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. 2025 Dec 15;10(51):62881–62894. doi: 10.1021/acsomega.5c08549

ZnO Nanocatalyst-Enabled Microwave-Assisted Solvent-Free Synthesis of Functional Amidoalkyl-2-naphthol Derivatives: A Synergistic Experimental and Quantum Chemical Study

Alphonse Raj Daniel Aroquiaraj †, Pichaiyappan Vivekanandan †, Kaddalae Sathiyanarayanan Satheeshkumar †,*, Francisxavier Paularokiadoss ‡,*, Aleksandr S Kazachenko §,∥,⊥, Bouzid Gassoumi #, Mohammed Bouachrine ∇, Sahbi Ayachi ○,*
PMCID: PMC12756830  PMID: 41487191

Abstract

Novel N-methyl-1-amidoalkyl-2-naphthol derivatives (HNM-1 and HNM-2) were synthesized via a solvent-free, microwave-assisted one-pot condensation of 2-naphthol, N-methylacetamide, and functionalized benzaldehydes. A recyclable ZnO nanoparticle catalyst (20 mol %) enabled the reactions to proceed efficiently, affording yields ≥80% within 15–18 min at 300 W, significantly outperforming montmorillonite K10 clay under comparable green conditions. The synthesized compounds were fully characterized using FT-IR, 1H- and 13C NMR, HR-ESI-MS, and UV–vis spectroscopies. Density functional theory (DFT) calculations (B3LYP/6-311G­(d,p)) provided optimized geometries and electronic structures. The HOMO and LUMO energy levels were determined as −5.97/–2.68 eV for HNM-1 and −5.95/–2.95 eV for HNM-2, corresponding to moderate energy gaps of 3.29 and 3.00 eV, respectively. Time-dependent DFT (TD-DFT) simulations accurately reproduced the experimental UV–vis spectra, revealing a distinct intramolecular charge transfer band at 379 nm for HNM-2. Mulliken population analysis, DOS, ELF/LOL maps, and MEP surfaces confirmed pronounced electron migration from the donor (naphthol-acetamide moiety) to the nitro-substituted aryl acceptor. Quantum Theory of Atoms in Molecules (QTAIM) and noncovalent interaction (NCI) analyses identified stabilizing hydrogen bonds (up to −59 kJ/mol) and van der Waals interactions, consistent with high predicted chemical hardness (η = 1.50–1.65 eV) and kinetic stability. Molecular docking studies against the SARS-CoV-2 main protease (PDB ID: 7U0N) revealed strong binding affinities (−7.0 and −6.2 kcal/mol for HNM-1 and HNM-2, respectively). HNM-1 formed five hydrogen bonds with residues Leu351, Lys403, and Gln409, while HNM-2 engaged in a single, well-oriented hydrogen bond with Asn322, highlighting effective complementarity with the viral active site.

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1. Introduction

In recent years, 2-naphthol derivatives, known for their remarkable biological and pharmacological properties, have been the focus of intensive research. , A significant body of work has been dedicated to naphthol-based drugs, such as terbinafine, tolnaftate, and nafcillin, which play a vital role in microbial control. These 2-naphthol derivatives exhibit a broad spectrum of antimicrobial activity. Recent studies have highlighted 2-naphthol as a promising lead compound for developing highly bioactive synthetic derivatives. − Specifically, many 3-chloro monocyclic β-lactams, substituted at positions 1 and 4, have shown excellent potential as antitubercular, antimicrobial, and anticonvulsant agents. − Organic transformations are often achieved with high efficiency using metal oxides as heterogeneous catalysts. Recent advances have focused on the development of novel nanocatalysts. Among these, nanosized zinc oxide (ZnO) has garnered attention as a heterogeneous catalyst due to its low cost, low toxicity, and, importantly, its ecological compatibility. ZnO is known for its short decomposition time, adequate corrosion resistance, and ease of recycling, transportation, and disposal. Additionally, several research teams focused on biological applications , have demonstrated the potential of ZnO nanoparticles in cancer treatment. The environmentally safe ZnO catalyst has been widely utilized in the modification of organic substances. Currently, the role of nanoparticles, which offer unique selective targeting, is rapidly growing in modern oncology, gradually surpassing traditional cancer treatments such as surgery, radiation, and chemotherapy. Biocompatible, highly selective, and easy-to-synthesize, ZnO nanoparticles show great promise as effective anticancer agents. Additionally, these nanoparticles can be efficiently separated with a minimum waste. ,, In this study, we aimed to synthesize new 2-naphthol derivatives through a condensation reaction under solvent-free conditions, using a microwave-assisted ZnO nanoparticle catalyst in combination with montmorillonite K10 clay.

2. Experimental Section

2.1. Synthesis of ZnO Nanoparticles

ZnO nanoparticles were synthesized following a reported procedure. Commercial zinc acetate (9.10 g, 0.05 mol) and oxalic acid (5.4 g, 0.06 mol) were mixed in a mortar at 27 °C for 1 h. To induce thermal decomposition, the resulting zinc oxalate dehydrate nanoparticles were irradiated by microwaves for 30 min at 150 W power. This process yielded ZnO nanoparticles with a 75% yield. The nanoparticles remained well separated during synthesis, preventing agglomeration and ensuring large surface areas suitable for various reactions. ZnO nanoparticles were thoroughly washed with ethanol and deionized water to remove residual precursors and byproducts. The resulting material was then dried under vacuum. This purification step ensures the removal of surface-bound impurities and enhances the reproducibility of catalytic performance. All chemical reagents employed in this study were commercially available and obtained from Sigma-Aldrich. Unless otherwise specified, the starting materials and solvents were used as received without any additional purification. The microwave-assisted reactions were carried out using a domestic microwave oven (Samsung MS23A3513AK, 800 W, 2450 MHz) operated in pulsed mode.

