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Department of Chemistry, Faculty of Science, The University of Maroua, Maroua, Cameroon
Contribution: ​Investigation, Writing – original draft
Corresponding Author
Department of Chemistry, Higher Teacher Training College Bertoua, The University of Ngaoundéré, Bertoua, Cameroon
Correspondence
Aymard Didier Tamafo Fouegue, Department of Chemistry, Higher Teacher Training College Bertoua, The University of Ngaoundéré, P. O. Box 652, Bertoua, Cameroon.
Email: didier_tamafo@yahoo.fr
Contribution: Conceptualization, ​Investigation, Writing – original draft
Department of Chemistry, Faculty of Science, The University of Douala, Douala, Cameroon
Contribution: Conceptualization, Validation
Department of Chemistry, Faculty of Science, The University of Bamenda, Bamenda, Cameroon
Contribution: Conceptualization, Validation
Department of Chemistry, Faculty of Science, The University of Maroua, Maroua, Cameroon
Department of Chemistry, Higher Teacher Training College Bertoua, The University of Ngaoundéré, Bertoua, Cameroon
Contribution: Conceptualization, Supervision, Validation
Department of Chemistry, Faculty of Science, The University of Maroua, Maroua, Cameroon
Contribution: ​Investigation, Writing – original draft
Corresponding Author
Department of Chemistry, Higher Teacher Training College Bertoua, The University of Ngaoundéré, Bertoua, Cameroon
Correspondence
Aymard Didier Tamafo Fouegue, Department of Chemistry, Higher Teacher Training College Bertoua, The University of Ngaoundéré, P. O. Box 652, Bertoua, Cameroon.
Email: didier_tamafo@yahoo.fr
Contribution: Conceptualization, ​Investigation, Writing – original draft
Department of Chemistry, Faculty of Science, The University of Douala, Douala, Cameroon
Contribution: Conceptualization, Validation
Department of Chemistry, Faculty of Science, The University of Bamenda, Bamenda, Cameroon
Contribution: Conceptualization, Validation
Department of Chemistry, Faculty of Science, The University of Maroua, Maroua, Cameroon
Department of Chemistry, Higher Teacher Training College Bertoua, The University of Ngaoundéré, Bertoua, Cameroon
Contribution: Conceptualization, Supervision, Validation
Funding information: Ministry of Higher Education of Cameroon
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Theoretical chemistry calculations were used in this work to investigate the ability of the B₁₂N₁₂ fullerene like nano-cage for sensing juglone (Jug) and one of its derivative (JugOH) in gas phase, pentyl ethanoate (PE) and water. Results obtained at DFT/M05-2X-D3/6-311+G(d,p) level of theory showed that B₁₂N₁₂ is able to adsorbed Jug preferentially by binding to one of the O-atom of its carbonyl groups. Based on natural bond orbital analysis, a charge transfer from the oxygen atoms of Jug and JugOH to the anti-bonding orbital of B was revealed. Quantum theory of atoms in molecule analysis showed that the B₁₂N₁₂Jug and B₁₂N₁₂JugOH complexes are stabilized by a partially covalent BO bond in addition to attractive non covalent interactions. The ability of Jug, JugOH as well as their complexes A and AOH to scavenge HO^● radical has been investigated via the usual hydrogen atom transfer mechanism in the three media of study previously stated. Theoretical evaluation of pH effect on this radical scavenging activity revealed that in water, the anionic forms of JugOH (86%) and AOH (96%) are dominant and mainly transfer their remaining H-atom to HO^● via a spontaneously reaction, the complex presenting the lowest Gibbs free energy. These results provide fundamental knowledge for the development of new antioxidant delivery careers.
One of the main objectives of chemistry has always been the discovery of new molecular systems bearing improved properties than already existing materials. This aim is hugely reinforced nowadays because of the great number of challenges faced by human beings. These challenges are found in all the fields of our daily life, including technology, health, agriculture and esthetics just to mention a few. The ongoing Covid-19 crisis is a perfect illustration. In that purpose, computational chemistry tools are hugely accepted by the scientific community, due to the fact that they are used to explore and solve chemical, physical and biological problems at the lowest level of particle size. Computational chemistry is applied to gain more insight into the mechanism of action of molecular systems, aiming at bringing more highlights to chemical changes and proposing new chemicals with improved properties as well as better reacting conditions.
