Azide–alkyne cycloaddition reactions in water via recyclable heterogeneous Cu catalysts: reverse phase silica gel and thermoresponsive hydrogels

Functionalized reverse phase silica gel and thermoresponsive hydrogels were synthesized as heterogeneous catalysts supports. Cu(i) and Cu(ii) catalysts immobilized onto two types of supports were prepared and characterized. The copper catalyzed azide–alkyne cycloaddition was performed in water via a one-pot reaction and yielded good results. These catalysts are air stable and reusable over multiple uses.


Introduction
Triazole is a very useful motif within the elds of medicinal chemistry, 1-4 carbohydrate chemistry, [5][6][7] and materials science. [8][9][10][11][12] Triazole has also been studied as a strong ligand for metal coordination with wide applicability. [13][14][15][16] The thermal Huisgen 1,3-dipolar cycloaddition of organoazides and alkynes is a classic method for the synthesis of triazole. 17,18 However, this method is slow even at high temperatures, producing a mixture of 1,4-and 1,5-disubstituted triazoles. Numerous synthetic methods using metal catalysts have been reported; [19][20][21][22][23][24][25][26][27][28][29] copper has been shown to especially accelerate the reaction. The copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction initiated by Sharpless 30 and Meldal 31 is considered to be a powerful pathway with a high regioselectivity and yield. However, copper catalyzed methods also possess drawbacks due to limited catalyst recyclability, the use of organic solvents, and the use of relatively expensive copper complexes that are difficult to remove. [32][33][34][35] Therefore, the development of copper immobilized heterogeneous catalysts has attracted attention due to its reusability and ease of catalyst separation. [36][37][38][39][40][41] A variety of solid supports have been applied including zeolites, 42 charcoal, 43,44 silica, 45,46 and polysaccharides. 47 Additionally, the use of water as a solvent is a promising approach with regard to green chemistry. 37,38,[48][49][50][51][52] Recently, we developed two types of solid supports. One is an aminopropyl-functionalized reverse phase silica gel, which is end capped with a hydrophobic alkyl group. The other one is a thermoresponsive poly(N-isopropylacrylamide-co-4-vinylpyridine) (pNIPAM-VP) exhibiting hydrophilicity and hydrophobicity depending on temperature. These properties make it possible to use water as a solvent for organic reactions. These solid supports were applied to the syntheses of Pd, Au immobilized heterogeneous catalysts and organic reactions such as hydrogenations, 53 Suzuki-Miyaura couplings, 54,55 Heck-Mizoroki couplings, 56 Sonogashira couplings, 56 Tsuji-Trost reactions, 57 and A-3 coupling reactions 58 that were performed in water. Herein, we wish to demonstrate that our supports can be extended to other metal catalyzed organic reaction applications. In this study, Cu(I) and Cu(II) catalysts immobilized onto two support types were synthesized and characterized. The copper catalyzed azide-alkyne cycloaddition was performed in water. Introduction of the 2-pyridinecarboxaldehyde ligand to the starting silica gel was conrmed via solid-state 13 C NMR (ESI). The copper catalysts possessed an irregular shape based on scanning electron microscopy (SEM) images acquired primarily from the shape of the starting silica gel. Energy dispersive X-ray analysis (EDXA) further conrmed that Cu was indeed present (Fig. 1). Copper loading values on the catalysts were determined via inductively coupled plasma (ICP); the results showed the loading values to be 0.498 mmol g À1 of Cu(I)@IPSi and 0.319 mmol g À1 of Cu(II)@IPSi. As a result of the Brunnauer-Emmet-Teller (BET) method, the catalysts possessed pore sizes of 6-8 nm similar to the starting silica gel and pore volumes of 0.332 cm 3 g À1 and 0.416 cm 3 g À1 for Cu(I)@IPSi and Cu(II)@Si, respectively (ESI). The oxidation number of copper supported on the catalyst was conrmed by X-ray photoelectron spectroscopy (XPS) (ESI).
The reverse phase silica gel possessed an end capped alkyl group yielding hydrophobicity. We anticipated that transport of the hydrophobic substrate towards the hydrophobic surface would enhanced reactivity by bringing the substrate and catalyst in close proximity. 47 This property would also enable the azide-alkyne cycloaddition reaction in water (Fig. 2).
Azide-alkyne cycloaddition. Azide-alkyne cycloaddition reactions were performed to explore the catalytic activity of the prepared catalysts. The reaction was performed via the one-pot reaction of benzyl bromide, sodium azide, and phenylacetylene. First, the reaction of benzyl bromide with sodium azide generated benzyl azide in situ. Then, benzyl azide reacted with phenylacetylene to form the triazole product. Optimization of the reaction has been assessed as shown in Table 1. The turnover number (TON) and turnover frequency (TOF) values were compared. Initially, the reaction was performed at room temperature using 5 mol% of catalyst with excellent yields   . Both catalysts were effective and Cu(I) @IPSi was more reactive than Cu(II)@IPSi. The reaction proceeded smoothly in water, an environmentally friendly solvent. All reactants, aryl bromides and arylacetylenes regardless of attached electron withdrawing and electron donating substituents, yielded good results (74%-quant. yield).
Recycling test. Recycling tests were performed using recovered catalysts under the established reaction conditions of 60 C in water (Table 1, entry 4 & 9). As can be seen in Fig. 3, both catalysts were reusable several times, exhibiting little to no change to the product yield (92%-quant.). Since there was a slight difference in the amount of catalyst recovered in each reaction, a difference in yield was inevitable. Aer the reaction, catalysts were collected by hot ltration and the ltrate was checked via ICP to conrm the leaching of copper. Fortunately, the ICP data showed no signicant copper loss from both catalysts. XPS analysis was performed to conrm the oxidation state of freshly prepared catalyst and recovered catalyst (more details, see ESI †).
The loading values of copper were determined via ICP and the results revealed loading levels of 0.374 mmol g À1 for Cu(I) @pNIPAM-VP and 0.166 mmol g À1 for Cu(II)@pNIPAM-VP. pNIPAM-VP supports featured a special low critical solution temperature (LCST) that imparted additional control to accelerate the reaction. According to the differential scanning calorimetry (DSC) data, the LCST of the synthesized polymer was 47 C, as can be seen in Fig. 5. At temperatures higher than 47 C, hydrogen bonds between the polymer and solvent molecules become weak and the polymer coils around itself, shrinking in size as intramolecular hydrogen bonding becomes signicant. 59,60 This mechanism was proposed for the coil-toglobule transition of polymer coils that took place in hydrophilic solvents (Fig. 5).

