key: cord-0766299-8c02aj85
authors: Ashfaq, Muhammad; Tahir, Muhammad Nawaz; Muhammad, Shabbir; Munawar, Khurram Shahzad; Ali, Saqib; Ahmed, Gulzar; Al-Sehemi, Abdullah G.; Alarfaji, Saleh S.; Ibraheem Khan, Muhammad Ehtisham
title: Shedding Light on the Synthesis, Crystal Structure, Characterization, and Computational Study of Optoelectronic Properties and Bioactivity of Imine derivatives
date: 2022-02-02
journal: ACS Omega
DOI: 10.1021/acsomega.1c06325
sha: 1908383eb55fcd7a083385fc042d9c6bcb04f491
doc_id: 766299
cord_uid: 8c02aj85

[Image: see text] Two imine compounds named as (E)-2-(((3,4-dichlorophenyl)imino)methyl)phenol (DC2H) and (E)-4-(((2,4-dimethylphenyl)imino)methyl)phenol (DM4H) are synthesized, and their crystal structures are verified using the single-crystal X-ray diffraction (XRD) technique. The crystal structures of the compounds are compared with the closely related crystal structures using the Cambridge Structural Database (CSD). The crystal packing in terms of intermolecular interactions is fully explored by Hirshfeld surface analysis. Void analysis is carried out for both compounds to check the strength of the crystal packing. Furthermore, a state-of-the-art dual computational technique consisting of quantum chemical and molecular docking methods is used to shed light on the molecular structure, optoelectronic properties, and bioactivity of indigenously synthesized compounds. The optimized molecular geometries are compared with their counterpart experimental values. Based on previous reports of biofunctions of the indigenously synthesized imine derivatives, they are explored for their potential inhibition properties against two very crucial proteins (main protease (M(pro)) and nonstructural protein 9 (NSP9)) of SARS-CoV-2. The calculated interaction energy values of DC2H and DM4H with M(pro) are found to be −6.3 and −6.6 kcal/mol, respectively, and for NSP9, the calculated interaction energy value is found to be −6.5 kcal/mol. We believe that the current combined study through experiments and computational techniques will not only pique the interest of the broad scientific community but also evoke interest in their further in vitro and in vivo investigations.

Schiff bases belong to an important class of ligands bearing an imine or azomethine (−CN−) functional group. Hugo Schiff, a German scientist and Nobel Prize laureate, prepared the first of these condensation products from primary amines and carbonyl compounds in 1864. 1, 2 The Schiff base is a structural counterpart of a ketone or aldehyde that has had the carbonyl group (CO) replaced with an imine or azomethine group. 3 Schiff bases are very vital due to their ease of synthesis, availability, and electrical characteristics, particularly in the synthesis of metal complexes via azomethine nitrogen. 4,5 Schiff base coordination chemistry has gotten a lot of interest because of its important functions in analytical chemistry, metal refining, organic synthesis, metallurgy, electroplating, and photography. 6,7 Schiff bases not only play an important role in advanced coordination chemistry but also are equally significant in bioinorganic chemistry. 8 They have a wide range of medical uses due to their pharmacological characteristics because of the presence of an azomethine (CN) linkage. 9 As a result, antibacterial, anticancer, antifungal, and diuretic properties have been described for many azomethines. 10, 11 In addition to this, Schiff bases have a wide range of uses in the food and dye industries and also in catalysis and agrochemical activities. 12 The relevance of metal complexes of Schiff bases in catalysis, supramolecular chemistry, separation and encapsulation processes, materials science, biological applications, and the creation of molecules with unique characteristics and molecular structures has long been recognized. 13 The azomethine nitrogen of Schiff bases offers a binding site for metal ions to be linked to different biomolecules such as proteins and amino acids for antigerm actions in biological systems. 14 Various studies have shown the enhanced biofunctionalities of Schiff bases as compared to their metal complexes. Depending on the transition metal ions present in Schiff bases, they exhibit antibacterial, antifungal, antiviral, antiulcer, and anticancer properties. 15, 16 Using ring closure, cycloaddition, and replacement processes, Schiff bases have been used as synthons in the creation of a variety of commercial and physiologically active chemicals such as formazans, 4-thiazolidinines, benzoxazines, and so on. 17, 18 The use of Schiff base derivatives in a variety of processes prompted researchers to create new Schiff bases for the development of environmentally friendly technologies. 19 Hirshfeld surface analysis 20 is an excellent way to explore the noncovalent interactions that are the key feature of the crystal packing of molecules in the solid state. We explore Hirshfeld surface analysis for DC2H and DM4H. Therefore, in continuation of our previous studies on Schiff bases and their metal complexes, 21−23 this time, we are reporting a completely experimental and computational study of two new Schiff bases named as DC2H and DM4H. A triple hybrid technique consisting of experimental, quantum chemical, and molecular docking methods will be used to investigate the above-synthesized molecules. The quantum chemical methods provide several fundamental insights into the structure− property relationship, which are incomprehensive with simple characterization techniques. Similarly, an in silico study through molecular docking highlights the potential of the studied ligands for their possible use as bioactive compounds against certain diseases, which we will assess for the inhibition of SARS-Co-V-2 in the current investigation.