Figure a presents the Scanning Electron Microscope (SEM) image of as- prepared zinc oxide (ZnO), clearly revealing its nanoscale morphology. The SEM micrographs were obtained using a JEOL JSM-IT800 instrument. Figure b shows SEM image of ZnO after catalytic use. A comparison between Figure a,b indicates that no significant alterations in crystallinity or morphology occur, confirming that the catalyst retains its structural integrity even after multiple catalytic cycles. Figure c displays the X-ray diffraction (XRD) pattern of the synthesized ZnO nanoparticles. The average crystallite size was estimated using the Scherrer equation, D=Kλβcosθ , where D represents the mean crystallite size perpendicular to the diffracting planes, K is the shape factor (0.9), λ is the X-ray wavelength, β is the full width at half-maximum (fwhm) of the diffraction peak, and θ is the Bragg angle.

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(a) SEM image of ZnO nanoparticles before reaction. (b) SEM image of ZnO nanoparticles after reaction. (c) XRD pattern of ZnO nanoparticles. (d) EDX spectrum of ZnO nanoparticles.

The XRD pattern exhibits sharp and well-defined diffraction peaks characteristics of the hexagonal wurtzite phase of ZnO (JCPDS No. 01-079-0208), with no evidence of secondary or impurity phases, confirming the high phase purity of the synthesized material. Prominent peaks observed at 2θ values of 31.56°, 34.22°, 36.09°, 56.45°, and 62.71° correspond to the (100), (002), (101), (110), and (103) planes, respectively, typical of ZnO crystal structure. The average crystallite size, calculated from the most intense (101) reflection, was approximately 25.09 nm. Figure d shows the Energy Dispersive X-ray (EDX) spectrum of ZnO nanoparticles.

The strong signals at ∼1.0 keV (Lα) and ∼8.6 keV (Kβ) correspond to Zn, while the peak near 0.5 keV arises from oxygen. The absence of additional elemental peaks confirms the high purity and stoichiometric composition of the synthesized ZnO nanoparticles.

2.1.1. Synthesis of 2-Naphthol Derivatives HNM-1 and HNM-2 Using ZnO Nanoparticles: Method A

A mixture of substituted benzaldehyde (1 mmol), N-methylacetamide (1.4 mmol), 2-Naphthol (1 mmol) and ZnO nanoparticles (0.25 mmol) was placed in a 25 mL beaker and irradiated in a microwave oven at 300 W (see Table ). To prevent overheating, the reaction mixture was irradiated in 30-s pulses and intermittently stirred with a glass rod to avoid localized temperature buildup and to ensure uniform energy distribution throughout the medium. This procedure effectively maintained thermal control and minimized the risk of degradation of thermally sensitive intermediates.

1. Comparative Efficiencies of Zinc Oxide Nanocatalyst and Montmorillonite K10 Clay Used in the Synthesis of the 2-Naphthol Derivatives .
  ZnONPs (method A)
 K10 clay (method B)
synthesized compound time (min) yield (%) time (min) yield (%)
HNM-1 15 89 30 65
HNM-2 18 80 30 63
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The times and yields are given for the reaction of 2-naphthol, substituted benzaldehyde, and N-methylacetamide.

The progress of the reaction was monitored using thin-layer chromatography (TLC) with n-hexane-ethyl acetate mixture (8:2) as the solvent. Once the reaction was complete, the mixture was allowed to cool to room temperature and then treated with ethyl acetate. The ZnO nanoparticles, being insoluble in ethyl acetate, were separated by simple filtration and thoroughly washed with water. The resulting 2-naphthol derivatives were purified by column chromatography on silica gel (60–120 mesh) using an ethyl acetate/hexane (2:8 v/v) eluent system. The isolated yields of each compound were determined after purification, calculated from the mass of the dried product relative to theoretical yield (Table ). The following Scheme illustrates the formation of HNM-1 and HNM-2 and the molecular structures of HNM-1 and HNM-2 are given in Scheme .

1. Synthesis of N-Substituted 1-Amidoalkyl-2-naphthols.

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2. Molecular Structures of Investigated Compounds: HNM-1 and HNM-2.

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The FT-IR analysis of the product HNM-1 showed key absorption bands, including a broad band at 3438 cm–1 for O–H stretching, a peak at 3068 cm–1 for aromatic C–H stretching, and a strong signal at 1685 cm–1 corresponding to amide CO stretching. Additional signals appeared at 1610–1465 cm–1 for CC stretching in the aromatic rings, 1518 cm–1 for N–O stretching, 1469 cm–1 for C–O stretching, 1252 cm–1 for C–N stretching, and a band at 831 cm–1 for aromatic C–H out-of-plane bending. The FTIR spectrum of another product HNM-2 revealed characteristic absorption bands, including a broad O–H stretching band at 3446 cm–1, aromatic C–H stretching at 3088 cm–1, and amide CO stretching at 1697 cm–1. Additional absorption bands were observed at 1626–1488 cm–1 for CC stretching in aromatic rings, 1516 cm–1 for N–O stretching, 1467 cm–1 for C–O stretching, 1230 cm–1 for C–N stretching, and 815 cm–1 for aromatic C–H out-of-plane bending, confirming the presence of expected functional groups in the synthesized compound. These FTIR bands confirm the presence of key functional groups in the synthesized compound. The FTIR spectra of the above compounds are given in Supporting Information Figure S4a,b.

2.1.2. Synthesis of 2-Naphthol Derivatives HNM-1 and HNM-2 Using Montmorillonite K10 Clay: Method B

A mixture of substituted benzaldehyde (1 mmol), 2-naphthol (1 mmol), and N-methylacetamide (1.1 mmol) was condensed in the presence of montmorillonite K10 (0.1 g) under the solvent-free conditions at 125 °C for 30 min. The reaction proceeded smoothly, yielding the 2-naphthol derivatives. After completion of the reaction, methanol was added to quench the mixture and facilitate product isolation.

