Baixe Cyclodextrin Methacrylate via Microwave-Assisted Click Reaction e outras Notas de estudo em PDF para Engenharia Elétrica, somente na Docsity!
Cyclodextrin Methacrylate via Microwave-Assisted Click Reaction
Maricica Munteanu,†^ SooWhan Choi,‡^ and Helmut Ritter*,†
Institute fu¨r Organische Chemie and Makromolekulare Chemie, Heinrich-Heine-Uni V ersita¨t Du¨sseldorf,
Lehrstuhl II, Uni V ersita¨tsstrasse 1, 40225 Du¨sseldorf, Germany, and S&V Technologies AG,
Neuendorfstrasse 20a, 16761 Henningsdorf, Germany
Recei V ed August 21, 2008; Re V ised Manuscript Recei V ed October 29, 2008
ABSTRACT: Click reaction of propargyl methacrylate ( 1 ) with 6I-azido-6I-deoxycyclomaltoheptaose ( 2 ) was carried out to synthesize mono-(1 H -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 conversion of ( 2 ) into 1,4-disubstituted triazole in a significant decreased reaction time. Under microwave conditions, the cycloaddition of ( 2 ) onto poly(propargyl methacrylate) ( 5 ) was conducted in excellent yields. The regioselectivity of click reactions in dependence of reaction conditions was evaluated by 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.
Introduction
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 multiappli-
cable 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, bioconjuga-
tion,^11 -^14 or drug discovery.^15 According to Huisgen^16 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-assisted copper-catalyzed 1,3-
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 cyclodextrin chemistry,^20 -^24 their use to obtain
cyclodextrin monomethacrylate has not been reported. Attempts
to synthesize monofunctional cyclodextrin esters led 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-cycloaddition of 6-monoazido-
6-monodeoxy--cyclodextrin with propargyl derivatives under
the synergistic effects of copper catalysis and microwave
irradiation was 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(propargyl methacrylate)
( 5 ) to obtain a polymer with potential applications in supramo-
lecular chemistry.
Experimental Section
Materials. Cyclodextrin (-CD) was obtained from Wacker- Chemie GmbH, Burghausen, Germany, and used after drying overnight in vacuum oil pump on P 4 O 10. 2-Propynyl 2-methacrylate (98%) was purchased from Alfa Aesar GmbH & CoKG, Germany. Sodium azide (99%) was obtained from Aldrich Chemicals, Germany, and used as received. Copper(II) sulfate pentahydrate (99%) was obtained form Carl Roth GmbH & Co. and sodium L(+)- ascorbate (99%) from AppliChem, Germany. R,R′-Azoisobutyroni- trile (AIBN) (96%) and N , N -dimethylformamide (DMF) were purchased from Fluka, Germany. Dimethyl- d 6 sulfoxide (99.9 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. 1 H spectra were recorded with a Bruker AC 500 at 20 °C. Chemical shifts were referenced to the solvent value δ 2.51 for dimethyl- d 6 sulfoxide. Matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI- TOF-MS) was performed on a Bruker Ultraflex TOF mass spectrometer. Ions formed with a pulsed nitrogen laser (25 Hz, 337 nm) were accelerated to 25 kV, the molecular masses being recorded 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 -dimethylformamide as 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 ( M n) and the polydispersity (PD) were calculated by a calibration curve generated by polystyrene standards with a molecular weight range from 374 to 1 000 000 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 autocor- relation 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: h.ritter@uni- duesseldorf.de. † (^) Heinrich-Heine-Universita¨t Du¨sseldorf. ‡ (^) S&V Technologies AG.
