Cu(OAc)₂·H₂O/NH₂NH₂·H₂O: an efficient catalyst system that in situ generates Cu₂O nanoparticles and HOAc for Huisgen click reactions

Abstract

A combination of Cu(OAc)₂·H₂O and NH₂NH₂·H₂O, which in situ generates Cu₂O-NPs and HOAc in water at room temperature, has been developed as a highly efficient catalytic system for Huisgen click reactions. Our results indicate that the in situ generated Cu₂O-NPs and HOAc play important roles in the Huisgen click reaction.

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Introduction

The azide–alkyne Huisgen cycloaddition, a 1,3-dipolar cycloaddition between an azide and a terminal or internal alkyne to give a 1,4- or 1,5-disubstituted 1,2,3-triazole, was developed by Rolf Huisgen.¹ The drawbacks of the classical Huisgen cycloaddition reaction are the requirement of high reaction temperatures and a lack of regioselectivity. Since Sharpless² and Meldal³ independently discovered that copper(I) catalysts could facilitate the Huisgen azide–alkyne cycloaddition in a regiospecific manner to give only 1,4-disubstituted triazoles, copper(I)-catalyzed azide–alkyne cycloaddition (CuAAC) reactions have attracted significant attention due to their application in the synthesis of pharmaceuticals, agrochemicals, dyes, corrosion inhibitors, biochemicals, polymers and functional materials.⁴ The usual sources of the copper(I) catalyst for CuAAC reactions are Cu(I) salts or their complexes,⁵ Cu(II) salts combined with a reducing agent (sodium ascorbate, metallic copper, hydrazine monohydrate, etc.)^2,6 and different sizes of metallic copper.⁷

Cu₂O is also a source of catalytic Cu(I) for CuAAC reactions. Using Cu₂O powder directly in a CuAAC reaction usually results in incomplete conversion, poor yields and long reaction times.⁸ Recently, efforts have been made to enhance the catalytic efficiency of Cu₂O.^9–13 In 2010, Kong et al.⁹ reported polyvinylpyrrolidone-coated Cu₂O nanoparticles as a catalyst for Huisgen click reactions in water at physiological temperatures (37 °C). The results in this paper indicated that Cu₂O-NPs were more efficient and less toxic than the commonly used CuSO₄/reductant catalyst systems. Hu et al.¹⁰ have established a practical and effective catalytic method using PhCO₂H as an additive. More recently, heterogeneous Cu₂O-NPs catalysts using charcoal,¹¹ and melamine–formaldehyde resin¹² as supports were prepared and applied in CuAAC reactions.

Hydrazine monohydrate¹⁴ is an attractive reductant for reducing Cu(II) salts due to its strong reducibility and environmentally friendly by-products (nitrogen gas and water) and has been successfully used in CuAAC reactions.^15–17 Recently, Pathigoolla¹⁶ and Kumar¹⁷ prepared copper nanoparticles from a CuSO₄·5H₂O/NH₂NH₂·H₂O catalyst system, which efficiently catalyzed the CuAAC reaction under ambient, open-air conditions. Unfortunately, the amount of NH₂NH₂·H₂O required was more than 10 times the stoichiometric amount, which is harmful to the environment because of the high toxicity of hydrazine itself. Thus, controlling the amount of the hydrazine is essential in order to be more environmentally conscious. In the work described in this paper, Cu(OAc)₂·H₂O was selected as the Cu(II) salt and a stoichiometric amount [Cu(II) to Cu(I)] of hydrazine was used as the reducing agent. It is well known that [(CuOAc)₂]_n is unstable in water and will immediately decompose to Cu₂O and HOAc,¹⁸ which could act as the catalyst for the CuAAC reaction. To the best of our knowledge, there have been no CuAAC reactions in water catalyzed by in situ generated Cu₂O and HOAc, which should show better catalytic efficiency than that of isolated Cu₂O combined with HOAc.

Results and discussion

NH₂NH₂·H₂O (0.1 mmol) was added to a solution of Cu(OAc)₂·H₂O (0.2 mmol) in water (10 mL) with vigorous stirring. The solution turned into a dark yellow colored suspension instantaneously (see ESI†). The suspension did not subside for a long time. After filtration, the precipitate was dried for three days under high vacuum at room temperature. The reduced product was characterized by X-ray powder diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) (see ESI†), which showed the product to be hollow spherical Cu₂O-NPs with sizes of 400–500 nm.

The reaction between propargyl phenyl ether and ethyl azidoacetate was selected as a model reaction. The reaction conditions were chosen as follows: propargyl phenyl ether (1 mmol), ethyl azidoacetate (1 mmol), Cu(OAc)₂·H₂O (2 mol%) and water (1 mL). The influence of the ratio of NH₂NH₂·H₂O to Cu(OAc)₂·H₂O on the isolated yields of the model reaction (Scheme 1) were investigated.