The resulting technical product was filtered, and the solvent was evaporated. The product required purification, which was achieved by isolating it from an ethanol: water (1:3) solution. The reaction progress was monitored using thin-layer chromatography (TLC) with an n-hexane–ethyl acetate mixture (8:2) as the solvent. Upon completion of the reaction, the mixture was cooled to room temperature and treated with ethyl acetate. As in method A, the ethyl acetate-insoluble montmorillonite K10 catalyst was separated by simple filtration, washed with distilled water. The resulting the 2-naphthol derivatives thus prepared were purified by column chromatography on silica gel (60–120 mesh) using an ethyl acetate/hexane (2:8, v/v) eluent system. The isolated yield of each compound was determined after purification by comparing the mass of the dried product with the corresponding theoretical yield (Table ).

2.2. Details of the Theoretical Calculations

The structural geometries of both compounds were optimized using the hybrid density functional theory (DFT) method, specifically B3LYP/6-311G­(d,p). Following optimization, molecular electrostatic potential (MEP) analysis and highest occupied molecular orbital–lowest unoccupied molecular orbital (HOMO–LUMO) calculations were performed to evaluate the reactivity and band gap of the molecules. All computations were conducted using Gaussian 09 W software and visualized with GaussView. Topological QTAIM parameters were derived using the Multiwfn package. , To further elucidate the nature of covalent and noncovalent bonding within the compounds, electron localization function (ELF) and localized orbital locator (LOL) iso-surfaces were analyzed. ,

3. Results and Discussion

The ZnO nanocatalyst and montmorillonite K10 clay were used to facilitate the reaction of substituted benzaldehyde, 2-naphthol, and N-substituted acetamide to determine the optimum reaction conditions. It was found that the yield was significantly higher when using ZnO nanocatalyst under microwave irradiation at 300 W. The percent yields are detailed in Table and the reported % yield was calculated based on the isolated mass of the purified product relative to the theoretical maximum, following completion of the reaction. The data indicate that the reaction was efficient for substituting arylaldehydes with both electron-donating and electron-withdrawing groups, resulting in excellent product yields. Notably, the reactions involving aromatic aldehydes with only electron-withdrawing groups were somewhat faster compared to those with electron-donating groups. The reaction using montmorillonite K10 clay as the catalyst, under similar solvent-free conditions, resulted in a lower % yield compared to the ZnO nanoparticles that occurred. Scheme illustrates the proposed mechanism for synthesizing N-methyl-1-amidoalkyl-2-naphthols catalyzed by ZnO nanoparticles in the reaction of 2-naphthol, substituted aryl aldehydes, and N-methylacetamide. They key steps in the mechanism involve activation of the aryl aldehyde through a Lewis acid interaction with the ZnO surface, which enhances its electrophilicity; subsequent nucleophilic attack by 2-naphthol to form a benzylidene-naphthol intermediate; and finally condensation with N-methylacetamide, facilitated by the ZnO’s surface acidity and polarizability, leading to the formation of the desired N-methyl-1-amidoalkyl-2-naphthol product.

In the case of HNM-1, the starting aldehyde was 3-nitrobenzaldehyde. The reaction yielded a compound containing a 2-naphthol ring, a meta-substituted nitrophenyl group, and an N-methylacetamide moiety. The product features key functional groups such as a hydroxyl group (−OH) on the naphthol ring and a nitro group (−NO2) on the aromatic ring. For HNM-2, the aldehyde used was 4-hydroxy-3-nitrobenzaldehyde, which contains both hydroxyl and nitro substituents on the benzene ring. The product, formed under identical conditions, includes a naphthol unit, an aromatic ring substituted with both OH and NO2 groups, and an N-methylacetamide side chain. These results confirm the successful synthesis of HNM-1 and HNM-2 via an efficient, microwave-assisted method using ZnO nanoparticles as a green catalyst. The synthesized products were identified using 1H NMR, 13C NMR, FTIR and HRMS spectral techniques, and the data were compared with previously reported results.

3.1. Analysis of 1H NMR Data for HNM-1 and HNM-2 Compounds

The 1H NMR spectra (400 MHz, CDCl3) of HNM-1 and HNM-2 (See Figure S1, Supporting Information) display distinct proton resonances consistent with their structural differences. In compound HNM-1, the methine proton resonates at δ 5.98 ppm, which is upfield of the corresponding signal in HNM-2 (δ 6.41 ppm). This deshielding in HNM-2 is likely a consequence of the distinct substitution pattern on its phenyl ring. The hydroxyl protons are observed as singlets at δ 5.70 ppm for the naphthyl group in HNM-1 and at δ 4.70 ppm for the phenyl group in HNM-2, with an additional hydroxyl resonance at δ 5.50 ppm also present in HNM-2. Both compounds exhibit signals for the N-methyl and acetyl methyl groups. In HNM-1, these appear as singlets at δ 2.87 ppm and δ 2.05 ppm, respectively, while in HNM-2 they are slightly shifted to δ 2.80 ppm and δ 2.11 ppm. These minor shifts reflect subtle differences in the local electronic environments. The aromatic regions for both compounds are complex, characterized by overlapping multiplet signals. HNM-1 displays multiplets integrating for 5H at δ 7.18–7.32 ppm and for 6H at δ 7.39–7.96 ppm. In contrast, HNM-2 shows multiplets for 4H at δ 7.10–7.40 ppm and for 6H at δ 7.50–7.97 ppm. The overall similarity in these aromatic profiles, alongside the subtle observed shifts, is consistent with the differing positions of the nitro and hydroxyl substituents. These NMR shifts are in agreement with previously reported data for amidoalkyl-2-naphthol analogues, where hydroxyl and nitro substituents cause characteristic deshielding of the methine and aromatic protons through resonance and inductive effects. , The 1H NMR spectra were recorded on a Bruker Avance III 400 MHz NMR spectrometer.