Boron nitride (BN) nanostructures (like B₁₂N₁₂ and B₃₆N₃₆ fullerene like compounds as well as boron nitride nanotubes) are receiving gradual interest in recent years, due to their unique surface, physical and chemical properties, conferring them a broad range of applications. In the area of biomaterials, BN nanostructures (boron nitride nanotubes) are progressively found to possess a promising future in the fields of cell targeting [1], drug delivery [2] and sensing [3]. Furthermore, the BN materials have been shown to possess better biocompatibility and lower cytotoxicity compared to the carbon materials [4, 5].
In relation to the domain of drug delivery, density functional theory (DFT) based theoretical studies have quite been used to substantiate the fact that pure and doped B₁₂N₁₂ fullerene like material can be applied as potential carrier for delivering thioguanine isomers anticancer drug [6], amantadine drug [7], 5-fluorouracil anticancer drug [8], Celecoxib [9], aspirin [10], alprazolam drug [11], and exemestane [12] just to mention a few. As a result, the numerous evidences is an indication of the improvement of the pharmacological properties of common drugs alongside the usage of nanocarriers. Theoretical studies also showed the sensing ability of pure and doped B₁₂N₁₂ toward HCN and ClCN [13], phosgene gas [14], hydrogen halides [15], NO₂ gas [16], and nitrosamine conformers [17]. Moreover, BN fullerene like cages have been found to improve the antioxidant activity of phenolic compounds through their adsorption on the external surface of the former. In this perspective [18], showed that B₃₆N₃₆ can efficiently improve the antioxidant activity as well as the delivery of hydroxyquinoline derivatives. Analysis of the antioxidative mechanisms of a complex formed from the adsorption of apigenin on B₁₂N₁₂ surface also revealed the improvement of radical scavenging activity of apigenin by B₁₂N₁₂ [19]. The same research group recently published the improvement of the antioxidant activity of Chrysin flavonoid when adsorbed on B₁₂N₁₂ nanocage external surface [20]. Such results open new clue for the manufacture of new antioxidant drug through chemical functionalization.
Naphthoquinones represent a class of compounds (mainly polyphenols) having as basic structure that of 1,4-naphthoquinone. They have been shown to possess among others interesting antibacterial [21], antifungal [22], antiviral [23], antitumor [24, 25], and antimalarial [26] properties. One of the most popular naphtoquinones is juglone (5-hydroxy-1,4-naphthoquinone) which is a phenolic allelochemical responsible for walnut allelopathy and the inhibitory effect of black walnut (Juglans nigra) in associated plant species [27]. In our previous works, the antioxidant activity (AOA) of juglone (Jug) based on hydrogen transfer mechanisms as well as the metal chelation ability have been substantially studied [27–29]. Our findings revealed a huge improvement in the AOA of (Jug) through the substitution of the H-atom ortho to its hydroxyl group by another OH group [29]. The present work is aimed at evaluating the effect of Jug and its derivative bearing a OH substituent (see Figure 1) adsorption at the external surface of B₁₂N₁₂ nanostructure on the AOA of the formers. To achieve this objective, the hydrogen atom transfer (HAT) mechanisms [30] are evaluated at DFT/M05-2X-D3/6-311+G(d,p) level of theory in gas phase, pentylethanoate (PE) and water.
The structure of the adsorbent (B₁₂N₁₂ nanocage) has first been allowed to relax at DFT/M05-2X-D3/6-311+G(d,p) level in gas phase. The structure obtained is shown at Figure 1 and presents six 4-membered rings (4-MR) as well as eight hexagonal 6-membered rings (6-MR). The fullerene-like nanocage presents two types of BN bonds: the first (1.438 Å) is in the 6-MRs and the second (1.485 Å) is shared by the 4-MRs and the 6-MR. These bond lengths are in perfect agreement with experimental and theoretical data found in the literature [37, 45]. In addition, the and bond angles are centered around 80.3° and 98.3° respectively in the 4-MR, as well as 110.7° and 126.0° in the 6-MR. Furthermore, the Mulliken atomic charges of B and N atoms of the cage are respectively 0.031 and −0.031 e, showing the purely ionic character of the BN bonds. The HOMO-LUMO gap (E_g) of the cage is found to be 9.69 eV. This important parameter is, however, very sensitive to the DFT method used [10]. As illustration, Javan et al. [8] published an E_g value of 4.99 eV at the PBE-D/6-311+G(d,p) level of theory [45] whereas Padash et al. [46] instead published an E_g value of 9.40 eV for B₁₂N₁₂ in gas phase at the M062X/6-311G(d,p) level of theory. The geometric parameters of B₁₂N₁₂ were found not to be sensitive to solvation in water and pentyl ethanoate.
