Exploration of the Mutual Effects Between Cation–π and Intramolecular Hydrogen Bond Interactions in the Different Complexes of Mesalazine with Metal Cations of Alkali and Alkaline-Earth: A DFT Study


 In the current research, a comparative study of the interplay effects between cation–π and intramolecular hydrogen bond (IMHB) interactions is performed on the complexes of mesalazine with Li+, Na+, K+, Be2+, Mg2+ and Ca2+ cations using density functional theory (DFT). For this purpose, the mesalazine analogue and the equivalent values of 3-aminobenzoic acid complexes with the cited cations are selected as a set of reference points. In order to understand the mutual effects between these interactions, the descriptors of geometrical, binding energies, topological properties and charge transfer values are examined on complexes using the atoms in molecules (AIM) and natural bond orbital (NBO) analyses. Results indicate that with the exception of Be2+ complex, the coupling simultaneously weakens both of the interactions. Finally, the physical properties such as energy gap, chemical hardness as well as electronic chemical potential of complexes are systematically analyzed by using frontier molecular orbitals.


Introduction
Mesalazine (MES), also known as mesalamine or 5-aminosalicylic acid, is a medication used to treat in ammatory bowel disease, including ulcerative colitis and Crohn's disease [1]. It is a bowel speci c aminosalicylate drug that after oral administration is metabolized in the gut and has its predominant actions there [2]. Consequently there are fewer side effects. The MES is structurally related to the salicylates. It differs both structurally and therapeutically from 4-aminosalicylic acid (or p-aminosalicylic acid). The mechanism by which MES acts during the treatment of in ammatory bowel disease remains unknown, but this drug is believed to work through modulation of the chemical mediators of in ammatory response, particularly prostaglandins and leukotrienes. The MES inhibits the cyclooxygenase enzyme in the arachidonic acid cascade, thereby reducing the production of in ammatory prostaglandins [3][4][5].
Noncovalent interactions (NCIs) such as hydrogen bond (HB), cation-π, anion-π, π-π, etc. play an important role in many areas of science and technology, as well as materials and catalysis. These interactions are essential in chemical reactions and regulation of biochemical processes [6]. The HB has been extremely well studied and recognized as the most important indicator of NCI [7,8]. The HB plays vital roles in biological structure, function, and conformational dynamics and is fundamental to life as it has evolved on Earth [9]. The characteristics of HBs (X-H•••Y) are not only dependent on the properties of X, Y, and H but also are related to other factors such as substituent, hybridization, and solvation [10][11][12]. Cation-π interactions, as another ensemble of NCIs, describe the association between a cation and the face of a molecule containing a π-system [13][14][15]. The importance of NCIs involving aromatic systems becomes major in drug receptor interactions, crystal engineering and protein folding [16]. The strength of cation-π interaction is usually greater than other NCIs associated with the π-system, such as π-π and π-HB [13] and its importance is depends on the character of both the π-system and the cation involved in the interaction [17][18][19].
The understanding of the interplay among NCIs is important for the improvement of elds such as supramolecular chemistry and molecular recognition [20]. Several theoretical calculations have been reported on the interplay between cation-π and HB interactions in the different systems. Frontera et al. [21] studied the interplay among three important NCIs (HB, cation-π and π-π) involving aromatic rings by means of ab initio calculations. They demonstrated that synergetic effects are present in complexes where these interactions coexist. In 2017, Nowroozi et al. [22] investigated interplay between the IMHB and cation-π interactions in the various complexes of salicylaldehyde, thiosalicylaldehyde and selenosalicylaldehyde with Li + , Na + , K + , Mg 2+ and Ca 2+ cations. Also, a comparative study of the cooperative effects between the cation-π and IMHB interactions in the various complexes of ortho-aminobenzaldehyde with its thio and seleno analogous analyzed in 2017 [23].
