Spectroscopic Investigation of Charge Transfer Interaction Between Five Antibiotics Depending on Density Functional Theory

The charge transfer complex of drugs is an important means to study the binding mechanism of drugs and receptors. In this study, the ground state structure and CT transition of the complex formed by the reaction of hydrogen peroxide (H₂O₂) with the five antibiotics (TMP, NOR, OFL, CIP, and SMR) were theoretically investigated by density functional theory (DFT). Excitations at 247.3 and 212.5 nm (f = 0.139 and f = 0.097) for H₂O₂-TMP, 280.2 and 239.2 nm (f = 0.142 and f = 0.358) for H₂O₂-NOR, 254.5 and 239.5 nm (f = 0.887 and f = 0.365) for H₂O₂-CIP, 285.2, 268.2, and 254.5 nm (f = 0.177, 0.832, and 0.226) for H₂O₂-OFL, and 241.3, 205.5, and 193.6 nm (f = 0.289, 0.318, and 0.169) for H₂O₂-SMR complex played a key role in the formation of UV-Vis spectra. HOMO and LUMO energies indicated calculation of molecular and atomic properties and shown CT occurrence in molecules. The synthesized CT complexes were characterized using various spectral techniques, including UV-Vis spectroscopy, IR spectroscopy and ¹H NMR spectroscopy, and the bonding sites between the H₂O₂ and antibiotics were identified. These theoretical calculation results provide a scientific basis for experimental validation.

Stable charge transfer (CT) complexes of receptors reacting with drugs or biological compounds have received significant attention. This interest originated from the important physical and chemical properties of these complexes (1–5). Charge-transfer complexes play a crucial role in molecular systems and have become a focus of researchers due to their significance in chemistry and biochemistry (5–7). The study of CT complexes of drugs is helpful to understanding the interaction between drugs and receptors and the mechanism of action of drugs (8–10). Furthermore, CT interactions are important in several fields, including biological systems, drug receptor binding mechanisms, surface science, and solar energy storage (11–15).

With the widespread use of pesticides, the residual problem of pesticides in the environment has become a major concern for environmental scientists, especially its pollution of water sources, which may pose potential risks to human drinking water. Antibiotics are widely used in clinical medicine, veterinary animal husbandry, and agriculture as effective herbicides (16,17). Studies have shown that TMP is difficult to biodegrade, trimethoprim easily accumulates in ecosystems, adversely affecting aquatic organisms and sometimes leading to chronic toxicity (18–22).

Density functional theory (DFT) method is one of the most effective tools for predicting CT interactions, molecular structure, and intramolecular hydrogen bond interactions (23–25). Additionally, HOMO and LUMO calculations can provide valuable insights into charge transfer within molecules (26,27). In the literature, molecular pairs formed by intermolecular CT complexes have been extensively studied using DFT method (28–31).The purpose of this work is to investigate the CT interaction between H₂O₂ and five antibiotic (TMP, CIP, NOR, OFL, and SMR) using density functional theory.

Experimental and Theoretical Details

Materials and Equipment

Hydrogen peroxide was obtained by Sigma-Aldrich Chemical Co. (TMP; C₁₄H₁₈N₄O₃; 290.32), Ofloxacin (OFL; C₁₈H₂₀FN₃O₄·1/2H₂O), Sulfamerazine (SMR; C₁₁H₁₂N₄O₂S), Ciprofloxacin (CIP; C₁₇H₁₈FN₃O₃), Norfloxacin (NOR; C₁₆H₁₈FN₃O₃) were purchased by Sigma-Aldrich with a stated purity greater than ≥98% (HPLC).

Computational Details

All computational studies were carried out on personal computers using density functional theory (DFT) at the Becke-Lee-Yang-Parr (B3LYP) level with the standard 6-31G* basis set via the Gaussian 09 package 18 (30,31). DFT/B3LYP was used to calculate the structure and vibration assignments of the antibiotics-H₂O₂ complex in the ground state, time-dependent density functional theory (TD-DFT) calculations were performed using the Integral Equation Formalism Polarizable Continuum Model (IEFPCM) solvation model with methanol as the solvent. The theoretical coordinates of the complex were generated using Gaussian view, which was also used to visualize the output files.

