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Olefin cross-metathesis is a valuable new approach for imparting functional variety to cellulose ethers. Starting from commercially available ethyl cellulose, terminally unsaturated alkyl groups were appended as metathesis handles by reaction with allyl chloride, 5-bromo-1-pentene, 7-bromo-1-heptene and 11-bromo-1-undecene, employing sodium hydride...
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... of using commer- cially available and easily handled ruthenium carbene-based catalysts, and has broad tolerance of functional groups. [33][34][35][36][37][38] While there are many variants of OM, we have focused on olefin cross-metathesis (CM) due to its high selectivity, excel- lent efficiency, and ability to append different functional groups. Fig. 1 illustrates the structure of Hoveyda-Grubbs' 2 nd generation catalyst which shows high catalyst reactivity and selectivity for olefin CM. [39][40][41][42][43] In using CM to modify polymers, the major issue is the selectivity for CM at the expense of self-metathesis (SM). SM leads to cross-linking, and cross-linking leads to poor ...
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... In order to ensure against undesired SM and crosslinking, we made three experimental choices: (1) use of Grubbs type II, electron-poor, less reactive olefins as part- ners; (2) use of the partner in excess to limit self-reaction of the cellulose derivatives; and (3) use of the highly reactive and selective Hoveyda-Grubbs' 2 nd generation catalyst (Fig. 1). For initial studies we selected type II olefin partners acrylic acid (AA) and its ester methyl acrylate (MA), both electron-poor, relatively unreactive olefins. Initial CM reaction of EC2.58C3 employed 5 mol% Hoveyda-Grubbs' 2 nd generation catalyst in 0.1 mol L −1 solution of terminal olefin under nitrogen protec- tion for 2 h. A ...
Citations
... For example, cationic HEC derivatives bearing quaternary ammonium groups can be prepared by etherification of HEC and have been demonstrated to be useful as surfactants in cosmetics (Svensson et al. 2003;Zhou et al. 2004). The Edgar group has applied various chemical methods including olefin cross-metathesis to append terminal carboxylic acid, ester, and amide groups to cellulose ethers for amorphous solid dispersion (ASD) applications (Dong and Edgar 2015;Dong et al. 2016aDong et al. , b, 2017b. Through this strategy, a wide range of cellulose ether derivatives with enhanced ASD performance was prepared, and their structureproperty relationships were thoroughly investigated, illustrating the potential of applying new chemistries to cellulose ether modification (Dong et al. 2017a). ...
Chemical modification of cellulose is challenging due to its low reactivity and poor solubility. Halogenation followed by displacement reactions has been demonstrated to be a valuable strategy for appending new functionalities to the anhydroglucose rings of cellulose and cellulose derivatives. In this paper, we report a simple and efficient pathway to modify the inexpensive, commercial cellulose ether, hydroxyethyl cellulose (HEC). First, methanesulfonyl chloride (MsCl) in N, N-dimethyl formamide (DMF) can selectively chlorinate the terminal primary hydroxyl groups from hydroxyethyl cellulose (HEC), thereby affording high terminal chloride content. Then, the resulting chlorinated HEC undergoes displacement reactions with various nucleophiles including azide (NaN3), amine (1-methylimidazole), and thiols (3-mercaptopropionic acid and 2-mercaptoethanol). All products were characterized by NMR and FT-IR spectroscopic methods. Exploiting this strategy, we prepared a library of HEC derivatives, including cationic and anionic derivatives, which are of great interest in various applications including as surfactants, in gas separation membranes, and as crystallization inhibitors in amorphous solid dispersions for oral drug bioavailability enhancement.
... HPC (M n 100,000 g/mol, degree of substitution (DS) (hydroxypropyl) = 2.2, molar substitution (MS) (hydroxypropyl) = 4.4, determined by 1 H NMR spectroscopy (Dong and Edgar 2015)), was purchased from Acros Organics. Aqueous sodium hypochlorite solution (11-15% available chlorine) was purchased from Alfa Aesar. ...
