Cluster formation between an oxadiazole derivative with metal nanoclusters (Ag/Au/Cu), graphene quantum dot sheets, SERS studies, and solvent effects

Interaction of an oxadiazole derivative, 5-(3,4-dimethoxyphenyl)-3-(3-methoxyphenyl)-1,2,4-oxadiazole (DPMO) with Ag/Au/Cu and graphene quantum dots with different solvents, is reported theoretically. The adsorption energy is maximum for the Cu6 cluster and minimum for the Ag6 cluster. The asymmetric charge redistribution between DPMO and M6s produces an improvement in dipole moment values. The decrease in energy gaps of complexes increased conductivity and metal clusters can be used as a drug sensor. The solvation energies are more negative in solvent media than in the gaseous media, indicating an enhancement in the solvent medium’s stability. Wave function studies show that there exist significant noncovalent interactions between metal clusters and oxadiazole that facilitate cluster formation. DPMO is found to form stable clusters with graphene which is evident from the enhancement of Raman activity of the system through SERS also enabling it for sensing DPMO in a mixture.


Introduction
One of the most fascinating fields of research is heterocyclic chemistry. Due to their intriguing biological actions, thiazoles, thiadiazoles, indoles, and oxadiazoles are among the most important heterocyclic compounds [1]. New infectious diseases have evolved in recent decades, while formerly treated diseases have resurfaced [2]. Despite the urgent need for novel antimicrobial medicines, progress on these agents is slowing [3]. Oxadiazoles have many properties, like antiviral, antibacterial, anti-neoplastic, antioxidant, antifungal, inhibitors of tyrosinase, and cathepsin K [4][5][6][7][8][9][10]. Oxadiazole can also significantly contribute to boosting pharmacological activity [11]. Zibotentan, an important anticancer drug, and nesapidil, as an antihypertensive agent, are two of the commercially available medicines having the oxadiazole molecule [12,13]. Oxadiazole derivatives are used in a variety of industries, including fluorescent materials, electro-optical devices, and high-performance materials in the polymer industry [14][15][16][17]. Xu et al. reported a biological evaluation of oxadiazole acetamide moiety as a novel linker [18]. Chortani et al. reported theoretical studies of oxadiazole linked with benzoypyrimidinones [19]. Synthesis and computational studies of three oxadiazoles are reported by Hamdani et al. [20]. Researchers have studied different oxadiazole derivatives as corrosion inhibitors [21]. Some methoxyphenyl compounds are photosensitizers that are frequently employed in biochemistry, medical therapies, cell, and sensor research [22][23][24]. Oxadiazole was widely employed as a preferred scaffold in drug development [25][26][27]. It was frequently utilized as bioisosteres for carbonyl-containing compound drugs interacting with receptors via hydrogen bonding interactions [28,29].
Cu, Ag, and Au, the coinage metals of group XI, have rich coordination chemistry as potent reagents [55,56]. Unlike their silver analogs, derivatives of copper and gold are known as the most active complexes in catalysis, allowing for the use of organo-metallic entities in catalysis and material research [57]. Silver derivatives on the other hand are the most widely used metal-based drugs in a variety of biological applications [58]. Kleinhans et al. reported photophysical effects of T-shaped coinage metal complexes [59]. Coinage metals with a lower oxidation state have been the subject of research into their usage in OLEDs [60]. In the field of coordination chemistry, complexes containing nitrogen donor atoms and coinage metals are commonly encountered protagonists. These compounds are intriguing not only because of their many structural motifs, but also because many investigations on the potential application of these materials have already been completed, demonstrating their versatility [61][62][63]. A large variety of luminous coinage metal complexes have been reported in the literature [64]. Interaction of 5-(3,4-dimethoxyphenyl)-3-(3-methoxyphenyl)-1,2,4-oxadiazole (DPMO) with M 6 (M = Ag/Au/Cu) clusters are predicted in the present work.

