Introduction

Block copolymers play an important role in polymer science due to their unique self-assembly behavior, which is rarely achieved by random copolymers and homopolymers1,2. Block copolymers can form materials with various morphologies such as vesicles, micelles, sheets, with sizes precisely controlled from a few nanometers to several micrometers3,4,5. They are significant in many fields, including biomedical materials, advanced plastic and energy materials4,6,7,8. However, despite the potential of many molecular architectures, only a few block copolymers have been developed into commercial materials as traditional approaches usually involve high-cost multi-step synthesis. Therefore, the development of concise synthetic methodologies for block copolymer is of great significance in the field of polymeric science9,10,11,12,13,14.

Recently, the one-pot/one-step synthesis of block copolymers using bifunctional initiators and the chemoselective copolymerization of two and more monomers using switchable catalysts have been used to perform two different types of polymerization reactions simultaneously on the same polymer chain11,15,16,17,18. Such methods promise a highly cost-efficient block copolymer fabrication and promising application opportunities. However, the monomers that are compatible with such polymerization mechanisms and do not interfere with each other are very limited19,20. Typical examples include cyclic ester/vinyl monomers that undergo orthogonal mechanisms of ring-opening polymerization and radical polymerization, and the combination of epoxides, cyclic anhydrides and cyclic esters that follow an anionic ring-opening pathway9,19,21,22,23,24,25,26. Cationic polymerization and anionic polymerization have been widely applied in industrial practice for the synthesis of various types of commercial polymers such as polyamides, polyethyleneimines, polyesters, and polyethers2,27,28,29,30,31. However, as cationic and anionic propagating species could easily undergo coupling reactions, which leads to chain termination, it has been a great challenge for these two polymerization pathways to occur simultaneously in one-pot for the preparation of block copolymers19. Therefore, the development of a one-pot/one-step copolymerization methods, where one monomer can be polymerized by anionic polymerization and the other by cationic polymerization, is of great importance.

2-Oxazoline (Ox) and cyclic ester (CE) are monomers that are typically used in cationic and anionic polymerization reactions, respectively31,32,33,34,35. Poly(2-oxazoline)-block-polyester (POx-b-PCE) block copolymers composed of these two monomers, have excellent biocompatibility, biodegradability, as well as assembly capabilities27,35,36. It is expected to be widely used in nanotechnology, biomedicine, energy, and other fields37,38. However, the synthesis of POx-b-PCE block copolymers typically requires a tedious process including the cationic ring-opening polymerization (CROP) of Ox, followed by terminal modification and the anionic ring-opening polymerization (AROP) of CE (Fig. 1A)27,37,38. It is attributed to the fact that the polymerization of 2-oxazolines and cyclic esters follows two distinct ring-opening mechanisms. The polymerization of 2-oxazolines proceeds via cationic ring-opening polymerization (CROP), where chain propagation occurs through a nucleophilic reaction of the 2-oxazoline monomer with the initiator or the growing chain end. The polymerization of cyclic esters catalyzed by metals usually follows a coordination-insertion mechanism. However, it is important to clarify that, while the coordination-insertion mechanism differs from anionic ring-opening polymerization (AROP), they share a key similarity in the critical step of nucleophilic attack. In both mechanisms, the driving force for ring-opening is the nucleophilic attack of an alkoxide species on the carbonyl group of the cyclic ester monomer, which initiates the polymerization process. Therefore, the term, cationic-anionic polymerization (CAP), is carefully selected to describe this unique one-pot polymerization system, where both cationic and anionic mechanisms coexist and proceed simultaneously.

Fig. 1: Synthetic process of POx-b-PCE block copolymer.
figure 1

A Traditional synthetic strategy that uses a multi-step process. B A polymerization method that cationic ring-opening polymerization of Ox and anionic ring-opening polymerization of CE are performed simultaneously on both ends of the same chain. There is a dynamic equilibrium between high-ionic active species and low-ionic dormant species at the propagation ends, which can effectively suppress the coupling of anionic and cationic propagation ends.

The tendency of chain-end coupling reactions between cationic and anionic propagation ends is the key issue that prevents the realization of synchronous cationic-anionic polymerization (CAP). It may be solved by a propagating species with dedicated structures. In a controlled polymerization such as atom transfer radical polymerization (ATRP), there is a dynamic equilibrium between dormant and active species at the propagation chain-end39,40,41. This dynamic equilibrium reduces the concentration of active species in the reaction system, thereby inhibiting chain termination and chain transfer reactions, ultimately achieving controlled polymer growth. Therefore, it is hypothesized that synchronous cationic and anionic polymerizations can be achieved through a similar dynamic dormancy mechanism.

Herein, we propose a cationic-anionic polymerization (CAP) method (Fig. 1B). Ox was selected as the cationic polymerization monomer and CE was selected as the anionic polymerization monomer due to the rich species and a wide range of applications of these two monomers. In CAP, the polymerizations of Ox and CE are initiated by a cascade initiation that 2-oxazoline is first initiated by bismuth salt to generate polyoxazoline with N-Bi chain end, which then initiates the polymerization of the cyclic ester. Afterwards, the ‘dormant’ mechanism ensures the successful cationic ring-opening polymerization (CROP) of Ox and anionic ring-opening polymerization (AROP) of CE simultaneously at both polymer chain ends. It enables the one-pot/one-step synthesis of polyoxazoline-block-polyester block copolymers.

