The functional epoxides have been synthesized from a large number of mentioned reactions for application in various fields such as cosmetics, detergents or surfactants, lubricating oils and textiles. This thesis describes the applications of functional epoxide for drug delivery systems and the sustainable lithium-ion battery. First, a broad time frame of micelle degradation was performed by varying the repeating unit of two monomers, tetrahydropyranyl glycidyl ether (TPGE) and 1-ethoxyethyl glycidyl ether (EEGE).
As increasing content of TPGE, the times of micelle degradation would have been controlled from 1 day to more than 10 days in weak acid condition. In addition, new acid-degradable epoxide, tetrahydrofuranyl glycidyl ether (TFGE) has been reported to reveal the role of monomer; the monomer structure or hydrophobic-hydrophilic balance of polymer. This study provides the insight that the balance of hydrophobicity is a critical factor for not only micelle formation but also micelle breakdown, although the monomer structures inversely affect the hydrolysis rate.
Second, the functional epoxides were reacted with the cheap, non-toxic, readily available CO2 to form functional cyclic compounds. These cyclic carbonates are expected to scavenge hydrofluoric acid or other acids, reducing lithium-ion battery performance.
Introduction of epoxide
Ethylene oxide (EO) is the simplest epoxide, a three-membered ring consisting of two carbon atoms and one oxygen. Therefore, a number of reactions using EO have been reported; hydration of EO providing ethylene glycol1, halide addition2, crown ether synthesis3, addition of ethylene carbonate producing carbon dioxide4, polymerization5, etc. However, it has been challenging to introduce the functional group into EO not only for wider application but also safe experimental process because it is difficult to control the gas and highly toxic.
Recently, many researchers have designed functional epoxide for easy control of liquid dissolution and further application (Figure 1.1). First of all, glycidol, which is methoxy-substituted ethylene oxide, would be polymerized via anionic ring-opening polymerization (AROP), resulting in hyperbranched polyglycerol compared to ethylene oxide polymerized to linear poly(ethylene glycol) via AROP. In 1987, Fitton and co-workers reported a method to protect the hydroxyl group by reacting glycidol with ethyl vinyl ether, yielding 1-ethoxyethyl glycidyl ether (EEGE). 6 Since the new epoxide EEGE is resistant to strong basic states, they performed ring expansion reaction with EEGE in ground state.
It is also easy to deprotect in the soft state, then they can proceed to further modification using the hydroxyl group. In this context, the design and synthesis of functional epoxides have been important for use in a variety of chemical developments.
Application of epoxide
In addition, Kleij and his colleague synthesized biorenewable polycarbonates using limonene oxide monomer.7 Interestingly, the functional polycarbonates they synthesized showed good modulation of the glass transition temperature (Tg) up to 180 °C, while the Tgof conventional aliphatic polycarbonates is up to 40 °C. As one of the most popular examples, hyperbranched polyglycerol (hbPG) has been synthesized using glycidol monomer via cationic or anionic ring-opening polymerization (Figure 1.2).11,12hbPG has many advantages, not only similar properties with PEG such as water solubility, low toxicity, immunogenicity and biocompatibility, but also the better properties compared to PEG, e.g. antifouling properties, oxidation stability, and easy synthesis using liquid monomer.13–15 It also has multihydroxy functionality, therefore it can be further modified, as well as having a variety of topologies (Figure 1.3). After these monomers are polymerized to linear polymers via AROP, they can be easily deprotected, yielding linear polyglycerol (linPG) (Figure 1.4).
The finished micelle showed superior stability compared to other micelles consisting of the polymer synthesized with mPEG and acyclic acetal monomer, EEGE. The preparation methods for drug-loaded micelles are broadly divided into two parts (Figure 1.6).21 The first method is the directional dissolution method, in which amphiphilic copolymer and drugs are dissolved in aqueous solution at the same time. Stimuli-responsive micelles have used for smart drug delivery that the release of drugs occurs upon special stimulus such as temperature, light, redox or pH.25-28 Among them, pH-responsive micelles are one of the most popular stimuli-responsive drug carriers , the existence of different pH values.
Among them, cyclic carbonate has attracted much attention because it could be used in various fields such as electrolytes for batteries, thickeners for cosmetics, polar aprotic solvents, reactants for the synthesis of polyurethanes and polycarbonates, etc.35–40 For example, ethylene carbonate (EC ), which is a five-membered ring carbonate, is commercially used as a lithium-ion battery electrolyte, and fluoroethylene carbonate (FEC) is a well-known additive for improving the performance of a lithium-ion battery (Figure 1.8). Therefore, there has been a lot of research on catalysts for the synthesis of cyclic carbonates, such as aluminum-based systems41, cobalt-based systems42, organic catalysts43, metal halides44, metal oxides45, etc.
