Cyclodextrin Methacrylate via Microwave-Assisted Click Reaction

Cyclodextrin Methacrylate via Microwave-Assisted Click Reaction

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Cyclodextrin Methacrylate via Microwave-Assisted Click Reaction

Maricica Munteanu,† SooWhan Choi,‡ and Helmut Ritter*,†

Institute fur Organische Chemie and Makromolekulare Chemie, Heinrich-Heine-UniVersitat Dusseldorf, Lehrstuhl I, UniVersitatsstrasse 1, 40225 Dusseldorf, Germany, and S&V Technologies AG, Neuendorfstrasse 20a, 16761 Henningsdorf, Germany

ReceiVed August 21, 2008; ReVised Manuscript ReceiVed October 29, 2008

ABSTRACT: Click reaction of propargyl methacrylate (1) with 6I-azido-6I-deoxycyclomaltoheptaose (2) was carried out to synthesize mono-(1H-1,2,3-triazol-4-yl)(methyl)2-methylacryl- -cyclodextrin (3). The process was investigated by varying the reaction time, temperature profiles, and copper catalyst. Microwave irradiation was compared with conventional heating. The microwave-assisted Cu(I)-catalyzed cycloaddition affords the complete conversionof (2) into 1,4-disubstitutedtriazole in a significantdecreasedreaction time. Under microwave conditions, the cycloaddition of (2) onto poly(propargyl methacrylate) (5) was conducted in excellent yields. The regioselectivityof click reactionsin dependenceof reaction conditionswas evaluatedby use of NMR spectroscopy. The reactions performed under microwave conditions led exclusively to 1,4-disubstituted triazole, while the conventional heating led to a regioisomeric mixture.


In recent years, cyclodextrins have been extensively used in polymer chemistry. For example, they are used to complex water-insoluble monomers and polymers.1-8 In this field, cyclodextrin monomethacrylates have not yet been studied extensively. Thus, we were encouraged to synthesize such polymerizable cyclodextrin monomers via “click chemistry”. This type of coupling introduced by Sharpless and summarized as “all searches must be restricted to molecules that are easy to make”9 has proven to be a versatile, powerful, and multiapplicable tool, intensively exploited in the past years.10 Cu(I)- catalyzed Huisgen-type 1,3-dipolar cycloaddition of azides and alkynes extended its area of applications in carbohydrate research, organic and supramolecular chemistry, bioconjugation,1-14 or drug discovery.15 According to Huisgen16 and confirmed by Meldal,17 thermal 1,3-dipolar cycloaddition of alkynes and azides is not a regiospecific reaction. A structural control can be achieved under mild conditions by using active Cu(I) species.18,19 The microwave-assistedcopper-catalyzed1,3- dipolar cycloaddition received recently much attention due its ability to afford a complete and regioselective conversion with a significant decrease in reaction time. Although click reactions are known in the cyclodextrinchemistry,20-24 their use to obtain cyclodextrinmonomethacrylatehas not been reported. Attempts to synthesizemonofunctionalcyclodextrinestersled to mixtures, and the desired compound was obtained in low yield afther chromatographic purification.25 By applying click reaction, cyclodextrin monomethacrylate can be obtained in high yields; the purification by chromatographic methods is not required, and the installation and removal of protecting groups are avoided. The triazol linker is relatively stable toward cleavage, oxidation,or reduction.Since 1,3-cycloadditionof 6-monoazido- 6-monodeoxy- -cyclodextrin with propargyl derivatives under the synergistic effects of copper catalysis and microwave irradiationwas less investigated,we decided to explore different reaction parameters in order to provide an easy and efficient way to obtain polymerizable cyclodextrin monomethacrylates. Furthermore, we describe the click reaction of 6I-azido-6I- deoxycyclomaltoheptaose(2) onto poly(propargylmethacrylate)

(5) to obtain a polymer with potential applications in supramolecular chemistry.

