Clove as a Versatile Resource: CuO Nanoparticles and Their Catalytic Role in Eugenol-Based Triazole Synthesis

Abstract

As eco-friendly processes become central to modern organic synthesis, plant-based materials are emerging as attractive alternatives for both nanoparticle fabrication and catalysis. In this study, we explore the use of clove extract, a natural and renewable resource, for the green synthesis of copper oxide (CuO) nanoparticles and their subsequent application in organic transformations. Clove extract was employed to reduce copper chloride via a simple co-precipitation method under mild conditions, yielding CuO nanoparticles characterized by XRD, FTIR, and SEM-EDX techniques. These nanoparticles were then used as catalysts in the copper-catalyzed azide–alkyne cycloaddition (CuAAC) to afford eugenol-based 1,2,3-triazoles in excellent yields. This dual use of clove extract exemplifies a sustainable approach that merges natural product valorization with efficient catalysis for triazole synthesis.

1. Introduction

Natural product research continues to be a cornerstone of scientific advancement, playing a vital role in drug discovery and development [1]. Natural compounds are distinguished by their complex structural diversity, including varied functional groups, multiple stereogenic centers, high heteroatom content, and unique core ring systems, which collectively contribute to their wide-ranging biological and pharmacological activities [2,3,4]. While these compounds offer valuable leads, they often require chemical modification to optimize pharmacokinetic and pharmacodynamic properties, as direct clinical application is frequently limited. Consequently, semisynthetic derivatives of natural products are widely pursued to improve selectivity, therapeutic efficacy, physicochemical properties, and patentability [5,6,7].

Among these derivatives, 1,2,3-triazoles, five-membered heterocycles containing three nitrogen atoms, have emerged as key structural motifs in medicinal and industrial chemistry [8,9,10]. These compounds possess the ability to form hydrogen bonds with biological targets due to their nitrogen content and have demonstrated a broad spectrum of biological activities [11,12]. Triazole moieties are incorporated in numerous clinical drugs [13], including itraconazole, fluconazole, voriconazole, ribavirin, rizatriptan, and letrozole [8]. Beyond pharmaceuticals, triazoles also serve roles in agriculture, corrosion inhibition, and material science [14,15].

The copper-catalyzed azide–alkyne cycloaddition (CuAAC), a hallmark of click chemistry [16], remains one of the most effective and reliable methods for synthesizing 1,2,3-triazoles [17,18]. However, traditional CuAAC protocols often rely on homogeneous copper(I) catalysts, which pose challenges that include a difficult recovery, the potential contamination of products, and poor reusability—factors that hinder both environmental and economic sustainability [19,20,21].

To mitigate these drawbacks, heterogeneous catalysts, particularly copper oxide nanoparticles (CuO NPs), have gained attention for their catalytic efficiency, reusability, and ease of separation [14]. Nevertheless, conventional methods for CuO NP synthesis—such as thermal decomposition or electrochemical techniques—often involve toxic reagents and high-energy conditions [22,23]. As a more sustainable alternative, green synthesis [24] using plant extracts has emerged, employing phytochemicals (e.g., flavonoids, terpenoids, or phenolic acids) as both reducing and stabilizing agents [23,25,26,27]. This approach aligns with the principles of green chemistry and offers a more environmentally responsible route for nanoparticle production [28,29].

While several studies have demonstrated the feasibility of using plant extracts for the green synthesis of metal nanoparticles [30], there remains a significant gap in integrating this biosynthetic approach with downstream catalytic applications derived from the same plant source. Specifically, no previous study has combined the green synthesis of CuO nanoparticles using clove (Syzygium aromaticum) extract with the catalytic transformation of its major bioactive compound, eugenol, in CuAAC reactions. Clove buds are particularly rich in eugenol, a phenolic compound with known reducing and stabilizing properties. This dual functionality presents a unique opportunity to both synthesize nanoparticles and utilize a natural precursor in catalysis from a single biomass source.

In this work, we present an innovative and sustainable strategy that unifies nanoparticle synthesis and catalytic application within a single plant system. We report the green synthesis of CuO nanoparticles via co-precipitation using clove extract as both the reducing and capping agent. The nanoparticles were thoroughly characterized using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy with energy-dispersive X-ray spectroscopy (SEM-EDX). Subsequently, we extracted eugenol from the same clove material and employed it as a reactant in CuO-catalyzed azide–alkyne cycloaddition reactions, leading to the formation of novel eugenol-derived 1,2,3-triazoles. This dual-purpose methodology not only addresses the environmental concerns of nanoparticle production but also advances the integration of green nanotechnology with heterocyclic drug synthesis. The proposed approach represents a novel contribution to the field of sustainable catalysis and medicinal chemistry.