Results

Cationic-anionic polymerization (CAP) of MOZ and CL

The ring-opening of 2-oxazoline is a nucleophilic reaction of the 2-oxazoline monomer to the initiator/growing end, while the ring-opening of the cyclic ester is an electrophilic reaction of the cyclic ester monomer to the initiator/growing end. Therefore, the CROP of 2-oxazolines and the AROP of cyclic esters are difficult to perform simultaneously in one-pot with a single initiator. Thus, the in situ generation of an initiator having both cationic and anionic propagation sites is a prerequisite for realizing the cationic-anionic synchronous polymerization of 2-oxazolines and cyclic esters. The CROP of 2-oxazolines can be initiated by electrophilic reagents such as methyl trifluoromethanesulfonate (TfOMe) and halogenated hydrocarbons (R − X, R = CnHm, X = Cl, Br, I), but the resulting poly(2-oxazoline)s usually have a cationic propagating chain end that cannot initiate the synchronous AROP of cyclic esters (Fig. S1a)35,36,42,43,44. Lewis acids such as bismuth chloride (BiCl3) can also initiate the CROP of 2-oxazolines45, and it is assumed that the N−Bi bond formed by the ring-opening of the first 2-oxazoline monomer with bismuth salt can initiate the AROP of cyclic esters (Fig. S1b).

To confirm the possibility of synchronous CAP using BiCl3 as an initiator, a copolymerization of 2-methyl-2-oxazoline (MOZ) and ε-caprolactone (CL) monomer mixture {[MOZ]0: [CL]0: [BiCl3]0 = 50: 50: 1} was performed at 100 °C in DMAc for 24 h, 1H NMR confirmed that the conversion of MOZ and CL were ~99.9% and 31.4% (entry 6 in Table 1). The 1H-13C HSQC (heteronuclear singular quantum correlation) NMR was conducted to confirm the formation of PMOZ block, PCL block and the junction unit (Fig. S2), respectively. The C3-H3 coupling located at [2.0 ppm (1H), 21.7 ppm (13C)] is due to PMOZ block, while the C6,11-H6,11 and C10-H10 couplings at [2.3 ppm (1H), 34.2 ppm (13C)] and [4.0 ppm (1H), 62.7 ppm (13C)] could be attributed to PCL block. The junction unit between PMOZ and PCL blocks at [1.8 ppm (1H), 23.1 ppm (13C)] (C5-H5 coupling in enlarged image in Fig. S2) was identified, indicating that the PMOZ-b-PCL block copolymer was successfully synthesized in one-step. To further prove that the synthesized copolymer is a block copolymer rather than a blend of PMOZ and PCL homopolymers, 1H DOSY (diffusion ordered spectroscopy) NMR characterization was performed. The PMOZ and PCL blocks in PMOZ-b-PCL exhibited the same diffusion coefficient (Fig. 2A), while the blend of PMOZ and PCL homopolymers exhibited two different ones (Fig. 2B) suggesting the successful synthesis of PMOZ-b-PCL block copolymer via CAP.

Table 1 Synchronous cationic-anionic polymerization of MOZ and CLa
Fig. 2: Cationic-anionic polymerization (CAP) of MOZ and CL.
figure 2

A DOSY NMR spectrum of PMOZ-b-PCL synthesized by CAP in DMSO-d6 as the solvent. B DOSY NMR spectrum of a blend of PMOZ and PCL homopolymers in DMSO-d6 as the solvent. C Characteristic signals monitored by 1H NMR spectra in DMSO-d6 as the solvent. D SEC traces of PMOZ-b-PCL samples taken at different reaction times.

Study of the initiation mechanism of CAP

To further investigate the initiation mechanism of CAP, a series of control experiments were performed. First, a copolymerization was performed by sequentially adding MOZ and CL monomers using BiCl3 and TfOMe as initiators. The tandem CROP of MOZ and AROP of CL can be initiated by BiCl3 to afford PMOZ-b-PCL block copolymer. In contrast, using TfOMe as an initiator yield only PMOZ homopolymer. Subsequently, the homopolymerization of CL was also performed, but no PCL was generated. These results support our original hypothesis that CAP initiated by BiCl3 follows a cascade initiation mechanism: BiCl3 first initiates the CROP of MOZ, and the resulting polyoxazoline oligomer subsequently initiates the AROP of CL. As CL also has the potential to undergo CROP, the tandem copolymerization of MOZ and CL using benzyl chloride as an initiator was performed to further verify that the propagation and initiation of CL occurs only at the N-Bi end and not at the chlorinated hydrocarbon end (Cl−C) during the polymerization. This polymerization led to no PCL formation, suggesting that CL polymerization cannot be initiated from the chlorinated hydrocarbon end, even after the full consumption of MOZ (detailed discussion shown in Table S1 and Figs. S3S8).

