Introduction

The cycloaddition between an azide and a terminal alkyne produce 1,2,3-triazoles aretypical nitrogen-containing heterocyclic molecules that have attracted enormous interestdue to their wide range of applications in biology1,2, medicinalchemistry3,4, design of new catalysts5 and also foundwide industrial applications such as corrosion inhibitors, agrochemicals, opticalbrighteners and photographic materials6. The cycloaddition process isbased on a copper-catalyzed reaction protocol, which is highly regioselective to producea 1, 4-disubstituted triazoles.

The azide-alkyne cycloaddition between an azide and a terminal or internal alkyne to givea 1,4- or 1,5-disubstituted 1,2,3-triazole, was developed by Rolf Huisgen7. The drawbacks of the Huisgen cycloaddition reaction are the requirement of highreaction temperatures and a lack of regioselectivity. Later, Sharpless8and Meldal9 independently discovered that Cu(I) catalysts couldfacilitate the azide-alkyne cycloaddition in a regiospecific manner to give only1,4-disubstituted triazoles.

Cycloaddition protocol was catalyzed with a Cu(I) source by using a Cu(I) salt10, CuSO4-ascorbate system11 and stabilized Cu(I)onto polymers12 or zeolite13. Copper nanoparticles14, metallic copper turnings15 and CuO nanoparticles16 have also successfully demonstrated activity for the title reaction.Cu2O is also a source of catalytic Cu(I) for azide-alkyne cycloadditionreactions. Applying Cu2O powder directly in a title reaction usually resultsan incomplete conversion and also require long reaction time16. Effortshave also been made to enhance the catalytic efficiency of Cu2O17,18,19,20. It is reported that17polyvinylpyrrolidone-coated Cu2O nanoparticles can act as an efficientcatalyst for cycloaddition reactions in water at physiological temperature. The resultsin this paper indicated that Cu2O-NPs were less toxic than the commonly usedCuSO4-reductant catalyst systems21,22. Polymers have thepotential benefit as a support of the catalyst for a wide range of applications23,24,25,26 due to the combination of both robust and flexiblenature27.

Scientists has given attention to develop the catalysts for the synthesis of1,2,3-triazoles in such a way so that Cu(I) efficiently catalyzed the reaction undermild conditions to give 1,4-disubstituted 1,2,3-triazoles. In connection with ouron-going research on the development of effective catalysts for synthetic organictransformations27,28,29,30,31,32, we have found that apolyaniline supported Cu(I) supramolecular composite system can be used for theazide-alkyne cycloaddition reaction where heterogeneous catalyst could be easilyseparated from the crude reaction mixture and recycled in a given process.

In recent years, the environmental aspects such as atom efficiency, waste production andenergy consumption are very important issues for consideration of a chemical reaction.In this regard, the combination of two or more synthetic steps into one operation is avery appealing methodology since time, energy and resources consuming workup andpurification steps can be minimized. Considering the above facts, in this presentcommunication we report a convenient one pot method for the synthesis of polymerstabilized Cu(I) catalyst and Cu(I) catalyzed azide-alkyne cycloaddition reaction underambient condition. In the reaction pot, polymer stabilized Cu(I) catalyst was formed dueto the ‘in-situ polymerization and composite formation’(IPCF) reaction33,34,35,36,37,38.

Figure 1
figure 1

Polyaniline immobilized Cu(I) formation.

Full size image

Result and discussion

Polymer immobilized Cu(I) formation (Figure 1):Proof of evidence

In a typical experiment, aniline monomer (5.0 mM) was diluted in methanol in aconical flask and an aqueous solution of CuSO4, 5H2O(10−2 M) was added drop-wise (1:2 molar ratio ofcopper sulphate to aniline) to it under stirring condition. During the addition,the solution took on a green colourization and at the end a parrot greenprecipitation was formed at the bottom of the conical flask. The entire reactionwas performed at room temperature and under open atmosphere. Here, IPCFsynthesis technique has been followed for the preparation of a Cu(I)-polyanilinesupramolecular composite material using copper (II) sulphate as an oxidizingagent for polymerizing aniline. During the polymerization process each step isassociated with a release of electron and that electron reduces theCu2+ ion to form Cu+ ion. TheCu+ ion binds with the chain nitrogen of the polyaniline toform an N→Cu(I) type of bond, where polymer acts as a micro ligand.The SEM image (Figure 2A) illustrates the fiber-likemorphology of the Cu(I)-polyaniline complex. The TEM image (Figure 2B) shows the surface morphology and internal microstructureof the polymer. A thin area of the sample was selected for viewing and acquiringthe TEM images. It is clear from the TEM image that the surface is very smoothas well as transparent and has no evidence for the presence of coppernanoparticles. Figure 2C represents the colour of theresultant dried sample. The sample was also characterized with X-ray diffraction(XRD) analysis (Figure 2D). The XRD pattern confirms thecrystalline character of the polyaniline and there is no indication for theformation of the metallic copper. To confirm the valence state of copper presentin the sample X-ray photoelectron spectroscopy (XPS) analysis was done. A highintensity peak at 932.5 eV could be assigned to the binding energies of Cu (I)(Figure 1D, in-set). No characteristic peaks areidentified for Cu (II) and Cu (0), suggesting that copper (II) precursor isconverted to Cu (I).