Azide-alkyne cycloaddition
One-pot azide-alkyne cycloaddition reactions were performed to explore the catalytic activity of the prepared catalysts. Initially, we chose benzyl bromide and phenylacetylene as substrates and the reaction was performed at 60 C above the LCST (47 C). The reaction was attempted by varying the quantity of catalyst and the TON and TOF values of the corresponding reaction were compared as can be seen in Table 3. Cu(II)@pNIPAM-VP (1 mol%) was able to effectively perform the reaction (91%). In case of Cu(I)@pNIPAM-VP (5 mol%), the product yield was 94% (Table 3, entries 1 & 4).
The azide-alkyne cycloaddition was performed using various substrates with electron withdrawing and electron donating substituents (Table 4). Reactions with both catalysts proceeded in water and Cu(II)@pNIPAM-VP was more reactive than Cu(I) @pNIPAM-VP.

Recycling test
Recycling tests were performed using recovered catalysts under the established reaction conditions of 60 C in water ( Table 3, entries 1 & 4). As can be seen in Fig. 6, the Cu(I)@pNIPAM-VP catalyst was reusable several times, exhibiting little to no change to the product yield (90-94%). Aer the reaction, catalysts were collected by hot ltration and the ltrate was checked via ICP to conrm the leaching of copper. Fortunately, ICP data revealed no signicant copper losses from the Cu(I)@pNIPAM-VP catalyst. On the other hand, in case of Cu(II)@pNIPAM-VP, the yield decreased remarkably aer being recycled three times. XPS analysis was also performed to conrm the oxidation state of freshly prepared catalyst and recovered catalyst (ESI).