The Cambridge Structural Database (CSD) search confirms that the crystal structures of the tilted compounds are new. Moreover, a CSD search is performed to find the crystal structures that are closely related to our crystal structure. The closely related crystal structures are compared with the crystal structures of the titled compounds in terms of molecular configuration and crystal packing. Table 1 provides complete  SC-XRD details of the titled compounds, whereas Table 2 provides a comparison of selected bond lengths and bond angles of the titled compounds.

2.1. SC-XRD Description of the Crystal Structure of DC2H and DM4H. In DC2H (Figure 1a , Table 1) , o-cresol group A (C1-C7/O1) and 3,4-dichloroaniline group B (C8-C13/N1/Cl1/Cl2) are oriented at the dihedral angle of 6.8 (9) °with respect to each other, which indicates that the whole molecule is almost planar. The titled compound adopts a phenolic tautomeric form instead of a keto tautomeric form, as evident from the O1−C1 bond length of 1.360 (4) Å and the N1−C7 bond length of 1.278 (4) Å. Important bond lengths and bond angles of the titled compounds are given in Table 2 . The molecular configuration is stabilized by the presence of intramolecular H-bonding of type O-H···N to form an S (6) H-bonded loop. The molecules are interlinked by the weak H-bonding of type C-H···Cl to form an infinite C12 zigzag chain that runs along the c crystallographic axis ( Figure 2 , Table S1 ). The neighboring chains are interlinked by a comparatively weak interaction of the off-set π···π stacking type. Phenyl rings (C1−C6) of symmetry-related In DM4H (Figure 1b , Table 1 ), p-cresol group A (C9-C15/O1) and 2,4-dimethylaniline group B (C1-C7/N1) are oriented at a dihedral angle of 72.4 (8)°with respect to each other. The important bond lengths and bond angles of the titled compound are given in Table 2 . The molecular configuration is stabilized by the presence of intramolecular H-bonding of type C-H···N to form an S (5) H-bonded loop. The molecules are interlinked by a strong O-H···N bonding to form a C8 zigzag chain that runs along the crystallographic a-axis, as given in Table S1 and shown in Figure 4 . A comparatively weak H-bonding of type C-H···O is found in the crystal packing that interlinks the molecules in such a way that an infinite C5 chain is formed that runs along the c crystallographic axis, where CH is from the phenyl ring (C10−C15). No other type of weak intermolecular interaction is found in the crystal packing. A Cambridge Structural Database search provides two crystal structures that are most closely related to the crystal structure of the titled compound that contains one 4-hydroxyl-substituted phenyl ring, while the substitution on the other phenyl ring is different from the dimethyl-substituted phenyl ring in DM4H. Reference codes are SECXAB 26 (with one methyl Powder XRD patterns (PXRD) of the simulation-based single-crystal XRD using a cif file were generated to get more details about the crystallinity of both compounds. This simulated XRD pattern represents sharp peaks for both DC2H and DM4H compounds ( Figure S1 ). The results showed that the obtained compound is highly crystalline. Xpert HighScore Plus software was used to obtain the simulated pattern. The five most intense peaks were hklindexed on a simulation basis.

Analysis. The Hirshfeld surface (HS) analysis tool is used by crystallographers and crystal engineers to see strong and weak intermolecular interactions that also exert influence on the molecular packing in crystals. This analysis was performed using Crystal Explorer version 21.5. 28 HS was mapped over d norm (function of normalized distances), d e (distance from a specific point on the mapped surface to the closest atom outside), and d i (distances from a particular point on the surface to the nearest atom inside). 29,30 HS d norm mapping uses blue, white, and red colors to distinguish between the interatomic contacts that are longer, at Van der Waals separations, and short interatomic contacts, respectively. 31,32 Figure 5a ,b represents the HS of DC2H and DM4H mapped with d norm to view the distinctive red spots, demonstrating specific points of contact in the crystal (see close contacts in a unit cell Figure S2a ,b). The red spots (bright and faint) can be classified as potential hydrogen bonds. The shape index property was used to map the HS views of DC2H and DM4H, which represent the red and blue triangular regions shown in Figure 5c ,d, respectively. Here, bright-red spots indicate the π···π stacking between the six-membered rings. 33, 34 Similarly, HS curvedness mapping also shows the π···π stacking, which is obvious because of the flat regions around the carbon rings ( Figure S3a,b) . Figure  5e ,f shows the electrostatic potential, while Figure 5g ,h shows the deformation density for DC2H and DM4H, respectively. Deformation of the electron density is displayed with positive (blue) and negative (red) isosurfaces.

