Long-Range Electronic Effect-Promoted Ring-Opening Polymerization of Thioctic Acid to Produce Biomimetic Ionic Elastomers for Bioelectronics

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLES1 Mar 2024Long-Range Electronic Effect-Promoted Ring-Opening Polymerization of Thioctic Acid to Produce Biomimetic Ionic Elastomers for Bioelectronics Hongfei Huang, Huijing Wang, Lijie Sun, Ruohan Zhang, Luzhi Zhang, Zekai Wu, Yaxuan Zheng, Yang Wang, Wei Fu, Youwei Zhang, Rasoul Esmaeely Neisiany and Zhengwei You Hongfei Huang State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Institute of Functional Materials, Donghua University, Research Base of Textile Materials for Flexible Electronics and Biomedical Applications (China Textile Engineering Society), Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Shanghai 201620 , Huijing Wang Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 , Lijie Sun State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Institute of Functional Materials, Donghua University, Research Base of Textile Materials for Flexible Electronics and Biomedical Applications (China Textile Engineering Society), Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Shanghai 201620 , Ruohan Zhang State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Institute of Functional Materials, Donghua University, Research Base of Textile Materials for Flexible Electronics and Biomedical Applications (China Textile Engineering Society), Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Shanghai 201620 , Luzhi Zhang State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Institute of Functional Materials, Donghua University, Research Base of Textile Materials for Flexible Electronics and Biomedical Applications (China Textile Engineering Society), Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Shanghai 201620 , Zekai Wu State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Institute of Functional Materials, Donghua University, Research Base of Textile Materials for Flexible Electronics and Biomedical Applications (China Textile Engineering Society), Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Shanghai 201620 , Yaxuan Zheng State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Institute of Functional Materials, Donghua University, Research Base of Textile Materials for Flexible Electronics and Biomedical Applications (China Textile Engineering Society), Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Shanghai 201620 , Yang Wang State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Institute of Functional Materials, Donghua University, Research Base of Textile Materials for Flexible Electronics and Biomedical Applications (China Textile Engineering Society), Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Shanghai 201620 , Wei Fu Institute of Pediatric Translational Medicine, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127 , Youwei Zhang State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Institute of Functional Materials, Donghua University, Research Base of Textile Materials for Flexible Electronics and Biomedical Applications (China Textile Engineering Society), Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Shanghai 201620 , Rasoul Esmaeely Neisiany Department of Materials and Polymer Engineering, Faculty of Engineering, Hakim Sabzevari University, Sabzevar 9617976487 and Zhengwei You *Corresponding author: E-mail Address: [email protected] State Key Laboratory for Modification of Chemical Fibers and Polymer Materials, College of Materials Science and Engineering, Institute of Functional Materials, Donghua University, Research Base of Textile Materials for Flexible Electronics and Biomedical Applications (China Textile Engineering Society), Shanghai Engineering Research Center of Nano-Biomaterials and Regenerative Medicine, Shanghai 201620 https://doi.org/10.31635/ccschem.023.202302995 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Poly(disulfide)s have been widely used in flexible wearable electronics, smart materials, and drug delivery. The synthesis of poly(disulfide)s usually utilizes external stimuli or toxic initiators to promote the polymerization. Here, we indicated that