Scale-Up Procedure for the Efficient Synthesis of ... - ACS Publications

Article pubs.acs.org/Macromolecules

Scale-Up Procedure for the Efficient Synthesis of Highly Pure Cyclic Poly(ethylene glycol) Claas H. Hövelmann, Sebastian Gooßen, and Jürgen Allgaier* Jülich Centre for Neutron Science JCNS and Institute for Complex Systems ICS Forschungszentrum Jülich GmbH, 52425 Jülich, Germany S Supporting Information *

ABSTRACT: Poly(ethylene glycol) (PEG) is ideally suited for the synthesis of cyclic polymers. The cyclization reaction of PEG via its tosylate intermediate is well established. We improved the cyclization reaction and obtained cyclic raw products in high yields. The quantities of linear precursor and higher molecular weight condensation byproducts were low. The latter byproducts can be removed efficiently by classical fractionation using chloroform/heptane as solvent/nonsolvent pair. For the removal of linear precursor a process was developed which comprises the quantitative oxidation of alcoholic PEG chain ends to carboxyl groups and their subsequent removal with the help of a basic ion-exchange resin. The efficient cleaning processes allowed carrying out the ring closure reaction at relatively high concentrations and so increasing sample quantities. As a result, cyclic poly(ethylene glycol) was obtained in high purity up to a molecular weight of 20 000 g/mol in quantities of several grams. In order to monitor the oxidation reaction and to prove the absence of linear chains, a 1H NMR characterization technique was developed, which is extremely sensitive up to high molecular weights.

■

based on azide/alkyne or thiol/ene click reactions16−21 but also other ring closure reactions.22,23 The cyclization of poly(ethylene glycol) (PEG) represents a special case as PEG contains by nature two alcohol end groups, which can be used for the ring closure reaction. Hence, PEG was used early on for the synthesis of oligomeric and polymeric cycles.24,25 Generally, the ring closure reaction must be carried out under high dilution to minimize the reaction of two or more precursor chains to higher MW linear and cyclic products. Consequently only small sample quantities are accessible. Another limitation of this technique is the removal of unreacted linear precursor, which is difficult to carry out because of similar physical properties of the linear and the cyclic analogues. The synthesis of cyclic polymers by ring expansion was pioneered by Grubbs et al. using metathesis polymerization of cyclic alkenes.26 Later this strategy was used to synthesize a variety of other cyclic polymers.27−29 A related technique based on zwitterionic reaction centers was applied to synthesize macrocycles out of low MW cyclic esters but also other monomers.7,30−34 The polymerization techniques used for the ring expansion approach result in polymers with broader MWD and the coexistence of linear chains in the cyclic products is difficult to verify. This is especially the case for high MWs. On the other hand, detailed physical studies rely on narrow MWDs and low contents of linear chains. This is especially the case for rheological studies, where both, experimental and simulation

INTRODUCTION Cyclic polymers display unique physical properties if compared to their linear analogues.1,2 Their synthesis follows in general one of three strategies: the exploitation of ring−chain equilibria, e.g., in the case of PDMS, the ring closure technique and the ring expansion technique.3−7 In particular, the latter two strategies are widely used to synthesize cyclic polymers. In the case of the ring closure technique, the reactive chain ends of a linear precursor are used to form the cyclic structure. By contrast, the ring expansion approach involves the insertion of cyclic monomers into a low molecular weight (MW) starting compound which itself is cyclic. Using the ring closure technique a large variety of reactions was used to form cyclic structures of different polymer types. A significant advantage of this method is the use of living or controlled polymerization techniques for the synthesis of the linear precursors. This allows for equipping the chain ends with the desired functionalities and results in cyclic polymers having predetermined MWs and narrow MW distributions (MWD). Roovers et al. polymerized anionically styrene and diene monomers with difunctional initiators and the subsequent reaction of the carbanionic head groups with difunctional dichlorosilane agents yielded the cyclic products.8,9 Later protected initiators were used to form the linear precursors in combination with a large variety of different linking approaches for the cyclization reaction.10−13 These techniques allowed also the synthesis of blocky structures and other architectures.14,15 In recent years a multitude of additional processes was developed using different monomers and polymerization processes in combination with cyclization techniques mainly © XXXX American Chemical Society

Received: February 20, 2017 Revised: April 21, 2017

A

DOI: 10.1021/acs.macromol.7b00361 Macromolecules XXXX, XXX, XXX−XXX

Article

Macromolecules

at a temperature of 475 °C in a crucible in order to remove water. After 24 h the melt was cooled down to 300 °C and finally was allowed to cool down to room temperature under vacuum conditions. The dry KOH was removed from the crucible and pestled inside a glovebox. PEG2k, PEG5k, and PEG10. These polymers were purchased from Merck (Polyethylenglycol 2000) and from Sigma-Aldrich (Poly(ethylene glycol) average Mn 4,600 and poly(ethylene glycol) average Mn 10 000). PEG6k, PEG11k, PEG20k, and PEG52k. The polymers were synthesized by polymerizing EO with the initiator TEG−OH/K in dry toluene or dry THF inside a jacketed steel pressure vessel (Buchi). In a typical example (PEG11k) 28.69 g of EO, 0.450 g of TEG−OH/K (2.78 mmol) and 78 mL of THF were used. The reaction mixtures under an initial argon overpressure of about 1 bar were heated to 100 °C within about 30 min and kept at that temperature for 5 to 16 h, depending on the speed of the pressure drop. After quenching with acetic acid the solvent was distilled off, the polymer was dissolved in chloroform, washed with water, precipitated in heptane and finally freeze-dried from its benzene solution. The amounts of isolated products indicated a full conversion of EO during the polymerization event. Oxidation of PEG Using Procedure I.44 For the synthesis of HO2C-PEG2k-CO2H, 15.68 g of PEG2k (16.9 mmol OH) was dissolved in 300 mL of water together with NaBr (3.97 g, 38.6 mmol) and TEMPO (0.376 g, 2.4 mmol). The mixture was warmed to accelerate the dissolution of TEMPO. After the mixure had cooled to room temperature, sodium hypochlorite solution (187 mL, 0.46 mol) was added, and the mixture was stirred for 30 min. After the reaction was cooled in an ice bath, 30 g of NaOH, dissolved in 180 mL of water, was added slowly, followed by 200 mL of NaHSO3 solution (40%). The mixture was stirred for 20 min. After acidification to pH 1−2 with 5 M HCl it was extracted several times with chloroform. The combined chloroform phases were washed several times with water. The solvent was evaporated under reduced pressure, the polymer was precipitated in ethanol at −20 °C and the product finally dried under high vacuum conditions. HO2C-PEG5k-CO2H was synthesized under identical conditions using PEG5k (15.69 g, 6.96 mmol OH). HO2CPEG10k-CO2H was synthesized from PEG10k (15.68 g, 3.07 mmol OH) dissolved in 150 mL of water. The quantities of all other ingredients were halved in order to keep their concentrations constant. HO2C-PEG52k-CO2H was synthesized from PEG52k (9.91 g, 0.38 mmol OH) dissolved in 98 mL of water, and the quantities of the other ingredients were reduced to one-third of the values described above. Oxidation of PEG52k Using Procedure II (Entry 11, Table 3). PEG52k (500 mg, 19 μmol OH) and NaBr (30 mg, 292 μmol) were dissolved in 19 mL of water. TEMPO (78 mg, 503 μmol) and sodium hypochlorite solution (142 mg, 560 μmol) were added, and the mixture was stirred for 1 day. After the mixture was cooled in an ice bath, 80 mg of NaOH, dissolved in 2 mL of water, was added slowly, followed by 2 mL of NaHSO3 solution (40%), and the mixture was stirred for 30 min. After acidification to pH 1−2 with 5 M HCl it was first extracted two times with ethyl acetate to remove TEMPO residues. The aqueous phase was then extracted three times with chloroform. The combined chloroform phases were washed with water, the solvent was evaporated under reduced pressure, and the product was finally dried under high vacuum conditions. Ion Exchange Resin Purification Tests. Experiments using the resins Amberlite IRA402, Amberlyst A26, and DOWEX Marathon together with the polymers HO2C-PEG2k-CO2H, HO2C-PEG5kCO2H, HO2C-PEG10k-CO2H, and HO2C-PEG52k-CO2H were carried out in the following way. The activated resin (30 g) was contacted with 0.5 g of HO2C-PEG-CO2H dissolved in 5 mL of water or THF for different times. Then the liquid was removed and the resin was washed several times with water or THF. After the evaporation of water or THF the quantities of extracted material were determined gravimetrically. A detailed description of the process is given in the Supporting Information. Cyclization Reactions. Cyclic PEG2k was synthesized according to ref 25 (method A) by adding slowly a THF solution of an