Macromolecules 2008 , 41 , 9619- 9623 9619
10.1021/ma8018975 CCC: $40.75 2008 American Chemical Society Published on Web 11/25/
performed at least five times to obtain statistical information. Microwave-assisted synthesis was performed using a CEM Discover Synthesis Unit (monomode system). The temperature was 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. mg, 0.01 mmol). The product was separated by simple filtration after precipitation with acetone (50 mL). We carried out microwave- assisted cycloaddition, by adding 2-propynyl 2-methacrylate ( 1 ) (24.80 mg, 0.2 mmol) to a solution of 6I-azido-6I-deoxycycloma- ltoheptaose ( 2 ) (116 mg, 0.1 mmol) in 2 mL of DMF in a pressure- resistant test tube. Sodium ascorbate (4 mg, 0.02 mmol) and copper(II) 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. FT-IR (film, cm-^1 ): 3351 (OH), 2927 (CH 2 ), 1714 (CdO), 1657 (CdC), 1153 (C-O-C), 1078 (OH), 1026 (C-O). 1 H (DMSO- d 6 ): δ (ppm) 1.86 (3H, CH 3 ), 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,
- C H 2 - ), 5.19 (H, - C H )), 5.73 (br, 14H, OH-2,3), 6.07 (H,
- C H )), 8.13 (1H, CH). MALDI-TOF: m / z 1306.5 [M + Na+]. Homopolymerization of the Triazol-CD-Monomer 3. Mono- (1 H -1,2,3-triazol-4-yl)(methyl)2-methylacryl--cyclodextrin ( 3 ) ( 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 stirred overnight. The solvent was removed under reduced pressure to afford 60 mg of product (46% conversion). FT-IR (film, cm-^1 ): 3303 (OH), 2929 (CH), 1720 (CdO), 1653 (CdC), 1558 (N-H), 1153 (C-O), 1023 (C-O). 1 H (DMSO- d 6 ): δ (ppm) 1.89 (3H, CH 3 ), 3.32-3.56 (br, 14H, H-2,4, 28H, H-3,5,6), 4.51 (br, 6H, OH-6), 4.84 (d, 6H, H-1), 5.03 (2H, - C H 2 - ), 5. (br, 14H, OH-2,3), 8.13 (1H, CH). M n ) 1.30 × 104 g mol-^1 , PD ) 1.4. 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 stirring 2 h at 65 °C (25% conversion). The reaction mixture was precipitated into methanol and filtered, and the solid was dried under vacuum. FT-IR (film, cm-^1 ): 3284 (≡C-H), 3002 (C-H), 2942 (CH 3 ), 2135 (CtC), 1723 (CdO), 1454 (CH 3 ), 1391 (CH 3 ), 1261 (C-O), 1128 (C-O-C). 1 H (DMSO- d 6 ): δ (ppm) 1.9 (3H, CH 3 ), 3. (CtCH), 4.78 (2H, - C H 2 - ), 5.76 (H, - C H )), 6.07 (H, - C H )). M n ) 1.04 × 105 g mol-^1 , PD ) 1.6.
Coupling Reaction of Poly(propargyl methacrylate) (5) with 6I-Azido-6I-deoxycyclomaltoheptaose (2). A solution of 128 mg of poly(propargyl methacrylate) ( 5 ) in 10 mL of DMF 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(II) sulfate pentahydrate (12.
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%). FT-IR (film, cm-^1 ): 3317 (OH), 2923 (CH), 1723 (CdO), 1653 (CdC), 1558 (N-H), 1348 (C-N), 1153 (C-O), 1021 (C-O). 1 H (DMSO- d 6 ): δ (ppm) 1.89 (3H, CH 3 ), 3.32-3. (br, 14H, H-2,4, 28H, H-3,5,6), 4.51 (br, 6H, OH-6), 4.84 (d, 6H, H-1), 5.03 (2H, - C H 2 - ), 5.76 (br, 14H, OH-2,3), 8.13 (1H, CH).
Results and Discussion
We carried out the “click reaction” of propargyl meth-
acrylate ( 1 ) with 6I-azido-6I-deoxycyclomaltoheptaose ( 2 )
to synthesize the new monomer mono-(1 H -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 CuSO 4
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 1 H 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 regiose-
lectively; however, extremely increased reaction time 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
disappearance of the specific IR bands for azide and CtCH
bonds at 2100 and 2135 cm-^1 and the presence of the peaks
for the hydroxyl groups of cyclodextrin at 3317 cm-^1 as well
as of the new peaks at 1558 and 1387 cm-^1 , indicating the
appearance of N-H and C-N bonds. The presence of the
triazole ring was also confirmed by NMR spectroscopy at 8.
ppm.
The size of polymers 6a and 6b was investigated in N , N -
dimethylformamide solution by DLS measurements. As ex-
pected, the hydrodynamic radius increased significantly after
the cycloaddition of 2 onto poly(propargyl methacrylate) ( 5 ).
Surprisingly, however, the yield of the product resulted after
microwave coupling reaction was significantly higher compared
to conventional coupling under oil bath conditions (Figure 5).
DLS measurements were also carried out for poly-
(monomethacrylate cyclodextrin) ( 6c ) in DMF solution. The
low hydrodynamic radius (5 nm) suggests intrachain interac-
tions due to cyclodextrin units. By repeating the measurement
using adamantyl carboxylate as guest molecules, we noticed
a slightly increased hydrodynamic radius (6 nm), which can
be the result of electrostatic repulsion between the carboxylate
groups and because of reducing the H-bonds interaction
between the dimerized cyclodextrin rings (Figure 6). Similar
results were obtained by exposure to LiCl (10%) as a conse-
quence of breaking the intrachain H-bond interactions.
Conclusions
On the basis of the advantages conferred by the MW-
assisted Cu-catalyzed “click reaction”, we developed an
elegant and efficient approach for the synthesis of polymer-
izable cyclodextrin monomethacrylate, under complete struc-
tural control and with an important decrease in the reaction
time. IR and NMR measurements correlated with DLS
investigations confirmed the polymerization of cyclodextrin
monomethacrylates as well as the coupling of 6I-azido-6I-
deoxycyclomaltoheptaose ( 2 ) with the acetylene units placed
onto poly(propargyl methacrylate) ( 5 ). The resulting polymer
with a significant content of covalently attached cyclodextrins
has potential applications in supramolecular chemistry, drug
delivery, and analytics.