The first part of this work was devoted to the evaluation of the sensing ability of B₁₂N₁₂ nanocage over Jug and its derivative. Here, three possible structures of B₁₂N₁₂-Jug complex have been considered. These complexes (coded herein as A, B, and C) are based on a Lewis acid–base interaction involving the O-atoms of Jug and a B-atom of the adsorbent. After relaxation at DFT/M05-2X-D3/6-311+G(d,p), the gas phase optimized structures of the complexes are depicted in Figure 1. The values of the gas phase adsorption energies are found to be −18.08, −8.98 and −11.74 kcal/mol respectively for complexes A, B, and C. These values of binding energies are negative for all three complexes, suggesting the possibility of sensing Jug with B₁₂N₁₂ fullerene like nanostructure. Among the complexes investigated, A presents the lowest value of the adsorption energy (E_bin = −18.08 kcal/mol), showing that this complex has the greatest probability to exist. B is found to be the least stable of the complexes with a binding energy of −8.98 kcal/mol. The BO bond lengths of the complexes increase in the order: A (1.595 Å) < B (1.638 Å) < C (1.649 Å). Accordingly, the great stability of A might be due to a strong adsorbent–adsorbate chemical interaction. Indeed, the values of the energy of the BO bonds of the complexes, calculated as half of the potential energy density V(r) (−1/2 V(r)) at the bond critical points (BCPs) [47] are 68.28, 51.86, and 53.56 kcal/mol respectively for A, B, and C. Accordingly, the BO bond energy is proportional to E_bin. The analysis of molecular diagrams of B and C (see Figure 2) obtained from Bader’s quantum theory of atoms in molecule (QTAIM) shows that apart from the B-O bond, these complexes are also stabilized by weak attractive CH…N interaction between Jug and the B₁₂N₁₂ nanocage. For the next parts of the work, only the most stable complex A will be considered.
Table 1 presents negative values of enthalpy ΔH and Gibbs free energy ΔG changes for the complexation reaction between B₁₂N₁₂ and Jug. The aforementioned parameters show the exothermic and the exergonic character of this reaction in standard conditions. A slight change in the values of E_bin, ΔH, and ΔG for the formation of A is observed upon solvation. E_bin is more negative in water but less negative in PE, indicating extra stability of the complexes in water. Similar results have been obtained by Kian and Tazikeh-Lemeski [12], in their molecular modeling investigation of B₁₂Y₁₂(Y: N, P) fullerene-like cages for exemestane-delivery; as well as Vessally et al. [10] in a DFT study on electronic and optical properties of aspirin-functionalized B₁₂N₁₂ fullerene-like nanocluster. The reaction also remains exothermic and spontaneous in the solvents than considered herein.
The adsorbed complex of JugOH was obtained by substituting the H-atom ortho to the hydroxyl group of Jug by an OH group, and a complex denoted as AOH was obtained and optimized. The gas phase binding energy of AOH is besides similar to that of A with a value of −17.73 kcal/mol. The BO bond length in AOH is found to be 1.601 Å, value which is closer to that of the BO bond of A (1.598 Å) in gas phase. Our results also reveal a discrepancy in the length of the BO bond of A with the polarity of the medium of study (Table 2). Indeed, the value of that parameter is found to be 1.574 and 1.564 Å respectively in PE and water solvents. The value of the BO bond length of AOH also decreases from 1.601 Å in the gas phase to 1.579 and 1.567 Å respectively in PE and in water.
