End group functionalization of poly(ethylene glycol) with phenolphthalein: towards star-shaped polymers based on supramolecular interactions

Summary The synthesis of a new phenolphthalein azide derivative, which can be easily utilized in polymer analogous reactions, is presented. The subsequent cycloaddition reaction with propargyl-functionalized methoxypoly(ethylene glycol) yielded polymers bearing phenolphthalein as the covalently attached end group. In presence of per-β-cyclodextrin-dipentaerythritol, the formation of stable inclusion complexes was observed, representing an interesting approach towards the formation of star shaped polymers. The decolorization of a basic polymer solution caused by the complexation was of great advantage since this behavior enabled following the complex formation by UV–vis spectroscopy and even the naked eye.

All solvents were used in analytically pure grades. N,N-Dimethylformamide was purchased in extra dry grade (Acros Organics, 99.8%) and additionally dried over molecular sieve prior to use.

Measurements
1 H-NMR spectroscopy was conducted on a Bruker Avance III 300 (300 MHz) and a Bruker AC 500 (500 MHz) at room temperature. Dimethyl sulfoxide-d6 (Deutero GmbH, 99.9%) was used as internal standard. ROESY spectra were recorded on a Bruker Avance III 600 (600 MHz) at room temperature.
ESI mass spectra were recorded with a mass spectrometer type Ion-Trap-API Finnigan LCQ Deca.
FTIR spectra were recorded on a Nicolet ATR-FTIR spectrometer type FT-IR-6700.
Elementary analyses were performed with a Perkin Elmer Series II Analyser 2400.
UV-vis spectroscopic measurements were performed using a dual-trace spectrometer Specord® 210 Plus from Analytik Jena AG. The solutions were placed in a quartz cuvette (d = 1 cm) and the measurements were performed at room temperature between 400 and 750 nm. All measurements were performed at a final polymer concentration of 0.05 mg/mL, for this, a stock solution containing 0.1 mg/mL PEG-PP was prepared and mixed in a 1:1 (v/v) ratio with a solution containing the complexing agent. Therefore, the solution of the complexing agent was prepared at a concentration twice as high as the desired final concentration. All solutions were prepared by use of distilled water adjusted to a pH of 12 by use of sodium hydroxide.
DLS data were recorded in backscattering mode on a Malvern Zetasizer Nano ZS ZEN 3600 at a temperature of 25 °C with a laser wavelength of 633 nm and a detection angle of 173°. The solutions were placed in a glass cuvette with a layer thickness of 1 cm. The non-negative-least-squares algorithm in the general-purpose mode was used for interpretation. Each experiment was performed at least 5 times (13-15 runs for each measurement, run duration 10 s) to obtain statistical information and the numberaveraged diameters were used for interpretation.
Flash chromatography was performed using a Combi Flash Companion from Teledyne Isco, Inc.
Microwave-assisted syntheses were conducted in a laboratory microwave Discover® 1 by CEM.
The microwave works at a frequency of 2.45 GHz and the maximum power available is 300 W. The experiments were supervised through a coupled temperature and pressure sensor (max. pressure: 20 bar). An IR sensor was employed as the temperature sensor. The reactions were performed in pressure resistant test tubes.
Freeze drying was performed with a construction by Christ, type 1-4 LD plus having a capacity of 4 kg and an ice condenser temperature of −42 °C. The vacuum of 0.1 mbar was achieved by application of a rotary vane pump by Vacuubrand, type RZ6.
The aqueous phase was then extracted with 3 mL dichloromethane (3 x), and the combined organic layers were washed with saturated sodium hydrogen carbonate solution.

Synthesis of α-methoxyethyl-ω-propargyloxypoly(ethylene glycol) (mPEG-prop)
Prior to synthesis, methoxypoly(ethylene glycol) (Mn= 350 g/mol) (6 mmol, 2.10 g) was dried at 50 °C in vacuum for 3 hours. Under nitrogen atmosphere, 10 mL dry dimethylformamide were added and the solution was cooled to 0 °C. Sodium hydride (720 mg of 60% dispersion in petroleum, 18 mmol) was added and the mixture stirred for 1.5 hours. Subsequently, propargyl bromide (18 mmol, 3.57 mL of a 80% solution in toluene) was slowly added and the resulting solution stirred for 48 hours at room temperature.
The reaction mixture was filtered before the solvent was removed in vacuum. The crude product was precipitated in petroleum ether, redispersed in tetrahydrofuran and then purified by filtration over silica gel (dichloromethane followed by methanol).

Synthesis of 3-(3-(3-(prop-2-ynyloxy)-2,2-bis((prop-2inyloxy)methyl)propoxy)-2,2-bis((prop-2-ynyloxy)methyl)propoxy)prop-1-yne [2]
2.00 g (7.87 mmol) dipentaerythritol were baked out prior to synthesis. Under nitrogen atmosphere, 150 mL dry dimethylformamide were added and the resulting suspension was cooled to 0 °C. Then, sodium hydride (56.6 mmol, 2.27 g of a 60% suspension in petroleum) was added and the dispersion was stirred at 0 °C for an hour and then another two hours at room temperature. Afterwards, the mixture was cooled to 0 °C again and propargyl bromide (56.6 mmol, 6.10 g of a 80% dispersion in toluene) was slowly added. The reaction mixture was then stirred at 65 °C for 72 hours and the resulting solution was then poured on 100 mL ice and the aqueous phase was extracted with ethyl acetate. The combined organic layers were washed with saturated sodium hydrogen carbonate solution (2x) and brine (1x), dried with magnesium sulfate and subsequently; the solvent was removed in vacuum. The crude product was purified by flash chromatography (dichloromethane/hexanes 4:1).

Synthesis of mono-6 I -tosyl-6 I -desoxy--cyclodextrin [2]
-CD (50.0 g, 44.0 mmol) was dissolved in 500 mL of a 0,4 M aqueous sodium hydroxide solution and cooled to 4 °C. While stirring vigorously, p-toluenesulfonyl chloride (35.0 g, 184 mmol) was added within 5 minutes. The resulting suspension was stirred for additional 30 minutes and was then filtered. The filtrate was neutralized by addition of hydrochloric acid and stirred for an hour. The precipitate that was formed thereby was isolated via filtration, washed with water (3x) and dried at 60 °C overnight.