the long-range electronic effect can significantly alter the reactivity of the disulfide group. Accordingly, we established deprotonation-promoted ring-opening polymerization of thioctic acid (TA) as a highly effective and simple method to synthesize poly(disulfide)s due to the long-range electronic effect and nucleophilic carboxylate. Without external stimuli and initiators, simple mixing of TA and deprotonation reagent, choline bicarbonate, in different ratios at room temperature rapidly produced a series of high molecular weight (up to 772 kDa) ionic liquid crystal poly(disulfide)s elastomers with room temperature self-healing ability, adjustable conductivity (2.39 × 10−2 ∼ 0.28 × 10−2 S m−1), degradability, biocompatibility, antibacterial property, and tissue-like softness (Young's moduli ranging from 18.2 ± 6.0 to 111.1 ± 36.7 kPa). The experiments and density functional theory calculations also revealed the principle of long-range electronic effect to establish a new synthetic strategy of poly(disulfide)s with superior properties favorable for bioelectronics. Download figure Download PowerPoint Introduction Disulfide bonds, as one of the most investigated dynamic covalent bonds, play a vital role in organisms, such as controlling protein conformations and mediating cellular redox homeostasis.1 In recent years, synthetic poly(disulfide)s have gained remarkable attention in the fields of smart materials,2 dynamic self-assembly,3 and cellular delivery of drugs.4–8 Traditional preparation methods of poly(disulfide)s include stepwise polymerization of disulfide-containing monomers or dithiol,9–12 thermally triggered,13–16 photoinduced,17 or anionic ring-opening polymerization (ROP) of cyclic disulfides.18,19 However, these polymerization methods require stimuli or external toxic initiators, which limit the applications of poly(disulfide)s.18,20 Overall, the development of a new method to synthesize poly(disulfide)s under mild conditions is crucial. Thioctic acid (TA), a bio-based renewable cyclic 1,2-dithiolane,19,21 has been used to prepare poly(disulfide)s as recyclable plastics,22 liquid crystal elastomers,23 and dynamic bottlebrush elastomers24 via thermal and light-stimulated polymerization, as well as solvent volatilization-induced assembly polymerization.25–27 However, these methods are limited by the toxic initiator, complex process, or requirement of external heating. In our previous work, we used the electronic effect to modulate the active energy of dynamic bonds.28 In general, the electronic effect can be transmitted in many ways, such as inductive effect, field effect, conjugation effect, and so on, where the inductive effect is known as a short-range force. Here, we demonstrate the power of the long-range electronic effect on the efficient synthesis of poly(disulfide)s via deprotonation-promoted ROP of TA. The deprotonation led to the formation of carboxylate, and the electron-donating properties of carboxylate across six carbons induced polarization of the S–S bond and significantly reduced its bond energy. Furthermore, the deprotonated carboxylate group in the system acted as a nucleophile to attack the disulfide bond to form sulfide ions.29–31 Both promoted the ROP of the cyclic dithiolane ring. Choline bicarbonate was chosen as an efficient and clean deprotonation reagent to form a biocompatible ionic liquid from choline and TA (ChoTA),32 which readily reacted with TA in situ without any external stimuli and initiators to rapidly produce high molecular weight ionic liquid crystal poly(disulfide)s (i-LCPDs). i-LCPDs showed spontaneous self-healing ability, tunable electrical conductivity, degradability, biocompatibility, antibacterial property, and tissue-like softness. Experimental Methods Materials The (±)-α-TA and dimethyl sulfoxide-d6 (DMSO-d6) were purchased from Adamas®beta (Shanghai, China). Choline bicarbonate was provided by Sigma-Aldrich (Shanghai, China). Ethanol was obtained from Sinopharm Chemical Reagent (Shanghai, China). Dulbecco's modified Eagle's medium (DMEM) and penicillin-streptomycin were purchased from Life Technologies (Shanghai, China). Fetal bovine serum was purchased from Gibco (Shanghai, China). Calcein/PI