O₁₈H₁₉
OH
0.979
0.965
0.972
0.965
0.979
0.981
0.966
0.972
0.966
0.979
0.967
0.972
0.967
O₁₈H₁₉…O₁₆
OH…O₁₈
1.759
2.113
1.806
2.095
1.729
1.741
2.128
1.799
2.105
1.772
2.161
1.812
2.122
O₁₈H₁₉…O₁₆
OH…O₁₈
142.96
113.46
136.25
112.61
143.79
112.80
136.71
112.04
142.59
111.61
136.65
111.60
The natural bond orbital (NBO) [48] analysis was performed at the same level of theory used for geometry relaxation as implemented in the Gaussian 09 software package. NBO analysis revealed that the BO bond of A and AOH are mostly due to a transition from the lone pair of electrons of the Oatom of Jug and JugOH to the empty orbital of the B-atom. In the case of A, the value of energy (E⁽²⁾) for the transition LP(2) O → LP*(1) B is 268.51 kcal/mol, while that of AOH is found to be 266.12 kcal/mol. The value of E⁽²⁾, in conjunction with E_bin as well as the potential energy density at the BCP of the BO bonds (0.1055 and 0.1047 a.u. respectively for A and AOH) account for a chemisorption of Jug and JugOH onto the external surface of the B₁₂N₁₂ nanocage. Indeed, the values of some important topological parameters (the electron density ρ(r), the Laplacian of electron density ∇²ρ(r), the energy density H(r) and the bond energy E_b) used in characterizing interatomic interactions are grouped in Table 3. It can be found from that table that the BO bonds of A and AOH have positive values of ∇²ρ(r) indicating that the bond belong to closed shell interactions [49]. Moreover, their H(r) values are negative, showing that the B-O interaction is partially covalent [46]. The great value of E_b (BO) (−64.09 and 63.37 kcal/mol for A and AOH respectively) corroborates that partial covalent character.
Obvious increments in the BN bond lengths are obtained upon adsorption of Jug and JugOH, though values of this parameter are similar in A and AOH. The BN bonds of the 6-MR for instance increases from 1.437 to 1.505 Å in A and 1.506 Å in AOH. The frontier molecular orbitals (FMOs) of the B₁₂N₁₂ fullerene-like compound have extensively been discussed in the literature [10, 45, 50]. The distribution of the FMOs of A and AOH depicted in Figure 3 are hugely centered on Jug and JugOH. Indeed, their HOMOs are greatly distributed around the cycles of the absorbate though a little part of these orbitals are found around nitrogen atoms of the fullerene-like nanocage. The LUMOs of the complexes are exclusively scattered around the absorbate moieties. Moreover, the distributions of the FMOs of Jug and JugOH are very similar to those of their respective complexes. This observation means that the binding of these compounds to the external surface of the nanocage used herein does not affect the distribution of their FMOs. The comparison of the density of state (DOS, calculated using the multiwfn 3.8 package) (see Figure S1) of B₁₂N₁₂, A and AOH shows an increase in the HOMO energy of the absorbent upon the adsorption of Jug and JugOH, as well as a discrepancy in its LUMO energy. This leads to a decrease in the bang gap (E_g) of B₁₂N₁₂ (Table 4) and consequently an improve of its electrical properties [17]. However, the adsorption of Jug and JugOH leads to a reduction in their E_LUMO, E_HOMO as well as the band gap, allowing to predict a greater reactivity of complexes than the naphtoquinone under investigation.
Furthermore, the dipole moment (DM) of the nanocage (which is formally null due to the lack of charge) greatly increases after the adsorption, reaching 8.45 Debye for A and 6.71 Debye for AOH as shown in Table 4. The value of the DM of the complexes are even greatly higher than those of their corresponding initial organic compounds (Jug and JugOH). The DM comes from the difference in charge distribution and account for the reactivity of compounds. Therefore, based on the changes in E_g value as well as DM, the complexes are found to be more reactive than B₁₂N₁₂, Jug, and JugOH. The vectors of representing the DM of the organic compounds and their complexes are depicted in Figure S2. An observation of that figure indicates that the DM of the complexes is oriented from the nanocage to the adsorbate. This observation agrees with the findings of other research teams in similar studies [51, 52]. Such improve in the electronic properties of the fullerene-like nanocages upon complexation of organic compounds has mainly been published in the literature [10, 12, 46, 51, 53]. From the aforementioned results, one can conclude that B₁₂N₁₂ can be used as sensor for Juglone and its derivative studied herein.