results show that already small quantities of linear impurities strongly influence the behavior of cyclic polymers.35−38 In this context it must be noted that not only the synthesis of cyclic polymers is challenging but also the analytical characterization. MALDI−TOF mass spectrometry is certainly a powerful tool to demonstrate the formation of cycles and to identify possible linear precursor residues. This method, however, is limited to smaller MWs due to the loss of resolution power for longer chains. Size exclusion chromatography (SEC), on the other hand, provides only limited separation efficiency for cyclic and linear chains.39 Therefore, the detection of smaller quantities of linear material is normally not possible using SEC. Liquid chromatography at the critical condition (LCCC) is a much better choice due to its superior resolution power in separating cycles from linear structures,39−42 but it is complex in the application as a routine method. Another obstacle for more detailed experimental investigations are small sample quantities, which in the case of the ring closure method usually lie in the 10−100 mg range. Only very recently, progress has been made to scale up sample quantities.43 With these limitations in mind we developed a new procedure, based on the known cyclization of PEG.24,25 In order to remove residual linear chains, an oxidation process was established to transform the alcoholic chain ends quantitatively into carboxylic groups. In the subsequent step, a basic ionexchange resin was used to separate linear from cyclic material. The absence of linear chains was proven by a newly developed NMR based method.

■

EXPERIMENTAL SECTION

All manipulations except the polymerization reactions were carried out at a high vacuum line or in a glovebox, filled with argon (M Braun, Unilab). The water level in the glovebox was usually below 1 ppm and the oxygen level below 0.1 ppm. The flasks for all manipulations were equipped with Teflon stopcocks that allowed transferring materials between the vacuum line and the glovebox without contamination with air. The flasks which were exposed to overpressure were pressure tested to 12 bar. Materials. CaH2 (Sigma-Aldrich, ≥ 99%), (potassium tertbutanolate (Sigma-Aldrich, sublimed grade), sodium bromide (Alfa Aesar, ≥ 99%), 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) (Alfa Aesar, ≥ 98%), sodium hydrogen sulfite solution (Sigma-Aldrich, 40%), p-toluenesulfonyl chloride (tosyl chloride) (Sigma-Aldrich, ≥ 99%), and sodium hypochlorite solution (Sigma-Aldrich, 10−15% available chlorine) were used as received. The exact concentration of the sodium hypochlorite solution was determined prior to use by iodometric titration to be 2.48 M. Triethylene glycol (Fluka, ≥ 99%) was evacuated under stirring and high vacuum conditions for 1 h prior to use. Toluene (Sigma-Aldrich, 99.9%) was degassed, distilled into another flask which contained sodium metal, stirred over the sodium for at least 24 h before being degassed again and heated to 110−115 °C for 3−4 h. THF (VWR Chemicals, ≥ 99.5%) was degassed, predried over CaH2 and then distilled into a flask containing potassium metal and benzophenone. nHexane (Sigma-Aldrich, ≥ 97%) was degassed, distilled into a flask containing solvent-free n-butyllithium. Ethylene oxide (EO) (Chemogas, ≥ 99.9%) was condensed into a flask, degassed and stirred over CaH2 for 1−2 days. Partially metalated triethylene glycol (TEG−OH/ K) was used as initiator for the polymerization of EO. It was synthesized by dissolving 0.767 g of potassium tert-butanolate (6.84 mmol) in 35 mL of dry THF and adding 3.403 g of triethylene glycol (22.66 mmol). The solvent was distilled off and the liquid residue was evacuated under stirring and high vacuum conditions for 5 days to remove the formed tert-butanol quantitatively. So, 3.625 g of product were obtained. Potassium hydroxide (pro analysi, Merck) was melted B