The main objective of this study is to explore the interplay effects between cation-π and IMHB interactions in the complexes of mesalazine with Li + , Na + , K + , Be 2+ , Mg 2+ and Ca 2+ cations. Hence, the different descriptors such as energetic, geometrical, spectroscopic and topological parameters are analyzed and their results are compared to the parent molecule of mesalazine and the 3-aminobenzoic acid (ABA) complexes with the cited cations as a set of suggestion points. For this work, the AIM and NBO analyses are performed by DFT calculations. The study is extended to the molecular orbital analysis to calculate the energy gap, global hardness and electronic chemical potential of the considered complexes. Due to the biological signi cance of these ions, it is important to study complexation with bioactive ligands to identify functions of their complexes and to discover new bioactive compounds.

Computational Methods
Theoretical calculations are performed using Gaussian 09 program package [24]. Density functional theory [25] has been shown to be a powerful and useful tool for the study of noncovalent complexes. In this work, the geometries are optimized by wB97XD method using 6-311 + + G(d,p) basis set [26]. This method involves the long-range correction with empirical atom-atom dispersion [27][28][29][30]. Frequency calculations are performed for complexes at the same level of theory. The absence of imaginary frequencies veri es that all structures are true minima. The binding energies (ΔE) are computed as the difference between the energy of the complex (AB) and the combination of the energies of the isolated species A and B as follows [31,32]: The binding energies are corrected for the basis set superposition error by the Boys-Bernardi counterpoise technique [33]. The QTAIM [34] analysis is performed with the help of AIM2000 program [35] on the wave functions obtained at the wB97XD/6-311 + + G(d,p) level of theory. The NBO analysis [36,37] gives an idea of the participation of each atomic orbital in the molecular bonds. This calculation is carried out using the version 3.1 of the NBO package [38] included in the Gaussian 09 program. Finally, the energies of the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) are computed to evaluate the physical properties of the studied complexes.

Results And Discussion
In order to study the mutual effects between IMHB and cation-π interactions, the complexes of MES level of theory are demonstrated in Table 1. As can be seen in this to the electrostatic attraction effects between the metal ions and the lone pairs of nitrogen and oxygen atoms of the NH 2 and OH functional groups connected to the benzene ring. In fact, the negative charges on these atoms can transfer a certain amount of electron density towards the metal ions. This leads to less attraction between the ions and the MES ring, which weakens the cation-π interaction strength in these systems.
In this investigation, the approximate values of the IMHB energies are estimated by the Espinosa and Molins method [39]. Herein, the hydrogen bond interaction energy (E HB ) may be correlated with the electronic potential energy at the bond critical point (Vr cp ) by the expression E HB = 1/2 V(r cp ) [39][40][41]. As observed in Table 1, the mutual in uences of the IMHB and cation-π interactions decrease the IMHB strength. It can be seen that the decline in the IMHB energies of MES complexes with respect to its monomer is in the range of 0.19-1.22, kcal mol −1 . Therefore, the IMHB strength for the studied complexes reduces in the following order: which has a reverse relationship with the ratio of charge-to-radius of cations. It is worth mentioning that the HB energies nicely correlate with the binding energies (ΔE BSSE ). The correlation coe cient (R 2 ) is equal to 0.9311. Table 1 The BSSE-corrected binding and IMHB energies (ΔE BSSE and E HB , in kcal mol -1 ), the the geometrical (bond lengths (d), in Å and bond angles (θ), in °) and spectroscopic descriptors (ν, in cm -1 ) of complexes calculated at the wB97XD/6-311++G(d,p) level of theory. The geometrical parameters of the quasi-ring created by the formation of HB are also analyzed to obtain a detailed insight into the nature of IMHB in the presence of cation-π interactions. For this purpose, we have considered the determining factors of HB strength, i.e., the HB distances and its corresponding angles [42]. As it is obvious from Figure 1, the predicted IMHB in the formation of complexes is O-H⋯O. It is well known that the which is in agreement with the charge-to-radius ratio of the cations. As shown in Figure 2, there are good correlations between the values of d H⋯O and d O-H versus the E HB ; the correlation coe cients (R 2 ) are equal to 0.9989 and 0.9365, respectively. These data also correlate very well with the binding energies (see Fig. 3).