2. Materials and Methods

2.1. Materials

Fresh clove powder was obtained from a reputable herbal supplier in Oran, Algeria The following chemicals were used as received, without further purification: CuCl₂, 2H₂O (≥99.99%), CuO (≥99.995%), CuI (≥99.5%), NaOH (≥99%, pellets), KOH (≥99%, pellets), propargyl alcohol (99%), p-Toluenesulfonyl chloride (98%), 1-Bromoheptane (98%), 1-Bromoundecane (98%), 1-Bromododecane (97%), 1-Bromotetradecane (97%), NaI (99,99%), Na₂SO₄ (≥99%), Dichloromethane (≥99.9%), Hexane (≥99%), Cyclohexane (≥99%), Diethyl Ether, N,N-Dimethyl formamide DMF (≥99%), Ethanol (98%), Acetone (≥99.5%), and Acetonitrile CH₃CN (≥99.8%). All chemicals and anhydrous solvents were obtained from Sigma-Aldrich (St. Louis, MO, USA) via Prochima (Tlemcen, Algeria).

2.2. Preparation of Clove Extract

2.2.1. Clove Extract for CuO Nanoparticles Synthesis

The clove extract used in this study was prepared according to the method previously described [31]. In brief, 10 g of finely powder clove was introduced into 100 mL of distilled water and heated at 80 °C for 15 min. The result solution was filtered to remove solid residues, and the clear filtrate was collected. The extract was stored in a dark vial at 4 °C to ensure stability and preservation.

2.2.2. Eugenol Extract from Clove as Precursor

Eugenol, the primary starting material, was obtained from clove buds (Syzygium aromaticum) through a two-step process consisting of hydro-distillation followed by purification. Briefly, 100 g of dried and finely crushed clove buds were placed in a 1 L round-bottom flask equipped with a Clevenger-type apparatus. Then, 500 mL of distilled water was added, and the mixture was heated under reflux for 3 h. During distillation, the volatile essential oil was co-distilled with steam and condensed in the Clevenger arm. After completion of the distillation, the essential oil layer was carefully collected, dissolved in dichloromethane (DCM), and successively washed with 5% aqueous sodium hydroxide solution to selectively extract the phenolic fraction containing eugenol. The alkaline aqueous layer was then acidified to pH = 2 with diluted hydrochloric acid, liberating eugenol from its phenolate salt. The released eugenol was re-extracted with dichloromethane, the organic phase was dried over anhydrous sodium sulfate (Na₂SO₄), and the solvent was evaporated under reduced pressure to afford pure eugenol as a pale-yellow liquid.

The product was stored in a sealed amber vial at 4 °C to prevent degradation. The identity and purity of the isolated eugenol were confirmed by proton (¹H) and carbon (¹³C) nuclear magnetic resonance (NMR) spectroscopy.

2.3. Synthesis of Copper Oxide Nanoparticles

A green synthesis approach was employed for the preparation of copper oxide (CuO) nanoparticles (NPs) using aqueous media. Initially, 2 g of CuCl₂ was dissolved in distilled water under stirring until complete dissolution. Clove extract was added to the CuCl₂ solution in a 20:80 volume ratio via dropwise addition. The pH of the solution was adjusted to 9 using 5 M NaOH, after which the mixture was continuously stirred at room temperature overnight to facilitate the reaction.

The resulting suspension was filtered, and the solid product was thoroughly washed with distilled water, followed by ethanol. The purified precipitate was dried in an oven at 60 °C and calcined at 500 °C for 1 h to obtain CuO nanoparticles.

2.4. Synthesis of 1,2,3-Triazoles

The synthesis of 1,2,3-triazoles from alkynes involves a multistep process. The initial step focuses on the preparation of propargyl tosylate (Figure 1). A 100 mL round-bottom flask equipped with a stirrer was charged with propargyl alcohol (2 mL, 34.68 mmol), p-toluenesulfonyl chloride (8.64 g, 45.32 mmol), and 35 mL of diethyl ether under a nitrogen atmosphere. The reaction mixture was cooled in an ice bath, and sodium hydroxide pellets (6.91 g, 172.75 mmol) were added in six portions at 0 °C with vigorous stirring. The resulting mixture was stirred continuously for 48 h at room temperature. After completion, the suspension was poured into cold water, and the aqueous layer was extracted with diethyl ether (3 × 20 mL). The combined organic phases were dried over anhydrous sodium sulfate (Na₂SO₄) and concentrated to yield pure propargyl tosylate as a dark liquid.

