7-Oxa-2,3-Diazanorbornene: A One-Step Accessible Monomer for Living Ring-Opening Metathesis Polymerization to Produce Backbone-Biodegradable Polymers

Open AccessCCS ChemistryRESEARCH ARTICLES20 Feb 20247-Oxa-2,3-Diazanorbornene: A One-Step Accessible Monomer for Living Ring-Opening Metathesis Polymerization to Produce Backbone-Biodegradable Polymers Xiaoyang Wang, Yixing Wen, Yu Wang, Wei Li, Xueguang Lu and Wei You Xiaoyang Wang Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Engineering Plastics, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 , Yixing Wen Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100049 , Yu Wang *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Engineering Plastics, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 , Wei Li Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100049 , Xueguang Lu *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Colloid, Interface and Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100049 and Wei You *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] E-mail Address: [email protected] Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Engineering Plastics, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190 University of Chinese Academy of Sciences, Beijing 100049 https://doi.org/10.31635/ccschem.024.202303697 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Traditional ring-opening metathesis polymerization (ROMP) reactions exhibit broad functional group compatibility and precise control over polymer architectures, albeit with non-biodegradable backbones. Recent progress has resulted in a series of biodegradable ROMP products with diverse cleavable functional groups, yet the majority of the monomers display moderate to low ring strain, which restricts their living polymerization reactivity. In this study, a novel category of readily available 7-oxa-2,3-diazanorbornenes (ODAN) is presented, which exhibits the highest ring strain (22.8 kcal/mol) compared to existing degradable ROMP monomers. This trait endows ODAN with the ability to perform living polymerization reactions, generating narrowly dispersed homopolymers, block copolymers, and statistical copolymers with various cyclic olefin comonomers, thereby enabling precise control over distribution of the biodegradable functional groups. Additionally, the resultant polymers comprise directly connected allyl hemiaminal ether and urethane units, which are hydrolyzable at controllable rates. Thus, these well-defined, structure-tunable, and backbone-biodegradable ROMP polymers are applied as nanoetching materials and biodegradable delivery carriers. Download figure Download PowerPoint Introduction The development of living polymerization enables the synthesis of precision polymers with well-controlled structures and properties.1,2 Among the diverse polymer properties, backbone biodegradability holds significant importance in the fields of environmental sustainability, biomedicine, and nanoetching materials.3–5 However, using living polymerization tools to precisely control the distribution of the biodegradable functional groups poses considerable challenges, as traditional living polymerization reactions give completely biodegradable backbones (e.g., polyesters, polyamides, and polyacetals) or nondegradable backbones (e.g., vinylic addition polymers). Although living polymerization reactions can generate block copolymers (BCPs) with different structures and functions, the covalent-tethering of degradable and nondegradable backbones usually requires complex chain end control and the use of macroinitiators to switch polymerization techniques.6,7 Olefin metathesis reactions, especially ring-opening metathesis polymerization (ROMP) reactions using commercially available Ru-based precatalysts, are highly versatile approaches for synthesizing functionalized macromolecular materials with diverse applications ranging from drug delivery to large-scale engineering plastics.8–11 The ROMP reactions that feature living polymerization characteristics enable the precise control of polymer architectures, such as linear, block, bottlebrush, and star shapes.12,13 ROMP polymers are intrinsically degradable due to the presence of alkenes that are cleavable under metathesis and strong oxidation conditions.14 To make the polymers capable of undergoing degradation into smaller fragments under physiological conditions, diverse heteroatoms and cleavable linkages need to be introduced,15,16 such as silicon,17–21 phosphorous,22–24 acetal/ketal,25–32 vinyl ether,33–42 ester,43–45 carbonate,46 and hemiaminal ether.47,48 However, mostly due to low to moderate ring strain (Figure 1a),49 when making BCPs containing biodegradable components, these monomers cannot form "pure homo-blocks" by living ROMP of themselves. They can only be used as sacrificial "end blocks,"24–29 or be copolymerized with highly reactive