Advantages of the use of heterogeneous catalyst for Huisgen cycloaddition reaction : synthesis and application of new metalorganic material capable of regeneration and reuse

This works evaluates the catalytic capacity of metalorganic materials synthesized, based on Cu+ and ambidentade ligand in Huisgen cycloaddition reaction. The synthesis of 1,2,3-triazole was made using CuCl and CuI salts, and the [Cu(4,4’-dipy)]Cl and [Cu(4,4’-dipy)]I compounds as catalysts, with or without base catalysis by triethylamine. The copper salts and compounds lead to formation of the desired triazole product; however, in the synthesis mediated by [Cu(4,4’-dipy)]I does not generate the product, even after 48 h of reaction. The reaction with [Cu(4,4’-dipy)]Cl mediated or not by triethylamine showed high yields of 88 % and 70 %, respectively. The [Cu(4,4’-dipy)]Cl compounds was reused five times, and regenerated by ascorbic acid, maintaining thus, the same reaction yield.


Introduction
Metalorganic materials have attracted attention owing to their potential applications in gas separation and storage 1 , as sensors 2 , in drug storage and delivery 3 , templated low-dimensional material preparations 4 , and principally, as catalysts 5 .Due to their high surface areas, pore sizes, ease and diversity of their ability to process, these compounds can be used in catalysis.The literature reports on several works that describe very recently the use of metalorganic materials as catalysts in solid-phase organic reactions, such as in Friedel-Crafts alkylation and acylation [6][7][8] , oxidation [9][10][11][12][13][14] , alkene epoxidation [15][16][17] , hydrogenation 18 , Suzuki cross-coupling 19 , 20 , the Sonogashira reaction 21 , transesterification reaction 22 , the Knoevenagel condensation [23][24][25] , aldol condensation 26 , 27 and 1,3dipolar cycloaddition reactions 28 .The Huisgen azide-alkyne 1,3-dipolar cycloaddition afford 1,2,3-triazole derivatives, through solid-phase catalyst that has a number of advantages, such as low consumption of reagents and solvents, possibility of regeneration and removal of the ABSTRACT: This works evaluates the catalytic capacity of metalorganic materials synthesized, based on Cu + and ambidentade ligand in Huisgen cycloaddition reaction.The synthesis of 1,2,3-triazole was made using CuCl and CuI salts, and the [Cu(4,4'-dipy)]Cl and [Cu(4,4'-dipy)]I compounds as catalysts, with or without base catalysis by triethylamine.The copper salts and compounds lead to formation of the desired triazole product; however, in the synthesis mediated by [Cu(4,4'-dipy)]I does not generate the product, even after 48 h of reaction.The reaction with [Cu(4,4'-dipy)]Cl mediated or not by triethylamine showed high yields of 88 % and 70 %, respectively.The [Cu(4,4'-dipy)]Cl compounds was reused five times, and regenerated by ascorbic acid, maintaining thus, the same reaction yield.catalyst from the reaction medium.In this context, metalorganic materials are widely used because of these advantages.The literature describes the use these compounds, for instance in cyclization reaction 29 ; however, some catalysts, it is shown low yields, difficulty in the removal of residues, as well as the impossibility of catalyst reuse.An explanation for these problems is the use of copper (II) ion, to constitute the metalorganic structure, since the 1,3-dipolar cycloaddition reaction needs the presence of copper(I) ions.The copper(I) catalyst promotes the formation of 1,2,3-triazoles from azides and terminal alkynes, with high yields, mild conditions and excellent regioselectivity 30,31 .Generally, in this reaction, the desired product is isolated by chromatography and the copper(I) residues are removed by an extraction process, using successive washes with ammonium hydroxide 32,33 .
In this work were synthesized and characterized copper(I) complexes containing 4,4´-dipyridyl (4,4´-dipy) as ligand, and CuCl or CuI as copper (I) font.To reduce the number of extraction steps and low yields, and to promote the reuse of the catalyst, we used two copper(I) compounds as catalysts in solid-phase for reaction between phenylacetylene (PhA) and 2-[2-azido-ethyl]-isoindole-1,3-dione (AID) in the presence or absence of base (triethylamine).The reactions were repeated five times and the catalyst was reuse, through of the regeneration process by ascorbic acid.