The second step involves the preparation of alkynes derived from eugenol (Figure 2). A solution of eugenol (3 mmol) in ethanol was mixed with a 50% excess of KOH in an ethanol solution containing 0.5% NaI as a co-catalyst. After stirring for 10 min, propargyl tosylate (3 mmol) was added to the mixture under a nitrogen atmosphere. The reaction mixture was refluxed for 24 h, with the progression monitored by thin-layer chromatography (TLC). The eluent was a mixture of dichloromethane and hexane (3:1). Upon completion, the mixture was poured into water and extracted with dichloromethane (3 × 10 mL). The organic layer was washed, dried over Na₂SO₄, and the solvent evaporated to yield the product.

For the synthesis of 1,2,3-triazoles derivatives (Figure 3), the reaction was carried out with bromoalkanes (1 mmol), sodium azide (3 mmol), and alkyne (1 mmol) in a DMF: water mixture (8:2). Copper oxide (CuO) nanoparticles were added at a concentration of 2 mg/mL. The reaction mixture was stirred vigorously for 2 h at 90 °C, and the reaction progress was monitored by TLC, while the eluent was a mixture of cyclohexane and acetone (3:2). Upon completion, the mixture was filtered, poured into water, and extracted with dichloromethane (3 × 10 mL). The combined organic layers were washed with water, dried over Na₂SO₄, and concentrated under reduced pressure. The crude product was purified by column chromatography using a cyclohexane: acetone (3:2) mixture as the eluent to afford the pure 1,2,3-triazole derivative.

2.5. Characterization Techniques

X-ray diffraction (XRD) analysis was performed using an X’Pert Pro diffractometer with Cu Kα radiation (λ = 0.154 nm) over a 2θ range of 0–80°. Functional groups were identified by Fourier transform infrared (FTIR) spectroscopy using a PerkinElmer Frontier instrument, covering the wavenumber range of 400–4000 cm⁻¹. The morphology and elemental composition of the CuO nanoparticles were examined using a Thermo Scientific Apreo 2 C scanning electron microscope (SEM) equipped with energy-dispersive X-ray spectroscopy (EDX). ¹H and ¹³C NMR spectra were recorded in CDCl₃. Some spectra were obtained using a Bruker 300 MHz spectrometer at the University of Oran 1 (Algeria), while others were recorded on a Bruker Avance Neo 400 MHz spectrometer at the University of Turin (Italy).

3. Results and Discussion

3.1. Characterization of CuO NPs

3.1.1. FTIR Analysis

Figure 4 presents the FTIR spectra of CuO nanoparticles (NPs) within the 400–4000 cm⁻¹ range. The bands at 1623 cm⁻¹ and 3432 cm⁻¹ correspond to the H–O–H bending and O–H stretching vibrations of adsorbed water molecules, respectively [32]. Additionally, the absorption bands observed at 780 cm⁻¹, 622 cm⁻¹, and 523 cm⁻¹ are attributed to the Cu–O stretching vibrations, characteristic of the monoclinic phase of copper oxide [33].

3.1.2. XRD Analysis

The XRD pattern of the synthesized CuO nanoparticles (NPs), as shown in Figure 5, confirms the formation of monoclinic CuO with high crystallinity. The diffraction peaks at the 2θ values of 32.47°, 35.49°, 38.68°, 48.65°, 53.41°, 58.24°, 61.45°, 66.14°, 68.01°, 72.32° and 74.92° correspond to the (110), (−111), (111), (202), (020), (202), (−113), (−311), (220), (311), and (004) crystal planes, respectively. These planes align with the JCPDS card for monoclinic CuO (No. 96-901-6327) [34], confirming the synthesized material’s phase purity.

The sharp and well-defined diffraction bands indicate the nanoscale dimensions of the CuO particles, as well as their high degree of crystallinity. No additional peaks corresponding to impurities or secondary phases are observed, which suggests the successful synthesis of pure CuO NPs.

• Determination of the average crystallite size

The crystallite size (D) is a measure of the coherent diffracting domains within a crystal structure. For nanoparticles, the crystallite and grain sizes are considered equivalent. In X-ray diffraction, line broadening is influenced by the crystallite size and lattice microstrain. The average crystallite size (D) was calculated using the Scherrer formula [35]:

$$D={\displaystyle \frac{k\lambda }{\beta \mathit{cos}\theta }}$$

(1)

where k = 0.9 is the shape factor, λ = 0.1541 nm is the X-ray wavelength, β is the full width at half maximum (FWHM) of the diffraction peak (radians), accounting for instrument broadening, θ is the Bragg diffraction angle (degrees or radians), and D represents the crystallite size (nm).

Using this equation, the average crystallite size of the synthesized material was calculated to be 15.29 nm.