Article

Macromolecules equimolar PEG2k/tosyl chloride mixture of into a reaction flask, containing an excess of KOH, dispersed in a mixture of THF and nhexane. Cyclic PEG6k, PEG11k, and PEG20k were synthesized under similar conditions but in higher dilution and adapting the THF/nhexane mixture to the solubility of the linear PEG. All reactions were carried out inside a glovebox, using dry solvents and dried compounds. The degree of ring formation was analyzed by SEC. The details of the syntheses and the work-up procedures are described in the Supporting Information. In order to increase the amount of ring formation for PEG20k, both the PEG concentration in the cyclization flask and the addition speed were reduced again and the ratio of tosyl chloride to PEG was varied, using molar ratios of 1.0, 1.5, 2.0, and 3.0 (method B). The synthetic details are described in the Supporting Information. Purification of Cyclization Raw Products. The raw products synthesized with method A were dissolved in chloroform and heptane was added in portions slowly under stirring. In between the heptane additions, the mixtures were stirred at low speed and room temperature for 24 h. During this period the insoluble polymer precipitated at the bottom of the flask and the supernatant liquid became clear. It was decanted into another flask and the process was repeated several times by adding more heptane. Between the heptane additions small samples were taken and after evaporation of the solvents the samples were analyzed by SEC to determine the progress of the separation procedure. After removal of all higher MW condensation products the polymer still solubilized in the solvent mixture was isolated by evaporating the solvents under reduced pressure and vacuum drying. In a typical example 19.5 g of cyclic PEG11k raw product, collected from 4 cyclization reactions, was dissolved in 0.75 L of chloroform and 2.25 L of heptane was added initially, followed by another 1.55 L over the next 5 days. After solvent removal 3.58 g of polymer was obtained. This material was dissolved in 300 mL of deionized water. The oxidation was carried out as described for procedure I using 3.89 g of NaBr (37.8 mmol), 0.366 g of TEMPO (2.3 mmol), and 187 mL of sodium hypochlorite solution (0.46 mol). The oxidized polymer (3.47 g) was isolated from its chloroform solution by evaporating the solvent under reduced pressure and vacuum drying. It was split into two portions, each dissolved in a few mL of THF. Both portions were successively contacted with the same 120 g quantity of Amberlyst A26 in dropping funnel overnight. The ion-exchange resin was prepared as described above. The cyclic PEG was separated after each treatment by continuously washing the resin with 200 mL of THF. The solvent was evaporated and the polymer was dissolved in 150 mL of ethanol. It was precipitated at −28 °C, washed with cold ethanol, and dried under vacuum conditions to obtain 2.89 g of product. The PEG20k cyclization raw product synthesized with method B was first oxidized using the procedure II and employing a slight excess of TEMPO compared to the oxidant to avoid overoxidation caused by the hypochlorite. In a typical example 4.5 g of crude material of cyclic PEG20k (synthesized using method B with a tosyl chloride/PEG ratio of 2) were used. The amount of OH end groups in the raw product mixture was estimated from 1H NMR data to be 0.17 mmol. TEMPO (270 mg, 1.73 mmol), NaBr (115 mg, 0.89 mmol), and NaOCl solution (0.65 mL, 1.61 mmol) were dissolved in 50 mL of water. The solution was stirred for 20 min whereupon it turned cloudy and yellow. The cyclic raw product was dissolved in another 50 mL of water and was added to the TEMPO solution. The mixture was stirred for 16 h at room temperature. It was cooled and quenched with 4 M NaOH solution, followed by 4 M NaHSO3 solution, each 5 mL. The mixture was stirred for 20 min. After acidification to pH 1−2 with 5 M HCl it was first extracted two times with ethyl acetate (100 mL) to remove TEMPO residues. Without this step, the higher amounts of TEMPO which were used under the optimized conditions caused problems in the product analysis by NMR because of very broad signals. The aqueous phase was then extracted three times with 100 mL of chloroform. The combined chloroform phases were dried with MgSO4 and the solvent was evaporated under reduced pressure. The resulting 4.2 g of oxidized cyclic raw product was dissolved in 50 mL of THF and added to 75 g of DOWEX Marathon ion-exchange resin

(hydroxide form) in an addition funnel. The funnel was shaken overnight; the solvent was removed and washed with 50 mL of THF obtaining the product fraction of 2.39 g. The further extraction of the ion-exchange resin yielded approximately 50 mg of product, which was contaminated with higher MW condensation products and was discarded. The prepurified first fraction still contained minor amounts of higher cyclic condensation products (see Figure 7). These were removed by fractionation with heptane fraction and chloroform. 2.39 g polymer PEG was dissolved in 60 mL chloroform. At 48 °C 130 mL of heptane fraction was added and the phases were separated by cooling to room temperature. In two additional fractionation steps 20 mL of heptane fraction was added each over 3 days to yield 1.5 g of pure cyclic PEG20k. The carboxylated linear PEG can be recovered from the ionexchange resin by regeneration with NaOH solution. 500 mL of 4% NaOH solution was added to the addition funnel with the used ionexchange resin (PEG20k, method B). The mixture was shaken for 3 h and all liquid was removed. The solution was acidified to pH 1−2 with 6 M HCl and extracted three times with 200 mL of chloroform. The organic phase was dried over MgSO4 and the solvent was removed under reduced pressure. A SEC chromatogram of the recovered oxidized polymer showed complementary signals to the nonadsorbed fraction (see Figure 6). Polymer Characterization. SEC experiments were carried out using a Polymer Laboratories PL 220 SEC instrument equipped with a differential refractive index detector and with three PolyPore columns at 50 °C. The solvent was a mixture of THF and DMA (85:15 by volume) at a flow rate of 1 mL/min. For the examination of samples, containing carboxylated PEG, 1 vol % of acetic acid was added to the solvent mixture. PEO standards were used for calibration. The SEC characterization results of the PEGs used in this work are summarized in Table 1. The data analysis of some SEC chromatograms was

Table 1. MW Characterization of the PEGs via SEC PEG

Mn

Mw/Mn

2k (commercial) 5k (commercial) 6k 10k (commercial) 11k 20k 52k

1860 4510 5600 10 200 10 900 20 300 52 200

1.03 1.03 1.01 1.04 1.02 1.01 1.02

performed with Origin Pro 9 (Origin Lab Corporation) using a Gaussian impulse fit with a maximum width of 25 to resemble the low polydispersity of the used PEG. All optimization reactions were fitted with the same routine comparing the amounts of cyclic and linear unimer, as well as higher MW cyclic and linear condensation products. NMR spectra were collected on a Bruker Avance III 600 MHz spectrometer equipped with a Prodigy cryoprobe with a 5 mm PFG AutoX DB probe. Samples of the polymers were dissolved in pyridined5 and measured at 295 K. Special conditions were used for the samples of oxidized linear or cyclic PEG, which contained possibly small residues of precursor polymers. In those cases 512 scans were collected at a delay time of 25 s and sample concentrations were 10 to 15 mg/mL.

■

RESULTS AND DISCUSSION The anionic ring-opening polymerization of EO with diol based initiators yields PEG with narrow MWDs up to high MWs. If the polymerization is performed at mild temperature conditions after acidic termination, the chain ends are quantitatively equipped with alcoholic groups without detectable amounts of other functionalities. Therefore, PEG suits perfectly the requirements for ring formation. In our work we used commercial PEG for the synthesis of cyclic PEG with Mn = C


Article

Macromolecules Scheme 1. Strategy for the Synthesis and Purification of Cyclic PEG

the cycles (Scheme 1). The cyclization reactions were performed at elevated concentrations to increase sample quantities. Linear and cyclic condensation products can be removed by fractionation using a solvent/nonsolvent pair. Unreacted linear precursor cannot be separated efficiently from the cyclic product by this method due to similar solubility properties. Its removal via end group carboxylation and selective fixation on an ion-exchange resin, however, are not standard procedures (Scheme 1). Both processes required detailed optimization to ensure the effective removal up to high MWs. Oxidation of Linear PEG and Removal of Carboxylated PEG with the Help of Basic Ion Exchange Resins. The oxidation of alcohols to carboxylic acids is a trivial reaction. However, in our case the conversion must be as high as possible, in order to bind the linear material quantitatively to the ion-exchange resin. First oxidation experiments were carried out using the technique described in ref 44 (oxidation procedure I). In this reaction NaOCl in combination with

