Synthesis of a novel nanomagnetic N₄ bis schiff base complex of copper(II) as an efficient catalyst for click synthesis of tetrazoles

Abstract

In this study, we have prepared a novel bis-Schiff-base copper(II) complex by modifying Fe₃O₄ with acetylacetone functionalities and subsequently forming a Schiff base with 2-picolylamine and CuCl₂ through a template method. Immobilization of 2,4-pentanedione and its reaction with 2-picolylamine enabled the synthesis of 1,3-diketimines (HNacNac) as an anionic ligand. This unique design resulted in a tetradentate N₄ coordination sphere for copper(II) ion complexation. The resulting heterogeneous catalyst, [Fe₃O₄@Sil-Schiff-base-Cu(II)], efficiently catalyzed the click condensation of diverse aryl nitriles with sodium azide to produce 5-substituted 1H-tetrazoles in high yields and selectivity. The catalyst demonstrated remarkable stability and recyclability without appreciable loss of catalytic activity, as confirmed by hot filtration and reusability studies.

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1. Introduction

Tetrazoles are indispensable nitrogen rich aromatic heterocyclic scaffolds that offer a broad spectrum of applications in various domains such as medicinal chemistry, high energy material science, biochemistry, pharmacology etc. They do not exist in nature and their preparation often involves artificial methods.^1,2 Tetrazoles can be synthesized through various methods, including the Schmidt reaction, 1,3-dipolar cycloaddition, and click chemistry. Catalysts like copper(I) salts, gold(I) complexes, and organic catalysts play a crucial role in enhancing reaction efficiency and selectivity.^3–8 In this sense, click chemistry is indeed a particularly valuable approach in tetrazole synthesis.^9–11 Its high efficiency, selectivity, and mild reaction conditions make it an ideal tool for constructing complex tetrazole-containing molecules.¹² The transition metals catalyzed azide–alkyne cycloaddition is the most prominent click reaction in this context.^13,14 By employing this strategy, researchers can rapidly build diverse tetrazole libraries for drug discovery, materials science, and other applications.¹⁵

Creating organic compounds through chemical reactions while protecting the environment is a major challenge in organic chemistry.¹⁶ The increasing concern for the planet has made it essential to find eco-friendly ways to perform these reactions. Therefore, scientists are actively searching for new catalysts that can produce desired compounds without harming the environment.¹⁷ Recent advancements have seen heterogeneous materials emerge as efficient catalysts for tetrazole synthesis, offering advantages like high surface area and ease of modification.^8,18 These developments have expanded the possibilities for creating diverse tetrazole derivatives with potential applications in medicine, agriculture, and materials science.^19–21 These studies have investigated a variety of materials as foundations for catalysts, such as graphene oxide,²² MCM-41,²³ SBA-15, charcoal,²⁴ boehmite¹³ and magnetic nanoparticles.^25,26 Among these, magnetic nanoparticles composed of magnetite have garnered significant attention. Their magnetic properties enable rapid and convenient separation, while their biocompatibility, cost-effectiveness, and durability make them ideal for industrial processes.^27,28 As a result, these nanoparticles have been employed across numerous applications, including catalysis and biomedical technologies.²⁹

A variety of metal-based catalyst complexes have been immobilized on magnetic supports for diverse applications.^30–32 Among these, copper complexes derived from Schiff bases have attracted considerable attention due to their facile synthesis and potential catalytic activity.^33,34 Conventional approaches for immobilizing Schiff base ligands on magnetic nanoparticles typically involve the nucleophilic reaction of amine-functionalized supports with aldehydes or ketones.^34–36 However, the heterogeneous distribution of amine groups on the nanoparticle surface often hinders the formation of multidentate ligands, which are crucial for creating efficient catalytic sites. This limitation, coupled with the complex and costly synthesis of pre-functionalized ligands, underscores the need for alternative support materials.