Materials and methods
The copper(I) chloride, copper(I) iodide, 4,4'dipyridyl, triethylamine, dichloromethane, phenylacetylene and 2-[2-azido-ethyl]-isoindole-1,3-dione (all from Aldrich) were all used as received.Carbon, nitrogen and hydrogen percentages for the two metalorganic compounds and 1,2,3-triazole were determined by analysis of the elements, using a Perkin-Elmer Model 240 microanalyzer.The infrared spectra were obtained with a KBr tablet using a Fourier transform IF66 model spectrophotometer in the 4000−400 cm -1 range, with a spectral resolution of 4 cm -1 .The NMR spectrum was obtained using VARIAN Unity Plus 300 equipment, at frequencies of 400 MHz to 1 H in DMSO and 75.5 MHz to 13 C in CDCl3.

Synthesis of Copper(I) complexes
The optimized synthesis of copper(I) complexes in the reactor system (Vmax = 5.0 mL per Teflon insert) is as follows: 0.5 mmol of CuCl (49.5 mg) or CuI (95.25 mg) and 0.5 mmol of 4,4'-dipyridyl (78.0 mg) were dissolved in 4 mL dried ethanol (0.068 mmol).The reactor was heated for 24 h at 120 ºC.After the reaction, the resultant solid was filtered and washed with water and ethanol three times.The powder obtained was then dried at room temperature in a fume hood and then dried under vacuum at 40 ºC for 4 h.

Results and discussion
In the synthesis of copper(I) complexes, a light green (from CuCl reagent) and a red (from CuI reagent) precipitant with crystalline characteristics were generated.The CHN elemental analysis results are in good agreement with the proposed formulas for the copper(I) complexes; with an error level less than 0.4 % (Table 1).The infrared spectroscopy was complementarily used through the assignment of bands to functional groups of the free ligands as well as with the possible band shifts which could be correlated with the copper ion coordination.In Figure 1, the infrared overlapped spectra of the [Cu(4,4'-dipy)]Cl and 4,4'-dipyridyl ligand are presented.Since the [Cu(4,4'-dipy)]I had the same spectral profile, this has not been dealt with in this text.It can be observed that the C=N stretch of the [Cu(4,4'-dipy)]Cl complex (1596 cm -1 ) are shifted to the red region in comparison to the free ligand (1629 cm -1 ), suggesting coordination with the copper (I) ion.In the absence of an X-ray structural analysis, because the mixture had polycrystalline properties, structure based on elemental analysis data and infrared spectroscopy could be suggested (see Figure 2).The copper (I) chloride and iodide were used to make the same synthesis in order to compare their catalytic capacity with regard to copper(I) complexes.After 23 h, the azide has been completely consumed and the mixture which had suffered reaction was then treated with NH4OH to remove the copper residues.When copper (I or II) salts are used, the NH4OH extraction step is always necessary, which generates soluble copper residues in the water, leading to a greater environmental contamination.The yield on the synthesis obtained by using copper (I) chloride with or without a base were 38.4 % and 16.3 %, respectively.With copper (I) iodide, with or without a base, they were 92.8 % and 54.8 %, respectively.