Figure 2
figure 2

The SEM image (A) of the Cu(I)-polyaniline complex whereas the TEM image (B)of the polymer and no evidence of the formation of copper nanoparticles hasbeen observed in the image. (C) The Cu(I)-polyaniline composite material(dried). (D) The XRD pattern indicates the crystalline character of thepolyaniline, there being no indication for the formation of the metalliccopper. X-ray photoelectron spectroscopy (XPS) analysis shows(in-site) the high intensity peak at 932.5 eV could be assigned to thebinding energies of Cu 2p3/2, indicating thepresence of Cu (I).

Full size image

Figure 3 shows the optical characterization of theresultant Cu(I)-polyaniline composite. The IR analysis of the fingerprint regionis useful for examining the resonance modes of the benzenoid and quinoid unitsof polyaniline. In the IR spectra (Figure 3A), the peak at1638 cm−1 corresponds to the group N = Q = N (where Qrepresents a quinoid ring), while the N-B-N group (where B represents abenzenoid ring) absorbs at 1496 cm−1. The N-Hstretching mode at 3400 cm−1 has been identified forthe Cu(I)-polyaniline sample. These results are in good agreement withpreviously reported spectroscopic characterizations data of the polyaniline39. The intensity of the peak for quinoid ring structure is higherindicates that the polymers are higher in oxidation state. The UV-vis spectrum(Figure 3B) of Cu-polyaniline show a shoulder-likeappearance at about 330 nm corresponds to π-π*transition of benzenoid rings (inter-band transition) and at about 400 nm aprominent broad peak represents polaron/bipolaron transition. A weak absorptionband with a curvilinear behaviour has been observed within the range of500–700 nm indicates the benzenoid to quinoid excitonic transition inboth the polymers40. All the above microscopic and spectroscopiccharacterization techniques proved the formation of Cu(I)-polyaniline during thereaction between aniline and copper sulphate.

Figure 3
figure 3

Fourier transform infrared (FT-IR) spectrum (A) of the resultant materialshowing the presence of benzenoid and quinoid rings at 1496 and 1638 in thepolymer, respectively. The UV-vis spectrum (B) of Cu-polyaniline show ashoulder-like appearance at about 330 nm corresponds toπ-π* transition of benzenoid rings and at about 400nm a prominent peak represents polaron/bipolaron transition.

Full size image

Polyaniline supported Cu(I) formation and azide-alkynecycloaddition

After confirmation of the formation of the Cu(I) species we have followed theprocedure mentioned in ‘Method: 1’ for the cycloadditionreaction between azide and alkyne (Figure 4A).

Figure 4
figure 4

(A) Cycloaddition reaction between azide and alkyne in presence of anilineand copper sulphate using methanol as a solvent. (B) The recyclability studyof the azide and alkyne cycloaddition reaction using Cu-polyanilinecomposite recovered from the reaction mentioned in Method 1, Figure 4 (A). All the reactions were done under room temperature(r.t.).