To address this challenge, acetylacetone (acac), a versatile β-diketone, emerges as a promising candidate. Acac can function as a bidentate ligand, forming stable complexes with metal ions.³⁷ Its two carbonyl groups provide opportunities for further functionalization through reactions with amines to generate Schiff base ligands.³⁸ The proximity of these carbonyl groups within the acac structure facilitates the formation of multidentate chelating systems.³⁹ Additionally, the active methylene group in acac allows for alkylation reactions,^40–42 enabling covalent attachment to various support and linker materials.

In this study, we aim to immobilize acetylacetone onto magnetic nanoparticles and subsequently synthesize a novel tetradentate salen-type Schiff base ligand and related complex through condensation with 2-picolylamine in the presence of CuCl₂. The resulting copper complex will be evaluated as a catalyst for 5-Substituted 1H-tetrazoles synthesis under green conditions.

2. Experimental

2.1. Typical procedure for synthesis of [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex

The synthesis began with the preparation of Fe₃O₄ MNPs using a previously established method.⁴³ Concurrently, 2 g of Fe₃O₄ MNPs were dispersed in 100 milliliters of toluene for 30 minutes. Subsequently, 3-(3-trimethoxysilylpropyl)–acetylacetone (5 mmol) was introduced into the reaction mixture, which was then refluxed under vigorous stirring and a nitrogen (N₂) atmosphere for 12 hours. Following this, the resulting Fe₃O₄@Sil–acac MNPs product was magnetically isolated, washed ethanol (3 × 25 mL), and subsequently dried at 80 °C for 6 hours. Subsequently, 3 grams of Fe₃O₄@Sil–acac were dispersed in 100 mL of degassed ethanol through sonication for 30 minutes. Then, 2-picolylamine (10 mmol) and copper(II) nitrate trihydrate (5 mmol) were sequentially added to the prepared suspension, followed by refluxing under vigorous stirring and a N₂ atmosphere for 48 hours. Upon completion of the reaction, the [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex was magnetically separated, washed multiple times with hot water and ethanol, and finally dried at 80 °C for 6 hours (Scheme 1).

Scheme 1 Stepwise synthesis of [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex.

2.2. General procedure for synthesis of 5-substituted 1H-tetrazoles catalyzed by [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex

To a 2 mL solution of aryl nitrile (1 mmol) and sodium azide (1.3 mmol) in PEG-400, [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex (5 mol%) was added. The mixture was stirred at 120 °C until reaction completion. After cooling to room temperature, the reaction mixture was diluted with hot water, and the catalyst was removed by magnetic separation. The aqueous phase was acidified to pH 1 with 1 M hydrochloric acid and extracted with ethyl acetate (45 mL). The organic phase was washed repeatedly with water, dried over magnesium sulfate, and concentrated under reduced pressure. The crude product was purified by preparative thin-layer chromatography (TLC).

3. Results and discussions

In this research, a novel Schiff base copper complex was synthesized via a three-step procedure. A template Hugo Schiff reaction of nanomagnetized acetyl acetone backbone with two equivalents of 2-picolylamine in the presence of one equivalent of copper salt, acting as both catalyst and coordination partner, yielded the desired five-coordinate copper(II) complex as the stabilized catalytic site (Scheme 1). The structure of the prepared nanoparticles was comprehensively characterized using FT-IR, XRD, TGA, EDAX, ICP-OES, EDS mapping, FE-SEM, TEM, and VSM analyses.