Experimental Section

Materials. Cyclodextrin ( -CD) was obtained from Wacker- Chemie GmbH, Burghausen, Germany, and used after drying overnightin vacuum oil pump on P4O10. 2-Propynyl2-methacrylate (98%) was purchased from Alfa Aesar GmbH & CoKG, Germany.

Sodium azide (9%) was obtained from Aldrich Chemicals, Germany, and used as received. Copper(I) sulfate pentahydrate (9%)was obtainedformCarlRothGmbH& Co. and sodiumL(+)- ascorbate (9%) from AppliChem, Germany. R,R′-Azoisobutyronitrile (AIBN) (96%) and N,N-dimethylformamide (DMF) were purchased from Fluka, Germany. Dimethyl-d6 sulfoxide (9.9 atom % D) was obtained from Deutero GmbH, Germany. 6I-Azido-6I- deoxycyclomaltoheptaose (2) was prepared according to a method described in the literature.6

Measurements. IR spectra were recorded with a Nicolet 5 SXB

FTIR (Fourier transform infrared) spectrometer equipped with an ATR unit. The measurements were performed in the range of 4000-300 cm-1 at room temperature. 1H spectra were recorded with a Bruker AC 500 at 20 °C. Chemical shifts were referenced to the solventvalue δ 2.51 for dimethyl-d6 sulfoxide.Matrix-assisted laserdesorption/ionization-time-of-flightmassspectrometry(MALDI-

TOF-MS) was performed on a Bruker Ultraflex TOF mass spectrometer. Ions formed with a pulsed nitrogen laser (25 Hz, 337 nm) were acceleratedto 25 kV, the molecularmassesbeingrecorded in linear mode. 2,5-Dihydroxybenzoic acid (DBH) in acetonitrile/ water (25 mg mL-1) was used as a matrix. The samples (1 mg mL-1 in water) were mixed with the matrix solution at volumetric ratios of 1:2. Gel permeation chromatography(GPC) analyses were performed on a GPC system from PSS with PSS-WIN-GPC software 4.01, 6.1 with N,N-dimethylformamideas eluent. The flow rate was 1 mL min-1, and the column temperature was maintained at 60 °C. 100 µL of a 0.1% (w/w) polymer solution was given to a hydroxyethyl methacrylate (HEMA) column combination that consisted of a precolumn of 40 Å and main columns of 40, 100, and 3000 Å porosities. The number-average molecular weight (Mn) and the polydispersity (PD) were calculated by a calibration curve generated by polystyrene standards with a molecular weight range from 374 to 1 0 0 Da. Dynamic light scattering (DLS) experiments were carried out with a Malvern HPPS-ET in the temperature range 17-75 °C. The particle size distribution was derived from a deconvolution of the measured intensity autocorrelation function of the sample by the general purpose mode algorithm included in the DTS software. Each experiment was

* Corresponding author. Fax: +49-211-8115840. E-mail:

† Heinrich-Heine-Universitat Dusseldorf. ‡ S&V Technologies AG.

10.1021/ma8018975 C: $40.75 2008 American Chemical Society Published on Web 1/25/2008 performed at least five times to obtain statistical information. Microwave-assistedsynthesiswas performedusinga CEM Discover SynthesisUnit (monomodesystem).The temperaturewas measured by infrared detection with continuous feedback temperature control and maintained at a constant value by power modulation. Reactions were performed in closed vessels under controlled pressure as well as in standard open vessels under reflux conditions.