Methods
The DFT analysis was used to investigate the essence of proposed structures' structural, chemical, electronic, and thermodynamic properties in order to find a viable DPMO drug detector. All M 6 clusters and DPMO were optimized before the complexation process using Gaussian 16 program's B3LYP functional and SDD basis set with non-relaxed positions for metal atoms [65,66]. Energy and frequency calculations were used to establish the structural integrity and natural existence of adsorbents. To create energetically appropriate and persistent conjugated nanostructures, we examined the adsorption process of DPMO on nanometal clusters. We investigated thermodynamic terms, changes in enthalpy, entropy, and Gibbs-free energy to find the thermal stability of DPMO and DPMO-M 6 systems. We conducted a thorough examination of the energy of the HOMO, LUMO, DOS, and NBO to get electronic confirmation of the interaction between M6 and DPMO. All DPMO-M 6 systems were optimized in various solvents, and key features such as solubility, adsorption properties, and electronic properties were estimated to better understand the biological influence [67,68]. Reaction sites of DPMO-M 6 s were examined using multi-wavefunction by analyzing ALIE, electron localized function, and noncovalent interactions [69].

Results and discussion
Optimized geometries of M 6 s and DPMO Figure 1 shows the DPMO and M 6 s' structures and FMOS and MEP plots. The electronic properties of DPMO including as HOMO, LUMO, and dipole moment were investigated ( Table 1). The dipole moment (DM) of DPMO is 4.8758 Debye, indicating the asymmetric charge distribution which is supported by MEP ( Fig. 1) with reactive sites around primarily on O, N, and C atoms. The Fermi level is given as −4.0764 eV, while E H and E L values are − 6.1875 and − 1.9652 eV (Table 1). In order to discover a good adsorbent for DPMO, we conducted a comparative analysis and selected three nanoclusters: M 6 (M = Ag/Au/Cu). The bond lengths for Ag/Au/Cu clusters 2.7299, 2.6989, and 2.3781 Å, respectively, which are perfectly consistent with various theoretical conclusions [70]. The M 6 s have zero dipole moments, which means the charges are evenly distributed across the structure. The FMO energy values were − 5.6128/ − 6.7837/ − 5.7301 eV and −2.5823/ − 3.3766/ −2.4718 eV, respectively, for Ag/Au/Cu clusters, and the band gaps are 3.0305/3.4071/3.2683 (Table 1) [71].

Adsorption and desorption processes
To begin, we used the DFT level of theory to examine the structural properties, adsorption energy, thermodynamic properties, and other features of DPMO with M 6 s in order to find the most energetically favorable conjugated configuration. The DPMO interacts with our studied adsorbents via the oxadiazole ring's O and N atoms. To further understand the adsorption process, we used the following equation to compute the adsorption energies (Eads) of all conjugated configurations, which are reported in Table 1 [72]: E ads = E M6-DPMO -E M6 -E DPMO ; E M6-DPMO refers to the energy of the conjugated structure; E M6 and E DPMO are the energies of M 6 and DPMO, respectively. The thermodynamic properties of conjugated structures were also examined to ensure their thermal stability. The reaction is endothermic if ΔH > 0 or exothermic when ΔH < 0 and ΔG tell us whether the DPMO and MCs have a spontaneous interaction (ΔG < 0) or not (ΔG > 0). The ΔG and ΔH are given as [73,74]: ΔU = U M6-DPMO -U M6 -U DPMO , where U represents the Gibbs-free energy (G) and enthalpy (H). In