2-[2-(4-Phenyl-[1,2,3]triazol-1-yl)-ethyl]isoindole-1,3-dione:
In the synthesis using [Cu(4,4'-dipy)]Cl complex, the reaction time varied between 19 and 22 h.In all the cases, the catalyst was removed by centrifugation process, eliminating the extraction step with NH4OH.The synthesis using a base lead to improved the yield, but not enough to justify their use.Table 2 shows the reaction yields with [Cu(4,4'-dipy)]Cl complex, with or without addition of base.On the other hand, the same reaction using [Cu(4,4'-dipy)]I complex even after it has been stirred for 48 h, did not promoted the formation of the desired product.In order to evaluate the capacity for reuse of the catalyst ([Cu(4,4'-dipy)]Cl complex), the reaction was repeated five times, recovering the catalyst by centrifugation and adjusting the amount of reagents (azide and alkyne).Before reuse, the catalyst was washed (5x) with dichloromethane to remove possible interferents.When triethylamine was used, after 5 cycles of reactions, the yield decreased to 33.5 % (Table 3, cycle 5).In the case of reactions which did not use the base, the yields lessened to 49.8 % after five cycles.86.4 71.9 a After added ascorbic acid (10 mol %).
To explain our poor results after five cycles, however, we need to have some considerations.The viability of the reductive elimination process (restitution of the copper to its lowest value oxidative) and the quality of the solvents used (type of oxidants present).Supposing the copper (II) generation, which would justify the reduction of active sites, Cu(I), as a reaction promoter, ascorbic acid was used as a reducing agent for recuperation of the catalyst.In both cases, with or without the use of a base, after use of ascorbic acid, the yields were restored.In the case of the drastic lessening of yields when trietilamine was used, it can be accounted for because of the base, before acting as a depronate of alkyne and after oxidation of copper (I) to the form (II), could be added as a ligant in the coordiation sphere of the first cupric ion, since the typical coordination numbers of these ions copper (I) and (II) are 2 and 4, respectively.The Scheme 2 shows the mechanism proposed to create the reaction using [Cu(4,4'-dipy)]Cl complex.Based on data in literature indicating that Cu(I) catalyzed alkyne-azide coupling begins with π complex A (Scheme 2), this first step was also proposed for the [Cu(4,4'-dipy)]Cl complex [30][31][32][33][34][35][36] .Some works suggest that an energetic compensation can occur depending on the solvent Eclética Química Journal, vol.43, n. 1, 2018, 39-47 ISSN: 1678-4618 DOI: 10.26850/1678-4618eqj.v43.1.39-47used in this reaction, i.e. an improvement can be perceived, concerning copper species formation B (Scheme 2), and then this copper coordination can reduce the C-H alkyne pKa, facilitating the deprotonation in aqueous systems without the use of a base 37 .In the case of the current work, the reaction was carried out, using dichloromethane (CH2Cl2) as the solvent, in the presence and absence of the base (triethylamine), in both cases the final product was obtained with yields of (88 %) and (70 %), respectively.This last reactional condition, using CH2Cl2, invites more significant studies, experimental and/or theoretical, involving different solvents and their interference on the catalytic cycle.In comparison with the usual mechanistic studies [37][38][39] , the current [Cu(4,4'dipy)]I complex reinforces and represent well the requirement of two catalytic copper atoms, here can be spaced by a 4,4'-dipyridyl ligand, which were part of an alkyne-azide cycloaddition.The first one changed the alkyne (acetylide complex) reaction and the second served as an azide activator which led to the D cyclization (Scheme 2).Some works have suggested that the size of the ring which surrounds the two acid centers of copper D may be easily converted into a copper triazole ring E (Scheme 2) 37 .There is a considerable need for experimental work to confirm the true proton source responsible for the protonation of the type shown in E, which will converge on the composite F, which may be the reaction which occurs in the presence or absence of a base 40,41 .Even with the extensive use of copper salts capable of catalyzing alkyne-azide coupling reactions, the anions of which generally look like sulfate and halogens (generally Cl, Br and I), the study of the influence of these anions as reactors have not been entirely understood by the scientific community.Thus we must emphasize that in the present study, the use of metalorganic compounds, [Cu(4,4'-dipy)]Cl and [Cu(4,4'-dipy)]I complexes, synthesized from the known types of copper salts, CuCl and CuI respectively, showed that the reaction yield was extremely dependent on the anion present in these complexes.In other words, the difference of these counter-ions (anions) present in the complexes were the determining factor as to the catalytic force of the same, making the type [Cu(4,4'-dipy)]I complex not viable for catalyzing the reaction proposed in this study (Scheme 1).Further studies need to be made to confirm which anions work best for high yields in copper(I)-catalyzed reaction.

Conclusions
The copper(I) complexes compounds were synthesized and characterized by elemental analysis and infrared spectroscopy; and applied as catalysts in the Huisgen reaction.There was a high yield from the reactions catalyzed by CuI (92.8 %) and [Cu(4,4'-dipy)]Cl complex (96 %).In the case of the same reaction catalyzed by CuCl (38 %) the yields were low.No product was obtained using [Cu(4,4'-dipy)]I complex.Reuse of the [Cu(4,4'dipy)]Cl catalyst was proven through a cycle of five consecutive syntheses, resulting in the desired product.The yield from the reactions, however, diminished gradually.The synthetic cycle's maintainer the same reactive good yields through a process of copper (II) ion reduction, which had generated in the complex structure after used ascorbic acid, justifying the preferential use of this matrix as the catalyst in Huisgen 1,3-dipolar cycloaddition reaction.