cell viability/cytotoxicity assay kit was obtained from Beyotime (Shanghai, China). The cell counting kit 8 (CCK-8) assay was obtained from Do Jindo Laboratories (Shanghai, China). All the reagents were used as received without further purification unless otherwise noted. Preparation of the ChoTA TA (5 mg, 1 mmol) and choline bicarbonate (5 mg, 1 mmol) were dissolved in 0.5 mL DMSO-d6 in a nuclear magnetic resonance (NMR) tube at 25 °C and left to react for 30 min. ChoTA as a yellow transparent liquid was obtained. Synthesis of compound i-LCPD n:m To prepare the ChoTA solution with excess TA, TA (5 g, m mmol) and choline bicarbonate (n mmol) with several molar ratios (n:m = 1∶1, 0.8∶1, 0.7∶1, and 0.6∶1) were dissolved in 5 mL ethanol in a glass vessel-equipped magnetic stirrer at 25 °C and left to react for 30 min. A transparent solution composed of ChoTA and TA in ethanol with a yellow color was obtained. Then, the solution was poured into a polytetrafluoroethylene mold and reacted at 25 °C for 12 h at ambient conditions followed by another 12 h maintained in a vacuum to produce i-LCPD n:m. Characterizations and measurements All NMR spectra were recorded on a Bruker AVANCE 600 NMR spectrometer (Bruker, Billerica, Germany) using DMSO-d6 as solvent. The attenuated total reflectance (ATR) Fourier transform infrared spectroscopy (FTIR) spectra were recorded on a Thermo Scientific Nicolet 8700 spectrometer (Thermo Fisher Scientific, Waltham, Massachusetts, United States). To measure the refractive index, an Abbe refractometer WYA-2W (Shanghai Instrument and Electrical Co., Ltd., Shanghai, China) was employed. A Jasco V-630 UV-visible spectrophotometer (JASCO, Tokyo, Japan) was used to evaluate the optical transmittance and the degradation of the polymers. The Raman tests were performed on a Laser Micro-Raman spectrometer (Renishaw, Wotton-under-Edge, England) equipped with a high-performance grade Leica microscope with a 532 nm excitation wavelength. The i-LCPDs were evaluated using an Agilent PL-GPC50 PL (Agilent Technologies Co. Ltd., Santa Clara, California, United States) gel Olexis column and a differential refractive index detector using DMSO as the eluent. Dextran (molecular weight: 410,000, 18,500, and 2800 g mol−1) was used for calibration. The morphology and elemental distribution of the samples were accessed using a field-emission scanning electron microscope (FE-SEM, HITACHI SU-8010, Tokyo, Japan) and energy-dispersive X-ray spectroscopy (Oxford Inca X-Max, Oxford, United Kingdom). Real-time detected viscosity tests were carried out on an Anton Paar MCR702 with a solution mode rotor by applying 5% strain at a frequency of 1 Hz. Frequency sweep viscosity tests were performed on an Anton Paar MCR702 (Anton Paar, Graz, Austria) with a solution mode rotor by applying 5% strain at shear rates from 0.1 to 100 s−1. The polarized optical images were obtained using a polarizing microscope (OLYMPUS BX53-p; Olympus Corporation, Tokyo, Japan). X-ray diffraction (XRD) patterns of the samples were recorded on a rotating anode X-ray powder diffractometer (Bruker D8 ADVANCE; Bruker, Billerica, Germany) with Cu Kα radiation at 2θ of 5–50°. The mechanical properties of the samples were investigated using an MTS E42 tensile machine (MTS Systems Corporation, Eden Prairie, Minnesota, United States) with a 100 N load cell. Uniaxial tensile tests and cyclic tensile tests were performed at a stretching speed of 50 mm min−1 unless otherwise noted. Impedance spectroscopy was recorded on a CHI670E electrochemical analyzer (Shanghai Chenhua, Shanghai, China). The ionic conductivity of the i-LCPDs was determined using the formula of σ = L/AR, where L represents the length of the i-LCPDs, A is the cross-sectional area of the i-LCPDs, and R denotes the bulk resistance. Thermogravimetric analysis (TGA) tests were performed on a TG 8209 F1 (NETZSCH, Selb, Germany) from 40 to 600 °C at a heating rate of 10 °C min−1 under a nitrogen atmosphere. Differential scanning calorimetry (DSC) tests were carried out on a DSC-822 (Mettler Toledo, Geneva, Switzerland) at a heating rate of 10 °C min−1 under a nitrogen atmosphere. Furthermore, dynamic mechanical analysis (DMA) tests were conducted