3.1. Catalyst characterization

Fig. 1 presents the FT-IR spectra of Fe₃O₄, Fe₃O₄@Sil–acac, and the [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex. Broad absorption band centered at around 3400 cm⁻¹ is observed in the curve a, indicative of hydroxyl groups, likely attributable to adsorbed water or surface hydroxyl functionalities. The characteristic peaks at 568 and 634 cm⁻¹ correspond to Fe–O vibrations within the iron oxide lattice, confirming the formation of the Fe₃O₄ MNPs.⁴⁴ The spectrum of Fe₃O₄@Sil-acac exhibits additional bands at around 2900 cm⁻¹, 1715 cm⁻¹, and 1063 cm⁻¹. These features can be assigned to C–H stretching, C=O stretching, and Si–O–Si stretching vibrations, respectively. The emergence of the Si–O–Si band confirms the successful immobilization of Sil–acac onto the Fe₃O₄ nanoparticles. In the spectrum of the [Fe₃O₄@Sil-c-Cu(II)] complex, the disappearance of the C=O band and the concomitant appearance of new peaks around 1637 cm⁻¹ strongly suggest the formation of the Schiff base and subsequent complexation with Cu(II) ions. These spectral alterations collectively provide evidence for the successful introduction of organic functionalities onto the Fe₃O₄ surface and the formation of the desired complex.

Fig. 1 FT-IR analysis of (a) Fe₃O₄, (b) Fe₃O₄@Sil–acac and (c) [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex.

Structural characterization of the [Fe₃O₄@Schiff-base-Cu(II)] complex was performed using X-ray diffraction (XRD) in the 10–80° 2θ range (Fig. 2). Characteristic peaks corresponding to magnetite (Fe₃O₄) were observed at 2θ values of 30.02°, 35.31°, 43.22°, 53.19°, 56.89°, and 62.89° which are corresponded to (220), (311), (222), (400), (422), (511), (440), lattice planes of Fe₃O₄ and confirming the successful incorporation of magnetic nanoparticles. Additional peaks at 2θ values of 32.67°, 36.21°, 39.43°, 49°, 54°, and 60.29° suggest the presence of copper and the formation of a Schiff base–Cu complex on the Fe₃O₄ surface.

Fig. 2 XRD analysis of [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex.

Thermogravimetric analysis (TGA) was conducted to assess the thermal stability of pristine Fe₃O₄ nanoparticles in comparison to their corresponding [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex (Fig. 3). The pristine Fe₃O₄ nanoparticles exhibited negligible weight loss across the entire temperature range, indicative of their high thermal stability. In contrast, the [Fe₃O₄@Schiff-base-Cu(II)] complex demonstrated a pronounced two-step weight loss profile. The weight loss occurring between 200 and 600 °C is attributed to the decomposition of the organic silane linker and Schiff base ligand situated on the Fe₃O₄ surface. These findings collectively highlight the substantial influence of the organic coating on the thermal properties of the composite material and corroborate the successful formation of the [Schiff-base-Cu(II)] complex on the Fe₃O₄ surface.

Fig. 3 TGA curves of pristine Fe₃O₄ NPs and [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex.

EDAX analysis confirms the successful synthesis of the [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex. The detected elements, including Fe, O, Si, C, N, Cu, and Cl, are consistent with the theoretical composition of the material (Fig. 4). The sharp peaks associated with Fe and O suggest the presence of Fe₃O₄ nanoparticles, while the detection of Si confirms the integration of the organosilica linker. The presence of C and N is indicative of the Schiff base ligand, and the detection of Cu verifies the coordination of the copper ion to the ligand. The identified chlorine supports its role in the formation of a five-coordinate copper(II) complex via coordination to the copper precursor. Additionally, ICP-OES analysis revealed a copper content of approximately 1.73 × 10⁻³ mol g⁻¹ in the sample.

Fig. 4 EDAX analysis of [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex.

EDAX mapping indicates a widespread distribution of Fe and O, suggesting the formation of Fe₃O₄. The mapping also revealed a homogeneous distribution of Si, C, and N elements throughout the Fe₃O₄ support, implying the presence of nitrogen-containing functional groups (Fig. 5). However, the silicon content appears lower than that of carbon and nitrogen, aligning with its approximate proportion in the stabilized complex composition. Conversely, copper and chlorine elements show a uniform distribution across the surface, facilitating optimal accessibility for guest reactant species.

Fig. 5 Elemental mapping images of [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex.