The 2D fingerprint plots are a way to explore the crystal packing of the single crystals in terms of interatomic contacts and their contribution to the crystal packing. 35 2D fingerprint plots is shown in Figure 6 . The central triangular region of sky-blue color in 2D fingerprint plots for overall interactions of DC2H ( Figure 6a ) and AWUSIV (Figure 6f) indicates the presence of the π···π stacking interaction in the crystal packing. The most important interatomic contact for DC2H is H···H with a percentage contribution of 28.1% (Figure 6b) , whereas for AWUSIV, the most important interatomic contact is Cl···H with a percentage contribution of 42.8% (Figure 6h ). In AWUSIV, the H···H interatomic contact has a percentage contribution of 16.9% (Figure 6g ). The Cl···H interatomic contact has a larger contribution in AWUSIV as compared to in DC2H because the crystal structure of AWUSIV contains a trichloro-substituted phenyl ring, whereas the crystal structure of DC2H contains a dichloro-substituted phenyl ring. The 2D fingerprint plots for the overall interactions of DM4H and TAMYOY contain two large spikes. These spikes show an N···H contact with a percentage contribution of 4.2% in DM4H (Figures 6o) and 5.2% in TAMYOY (Figure 6t ). The most important interatomic contact for DM4H and TAMYOY is H···H with a percentage contribution of 56% in DM4H (Figures 6l) and 51.5% in TAMYOY (Figure 6q ). The 2D plots of C···H and O···H for DM4H and TAMYOY are also compared in Figure 6 with their contribution to the crystal packing.

Crystal Explorer 21.5 was used to calculate the interaction energy between pairs of molecules 37 ( Figure S4a,b) . The interaction energies were calculated based on two models: CE-B3LYP/6−31G(d,p) and CE-HF/3−21 G; furthermore, the 6−31 G basis set was used for both compounds. The total energy E was calculated in kJ/mol. E tot is the individual sum of four factors: electrostatic (E ele ), polarization (E pol ), dispersion (E dis ), and exchange repulsion (E rep ). All calculations for the pairs of molecules are provided in Table S2 for DM4H and in Table S3 for DC2H. The total energy stabilizes the crystal packing with interaction energies of −32.8 kJ/mol (DC2H) and −57.6 kJ/mol (DM4H) for both molecules. Our analysis for these two molecules shows that they have the following components: electrostatic (4.5 kJ/mol), polarization (−3.2 kJ/mol), dispersion (−66.3 kJ/ mol), and repulsion (+33.1 kJ/mol) for the DC2H molecule and electrostatic (−69.7 kJ/mol), polarization (−23.7 kJ/ mol), dispersion (−34.6 kJ/mol), and repulsion (+74.0 kJ/ mol) for the DM4H molecule. Based on the analysis of interactions in the crystal structure, it is implied that DM4H can be preferred at a supramolecular level.

The energy frameworks were simulated to give information about the contribution of the total energy. 38 Figure S5 shows the energy framework that gives visual understanding as cylinders joining the molecules (interaction pairs). Here, we fixed the radius of the cylinder at 100 kJ/mol. The color of the cylinders represents the specific type of energy, such as red cylinders for E ele (Coulomb's interaction energy), green cylinders for E dis (dispersion energy), and blue cylinders for E tot (total energy). This approach is very useful for crystal engineers to deeply understand the mechanical behavior of the compounds at a molecular level. The energy frameworks revealed that the packing topology in terms of electrostatics is predominantly guided by DM4H and the dispersion energy topology is supported by π···π stacking.