Some relevant geometric parameters of the compounds studied in this research endeavor are presented in Table 2. The length of the OH bonds of Jug and JugOH calculated herein at M05-2X-D3/6-311+G(d,p) are respectively 0.977 and 0.979 Å in the gas phase. These values are close to those obtained by Jin [46] which are 0.986 0.989 Å at B3LYP/6-311++G(d,p) level. A small discrepancy in the values of those bond lengths is observed upon adsorption of Jug and JugOH. Indeed, the change in that of Jug is found to be 0.006 Å while that of its derivative is 0.007 Å. Concerning JugOH, the length of the additional OH group (the substituent) is not affected by the adsorption. Moreover, an obvious difference in the length of the C═O bonds of the compounds is noticeable. In the case of the pure organic compounds under investigation, this difference is smaller and is due to the intra-molecular hydrogen bond (HB) in which one of the carbonyl oxygen atom is engaged. However, the difference is significant after complexation because the O-atom of the same carbonyl group is involved in the B₁₂N₁₂Jug (JugOH) interaction, in addition to the hydrogen bonding. The effect of solvents on these parameters is very slight.
The length of the HB of Jug and JugOH obtained in this work are respectively 1.753 and 1.759 Å, values which are in good agreement with those found in the literature [29, 52]. The length of this parameter greatly increase upon the adsorption of Jug and JugOH, due to the involvement of the HB acceptor O-atom in the adsorbent-absorbate interaction. The length of the HB of Jug and JugOH passes respectively from 1.753 to 1.794 Å and 1.759 to 1.806 Å after their adsorption on the external surface of the fullerene like nanocage. The weakening of this HB may free the H-atom of the OH group, thereby increasing its availability to radicals, and improving the AAO. The length of the additional HB of JugOH (OH…O₁₈) is however found to decrease from 2.113 to 2.095 Å in gas phase after its adsorption. Moreover, this bond length is found to slightly increase in the two solvent media simulated herein. Some bond angles are also exposed in Table 2 and perfectly agree with the results of Jin [52]. Finally, the geometric parameters do not really vary when passing from water to PE solvents.
The molecular diagram of Jug, JugOH, A, and AOH are depicted in Figure 2. The HB found in the structures of these compounds have been characterized using the Bader’s QTAIM method [54], via the multiwfn 3.8 package [55]. This method was developed by Bader and coworkers and is used in determining the types of bonding interactions between two neighboring atoms. This done by calculating the values of some parameters at the real space functions as electron density at the BCPs. The Laplacian of electron density ∇²ρ(r), the electron density ρ(r), the Lagrangian kinetic energy G(r), the potential energy density V(r), the Hamiltonian kinetic energy H(r) = G(r) + V(r), and bond energy E_b = V(r)/2 are some relevant parameters used for that purpose. According to Rozas et al. [56], the nature of HB can be best explained as: (i) strong HBs are associated to ∇²ρ(r) < 0 and H(r) > 0, (ii) intermediate type HBs are linked to ∇²ρ(r) > 0 and H(r) < 0, (iii) values of ∇²ρ(r) > 0 and H(r) > 0 are characteristics of weak HB interactions. The values of the aforementioned parameters calculated at the BCPs of the HBs of the compounds studied are grouped in Table 3. The table shows a decrease in the value of ρ(r) at the BCPs of the HB of Jug and its derivative after their adsorption. Indeed the value of ρ(r) passes from 0.0379 to 0.0338 a.u. and from 0.0373 to 0.0330 a.u. respectively after the adsorption of Jug and JugOH. In the same manner, the values of the energy of these HBs decrease from 10.65 to 9.58 kcal/mol and from 10.45 to 9.20 kcal/mol after the adsorption of Jug and its derivative respectively. These observations are in line with the increase in the HB bond length (or the weakening) previously observed upon complexation. In addition, the increase in the value of ρ(r) as well as that of the absolute value of E_b at the BCP of the second HB (the HB involving the substituent OH group) of JugOH agrees with the decrease in the length of that HB. Moreover, the main HBs of all studied compounds are associated with positive values of ∇²ρ(r) as well as negative values of H(r) (for Jug and JugOH) and positive values of H(r) for A and AOH. Therefore, the HB of Jug and JugOH are intermediate type, while those of their complexes are weak interactions.