- Experimental Section
- Results and Discussion
Excitation spectra of pyrene in aqueous solution and CMC determination for PEG114-b-P(EEGE-co-TGE)0/27 (T4) micelles (λem= 372 nm). The percent decomposition was plotted using the I339/I332 values for pyrene calculated from the excitation spectra. The concentrations of all polymers are fixed at 0.10 mg/mL. Changes in the excitation spectra of pyrene encapsulated by micelles T0 – T4 at pH 5.0.
In vitro FRET studies for T2, T3 and T4 micelles after incubation in HeLa cells for different time periods. The green and red colors represent the DiO and DiI signals, respectively, and the yellow color indicates the overlapping signals of the two FRET dyes. The green and red colors represent the DiO and DiI signals, respectively, and the yellow color indicates the overlapping signals of the two FRET dyes.
In vitro FRET studies for T4micelles after incubation at different times by live imaging in HeLa cells. Extended 1H NMR spectra of PEG114-b-P(EEGE-co-TGE)m/ncopolymers (T0 –T4), showing the clear disappearance of the remaining phosphazene base, t-BuP4.
Potential energy profiles of the ring opening step for the protonated model compounds with respect to the interatomic distance between a carbon atom and the oxygen of a nearby water molecule. A longer bond length represents a reactant side. a) Hydrolysis mechanism and (b) 1H NMR spectra before and after hydrolysis of TFPE model compound (see Figure S4 for EEPE and TPPE), and (c) percent hydrolysis rate of all model compounds determined by 1H NMR spectra. a–b) (top) Schematic representation of the hydrolysis process and (bottom) the corresponding 1H NMR spectra before and after hydrolysis of a) EEPE and b) TPPE model compounds. Kinetic study of hydrolysis of model compounds after the first-order reaction, [A]t= concentration of model compound over time. a) Design and synthesis of TFGE epoxide monomer, (b) block copolymerization of TFGE with mPEG macroinitiator by AROP, and (c) the structures of mPEG-b-PTPGE and mPEG-b-PEEGE.
Emission spectra of pyrene with different concentrations of (a) F11, (b) F30 and (c) F47 copolymers and determination of CMC values by plotting I339/I332 as a function of polymer concentration using pyrene emission spectra. a) Hydrodynamic radius (Rh) distribution of F-series polymer micelles measured by DLS.
The size distribution analysis of the micelles was performed by dynamic light scattering (DLS, BI-APD, Brookhaven Instrument) at 90° and 30°. A 10 μL solution of pyrene (5.2 mg L−1 in DMF) was added to the solution of the PEG-b-P(EEGE-co-TGE) copolymer and the mixture was stirred for 30 min at room temperature. The encapsulation efficiency (EE) of the micelles was calculated from the fluorimeter analysis results as follows.
Then, 0.10 mL of the pyrene-containing micelle solution was slowly added to 0.9 mL of the buffer solution, and the changes in the excitation spectra were recorded. We first investigated the degradation of micelles at pH 7.4 by monitoring the change of the I339/I332 ratio of pyrene in the excitation spectra (Figure 2.16b and Figure 2.17). The rate of pyrene release was slow for the copolymers containing a higher percentage of the TGE monomer.
One is the increased stability of the micelles, as the hydrophobicity of the core was increased by the hydrophobic TGE monomers. However, the cell viability of the T3 micelle (micelle with a longer hydrophobic chain) was slightly decreased at a concentration of 500 μg mL-1. Glass transition temperature (Tg) of PEG114-b-P(EEGE-co-TGE)m/n copolymers as a function of TGE monomer mass fraction.
The encapsulation efficiency (EE) of the micelles was calculated from the fluorometer analysis results as follows. Hydrolysis of model compounds was monitored for two weeks by 1H NMR under acetic acid/sodium acetate buffer at pH 5.0 (Figure 3.12). In addition, the hydrolysis kinetics of the model compounds were evaluated by integrating the reduced methine peak (a) relative to the unchanged methyl peak of the propyl group (c).
As shown in Figure 3.2, the structural properties of the obtained polymers were characterized by 1H NMR. Interestingly, all copolymers exhibited a single Tg, indicating that the block copolymers consisted of the polyether backbone.23,24. Here, we investigated the encapsulation efficiency using a hydrophobic dye, Nile Red, in the core of the micelles.
Moreover, the micelles composed of the polymer F30 showed faster degradation (4 h) than others with a similar degree of hydrophobic block polymerization, for example E27 (12 h) and P27 (> 30 h). Finally, we demonstrated the non-toxicity of the micelles for potential pharmaceutical applications in the human body. Potential energy profiles of the protonation step for model compounds with respect to the interatomic distance between a proton and the oxygen of a ring.
19F NMR spectra of electrolyte solutions after hydrolysis tests (a) without additive, (b) with EEPC additive, (c) with TFPC additive, (d) with TPPG additive and (e) with TMSPC additive.