on a DMA1 (Mettler Toledo, Geneva, Switzerland) at a heating rate of 5 °C min−1 and frequency of 1 Hz under an air atmosphere. The electrical resistance of the samples was monitored using a Keithley DMM7510 multimeter (Keithley, Cleveland, Ohio, United States). Continuous scanning rheological tests were also performed in a TA Instruments Discovery HR-2 rheometer (TA Instruments, New Castle, Delaware, United States) with a 25 mm plate–plate geometry of samples with thicknesses of 1 mm by applying different strains at a frequency of 1 Hz. The treated cells were imaged by a fluorescent microscope (DMI3000B, Leica, Wetzlar, Germany). The absorbance at optical density (OD) 450 nm was detected by a microplate reader (Synergy, Biotech, Winooski, Vermont, United States). Computational methods The molecular structure of TA/ChoTA was optimized using Gaussian 09 software at the B3LYP/6-31G** level.33,34 The Implicit Solvent Electrostatic Potential Continuum Model solvation model was undertaken to execute the geometrical optimization of TA/ChoTA using ethanol as solvent. The theoretical calculations of electrostatic potential (ESP) distribution were obtained by wave function analysis with Multiwfn 3.8,35,36 and the color-mapped iso surface graphs of the ESP were obtained using the VMD 1.9.4 program.37 We employed the Vienna Ab initio Simulation Package to perform all density functional theory calculations with the generalized gradient approximation using the Perdew–Burke–Ernzerhof functional. We chose the projected augmented wave potentials to describe the ionic cores and take valence electrons into account using a plane wave basis set with a kinetic energy cutoff of 400 eV. Geometry optimizations were performed with a force convergency less than 0.05 eV/Å, and the electronic energy was considered self-consistent when the energy change was smaller than 10−5 eV, where the same convergency was applied for the locating of transition states through the constrained optimizations. Γ-centered (1 × 1 × 1) Monkhorst−Pack K-point grids were used for calculation. All atoms were relaxed in all the calculations. Results and Discussion Design, synthesis, and chemical structural characterization of i-LCPDs Neutralization of TA and choline bicarbonate yielded ionic liquid ChoTA ( Supporting Information Scheme S1). The chemical structure of ChoTA was confirmed by proton and carbon NMR (1H NMR, 13C NMR) spectra ( Supporting Information Figures S1 and S2). The copolymerization of ChoTA and excessive TA via ROP produced i-LCPD n:m, where n:m denoted the molar ratio of choline bicarbonate and TA ( Supporting Information Schemes S2 and S3), and their structures were proved by 1H NMR ( Supporting Information Figures S3–S5) and 13C NMR analysis ( Supporting Information Figures S6 and S7). The proposed method of the polymerization process is illustrated in Figure 1a,b. The ChoTA and TA were dissolved in ethanol and poured into a mold. ChoTA self-assembled to form a liquid crystal phase under the influence of solvent evaporation and the electrostatic effect of the anion and cation pairs.25,38 After a period of time, polymeric films were obtained. The characteristic peaks of TA, choline bicarbonate, ChoTA, and i-LCPD 1∶1 were investigated by FTIR tests ( Supporting Information Figure S8). After the addition of choline bicarbonate to TA, the stretching vibration of the C=O bond in the –COOH group shifted from 1686 cm−1 to an asymmetric stretching vibration at 1557 cm−1 and a symmetrical stretching vibration at 1390 cm−1. This change confirmed the deprotonation of TA by choline bicarbonate. Figure 1 | The polymerization process of i-LCPDs. (a) The proposed chemical reaction for the synthesis of i-LCPDs. (b) The schematic illustration of self-assembly and polymerization of i-LCPDs. Download figure Download PowerPoint Several techniques were employed for further characterization of the chemical structure of the prepared i-LCPDs. 