3.2. Analysis of 13C NMR Data for HNM-1 and HNM-2 Compounds

The 13C NMR spectrum of HNM-1 in CDCl3 (Figure S2 see Supporting Information) reveals key signals at 21.4 and 32.1 ppm, corresponding to the methyl groups in the acetamide and N-methyl groups, respectively. In comparison, the aromatic region (109.54–152.2 ppm) includes signals from the naphthalene and nitrophenyl rings. Carbons near electron-donating groups like hydroxyls appear in the range of 109.54–117.94 ppm, and those influenced by the electron-withdrawing nitro group are in the range of 128.6–152.2 ppm. A highly deshielded signal at 172.0 ppm corresponds to the acetamide carbonyl, and a typical solvent peak for CDCl3 is observed at 77.1 ppm. Similarly, the 13C NMR spectrum of HNM-2 in CDCl3 (see Figure S2b) shows signals at 23.1 and 31.22 ppm for the methyl group (−CH3) in acetamide and the N-methyl group (N–CH3), respectively. The aromatic region (109.54–133.8 ppm) includes carbons from naphthalene and nitrophenyl rings, with signals near hydroxyl groups at 109.54 and 118.94 ppm, while carbons influenced by a nitro group appear at 128.6–133.8 ppm. Highly deshielded carbons, including a hydroxyl-attached carbon in the nitrophenyl ring (151.1 ppm) and a deshielded aromatic carbon near a hydroxyl group (164.0 ppm), are also present. The acetamide carbonyl appears at 170.6 ppm. The solvent peak for CDCl3 appears at 76.2 ppm, indicating a rich variety of environments in both spectra, including aliphatic, aromatic, hydroxylated, and carbonyl carbons. The carbon chemical shifts, particularly the carbonyl signals near 170 ppm and the aromatic carbon resonances between 110 and 150 ppm, are consistent with earlier reports on N-aryl-naphthamide systems and hydroxy-substituted amides. , The 13C NMR was taken using Bruker Avance III 100 MHz NMR spectrometer.

3.3. Analysis of Mass Spectrometry Data for HNM-1 and HNM-2 Compounds

The mass spectrometry data for HNM-1 (C20H18N2O4) and HNM-2 (C20H18N2O5) (Figure S3 see Supporting Information) show excellent agreement between their calculated and experimental molecular masses. For HNM-1, the calculated mass is 350.13 g/mol, with an experimental mass of 350.6016 g/mol, showing a difference of only 0.4716 g/mol, while for HNM-2, the calculated mass is 366.12 g/mol and the experimental mass is 366.6014 g/mol, differing by just 0.4814 g/mol. These minimal discrepancies likely result from instrument precision, isotopic variations, and rounding in the calculations, confirming the accuracy of the mass measurements and supporting the integrity of the molecular structures and compositions of both compounds. The HRMS was analyzed using Agilent 6545 Q-TOF LC/MS system.

3.4. UV–Visible Spectral Analysis HNM-1 and HNM-2 Compounds

The UV–vis spectra for both HNM-1 and HNM-2 (Figure ) exhibit characteristic absorption peaks indicative of π → π* transitions in their respective structures.

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Experimental UV–visible spectra in ethyl acetate of HNM-1 and HNM-2 synthesized compounds.

Table presents the deconvoluted UV–vis optical absorption spectra of HNM-1 and HNM-2, detailing their peak wavelengths (λ), full width at half-maximum (fwhm), intensities of absorption bands, and R 2 values that indicate the goodness of fit for the Lorentzian profiles. HNM-1 exhibits major absorption peaks at shorter wavelengths, ranging from 282.319 to 372.182 nm, while HNM-2 displays red-shifted peaks between 288.843 and 393.129 nm. This shift suggests an extension of conjugation or stronger electronic interactions in HNM-2. The widths of the peaks for HNM-1 are generally narrower, indicating less vibronic coupling, whereas HNM-2 features broader peaks, particularly at 313.815 and 393.129 nm, reflecting enhanced vibronic coupling or more complex interactions within the excited states. Regarding intensity, HNM-1 is dominated by a single transition, with its highest peak observed at 282.319 nm.

2. Results of Deconvoluted UV–Vis Optical Absorption Spectra into Lorentzian Profiles for HNM-1 and HNM-2 Compounds.

compounds parameters (1) (2) (3) (4) (5) R 2
HNM-1 λ (nm) 282.319 317.154 332.584 353.106 372.182 0.9997
fwhm (nm) 40.902 18.564 21.783 12.189 56.530
intensity 131.224 18.968 21.797 3.334 7.658
HNM-2 λ (nm) 288.843 313.815 333.747 365.461 393.129 0.9998
fwhm (nm) 17.756 54.048 13.742 51.884 62.397
intensity 54.298 84.279 6.806 21.406 14.112
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Conversely, HNM-2 has a more balanced intensity distribution, with a prominent peak at 313.815 nm, suggesting a wider array of electronic transitions contributing to its absorption spectrum. Both compounds exhibit high R 2 values (0.9997 for HNM-1 and 0.9998 for HNM-2), confirming the accuracy and reliability of the deconvolution process. These findings highlight significant structural differences between the two compounds, providing valuable insights into their electronic properties and potential applications in photophysical contexts. The observed π → π* and n → π* transition bands between 280 and 395 nm agree well with reported optical absorption data of conjugated naphthol-amide derivatives exhibiting donor–acceptor intramolecular charge transfer. −

3.5. Ground State Optimized Structure of Synthesized Compounds (HNM-1 and HNM-2)

At the first stage of our theoretical study, the structures of HNM-1 and HNM-2 were optimized to find their most favorable molecular conformations. The optimized structures are depicted in Figure . Bond parameters were analyzed and compared with the available data. The structure includes various bond types: N–O, N–C CN, CO, C–H, C–C, and CC. Specifically, the CC bond length in the hydroxyl naphthalene ring is 1.36 Å and the average C–C bond length is 1.42 Å. The average C–C bond length in the nitrophenyl ring is 1.395 Å, while the calculated C–N bond length is calculated to be 1.46 Å, which is shorter than the bond length observed in N-methyl acetamide (4.88 Å). The reduction in bond length is attributed to the presence of two oxygen atoms in the nitrophenyl ring.

