr2O7 2and Pd 2+ was largely overlapped with the PL spectra of P1a/2a/3a (within 410-530 nm and 410-620 nm), which led to the energy transfer from the excited state of P1a/2a/3a to the ground state of these two ions to result in the emission quenching. 59 It is worth noting that the absorption spectrum of Fe 3+ also overlaps with the PL spectrum of the polymer but in a much smaller extent, and the Fe 3+ solution has less molar absorptivity within this wavelength range. This led to the less efficient energy transfer and much weaker PL quenching. was drawn on a filter paper by a glass tube using the Cr2O7 2solution as the "ink".

Conclusions
In this work, we developed a facile access to diverse functional polymers with multisubstituted small heterocycles by multicomponent polymerizations. This strategy enjoys the advantages of readily available monomers, mild conditions, outstanding efficiency, and good tolerance to different functional groups. Based on the readily bifunctionalized alkynes, sulfonyl azides and Schiff bases, possible monomer combination ways are fully achieved to realize the diversity of multicomponent polymerization. The tolerance of 4-membered heterocycles to acid and base was improved by optimizing the ring electron density and confirmed by DFT calculation. The obtained polymers possessed distinguished properties such as good stability and stereoselectivity. The AIE characteristics inherited from the TPE moieties enabled the polymers to serve as potential bifunctional chemosensor for Pd 2+ and Cr2O7 2detection. Simple prototype devices using P1a/2a/3a on solid support for daily detection was explored. In all, the feasible strategy used in this work will promote further research on multicomponent polymerization to construct and expand the small-membered heterocyclic polymers. It provides a useful guidance to manipulate the properties and functionalities of materials by appropriate structure design.

Notes
The authors declare no competing financial interest.