Oligo(hydroxypropyl)-substituted polysaccharides can be chemoselectively oxidized to introduce ketone groups at the termini of the side chains. These ketone-substituted polysaccharides, including oxidized hydroxypropyl cellulose, have been shown to be suitable components for preparation of in situ forming, all-polysaccharide hydrogels where chitosan is the reactive partner. This class of hydrogels exhibits several advantages including injectability, the ability to self-heal, and the absence of small molecule crosslinkers, therefore they have considerable promise for biomedical applications. Their strong potential inspires us to broaden the range of their application to include thermoresponsive hydrogels. Herein, we design and prepare a series of oxidized hydroxypropyl cellulose hydrogels by reaction with Jeffamines. Jeffamines themselves are polyethylene oxide-b-polypropylene oxide-b-polyethylene oxide triblock copolymers with two terminal amines. They display thermal responsivity, and are biocompatible with some tissues and under some circumstances. The mechanical properties of these Jeffamine/oxidized hydroxypropyl cellulose hydrogels were characterized by rheometry, revealing that hydrogel storage modulus could be tuned (3, 300–21, 000 Pa) by controlling temperature (25–60 °C) and Jeffamine chain length (600, 900, 1900 g/mol). Furthermore, these hydrogels display self-healing properties and high swelling ratios. Hydrogel microstructures were characterized by scanning electron microscopy. We investigated the potential for drug incorporation into the hydrogels. Overall, this study demonstrated synthesis and potential of these Jeffamine/oxidized hydroxypropyl cellulose hydrogels for in situ formation and thermally responsive behavior, thereby broadening the family of oxidized hydroxypropyl cellulose-based hydrogels.
Graphical abstract
... In recent decades, "click chemistry" methods have been developed that share attractive features (e.g., rapid kinetics, mild conditions, high efficiency, high yield) and some have been applied to polysaccharides [4]. Azide-alkyne Huisgen cycloaddition [5], olefin cross-metathesis [6][7][8], and the thiol-ene reaction [9,10], are among those reported to have been applied to polysaccharides [6,11,12], affording a broad range of pathways for designing bioconjugates. ...
Polysaccharide conjugates are important renewable materials. If properly designed, they may for example be able to carry drugs, be proactive (e.g., with amino acid substituents) and can carry a charge. These aspects can be particularly useful for biomedical applications. Herein, we report a simple approach to preparing polysaccharide conjugates. Thiol-Michael additions can be mild, modular, and efficient, making them useful tools for post-modification and the tailoring of polysaccharide architecture. In this study, hydroxypropyl cellulose (HPC) and dextran (Dex) were modified by methacrylation. The resulting polysaccharide, bearing α,β-unsaturated esters with tunable DS (methacrylate), was reacted with various thiols, including 2-thioethylamine, cysteine, and thiol functional quaternary ammonium salt through thiol-Michael addition, affording functionalized conjugates. This click-like synthetic approach provided several advantages including a fast reaction rate, high conversion, and the use of water as a solvent. Among these polysaccharide conjugates, the ones bearing quaternary ammonium salts exhibited competitive antimicrobial performance, as supported by a minimum inhibitory concentration (MIC) study and tracked by SEM characterization. Overall, this methodology provides a versatile route to polysaccharide conjugates with diverse functionalities, enabling applications such as antimicrobial activity, gene or drug delivery, and biomimicry.
... The proton peaks of the cellulose structure can be all observed at 3.32-4.18 ppm region (25,(27)(28)(29). ...
In this study, the hydroxyl groups of cellulose acetate butyrate (CAB) oligomer were reacted with toluene diisocyanate-hydroxyethyl methacrylate (TDI-HEMA) adduct, in order to improve properties of CAB such as flexibility, thermal stability etc. Then the obtained modified CAB oligomer was characterized by FTIR and 1H NMR analysis. UV-curable coating formulations were prepared by using the modified CAB oligomer, and then applied on cotton fabrics in order to reinforce cotton fabrics and make them durable to outdoor environments. Cotton fabrics were treated with a commercial washing detergent, alkali solution, and an enzyme prior to the UV-coating, in order to increase the adhesion between the cotton fabric and coating layer. Washed and coated fabrics were evaluated in terms of absorbency, tensile, and adhesion properties, respectively. Light microscopy was employed to observe the effects of washing processes on fibre, and to show the abrasion deformation on coated fabric. Results proved that the best washing process in fibrillation was found as enzymatic washing due to the having the highest adhesion strength and the least deformation against abrasion.
... The Peaks appeared in the regions 3.0-4.5 ppm, especially in the HPC and CMC, corresponding to cellulose backbone. [41] The interaction between the drug and polymer blends could not be seen in 1 H NMR, as in the case of emulsion the drug was dissolved in oil and the polymer was dissolved in water. ...
Cephalexin loaded electrospun nanofibers with core-shell structures were prepared from poly(vinyl alcohol) (PVA) blended with various biopolymers such as chitosan (CH), carboxymethyl cellulose (CMC), carboxymethyl starch (CMS), and hydroxyproyl cellulose (HPC) in PVA:biopolymer ratio of 90:10. The electrospun nanofiber mats were cross-linked by heat treatment to avoid disintegration in water. Molecular interactions between the polymeric chains and the drug were analyzed by Fourier transform infrared spectroscopy (FTIR), nuclear magnetic resonance spectroscopy (NMR), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). The morphology of nanofiber mats was studied by field emission scanning electron microscope (FE-SEM), and the core-shell structure formation through emulsion electrospinning was confirmed by transmission electron microscope (TEM) and confocal laser scanning microscope (CLSM). The in vitro drug release profile was studied and the mechanism was determined through kinetic models using non-linear regression methods. Drug release was gradual within the first 8 h. Furthermore, release predominantly occurred by a diffusion mechanism which makes this system suitable for wound healing treatment.