3.1.3. SEM and EDX Analysis

The combined EDX and SEM analyses of CuO nanoparticles synthesized via green synthesis using clove extract provide detailed insights into their elemental composition, morphology, and structural characteristics. In Figure 6, the EDX results confirm the formation of copper oxide (CuO), with a predominant copper (Cu) content of 90.0 wt% and 80.6 at%, alongside oxygen (O) at 1.8 wt% and 6.3 at%. The detection of chlorine (Cl) at 8.2 wt% and 13.1 at% is likely to result from incomplete washing during purification, leaving residual CuCl₂ counter ions from the precursor rather than the clove extract. This aligns with chemical precipitation studies, where Luna et al. [36] noted that CuO synthesis from CuCl₂ requires thorough rinsing to remove Cl-containing byproducts like NaCl, with insufficient washing leading to detectable residues in EDX. Conversely, clove extract (Syzygium aromaticum), rich in organic compounds like eugenol but lacking significant Cl, is an improbable source [37]. Thus, the Cl presence underscores precursor-derived impurities, emphasizing the need for enhanced purification in green synthesis. Figure 7 shows that the SEM images reveal a cubic morphology with relatively uniform particle size and smooth surfaces, suggesting controlled growth mediated by the bioactive compounds in the clove extract. The observed agglomeration is likely attributable to van der Waals forces or residual organic molecules, a common occurrence in nanoparticle systems [38,39]. These findings underscore the successful green synthesis of CuO nanoparticles with well-defined structural features while highlighting the potential need for further optimization to improve the washing procedure and reduce agglomeration.

3.2. The Role and Mechanism of Clove Extract in CuO Nanoparticle Formation

Green synthesis of nanoparticles, including copper oxide (CuO), harnesses the reducing and stabilizing properties of plant-derived biomolecules, offering an environmentally benign and cost-effective alternative to traditional chemical methods [28,40]. Clove extract, derived specifically from the buds of Syzygium aromaticum, has been effectively employed in the biosynthesis of spherical copper nanoparticles [41]. This plant extract is rich in phytochemicals—bioactive molecules that are capable of reducing metal ions and stabilizing the resulting nanoparticles [42]. Among these phytochemicals, eugenol plays a central role as a bioreductant in the synthesis process [43]. In addition to eugenol, other phenolic constituents with nucleophilic aromatic rings and phenolic hydroxyl groups significantly contribute to the reduction and stabilization of metal nanoparticles [44,45]. This synergistic interaction among various compounds is considered a major advantage of plant-mediated nanoparticle synthesis.

The mechanism of green synthesis typically proceeds through three distinct stages, as shown in Figure 8:

• Activation Phase: In this initial phase, metal ions (e.g., Cu²⁺) are reduced by plant metabolites possessing inherent reducing capabilities. These metabolites interact with copper salt precursors, facilitating the transition of copper ions to a zero-valent state and initiating the nucleation of condensed metal atoms [46,47].
• Growth Phase: Following nucleation, a continued bioreduction of residual metal ions supports the growth and self-assembly of nanoparticles into defined morphologies. In the case of clove-mediated synthesis, this results in predominantly spherical copper nanoparticles [32].
• Stabilization Phase: In the final stage, plant metabolites cap the nanoparticle surfaces, thereby enhancing their stability and preventing agglomeration [48].

Furthermore, the synthesis was conducted at pH 9, a mild alkaline condition that facilitates the precipitation of copper hydroxide (Cu(OH)₂) as an intermediate species. The hydroxide precipitate forms according to the reaction:

$${\mathrm{C}\mathrm{u}}^{2+}+2\mathrm{O}{\mathrm{H}}^{-}\to \mathrm{C}\mathrm{u}(\mathrm{O}\mathrm{H}{)}_2\downarrow$$

This intermediate is crucial for the subsequent formation of copper oxide. Upon calcination at 500 °C in ambient air, Cu(OH)₂ and any reduced copper species (e.g., Cu⁰ or Cu₂O) undergo thermal decomposition and oxidation to form monoclinic CuO nanoparticles by following the reaction:

$$\mathrm{C}\mathrm{u}(\mathrm{O}\mathrm{H}{)}_2\stackrel{∆,{\mathrm{O}}_2}{\to }\mathrm{C}\mathrm{u}\mathrm{O}+{\mathrm{H}}_2\mathrm{O}$$

This final thermal step ensures a complete conversion to CuO and enhances the crystallinity and phase purity of the synthesized nanoparticles.

Several factors influence the size and morphology of CuO nanoparticles synthesized via green methods, including the type and concentration of plant extract, pH, temperature, and reaction time. For example, K.M. Rajesh et al. [49] synthesized CuO nanoparticles using clove extract and reported crystallite sizes of approximately 12 nm (Debye–Scherrer method) and 15 nm based on TEM analysis. In contrast, Anindita De et al. [33] obtained a larger average crystallite size of 70 nm under different synthesis conditions, also using the Debye–Scherrer equation. These discrepancies can likely be attributed to variations in experimental parameters. Furthermore, Dina A. Ali et al. [34] also employed clove extract in their synthesis but did not report crystallite sizes in their study.