2k. Its narrow MWD (PEG2k, Table 1) indicates a clean polymerization process without termination reactions and the quantitative OH-functionalization of the end groups. Higher MW commercial PEGs show broader MWDs. Therefore, these polymers were synthesized in our lab using partially metalated TEG as initiator. The only partial metalation is necessary for solubility reasons but requires elevated polymerization temperatures. Nevertheless, narrow MWDs were obtained. It has already been demonstrated that the cyclization reaction of PEG under the formation of an ether bond can be performed efficiently with tosyl chloride in the presence of KOH for MWs up to 3000 g/mol.25 If the ether formation is carried out with CH2Cl2 instead of tosyl chloride an acetal is formed in the ring closure event and higher MWs were accessible.45 However, these studies lack a detailed characterization of the product purity. As acetals have a reduced hydrolytical stability, the cyclization reaction via CH2Cl2 was not considered in this work. In our approach we used instead tosyl chloride to form D


Article

Macromolecules

which is identical with the value measured by SEC. The PEG/ end group intensity ratio for the experiments up to 24 h is close to the initial value for the PEG precursor, but gets visibly smaller at 72 h. This indicates an oxidative chain scission reaction likely by oxidation of the α-CH bond of the polyether. The resulting hemiacetal can easily be cleaved under the basic conditions of the TEMPO oxidation resulting in two chain fragments with alcohol and aldehyde end groups. While no aldehyde could be detected in the product mixtures, these groups would be highly unstable under the oxidizing conditions. The continuous production of shorter chain alcohol terminated PEG can, however, be responsible for the residual OH end groups. The reduction of the OH end group fraction up to 24 h and its subsequent increase is understandable if the chain scission reaction is considered. The reduction of the temperature to 0 °C suppressed chain scission but resulted in products with incompletely oxidized end groups (entries 5, 6). The omission of the nitroxyl catalyst increased drastically the chain scission reaction (entry 7). This suggests that the chain scission is caused by direct oxidative attack of the hypochlorite at the polymer backbone. With this knowledge the NaOCl quantity was drastically reduced (entries 8, 9). This resulted in complete oxidation and slightly reduced IPEG values for . This might indicate that still some

TEMPO was used for the oxidation. The nitroxyl radical acts in the reaction as a catalyst.46 It turned out that 1H NMR using pyridine-d5 as solvent is ideally suited to quantify the conversion (see Figure 1). The fractions of OH and COOH

Figure 1. Relevant sections of the 1H NMR spectra in pyridine-d5 of PEG52k (top) and HO2C-PEG52k-CO2H (bottom) using oxidation procedure II (Table 3, entry 1).

chain ends can be calculated precisely from the signal at 3.99 ppm, representing the CH2− group next to the OH end group of nonoxidized chain ends, and the signal at 4.42 ppm, representing the CH2− group next to the COOH-group of oxidized chain ends. The results are summarized in Table 2. In the case of PEG MWs up to 10k no more than marginal residues of nonoxidized chain end were found. Only oxidized PEG52k contained still 12% of OH-groups.

ICH2 − OH + ICH2 − COOH

minor chain scission takes place. Therefore, in the next experiments equimolar quantities of NaOCl and TEMPO were used (entries 10, 11), resulting in complete oxidation after 1 day and chain scission could not be detected. This procedure was later used as oxidation procedure II in the purification process of the high MW cyclic raw products. For the sake of completeness it should be mentioned that other oxidation procedures using for example KMnO4 based systems resulted in complete oligomerization of PEG52k, even after short reaction times. It is obvious that the comparison of the end group signals with the signal of the inner PEG protons is not very precise as the intensities differ by 3 orders of magnitude for PEG52k. Therefore, small degrees of chain scission are difficult to detect using the NMR method. Alternatively, we tested SEC for this purpose. PEG samples were run in a solvent mixture of DMA and THF. Carboxy-terminated PEG cannot be examined under these conditions. The signals show significant low MW tailings due to adsorptive interactions with the column material. Therefore, 1% of acetic acid was added to the solvent mixture in order to suppress these interactions. Nevertheless, the SEC signals of carboxylated PEG are slightly broader than the signals of the PEG precursors. This effect is more prominent for lower MWs, where less chain scission is expected but the end group influence is larger. Because of the incomplete suppression of polymer adsorption, the detection of small degrees of chain scission by SEC is unreliable. Therefore, the comparison of the different oxidation procedures was done using the NMR method. For larger degrees of chain scission, however, SEC is a useful tool. Figure 2 shows SEC traces of PEG52k and the oxidation product using a large excess of NaOCl after 24 h (entry 3). The significant fraction of low MW material confirms the chain scission reaction. Under ideal oxidation conditions (entry 11) the traces of the oxidized PEG and the precursor are almost identical, indicating that chain scission is at least largely absent. The use of resins for the removal of linear polymers from product mixtures with cyclic material is largely unexplored.

Table 2. Fractions of Residual Alcoholic PEG Chain Ends after Oxidation with TEMPO/NaOCl HO2C-PEG-CO2H

oxidation procedure Ia Ia Ia Ia IIb

2k 5k 10k 52k 52k a

ICH2 − OH ICH2 − OH + ICH2 − COOH

(%)

0 0 0.5 12 0

According to ref 44. bEntry 11 in Table 3.

In the next step, the oxidation reaction was optimized for low end group concentrations. This scenario is relevant for high MW polymers and especially product mixtures with cyclic polymer where only a fraction of the material is present as linear chains. PEG52k was used for these experiments. The results are summarized in Table 3. Leaving the other parameters unchanged, first the reaction time was varied (entries 1−4). Entry 2 corresponds to the procedure, described in ref44 (oxidation procedure I). Increasing the reaction time led to an initial reduction of residual nonoxidized end groups at reaction times up to 24 h, but increased again for 72 h (entry 4). This behavior gets understandable by examining the intensity ratio of the inner EO units (IPEG) and the end groups (ICH2−OH + ICH2−COOH). This ratio is similar to the polymerization degree as both the EO unit and the methylene groups next to the end groups of the chain ends comprise 4 hydrogen atoms. The values are listed in the right column of Table 3. For I the PEG precursor I PEG = 1.190 translates into a MW of 52k CH2 − OH

E


Article

Macromolecules Table 3. Screening Parameters for the Oxidation of PEG52k entry PEG52k 1 2 3 4 5 6 7 8 9 10 11

n nitroxyl

ICH2 − OH

nOH

ICH2 − OH + ICH2 − COOH

conditions

nNaOCl nOH

TEMPO 10 min, RT TEMPO 0.5 h, RT TEMPO 24 h, RT TEMPO 72 h, RT TEMPO 0.5 h, 0 °C TEMPO 1 h, 0 °C − 72 h, RT TEMPO 0.5 h, RT TEMPO 24 h, RT TEMPO 0.5 h, RT TEMPO 24 h, RT

440

2.1

28

1190 870

430

2.1

12

990

430

2.1

7

890

430

2.1

13

623

430

2.1

18

900

430

2.1

16

1020

43

90

430

−−

(%)