Acknowledgment. Financial support by the Deutsche Fors-
chungsgemeinschaft is gratefully acknowledged (DFG, Project RI 410/33-3).
References and Notes
(1) Kretschmann, O.; Steffens, C.; Ritter, H. Angew. Chem., Int. Ed. 2007 , 46 , 2708–2711. (2) Koopmans, C.; Ritter, H. J. Am. Chem. Soc. 2007 , 129 , 3502–3504. (3) Kretschmann, O.; Choi, S. W.; Miyauchi, M.; Tomatsu, I.; Harada, A.; Ritter, H. Angew. Chem., Int. Ed. 2006 , 45 , 4361–4365. (4) Ko¨llisch, H.; Barner-Kowollik, Ch.; Ritter, H. Macromol. Rapid Commun. 2006 , 27 , 848–853. (5) Schmitz, S.; Ritter, H. Angew. Chem., Int. Ed. 2005 , 44 , 5658–5661. (6) Ohga, K.; Takashima, Y.; Takahashi, H.; Kawaguchi, Y.; Yamaguchi, H.; Harada, A. Macromolecules 2005 , 38 , 5897–5904. (7) Harada, A.; Hashidzume, A.; Takashima, Y. Ad V_. Polym. Sci._ 2006 , 201 , 1–43. (8) Wenz, G. Angew. Chem., Int. Ed. 1994 , 33 , 803–822. (9) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed. 2001 , 2004–2021. (10) (a) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem. 2002 , 114 , 2708–2711. (b) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem., Int. Ed. 2002 , 41 , 2596–2599. (11) Chittaboina, S.; Xie, F.; Wang, Q. Tetrahedron Lett. 2005 , 46 , 2331–
(12) Breinbauer, R.; Ko¨hn, M. ChemBioChem 2003 , 4 , 1147–1149. (13) Gupta, S. S.; Raja, K. S.; Eiton, K. S.; Kaltgrad, E.; Strable, E.; Finn, M. G. Chem. Commun. 2005 , 4315–4317. (14) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.; Sharpless, K. B.; Finn, M. G. J. Am. Chem. Soc. 2003 , 125 , 3192–3193. (15) Kolb, H. C.; Sharpless, B. Drug Disco V ery Today 2003 , 8 , 1128–
(16) Huisgen, R. Angew. Chem., Int. Ed. 1963 , 2 , 565–598. (17) Tornoe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem. 2002 , 67 , 3057–3064. (18) Kaval, N.; Ermolat’ev, D.; Appukkuttan, P.; Dehaen, W.; Kappe, O.; Van der Eycken, E. J. Comb. Chem. 2005 , 7 , 490–502. (19) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman, L.; Sharpless, B. K.; Fokin, V. V. J. Am. Chem. Soc. 2005 , 127 , 210–
(20) Perez-Balderas, F.; Ortega-Munoz, M.; Morales-Sanfrutos, J.; Her- nandez-Mateo, F.; Calvo-Flores, F. G.; Calvo-Asin, J. A.; Isac-Garcia, J.; Santoyo-Gonzalez, F. Org. Lett. 2003 , 5 , 1951–1954. (21) Ortega-Mun˜oz, M.; Morales-Sanfrutos, J.; Perez-Balderas, F.; Her- nandez-Mateo, F.; Giron-Gonzalez, M. D.; Sevillano-Tripero, N.; Salto-Gonzalez, R.; Santoyo-Gonzalez, F. Org. Biomol. Chem. 2007 , 5 , 2291–2301.
Figure 5. Hydrodynamic volumes of polymer 5 in N , N -dimethylfor- mamide solution before and after coupling with 2 under conventional reflux conditions ( 6a ) and MW irradiation ( 6b ) (polymer concentration ) 10 g/L, 25 °C).
Figure 6. Hydrodynamic volume of poly(methacrylate cyclodextrin) ( 6c ) in N , N -dimethylformamide solution before (s) and after (- - -) complexation with guest molecules (polymer concentration ) 10 g/L, 25 °C).
Scheme 1. Synthesis of Triazol-CD-Monomer (3) via “Click Chemistry”
9622 Munteanu et al. Macromolecules, Vol. 41, No. 24, 2008
(22) Chan, T. R.; Hilgraf, R.; Sharpless, K. B.; Fokin, V. V. Org. Lett. 2004 , 6 , 2853–2855. (23) Hoogenboom, R.; Moore, B. C.; Schubert, U. S. Chem. Commun. 2006 , 38 , 4010–4012. (24) Barr, L.; Lincoln, S.; Easton, C. J. Supramol. Chem. 2005 , 17 , 547–
(25) Harada, A.; Furue, M.; Nozakura, S. Macromolecules 1976 , 9 , 701–
(26) Sumerlin, B. S.; Tsarevsky, N. T.; Louche, G.; Lee, R. Y.; Matyjas- zewski, K. Macromolecules 2005 , 38 , 7540–7545.
MA
Macromolecules, Vol. 41, No. 24, 2008 Cyclodextrin Methacrylate 9623