SEM analysis of the [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex revealed a heterogeneous population of agglomerated spherical particles with rough surface textures (Fig. 6). The particles exhibited a broad size distribution, averaging approximately 47.46 nm in diameter. These morphological features suggest a complex microstructure composed of both agglomerated and discrete nanoparticles.

Fig. 6 SEM images of [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex.

TEM analysis of [Fe₃O₄@Sil-Schiff-base-Cu(II)] complexes revealed well-defined, spherical nanoparticles with a smooth surface and a narrow size distribution centered around 20–25 nm (Fig. 7). These nanoparticles were evenly dispersed without aggregation, indicating high-quality synthesis. These characteristics, including uniform shape and size, suggest promising potential for various applications due to the nanoparticles' consistent behavior and reactivity.

Fig. 7 TEM images of [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex.

VSM analysis corroborated ferromagnetic behavior for the [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex, as evidenced by a hysteresis loop (Fig. 8). This finding indicates the retention of Fe₃O₄ intrinsic magnetic properties. Nevertheless, the complex exhibited a reduced saturation magnetization (Ms = 39.87 emu g⁻¹) compared to pristine Fe₃O₄ (Ms ≈ 63 emu g⁻¹),⁴⁵ indicating a lower magnetic moment. Conversely, an augmented coercivity was observed, implying enhanced resistance to magnetic field reversal. These magnetic property modifications are likely attributable to surface interactions, potential spin canting, and magnetic dilution arising from the organic ligand, which confirm the successful stabilization of [Sil-Schiff-base-Cu(II)] complex on Fe₃O₄ surface.

Fig. 8 VSM analysis of [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex.

The [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex exhibits a moderate BET surface area of 145.17 m² g⁻¹, indicating a sufficient surface area for adsorption (Fig. 9). The total pore volume of 0.1375 cm³ g⁻¹ and mean pore diameter of 17.369 nm reveal a relatively narrow pore size distribution. t-plot and BJH analyses further confirm the micropore volume and pore size distribution characteristics of the catalyst. These combined properties make the catalyst well-suited for a range of applications in heterogeneous catalysis processes.

Fig. 9 N₂ adsorption/desorption isotherms of [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex.

3.2. Catalytic study

The catalytic efficacy of the [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex was evaluated in the click reaction of benzonitrile and sodium azide for the synthesis of 5-substituted 1H-tetrazoles, serving as a model reaction for the optimization of effective reaction parameters (Table 1). Blank test demonstrated that the reaction did not proceed in the absence of a catalyst, even after a long reaction time of 10 hours (Table 1, entry 1). Upon introduction of the [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex to the reaction mixture, the conversion initiated, with a concomitant increase in yield as the catalyst loading was augmented. Optimal results were achieved with a 5 mg catalyst loading, affording complete conversion within 10 minutes. Further increasing of the catalyst amount to 7 mg did not result in enhanced reaction kinetics or product yield. Given the established utility of polyethylene glycols as solvents in analogous processes, the influence of average molecular weight on the current reaction was examined. While comparable results were obtained across different polyethylene glycol variants, PEG-400 exhibited marginally superior performance and was consequently selected as the optimal solvent. A reduction in reaction temperature led to diminished product yields, thereby establishing 120 °C as the preferred reaction temperature.

Table 1 Optimization of click reaction of benzonitrile and sodium azide over the catalysis of [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex

Entry	Amount of catalyst (mol%)	Solvent	Temperature (°C)	Time (min)	Yield^a^,^b (%)
a Isolated yield. b Conditions: benzonitrile (1 mmol), sodium azide (1.3 mmol), [Fe3O4@Sil-Schiff-base-Cu(II)] complex (mol%) and solvent (2 mL).
1	—	PEG-400	120	600	NR
2	1	PEG-400	120	10	64
3	2	PEG-400	120	10	72
4	4	PEG-400	120	10	93
5	5	PEG-400	120	10	99
6	7	PEG-400	120	10	99
7	5	Ethanol	120	10	43
8	5	Ethylene glycol	120	10	71
9	5	PEG-200	120	10	98
10	5	PEG-600	120	10	98
11	5	PEG-1000	120	10	95
12	5	PEG-400	90	10	88
13	5	PEG-400	60	10	53
14	5	PEG-400	40	10	24
15	5	PEG-400	r. t.	10	NR