IPEG ICH2 − OH + ICH2 − COOH

15

2.1

1

1040

15

2.1

0

1030

26

26

79

1290

26

26

0

1250

resin. For higher MWs, the method progressively failed. As with increasing PEG MW the attractive interactions between the resin and the polymer end groups become less prominent, water was replaced by THF to minimize end group interactions with the solvent. The resins Amberlyst A26 and DOWEX Marathon were used for these experiments due to their tolerance against organic solvents. Amberlyst A26 could remove the carboxylated PEG up to HO2C-PEG10k-CO2H quantitatively and HO2C-PEG52k-CO2H largely. With the aid of DOWEX Marathon even HO2C-PEG52k-CO2H could be removed quantitatively. However, contact times up to about 4 days were necessary to fix all polymer. A more detailed description of the experiments is given in the Supporting Information. Cyclization Reactions. First experiments were carried out with PEG2k using commercially available polymer and repeating the procedure described in ref 25 (method A). nHexane was added to the solvent THF to reduce the solvent quality and so favoring the cyclization reaction. The higher MW cyclic polymers were synthesized with PEGs produced in our lab to have as narrow MWDs as possible and fully OH functional end groups (see Table 1). In all cases the molar ratio of tosyl chloride to PEG chains was in between 1.00 and 1.05, as in ref 25 this parameter was not specified. As the polymer concentration given in this reference was fairly high for a cyclization reaction with 24 g/L in the final reaction mixture, for the higher MW polymers the concentration was reduced by a factor of 3 to 4. In addition, for the cyclization reactions with PEG6k and PEG11k more hexane was added to the solvent mixture to push the polymer solubility close to theta-conditions (see Experimental Section and Supporting Information). This measure was not possible for PEG20k, where the polymer started to precipitate already at low hexane contents. Figure 3 shows SEC traces of the raw products obtained in the cyclization reactions. The rightmost signals represent the

Figure 2. SEC chromatograms of PEG52k (black), overoxidized PEG52k (entry 3) (red) and after oxidation (entry 11 in Table 3) (blue).

Touris and Hadjichristidis suggested the use of an azidofunctionalized Merrifield resin to remove linear residues from cyclic polymers synthesized via an azide/alkyne click reaction.14 Already before the use of an ion exchange resins was demonstrated for the purification of low MW poly(dimethylsiloxane).47 It is obvious, that with increasing MWs the fixation of polymers to an ion-exchange resin gets more difficult. Therefore, we first tested this purification step using the HO2C-PEG-CO2H samples listed in Table 2. The anion exchange resins used in this work consist of crosslinked polystyrene functionalized with trimethylbenzyl ammonium groups and a lower cross-linking density compared to standard resins. This should improve diffusion of larger anions into the resin material.48 Nevertheless, under aqueous conditions and using the resin Amberlite IRA402 only HO2C-PEG2k-CO2H could be fixed quantitatively to the F


Article

Macromolecules

planned to obtain the purified cyclic polymers in the 1−10 g scale, the dosing rate could not be reduced drastically. The same holds for working under more dilute conditions. The solvents were rigorously dried, which limits the solvent quantities used for the cyclization reactions. Experiments with less rigorous conditions showed lower degrees of cyclization compared to the use of dried solvents and glovebox conditions. While these rigorous conditions are not necessary for the tosylation or the subsequent ether formation, benchtop experiments resulted in generally lower amounts of cyclization and condensation. This can be attributed to an increasing amount of water within the reaction setup. The use of THF and powdered dry KOH will increase the uptake of moisture during the long reaction times which can influence several parameters of the reaction like the soluble fraction of KOH or the hydrolysis of tosyl chloride. As an alternative measure to optimize the reaction conditions, we investigated the influence of the PEG/tosyl chloride ratio on the byproduct formation. Moreover, the addition speed of the starting materials was reduced by a factor of about 3 and the solvent volume in the reactor was increased in these experiments (method B). The results are summarized in Figure 5 and Table 4. For the comparison of methods A and

Figure 3. SEC chromatograms of cyclization raw products synthesized following the procedure given in ref 25. The dashed lines below the product signals represent the baselines.

unimeric cyclization products. To the left the signals appear which are related to the linear precursor and higher MW linear and cyclic structures. The fraction of precursor is minimal for the 2k material and becomes increasingly prominent for the higher MWs. Samples were taken during the addition of starting materials to monitor the ring formation. Figure 4 shows SEC results for

Figure 5. SEC chromatograms of cyclization raw products synthesized with different tosyl chloride/PEG ratios using method B.

Table 4. Raw Product Compositions at Different Tosyl Chloride/PEG Ratios, Calculated from the SEC Chromatograms Figure 4. SEC chromatograms of samples taken at different times during the addition of PEG11k and tosyl chloride to the reaction vessel.

composition (%) equiv of tosCl 1 1 1.5 2 3

PEG11k. After addition of 25% of the starting materials, the mass-fraction of unimeric cycyle was 74%. This high quantity is only possible if the cyclization is faster than the tosylation of the chain ends. In the opposite case one would expect in a simple view the composition of nontosylated, monotosylated, and bis-tosylated chains being 1:2:1. This would result in a maximum fraction of unimeric cycles of 50%. Furthermore, the SEC traces shown in Figure 4 show, that progressively the fraction of byproducts gets larger, a result of the increasing polymer concentration in the reaction flask. Especially the increasing amount of linear precursor suggests optimizing the cyclization reaction by adding the starting materials slower. However, in the experiments described above the dosing rate was about 1−2 g of PEG per day. As it was

method method method method method

A B B B B

unimeric cycle

linear precursor

condensation products (linear and larger cycles)

18 19 48 61 11

10 15 11 23 40

72 66 41 16 49

B equimolar mixtures of PEG and tosyl chloride were used. The results are summarized in the first two lines of Table 4. They show that the fraction of unimeric cycle increased only marginally as a result of higher dilution and reduced addition speed. The larger fraction of linear precursor is insofar advantageous as this compound can be removed efficiently with the ion-exchange resin. The increase of the tosyl chloride to PEG ratio up to 2 equiv raised the fraction of unimeric cycle G


Article

Macromolecules

purification step. Not only the unimeric linear polymer but also the higher MW linear condensation products are removed by this procedure efficiently, although the carboxylated linear PEG represents only a fraction of the raw product. It therefore is present in a smaller concentration compared to the preexperiments where pure carboxylyated PEG was used. The cyclic PEG20k contained after the ion exchange purification process still 12 mass % of higher MW cycles. After two fractionation steps with chloroform and heptane, most of these byproducts were removed (Figure 7). Some residual dimeric cycle was eliminated in the final fractionation step almost quantitatively.