Full size image

The 1,3-dipolar cycloaddition reaction has been tested using benzyl azide,1a, with phenyl acetylene, 2a, for the synthesis ofdi-substituted 1,2,3-triazoles, 3a, at room temperature under differentsolvent conditions such as dichloromethane, chloroform, toluene, ethanol,methanol, water and methanol : water (1:1) mixture in the presence of coppersulphate and aniline. Among the above solvents, methanol and the combination ofmethanol-water system gave the highest product conversion, product yield 99% forthe period of 7h (Table 1). Considering the aboveresults we have decided to use methanol as a solvent for the rest of the studyto ease the work-up procedure. Due to the basic nature of aniline, in this studywe did not add any external base as per recommendation for the 1,3-dipolarcycloaddition reaction41. The best result was achieved when thecatalyst concentration was 3.0 mol% Cu (on the basis of the amount of anilinepresent in the reaction mixture and also considering all the aniline to beconverted to polyaniline as a support). By increasing the amount for Cuconcentration, no further improvement of the reaction has been identified interms of time (Table 1, entry 6). Besides that, thereaction between benzyl azide with acetylene was also carried out in thepresence of Et3N under the same reaction condition to find out thesignificance of Et3N in the reaction. We have observed the presenceof Et3N delayed the reaction significantly may be due to thecoordination between Et3N and copper sulphate forms relatively stableintermediate complex,[Cu(NEt3)4]2+,which require more energy to breakup and for the participation of thereaction42. The product,1-benzyl-4-phenyl-1H-1,2,3-triazole (3a), was characterised byspectroscopic method and found to be identical with the previously reportedone43.

Table 1 Solvent and catalyst optimization studiesa.
Full size table

Based on the above optimized reaction condition, we have explored the versatilityof the in-situ generated catalyst for the 1,3-dipolar cycloaddition ofvarious azides and alkynes and the results are summarized in Tables 2. In this study, we also have used structurally diverseazides and alkynes. All the substrates produced the expected cycloadditionproduct with very good to excellent yields and selectivity. Phenylacetylene andits derivatives (Table 2, entries 1–3) gave ahigher isolated yield when coupled with azides. It was found that the yield wasas high as 99% for the coupling of benzyl azide with phenylacetylene (Table 2, entry 1). When benzyl azide coupled withphenylacetylene with electron withdrawing and donating groups no such noticeabledifference has been observed in terms of yield for the cycloaddition product(Table 2, entries 2 and 3 respectively). Alkyneattached with heteroaromatic molecule afforded the product1-benzyl-4-(thiophen-3-yl)-1H-1,2,3-triazole when coupled with benzylazide and a decrease of yield has been observed in comparison with the aromaticsubstituted molecules (Table 2, entry 4). Cycloadditionbetween aliphatic alkynes and benzyl azide (Table 2,entries 5–8) is comparatively less efficient than alkynes attachedwith aromatic and heteroaromatic molecules. The cycloaddition of 2-bromobenzylazides (bromine substituted benzyl azide) with different alkynes (Table 2, entries 9–16) shows an identicalreactivity trend that found for the benzyl azide (Table2, entries 1–8). All the above products have beenachieved over the period of 7 h under the ambient atmospheric condition.

Table 2 Azide-alkyne cycloaddition of benzyl and o-bromobenzyl azides with different alkynes in presence of aniline and copper sulphatea.
Full size table

Performance of the recovered catalyst

In heterogeneous catalysis, the durability of the catalyst is an important issuefrom the economic and sustainability point of view.

To study the performance of the recovered catalyst, for the reaction mentioned inTable 2, entry 1, we have increased the amount ofthe reactants by a factor of 10 (for convenience, the concentration of thecopper sulphate has been changed to 0.1 mol dm−3) andmonitored the reaction using thin layer chromatography technique. Aftercompletion of the reaction, which took about 7 h, the product (3a, asconfirmed by spectroscopic analysis and with a yield of ~98%) was extracted andthe other product, Cu-polyaniline, was separated. The stability andrecyclability performance of the in-situ synthesized, Cu-polyaniline, wastested as a catalyst for the above cycloaddition reaction using the followingprocedure, Figure 4B. Alkyne (1a) and azide(2a) were mixed in the presence of methanol and to this solutiontriethylamine and recovered Cu-polyaniline catalyst were added. In thecycloaddition reaction, the role of triethylamine is to activate the acetylenicproton to form the phenyl acetylide which further react with the copper catalystto form copper acetylide. Copper acetylide then reacted with azide to formtrizole derivative. Whereas, in one pot reaction aniline performed the role ofbase and no need to use an external base like triethylamine. The recoveredcatalyst (Cu-polyaniline) was also characterized by TEM. The presence of thecopper nanoparticles was clearly noted with a wide range of size distribution(10–40 nm) on the polymer matrix (Figure 5). Sofar as the nanoparticles are concerned, the surface of the particles isconsidered to be more reactive as a catalyst and the present study revealed thesimilar experience during the reaction process. A yield of 98% of the coupledproduct (3a) has been achieved for the reaction between 1a and2a and that took about 5 h, which is two hours less than the originalsingle pot reaction, indicates the catalytic effect of the nanoparticles. At theend of the fifth cycle, a yield of 87% of cycloaddition product was achieved atabout 5 h. The recyclability study has also been performed using the recoveredcatalyst in the absence of base (NEt3) and only 53% of the producthas been achieved under the same reaction condition for 7h.