alkenes to form nearly "alternating blocks."17,34,35,37–40 Figure 1 | (a) Representative ROMP monomers for biodegradable polymers, showing their number of synthetic steps and approximate ring strain energies. (b) Design rationale of ODAN as biodegradable living ROMP monomers. Download figure Download PowerPoint The insufficient ring strain in previously reported biodegradable ROMP monomers can be regarded as a compromise of structural design to the synthetic feasibility,16 as formation of strained rings usually requires more energy input to overcome the enthalpy penalty in a highly strained system. To overcome this challenge, we are inspired by norbornenes, which are the most common living ROMP monomers bearing [2.2.1]-bicyclic motifs and can be easily accessed through Diels–Alder (DA) reactions. It is hypothesized that if multiple heteroatoms are used to substitute norbornenes, the living ROMP feature and biodegradability can be simultaneously achieved. More specifically, as shown in Figure 1b, 7-oxa-2,3-diazanorbornene (ODAN) consisting of one oxygen atom and two nitrogen atoms within the [2.2.1]-scaffold is utilized for living ROMP to form structurally well-defined biodegradable polymers. Like norbornenes, highly strained ODAN derivatives can be prepared through a one-step solvent-free hetero-DA cycloaddition reaction using commercial furan and azodicarboxylate as starting materials.50 More importantly, the resulting ROMP polymers are demonstrated to have hydrolyzable hemiaminal ether groups, and the hydrolysis rates are tunable by varying the substituents on ODAN derivatives. This approach allows for the synthesis of diverse biodegradable ROMP multiblock and statistical copolymers that possess well-controlled biodegradable sequence, controlled nanoetching morphology, controlled fragments after degradation, and controlled degradation rates. Experimental Methods Materials and characterization Materials and characterization by nuclear magnetic resonance (NMR) ( Supporting Information Figures S57–S74), gel permeation chromatography (GPC), thermogravimetric analysis (TGA), differential scanning calorimetry (DSC), scanning electron microscope (SEM), and small-angle X-ray scattering (SAXS) involved in this work are all represented in the Supporting Information. Monomers synthesis Diethyl azodicarboxylate (DEAD; 1.74 g, 10 mmol) and distilled furan (2.2 mL, 30 mmol) were placed in a 10 mL flask equipped with a magnetic stir bar, and the mixtures were stirred at 25 °C for 2.0 h until the color changed from orange red to colorless. The ODAN1 was obtained in quantitative yield as colorless oil without further purification after the excess furan was removed through evaporation. It is noteworthy that the monomer is unstable at room temperature, but it can be kept in the freezer (−20 °C) for six months without deterioration. The detail for the synthesis of ODAN2, ODAN3, and ODAN4 and the scalable synthesis of ODAN1 are all represented in the Supporting Information. Homopolymers synthesis In a N2-filled glovebox, the desired amounts of monomers were added to 5 mL vials equipped with a magnetic stir bar, then anhydrous tetrahydrofuran (THF) was added to the vials. The required amount of Grubbs III catalyst solution in THF was then added to the vial and the concentration of monomers was ensured to be 0.5 M. The solution was stirred at 0 °C. When the polymerization was completed, the reactions were quenched with excess ethyl vinyl ether and the SiliaMetS DMT metal scavenger was added to remove the catalyst residue. After filtration, the polymers were obtained without further purification after the THF was removed through evaporation. Penta-BCP synthesis In a N2-filled glovebox, NB1 (51 mg, 0.2 mmol, 50 equiv) were dissolved in 0.5 mL of THF. 0.5 mL of freshly prepared 1.5 mg Grubbs III catalyst in 0.5 mL THF was added. The mixture was stirred at room temperature for 0.5 h. Next, a solution of ODAN1 (48 mg, 0.2 mmol, 50 equiv) in 0.5 mL THF was added, and after the solution was stirred at 0 °C for 1.0 h, a solution of NB2 (41 mg, 0.2 mmol, 50 equiv) in 0.5 mL THF was added, where the resultant mixture was stirred at room temperature for 0.5 h. Then, a solution of ODAN4 (60 mg, 0.2 mmol, 50 equiv) in 0.5 mL THF was added and stirred at 0 °C for 1.0 h. Finally, a solution of NB3 (41 mg, 0.2 mmol, 50 equiv) in 0.5 mL THF was added, and the solution was stirred at room temperature for 0.5 h, quenched with excess ethyl vinyl ether, concentrated under vacuum, and the formation of penta-BCPs with five different components was finished. Details for the synthesis of copolymers and bottlebrush polymers are available in the Supporting Information. Acidic hydrolysis of the polymers Twenty milligrams of polymer were dissolved in 2 mL of THF, and 20 μL 1 M HCl was added to the solution. The mixture was stirred for 4 h. Excess sodium bicarbonate and sodium