3.3. Structural Characterization of 1,2,3 Triazoles Derivatives

3.3.1. FTIR Analysis

The C–H stretching bands observed between 3127 and 2849 cm⁻¹ indicate the presence of both aromatic and alkyl groups. A strong C=N stretching band around 1589–1636 cm⁻¹ supports the presence of the triazole ring. The bands between 1508 and 1256 cm⁻¹, attributed to C=C and C–N stretching, are consistent with a nitrogen-containing aromatic system. Additionally, signals in the 600–1000 cm⁻¹ region, corresponding to C–H bending and out-of-plane deformations, further support aromatic substitution. The absence of an absorption band near 3300 cm⁻¹, which is characteristic of terminal alkynes, confirms the consumption of the acetylenic group and thus supports the successful formation of the triazole ring.

3.3.2. NMR Analysis

• ¹H NMR spectrum

The singlet observed in the range δ = 6.95–7.60 ppm is characteristic of the triazole ring proton, confirming its successful formation. The signal at δ = 1.27 ppm represents methylene groups (-CH₂-) that are not directly connected to the triazole ring. These protons are located farther from the ring and are part of an alkyl chain. Additionally, the signal at δ = 0.85 ppm corresponds to a terminal methyl group (-CH₃), further confirming the presence of a straight-chain alkyl group. The disappearance of the chemical shift corresponding to the acetylenic proton (around 2.5 ppm) in the starting material and the appearance of the singlet around 7.60 ppm (corresponding to the proton attached to the sp² carbon of the triazole ring) provide strong evidence for the formation of the triazole ring.

• ¹³C NMR spectrum

The range of signals between δ = 40.51 and δ = 12.05 ppm corresponds to the newly introduced alkyl chain, which is consistent with the observations in the proton NMR spectrum (terminal methyl group and methylene groups). The carbons that are part of the triazole ring fall in the region of δ = 120–150 ppm, with a distinct peak at 133.3 ppm corresponding to the carbon of the triazole ring. This further supports the formation of the expected triazole products. Additionally, a peak observed around 137.52 ppm further confirms the aromatic nature of the triazole ring and its successful synthesis.

Eugenol

Colorless oil, Yield: 90%

¹H NMR (300 MHz, CDCl₃): δ = 6.79 (d, 1H), δ = 6.70 (m, 2H), δ = 6.27 (s, 1H), δ = 5.93 (t, 1H), δ = 5.09 (d, 2H), δ = 3.82 (s, 3H), δ = 3.31 (d, 2H).

¹³C NMR (75 MHz, CDCl₃): δ = 147.09, 145.05, 138.13, 132.16, 121.69, 115.60, 114.82, 111.83, 55.99, 40.15.

Propargyl tosylate

Liquid, yield = 82.4%

¹H NMR (300 MHz, CDCl₃): δ = 7.76 (m, 2H), δ = 7.32 (m, 2H), δ = 4.65 (d, 2H), δ = 2.48 (t, 1H), δ = 2.41 (s, 3H).

¹³C NMR (75 MHz, CDCl₃): δ = 145.40, 132.68, 129.96, 128.08, 77.52, 75.34, 57.49, 21.68.

4-allyl-2methoxy-1(prop-2-yn-1-yloxy) benzene

Brown liquid, yield = 88%

¹H NMR (300 MHz, CDCl₃): δ = 6.97 (d, 1H), δ = 6.74 (m, 2H), δ = 5.95 (m, 1H), δ = 5.09 (s, 2H), δ = 4.74 (s, 2H), δ = 3.86 (s, 3H), δ = 3.35 (m, 2H), δ = 2.49 (d, 1H).

¹³C NMR (75 MHz, CDCl3): δ = 149.62, 145.08, 137.54, 134.22, 120.32, 116.86, 114.56, 112.28, 78.80, 75.68, 57.75, 55.26, 42.37.

R = 7: 4-((4-allyl-2-methoxyphenoxy) methyl) -1-heptyl-1H-1,2,3-triazole

red semi-solid, yield = 95%

¹H NMR (400 MHz, CDCl₃): δ = 7.59 (s, 1H), δ = 6.93 (d, 1H), δ = 6.68 (m, 2H), δ = 5.92 (ddd, 1H), δ = 5.25 (d, 2H), δ = 5.04 (m, 2H), δ = 4.30 (t, 2H), δ = 3.84 (m, 3H), δ = 3.28 (m, 2H), δ = 2.89 (dd, 2H), δ = 1.85 (q, 2H), δ = 1.27 (m, 6H), δ = 0.85 (t, 3H).