... The -carboxy cellulose ester/ether derivatives used in this study were prepared through a previously reported olefin cross-metathesis (CM) pathway, and are fully described including degree of substitution (DS) values in Table 1. [32][33][34][35] The mild nature of CM (37 ˚C, 2-3 h) permits attachment of a wide variety of functional groups (including carboxyl and different esters), and subsequent hydrogenation eliminates the tendency to crosslink, which would lead to loss of solubility of ,-unsaturated CM products. 13,36 Furthermore, instead of hydrogenation, a tandem CM/thiol-Michael addition also removes ,-unsaturation, while affording branched structures and additional functionality through the thioether. ...
Amorphous solid dispersions are widely used to enhance the oral bioavailability of poorly water soluble drugs. Polymeric additives are commonly used to delay crystallization of the drug from the supersaturated solutions formed upon ASD dissolution by influencing the nucleation and growth of crystals. However, there is limited evidence regarding the mechanisms by which polymers stabilize supersaturated drug solutions. The current study used experiments and computational modeling to explore polymer‒drug interactions in aqueous solutions. Nucleation induction times for supersaturated solutions of nine drugs in the presence of five newly synthesized cellulose-based polymers were evaluated. The polymers had carboxylic acids substituents with additional variations in the side-chain structure; (1) one with a single side chain and a carboxylic acid termination, (2) three with a branched side chain with terminated with a carboxylic and an alcohol group (varying the cellulose linkage and the length of the hydrocarbon side-chain), and (3) one with a branched side chain with two carboxylic acid end groups. The polymers with a short side chain and one carboxylic acid were effective, whereas the polymers with the two carboxylic acids or a long hydrocarbon chain were less effective. Atomic force microscopy experiments, evaluating polymer adsorption onto amorphous drug films, indicated that the effective polymers were uniformly spread across the surface. These results were supported by molecular dynamics simulations of a polymer chain in the presence of a drug aggregate in an aqueous environment, whereby the effective materials had a higher probability of establishing close contacts and more negative estimated free energies of interactions. The insights provided by this study provide approaches to design highly effective polymers to improve oral drug delivery.
... 13 In recent years, a number of cellulose derivatives has been produced, taking advantage of innovative synthetic approaches. 10,[14][15][16][17][18][19][20] The ability of these polymers to inhibit the crystallization of poorly water soluble drugs has been evaluated in turn. 8, 21 Ilevbare, et al. reported nucleation induction times for three model drugs in the presence of newly synthesized and commercial polymers. ...
Polymers play a key role in stabilizing amorphous drug formulations, a recent strategy employed to improve drug solubility and bioavailability of drugs delivered orally. However, the molecular mechanism of stabilization is unclear, therefore, the rational design of new crystallization-inhibiting excipients remains a substantial challenge. This article presents a combined experimental and computational approach to elucidate the molecular features that improve the effectiveness of novel cellulose polymers as solution crystallization inhibitors, a crucial first step towards their rational design. Polymers with chemically diverse substituents including carboxylic acids, esters, ethers, alcohols, amides, amines, and sulfides were synthesized. Measurements of nucleation induction times of the model drug telaprevir show that the only effective polymers contained carboxylate groups in combination with an optimal hydrocarbon chain length. Computational results indicate that polymer conformation as well as solvation free energy are important determinants of effectiveness at inhibiting crystallization, and show that simulations are a promising predictive tool in the screening of polymers. This study suggests that polymers need to have an adequate hydrophilicity to promote solvation in an aqueous environment, and sufficient hydrophobic regions to drive interactions with the drug. Particularly, the right balance between key substituent groups and lengths of hydrocarbon sidechains is needed to create effective materials.
... Preparation of Ethyl Pent-4-enyl Cellulose (EC2.58C5). This etherification procedure follows one in our previous paper; 30 we summarize it here. In brief, EC2.58 (1.0 g, 4.30 mmol AGU, 1.85 mmol −OH) was first dissolved in 10 mL of anhydrous THF at room temperature and then NaH (95%, 0.47 g, 18.5 mmol, 10 equiv) was added. ...