Another way of studying HBs as well as other weak interactions is via non-covalent interactions (NCI) method. NCI can be regarded has an extension of the QTAIM method which is based on the reduced density gradient (RDG) [50, 57]. A map of RDG isosurface is used in that purpose to identify and distinguish weak interactions in molecular systems. Accordingly, the blue color in interatomic regions accounts for strong interactions like H-bonds (with ρ > 0 and λ₂ < 0), while attractive Van der Waals interactions can be identified by green isosurfaces in the interatomic regions (ρ ≈ 0 and λ₂ ≈ 0). Steric effects in rings and cages (strong repulsions) are identified by the red color (with ρ > 0 and λ₂ > 0). λ₂ here is the second largest eigenvalue of Hessian matrix of electron density. The RDG isosurface of A, AOH, Jug, and JugOH are presented in Figure 4. An observation of that figure shows a blue colored isosurface in the region of the main HB of all these molecules. Attractive VdW interactions are also depicted between the third O-atom of Jug not involved in the HB and one H-atom of its phenyl ring, contributing to the stabilization of the molecules. The multiwfn 3.8 and VMD visualization [58] programs were used concomitantly to compute the NCI isosurfaces. A close look at the isosurfaces of JugOH and AOH confirms that the HB involving the substituting OH group, characterized by a green color isosurface is weaker than the former HB. Moreover, the weak CH…N interactions previously identified in the complexes are confirmed by visualizing the NCI presented in Figure 4 which showed weak attractive interactions colored in green between the aforementioned atoms of B₁₂N₁₂ and Jug. Finally, strong repulsive ring and cage interactions are found in the structure of the studied compounds.
The ability of the compounds studied herein to scavenge radicals have been evaluated via three usual mechanisms of H-atom transfer described in the computational details section. In this part of the work, only the parameter describing the rate determining steps of each mechanisms are considered. The values of BDE, IP and PA are thus reported in Table 5. Those of ETE, PDE as well as their free energies are reported in Table 1S. The BDE value of Jug obtained in this work in the gas phase is 102.39 kcal/mol, which though slightly greater, agrees with that obtained in our previous works (99.64 kcal/mol) at the B3LYP/6-31+G(d,p) level [27]. Jin found for Jug, a BDE value of 98.5 kcal/mol at the B3LYP/6-311++G(d,p) level theory [52]. Concerning JugOH, the BDE values of the original and substituting OH groups are respectively 94.55 and 90.57 kcal/mol in gas phase. Jin found BDE values of 89.6 and 85.1 kcal/mol respectively for these groups. We obtained BDE values of 90.80 and 85.78 kcal/mol at the B3LYP/6-31+G(d,p) level of theory in a previous research endeavor [27]. The differences observed between the values obtained herein and those formerly published might arise from the fact that the B3LYP functional is known to underestimate the reaction energy of the HAT [59–62].
94.55
90.57
85.19
81.96
92.58
88.52
83.43
80.03
92.06
89.57
83.21
81.29
94.03
92.15
84.98
83.53
91.15
90.00
81.91
81.27
91.47
90.63
82.48
81.99
329.52
327.80
334.26
332.84
56.49
55.02
55.39
54.93
40.72
40.54
39.59
40.03
299.22
307.49
304.29
312.67
38.11
46.18
37.88
46.16
19.14
25.08
18.31
24.02
Little increments in the BDE values of Jug and JugOH can be observed when they are adsorbed at the external surface of the B₁₂N₁₂ nanocage. A similar observation has been made by Khalili and coworkers in their evaluation of the effect of adsorption of apigenin by the B₁₂N₁₂ nanocluster on the antioxidative activity of the former [19]. The BDFE values presented in Table 5 follow the same trend with BDEs and are found to be smaller. Both BDEs and BDFEs decrease upon solvation, the smallest value being obtained in the polar water solvent.