¹³C NMR (100 MHz, CDCl₃): δ = 148.96, 145.98, 137.52, 133.30, 123.82, 120.53, 117.38, 114.50, 112.33, 63.52, 55.26, 49.54, 39.35, 36.45, 31.53, 29.87, 28.62, 26.41, 21.78, 12.05.

FTIR: 3124, 3069, 2998, 2919, 2852, 2094, 1668, 1636, 1587, 1510, 1462, 1417, 1381, 1334, 1257, 1227, 1138, 1058, 1036, 993, 951, 909, 871, 849, 834, 801, 742, 721, 662, 639, 592, 543, 512.

R = 11: 4-((4-allyl-2-methoxyphenoxy) methyl)-1-undecyl-1H-1,2,3-triazole

Garnet semi-solid, yield = 92%

¹H NMR (400 MHz, CDCl₃): δ = 7.60 (s, 1H); δ = 6.95 (d, 1H); δ = 6.70 (m, 2H); δ = 5.94 (q, 1H); 5.26 (s, 2H); δ = 5.07 (m, 2H); δ = 4.31 (t, 2H); δ = 3.85 (s, 3H); δ = 3.30 (d, 2H); δ = 1.88 (s, 2H); δ = 1.27 (d, 16H); δ = 0.87 (t, 3H).

¹³C NMR (100 MHz, CDCl₃): δ = 149.54, 145.99, 137.53, 137.43, 133.78, 120.55, 115.70, 114.50, 112.33, 63.55, 55.87, 55.34, 50.42, 39.82, 31.84, 30.25, 29.46, 29.37, 29.24, 29.04, 28.98, 26.49, 22.66, 14.09.

FTIR: 3127, 3074, 2948, 2918, 2849, 1669, 1636, 1589, 1508, 1461, 1417, 1375, 1335, 1256, 1218, 1138, 1032, 992, 951, 910, 847, 817, 801, 744, 720, 644, 595, 560.

R = 12: 4-((4-allyl-2-methoxyphenoxy) methyl)-1-dodecyl-1H-1,2,3-triazole

Brown semi-solid, yield = 98%

¹H NMR (400 MHz, CDCl₃): δ = 6.95 (d, 1H), δ = 6.71 (m, 2H), δ = 5.94 (q, 1H), δ = 5.26 (s, 2H), δ = 5.07 (m, 2H), δ = 4.31 (t, 2H), δ = 3.85 (s, 3H), δ = 3.32 (d, 2H), δ = 1.88 (s, 2H), δ = 1.27 (d, 18H), δ = 0.87 (t, 3H).

¹³C NMR (100 MHz, CDCl₃): δ = 149.54, 145.99, 144.44, 143.53, 138.12, 133.78, 122.59, 120.55, 115.69, 114.50, 112.33, 63.56, 55.87, 50.42, 39.82, 31.90, 30.25, 29.59, 29.51, 29.37, 29.33, 28.99, 26.67, 26.49, 22.68, 14.11.

FTIR: 3131, 3097, 3073, 2999, 2910, 2844, 2091, 1673, 1636, 1587, 1510, 1464, 1417, 1383, 1334, 1258, 1227, 1187, 1137, 1055, 1029, 1011, 992, 911, 848, 826, 803, 777, 747, 718, 646, 596, 543, 516.

R = 14: 4-((4-allyl-2-methoxyphenoxy) methyl)-1-tetradecyl-1H-1,2,3-triazole

Dark brown semi-solid, yield = 96%

¹H NMR (400 MHz, CDCl₃): δ = 7.60 (s, 1H), δ = 6.95 (d, 1H), δ = 6.70 (m, 2H), δ = 5.94 (ddt, 1H), δ = 5.26 (s, 2H), δ = 5.07 (m, 2H), δ = 4.32 (t, 2H), δ = 3.85 (s, 3H), δ = 3.29 (dd, 2H), δ = 1.88 (m, 2H), δ = 1.27 (d, 22H), δ = 0.88 (t, 3H).

¹³C NMR (100 MHz, CDCl₃): δ = 149.54, 146.04, 143.46, 137.54, 133.24, 122.53, 120.55, 116.14,

114.49, 112.33, 63.55, 55.88, 52.49, 50.40, 40.51, 31.92, 30.26, 29.68, 29.64, 29.60, 29.51, 29.38, 29.35, 28.99, 26.45, 22.69, 14.11.

FTIR: 3131, 3078, 2997, 2949, 2913, 2845, 2094, 1679, 1636, 1589, 1510, 1417, 1375, 1334, 1258, 1228, 1189, 1058, 1033, 992, 909, 847, 833, 806, 778, 745, 721, 648, 582, 538, 513.