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Optimized (a) HNM-1 and (b) HNM-2 geometry structures.

In the substitution of NO2 into nitrophenol, it was observed that the NO2 groups were incorporated at the C1 and C3 positions. The N42 and C3–N30 bonds were found to interact with the adjacent methyl acetamide group. No changes were observed in the nitrophenyl ring or the hydroxyl naphthalene groups. The only significant modification was in the substitution pattern of the nitrophenol.

3.5.1. Frontier Molecular Orbital (FMO) Analysis

Key parameters for the material characterization include electron energy levels, particularly those related to excess carriers. The HOMO–LUMO energy gap is a valuable indicator of both kinetic and low chemical stability. A broad HOMO–LUMO gap suggests significant kinetic stability and low chemical reactivity, as it indicates that adding electrons to the higher-lying LUMO or removing electrons from the lower-lying HOMO is energetically unfavorable. This makes the formation of an activated complex less likely. The HOMO and LUMO levels, which govern molecular reactivity, were used to assess electronic stability. The HOMO and LUMO values for HNM-1 and HNM-2 were found to be −5.97 and −5.95 eV for HOMO and −2.68 and −2.95 eV for LUMO, respectively. The small bandgap energies indicate that both molecules exhibit high reactivity, with bandgap energies of 3.29 and 3.00 eV. The electronegativity and electrophilicity index, which reflect the number of electrons attracted to a molecule, was calculated to be 4.33, 4.55 and 2.23, 1.69 eV. The chemical hardness and softness of molecules were also determined (see Table ). Generally, the HOMO–LUMO descriptors for HNM-1 and HNM-2 are similar, with the maximum difference observed in the electrophilicity index, which is 0.54 eV.

3. Global Descriptors for HNM-1 and HNM-2 Compounds.
derivatives εHOMO (eV) εELUMO (eV) energy gap (eV) ionization potential (IP) electron affinity (EA) chemical hardness chemical potential chemical softness (S) electronegativity (X) electrophilicity index (w)
HNM-1 –5.97 –2.68 3.29 +5.97 +2.68 1.65 –1.65 0.61 4.33 2.23
HNM-2 –5.95 –2.95 3.00 +5.95 +2.95 1.50 –1.50 0.67 4.45 1.69
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Based on the given FMO plots, it appears that the synthesized products consist of a donor/acceptor system, facilitating intramolecular charge transfer. Specifically, the electron-withdrawing groups (EWGs) of nitrobenzene and nitrophenol are identified within the molecular structures of HNM-1 and HNM-2, respectively (See Figure ). The remaining common fragment, N-((2-hydroxynaphthalen-1-yl)­methyl)-N-methylacetamide, is recognized as an electron-donating group (EDG), contributing to the overall charge transfer within the molecules.

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Electronic structure along with the FMOs of (a) HNM-1 and (b) HNM-2.

3.5.2. Density of States (DOS) Analysis

The density of states (DOS) analysis (Figure ), based on the frontier molecular orbitals (FMOs), provides further insights into the electronic properties of HNM-1 and HNM-2. For HNM-1, the DOS plot (Figure a) indicates a significant contribution from the electron-donating fragment around the HOMO, while the electron-withdrawing nitrobenzene group predominantly contributes to the LUMO. This distribution supports the intramolecular charge transfer (ICT) observed in the UV–vis spectrum, with the charge moving from the donor to the acceptor region. In the case of HNM-2 (Figure b), the DOS analysis reveals an even greater separation between the HOMO and LUMO, with the HOMO being primarily localized on the electron-donating N-((2-hydroxynaphthalen-1-yl)­methyl)-N-methylacetamide fragment and the LUMO on the nitrophenol group. The increased electron density in the LUMO of HNM-2 compared to HNM-1, as indicated by the DOS, correlates with the observed red shift in the UV–vis spectrum, further highlighting the enhanced ICT in HNM-2. This enhanced ICT is attributed to the stronger electron-withdrawing nature of the nitrophenol group, which stabilizes the LUMO and lowers the energy gap, resulting in the redshift and increased absorption in the visible region.

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DOS spectra of (a) HNM-1 and (b) HNM-2.

3.5.3. Mulliken Population Analysis

Mulliken population analysis is used to characterize the electronic charge distribution within a molecule, which is crucial for understanding molecular substitutions and advancing drug discovery. In this study, nitrogen and oxygen atoms are found to have more negative charges, ranging from −0.39 to −0.4 a.u, while nitrogen bonded with oxygen exhibited a positive charge. Additionally, the C13 and C14 atoms were found to be more positively charged, likely due to their proximity to the electron-accepting nitro group. The molecular charge distribution is illustrated in Figure .

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Mulliken charge distribution of 2-naphthol derivatives (a) HNM-1 and (b) HNM-2.

3.5.4. Molecular Electrostatic Potential (MEP) Analysis

The molecular electrostatic potential (MEP) represents the energy of interaction between the charge distribution of a molecule and a unit positive charge. In MEP maps (Figure ), different colors reflect the electrostatic potentials at the surface.

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MEP maps of 2-naphthol derivatives (a) HNM-1 and (b) HNM-2.

In this study, MEP maps and contour plots were generated using DFT with the B3LYP/6–31G­(d)­level. These maps were used to analyze the electro- or nucleophilic properties and physiochemical characteristics of the molecules, as well as to evaluate their potential for drug modeling.