Dipole moment and MEP maps
The non-uniform charge distribution over DPMO causes a dipole moment in the molecule. All adsorbents, M 6 s, have zero dipole moment due to symmetric charge distribution across the entire structure. All conjugated configurations achieved a dipole moment after contact with the DPMO molecule with all M 6 s ( We also calculated the PDOS to demonstrate the availability of newly created states in the energy band and therefore realize the orbital hybridization. In the energy gap of M 6 s following interaction with DPMO, as shown in Fig.  S1 (supplementary figure), many energy states may be seen. This suggests that all of the suggested DPMO-M 6 -conjugated nanostructures have experienced orbital hybridization. As a result, the energy gap of all the DPMO-M 6 s has reduced, supporting the change in E g . The E g and conductivity (σ) are given by σ = AT 3/2 exp (− Eg/2kT) [76]. Accordingly, when the energy gap shrinks, the conductivity increases exponentially. This means that the reduction in energy band, which is a critical property for sensing drugs M 6 s, generates an electrical signal. Hence, the sensitivity of M 6 s toward DPMO follows the trend: σ(Cu6) > σ(Ag6) > σ(Au6). As a result, Cu 6 might be said to be more sensitive to DPMO than the other two adsorbents and a suitable nanomaterial for detecting DPMO.

Quantum molecular descriptors (QMD)
To decode the details of chemical stability and reactivity of DPMO and M 6 s, QMD analyses are required. The QM descriptors are hardness, η = (E L -E H )/2 and electrophilicity index ω = μ 2 /2η [77]. From Table 1, we can observe that η of M 6 s has been reduced after interaction with DPMO from 1.5153/1.7036/1.6342 (Ag/Au/Cu) to 1.1011/1.4174/0.9868 (DPMO-Ag/Au/Cu). This indicates that the chemical reactivity of the M 6 s has increased as compared to bare M 6 s. DPMO-MC's softness on the other hand has increased from their original structures. In summary, DPMO-Cu 6conjugated structures have been found to have greater variances in hardness and softness, as well as in the electrophilicity index, when compared to Ag 6 and Au 6 . As a result, we can deduce that Cu 6 interacts with the MPDO molecule more than other adsorbents.

NBO analysis
Through charge transfer interaction between adsorbate and adsorbents, NBO analysis provides information on bonding and hybridization [78]. The interaction energy between filled and empty NBOs has been estimated (supplementary table S2). We can see that more electronic charge has passed between intra-molecular NBOs, suggesting stabilization.

Solvent effects
We optimized the DPMO-M 6 s using the PCM model and computed SFE, DM, FMOs, and E g among other things, to understand the influence of polar media with different dielectric constants: 2.38 (toluene), 8.93 (dichloromethane), 32.70 (methanol), and 80.40 (water) ( Table 1) [79]. The SFE of the DPMO-M 6 s in solvents follows the same trend as the adsorption energies of DPMO-M 6 s with a gaseous state with high values for Cu 6 -DPMO. This indicates that DPMO-M6-conjugated structures produced slightly more negative SFE in solvent media than in the gaseous media, indicating an enhancement in the solvent medium's stability (Table 1). Furthermore, the DM of DPMO-M 6 s in solvents has increased as compared to gaseous media, implying that the reactivity and solubility of the examined DPMO-M 6 s have increased. The ΔEg of DPMO-M 6 -conjugated structures in solvents was also calculated and discussed in order to nominate an electrical sensor for the DPMO. In Au/Cu-DPMO clusters, the energy gap increases in all solvents while for Ag6-DPMO, there is a decrease in the E g values. It means Au 6 and Cu 6 clusters are good sensors as supported by their solvation or adsorption energies. This is also evident from the Raman spectra (supplementary figure Fig. S2) in which in the fingerprint regions maximum enhancements are for Au/Cu-DPMO clusters due to SERS effects [80,81].