3.4. Cu-Based Azide–Alkyne Cycloaddition Catalyst Comparison

A systematic evaluation of copper-based catalysts—green-synthesized CuO nanoparticles, commercial CuO, and CuI—was conducted to assess their efficacy in the azide–alkyne cycloaddition (CuAAC) reaction. The results clearly illustrate the crucial influence of both catalyst nature and reaction conditions on catalytic performance and product yield, as shown in

Table 1. Comparative evaluation of green-synthesized CuO nanoparticles, commercial CuO, and CuI catalysts in the azide–alkyne cycloaddition reaction.

Entry	Catalyst	Temperature (°C)	Time	Solvent	Yield (%)
1	2 mg/mL Green CuO NPs	RT	2	DMF/H2O (8:2)	0
2	2 mg/mL Green CuO NPs	90	2	DMF/H2O (8:2)	98
3	2 mg/mL Commercial CuO	RT	2	DMF/H2O (8:2)	0
4	2 mg/mL Commercial CuO	90	2	DMF/H2O (8:2)	0
5	20 mg/mL Commercial CuO	RT	2	DMF/H2O (8:2)	0
6	20 mg/mL Commercial CuO	90	14	DMF/H2O (8:2)	39
7	20 mg/mL CuI	75	96	CH3CN	41

Green CuO NPs—green-synthesized CuO nanoparticles; RT—room temperature; DMF—Dimethylformamide.

.

Among the tested catalysts, the biosynthesized CuO nanoparticles demonstrated superior activity, affording a 98% yield of the target triazole within only 2 h at 90 °C in a DMF/H₂O (8:2) solvent system. This high reactivity is ascribed to the nanoscale dimensions, large specific surface area, and enhanced dispersion of the particles. The presence of phytochemicals from Syzygium aromaticum (clove extract), used in the green synthesis process, likely contributes to the stabilization of surface-active sites and improved catalytic efficiency.

At an ambient temperature, the same green CuO catalyst was catalytically inactive, underscoring the requirement for thermal activation to initiate and sustain the cycloaddition process. In contrast, commercial CuO—regardless of its concentration or temperature—exhibited minimal catalytic performance. Even at an elevated temperature (90 °C) and higher catalyst loading (20 mg/mL), commercial CuO produced only a modest yield after a prolonged reaction time of 14 h. These observations suggest that the morphological characteristics and physicochemical properties of the catalyst, rather than the copper content alone, govern its activity in this transformation.

CuI, although widely employed in CuAAC chemistry, delivered a significantly lower yield (41%) under relatively harsh conditions, namely, 75 °C for 96 h in acetonitrile. Despite its effectiveness in homogeneous systems, CuI is highly sensitive to air and moisture and poses challenges for recovery and reuse. These drawbacks further highlight the practical and environmental advantages of using heterogeneous nanoparticle-based catalysts.

Overall, the green-synthesized CuO nanoparticles clearly outperformed both commercial CuO and CuI under comparable or milder conditions. Beyond their remarkable catalytic performance, the biosynthesized CuO NPs offer distinct benefits aligned with green chemistry principles, including the use of renewable botanical resources, an environmentally benign preparation method, and ease of catalyst recovery. This study affirms their potential as a highly effective and sustainable alternative for copper-catalyzed click reactions.

3.5. Influence of Bromoalkene Chain Length on the CuACC Reactions

A series of bromoalkenes bearing alkyl chains of varying lengths (R = 7, 11, 12, and 14) were investigated to assess the influence of the chain length on the efficiency of the cycloaddition reaction. In all cases, the transformation proceeded smoothly, yielding the desired triazoles in consistently high yields exceeding 90%. These results indicate that the CuO catalyst maintained its activity regardless of the alkyl chain length, suggesting that the increased steric bulk associated with longer chains did not significantly hinder azide formation or the subsequent CuAAC process. Overall, the catalytic system exhibited excellent substrate tolerance, underscoring its robustness and versatility in accommodating structurally diverse bromoalkyl derivatives.

3.6. Reuse of the CuO Nanoparticles Catalyst

To assess the reusability of the green-synthesized CuO nanoparticles, five consecutive catalytic cycles were conducted under identical reaction conditions. The reusability study was performed using the derivative that exhibited the highest yield (98%) among the four synthesized triazole compounds. Each catalytic cycle was repeated in triplicate to ensure the accuracy and reproducibility of the results. As summarized in Figure 9, the catalyst maintained high activity during the first three cycles, with yields gradually decreasing from 98% to 89.00% and then to 80.50%. A more pronounced decline was observed in the fourth and fifth cycles, with yields dropping to 72.34% and 46.70%, respectively. This reduction in efficiency is likely attributable to partial loss of catalyst during recovery, nanoparticle aggregation, or progressive deactivation of active sites.