Synthesis of the Triazol-CD-Monomer (3). The reaction of 6I- azido-6I-deoxycyclomaltoheptaose (2) (116 mg, 0.1 mmol) with 2-propynyl 2-methacrylate 2 (24.80 mg, 0.2 mmol) was carried out in DMF, in the presence of Cu(I) generated in situ by the reduction of copper sulfate(1.2 mg, 0.005 mmol) with sodium ascorbate(1.98 mg, 0.01 mmol). The product was separated by simple filtration after precipitationwith acetone(50 mL). We carriedout microwaveassisted cycloaddition, by adding 2-propynyl 2-methacrylate (1) (24.80 mg, 0.2 mmol) to a solution of 6I-azido-6I-deoxycyclomaltoheptaose (2) (116 mg, 0.1 mmol) in 2 mL of DMF in a pressureresistant test tube. Sodium ascorbate (4 mg, 0.02 mmol) and copper(I) sulfate pentahydrate (2.50 mg, 0.01 mmol) were added to the clear solution. The tube was placed in the CEM monomode microwave and irradiated at 140 °C and 100 W for 30 min. After precipitating the reaction mixture with acetone, 108 mg of product was isolated (84% yield). In order to ensure the equivalence of the reaction parameters, we conducted the reaction under reflux conditions, in oil bath as well as under microwave irradiation. The conventional reaction was performed by preheating the solvent, the reaction mixture being maintained 30 min at reflux temperature, after adding the reagents and catalytic system. The standard open vessel was placed in the CEM monomode microwave, and the reaction was conducted under reflux for 30 min, with a preheating time of 2 min. The product was collected by filtration, after precipitating with 50 mL of acetone (57% yield). By increasing the reaction time under conventional heating, the ratio monomer 3:monomer 4 was 3:1 after 24 h.

d6): δ (ppm) 1.86 (3H, CH3), 3.34 (br, 14H, H-2,4), 3.65 (br, 28H, H-3,5,6), 4.52 (br, 6H, OH-6), 4.84 (d, 6H, H-1), 5.03 (2H,

Homopolymerization of the Triazol-CD-Monomer 3. Mono- (1H-1,2,3-triazol-4-yl)(methyl)2-methylacryl- -cyclodextrin(3) (128 mg, 0.1 mmol) was solved in 1 mL of DMF and flushed with argon for 5 min. AIBN (R,R′-azoisobutyronitrile) (1.6 mg, 0.005 mmol) was added under an argon atmosphere. The mixture was heated to 65 °C and stirredovernight.The solventwas removedunderreduced pressure to afford 60 mg of product (46% conversion). FT-IR (film, cm-1): 3303 (OH), 2929 (CH), 1720 (CdO), 1653

Poly(propargyl methacrylate) (5). Propargyl methacrylate (1) (1.241 g, 0.1 mol) was solved in 4 mL of dioxane and flushed with argon for 5 min, and AIBN (R,R′-azoisobutyronitrile) (16.4 mg, 0.01 mmol) was added under an argon atmosphere. The reaction was stopped after stirring2ha t6 5 °C (25% conversion). The reaction mixture was precipitated into methanol and filtered, and the solid was dried under vacuum.

Coupling Reaction of Poly(propargyl methacrylate) (5) with 6I-Azido-6I-deoxycyclomaltoheptaose(2). A solution of 128 mg of poly(propargyl methacrylate) (5)i n1 0m Lo fD MF was prepared, and 6I-azido-6I-deoxycyclomaltoheptaose (2) (1.16 g, 1 mmol) was added under vigorous stirring. Sodium ascorbate (19.8 mg, 0.1 mmol) and copper(I) sulfate pentahydrate (12.45 mg, 0.05 mmol) were added to the clear solution. The reaction was conducted under conventional reflux conditions as well as under microwave irradiation. The reaction in oil bath was performed by preheating the polymeric solution, the reaction mixture being maintained 30 min at reflux temperature, after adding 6I-azido-6I-deoxycyclomaltoheptaose (2) and catalytic system. The standard open vessel was placed in the CEM monomode microwave, and the reaction was conducted under reflux for 30 min, with a preheating time of 2 min. The product was collected by precipitating the reaction mixture with 100 mL of acetone followed by filtration. The dry polymeric material was dissolved in water, dialyzed 3 days against distillated water using MWCO 3500 membrane, and freeze-dried. The polymer was obtained in a low yield (16%) under conventional heating, while the microwave conditions afforded a higher yield (27%).