Polymerization kinetics study of CAP

A detailed kinetic study provided insights into the CAP process. A synchronous CAP of MOZ and CL (MOZ: CL: BiCl3 = 50: 50: 1) was performed at 100 °C in DMAc, monitored by 1H NMR and SEC analyses (Fig. 2C, D). SEC traces shifted towards higher molecular weights over time, maintaining unimodal distributions. In the 1H NMR spectra, signals 1 and 2 (due to MOZ) decreased rapidly and disappeared completely within 24 h. Concurrently, new signals a and b indicate the formation of PMOZ. The decrease of signals 3 and 4 (due to CL) and the increase of signals c and d (due to PCL) occurred ~3 h after the initiation of MOZ. This delayed initiation phenomenon could most likely be due to the requirement of a longer PMOZ chain for the initiation of CL, which reduces the spatial interference from the cationic propagation chain end. The polymerization kinetics showed that MOZ polymerized earlier and at a higher propagation rate than CL, yet both polymerizations proceeded simultaneously. The polymerization rate constants of MOZ (kp, MOZ) and CL (kp, CL) were calculated to be 1.03 × 10-4 s-1 and 3.19 × 10-6 s-1, respectively (Fig. 3A).

Fig. 3: Polymerization kinetics study of CAP.
figure 3

A Kinetic plots for the CAP of MOZ and CL using BiCl3 as an initiator in DMAc ([BiCl3]0: [MOZ]0: [CL]0 = 1: 50: 50); (▲) MOZ; () CL; [BiCl3]0 = 0.0392 mol/L, [MOZ]0 = [CL]0 = 1.96 mol/L (corresponding to Table 1). The polymerization rate constant (kp) was obtained from this figure by the following equation: ln([MOZ]0/[MOZ]t) = kpt, where M represents MOZ or CL, t represents reaction time. The polymerization rate constant of MOZ (kp, MOZ) was 1.03 × 10−4 s−1; the polymerization rate constant of CL (kp, CL) after 3 h was calculated to be 3.19 × 10−6 s−1. B Dependence of molecular weights (Mn) and molecular weight distributions (Ɖ) on the conversion of MOZ during the CAP (corresponding to Table 1). The linear increasing number-average molecular weights (Mn,SEC) versus MOZ conversions (Conv.MOZ) confirm a living cationic ring-opening polymerization (CROP) of MOZ. C Turnover frequency (TOF) of CL versus the molar ratio of MOZ/BiCl3 (corresponding to Table 2); All polymerizations feature the same CL/BiCl3 molar ratio of 50/1, but with different MOZ/BiCl3 molar ratios. The TOF values and CL conversion increased monotonically with the MOZ/BiCl3 molar ratio.

The plot of Mn versus conversion is usually used to verify livingness of the polymerization, where a linear relationship indicates a living process. However, in CAP, where two polymerizations occur simultaneously, the hydrodynamic volume of the copolymer can be affected by both its molecular weight and block ratio, potentially leading to significant error. Therefore, only the Mn versus conversion of MOZ during the initial 0.5 ~ 5 h was plotted, where MOZ propagation was dominant (Fig. 3B) and the molecular weight contributed by CL was minimal (conv. <~10%). The linear increase in Mn with MOZ conversions confirms a living cationic ring-opening polymerization (CROP) of MOZ.

To further confirm the living nature of the terminal, a chain extension experiment using BiCl3 as an initiator was performed. Firstly, the mixture of MOZ, CL and BiCl3 (MOZ: CL: BiCl3 = 50: 50: 1) was heated at 100 °C for 24 h. The mixture was taken for SEC and 1H NMR measurements. 1H NMR analysis (Fig. S11) confirmed that the conversions of MOZ and CL were 96.2% and 40.8%, respectively. Afterwards, MOZ (50 equiv.) and CL (50 equiv.) were added to the mixture and heated for 24 h. The mixture was once again subjected to SEC and 1H NMR measurements. The total conversions of MOZ and CL became to 94.1% and 53.6%, respectively. It indicates that both MOZ and CL can be continued to polymerize by adding new monomers. As shown in SEC trace (Fig. S12), the apparent increase in molecular weight between first heating and second heating, further explains the living nature of both the cationic and anionic propagation ends.

Effect of molar ratio of MOZ/BiCl3 on CAP

As CL cannot be initiated by BiCl3 itself without the presence of MOZ (entry 3 in Table S1), the active site for CL initiation must be formed during the polymerization of MOZ. It may follow a cascade mechanism in which CROP of MOZ was first initiated by BiCl3, and then the PMOZ oligomers with N−Bi end groups participated in the tandem initiation of CL. This could be the reason why CL initiation occurred later than the initiation of MOZ (Fig. 2C). To verify this phenomenon of cascade initiation, a series of copolymerizations of MOZ and CL with different MOZ/BiCl3 molar ratios were performed at 100 °C for 24 h, and the conversions of MOZ and CL were obtained using 1H NMR (Table 2, Fig. S14). A signal at 3.6 ppm that relates to the MOZ ring can be clearly observed in the NMR spectrum with a MOZ/BiCl3 molar ratio of 1/1, but disappears completely upon the increase of MOZ/BiCl3 molar ratios (enlarged image in Fig. S14). It is indicated that when the ratio of MOZ: BiCl3 is <1:1, almost all MOZ molecules tend to form a complex with BiCl3 via coordination of Bi and N atoms, leaving barely no extra MOZ molecules to participate in the ring-opening reaction. This leads to very slow or even no ring-opening of MOZ. Therefore, the peak of MOZ can still be observed in the 1H NMR spectrum even after 24 h of reaction. As the MOZ/BiCl3 molar ratio increases, this complex undergoes nucleophilic attack from other MOZ monomers and initiates CROP of MOZ. The disappearance of the signal at 3.6 ppm indicates the complete conversion of MOZ (Table 2 entries 2 ~ 9). Although the conversion of MOZ in entries 10-11 did not reach 100%, due to the high molar ratio of MOZ/BiCl3, MOZ was not completely consumed within 24 h. Moreover, the amount of MOZ used in the copolymerization affects the initiation and conversion of CL. At low molar ratio of MOZ/BiCl3 (≤5/1), barely any CL conversion (<6%) was observed, while higher ratio (≥7/1) led to an increased conversions of CL. Especially, the turnover frequency (TOF) of CL calculated by its conversion (Table 2) was plotted against MOZ/BiCl3 molar ratio. It is noteworthy that the TOF values and the CL conversion increased monotonically with the MOZ/BiCl3 molar ratio (Fig. 3C). This observation supported that a high molar ratio of MOZ/BiCl3 ensured the complete formation of N-Bi between MOZ and BiCl3 (more initiation sites for CL), which facilitates the formation of a longer PMOZ chain that can significantly decrease interference between the PMOZ and CL propagation chain-ends (less interfered propagation sites for CL). In addition, a higher molar ratio of MOZ/BiCl3 improved the conversion of CL. When the MOZ/CL/BiCl3 molar ratio was 200/50/1, the conversion of CL reached 83.4% within 24 h (entry 11 in Table 2). These results indicate that the chain propagation and coupling termination reactions compete with each other, and the coupling termination is more likely to occur after the complete consumption of MOZ. Therefore, a reasonable feed ratio of MOZ and CL can effectively inhibit terminal coupling reactions in CAP.