Shift of stretching frequencies is another quantity that can be useful to evaluate the strength of NCIs. It is prominent that the stronger the binding energy is accompanied with the larger the frequencies shifting. Table 1 shows the stretching frequencies of the cation-π contact (ν π•••M ) for the analyzed complexes. As can be seen in this Shift of stretching frequencies is another quantity that can be useful to evaluate the strength of NCIs. It is prominent that the stronger the binding energy is accompanied with the larger the frequencies shifting. Table 1 shows the stretching frequencies of the cation-π contact (ν π•••M ) for the analyzed complexes. As can be seen in this which con rms the cation-π interaction for this complex is stronger than the ABA•••Be 2+ one.
In the quantum theory of atoms in molecules (QTAIM) [34,45], the electron density (ρ) and its Laplacian (s 2 ρ) along with the ρ gradient paths, reveal the structure of the system through its stationary points. The total electron energy density (H) and its components (G, kinetic electron energy density, and V, potential electron energy density) at the bond critical points (BCPs) are the other characteristics to investigation of these systems.
In the present study, the existence of cation-π interactions is con rmed by the BCPs formed between the different cations and the MES ring. The molecular graph of complexes shows one or two bond critical points in its structures, depending on the type of cation and π-system (see Fig. 4).
The topological properties of electron density calculated by AIM analysis are reported in Table 2. As it is obvious from this Table, in  Nevertheless in Be 2+ complexes, the corresponding H(r) value is negative, which means these interactions are at least partly covalent. Furthermore, the -G/V ratio can be applied as a criterion of the NCIs character [46,47]: for -G/V ≥ 1 the interaction is electrostatic, while for 0.5 < -G/V < 1, it is partly covalent. With the exception of Be 2+ complexes, the obtained −G/V π•••M values demonstrate that the cation-π interactions in the systems under consideration have the electrostatic nature (see Table 2). These results also con rm that the Be 2+ complexes are at least partly covalent.  Table 2 also displays the computed electron density properties of HB critical points for MES and its derivatives.
The existence of HB in the considered complexes is con rmed by the presence of corresponding bond path in the electron density (see Figure 4a). Theoretical results show that the coupling of the cation-π and IMHB  Table 2).
A better understanding of the molecular interactions in the complexes is provided by natural bond orbital (NBO) analysis. There is a signi cant π C=C → LP* M charge transfer between the cations and the MES ring in the studied complexes. The results of NBO analysis including second order perturbation interaction energy (E (2) ), charge transfer (Δq CT ) and occupancy of NBOs at the wB97XD/6-311++G(d,p) level of theory are given in Table 3. As observed in this show that the E (2) value of complexes increases in the following order π•••Be 2+ > π•••Mg 2+ > π•••Ca 2+ > π•••Li + > π•••Na + > π•••K + , which is in agreement with the ratio of charge-to-radius of cations. Table 3 displays the values of charge transfer (Δq (CT1) ) obtained for the explored complexes. From the difference of charges between free cation and complexed cation, the charge transfer amount between the aromatic ring and cation is calculated. Our data exhibit that the simultaneous presence of cation π and IMHB interactions diminishes the charge transfer (Δq (CT1) ) values for the MES complexes in comparison with ABA ones. These outcomes are directly proportional to charge transfer energyies (E (2) ).
In  Table 3. As can be seen in this  (2) is related to the K + and Be 2+ complexes, respectively. As shown in Table 3 Table 3 The values of E (2)   The amounts of the charge transfer (Δq (CT2) ) related to the IMHB are also reported in Table 3. As seen in this Table,  that the highest charge transfer (Δq (CT2) ) is observed for the K + complex and the lowest that is belonged to the Be 2+ complex. Therefore, the charge transfer may be a significant characteristic in determining the strength of these interactions.