to 61%. As previously mentioned the tosylation step seems to be slower than the cyclization step at equimolar tosyl chloride to PEG ratios. If however too much tosyl chloride is used, this will result in a scenario where the tosylation is the fastest step in the reaction sequence. This is especially important as any excess of tosyl chloride is accumulated in the reaction flask and will additionally increase the tosylation rate. The use of 3 equiv of tosyl chloride results not only in a decrease in yield of the cyclic product but it is interesting to notice that the amount of linear precursor in the product mix is also increased compared to the examples with less tosyl chloride. A likely explanation is that the faster tosylation causes an increased concentration of double tosylated linear PEG which can condensate with freshly added nontosylated PEG but is unable to form cycles. This increase in linear precursor can already be detected at 2 equiv of tosyl chloride, but in that case it is not accompanied by an increase of condensation products. Purification of Cyclic Raw Products. The cyclization reactions were performed 3 to 4 times for each MW in order to obtain sufficient quantities. In the case of the raw products synthesized with method A, first higher MW cyclic and linear condensation products were removed from the raw products by fractionation using chloroform as solvent and heptane as nonsolvent. The linear precursor was partially removed in this process at lower efficiency with increasing MW. After this procedure the remaining material was oxidized using procedure I and residual precursor residues were removed using the ionexchange resin Amberlyst A26 (standard procedure). In the case of the cyclic PEG20k, synthesized using method B with a molar tosyl chloride/PEG ratio of 2, the raw product was oxidized directly after the cyclization step (oxidation procedure II) and treated with the ion-exchange resin DOWEX Marathon (advanced procedure). Figure 6 shows the SEC traces of the

Figure 7. SEC chromatograms of the PEG20k cyclization product, synthesized with a molar tosyl chloride/PEG ratio of 2 after the purification step with the ion-exchange resin (red) and after two and three fractionation steps with chloroform/heptane (blue and black).

High resolution SEC is a precise method to examine the presence of higher MW condensation products in cyclic PEGs. However, it is insensitive to separate the cyclic product from smaller quantities of its linear precursor. Therefore, we used again 1H NMR spectroscopy in pyridine-d5 to analyze the products. Figure 8 summarizes the results for the advanced PEG20k cyclization. The signal at 3.99 ppm, representing the CH2−groups next to the OH end groups in PEG indicates the presence of linear chains in the raw product (upper spectrum). Still tosylated PEG is not expected due to the previous alkaline work-up. In the oxidized product no residual alcohol can be

Figure 6. SEC chromatograms of the cyclization raw product of PEG20k, synthesized with a molar tosyl chloride/PEG ratio of 2 after the oxidation step (blue), soluble polymer fraction not bound to the ion-exchange resin DOWEX Marathon (black), and polymer fraction fixed to the resin after extraction with NaOH solution (red).

oxidized 20k raw product and the prepurified polymer eluted from the resin using the advanced procedure. The separated linear caboxylated PEG was removed from the resin afterward with NaOH solution and also examined by SEC. The comparison of the results shows that the byproduct mixture mainly consists of linear PEG whereas higher MW cyclic structures are present only in marginal amounts. Furthermore, this examination reveals the power of the ion exchange

Figure 8. Relevant sections of the 1H NMR spectra in pyridine-d5 of the cyclization raw product of PEG20k, synthesized with a molar tosyl chloride/PEG ratio of 2 (top), after the oxidation step (middle), and after the purification step with the ion-exchange resin (bottom). H


Article

Macromolecules Table 5. Characterization of the Cyclic PEGs and Their Linear Precursorsa linear PEG 2k 6k 11k 20k 20k

cyclic PEG

Mn

Mw/Mn

method

Mw/Mn

residual linear PEG (%)

unimeric cycle in raw product (%)

yield final product (%)

1860 5600 10900 20300 20300

1.03 1.01 1.02 1.01 1.01

standard standard standard standard advanced

1.02 1.01 1.02 1.03 1.02

0.3 0.4 1.0 3.7 0

44 43 42 18 61

n.d. 12 15 5 30

a

Standard method: cyclization reaction according to method A; oxidation according to ref 44 (procedure I) and ion-exchange resin purification with Amberlyst A26. Advanced method: cyclization reaction according to method B with 2 equiv of tosyl chloride; oxidation procedure II and ionexchange resin purification with DOWEX Marathon MSA; the values for Mn and Mw/Mn were measured by SEC and the contents of linear PEG were quantified by 1H NMR.

detected (middle spectrum). The sharp signal at 4.42 ppm of the CH2−groups next to the COOH-end groups allows a precise detection of linear residues. After the treatment with the ion-exchange resin this signal disappeared fully, indicating the quantitative removal of linear chains. The important characteristics of the cyclization reactions and products are summarized in Table 5. Cyclic PEG2k contained 44% of unimeric cycles in the raw product. It was synthesized according to standard procedures including cyclization method A. The values are only marginally smaller for the 6k and 11k cycles because the cyclization reactions were carried out in 4 times higher dilution and using more hexane to reduce the solvent quality. However, the yields of clean product after the cleaning procedures were much smaller, mainly because of the losses in the fractionation process. The method reaches its limits by increasing the MW to 20k. Not only the low cyclization efficiency but also the fractionation procedure, which generally gets less selective with increasing MWs, reduced the yield of final product to 5%. The scenario is similar for the product purity. The cyclic materials oxidized according to procedure I show progressively a higher content of linear precursor with increasing MW. The NMR analysis showed that the linear chains consisted of only nonoxidized PEG. Despite the use of the nonideal ion-exchange resin Amberlyst A26 all oxidized material was removed. It is likely that not incomplete chain end oxidation but overoxidation is the reason. For cyclic PEG11k the polymer fraction fixed to the resin in the purification process was extracted with NaOH solution. Its SEC trace showed a pronounced low MW tailing indicating chain scission. The advanced synthetic (method B) and purification procedures (oxidation procedure II, ionexchange resin DOWEX Marathon MSA) for PEG20k resulted in the complete removal of the linear material after the oxidation/ion exchange step. Despite visible losses during the final fractionation process, the overall yield of purified unimeric cyclic product was as high as 30% when the optimized amount of two equivalents of tosyl chloride was used for the cyclization. The SEC traces of cyclic PEG20k synthesized with standard and advanced procedures are shown in Figure 9 together with the chromatogram of the linear PEG20k. The small shoulder at lower elution times in the chromatogram of the cycle, synthesized with standard procedures, represents linear PEG. The content was quantified by NMR to be 3.7%. In the cyclic PEG20k, synthesized with advanced procedures, no precursor could be detected, which is in agreement with the NMR analysis.

Figure 9. SEC chromatograms of linear and cyclic PEG20k, synthesized according to standard and advanced procedures.