The stability of the phenoxy radical after the departure of the H-atom from OH group is of paramount importance in evaluating the antioxidant activity of phenolic species. Several parameters influencing the stability of this radical have been recognized [63–65]. Among these parameters, the distribution of the free electron (known as spin density) carried by the hydroxyl O-atom after the departure of the H-atom has received a considerable attention. Indeed, it has been shown that a large distribution of the spin density (SD) over the structure of the phenoxy radical improves its stability and thus the AOA of the parent molecule. The SD distribution of the radicals obtained in this work is depicted in Figure S3 and are scattered around the two cycles of the juglone moiety. Moreover, the repartition of these isosurfaces are almost similar in the different compounds and are not found around the atoms of the nanocage of A and AOH. Furthermore, some attractive VDW interactions are also visible when looking at the molecular diagrams of the radicals (Figure S4). In the cases of Jug, A, JugOH, and AOH, a O…O attractive weak interaction is found to stabilize the radicals after the abstraction of the H-atom of the original OH group of juglone. In addition to the aforementioned interactions, a CH…N non covalent HB is found in the molecular diagram of A. Despite the fact that the substituting OH group of JugOH and its complex present the lowest BDE and BDFE values, the former attractive interactions are not found in their radicals. Indeed, these radicals are stabilized by the OH…O HB, thus showing the importance of HBs in the AOA of phenolic compounds [62, 63].
The values of the ionization potential of Jug, JugOH, A as well as AOH grouped in Table 5 are greater than the BDEs. In addition, an increase in the IP values of Jug and JugOH is observed upon their adsorption in all media, that in the gas being the lowest. This may be due to the fact that in establishing the adsorbent-adsorbate interaction, the B₁₂N₁₂ nanocage acts as an electron withdrawing group. This interaction thus leads to the decrease in the availability of transferable electrons. Indeed, the changes in the IPs of Jug and JugOH after their adsorption are respectively 10.82 and 9.85 kcal/mol in PE. As concerning JugOH, the change in IP in the solvents simulated herein have values of 8.53 and 4.96 kcal/mol in PE and water respectively. The IPFEs also follow the trend of IPs. A great discrepancy in both IP and IPFE values is observed because of solvation, due to the small values of enthalpy and free energy for the solvation electron. Finally, the gas phase IP value of Jug obtained here (204.92 kcal/mol) is greater than that of Jin (192.2 kcal/mol at B3LYP/6-311++G(d,p) level) [52] and that of Tamafo et al. (199.52 kcal/mol calculated at B3LYP/6-31+G(d,p) level) [27]; still due to the fact that the B3LYP functional underestimates IP values of polyphenol antioxidants.
Analysis of the PA values of the compounds studied reported in Table 5 show that those of Jug and JugOH are respectively 340.03 and 329.52 kcal/mol (as well as 327.80 kcal/mol for the substituting hydroxyl group) in the gas phase. The adsorption of Jug and its derivative at the external surface of the B₁₂N₁₂ nanocage leads to a decrease in these PA values. In all phases simulated herein, PA and PAFE values of the substituting hydroxyl group of JugOH are clearly smaller than those of Jug, showing that the former has a greater acidic character than the latter. The values of these parameters greatly decrease in solution, AOH having the smallest values.
Phenolic compounds are weak acids and can exist in both acid and base forms depending on the pH of the medium. Therefore, both forms must be considered especially when studying properties related to the transfer of hydroxyl H-atom. The pKa values of the compounds under investigation have been calculated at the M05-2X/6-311+G(d,p) level of theory in water using the procedure published by Galano and coworkers in water [66]. The pKa values obtained are found in Table 6, as well as the percentage of base calculated in physiological conditions (pH = 7.4). It turns from Table 6 that apart from Jug (having 9.10% of basic form at the physiological pH), the anionic form (basic) of the other antioxidants is more abundant than the neutral form. Moreover, the basic forms of molecular complexes A and AOH exist respectively at around 86% and 96% in physiological conditions.
7.1
7.0
6.0
6.8
In order to deepen the evaluation of the radical scavenging activity of the compounds under investigation, the Gibbs free energy value (ΔG) of the first steps of the three mechanisms previously described was calculated considering the direct reaction between the antioxidants and the HO^● radical. This was done in standard conditions for both the acid and the basic forms of compounds studied.