Despite the observed decline, the catalyst remained functionally active over multiple cycles, underscoring its potential for reuse in practical applications. To further investigate the structural integrity of the catalyst after repeated use, the recovered CuO nanoparticles were analyzed by FTIR spectroscopy following the fifth cycle (Figure 10). The spectrum retained the characteristic Cu–O vibrational bands in the range of 530–610 cm⁻¹, indicating that the crystalline framework of CuO was preserved. Additionally, broad absorption bands around 3430 and 1625 cm⁻¹, associated with adsorbed water, were present as expected. Importantly, no new peaks indicative of organic residues or surface contamination were detected. These findings confirm the structural robustness of the CuO nanoparticles and support their recyclability, reinforcing their suitability for sustainable and environmentally friendly catalytic processes.

3.7. Comparative Evaluation of Reported Copper-Catalyzed Triazole Syntheses

To further assess the efficiency of our green-synthesized CuO nanoparticles, we compared their catalytic performance with several literature-reported protocols for the synthesis of 1,2,3-triazoles using copper-based catalysts (Table 2). These methods vary significantly in terms of catalyst type, loading, reaction time, and yield.

Our approach afforded an excellent yield of 95.25% using only 2 mg/mL of CuO nanoparticles at 90 °C within 2 h, placing it among the most efficient systems reported to date. In comparison, Ardiansah et al. [15] achieved a 92% yield under similar conditions but required a prolonged reaction time of 23 h. Abdelbaki et al. [50] employed 20 mg/mL of Cu₂O microbeads and obtained only a 70% yield, despite comparable thermal conditions.

Other reported methods utilizing copper (II) sulfate-based catalysts typically involve additional reagents or extended reaction times and often result in moderate yields ranging from 60% to 87%. In contrast, our catalyst enabled rapid and high-yielding transformations under straightforward and environmentally benign conditions, using minimal catalyst loading.

Given the high efficiency observed, further optimization was deemed unnecessary. The results clearly demonstrate the strong catalytic activity and practical applicability of the green CuO nanoparticles.

Table 2. Reported methods for triazole synthesis under different conditions, compared to the present CuO nanoparticles catalytic system.

Product	Solvent	Condition	Catalyst	Yield (%)	Reference
	DMF/Water	23 h, at room temperature.	Copper (II) sulfate pentahydrate and ascorbic acid	92	[15]
	t-BuOH/H2O	3 h	Copper (II) sulfate pentahydrate and sodium ascorbate	65	[51]
	EtOH/H2O	24–48 h, at 50 °C	Copper (II) sulfate pentahydrate, sodium ascorbate	60,5	[21]
	THF	12 h, at room temperature.	Copper iodide	87	[18]
	DMF/ H2O	3 h, 90 °C	Cu2O microbeads 20 mg/mL	70	[50]
	DMF/ H2O	2 h, 90 °C	CuO nanoparticles 2 mg/mL	95.25	Our work

Table 2. Reported methods for triazole synthesis under different conditions, compared to the present CuO nanoparticles catalytic system.

Product	Solvent	Condition	Catalyst	Yield (%)	Reference
	DMF/Water	23 h, at room temperature.	Copper (II) sulfate pentahydrate and ascorbic acid	92	[15]
	t-BuOH/H2O	3 h	Copper (II) sulfate pentahydrate and sodium ascorbate	65	[51]
	EtOH/H2O	24–48 h, at 50 °C	Copper (II) sulfate pentahydrate, sodium ascorbate	60,5	[21]
	THF	12 h, at room temperature.	Copper iodide	87	[18]
	DMF/ H2O	3 h, 90 °C	Cu2O microbeads 20 mg/mL	70	[50]
	DMF/ H2O	2 h, 90 °C	CuO nanoparticles 2 mg/mL	95.25	Our work

4. Conclusions

In this work, we demonstrated a simple and eco-friendly method for synthesizing copper oxide nanoparticles using clove extract, a natural and renewable resource. The resulting CuO nanoparticles were well-characterized and showed good crystallinity and purity. Thanks to the bioactive compounds in the clove extract, the synthesis could be carried out under mild conditions without the need for harmful reagents. We then used these green-synthesized nanoparticles as catalysts in the copper-catalyzed azide–alkyne cycloaddition to produce eugenol-based 1,2,3-triazoles. The reactions proceeded smoothly, with excellent yields and only a small amount of catalyst. This highlights the efficiency of the CuO nanoparticles and the value of natural extracts in sustainable chemical processes. Overall, this study shows how plant-derived materials like clove can play a meaningful role in green nanotechnology and organic synthesis, combining simplicity, effectiveness, and environmental responsibility.