The frontier orbitals (HOMO and LUMO) of the chemical species are very important in defining its chemical stability and reactivity [49,50]. An instance from the plots of HOMO and LUMO for the Li + complexes is illustrated in Figure 6. The HOMO energy describes the ability of electron giving; LUMO characterizes the capability of electron accepting [51]. The HOMO-LUMO energy gap (E g ), which is de ned as the HOMO-LUMO energy separation of a molecule, is a simple indicator of kinetic stability [52]. The quantum molecular descriptors such as softness (S), chemical hardness (η) [53], electronic chemical potential (μ) [54], global electrophilicity power (ω) [55] and electronegativity (χ) [56] for the studied complexes are presented in Table 4.
These descriptors are able to measure the whole response of an electronic system to a chemical perturbation [57]. The obtained relationships are as follows: where E HOMO and E LUMO are the energies of the HOMO and LUMO orbitals, respectively. The equation of electrophilicity index can be also evaluated as follows: From energy gap between HOMO and LUMO, one can nd whether the molecule is hard or soft. The larger the E g is attributed to the harder the molecule. It is well known that a large gap indicates high stability and a small gap shows high chemical reactivity. The η and μ are appropriate parameters for estimating the reactivity of molecules. In other words, the compounds with the values of lower η and higher |μ| will be more reactive because necessary electron transmissions for performance of a chemical reaction can be done in them more suitably [58,59]. It is clear from Table 4 that the values of negative μ indicate that all complexes are stable. The χ is de ned as the negative of μ, as: χ = -μ. Hence, the complexes having the highest χ value are the best electron acceptors. The ω is also a useful tool in predicting the reactivity of the molecule. It has been found that there is a correlation between the ω of various chemical compounds and the rate of reaction in the biochemical systems [60]. As it is apparent from Table 4, the presence of IMHB decreases the E g , η and χ descriptors for MES complexes in comparison with the ABA ones. In contrast, the indices of S, μ and ω show the greater values for these complexes. Our ndings also show that with the exception of Mg 2+ and Ca 2+ complexes, the coexistence of cation π and IMHB interactions increases the values of E g , η, χ and ω and decreases the descriptors of S and µ for MES complexes with respect to the parent molecule. As can be seen, both cation-π and HB interactions have reverse trend for these indices (except for ω), indicating that the effect of HB on the cation-π interaction is different from the effect of the cation-π interaction on HB.

MES•••Li + ABA•••Li +
In addition to the above-mentioned electronic descriptors, another index that gives the visual representation of the chemically active sites and comparative reactivity of atoms is the molecular electrostatic potential (MPE).
The MEP 3D plots of the Li + complexes are drawn in Figure 7. As observed, while regions having the negative potential are over the oxygen electronegative atoms (red and yellow colors), the regions having the positive potential are over Li + cations and plane of the MES ring (blue color).

Conclusions
In the present research, the effects of interplay between cation-π and IMHB interactions in the MES complexes with Li + , Na + , K + , Be 2+ , Mg 2+ and Ca 2+ cations are evaluated. In order to understand the mutual effects of these interactions, the geometrical parameters, binding energies, topological properties and charge transfer analysis are examined on the studied complexes and their results are compared to the corresponding values of ABA complexes and the parent molecule of MES as a set of reference points. According to the calculated descriptors, it can be concluded that the coupling simultaneously weakens both of the interactions (with the exception of Be 2+ complex). Our ndings also demonstrate that with the increment in the ratio of charge-to-radius of cations, the strength of cation-π interactions increases, while for IMHB interactions, the reverse process is observed. The results of molecular orbital analysis also show that both cation-π and HB interactions have reverse trend for the quantum molecular descriptors (except for ω), indicating that the effect of HB on the cation-π interaction is different from the effect of the cation-π interaction on HB. Several correlations are found between the energetic, geometrical and topological parameters. Hence, the interplay between these NCIs that are ubiquitous in biological systems may be important in many areas of the supramolecular chemistry.