Table 2 Cationic-anionic polymerization of MOZ and CL with different ratios of monomer MOZ to initiator BiCl3a

Effect of propagation chain-ends on CAP

Terminal coupling reactions pose an inherent challenge in CAP and can be influenced by the structure of the propagating ends. In the CAP of MOZ and CL using BiCl3 as an initiator, the cationic propagating end is a chloroalkyl group (polymer-chain−CH2Cl), while the anionic propagating end is an alkoxide with dichloro bismuth {(polymer-chain−O)δ− (BiCl2)δ+}. The inhibition of coupling reactions between these chain-ends may be due to their relatively low ionicity caused by the strong nucleophilicity of Cl, ensuring the copolymerization progress. To investigate the effect of the counterpart of propagating ends on the CAP, polymerizations were carried out using BiBr3, BiI3 and Bi(TfO)3 as initiators, respectively (entries 8 ~ 10 in Table 1), and compared with BiCl3-initiated copolymerization (entry 6 in Table 1). MOZ was completely consumed with all initiators, but the conversions of CL using BiBr3, BiI3 and Bi(TfO)3 were 66.1, 84.0 and 100%, respectively, higher than using BiCl3. Interestingly, SEC traces showed that products obtrained using Bi(TfO)3 had the lowest molecular weight, despite the highest CL conversion (ca. 100%). Larger anions, being less nucleophilic (nucleophilicity: Cl− > Br− > I− > TfO)28,46,47,48, promote ionization of the propagating ends, enhancing their polymerization activity, resulting in faster propagation rates and higher conversions of MOZ and CL. However, high ionic propagating chain-ends are prone to cationic-anionic coupling, terminating the polymerization. Moreover, the type of counter anion also affects the propagating species of MOZ CROP. When the counter anion is Cl, the propagating chain-end exhibits reduced cationic character. Conversely, Br, I and TfO yield propagating chain-ends that form cationic oxazolinium species28,47,48, leading to high affinity for the anions/anionic-growth ends. Therefore, with Bi(TfO)3 as an initiator, propagating ends are easily ionized, leading to coupling termination and regeneration of Bi(TfO)3. The regenerated Bi(TfO)3 then triggers new polymerization, achieving high CL conversion while limiting the production of high molecular weight PMOZ-b-PCL block copolymers (red line in Fig. 4A).

Fig. 4: Hydrolysis of PMOZ-b-PCL and amidation of resulting PEI.
figure 4

A SEC traces of PMOZ-b-PCL synthesized using different bismuth salt initiators. B SEC trace of PMOZ prepared via hydrolysis of PMOZ-b-PCL and amidation of resulting PEI.

The terminal coupling of anionic and cationic propagation-ends is an inherent challenge of CAP. Once the terminal coupling occurs during the chain-propagation, multi-block or cyclic block copolymers composed of short blocks would be generated. Thus, the hydrolysis of these 4 PMOZ-b-PCL block copolymers using 5.0 M HCl was examined; here, PCL should be completely hydrolyzed to the small molecule 6-hydroxyhexanoic acid, PMOZ will form polyethyleneimine (PEI). The PEI with smaller molecular weight obtained indicates that more terminal coupling reactions have occurred during MOZ propagation in CAP. It is noteworthy that PEI tends to adsorb to the column and cause irreversible damage owing to its insolubility in DMF and repeated ethylamine units. Therefore, it is not possible to directly characterize PEI by SEC. Therefore, the obtained PEI were further amidated with acetyl chloride to form PMOZ, and the molecular weights were obtained SEC (PMOZ in Fig. 4B; Table S2). As shown in Fig. 4B (red line), the PMOZ initiated by Bi(TfO)3 showed the lowest molecular weight. This could be due to the coupling termination occurred during the MOZ propagation when using Bi(TfO)3 as an initiator. Moreover, the occurrence of the coupling reaction at the chain-end leads to the reduction of the MOZ propagating chain-ends, so the occurrence of terminal coupling can also be investigated by examining the amount of the MOZ propagating chain-ends. However, the signal of the MOZ propagating chain-ends was overlapped with the repeat units in the 1H NMR analysis (see Table S2 and Figs. S15S17 for details).