sulfate were added and the mixture was allowed to sit for 10 min. Finally, the mixture was extracted with dichloromethane (DCM), concentrated, and subjected to GPC analysis. Casting and etching of the diblock copolymer films Diblock copolymers P-NB1100- b -ODAN1 m films were prepared by dissolving the polymer (100 mg) in dimethylformamide (10 mL) and casting on a clean 6 cm × 6 cm glass plate with a glass dish to slow down the rate of solvent evaporation at 40 °C for 72 h. The final thicknesses of the films were between 90 and 120 μm. The diblock copolymer films were soaked in 1 M HCl methanol solution for 5 days. After that, the films were soaked and washed in methanol five times for 20 min each time. Finally, the residual methanol was removed through evaporation. Degradation of bottlebrush polymers under buffered conditions Ten milligrams of bottlebrush polymers prepared as described above were placed in a vial containing 2 mL of the requisite pH ≈ 7.4 phosphate-buffered saline (PBS) buffer. The solution was stirred at 25 °C for the indicated times. The water was removed through evaporation and the mixture was suspended in DCM, then excess sodium sulfate was added and the reaction mixture was allowed to sit for 5 min. Finally, the DCM solution was filtered with a 0.2 μm Nylon filter, concentrated under vacuum, dissolved in THF, and subjected to GPC analysis. Results and Discussion Controlled sequence The hetero-DA cycloaddition reactions between furan and DEAD were first reported in the 1950s, and the cycloadduct ODAN1 can be produced under ambient temperatures and neat conditions.50,51 The reaction conditions are much milder than traditional DA reactions to form norbornenes, because the diene component furan is electron-rich and the dienophile azodicarboxylate is electron-deficient.42 In this study, we revised the synthesis of ODAN1 to a scale exceeding 100 g ( Supporting Information Figure S1), characterized its rotational isomers by two-dimensional nuclear magnetic resonance (2D-NMR) analysis ( Supporting Information Figures S3–S11),52 and confirmed its stable storage at −20 °C for more than 6 months ( Supporting Information Figure S12). Other ODAN derivatives, ODAN2– ODAN4, were synthesized from other commercial azodicarboxylate compounds (Table 1) and stored in the same way as ODAN1. Notably, density functional theory (DFT) was utilized to estimate the ring-strain energy of ODAN1, which was found to be ∼22.8 kcal/mol ( Supporting Information Figure S2). This value was even higher than that of norbornene (15.8 kcal/mol when calculated using the same method),17,53 showing apparent differences to previously reported biodegradable ROMP monomers. Table 1 | ROMP Homopolymers Containing ODAN Derivativesa Entry Polymer Time (h) Mn (kDa)b Mn,theo (kDa) Đb 1 P-ODAN150 2 11.6 12.1 1.04 2 P-ODAN1100 2 22.1 24.2 1.04 3 P-ODAN1150 2 29.5 36.1 1.05 4 P-ODAN1200 2 37.2 48.4 1.08 5 P-ODAN1300 4 48.6 72.6 1.11 6 P-ODAN1500 8 71.2 121.1 1.16 7c P-ODAN1100 2 21.9 24.2 1.04 8c P-ODAN1500 4 66.4 121.1 1.42 9d P-ODAN1100 2 22.8 24.2 1.04 10e P-ODAN1100 2 9.3 13.3 1.41 11 P-ODAN2100 2 25.4 27.0 1.06 12 P-ODAN3100 2 33.3 36.6 1.04 13 P-ODAN4100 2 29.4 29.8 1.05 aROMP was performed under an N2 atmosphere in THF with [M] = 0.5 M at 0 °C. All reactions achieved complete monomer conversion expect of entry 10. See Supporting Information Table S1 for more results. bDetermined by GPC analysis in THF. cThe polymerization was performed at 25 °C. dFuran (20 equiv to Grubbs III) was added. eDEAD (20 equiv to Grubbs III) was added. Only 55% monomer conversion was achieved. When the ODAN monomers were polymerized using the Grubbs III catalyst in THF, complete monomer conversion and obvious living polymerization features were observed (Figure 2a,b, Table 1, and Supporting Information Table S1). The number average molecular weight (Mn) increased linearly with the monomer to initiator ratio ([M]/[I]), while the polydispersity (Đ) remained narrow (Figure 2b). At a [M]/[I] ratio of 100, the reactions performed at 0 and 25 °C gave similar Mn and Đ results (Table 1, entries 2 and 7). However, at a [M]/[I] ratio of 500:1, the ROMP of ODAN1 was better controlled at 0 than at 25 °C, possibly due to higher monomer stability at colder temperatures (Table 1, entries 6 and 8). The ODAN monomers are prone to slowly undergo retro-DA reactions in solution at room temperatures, which would regenerate furan and azodicarboxylate.50 It was confirmed that the presence of furan had minimal influence on the living ROMP reaction (Table 1, entry 9). However, the presence of DEAD led to incomplete monomer conversion and significantly broadened polymer distribution (Table 1, entry 10). Nevertheless, the Mn of the biodegradable homopolymers reached 71.2 kDa, while the polydispersity remained narrow (Đ = 1.16, Table 1, entry 6), likely owing to the high ring strain of the ODAN derivatives. The