Figure a,b show the MEP maps and contour plots for the target molecule. In these figures, red indicates regions of electron enrichment, blue denotes electron deficiency, yellow represents slight electron enrichment, and green corresponds to zero potential. The color contour in the MEP maps highlights the negative (electrophilic) regions, which are predominantly located around the oxygen and nitrogen atoms. Conversely, the positive (nucleophilic) region is concentrated over a hydrogen atom, indicating that hydrogen atoms exhibit the strongest attraction, while nitrogen and oxygen atoms show the greatest repulsion. Additionally, the plotted electron density for the entire molecular system displays a relatively homogeneous distribution.

3.5.5. DFT Simulated Infrared and Raman Spectra of HNM-1 and HNM-2

FTIR spectroscopy is extensively used for both qualitative and quantitative analysis by examining vibrational transitions in molecules. This technique is effective for identifying functional groups in organic and inorganic substances, as different functional groups absorb in distinct frequency ranges. The simulated infrared spectra reveal characteristic vibrational modes, which provide insights into the molecular bonding and structure of HNM-1 and HNM-2. Peaks in the infrared spectra correspond to various vibrational transitions, offering valuable information about the functional groups and molecular interactions within the compounds. Similarly, the Raman spectra highlight different vibrational modes that are sensitive to changes in the molecular environment. The analysis of these spectra helps in understanding the molecular dynamics and confirming the theoretical models of HNM-1 and HNM-2. The correlation between simulated and experimental spectra can further validate the accuracy of the DFT calculations and enhance our interpretation of the molecular properties. Additionally, both molecules exhibit vibrational energy; with sharp peaks observed between 4000 and 400 cm–1. Each molecule has 126 vibrational modes, categorized into stretching and bending modes, corresponding to the functional groups present in the molecules. The infrared and Raman spectra (Figure ) of HNM-1 and HNM-2 were simulated using the DFT/B3LYP/6-31G­(d,p) level of theory.

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Theoretical FTIR spectra of 2-naphthol derivatives (a) HNM-1 and (b) HNM-2.

3.5.5.1. Vibrations of the O–H Group

The stretching frequency of the O–H group is typically observed within a broad range from 3700 to 3100 cm–1. Specifically, the vibrations of a free hydroxyl group are found in the narrower range of 3600–3500 cm–1.

3.5.5.2. Vibrations of the C–H Group

The stretching frequencies for the C–H group generally occur between 3100 and 3000 cm–1, appearing as broadband. In this study, the C–H vibrations for HNM-1 and HNM-2 were detected in the range of 3100 to 3050 cm–1.

3.5.5.3. Vibrations of the CO Group

The IR stretching peak of the CO in carbonyl compounds typically appears around 1700 cm–1. However, the exact position of this peak can vary depending on the specific type of carbonyl functional group (such as carboxylic acid, ester, aldehyde, or ketone), and the surrounding chemical environment of the CO double bond. For the substances investigated in this study, the absorption band for the CO bond is observed in the range of 1650 to 1700 cm–1.

3.5.5.4. Vibrations of the CC Group

The stretching modes of the carbon–carbon bonds in a benzene ring generally occur between 1650 and 1200 cm–1. In this work, the vibrations of the carbon–carbon bonds in the aromatic ring were detected within the range of 1650 to 1400 cm–1.

3.5.5.5. Vibrations of the N–O Group

The asymmetric and symmetric stretching vibrations of the N–O bond typically appear around 1550–1450 cm–1 and 1360–1290 cm–1, respectively. In this work, the absorption bands for the N–O group in the investigated molecules were found within these ranges.

3.5.5.6. Vibrations of the C–N Group

The stretching mode of the C–N bond is often associated with the C–O deformation and significantly contributes to the Raman band observed around 1260–1250 cm–1. This finding is consistent with the results obtained in our study.

3.6. TD-DFT Predicted UV–Vis Spectra of HNM-1 and HNM-2 Synthesized Compounds

Ultraviolet–visible (UV–vis) spectroscopy, on the other hand, offers various methods for structure determination and monitoring of reactions in different compounds. It involves analyzing the interaction between a light source and a sample through absorption, transmission, or reflection in the UV–visible spectral range. , The TD-DFT//B3LYP/6-311 g­(d,p) simulated spectra for both compounds in ethyl acetate solvent (Figure ) provide further insights, revealing at least three distinctive absorption bands for HNM-1 at 229, 280, and 309 nm, while HNM-2 displays bands at 230 nm, 280 nm, 309 nm, and a new peak at 379 nm, which is probably associated with intramolecular charge transfer (ICT) within the HNM-2 molecule. This comprehensive analysis of the UV–vis spectra highlights the electronic transitions within both compounds, emphasizing their structural similarities and differences.

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Simulated UV–visible spectra in ethyl acetate of (a) HNM-1 and (b) HNM-2.

3.7. Topological QTAIM Analyses

The Quantum Theory of Atoms in Molecules (QTAIM), developed by Richard Bader, provides a robust framework for analyzing various intra- and intermolecular interactions within a compound. − This method focuses on identifying bond critical points (BCPs), which are pivotal in understanding bonding characteristics. At these BCPs, several critical topological parameters can be determined, including:

  • Electron Density (ρ­(r)): Represents the distribution of electrons at a specific point.

  • Laplacian of Electron Density (∇2ρ­(r)): Indicates the curvature of the electron density distribution.

  • Lagrangian Kinetic Energy Density (G(r)): Measures the kinetic energy associated with electron density.

  • Potential Energy Density (V(r)): Reflects the potential energy at a given point.

  • Ellipticity of Electron Density (ε­(r)): Describes the anisotropy of the electron density distribution.

  • Interaction Energy (E(r) = V(r)/2): Provides insight into the energy associated with the interaction at the BCPs.

These parameters collectively offer a comprehensive view of the electronic environment within the molecule, facilitating a deeper understanding of its bonding and interaction characteristics. Based on these topologic parameters, we can discern the nature of interactions of the bonds and provide insights into charge concentration or depletion at each bond critical point (BCP). The NCI extension of QTAIM offers a clear color-coded representation of interaction types: blue indicates hydrogen-bonding interactions, green corresponds to van der Waals forces, and steric effects in the active region signify neutral charges. Figure presents the QTAIM-NCI plots, while Table summarizes the selected Topological QTAIM graphs.