Average localized ionization energy (ALIE) assay
The ALIE explains the structure and stability of molecules by the nature of electrons. Oxadiazole formed complex with Ag, Au, and Cu metal sheets. The metal sheets like Ag, Au, and Cu have colors from blue to red of the scale value from 0.00 to 2.00, and complex size ranges from 9.27 to −7.42, from 7.36 to −7.36, and from 8.83 to −6.85 Å 3 , respectively. Figure 3 shows the ALIE of all three metal complexes. The color blue (range 0.00-0.20 Å) represents lone-pairs/unreacted electrons within complexes, and the sites are all nitrogen (N), oxygen (O), and metals (Ag, Au, and Cu); like red (range 1.80-2.00 Å) represents the localized/core electrons of complexes, and the sites are all heavy atoms like carbon (C), nitrogen (N), oxygen (O), and metals (Ag, Au, and Cu); in the same way, bluishgreen (range 0.80-1.10 Å) represents the delocalized/mobile electrons, and these produce number of resonance structure of those complexes can explain the stability and also create electron-rich and poor sites for a potential chemical reactivity like the methoxyphenyl, 1,2-dimethoxyphenyl, and imidazole groups and few metals close to the molecule [82,83].

Electron localized function (ELF) assay
The ELF explains the structure and stability of molecules by the position of electrons. Oxadiazole-metal cluster that showed colors from blue to red mentions the probability of electron sites 0.00 to 1.00, and complex size ranges from 9.27 to −7.42, from 7.36 to −7.36, and from 8.83 to −6.85 Å 3 , respectively. Figure 4 shows the ELF of all three metal complexes. The colored ones (range 0.80-1.00) represent the most probability of electrons staying at hydrogen (H) atoms, bonds of C-C, C-N, C-O, and some metals; blue (range 0.00-0.25) represents the least probability of electron sites and also called the delocalized/resonance electrons at the methoxyphenyl, 1,2-dimethoxyphenyl, and imidazole groups with a few metals close to the molecule [84,85].

Noncovalent interactions (NCI) assay
The NCI explains the stability of complexes by the types of hydrogen bonds; these are noncovalent/nonbonded bonds. It is found that there exists a significant interaction between the oxadiazole and the clusters. The metal sheets like Ag, Au, and Cu having the color from blue to red scale from − 0.05 to 0.05 a.u. are the strength of the hydrogen bonds from strong to weak type. Figure 5 shows the NCI of complexes. A strong hydrogen bond was formed from metals Ag, Au, and Cu to hydrogens in the methoxyphenyl, 1,2-dimethoxyphenyl, and imidazole groups, and the descending order of them is Cu > Ag > Au; likewise, there is a weak hydrogen/van der Waals hydrogen bond formation from metals Ag, Au, and Cu to hydrogens in the methoxyphenyl, from O and N atoms to the methoxyphenyl and 1,2-dimethoxyphenyl groups, and from O in methoxy to hydrogens in the methoxyphenyl and 1,2-dimethoxyphenyl groups, and the descending order of them is Cu > Au > Ag. The red color represents the hydrogen-hydrogen repulsions, bulky group repulsions, and aromatic ring repulsions; there are interactions between the oxadiazole and methoxyphenyl, oxadiazole and 1,2-dimethoxyphenyl, oxygen and carbon in 1,2-dimethoxyphenyl, oxygen in methoxy and phenyl groups and all metals; and the descending order of them is Au > Cu > Ag [86,87].