A strong ionic chain-end could promote the occurrence of an end-coupling reaction, thereby reducing the number of the propagation chain-ends in the reaction solution. Therefore, the occurrence of termination by coupling was investigated by examining the amount of the propagating chain-ends. On other words, the occurrence of terminal coupling leads to the decrease of propagating ionic chain-ends. In 1H NMR analysis, the signal of the MOZ/CL propagating chain-ends was unfortunately overlapped by the signals of the repeat units. Therefore, to better investigate the amount of MOZ propagating chain-ends, we performed a modification reaction of MOZ propagation to change its structure by adding excess 4-dimethylaminopyridine (DMAP) after CAP of MOZ and CL (as shown in Fig. S10). It is noteworthy that the chain-end modification of MOZ propagation using DMAP is a quantitative reaction45. The obtained DMAP endcapped PMOZ-b-PCL block copolymers were characterized using 1H NMR spectroscopy (detailed operation was described in supplemental information). We calculated the molar ratio (percentage) of DMAP to bismuth salt initiator based on the integrated area of the DMAP terminal and the signal of PMOZ (as shown in Table S3). The DMAP chain-end in the copolymer synthesized by using Bi(TfO)3 (the molar ratio of DMAP/Bi was ca. 44.5%) was much lower than that in copolymers synthesized using other initiators, indicating the strong ionic chain-end could easily undergo coupling termination (see Table S3 and Figs. S18S22 for details).

To further explain the polymerization reaction using Bi(TfO)3 as an initiator, a chain extension experiment was performed. 1H NMR confirmed that both MOZ and CL were completely consumed after the first and second propagation (Fig. S24). However, the SEC traces (Fig. S25) revealed that the molecular weight distribution after the second propagation was significantly broader than after the first propagation, with considerable overlap. Furthermore, an increased presence of low molecular weight polymers was observed after the second propagation. These results indicate that, when Bi(TfO)3 is used as the initiator, a substantial proportion of the anionic and cationic propagation ends become inactivated and cannot resume chain growth after the addition of new monomers. This chain-end inactivation could most likely be due to the chain-end coupling, potentially leading to the regeneration of Bi(TfO)3, which subsequently initiates new CAP of MOZ and CL, resulting in the formation of lower molecular weight copolymers (Fig. S23).

Density Functional Theory (DFT) studies of CAP

To reveal the mechanism of CAP and the thermodynamic reasons for the inhibition of cationic-anionic terminal coupling, DFT simulations of MOZ and CL propagation, as well as the coupling of cationic and anionic propagation chain-ends were analyzed. Here, N-(2-chloroethyl)-N-ethylacetamide (T1) was used to simulate the cationic propagation end due to it has the same structure as the propagation end of homopolymeriztion of MOZ using BiCl3 (Fig. S1b). Propyl 6-((dichlorobismuthaneyl)oxy)hexanoate (T2) was used to simulate the polyester propagation end (Fig. S1b). It is noteworthy that in order to ensure the feasibility of the DFT calculations and provide mechanistic insights into both MOZ and CL propagation pathways, the simulated chain-end structures, T1 and T2, were used as the starting points for our analysis. While starting from the initial reactants is often considered a more appropriate and commonly adopted approach for evaluating the thermodynamic favorability of polymerization pathways, it poses significant computational challenges in this case. For the CL propagation pathway, initiating the calculations directly from the reactants would require several propagation steps of MOZ to generate the oligoMOZ-BiCl2 initiating end. This cascade initiation process significantly increases the size and complexity of the structure, making accurate calculations computationally prohibitive. For the MOZ propagation pathway, while it is computationally feasible to start from the reactants, using T1 as the starting point ensures consistency with the approach taken for CL propagation. This unified methodology allows for a direct comparison of the two propagation pathways under the same conditions and highlights the mechanistic differences in their respective energy profiles.

The comprehensive energy profiles of polymerizations initiated by BiCl3 are shown in Fig. 5. The propagation of MOZ follows a typical SN2 nucleophilic substitution reaction, initiated by the nucleophilic attack of alkyl chloride (terminal 1, T1) by the MOZ monomer. This forms an ion pair (intermediate 1, IM1) of cationic oxazolium and Cl via a high-energy barrier transition state (transition state 1, TS1, energy barrier of 64.8 kcal/mol). Subsequently, the oxazolium ring opens to form a more stable alkyl chloride (product 1, P1). The unexpectedly high energy barrier for TS1 (64.8 kcal/mol) could be attributed to the constrained geometry of the transition state, involving simultaneous ring-opening of the monomer and interaction with BiCl3, which introduces steric and electronic strain. Additionally, MOZ propagation proceeds via a typical SN2 nucleophilic substitution mechanism, requiring a high-energy transition state for stereochemical inversion. Similar high-energy barriers have been reported in the polymerization of oxazolines with varying structures49. For CL polymerization, the propagation and coupling termination reactions compete with each other. Both reactions have high-energy barrier of the transition states. However, the energy barrier of transition state TS3 of CL propagation is significantly lower than that of the transition state TS5 for the coupling reaction (24.6 verse 40.3 kcal/mol, Fig. 5). This indicates CL propagation is a more thermodynamically favorable pathway than the coupling of chain-ends. Moreover, the high computed Gibbs free energy for the product in the CL propagation process could arise from the coordination state. This effect has been noted in similar systems50,51. Additionally, while the PBE0-D3BJ functional and 6–31 G* basis set are effective for many organometallic systems, they may not fully capture the relativistic and multi-electron interactions of the heavy bismuth center. Despite using the 6-311 + G(d,p) basis set for single-point energy calculations to improve accuracy, the limitations of these approximations for heavy elements should be acknowledged.