Figure 5
figure 5

The TEM image of the used catalyst (after the end of the first cycle) showedthe formation of copper nanoparticles (some of them are indicated withincircles) with a wide range of size distribution.

Full size image

We have also performed the kinetic studies of the cycloaddition reaction (Table 2, entry 1) for the (1) in-situ reaction, (2)reaction where the recovered Cu-polyaniline was used as a catalyst in presenceof base and also (3) for the reaction using recovered Cu-polyaniline as acatalyst in absence of the base. The results are shown in the graph (Figure 6). From the graph it is clear that the recoveredcatalyst is more active in presence of a base than the in-situsynthesized catalyst but for the first 30 min of the reaction an identicalamount of product (~5% of the yield) has been achieved for the first tworeactions. So, from the kinetic study it is confirmed that Cu(I) and Cu(0) arethe catalyst species, for the cycloaddition reaction between organic azides andterminal alkynes, for the reaction (1) and (2), respectively and it is alsoevident from the recyclability study that the catalytic activity of coppernanoparticles are higher than copper (I). The results are also supported by thepreviously reported literature44. For the reaction usingpreformed Cu(0)-polymer as a catalyst in absence of base (3), the reaction wasslow, only ~5% product has been formed in the first 60 min of the reaction andtotal 53% product has been achieved at the end of the reaction.

Figure 6
figure 6

Comparative kinetic study of the cycloaddition reaction between benzyl azideand phenyl acetylene using in-situ synthesized Cu(I)-polyaniline catalyst(▪) and preformed Cu(0)-polyaniline catalyst in the presence(●) and in the absence (▴) of triethylamine.

Full size image

Various sources of the active Cu(I) catalyst for the alkyne-azide cycloadditionhas been reported. Cu(II) sulphate has also been successfully used as acatalytic precursor in the presence of sodium ascorbate to generate thecatalytically active Cu(I) species45. The Cu-carbon catalystusing charcoal and Cu(NO3)2 as the precursor in presenceof water as a solvent works very efficiently for the title reaction46. Both Cu(I) and Cu(II) oxide show the catalytic activity for thesynthesis of 1,2,3-triazole products in the multicomponent click synthesis underambient conditions43. There is also an evidence of directparticipation of Cu(II) for the synthesis of 1,2,3-triazoles using high catalystloading in aqueous solutions for 20 h47, indicates Cu(II) may notbe an efficient solution for alkyne-azide cycloaddition reaction. We found thatthe use of only CuSO4, 5H2O as a catalyst need more than24 h to achieve a 55% yield of the cycloaddition product between azide and alkylin presence of excess base.

For the synthesis of the desired compound, metal contamination in the product isa matter of serious concern48. Leaching of the catalyst into theproduct would implicate a time-consuming and costly process, which would makethe whole process more expensive. Several methods have been developed todistinguish between soluble and insoluble catalysts49 and some ofthese methods were also used for the current study in order to investigatewhether the solid catalyst is heterogeneous or not.

As our study was carried out at ambient temperature so room temperaturefiltration test was performed. During this test, the catalytically activespecies were removed from the reaction mixture by filtration and the filtratewas monitored for catalytic activity. It was observed that after removal of thecatalyst; the reaction did not proceed, indicating that no catalytically activecopper remained in the filtrate. However, the filtration test alone cannot provethe heterogeneous nature of the reaction as the leached metal species may not besufficient enough to show the catalytic performance. To confirm that, thereaction supernatant was analysed by ICP-MS (Inductively coupled plasma massspectrometry) technique, a type of mass spectrometry which is capable ofdetecting metals at concentrations as low as one part in 1012(part per trillion) level and no detectable amount of copper species was foundin the solution suggest a heterogeneous mechanism for the cycloaddition reactionusing Cu(I)-polyaniline as a catalyst.