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QTAIM/NCI plots of the studied systems (HNM-1 (a, b); HNM-2 (c, d)).

4. Selected Topological Parameters Were Calculated for the Active Bonding (BCPs).

  BCPs ρ( r ) ∇ 2 ρ( r ) G ( r ) G(r)/ρ(r) V ( r ) ε( r ) E int (kJ/mol)
HNM-1 1 0.0085 0.0286 0.0058 0.68 –0.0045 0.48 –5.90
2 0.0230 0.0943 0.0205 0.89 –0.0174 0.84 –22.84
3 0.0409 0.1290 0.0346 0.84 –0.0370 0.05 –48.57
4 0.0177 0.0704 0.0152 0.70 –0.0128 1.22 –16.80
5 0.0117 0.0383 0.0080 0.68 –0.0066 0.12 –8.66
HNM-2 1 0.0462 0.1438 0.0401 0.86 –0.0444 0.02 –58.28
2 0.0085 0.0285 0.0058 0.68 –0.0045 0.44 –59.07
3 0.0120 0.0390 0.0082 0.68 –0.0068 0.07 –8.92
4 0.0229 0.0938 0.0204 0.89 –0.0173 0.87 –22.57
5 0.0412 0.1295 0.0348 0.84 –0.0373 0.05 –47.25
6 0.0176 0.0703 0.0152 0.86 –0.0128 1.20 –16.80
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In the analysis, HNM-1 demonstrated a notably higher positive electron density-to-Laplacian ratio at BCP2 and BCP3. Specifically, the values of approximately 0.0230 au/0.0943 au and 0.0409 au/0.1290 au, respectively. This indicates a significant concentration of electron density and a corresponding decrease in the Laplacian at these points. This observation suggests the presence of noncovalent interactions between oxygen and hydrogen atoms. These interactions exhibit binding energies of −22.84 and −48.57 kJ/mol, indicating a significant degree of stability. The ellipticity of electron density supports this finding, with low values of 0.84 au and 0.05 au Furthermore, the ratio of Lagrangian kinetic energy density to electron density (G(r)/ρ­(r)) is less than unity, which further confirms the presence of noncovalent interactions within the compound. The NCI index reveals a blue spot between the oxygen and hydrogen atoms, indicating the formation of hydrogen bonds that contribute to the stability of the studied material. Additionally, green regions observed between the groups in the newly synthesized compound suggest stabilization through Vander Waals forces, with interaction energies of −5.90, −8.66, and −16.80 kJ/mol, respectively.

For the HNM-2 molecule, the positive and elevated electron density ratio of electron density to the Laplacian of electron density (ρ­(r)/∇2ρ­(r)) ranges from 0.0085 au/0.0285 au at BCP2 to 0.0462 au/0.1438 au at BCP1. These values indicate a significant electronic density in the surface region of the compound, suggesting strong noncovalent interactions among the functional groups, which enhance the overall stability of the molecule. These findings suggest the potential for significant electronic charge transfer (ECT) within the compound, which could be associated with its prospective biological activities. The system is characterized by three substantial interaction energies: −58.28 kJ/mol (BCP1), −59.07 kJ/mol (BCP2), and −47.25 kJ/mol (BCP3). These energies, resulting from interactions between oxygen, hydrogen, and carbon atoms, significantly enhance the stability of this molecule. This conclusion is supported by the low ellipticity value ε­(r) observed in these active regions. Additionally, the ratio of G(r)/ρ­(r) being less than unity further indicates the presence of noncovalent interactions among the molecular groups, contributing to stability. The NCI index reveals two blue spots between the O and H atoms, signifying hydrogen-bonding interactions. The green regions observed between other groups indicate the presence of Vander Waals forces. Overall, QTAIM and NCI analyses confirm that the newly synthesized materials are robustly stabilized through both hydrogen-bonding and Vander Waals interactions.

3.8. ELF and LOL Analyses

The Electron Localization Function (ELF) and Localized Orbital Locator (LOL) are advanced techniques used to analyze localized, nonlocalized electron distributions, as well as lone-pair regions within compounds. , The ELF and LOL iso-surfaces are derived from electron pair density and localized orbital gradients, respectively. , These methodologies are particularly effective for quantifying the biological activities of the studied systems, providing valuable insights into their electronic properties. These analyses (see Figure ) provide significant insights into the electronic properties of our materials. The color-code mapping is as follows: red indicates bonding and nonbonding electrons, while blue represents delocalized electrons. The values for the ELF range from 0 to 1, and the LOL, range is 0 to 0.8. Both ELF and LOL offer comparable chemical mappings, as they are based on kinetic energy density. The 2D-ELF and 2D-LOL plots are illustrated in Figure . In the analysis of HNM-1, red regions are observed around H27, C35–C31, C35–C36, H42, C2, and O43, indicating a high localization of both bonding and nonbonding electrons in these areas, with an ELF value reaching up to 1. Additionally, blue areas surrounding C1, C35, C31, N41, C23, and C33–C37 signify the presence of delocalized electrons. This observation is reinforced by the LOL iso-surfaces, suggesting significant electronic charge transfer (ECT) occurring between groups on the compound’s surface, which could make it a promising candidate for biological applications.

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2D electron localization function (ELF) and localized orbital locator (LOL) maps for molecules HNM-1 (a,b) and HNM-2 (c,d).

For HNM-2, red spots are found around H27, H42, O42, C1–C2, C31–C35, and C35–C36, indicating regions with high localization of no-bonding electrons, while blue regions surrounding N41, C1, C35, C31, and C33–C37 point to delocalized electron clouds. This distribution suggests that the surface of HNM-2 has highly active regions that might enhance its biological activity. The 2D-ELF and 2D-LOL analyses further support the conclusion that both materials have the potential for biological activity.