Material and characterization
All chemicals were purchased from commercial sources (Sigma Aldrich, TCI and Alfa Aesar) and were used without further purication unless specically mentioned. 2-Pyridinecarboxaldehyde and 4-vinylpyridine (4-VP) were distilled under reduced pressure prior to use. The silica gel support used to prepare the catalysts was commercially available 9% functionalized 3-aminopropyl silica gel with 1 mmol NH 2 per gram (particle size 40-63 mm; pore size 60 A; surface area 550 m 2 g À1 ).
The copper catalyst loading on the silica support and the azidealkyne cycloaddition reaction were performed using a shaker (Eyela, Mixer CM-1000) at 12 Â 10 3 rpm. Scanning electron microscopy (SEM) and energy dispersive X-ray analysis (EDXA) were performed on a HRTEM JEOL electron microscope at an acceleration voltage of 300 kV. The copper catalyst loading values were estimated via inductively coupled plasma (ICP) analysis with a JY Ultima2C. ICP analysis was also used to check for Cu leaching aer the recycle test. X-ray photoelectron spectroscopy (XPS) analysis was performed on a VG SCIENTA R3000 to show the electronic state of copper. 1 H and 13 C NMR spectra were obtained in CDCl 3 with a Bruker NMR at 400 MHz for 1 H and at 100 MHz for 13 C with TMS as an internal standard. For solid-state NMR experiments, 1D 13 C spectra were measured via a cross polarization (CP) pulse sequence (contact time: 2 ms) on a Bruker 400 MHz NMR spectrometer equipped with a 4 mm magic angle spinning (MAS) probe (Bruker Biospin, Billerica, MA) operating at a 10 kHz spinning rate. Low temperature nitrogen adsorption-desorption isotherms were measured at À196 C on an absorption volumetric analyzer BEL MINI manufactured by BEL, Inc. (Japan). Specic surface areas were determined using the Brunnauer-Emmet-Teller (BET) method from nitrogen adsorption isotherms of gas adsorbed at the relative pressure P/P 0 ¼ 0.99. Infrared spectra were recorded on a Bruker Alpha FT-IR spectrometer. Melting points were determined with a Sanyo Gallenkamp melting point apparatus. Analytical thin layer chromatography (TLC) was performed with E. Merck 60 F254 aluminum-backed silica gel plates (0.2 mm) containing a uorescent indicator.

Synthesis of Cu(I)@IPSi and Cu(II)@IPSi
3-Aminopropyl functionalized silica gel (3 mmol NH 2 unit, 1.0 equiv., 3 g) was added to a jacketed vial containing a solution of 2pyridinecarboxaldehyde (1.1 equiv., 0.34 mL) in 15 mL of distilled CH 2 Cl 2 . Aer 3 hours of vigorous stirring, the reaction mixture was ltered, washed with CH 2 Cl 2 , and dried under vacuum at 40 C. To coordinate Cu(I) with silica, imine functionalized silica gel (IPSi, 1.0 equiv., 1.1 g) and [Cu(CH 3 CN) 4 ]PF 6 (1.1 equiv., 0.21 g) were added to 25 mL of methanol. The reaction mixture was shaken at room temperature for 12 hours, followed by ltration, washing with methanol, and drying under vacuum at 40 C. The loading value of Cu(I)@IPSi was 0.498 mmol g À1 . For the preparation of Cu(II)@IPSi, imine functionalized silica gel (1.0 equiv., 1.1 g) was added to a jacketed vial containing CuSO 4 $5H 2 O (1.1 equiv., 0.27 g) dissolved in 25 mL of H 2 O. The mixture was stirred for 12 hours at room temperature, followed by ltration, washing with H 2 O, and drying under vacuum at 40 C. The loading value of Cu(II)@IPSi was 0.319 mmol g À1 .

Conclusions
Two types of solid supports were synthesized for the preparation of heterogeneous catalysts. One was aminopropyl-functionalized reverse phase silica gel, which possessed an end capped hydrophobic alkyl group. The other was a thermoresponsive poly(Nisopropylacrylamide-co-4-vinylpyridine) (pNIPAM-VP), which exhibited hydrophilicity and hydrophobicity according to temperature. These catalyst properties enabled one-pot azidealkyne cycloaddition reactions in water. A series of 1,4disubstituted-1,2,3-triazoles were synthesized with good results and the catalysts could be reused multiple times.

Conflicts of interest
There are no conicts to declare.