A single pot multicomponent reaction both for Cu(I) catalyst formation andazide-alkyne cycloaddition

Most of the copper catalysed azide-alkyne cycloaddition reports are on twocomponent (organic azide and alkyne) reaction systems. In the two componentsynthesis method, the organic azides need to be synthesized in advance and theisolation process can be problematic. It is thus desirable to develop anefficient one-pot methodology that uses alkyl halides and sodium azide fordirect cycloaddition with alkynes in the presence of suitable catalyst.Multicomponent reactions have many advantages in comparison with multi-stepreactions according to environmental and economic considerations. Therefore, thedesign of novel multicomponent system has attracted a lot of attention fromresearch groups working in various areas of organic synthesis. In the presentwork, we also turned our attention towards the one-pot, three-component Clickreaction (Table 3) in which the azide-alkynecycloaddition products were generated in-situ from their precursor, arylbromides, sodium azide and alkyne, by minimising one step. The presence ofaniline and copper sulphate in the multicomponent system acts as the precursorof Cu(I)-polyaniline catalyst in presence of methanol as a solvent for theperiod of 9 h to give the desired products (Table 3,entries 1–6) with the isolated yields ranging from 81–92%(Method 2). To perform the recyclability test of the catalyst for the single potmulticomponent reaction (Table 3, entry 1), we haveincreased the amount of all the reactants by a factor of 10 and achieved about92% of the cycloaddition product, 1-benzyl-4-phenyl-1H-1,2,3-triazole(3a), in 9h. After the first run, we have recovered thecopper-polymer composite and used for the recyclability test to find out theperformance of the reused catalyst. At the end of first cycle a yield of 92% ofthe coupled product (3a) has been achieved and that took about 8 h, whichis one hour less than the original single pot multicomponent reaction. Thereason for the improved performance can be addressed in terms of nanoparticleformation (as discussed before). At the end of the fifth cycle, a yield of 76%of cycloaddition product was achieved at 8 h (Figure7).

Table 3 One pot multicomponent azide-alkyne cycloaddition reactiona.
Full size table
Figure 7
figure 7

Recyclability study of the catalyst (preformed Cu(0)-polyaniline in thepresence of triethylamine) was tested for the reaction mentioned in Table 3, entry 1.

Full size image

The in situ generated Cu(I) plays the catalytic role for the titlereaction. Polyaniline acts as a ligand to coordinate to the Cu(I) species whichinvolves the formation of a Cu(I)-acetylidine complex through the coordinationwith alkyne followed by the addition with the azide group to give1,2,3-triazole. It is also important to mention that in the present study wefound that all reactions were highly regioselective towards the formation of1,4-disubstituted triazoles with a wide range of diversely substituted terminalalkynes and azides under the optimized conditions.

Conclusion

In this report, we have presented an interesting method where the catalyst formationoccurs in the reaction medium that prevents the catalyst from the environmentaldegradation. The elimination of the separate catalyst synthesis step may beeconomical by saving the time as well as the solvents. Aniline was used as one ofthe reactant components so there was no requirement of adding additional base forthis reaction as recommended by the original protocol of the azide-alkynecycloaddition (Click) reaction. Furthermore, the catalyst can be readily recoveredby filtration and efficiently used for the similar reaction without any significantloss of catalytic activity. The operational simplicity and the purity(regeioslectivity) of the products make this method attractive for wide range ofapplications.

Methods

General procedure for azide and alkyne cycloaddition reaction

In a 25 mL round bottom flask, alkyne (1 equiv.) and azide (1 equiv., benzylazide/o-bromo benzyl azide) were taken and dissolved in 5 mlmethanol. To this reaction mixture 1 ml of 0.1 M of aniline in methanol wasadded and stirred at room temperature. To this solution 5 ml of 0.01 M solutionof CuSO4, 5H2O (in water) was added drop wise. A greencolourization was appeared during the addition of the CuSO4,5H2O. The reaction mixture was stirred for 7 h at roomtemperature and progress of the reaction was monitored using thin layerchromatography technique. After completion, the reaction mixture was filteredand the residue was dissolved with methanol. The remaining solid catalyst wasrecovered, dried and reused for the recyclability experiment. The methanol wasevaporated from the filtrate and extracted with ethyl acetate, washed with waterand dried over anhydrous sodium sulphate. Combined organic layer wasconcentrated in vacuum to give the corresponding triazoles which was pure enoughor was purified by column chromatography technique. The products werecharacterised by spectroscopic analysis or by comparison of the spectroscopicdata with those described in the literature.

General procedure for multicomponent azide-alkyne cycloaddition

The above mentioned procedure was followed in a 25 mL round bottom flask usingalkyl halide (1 equiv.), NaN3 (1 equiv.) and an alkyne (1 equiv.) inmethanol (5.0 mL) in the presence of 1 ml of 0.1 M of aniline. To this solution5 ml of 0.01 M solution of CuSO4, 5H2O (in water) wasadded drop wise for the cycloaddition reaction.