Results and Discussion

Geometric Parameters and Spectral Characteristics

The geometry of the hydrogen peroxide/five antibiotics complex was optimized under gas-phase conditions, as shown in Figure 1. The geometry of a molecule depends on the balance of Coulombic attraction and repulsion between the charged particles in the molecule, including both nuclei and electrons, resulting in a minimum energy point on the potential energy surface. The lowest energy binding site for hydrogen peroxide was found to be the oxygen-containing functional groups of the antibiotics, such as carboxyl and amino groups (32–34).

Figure 1: Optimized ground state geometric structure of the (a) H₂O₂-TMP, (b) H₂O₂-NOR, (c) H₂O₂-CIP, (d) H₂O₂-OFL, and (e) H₂O₂-SMR) in the gas phase.

In addition, the theoretical absorption spectrum of the obtained complex was derived and the calculation of scaling factor was 0.96. The accurate absorption wavelength of the five complex systems was detected using the TDDFT method at a relatively small computing time (Tables S1-S5). Five tables indicated the electronic leaps, vibronic strengths and their energies calculated at specific wavelengths based on the ground state geometry. The peak maximum for the H₂O₂-TMP, H₂O₂-NOR, H₂O₂-CIP, H₂O₂-OFL, and H₂O₂-SMR complexes were observed at 247, 239, 254, 268, and 205 nm, respectively.

Several excited states were calculated for the studied complexes. For the H₂O₂-TMP complex, 237.5 and 225.7 nm have very little values of (f) and do not contribute significantly to the formation of the UV-Vis spectrum of the complex (Table S1). Only excitations at 247.3 and 212.5 nm (f = 0.139 and f = 0.097) play role in formation of the UV-Vis spectrum of the complex. Similarly, 289.1, 247.2 and 209.9 nm have very little values of (f)in the H₂O₂-NOR complex, and do not play role in the formation of the UV-Vis spectrum of the complex (Table S2). Excitations at 280.2 and 239.2 nm (f = 0.142 and f = 0.358) play a vital role in formation of the UV-Vis spectrum of the complex. For the H₂O₂-CIP complex, 289.7, 247.3,209.9 and 201.7 nm have very little values of f and cannot play role in the formation of the UV-Vis spectrum of the complex (Table S3). Excitations at 254.5 and 239.5 nm (f = 0.887 and f = 0.365) play an important role in formation of the UV-Vis spectrum of the complex. For the H₂O₂-OFL complex, 246.5, 210.9, and 201.1 nm have very little values of f and cannot play a role in the formation of the UV-Vis spectrum of the complex (Table S4). Excitations at 285.2, 268.2, and 254.5 nm (f = 0.177, 0.832, and 0.226) play a pivotal role in the formation of the UV-Vis spectrum of the complex. For the H₂O₂-SMR complex, 225.5, 214.6, and 192.6 nm have very little values of f and cannot play a role in the formation of the UV-Vis spectrum of the complex (Table S5). Excitations at 241.3, 205.5, and 193.6 nm (f = 0.289, 0.318, and 0.169) play a pivotal role in the formation of the UV-Vis spectrum of the complex.