■

CONCLUSIONS The procedure presented in this work enables the production of cyclic PEG up to high MWs. The materials are accessible in high structural purity and in gram quantities, what so far has not been possible for cyclic model polymers. From the synthetic standpoint PEG is ideally suited for the production of cyclic polymers as it contains by nature alcoholic end groups. In addition, the entanglement MW of linear PEG is very low at 2k. This eases the study of entanglement dependent effects on the conformational behavior of the cyclic polymers. Here a transformation from a global Gaussian behavior to a collapsed state is expected at higher equivalents of the entanglement MW of the linear counterpart. The alcoholic end groups allow the efficient removal of linear material from the raw products by binding the chain end oxidized linear PEG to an ion-exchange resin. As oxidizing agents also cleave backbone ether bonds, the optimization of the reaction conditions is of crucial importance. This is especially the case for high MWs as the probability for chain scission is proportional to the chain length. The analysis of the material bound to ion-exchange resin in the 20 k case showed that also higher MW linear condensation products were removed efficiently from the raw product mixture. Therefore, it will be possible to extend the procedure to considerably larger cycles. The proper analysis of the cyclic products is a more limiting factor. For the 20k cycle, our NMR based procedure still allowed a precise characterization of linear contaminations. However, it is obvious that with increasing chain length the NMR method gets more difficult. LCCC might provide an alternative as the alcoholic and carboxylated chain ends increase the separation efficiency between cyclic and linear structures. Interestingly, it is not so much the dilution and the addition I


Article

Macromolecules

(13) Cho, D.; Masuoka, K.; Koguchi, K.; Asari, T.; Kawaguchi, D.; Takano, A.; Matsushita, Y. Preparation and Characterization of Cyclic Polystyrenes. Polym. J. 2005, 37, 506−511. (14) Touris, A.; Hadjichristidis, N. Cyclic and Multiblock Polystyrene-block-polyisoprene Copolymers by Combining Anionic Polymerization and Azide/Alkyne “Click” Chemistry. Macromolecules 2011, 44, 1969−1976. (15) Doi, Y.; Iwasa, Y.; Watanabe, K.; Nakamura, M.; Takano, A.; Takahashi, Y.; Matsushita, Y. Synthesis and Characterization of CombShaped Ring Polystyrenes. Macromolecules 2016, 49, 3109−3115. (16) Laurent, B. A.; Grayson, S. M. An Efficient Route to WellDefined Macrocyclic Polymers via “Click” Cyclization. J. Am. Chem. Soc. 2006, 128, 4238−4239. (17) Goldmann, A. S.; Quémener, D.; Millard, P.-E.; Davis, T. P.; Stenzel, M. H.; Barner-Kowollik, C.; Müller, A. H. E. Access to cyclic polystyrenes via a combination of reversible addition fragmentation chain transfer (RAFT) polymerization and click chemistry. Polymer 2008, 49, 2274−2281. (18) Schulz, M.; Tanner, S.; Barqawi, H.; Binder, W. H. Macrocyclization of Polymers via Ring-Closing Metathesis and Azide/Alkyne-“Click“-Reactions: An Approach to Cyclic Polyisobutylenes. J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 671−680. (19) Lonsdale, D. E.; Bell, C. A.; Monteiro, M. J. Strategy for Rapid and High-Purity Monocyclic Polymers by CuAAC “Click” Reactions. Macromolecules 2010, 43, 3331−3339. (20) Stanford, M. J.; Pflughaupt, R. L.; Dove, A. P. Synthesis of Stereoregular Cyclic Poly(lactide)s via “Thiol-Ene” Click Chemistry. Macromolecules 2010, 43, 6538−6541. (21) Zhao, J.; Zhou, Y.; Zhou, Y.; Zhou, N.; Pan, X.; Zhang, Z.; Zhu, X. A straightforward approach for the one-pot synthesis of cyclic polymers from RAFT polymers via thiol-Michael addition. Polym. Chem. 2016, 7, 1782−1791. (22) Nicolaÿ, R.; Matyjaszewski, K. Synthesis of Cyclic (Co)polymers by Atom Transfer Radical Cross-Coupling and Ring Expansion by Nitroxide-Mediated Polymerization. Macromolecules 2011, 44, 240− 247. (23) Glassner, M.; Blinco, J. P.; Barner-Kowollik, C. Diels-Alder Reactions as an Efficient Route to High Purity Cyclic Polymers. Macromol. Rapid Commun. 2011, 32, 724−728. (24) Antonini Vitali, C.; Masci, B. Template Effects. 7. Large unsubstituted crown ethers from polyethylene glycols: Formation, Analysis, and purification. Tetrahedron 1989, 45, 2201−2212. (25) Sun, T.; Yu, G.-E.; Price, C.; Booth, C.; Cooke, J.; Ryan, A. J. Cyclic polyethers. Polymer 1995, 36, 3775−3778. (26) Bielawski, C. W.; Benitez, D.; Grubbs, R. H. An “endless” route to cyclic polymers. Science 2002, 297, 2041−2044. (27) Gonsales, S. A.; Kubo, T.; Flint, M. K.; Abboud, K. A.; Sumerlin, B. S.; Veige, A. S. Highly Tactic Cyclic Polynorbornene: Stereoselective Ring Expansion Metathesis Polymerization of Norbornene Catalyzed by a New Tethered Tungsten-Alkylidene Catalyst. J. Am. Chem. Soc. 2016, 138, 4996−4999. (28) Nadif, S. S.; Kubo, T.; Gonsales, S. A.; VenkatRamani, S.; Ghiviriga, I.; Sumerlin, B. S.; Veige, A. S. Introducing “Ynene” Metathesis: Ring-Expansion Metathesis Polymerization Leads to Highly Cis and Syndiotactic Cyclic Polymers of Norbonene. J. Am. Chem. Soc. 2016, 138, 6408−6411. (29) Roland, C. D.; Li, H.; Abboud, K. A.; Wagener, K. B.; Veige, A. S. Cyclic polymers from alkynes. Nat. Chem. 2016, 8, 791−796. (30) Culkin, D. A.; Jeong, W.; Csihony, S.; Gomez, E. D.; Balsara, N. P.; Hedrick, J. L.; Waymouth, R. M. Zwitterionic Polymerization of Lactide to Cyclic Poly(Lactide) by Using N-Heterocyclic Carbene Organocatalysts. Angew. Chem., Int. Ed. 2007, 46, 2627−2630. (31) Shin, E. J.; Brown, H. A.; Gonzalez, S.; Jeong, W.; Hedrick, J. L.; Waymouth, R. M. Zwitterionic Copolymerization: Synthesis of Cyclic Gradient Copolymers. Angew. Chem., Int. Ed. 2011, 50, 6388−6391. (32) Stukenbroeker, T. S.; Solis-Ibarra, D.; Waymouth, R. M. Synthesis and Topological Trapping of Cyclic Poly(alkylene phosphates). Macromolecules 2014, 47, 8224−8230.

speed during the cyclization reaction but the tosyl chloride to PEG ratio which determines the cyclization efficiency. At a ratio of these components above 1 product yields are much better, but tosyl chloride is enriched during the reaction. Therefore, the process might even be optimized if the tosyl chloride excess is kept constant by dosing an equimolar tosyl chloride/PEG mixture to the reaction flask, which contains already some tosyl chloride.