Fig. 5: DFT calculation to simulate the chain propagations and chain-end coupling processes when using BiCl3 as an initiator.
figure 5

A Proposed intermediates (IM) and transition states (TS) for the pathway of MOZ, CL propagation and chain-end coupling using BiCl3 as an initiator. B Free energy profiles for each IM and TS calculated by DFT. DFT data suggested that CL propagation is a more thermodynamically favorable pathway than coupling of chain-ends. The energy barrier difference between the transition state of CL propagation (TS3) and coupling reaction (TS5) is 15.7 kcal/mol.

DFT studies were also performed on the copolymerization using Bi(TfO)3 as an initiator (Fig. S26). P4 with an ionic pair structure (8.0 kcal/mol) showed a lower energy than the covalent structure of P5 (11.0 kcal/mol). This indicates that the MOZ propagating chain-end should be ionic using Bi(TfO)3, consistent with previous reports and our experimental results52. Although CL propagation remains more thermodynamically favorable compared to coupling termination, the energy barrier difference between their respective transition states (TS9 verse TS7) is only 8.8 kcal/mol when using Bi(TfO)3, which is smaller than that using BiCl3 (15.7 kcal/mol). The smaller difference leads to a higher tendency of coupling termination. These findings indicate that the ionicity of propagating chain-ends is crucial for achieving CAP, and propagating chain-ends with a relatively lower ionicity could reduce the possibility of termination by coupling.

Proposed Mechanism of CAP

Based on the experimental data and DFT results, a possible mechanism for CAP is proposed (Fig. 6). First, an oxazolinium cation is formed by nucleophilic attack of MOZ on bismuth salt. This oxazolinium cation can then be attacked by another 2-oxazoline monomer, allowing the poly(2-oxazoline) to grow. As the poly(2-oxazoline) propagates longer, the other end (N−Bi) gains the ability to initiate cyclic ester polymerization, enabling synchronous polymerization of 2-oxazolines and cyclic esters on both chain ends. This cascade initiation mechanism offers a approach to the design of dual-active initiators. The resulting cationic/anionic polymer chain ends are dynamic species that have an equilibrium between active ionic propagating species and low ionic dormant species. This equilibrium is influenced by the nucleophilicity of the anion of the bismuth salt, which controls the competition between polymeric propagation and coupling termination. High concentrations of ionic active species promote termination by cationic-anionic coupling, while high concentrations of ionic dormant species could significantly reduce the possibility of this coupling termination pathway. Therefore, a rational cascade initiation strategy and less ionic propagating chain ends are the key factors for controlling CAP.

Fig. 6: Illustration of CAP of MOZ and CL based on mechanisms of cascade initiation and dynamic dormant terminal.
figure 6

The CAP process begins with bismuth salt initiating MOZ to form oligoMOZ-BiCl2, which then polymerizes CL. Subsequently, the synchronous propagation of CROP and AROP is achieved via a dynamic dormant terminal mechanism, balancing active and dormant species, tunable by bismuth salts with different anions.

Universality of CAP

To demonstrate the universality of this copolymerization method, combinations of different 2-oxazolines and cyclic esters, including MOZ, 2-ethyl-2-oxazoline (EOZ), 2-phenyl-2-oxazoline (POZ), rac-lactide (LA) and CL were used in CAP to synthesize various diblock co-polymers. All SEC traces displayed unimodal/narrow peaks (Fig. S28, Table 3). 1H NMR spectra also indicate the successful formation of the corresponding block copolymers (Fig. S27). Then, we subjected these polymers to DOSY NMR analysis to further verify their block structure. As shown in Fig. S32, PEOZ-b-PCL, PPOZ-b-PCL, and PMOZ-b-PLA exhibited a single diffusion coefficient, indicating that these copolymers were block copolymers. These results suggest good generalizability of cationic-anionic polymerization for combinations of 2-oxazoline and cyclic ester monomers. In addition, the conversions of 2-oxazoline and cyclic ester monomers within 24 h were monitored using 1H NMR spectroscopy (Figs. S29S31). In the copolymerization of EOZ and CL, the conversions of EOZ and CL were 93.1% and 21.6%, respectively. In the copolymerization of POZ and CL, POZ and CL had 12.0% and 9.90% conversions, respectively. The order of nucleophilicity of 2-oxazoline monomers was MOZ > EOZ > POZ52,53, which resulted in reaction rates of EOZ and POZ being less than that of MOZ (entry 6 in Table 1). It is noteworthy that the conversion of CL in the copolymerization CL with EOZ or POZ is also lower than that in copolymerization of MOZ and CL, further confirming the cascade initiation mechanism. The fast polymerization rate of MOZ could trigger earlier initiation of cyclic ester, resulting in higher conversion of CL within the same reaction duration.