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The optimized method was applied to a diverse array of aryl nitriles to assess the method scope and the influence of electronic and steric factors on reaction efficiency (Table 2). Electron-withdrawing substituents on aryl nitriles exhibited enhanced reactivity compared to electron-donating groups due to increased electrophilicity of the nitrile carbon. Furthermore, the substituent's position significantly impacted reactivity, with ortho substituents generally affording lower yields and requiring longer reaction times than their para counterparts. This behavior can be attributed to both steric hindrance and electronic effects. Despite these variations, the majority of investigated aryl nitriles produced the corresponding products in satisfactory to excellent yields. To assess the selectivity of our method, we conducted comparative experiments with aliphatic nitriles. Under identical reaction conditions, no product formation was observed after 4 hours, suggesting a high degree of selectivity toward aromatic nitriles. This selectivity allows for the selective conversion of aromatic nitriles to tetrazole derivatives in the presence of aliphatic nitrile functionalities without interference.

Table 2 The scope of click condensation of aryl nitriles and sodium azide over the catalysis of [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex

Entry	Aryl nitrile	Product	Time (min)	Yield^a^,^b (%)	TON	TOF (min^−1)	M. P.	Ref.
a Isolated yield. b Conditions: aryl nitrile (1.0 mmol), sodium azide (1.3 mmol) and [Fe3O4@Sil-Schiff-base-Cu(II)] complex (5 mg) in PEG-400 (1 mL) at 120 °C.
1			10	98	1960	10 172	219–221	46
2			25	91	10 520	25 248	158–161	47
3			12	97	11 213	56 069	155–157	46
4			10	99	11 445	68 670	220–22	46
5			25	89	10 289	24 693	209–211	48
6			15	96	11 098	44 393	210–212	48
7			8	98	11 329	84 971	254–256	48
8			20	88	10 173	30 520	153–155	49
9			15	95	10 982	43 930	151–152	50
10			15	95	10 982	43 930	248–25	46
11			20	93	10 751	32 254	180–181	51
12			15	97	11 213	44 855	139–141	52
13			10	98	11 329	67 976	155–156	46
14			45	89	10 289	13 718	224–225	53
15			20	95	10 982	32 947	245–246	54
16			30	93	10 751	21 502	233–23	46
17			65	86	9942	9177	220–222	55
18			20	95	10 982	32 946	199–200	56
19			40	91	10 520	15 780	266–268	46
20			240	N. R.	—	—	—	—
21			240	N. R.	—	—	—	—

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The proposed mechanism for the synthesis of 5-aryl-1H-tetrazoles catalyzed by [Fe₃O₄@Sil-Schiff-base-Cu(II)] is outlined in Scheme 2.^6,57,58 The catalytic cycle is initiated by the coordination of the nitrile substrate to the copper center within the catalyst, thereby activating the nitrile group. Subsequently, a nucleophilic attack of the azide ion on the activated nitrile species triggers a [2 + 3] cycloaddition cascade, resulting in the formation of the tetrazole ring. The reaction is finalized during the workup stage, where acidification protonates the intermediate sodium salt to afford the desired 5-aryl-1H-tetrazole product.

Scheme 2 Possible mechanism for the click condensation of aryl nitriles and sodium azide over the catalysis of [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex.