1H NMR spectra ( Supporting Information Figure S3) and Raman spectra ( Supporting Information Figure S9) confirmed the successful ROP and consequently, a facile preparation of i-LCPDs. Gel permeation chromatography (GPC) determined the number-average molecular weight (Mn) of the synthesized i-LCPDs n:m (1∶1, 0.8∶1, 0.7∶1, and 0.6∶1) to be 522, 571, 310, and 772 kDa, respectively ( Supporting Information Figure S10). The polymer dispersity indices of the aforementioned i-LCPDs were approximately determined to be 5.7, 5.5, 7.4, and 4.9, respectively. In the i-LCPDs, the hydrogen atoms of –OH groups functioned as hydrogen bond donors, while the oxygen atoms of C=O in –COOH and –COO− groups acted as hydrogen bond acceptors.39–41 In FTIR spectra ( Supporting Information Figures S11 and S12), the i-LCPDs n:m (0.8∶1, 0.7∶1, and 0.6∶1) showed C=O stretching vibration bands of –COOH at 1708, 1701, and 1698 cm−1, while the asymmetric stretching vibration bands in –COO− were located at 1555, 1552, and 1551 cm−1, respectively. The peak intensity of -COOH increased, while that of COO− decreased. This observation confirmed that with the increase in TA content, the number of –COOH groups in the system increased, while the number of COO− groups decreased. The increase of –COOH increased the number of hydrogen bonds in the polymer network. Scanning electron microscopy (SEM) ( Supporting Information Figure S13) showed the highly dense and smooth surface of i-LCPDs film with a uniform elemental distribution. Reaction kinetics analysis It was interesting to find that the polymerization rate of ChoTA was higher than that of TA. 1H NMR spectra and 13C NMR spectra were used to compare the chemical structures of TA and ChoTA. After the deprotonation, the chemical shifts of the farthest protons (Ha, Hb) on the cyclic dithiolane ring shifted upfield (Figure 2a), which was induced by the electron-donating performance of carboxylate. As the degree of deprotonation in the i-LCPDs increased, the chemical shifts of the protons on the side chain moved upfield ( Supporting Information Figures S4 and S5). In addition, the chemical shifts of the carbon atoms that were distant from the deprotonated carboxyl group were significantly shifted to higher magnetic field values (upfield) with an increase in the degree of deprotonation ( Supporting Information Figures S6 and S7). Therefore, it was concluded that upon deprotonation, the carboxyl group likely transformed into a carboxylate group, acting as an electron-donating substituent. The combined inductive and field effects resulted in a redistribution of the electron density on the cyclic dithiolane ring, leading to polarized disulfide bonds. This polarization facilitated the formation of sulfur anions when subjected to nucleophilic attack by carboxylate ions. As a result, the ROP process was greatly enhanced. The molecular simulation of TA and ChoTA in ethanol was carried out, and the quantitative molecular analysis of the obtained wave functions was carried out by Multiwfn. The ESP at the nuclear position (Figure 2b) and the average ESP at the local van der Waals surface of the atom ( Supporting Information Figure S14) were obtained. Figure 2b exhibited the ESP of carbon and hydrogen atoms in ChoTA, revealing that these atoms had a more negative potential compared to TA. This observation suggested that after deprotonation, the atoms on the cyclic dithiolane ring experienced an increase in electron density, indicating a higher electron density on the ring. The ESPs of sulfur atoms S1 and S2 changed from –59.19068 a.u., –59.19522 a.u. to –59.19067 a.u., –59.20151 a.u., respectively. This inverse variation further confirmed the polarization of the S–S bond. Additionally, the average ESP on the local van der Waals surface of the ChoTA atoms was lower compared to TA, indicating an increase in electron density on the molecule's surface after deprotonation. Furthermore, the absolute difference in surface potential between S1 and S2 increased from 2.11 to 4.31 kcal/mol, providing further evidence of S–S bond polarization. Figure 2 | Deprotonation in dynamic disulfide bond system. (a) Magnified view of 1H NMR spectra of TA, choline bicarbonate, and ChoTA. (b) The ESP at the nuclear position (c) Real-time detected Raman spectra of ChoTA solution. (d) The energy required for S–S bond breaking in TA and ChoTA simulated by climbing image nudged Download figure Download PowerPoint The of the cyclic dithiolane