■

ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.macromol.7b00361. Descriptions of the cyclization reactions and the removal of carboxylated PEG using basic ion exchange resins. (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*(J.A.) E-mail: [email protected]. ORCID

Jürgen Allgaier: 0000-0002-9276-597X Notes

The authors declare no competing financial interest.

■

REFERENCES

(1) Roovers, J. Overview on physical properties of cyclic polymers. In Topological Polymer Chemistry: Progress of Cyclic Polymers in Syntheses, Properties and Functions; Tezuka, Y., Ed.; World Scientific Publishing Co. Pte. Ltd.: Singapore, 2013; pp 137−156. (2) Richter, D.; Goossen, S.; Wischnewski, A. Celebrating Soft Matter’s 10th Anniversary: Topology matters: structure and dynamics of ring polymers. Soft Matter 2015, 11, 8535−8549. (3) Endo, K. Synthesis and Properties of Cyclic Polymers. Adv. Polym. Sci. 2008, 217, 121−183. (4) Laurent, B. A.; Grayson, S. M. Synthetic Approaches for the preparation of cyclic polymers. Chem. Soc. Rev. 2009, 38, 2202−2213. (5) Kricheldorf, H. R. Cyclic Polymers: Synthetic Strategies and Physical Properties. J. Polym. Sci., Part A: Polym. Chem. 2010, 48, 251− 284. (6) Tu, X.-Y.; Liu, M.-Z.; Wei, H. Recent Progress on Cyclic Polymers: Synthesis, Bioproperties, and Biomedical Applications. J. Polym. Sci., Part A: Polym. Chem. 2016, 54, 1447−1458. (7) Brown, H. A.; Waymouth, R. M. Zwitterionic Ring-Opening Polymerization for the Synthesis of High Molecular Weight Cyclic Polymers. Acc. Chem. Res. 2013, 46, 2585−2596. (8) Roovers, J.; Toporowski, P. M. Synthesis of High Molecular Weight Ring Polystyrenes. Macromolecules 1983, 16, 843−849. (9) Roovers, J.; Toporowski, P. M. Synthesis and Characterization of Ring Polybutadienes. J. Polym. Sci., Part B: Polym. Phys. 1988, 26, 1251−1259. (10) Schappacher, M.; Deffieux, A. α-Acetal-ω-bis(hydroxymethyl) Heterodifunctional Polystyrene: Synthesis, Characterization, and Investigation of Intramolecular End-to-End Ring Closure. Macromolecules 2001, 34, 5827−5832. (11) Quirk, R. P.; Wang, S.-F.; Foster, M. D.; et al. Synthesis of Cyclic Polystyrenes Using Living Anionic Polymerization and Metathesis Ring-Closure. Macromolecules 2011, 44, 7538−7545. (12) He, Q.; Yol, A. M.; Wang, S.-F.; Ma, H.; Guo, K.; Zhang, F.; Wesdemiotis, C.; Quirk, R. P.; Foster, M. D. Efficient Synthesis of well-defined cyclic polystyrenes using anionic polymerization, silicon chloride linking chemistry and metathesis ring closure. Polym. Chem. 2016, 7, 5840−5848. J


Article

Macromolecules (33) Kammiyada, H.; Konishi, A.; Ouchi, M.; Sawamoto, M. RingExpansion Living Cationic Polymerization via Reversible Activation of a Hemiacetal Ester Bond. ACS Macro Lett. 2013, 2, 531−534. (34) Kammiyada, H.; Ouchi, M.; Sawamoto, M. Ring-Expansion Living Cationic Polymerization of Vinyl ethers: Optimized Ring Propagation. Macromol. Symp. 2015, 350, 105−116. (35) Kapnistos, M.; Lang, M.; Vlassopoulos, D.; Pyckhout-Hintzen, W.; Richter, D.; Cho, D.; Chang, T.; Rubinstein, M. Unexpected power-law stress relaxation of entangled ring polymers. Nat. Mater. 2008, 7, 997−1002. (36) Subramanian, G.; Shanbhag, S. Conformational properties of blends of cyclic and linear polymer melts. Phys. Rev. E 2008, 77, 011801. (37) Vasquez, R.; Shanbhag, S. Percolation of Trace Amounts of Linear Polymers in Melts of Cyclic Polymers. Macromol. Theory Simul. 2011, 20, 205−211. (38) Halverson, J. D.; Grest, G. S.; Grosberg, A. Y.; Kremer, K. Rheology of Ring Polymer Melts: From Linear Contaminants to RingLinear Blends. Phys. Rev. Lett. 2012, 108, 038301. (39) Lee, H. C.; Lee, H.; Lee, W.; Chang, T.; Roovers, J. Fractionation of Cyclic Polystyrene from Linear Precursor by HPLC at the Chromatographic Critical Condition. Macromolecules 2000, 33, 8119−8121. (40) Lee, W.; Lee, H.; Lee, H. C.; Cho, D.; Chang, T.; Gorbunov, A. A.; Roovers, J. Retention Behavior of Linear and Ring Polystyrene at the Chromatographic Critical Condition. Macromolecules 2002, 35, 529−538. (41) Lepoittevin, B.; Dourges, M. A.; Masure, M.; Hemery, P.; Baran, K.; Cramail, H. Synthesis and Characterization of Ring-Shaped Polystyrenes. Macromolecules 2000, 33, 8218−8224. (42) Takano, A.; Kushida, Y.; Aoki, K.; Masuoka, K.; Hayashida, K.; Cho, D.; Kawaguchi, D.; Matsushita, Y. HPLC Characterization of Cyclization Reaction Product Obtained by End-to-End Ring Closure Reaction of a Telechelic Polystyrene. Macromolecules 2007, 40, 679− 681. (43) Sun, P.; Liu, J.; Zhang, Z.; Zhang, K. Scalable preparation of cyclic polymers by the ring-closure method assisted by the continuousflow technique. Polym. Chem. 2016, 7, 2239−2244. (44) Araki, J.; Zhao, C.; Ito, K. Efficient Production of Polyrotaxanes from α-Cyclodextrin and Poly(ethylene glycol). Macromolecules 2005, 38, 7524−7527. (45) Yu, G.-E.; Sinnathamby, P.; Price, C.; Booth, C. Preparation of large cyclic poly(oxyethylene)s. Chem. Commun. 1996, 31−32. (46) Tojo, G.; Fernandez, M. I. Oxidation of Primary Alcohols to Carboxylic Acids. A Guide to Current Common Practice; Springer: 2007; Chapter 6: TEMPO mediated oxidations. (47) White, B. M.; Watson, W. P.; Barthelme, E. E.; Beckham, H. W. Synthesis and Efficient Purification of Cyclic Poly(dimethylsiloxane). Macromolecules 2002, 35, 5345−5348. (48) Abrams, I. M.; Millar, J. R. A history of the origin and development of macroporous ion-exchange resins. React. Funct. Polym. 1997, 35, 7−22.

K


Scale-Up Procedure for the Efficient Synthesis of ... - ACS Publications

Recommend Documents