3.3. Reusability of catalyst

To evaluate the [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex recyclability, it was magnetically separated from the reaction mixture after each cycle using an external magnet, followed by washing with hot ethanol and water. The recovered catalyst was reused in subsequent reaction cycles without significant loss of activity, demonstrating its robustness and potential for multiple applications. The catalyst exhibited consistent catalytic performance over eight consecutive cycles, highlighting its promising recyclability and economic viability (Fig. 10). To assess the structural integrity and functional group composition of the recovered catalyst, FT-IR analysis was conducted. As depicted in Fig. 11, the spectrum closely resembles that of the pristine catalyst, indicating its structural stability.

Fig. 10 The reusability of [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex.

Fig. 11 FT-IR analysis of recovered [Fe₃O₄@Sil-Schiff-base-Cu(II)] catalyst.

3.4. Hot filtration test

To investigate the heterogeneous nature of the [Fe₃O₄@Sil-Schiff-base-Cu(II)] catalyst, a hot filtration test was performed. At the midpoint of the reaction, the catalyst was magnetically separated from the reaction mixture, which was subsequently allowed to proceed for an additional eight hours. The negligible product formation observed post-filtration confirmed the catalyst's predominantly heterogeneous character and indicated minimal metal leaching.

3.5. Comparison study of catalytic activity

A comparative analysis of the catalytic efficiency of the herein reported [Fe₃O₄@Sil-Schiff-base-Cu(II)] catalyst with those previously documented in the literature was conducted, with particular attention to reaction conditions and isolated product yields (Table 3). While prior studies exhibit commendable attributes, they often necessitate extended reaction times, high catalyst loadings, or the employment of precious metal catalysts. In contrast, the Cu complexes presented herein demonstrate competitive product yields, coupled with advantages such as reduced catalyst loading, enhanced turnover frequencies, facile separation protocols, the use of environmentally conditions, and the absence of hazardous byproducts.

Table 3 Comparison the efficiency of [Fe₃O₄@Sil-Schiff-base-Cu(II)] complex click reaction

Entry	Catalyst	Time (min)	Yield (%)	Reference
1	CoFe2O4/MCM-41/PA/Cu	20	91	59
2	Amberlyst-15	720	91	60
3	ZnFe2O4@SiO2–SO3H	60	100	61
4	CuFe2O4@SiO2–MnCl	60	97.8	62
5	Cu–Amd–RGO	30	96	63
6	CAES	60	95	64
7	f Cu–DPMI@biochar	60	98	65
8	MCM-41@Gln@Cu–Fe	25	73	66
9	[Fe3O4@Sil-schiff-base-Cu(II)]	10	99	This work

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Conclusions

A novel copper(II) bis-Schiff base complex was synthesized through post-synthetic modification of nanomagnetic Fe₃O₄ using HNacNac and pyridine building blocks. The complex features a tetradentate N₄ coordination sphere, resulting in a five-coordinate copper center upon reaction with CuCl₂. The resulting complex exhibited high catalytic activity in the synthesis of 5-substituted 1H-tetrazoles from diverse aromatic nitriles and sodium azide under mild conditions. The catalyst performance was influenced by electronic and steric factors of the substrates. Remarkably, the catalyst demonstrated exceptional stability and reusability, maintaining its catalytic activity over eight consecutive cycles without significant loss of efficiency. This work introduces a promising and sustainable catalytic system for the efficient production of tetrazoles.

Data availability

The authors declare that all the data in this manuscript are available upon request.

Author contributions

Chou-Yi Hsu: characterization of catalyst. Ahmed Rafiq AlBajalan: conceptualization, analysis, review draft, acquiring research funding and supervision. Sameer A. Awad: writing original draft, laboratory works. Muath Suliman: laboratory works. Nizomiddin Juraev: catalysis studies and analysis. Carlos Rodriguez-Benites: software and review/editing. Hamad AlMohamadi: conceptualization, laboratory works, analysis, review/editing. Abed J. Kadhim: software and review/editing.

Conflicts of interest

The authors declare that they have no competing interests.

Acknowledgements

The authors express their gratitude to the Deanship of Scientific Research at King Khalid University for funding this work through the Large Research Group Project under grant number RGP.02/375/44.

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