Scheme 1 Model reaction for selecting the ratio of NH₂NH₂·H₂O to Cu(OAc)₂·H₂O.

As shown in Fig. 1 (line a), the yield increased significantly over the ratio range of 0 : 1 to 1 : 2, from 0 to 92%, and then decreased over the ratio range of 1 : 2 to 3 : 1, from 92% to 24%. Meanwhile, the pH value of the reaction mixture without adding the model substrates (as shown in Fig. 1, line b) decreased from 5.55 to 4.61, over the ratio range of 0 : 1 to 1 : 2, which can be attributed to the generation of HOAc in the solution. In addition, the pH value increased from 4.61 to 6.24, between the ratio range of 1 : 2 to 3 : 1, which can be attributed to neutralization of the generated HOAc and excess hydrazine. The relationship between the yield and the pH value indicates that the in situ generated HOAc is critical for the catalytic efficiency of Cu₂O-NPs. Thus, the optimum ratio of NH₂NH₂·H₂O to Cu(OAc)₂·H₂O is 1 : 2, at which ratio the generated amount of HOAc reaches its peak while hydrazine has been completely consumed.

Fig. 1 Effect of the ratio of NH₂NH₂·H₂O to Cu(OAc)₂·H₂O on the yield and pH value.

In order to verify the relationship between the yield and the pH value again, the model reaction was carried out separately in varying amounts of water using NH₂NH₂·H₂O (1 mol%)/Cu(OAc)₂·H₂O (2 mol%) (molar ratio of 1 : 2) as the catalyst at room temperature. As shown in Fig. 2, the higher the amount of water, the higher the pH value and the lower the yield, which is consistent with the results mentioned above. Another experiment, using separate Cu₂O-NPs (1 mol%) and HOAc (4 mol%) as the catalyst for the model reaction, was carried out in water (1 mL) at room temperature. Unfortunately, the product yield was only 21% after 20 min, while the pH value was 3.84 and it took 110 min to finish the model reaction. The above result indicated that the catalytic activity of Cu₂O-NPs generated in situ was higher than that of separate Cu₂O-NPs. The reason for this is probably that the chemical equilibrium between the in situ generated Cu₂O-NPs and HOAc is shifted more to the side of CuOAc.^19–21 Therefore, the optimum amount of water is 1 mL.

Fig. 2 Effect of the amount of H₂O on the model reaction.

Reactions involving a wide range of diversely substituted terminal alkynes and azides were carried out using the optimized conditions. As shown in Table 1, the reaction works well not only with alkyl azides, but also with aryl azides. All of the reactions were highly regioselective towards the 1,4-disubstituted triazoles within 30 min.

Table 1 Synthesis of triazoles using the Cu(OAc)₂·H₂O/NH₂NH₂·H₂O system

Entry	Azide	Alkyne	Product^a	Time (min)	Yield^b (%)
a Reaction conditions: terminal alkyne (1 mmol), azide (1 mmol), NH2NH2·H2O (1 mol%), Cu(OAc)2·H2O (2 mol%), H2O (1 mL), at room temperature.b Isolated yield.
1	N3CH2COOEt			20	92
2				15	93
3				10	93
4				12	92
5	N3CH2COOEt			8	94
6				10	92
7				9	90
8				12	91
9				18	93
10				25	92
11				20	90
12				22	90
13				18	89
14				20	86
15				10	94
16				16	92
17	N3CH2COOEt			25	91
18				22	90
19				28	89
20				12	91

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The proposed mechanism (Scheme 2) for the reaction is the same as the established mechanism shown in earlier reports.²² The in situ generated HOAc plays many important roles in the reaction:^10,19–21 (a) HOAc breaks the crystal structure of Cu₂O to allow the formation of copper(I) carboxylates, which are highly efficient catalysts for the CuAAC reaction; (b) the acidity of HOAc is also necessary for the success of this conversion; (c) AcO⁻ acts as a bidentate ligand coordinated to the Cu(I) species of the monomer to promote the formation of dinuclear alkynyl–copper(I) intermediate (3) (see step 2); (d) it has an active effect on the cycloaddition (step 3) and protonation of the C–Cu bond (step 4).

Scheme 2 Proposed mechanism for the CuAAC reaction.

Conclusions

In summary, we have presented a novel and high yielding Cu(OAc)₂·H₂O/NH₂NH₂·H₂O catalyst system, which could in situ generate Cu₂O-NPs and HOAc to catalyze Huisgen click cycloadditions in water at room temperature with relatively short reaction times. Such a method is interesting as it avoids not only the use of stabilizers, additional ligands and supports, but also the production of harmful substances.

Acknowledgements

This work was supported financially by the Natural Science Foundation of China (No. 21172058) and Scientific Research Foundation for Doctors (No. 01036500508) and the Youth Foundation (2012QK11) of Henan Normal University.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3ra45437a

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