Prediction of bio-activity through TD-DFT calculations
TD-DFT is always essential for effective molecular modeling. The electronic transition between molecular orbital is a time-dependent phenomena [88]. UV absorption spectra and oscillator strength (f) of DPMO attached with small Ag, Au, and Cu clusters were calculated with the TD-DFT method at the B3LYP/SDD level of theory to obtain electronic transition states. Our calculated data for the Ag cluster attached DPMO molecule shows there are six electronic transitions in the UV region as shown in electronic supplementary Fig. S3 (supplementary figure) with blue vertical lines and the one with the highest oscillator strength "0.029" at 7000 cm −1 which corresponds to the movement of an electron from H to L states (where H presents HOMO and L presents LUMO). This may be attributed to MLCT (metal to ligand charge transfer), i.e., the charge is transferring from the Ag cluster to DPMO [89] and it also supports our charge transfer mechanism. The other transition corresponds to H-1 to L, H-2 to L, H-1 to L, H-1 to L, and H to L. Similarly for Au cluster attached with DPMO exhibit only one electronic transition state with oscillator strength 0.0032 at 15,000 cm −1 (supplementary figure: Fig. S3). In this transition, the main contribution comes when the electron moves from HOMO to LUMO stated and it is also ascribed as a ligand to metal charge transfer. Similarly, Cu clusters with DPMO exhibit six electronic transitions in the UV region with the highest oscillator strength of 0.068 at 7500 cm −1 which is again due to the jump of an electron from the HOMO to LUMO site. The importance of the result obtains from Ag; Cu cluster with DPMO decides the use of this system in bacterial culturing. Optical density measurements use a wavelength of 600-620 nm to estimate the cell concentration and to track growth patterns [90]. According to the reported literature [53], gold nanoclusters have tunable emission wavelengths ranging from 510 to 590 nm in an aqueous medium and these clusters demonstrated the application of highly luminescent gold nanoclusters for Ph2 + sensing. For copper nanoclusters, Maity et al. [54] reported a UV absorption at around 365 nm, and in this case, the absence of the peak around 560-600 nm confirms the absence of surface Plasmon resonance indicating the formation of copper nanoclusters instead of copper nanoparticles.

Interaction of DPMO and metal cluster + DPMO over graphene QD sheet
We know graphene is a single-atom-thick, two-dimensional sheet of hexagonally arranged carbon atoms. Graphene has free surface π electrons and is capable of forming π-π interactions for loading drugs as well as covalent modifications [91,92]. On the other hand, it is well known that biological activity describes the beneficial or adverse effects of a drug on the living matter [93]. If anyhow the biological activity of drug molecules can be increased, it will be beneficial for us. To enhance this biological activity, we studied the vibrational Raman properties of the present DPMO molecule over the graphene quantum dots (G-QD). Here, we used graphene as a substrate rather than a metal surface. The interaction of π electrons (2p orbital) of carbon on graphene with the 2p orbital of oxygen or nitrogen as well as Ag, Au, and Cu increases the signal strength of Raman frequency.
As we can see in Fig. S4 (supplementary figure), the intensity of Raman activity for DPMO over graphene QD is 2390au at the frequency of 1652.88 cm −1 while the individual DPMO molecule has the intensity of 1889au at the frequency of 1659.05 cm −1 . We have also analyzed the Raman activity with metal clusters and found that there is a very little bit difference at the frequency level. It can be seen that the Raman activity intensities for Ag 6 , Au 6 , and Cu 6 attached with DPMO over graphene QD are 2420au, 2391au, and 2253au at the frequency levels of 1652.88 cm −1 , 1652.5 cm −1 , and 1653.18 cm −1 , respectively. The Raman vibrational data for Ag, Au, and Cu clusters with DPMO over graphene quantum dots shows enhancement of Raman signals. It is very interesting that this combination can be used as a detection of this DPMO molecule in a biological sample.

Conclusion
The cluster formation of DPMO with different metals was reported with the help of chemical descriptors, solvation effects, and wave function analysis. Changes in thermodynamic characteristics observed for different M 6 s are exothermic, spontaneous, and thermodynamically ordered interactions. DPMO-Cu 6 has been found to have greater variances in chemical descriptors when compared to Ag 6 and Au 6 , and hence, Cu 6 interacts with the MPDO molecule more than other adsorbents. The increased energy gap in Au/Cu-DPMO clusters in all solvents with respect to the gaseous state means Au and Cu clusters are good sensors. The cluster formation is stabilized by various noncovalent interactions, and it led to a favorable change in electron delocalization in the system. DPMO is found to interact with graphene quantum dots also. The enhancement of Raman activity using both clusters indicate its suitability for the development of sensors based on the clusters.