... We have reported successful CM of derivatives of ethyl cellulose EC2.58, bearing ω-unsaturated alkene substituents of ≥5 carbons (5, 7 and 11). 30 We chose to focus on C5 substituents for this study because reaction with C5 alkene substituents was most efficient, reaching 100% CM conversion within 2 h and because the relatively shorter length would provide higher hydrophilicity than C7/C11. To overcome the hydrophobicity of commercial ethyl cellulose, we first explored another commercially available cellulose ether, methyl cellulose with DS(Me) 1.82 (MC1.82) and DS(OH) 1.18, which is more hydrophilic and has a high , illustrating that it is substantially more hydrophilic than EC2.58. ...
... The ratio of E to Z configurations is >10 for all CM products, which is in accordance with previous reports using the HG II catalyst. 29,30 For CM partners like MA, HEA, tBuA, and BA, the proton resonances of the corresponding ester substituents, for example, the MA methyl singlet (3.61 ppm) or the BA aromatic resonance (7.32 ppm), are also diagnostic of successful CM. ...
Design of cellulose ether-based amphiphiles has been difficult and limited because of the harsh conditions typically required for appending ether moieties to cellulose. Olefin cross-metathesis recently has been shown to be a valuable approach for appending a variety of functional groups to cellulose ethers and esters, providing that an olefin handle for metathesis can be attached. This synthetic pathway gives access to these functional derivatives under very mild conditions and at high efficiency. Modification of ethyl cellulose by metathesis to prepare useful derivatives, for example for solubility and bioavailability enhancement of drugs by amorphous solid dispersion (ASD), has been limited by the low DS(OH) of commercial ethyl cellulose derivatives. This is problematic since ethyl cellulose is otherwise a very attractive substrate for synthesis of amphiphilic derivatives by olefin metathesis. Herein we explore two methods for opening up this design space for ether-based amphiphiles, for example permitting synthesis of more hydrophilic derivatives. One approach is to start with the more hydrophilic commercial methyl cellulose, which contains much higher DS(OH) and therefore is better suited for introduction of high DS of olefin metathesis "handles". In another approach, we explored a homogeneous one-pot synthesis methodology from cellulose, where controlled DS of ethyl groups was introduced at the same time as the ω-unsaturated alkyl groups, thereby permitting complete control of DS(OH), DS(Et), and ultimately DS of the functional group added by metathesis. We describe the functionalized derivatives available by these successful approaches. In addition, we explore new methods for reduction of the unsaturation in initial metathesis products, in order to provide robust methods for enhancing product stability against further radical-catalyzed reactions. We demonstrate initial evidence that the products show strong promise as amphiphilic matrix polymers for amorphous solid dispersion and other applications.
... In previous studies (Dong & Edgar, 2015;Meng, Matson, & Edgar, 2014a,b), our group discovered that olefin cross-metathesis chemistry (CM) can be successfully applied to polysaccharides to synthesize discrete, non-crosslinked derivatives, enabling mild and modular side-chain modification of polysaccharides to afford products with carboxylic acid and a variety of other terminal functionalities. In the CM approach, terminally olefinic cellulose esters react with other functionalized alkenes under ruthenium catalysis (Meng et al., 2014b), and thus incorporate the corresponding functional group onto the cellulose side-chain. ...
... cellulose derivatives) with terminally olefinic side-chain react with different CM partners such as acrylic acid and its esters. With the help of this chemistry, we (Dong & Edgar, 2015;Meng et al., 2014a,b) and others (Malzahn et al., 2014) have been able to introduce a variety of functional groups onto polysaccharide backbone in a mild, modular and efficient manner. In the current study, we examined the feasibility of using acrylamides as CM partners to obtain cellulose esters bearing amide functionalities, by the reaction scheme illustrated by Fig. 2. Terminally olefinic cellulose esters were used as the substrates for CM reaction, for example cellulose undec-10-enoate with DS(Un) 0.67 (CA-Un067). ...
Cellulose esters with amide functionalities were synthesized by cross-metathesis (CM) reaction of terminally olefinic esters with different acrylamides, catalyzed by Hoveyda-Grubbs 2nd generation catalyst. Chelation by amides of the catalyst ruthenium center caused low conversions using conventional solvents. The effects of both solvent and structure of acrylamide on reaction conversion were investigated. While the inherent tendency of acrylamides to chelate Ru is governed by the acrylamide N-substituents, employing acetic acid as a solvent significantly improved the conversion of certain acrylamides, from 50% to up to 99%. Homogeneous hydrogenation using p-toluenesulfonyl hydrazide successfully eliminated the α,β-unsaturation of the CM products to give stable amide-functionalized cellulose esters. The amide-functionalized product showed higher Tg than its starting terminally olefinic counterpart, which may have resulted from strong hydrogen bonding interactions of the amide functional groups.