(C-O). 1H (DMSO-d6): δ (ppm) 1.89 (3H, CH3), 3.32-3.56 (br, 14H, H-2,4, 28H, H-3,5,6), 4.51 (br, 6H, OH-6), 4.84 (d,

Results and Discussion

We carried out the “click reaction” of propargyl methacrylate (1) with 6I-azido-6I-deoxycyclomaltoheptaose (2) to synthesize the new monomer mono-(1H-1,2,3-triazol-4- yl)(methyl)2-methylacryl- -cyclodextrin (3) useful for the design of polymeric supramolecular architectures. Because of our interest in optimizing the process, we focused on the synergistic effects of microwave irradiation and Cu(I) catalysis. Although the conditions of the microwave-assisted reaction cannot be easily reproduced by the conventional heating, we duplicated some controllable parameters, such as temperature, time, catalyst, and solvent in order to ensure the comparability of the procedures. The active copper(I) catalytic species were generated in situ by reduction of CuSO4 with sodium ascorbate. We used N,N-dimethylformamide as solvent due its high dielectric constant, high boiling point, and ability to solve both starting materials. We performed also the process in water, but no reaction occurred under microwave irradiation. Regarding our interest to investigate the microwave effect on the Cu(I)-mediated cycloaddition and the possible interaction between the dielectric irradiation and the metal catalysis, we approached three different procedures. Cu(I)-free cycloaddition conducted in N,N- dimethylformamide took place rapidly under MW irradiation. Applying the conventional heating, we obtained slowly a relatively low conversion, which remained constant with increasing reaction time (Figure 1).

Cu(I)-mediated click reaction conducted under microwave irradiation favored the selective 1,4-conversion in 3 (Figure 2).

The reaction was completed after 30 min. In contrast, the oil bath procedure under similar conditions afforded a mixture of 3 and 4 with a relatively high conversion in 3 after increased reaction time (Figure 3).

The regioisomeric proportion was determined by 1H NMR spectroscopy. The chemical shifts of the triazole ring protons were used to distinguish isomers 3 and 4. The H4 proton of the 1,5-disubstituted triazole is located at 8.23 ppm. The resonance of the H5 proton of the 1,4-disubstituted triazol isomer is at 8.13 ppm.

Without any heating, the cycloaddition proceeded regioselectively;however,extremelyincreasedreactiontime is required (74% conversion after 1 week).

As mentioned above, the Huisgen cycloaddition is not a selective process, while Cu(I)-mediated reactions afford exclusively 1,4-disubstituted regioisomers. 16,17 As the mild catalyzed reaction resulted in extremely long reaction time, we

9620 Munteanu et al. Macromolecules, Vol. 41, No. 24, 2008

pursuedthe workupunderthermalconditions.In orderto explore and compare the effects induced by the microwave irradiation and the conventional heating under copper catalysis, we applied a fixed temperature for the same reaction time in both cases. We found that under conventional heating, even mediated by Cu(I), the reactionaffordsa mixtureof 1,4- and 1,5-disubstituted regioisomers, while the tandem Cu(I) microwave assures structural control and a significant higher conversion for the same time. Furthermore,we performedthe Cu(I)-mediatedclick reaction under reflux in MW and also in oil bath. The same reaction time was achieved by preheating the solvent under conventionalreflux conditions.A higher conversionof 87% was obtainedundermicroaweirradiationin comparisonwith 62% obtained under conventional heating. By comparing the results obtained under different reaction conditions (microwave, oil bath, and room temperature, with or without catalyst), we can conclude that the synergy Cu(I) microwave assured the highest conversionin compound3 with a significantdecreasein reaction time (Figure 2).

Attempts to polymerize the monomethacrylate cyclodextrin

Na+]). The reason for the low molecular weight may be due to the bulky cyclodextrin ring. Thus, a polymer analogous coupling of 6I-azido-6I-deoxycyclomaltoheptaose (2) onto poly(propargyl methacrylate) (5) was carried out (Figure 4). Since atom transfer radical polymerization(ATRP) of propargyl methacrylate was reported to result in high polydispersities (PD > 3) and cross-linkednetworks,26 we used classical free-radical-

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