Although microwave-assisted and ZnO-catalyzed syntheses of 1-amidoalkyl-2-naphthols are well-documented, , the present study advances this chemistry through the rational design of N-methyl-substituted analogs (HNM-1 and HNM-2) bearing nitrophenyl and hydroxynitrophenyl groups. These substitution patterns modulate intramolecular charge transfer and narrow the HOMO–LUMO gaps (3.29 and 3.00 eV) relative to typical amidoalkyl-2-naphthol derivatives (>3.5 eV). The integration of DFT/TD-DFT, QTAIM, and ELF/LOL analyses further elucidates electronic delocalization and donor–acceptor interactions not previously reported for this scaffold. Thus, while the synthetic route is established, the present work provides new insight into how substitution and nanocatalytic control govern the electronic and potential bioactive behavior of these compounds.

3.9. Molecular Docking Analysis

Molecular docking analysis was conducted to evaluate the interaction of the ligands with the target protein molecule. Both ligands were docked with the SARS-CoV-2 protein (7U0N), and the interactions between the ligands and the protein were found to be efficient. The protein structure was obtained from the Protein Data Bank and Pass online prediction, and the optimized structure was used for the docking process. Autodock 2 docking tools facilitated the binding of the protein and ligand, with the active sites determined using the grid box and the Autogrid method. The docking interactions were visualized and analyzed using PyMOL software. As shown in the docking results (Figure ), the HNM-2 molecule formed a single hydrogen bond with the Asparagine-322 residue at 2.4 Å, while the HNM-1 molecule established five hydrogen bonds with leucine, lysine, and glycine residues (see Table ), suggesting a stronger binding affinity for HNM-1. The binding affinities obtained from the docking study were −6.2 kcal/mol for HNM-2 and −7.0 kcal/mol for HNM-1, indicating that HNM-1 exhibit notable potential activity against the 7U0N protein. Based on these findings and in comparison with reported studies, the synthesized compounds represent promising novel inhibitors of SARS-CoV-2, warranting further investigation for potential therapeutic applications. −

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Molecular docking analysis of 2-naphthol derivatives (a) HNM-1 and (b) HNM-2.

5. Molecular Docking Data for the Investigated Ligands with Targeted Protein.

protein (PDB ID) ligand bonded residues hydrogen bond no. bond length, Å
7U0N HNM-1 LEU-351 1 2.5
LYS-403 1 2.1
GLN-409 3 1.9/2.4/2.2
HNM-2 ASN-322 1 2.4
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4. Conclusions

In this work, we have established a green, efficient, and environmentally benign strategy for the synthesis of functionalized 1-amidoalkyl-2-naphthol derivatives (HNM-1 and HNM-2) through a ZnO-mediated, microwave-assisted, solvent-free protocol. The methodology demonstrates notable advantages over conventional approaches, including shorter reaction times, higher yields, and the use of recyclable nanocatalysts, thereby highlighting its practical and sustainable value. Comprehensive spectroscopic analyses confirmed the molecular structures of the synthesized compounds, ensuring the reliability of the synthetic outcomes.

Quantum chemical investigations using Density Functional Theory (DFT) at the B3LYP/6-311G­(d,p) level revealed moderate HOMO–LUMO gaps, pronounced intramolecular charge transfer, and significant chemical hardness, indicative of both thermodynamic stability and potential for electronic tunability. Topological and real-space analyses, including QTAIM, NCI, ELF, and LOL, further elucidated a rich network of noncovalent interactions, such as hydrogen-bonding and van der Waals forces, which reinforce molecular stabilization and conformational integrity.

Molecular docking studies highlighted the biological relevance of these derivatives, revealing submicromolar binding affinities toward the SARS-CoV-2 main protease. Specifically, HNM-1 engaged multiple critical catalytic residues, whereas HNM-2 displayed a distinct, strategically positioned interaction within the active site, suggesting complementary modes of engagement with potential therapeutic significance.

Overall, this study demonstrates that ZnO-mediated, microwave-assisted synthesis provides a versatile and sustainable platform for generating electronically and structurally diverse 2-naphthol derivatives. The HNM-type compounds reported herein present promising scaffolds for further optimization in antiviral drug discovery, particularly as potential leads targeting SARS-CoV-2, bridging synthetic chemistry with computational insights and biological applications.

Supplementary Material

ao5c08549_si_001.pdf (540.4KB, pdf)

Acknowledgments

The authors extend their sincere appreciation to the Ministry of Higher Education and Scientific Research (MHESR) in Tunisia for the technical and financial support provided for this study based on an agreement between (MHESR) in Tunisia and the American Chemical Society (ACS).

All data supporting the findings of this study are available within the article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.5c08549.

  • Detailed experimental data, including the proton and carbon-13 nuclear magnetic resonance (1H and 13C NMR) chemical shifts (in ppm) (Bruker Avance III 400 MHz for 1H and 100 MHz for 13C NMR) and high-resolution mass spectra (Agilent 6545 Q-TOF LC/MS system) for both synthesized compounds, HNM-1 and HNM-2 (PDF)

A.D.A.: investigation, writing-original draft, and formal analysis. P.V.: investigation and writing-original draft. K.S.S.: visualization, validation, investigation, writing-original draft, and writing-review and editing. F.P.: writing-review and editing, writing-original draft, visualization, and validation. A.S.K.: visualization, validation, investigation, writing-original draft, and writing-review and editing. B.G.: methodology, software, investigation, and writing-original draft. M.B.: visualization, validation, and writing-review and editing. S.A.: investigation, methodology, conceptualization, software, writing-review and editing, visualization, and validation.

The authors declare no competing financial interest.

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Supplementary Materials

ao5c08549_si_001.pdf (540.4KB, pdf)

Data Availability Statement

All data supporting the findings of this study are available within the article and its Supporting Information.

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