ring-opening reaction was monitored by a Raman the in peak and chemical of the S–S bond peak in the Raman spectra of with different ChoTA and TA the reactivity of the S–S bond in ChoTA and TA was The peak of the S–S bond shifted from to and cm−1 after deprotonation ( Supporting Information Figure indicating the of the cyclic dithiolane In addition, the S–S peak of ChoTA changed rapidly (Figure As the ratio of TA increased, the rate of the S–S bond peak ( Supporting Information Figures The viscosity change of for the with different ratios was monitored in using a rheometer at a The of viscosity change of the solution ChoTA was significantly than for As the of TA increased, the viscosity change was ( Supporting Information Figure further density functional theory calculations were conducted to the energy required for the ROP of TA and ChoTA. The climbing image nudged method was employed to the ROP process of the cyclic dithiolane ring structure ( Supporting Information Figure The bond energy of the S–S in the TA was determined to be and to after the deprotonation of TA to form ChoTA (Figure Accordingly, the of the S–S bond be after deprotonation. the in reaction kinetics from the molecular structure to the it was confirmed that deprotonation significantly promoted the ROP crystal structural and thermal characterization of the prepared i-LCPDs As solvent Accordingly, be an structure in the polymer The of the optical images of i-LCPDs under and polarized revealed the formation of liquid crystal structures (Figure and Supporting Information Figures polarized the polymer film a liquid crystal In the i-LCPD 1∶1 in Figure remarkable under polarized The frequency sweep mode of the rheological tests was employed to evaluate the viscosity at 1 and h after the of the i-LCPD n:m (Figure The viscosity of the solution of i-LCPD 1∶1 at 1 h was significantly higher than the at the its viscosity was several of higher than for the This observation suggested that the reaction rate of the i-LCPD 1∶1 solution rapidly increased the polymerization, for the ionic liquid to into liquid the of liquid under polarized be As the degree of deprotonation increased, the of the i-LCPDs (Figure This confirmed our the between reaction and As the reaction rate increased, the rate of viscosity also was for the to into an Figure | i-LCPDs (a) and polarized microscopy images of the prepared i-LCPDs. i-LCPD i-LCPD i-LCPD i-LCPD (b) Frequency sweep viscosity of the i-LCPDs at 1 and (c) The patterns of the i-LCPDs Download figure Download PowerPoint i-LCPDs were yellow elastomers with high ( Supporting Information Figure The average transmittance of the i-LCPDs with a of 0.5 mm at of nm was ( Supporting Information Figure The the i-LCPDs exhibited between 100 and while the thermal were the of °C ( Supporting Information Figure an increase in TA content, the polymerization rate providing more for ChoTA to and form a liquid crystal the thermal of the i-LCPDs, such as i-LCPD i-LCPD i-LCPD and i-LCPD In addition, was employed to evaluate the thermal properties ( Supporting Information Figure of the prepared i-LCPDs. The confirmed glass transition in the of to The of i-LCPD n:m and increased and when the structure of the liquid was more In the the i-LCPDs showed a lower glass transition temperature where with the increase of the liquid crystal the from to approximately °C ( Supporting Information Figure performance of the mechanical and electrical properties of the prepared i-LCPDs The mechanical properties of i-LCPDs be by the of the liquid crystal i-LCPD and with a refractive of ± ( Supporting Information Figure Uniaxial and cyclic tensile tests were performed to the mechanical properties of the i-LCPDs. As the liquid crystal phase in the polymer increased, the mechanical properties of the (Figure and Supporting Information Figure In the tensile the breaking of the i-LCPD n:m and at a stretching rate of 50 mm min−1 increased from ± to ± the at increased from ± to ± the of the was greatly ± to ± 0.1 ( Supporting Information Figure The at increased from ± to ± In addition, the cyclic tensile tests showed in the prepared i-LCPDs ( Supporting Information

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