homopolymers of other ODAN derivatives can also be prepared through living ROMP (Table 1, entries 11–13) with diverse glass transition and thermal decomposition temperatures ( Supporting Information Figures S82–S88 and Tables S2–S3). Figure 2 | Living polymerization of ODAN derivatives. (a) GPC traces for homopolymerization of ODAN1. (b) Linear plots of Mn versus [M]/[I] for P-ODAN1m. Linear regression R2 = 0.993. (c) GPC traces for ABCDE-type penta-BCPs with five different repeating units. Download figure Download PowerPoint The living ROMP of ODAN derivatives was then applied to prepare multiblock copolymers with well-defined sequences. Through sequential addition of classical living ROMP monomers ( NB1– NB3) and ODAN monomers ( ODAN1 and ODAN4), a penta-BCP with five different components was formed with narrow dispersity, further confirming the well-controlled living ROMP process (Figure 2c). This is in stark contrast to previously reported biodegradable ROMP polymers. For example, the ABABA-type penta-block and ABABABA-type hepta-block hydrolysable ROMP polymers prepared by Kilbinger and coworkers28 used cyclic acetals as the sacrificial "A" blocks. However, due to insufficient ring strain of the degradable dioxepine monomers, the chain-extension from the "A" blocks to the nondegradable B blocks displayed low efficiency, resulting in obvious polymodal GPC peaks.28 Therefore, partially biodegradable ROMP BCPs more frequently use the sacrificial components as "end-blocks" without further block growth due to the loss of controllability.24–29 More recently, the use of 1,2-dihydrofuran (DHF) in biodegradable ROMP polymers has received much attention.34,35,37–40 Although its entropy-driven homo-polymerization require neat conditions,33 DHF can undergo nearly alternating copolymerization with reactive alkenes.37 By regarding the alternating copolymers as a whole biodegradable block, well-controlled biodegradable ROMP copolymers were prepared.34,35,37–40 However, the DHF-based alternating "mixed-block" can only be extended by another DHF-based block, and no controlled growing of nondegradable blocks was reported. This is mostly because in these alternating copolymerization systems, DHF has to be used in excess to ensure degradability, while DHF cannot be fully converted. Therefore, the ABCDE-type penta-block results reported herein (Figure 2c and Supporting Information Figures S75–S81) clearly indicate that the ODAN monomers can not only lead to efficient chain-extension from the Ru-carbene active centers, but can also maintain the viability for other ROMP monomers to propagate, showing obvious advancement over other biodegradable ROMP monomers with moderate to low ring-strain energies. Controlled nanoetching morphology After the ROMP reactions, the ODAN monomers are transformed into 1,3,4-oxadiazolidine-3,4-dicarboxylate scaffolds within the polymer backbones, featuring directly connected allyl hemiaminal ether and carbamate units. As a consequence, it is hypothesized that the polymer backbones are hydrolyzable under biorelevant conditions.47,54 Specifically, although the ODAN-derived polymers can be stably stored at room temperature as solids for over 3 months without significant changes in Mn and Đ ( Supporting Information Figure S13), rapid degradation of P-ODAN1100 homopolymers was observed when subjected to a dilute HCl/THF solution (0.02 M) for 4 h, as evidenced by comparison of GPC traces in Supporting Information Figures S14–S18. The degradation processes were accelerated to completion within 2 and 1 h when the temperatures were raised to 40 and 60 °C, respectively. By analyzing degradation products of the small molecular model compound ROM1, the degradation mechanism was proposed to be hydrolysis of the 1,3,4-oxadiazolidine-3,4-dicarboxylate core into α,β-unsaturated aldehydes and 1,2-hydrazinedicarboxylate (Scheme 1 and Supporting Information Figure S20).47,54 The former acrolein derivatives are volatile and unstable, thus giving rise to complicated further decomposition products,55 while the latter one has the potential to be oxidized to DEAD,56 indicating partial recyclability to ODAN1. Scheme 1 | Hydrolysis of small molecular model compound ROM1 and homopolymer P-ODAN1m. Download figure Download PowerPoint Self-assembly is one of the most charming features of BCPs,57 and the attachment of a sacrificial degradable block enables the preparation of nanoetching materials.5 The use of ROMP reactions has the potential to generate these etchable BCPs through a one-step process, avoiding the complicated controlling of chain-ends and switching of polymerization methods via traditional methods.6,58,59 However, the self-assembly properties were not evaluated in earlier biodegradable ROMP BCPs, and there are two plausible reasons: On the one hand, the controllability of biodegradable ROMP polymers from low to moderately