Table 3 Copolymerization of various combinations of 2-oxazolines and cyclic esters using BiCl3 as an initiatora

Self-assembly of block copolymer synthesized by CAP into micellar aggregates and study on their antimicrobial activity

To demonstrate the application potential of CAP in biomedicine, an antimicrobial block copolymer, PAPOZ20-b-PCL5, was successfully synthesized via CAP of 2-(N-tert-butoxycarbonyl-γ-aminopropyl)-2-oxazoline (Boc-APOZ) and CL, and de-Boc reaction using trifluoroacetate (see Fig. S35 and Fig. S36). Subsequently, the obtained PAPOZ20-b-PCL5 was dispersed in methanol, followed by a dialysis-induced self-assembly in water to yield nanoparticles (Fig. 7A). Transmission electron microscopy (TEM) study revealed that the morphology of these nanoparticles are micellar aggregates with a shell-corona structure comprising a soft cavity within a dense shell surrounded by a loose corona (Fig. 7B)54,55. The diameter, shell thickness, and corona thickness of the micellar aggregate were ~300, 60 and 50 nm, respectively.

Fig. 7: Block copolymer synthesized by CAP and its self-assembly and antibacterial properties.
figure 7

A Self-assembly process of CAP-synthesized PAPOZ20-b-PCL5 copolymer into micellar aggregates. B TEM images of micellar aggregates. C DLS studies (by number) of PAPOZ20-b-PCL5 block copolymer particles in methanol (red line) and water (blue line). D The relative solvation mass ratio (MPAPOZ/MPCL) of PAPOZ to PCL in DMSO-d6 (red square dot), and in methanol-d4/D2O mixture with different D2O contents (black dots and lines). E Antibacterial tests of PAPOZ20-b-PCL5 micellar aggregates against S. aureus. F Digital photos of bacterial colony taken out from each well at different polymer concentrations in the antibacterial experiment.

To elucidate the formation process of micellar aggregate, DLS, 1H NMR, and TEM analyses of PAPOZ20-b-PCL5 dispersed in the mixture of methanol and water with different water contents were performed. DLS data show the hydrodynamic diameter of assemblies of PAPOZ20-b-PCL5 were 60 nm in methanol and 270 nm in water, respectively (Fig. 7C). It indicated that these micellar aggregates were formed by a hierarchical self-assembly process. Figure 7D shows the relative solvation mass ratio (MPAPOZ/MPCL that was calculated by Equation S5) of PAPOZ to PCL in methanol-d4/D2O mixture with a differing D2O content (black dots and lines) obtained by 1H NMR analysis (Fig. S37). The MPAPOZ/MPCL ratio in methanol-d4 is larger than that in DMSO-d6 where the copolymer is full soluble (red square dot), indicating that the PCL segment is only partially soluble in methanol. As the D2O content increases, the MPAPOZ/MPCL ratio decreases significantly, which indicates that higher water content decreased the solubility of PAPOZ block. TEM analysis also revealed the formation of micellar aggregates (see Fig. S38 and Fig. S39). First, irregularly shaped proto-micelles with a PCL core and a PAPOZ corona are formed by micellization of PAPOZ20-b-PCL5 in methanol. Subsequently, as the water content increases, due to the strong tendency of hydrogen bonding effect between the PAPOZ corona, the proto-micelles further self-assemble into a micellar aggregate with a shell-corona structure. Such hierarchical self-assembly behavior due to the hydrogen bonding effect of polyoxazoline has also been observed previously56,57,58. PAPOZ is an amphiphilic polymer with hydrophilic amino groups and amide structures that easily forms intra-/inter-molecular hydrogen bonds and its hydrophilicity is affected by the molecular weight. As the self-assembly of polymer is a nonergodic process, the average chain lengths of PAPOZ on each self-assembled nanostructures are also different, leading to proto-micelles with different water solubility59,60. Therefore, during the second aggregation process, the proto-micelles with longer average PAPOZ chain lengths are less hydrophilic and first aggregate to form a dense shell. The proto-micelles that aggregate later have shorter average PAPOZ chain lengths and are more hydrophilic, which tend to form a loose corona.

This micellar aggregate holds promise as an antibacterial nanomaterial due to its high amine density, evidenced by a ζ-potential of +43.4 mV (Fig. S40). Therefore, minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays against S. aureus confirmed the antibacterial properties of these micellar aggregates. The MIC value was determined to be 50 μg/mL (Fig. 7E), with a corresponding 99.6% bactericidal effect (Fig. 7F). Comparison with representative polymeric nanoparticles reported recently (as shown in Table S5) highlights the excellent antibacterial capability of our micellar aggregates, characterized by relatively low MIC and MBC values. Furthermore, the hydrophobic PCL core offers the potential to load hydrophobic drugs such as auxins and antibiotics61,62, which could enhance the antibacterial effects. These results underscore the application potential of CAP in the realms of nanomaterials and biomedicine.