Results summarized in Table 7 suggest that for the neutral forms, only the HAT mechanism from the antioxidants to the HO^● radical is spontaneous in all media of study. Therefore, only the data obtained from, that mechanism are discussed. Concerning Jug and A, their ΔG values are almost the same in gas phase. In PE, A has a lower ΔG value than Jug, with a difference of about 1.80 kcal/mol. However, the reverse of this result is observed in water, the ΔG value of Jug being 2.40 kcal/mol smaller than that of A. It also turns from Table 7 that the H-Atom of the substituting hydroxyl group of both JugOH and AOH has a lower ΔG value than the original HO group. Furthermore, the HAT reaction from JugOH is more spontaneous than that from AOH in all media of study, but the difference does not reach 2 kcal/mol.
−23.62
−26.86
−26.53
−29.92
−30.09
−32.01
190.01
188.60
98.40
97.94
45.55
45.47
−23.83
−25.28
−28.04
−28.68
−30.82
−31.31
160.05
168.43
80.89
89.17
35.99
41.71
In other to evaluate the AOA of the basic forms, only the transfer of electron (via the Gibbs free energy) from the basic forms of Jug and A to HO^● radical is evaluated in water since they do not more have any other labile H-atom. Concerning the basic forms of JugOH and AOH, the HAT, electron and proton transfers are considered, based on the remaining OH after the loss of the most acidic proton. The values of the free energy in water for the first steps of the mechanisms considered in this work in presence of the HO^● radical are exposed in Table 7. Results show that the HAT from JugOH (−41.50 kcal/mol) and AOH (−47.19 kcal/mol) to the radical is spontaneous. Moreover, these anions are found to be more reactive than their respective neutral counterparts. It is also observed that the reaction with the molecular complex AOH is more spontaneous than that with JugOH, showing that the B₁₂N₁₂ nano-cage improves the radical scavenging activity of the latter. It also turns from Table 7 that apart from A, the other compounds spontaneously transfer one electron to hydroxyl radical, JugOH and AOH being the most active via this mechanism. It is confirmed that complexation increases the free energy ionization potential of Jug and JugOH in water. The proton transfer from the anionic forms of JugOH and AOH is found to be endergonic in standard conditions.
DFT/M05-2X-D3/6-311+G(d,p) level of theory was used to investigate the ability of B₁₂N₁₂ for sensing Jug and one of its derivative in gas phase, PE as well as water. For this purpose, the interactions between the three O-atoms of Jug and B₁₂N₁₂ have been considered. Our results revealed that all of them can form stable complexes with the nano-cage, the complex named A being the most prominent (with the lowest adsorption energy) in gas phase. NBO analysis showed that the interaction between Jug (as well as JugOH) and the nano-cage is due to strong charge transfers from the lone pair of the O-atom and the free anti-bonding orbital of B₁₂N₁₂. Based on QTAIM results, the B-O in both A and AOH was found to have a partial covalent character. Weak attractive NCI improving the stability of the complexes were also found based on both QTAIM and NCI analysis. The effect of that adsorption on the radical scavenging activity of both Jug and JugOH was our second main objective. This was achieved via the three usual main hydrogen transfer mechanisms. Results showed that the neutral form all compounds considered herein spontaneously scavenge HO^● radical in gas phase, PE as well as in water. Furthermore, the anionic forms of A, JugOH, and AOH dominate at physiological pH (in water). The theoretical study of the AOA of these anions revealed that AOH and JugOH react with the above mentioned radical preferentially through the HAT mechanism, AOH presenting the lowest free energy value. Adsorption thus improves the AOA of JugOH via the direct HAT in water. To gain further inside into these AOA mechanisms, current research works are being performed on the kinetic aspects.
The authors gratefully acknowledge the research modernization grant to lecturers by the Ministry of Higher Education of Cameroon.
The authors declare no conflict of interest.
Vincent de Paul Zoua: Investigation; writing – original draft. Aymard Didier Tamafo Fouegue: Conceptualization; investigation; writing – original draft. Désiré Bikélé Mama: Conceptualization; validation. Julius Numbonui Ghogomu: Conceptualization; software; validation. Rahman Abdoul Ntieche: Conceptualization; supervision; validation.
All data used in this work are available upon request
Appendix S1: Supporting Information
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