Energy Calculation

As shown in Figure 2, a LUMO-HOMO analysis of the hydrogen peroxide/five antibiotic complexes was performed. The results of the wave function indicated that the LUMO-HOMO value of the H₂O₂-TMP complex was calculated as HOMO energy = -5.85 eV, LUMO energy = -0.49 eV, and LUMO-HOMO gap = 5.85 eV (Figure 2a). The LUMO-HOMO value of the H₂O₂-NOR complex was calculated as HOMO energy = -5.82 eV, LUMO energy = -1.39 eV, and LUMO-HOMO gap = 4.43 eV (Figure 2b). The LUMO-HOMO value of the H₂O₂-CIP complex was calculated as HOMO energy =-5.81 eV, LUMO energy = -1.39 eV, and LUMO-HOMO gap = 4.42 eV (Figure 2c). The LUMO-HOMO value of the H₂O₂-OFL complex was calculated as HOMO energy = -5.56 eV, LUMO energy = -1.36 eV, and LUMO-HOMO gap = 4.20 eV (Figure 2d). The LUMO-HOMO value of the H₂O₂-SMR complex was calculated as HOMO energy = -5.98 eV, LUMO energy = -1.27 eV, and LUMO-HOMO gap = 4.71 eV (Figure 2e).

Figure 2: HOMO and LUMO plot of the (a) H₂O₂-NOR, (b) H₂O₂-OFL, (c) H₂O₂-SMR (d) H₂O₂-NOR, (e) H₂O₂-OFL, and (f) H₂O₂-SMR complexes.

The molecular orbitals indicated that H₂O₂-NOR and H₂O₂-CIP have essentially the same HOMO, LUMO, and LUMO-HOMO gap values due to their similar molecular structures. Furthermore, the electron densities of the five complexes were primarily concentrated on the benzene ring of antibiotics, particularly around carboxyl, hydroxyl, and nitro groups. The chemical reactivity and kinetic stability of the molecules can be determined by the front orbital gap. It was observed that the LUMO-HOMO gap of H₂O₂-OFL was minimal, indicating that it had high chemical reactivity (35-37).

Mulliken Analysis

Mulliken analysis provides an effective method for studying inter-bonding interactions as well as intra- and intermolecular bonding (38). The Mulliken atomic charge calculation results of hydrogen peroxide/five antibiotic complexes are shown in Figure 3. The charge distribution in the H₂O₂-TMP complex ranges from -0.820 in N17 to 0.636 in C2. The charge distribution in the H₂O₂-NOR complex ranges from s from -0.629 in O21 to 0.573 in C20. The charge in the H₂O₂-CIP complex studied changes from -0.628 in O20 to 0.573 in C19. The charge in the H₂O₂-OFL complex studied changes from -0.630 in O11 to 0.574 in C10. The charge in the H₂O₂-SMR complex studied changes from -0.614 in O1 to 1.238 in S2. It was clear that the distribution of atomic charges of the five complex species was closely related to their mechanism. Oxygen atoms exhibited a negative charge, while carbon (C) and sulfur (S) atoms positively charged. The dispersion of electron density between non-Lewis NBO orbitals and occupied Lewis NBO orbitals corresponds to stable donor-acceptor interactions (39). This approach provides a convenient basis for studying conjugate interactions or charge transfer interactions in molecular systems.

Figure 3: Mulliken’s atomic charges of (a) H₂O₂-TMP, (b) H₂O₂-NOR, (c) H₂O₂-CIP, (d )H₂O₂-OFL, and (e) H₂O₂-SMR complexes.

Spectra Analysis

The electronic absorption spectrum of the CT complexes formed from the reaction of the NOR, OFL, and SMR acceptors (5.0 × 10⁻³ M) and the H₂O₂ (5.0 ×10⁻³ M) in methanol were observed in the region of 200–600 nm and are displayed in Figure 4a,4b, and 4c. These bands were observed at 275, 282 and 268 nm for the H₂O₂-NOR, H₂O₂-OFL, and H₂O₂-SMR complexes, respectively. The IR absorption spectra of the H₂O₂-NOR, H₂O₂-OFL, and H₂O₂-SMR complexes were registered in the frequency range of 4000–400 cm^-1 using KBr discs. The IR spectra of these complexes were characterized by a broad, strong-to-medium band appearing at 2720–2880 cm^-1, which is absent in the spectra of the free H₂O₂ donor or the NOR, OFL, and SMR acceptors.Common aromatic nitro compounds exhibit strong absorption bands in the 1625–1540 and 1200–1460 cm^-1 ranges due to asymmetric and symmetric vibrations of the nitro group, respectively. In the H₂O₂-NOR, H₂O₂-OFL, and H₂O₂-SMR complexes, these bands exhibit at 1570–1485 and 1370–1320 cm⁻¹, respectively. Carboxylic acids show bands in the region 1680-1715 cm^-1 due to C=O stretching. The intensity of this band can increase due to conjugation or hydrogen bond formation. The carboxylate C-O stretching mode is observed as an intermediate band at 1620 cm^-1 in the IR spectrum of the complex. The moderate band observed near 3279 cm^-1 was attributed to the O-H stretching mode of the carboxyl group (39,40).