Discussion

In summary, a cationic-anionic polymerization (CAP) method that combines the cationic ring-opening polymerization of 2-oxazolines and the anionic ring-opening polymerization of cyclic esters was proposed, simply using bismuth salt as initiators. For the initiation of copolymerization, 2-oxazoline is first initiated by bismuth salt to generate polyoxazoline with N-Bi chain end, which then initiates the polymerization of the cyclic ester. This cascade initiation strategy enables the simultaneous propagation of cationically polymerizable monomers (such as 2-oxazoline) and anionically polymerizable monomers (such as cyclic ester) in one-pot. It is noteworthy that the key to assure the successful synchronous propagation of CROP and AROP is the dormant mechanism—the dynamic equilibrium of high-ionic active propagating species and low-ionic dormant species, which can be adjusted using bismuth salts with different anions. Anions with strong nucleophilicity (such as Cl) tend to shift the dynamic equilibrium from high-ionic active propagating species to low-ionic dormant terminal, reducing the possibility of termination by coupling. This approach is expected to inspire future designs for multicomponent reactions. Furthermore, CAP displays good generalizability for combinations of 2-oxazolines and cyclic esters, efficiently synthesizing functional block copolymers such as antibacterial materials. Overall, CAP is expected to promote the development of multi-component polymerization methodology, offering a concise synthesis method for block copolymers. This presents significant opportunities to facilely produce exquisitely tailored materials for energy storage, biomedicine, nanotechnology and even surface patterning for microelectronics.

Methods

Copolymerization procedure

All copolymerizations were performed under similar conditions. In a glovebox with nitrogen atmosphere, monomers, initiator, solvent and a magnetic bar were added to a dried vessel and sealed. Afterwards, the sealed vessel was heated to 100 °C to start the polymerization.

Sequential copolymerization

The typical sequential copolymerization procedure using BiCl3 is as follows: In a glovebox with nitrogen atmosphere, BiCl3 (20.0 mg, 0.063 mmol, 1 equiv.), MOZ (271 mg, 3.17 mmol, 50 equiv.) and dimethyl acetamide (DMAc, 1.0 mL) were mixed in a dried vessel with a magnetic bar. The mixture was heated at 100 °C for 24 h. Then one drop of mixture was taken for 1H NMR and SEC measurements. Continuously, CL (361 mg, 3.17 mmol, 50 equiv.) was added to the mixture and heated to 100 °C for 24 h. Finally, the mixture was analyzed by 1H NMR and SEC. The sequential copolymerization of MOZ and CL using methyl trifluoromethanesulfonate (TfOMe) and benzyl chloride as initiators and polymerization of CL using BiCl3 were performed in similar processes. When benzyl chloride was used as the initiator, in order to fully react the MOZ, CL was added after 48 h of MOZ polymerization, due to benzyl chloride showed lower initiating activity than BiCl3 and TfOMe for MOZ.

Cationic-anionic polymerization

The cationic-anionic polymerization was a one-pot/one-step process. The typical procedure was as follows (entry 6 in Table 1): In a glovebox with nitrogen atmosphere, BiCl3 (20.0 mg, 0.0630 mmol, 1 equiv.), MOZ (271 mg, 3.17 mmol, 50 equiv.), CL (361 mg, 3.17 mmol, 50 equiv.) and DMAc (1.0 mL) were mixed in a dried vessel with a magnetic bar. The mixture was heated at 100 °C in an oil bath. After quenching the reaction by exposing mixture to air, the mixture was immediately taken for 1H NMR and SEC measurements. Afterwards, the mixture was dissolved in CHCl3 and precipitated into a large amount of diethyl ether twice. A white powder of PMOZ-b-PCL was obtained. PMOZ-b-PCL was subjected to 1H NMR, 1H-13C HSQC NMR, DOSY NMR and SEC measurements. The experiments of another monomers and bismuth salt were performed in similar processes, all were heated at 100 °C for 24 h. The monitoring results were obtained by heating multiple reaction vessels containing reaction solutions with the same concentration and the same volume for different times. The typical procedure is as follows: In a glovebox with nitrogen atmosphere, BiCl3 (200 mg, 1 equiv.), MOZ (2.71 g, 50 equiv.), CL (3.61 mg, 50 equiv.) and DMAc (11 mL) were mixed in a bottle (20 mL). Then, the mixture (1.0 mL) was added to 10 identical vials with the same type of stir bar. The 10 vials were heated simultaneously in the same oil bath and individually removed at different predetermined time intervals for 1H NMR and GPC analyses. Figure 2C, D was plotted by these data.

Chain extension experiment

The typical procedure of chain extension experiment using BiCl3 as initiator was as follows: In a glovebox with nitrogen atmosphere, BiCl3 (20.0 mg, 0.0630 mmol, 1 equiv.), MOZ (271 mg, 3.17 mmol, 50 equiv.), CL (361 mg, 3.17 mmol, 50 equiv.) and DMAc (1.0 mL) were mixed in a dried vessel with a magnetic bar. The mixture was heated at 100 °C in an oil bath for 24 h. The mixture was taken for SEC and 1H NMR measurements. Afterwards, MOZ (271 mg, 3.17 mmol, 50 equiv.) and CL (361 mg, 3.17 mmol, 50 equiv.) were added to the mixture and heated for 24 h. The mixture was once again subjected to SEC and 1H NMR measurements. The chain extension experiment using Bi(TfO)3 was performed in a similar processes. In the first propagation, the polymerization was performed in a mixture containing of MOZ (50 equiv.), CL (50 equiv.) and Bi(TfO)3 (1 equiv.). In the second propagation, MOZ (20 equiv.) and CL (20 equiv.) were added to the mixture, and the polymerization was continued.

Reporting summary

Further information on research design is available in the Nature Portfolio Reporting Summary linked to this article.