strained monomers does not meet the requirements of BCP self-assembly study;24–29 On the other hand, the BCPs involving the multicomponent alternating DHF blocks may have too complicated microphase separation and self-assembly behaviors to be thoroughly evaluated.17,34,35,37–40 While in the ODAN-based biodegradable polymers reported herein, both problems are easily circumvented. The diblock copolymer P-NB1100- b -ODAN1 m, featuring one nondegradable block of NB1 and a second degradable block ODAN1, was subjected to heterogeneous acidic hydrolysis and maintained a polydispersity index of 1.02 afterwards (Figure 3a,b and Supporting Information Figures S21–S26). By varying the composition of ODAN1 blocks, we obtained various microscopically ordered morphologies of well-defined P-NB1100- b -ODAN1 m copolymers through a one-step process. By selectively etching the degradable ODAN1 block, we prepared ordered nanoporous P-NB1100 blocks with different morphologies (Figure 3c–e). Figure 3 | Controlled nanoetching morphology of degradable BCPs. (a) GPC traces and (b) stacked 1H NMR spectra of P-NB1100-b-ODAN175 before and after acidic etching. The grey "b-ODAN1m" indicates postdegradation of the ODAN components. (c–e) Comparison of 1D SAXS profiles of P-NB1100-b-ODAN1m solvent-casting films ("raw" in black color) and their selectively etched films (in blue color), m = (c) 25, (d) 50, and respectively. and the of of the etched (c) (d) and indicated by the Download figure Download PowerPoint The solvent-casting films morphologies as the of degradable ODAN1 block increased from to in Supporting Information Figures although their small-angle X-ray scattering were not strong to the structures due to the similar electron density differences between the two blocks (Figure black After the etching of ODAN1 blocks under heterogeneous acidic conditions, the nondegradable blocks and morphologies (Figure blue and Supporting Information Figures The and (d) of the etched P-NB1100- b films were in detail on the of the and multiple in the 1D SAXS A with of 2 was for P-NB1100- b (Figure The was to be by the of scattering at the first which was with that from the The etched P-NB1100- b a as by both and SAXS profiles (Figure The were 3 and of the may in the microphase by the of the scattering The of the was to be while the average from the was further in the ODAN1 block to ( P-NB1100- b were observed (Figure The the between from to as a of the due to the of from ODAN1 blocks. Therefore, by the block the of microphase the living ROMP of ODAN monomers, we can precisely control the and of the in a classical ROMP polymer P-NB1100 ( Supporting Information Figures This approach a and for the preparation and development of well-defined etchable materials with ordered Controlled fragments copolymerization is another approach to degradable functional groups polymer to previously reported biodegradable ROMP monomers, ODAN derivatives have significantly higher ring strain, thus to a of comonomers, ranging from strained norbornene derivatives to strained and (Table The statistical copolymerization with norbornene derivatives remained in the living polymers with narrow polydispersity (Đ By the [M]/[I] statistical copolymers with high molecular can be easily achieved (Table entries 2 and When was subjected to the statistical copolymerization with ODAN1, both monomers were completely although the polydispersity was broad due to the metathesis of 9). in the presence of ODAN1 achieved complete with 10). Table 2 | Containing ODAN Derivativesa Entry Polymer Time (h) Mn Mn,theo (kDa) 1 2 1.05 2 8 2 4 2 5 8 2 2 2 1.04 2 2 aROMP was performed under an N2 atmosphere in THF with [M] = 0.5 M at 0 °C. The reactions achieved complete monomer conversion of See Supporting Information Table S1 for more results. polymerization was performed at 25 °C. of was to be by 1H NMR analysis with conversion of ODAN1. by GPC analysis in THF. For statistical copolymers, the distribution of the degradable functional groups directly the and the degradable while the monomer distribution is by both and monomer The monomer distribution can be easily by the only when the of the are because of the of the of high ring-strain and the of the urethane groups ROMP of ODAN monomers ( Supporting Information Figure the of ODAN1 with classical ROMP monomers in a broad plots in Supporting Information Figures For example, the mixture of ODAN1 and the which is one of the most common living ROMP monomers, gave nearly as both were to 1 ODAN1 = NB2 = When with the ODAN1 significantly ODAN1 = NB3 = In when with the ODAN1 more slowly ODAN1 = = possibly due to functional group of ODAN1 ROMP ( Supporting Information Figure It is noteworthy that copolymers of and ODAN1 both smaller than 1 ODAN1 = = the to form alternating copolymers, which is likely due to the and smaller strain in than ODAN1 ( Supporting Information Figure In