Figure 4: Experimental absorption spectrum of the (a) H₂O₂-NOR, (b) H₂O₂-OFL, and (c) H₂O₂-SMR complexes. Experimental IR spectrum of the (d) H₂O₂-NOR, (e) H₂O₂-OFL, and (f) H₂O₂-SMR complexes.

The ¹H NMR chemical shifts were calculated using the Gauge-Independent Atomic Orbital method at the B3LYP/6-31G* level in methanol solvent, consistent with experimental conditions. NMR spectroscopy was a useful technique for collecting chemical information. NMR spectroscopy was very sensitive to any change in molecular structure. The obtained NMR spectra provide insights into the interaction modes between H₂O₂ and the antibiotics NOR, OFL, and SMR. The signals in the 1-5 ppm range correspond to CH, CH₂, and CH₃ groups in the H₂O₂-NOR, H₂O₂-OFL, and H₂O₂-SMR complexes (Figure 5). The appearance of a characteristic broad band at 5–10( ppm), attributed to the formation of (+NH), indicates the involvement of the N (1) atom of donor (NOR, OFL, SMR) and the (–OH) group of H₂O₂ acceptor in chelation, facilitated by deprotonation from the donor to the acceptor.

Figure 5: ¹H NMR spectra of the (a) H₂O₂-NOR, (b) H₂O₂-OFL, and (c) H₂O₂-SMR complexes.

Conclusion

In this work, the geometric structures of the H₂O₂-TMP, H₂O₂-NOR, H₂O₂-CIP, H₂O₂-OFL, and H₂O₂-SMR complexes have been studied by means of computational methods. The theoretical studies have revealed the existence of charge transfer transitions in the five complexes. The electron spectra of the compounds were determined and the important molecular orbitals of the compounds were determined by TD-DFT method. The electron density in HOMO was mainly concentrated on the benzene ring, particularly around the hydroxyl group and the two nitro groups, while the electron density in LUMO was mainly concentrated on the entire benzene ring. The calculated LUMO-HOMO orbital energy can be used to estimate molecular hardness, ionization energy, and other physical parameters. The synthesized CT complexes were characterized using various spectroscopic techniques including UV–Vis, IR, and ¹H NMR spectroscopy.

Competing Interest

The authors have no relevant financial or non-financial interests to disclose.

Author Contributions

All authors contributed to the study conception and design. The first draft of the manuscript was written by Hui Wang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Funding

This work was by Shanghai Municipal Education Commission Project for Teacher’s Professional Development; Shanghai Private Education Development FoundationProject for Teacher’s Professional Development.

Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Hui Wang and Meng Ye are with the School of Health Science and Nursing at Shanghai Sipo Polytechnic, in Shanghai, China. Wang, Siyamak Shahab, and Fulei Shang are with the International Sakharov Environmental Institute of Belarusian State University, in Minsk, Belarus. Shahab is also with the Institute of Physicаl Organic Chemistry at the National Аcаdemy of Sciences of Belаrus, in Minsk, Belarus. Haoliang Wang is with the College of Marine Technology and Environment at Dalian Ocean University, in Dalian, China. Direct correspondence to Hui Wang at wanghui@iseu.by, Siyamak Shahab at siyamakshahab@mail.ru or Meng Ye at 295132911@qq.com