3.1. Computational Methodology. All the quantum chemical calculations have been performed using the Gaussian 16 suite of programs. 39 The density functional theory method has been used to optimize the geometries of compounds DC2H and DM4H with the M06/6-31G* method. After optimizations, frequency calculations have been performed to get the global minimum structures with all positive frequencies for the compounds DC2H and DM4H. The AutoDock Vina program 40 is used for performing molecular docking studies with all default parameters. MGL tools 41 and Discovery Studio Visualizer 42 were used for input file preparation and output result visualization, respectively. Several attempts were made to get the most suitable docking models by doing several replicated docking calculations. Further essential details for protein and ligand preparations and other default parameters for docking studies can be seen in the Supporting Information of the article and also in our previous studies. 43 3.2. Optimized Molecular Geometries of DC2H and DM4H. The optimized geometries of compounds DC2H and DM4H are given in Figure 7 , where their respective experimental values are given in parenthesis. A careful analysis of Figure 7 shows that calculated and experimental geometries are in reasonable agreement. For DC2H, the experimental and calculated C 18 -N 5 bonds are found to be 1.409 and 1.404 Å, respectively. Similarly, the experimental and calculated C 16 -N 5 bonds are found to be 1.278 and 1.289 Å, respectively, in DC2H. The two calculated (experimental) halogen carbon bonds, C 21 -C l1 and C 22 -Cl 2 , are illustrated as 3.3. Frontier Molecular Orbitals (FMOs) and Molecular Electrostatic Potentials (MEPs). The FMOs play a very vital role in the reactivity and stability of molecular compounds. To comprehend the insights into the distribution of FMOs, we depict the HOMO and LUMO of the entitled compounds as shown in Figure 8a . There is a uniform distribution of electron density for the respective HOMO and LUMO orbitals over the surface of both entitled molecules. The dimethyl phenyl group of DM4H shows a slight donor behavior owing to its two methyl groups, where electron density moved away from the dimethyl phenyl moiety as seen in the HOMO and LUMO of DM4H. The HOMO−LUMO energy gaps of DC2H and DM4H compounds are also shown along with their individual orbital energies. The orbital energy gap of the DM4H compound is 4.59 eV, which is slightly larger (0.1 eV) as compared to that of DC2H (4.49 eV). The slight difference is due to the similar skeleton of both molecules. Furthermore, the electrostatic molecular potentials are also depicted to see the distributions of the local potential over the total electron density surface as color coding (Figure 8b) . The red and blue colors indicate the negative and positive regions of electron density of the total electron density surface, respectively. In DC2H and DM4H molecules, the negative potentials are seen around the Cl and OH groups, making them vulnerable to electrophilic attacks, while positive regions can be seen as less prominent.

Computational chemistry has emerged significantly as a tool of trust with recent progress in algorithm developments. Molecular docking, a subfield of computational chemistry and bioscience, is providing several quick insights into the modern drug designing process. The cornerstone of molecular docking is based on the fact that most biological functions are controlled by specific proteins, and if a molecule shows the potential to interact with such specific proteins, it may also have the potential to inhibit the function of such proteins. Recently, several cutting-edge research reports from nature and science journals have also employed molecular docking methods to get insights into their research results. 44, 45 Along these lines, two very crucial proteins, M pro and NSP9 of SARS-CoV-2, are selected to study their interactions with indigenously synthesized ligands. Phenols constitute the largest class of bioactive compounds on the earth, which are usually formed through the secondary metabolites of plants. The antioxidant and anti-inflammatory properties of phenols are well-reported. Recent studies have highlighted their potential for possible antiviral potential as demonstrated by their efficacy against several pathogens, including influenza virus, enterovirus, and a class of coronaviruses. 46 As the COVID-19 disease (caused by SARS-CoV-2) has divested the world health sector and created a pandemic, it is very imperative to turn every stone to find a potential therapeutic drug candidate. Along the abovementioned lines, using molecular docking techniques, the current study also explores a few promising pieces of evidence for the antiviral potential of the above-entitled compounds.

4.1. Calculation of Binding Energy. The binding energy of docked ligands and protein molecules is a combination of many kinds of interaction energies, which are calculated during the docking of the ligand with a protein.

Binding energy plays a crucial role in establishing the stability of a ligand−protein complex. More negative binding energy reflects a more stable protein−ligand complex. Table 3 discloses the binding energy and inhibition constant values for both proteins (M pro and NSP9). The binding energy values of DC2H and DM4H with M pro are −6.3 and −6.6 kcal/mol, respectively (see Table 3 ). The inhibition constant values of these two compounds with M pro and NSP9 are 23.18 and 13.94 μmol, respectively. DC2H and DM4H have similar binding energies and inhibition constant values with the NSP9 protein, which are −6.5 kcal/mol and 16.52 μmol, respectively (see Table 3 ). The negative binding energies indicate the favorable interactions of the synthesized compounds with M pro and NSP9 proteins of SARS-CoV-2. Recently, Burkhanova et al. studied aniline dyes through molecular docking, which showed binding affinity towards M pro with a binding energy value of about −7.6 kcal/mol. 47 A more relevant molecular docking study was about hydroxystilbamidine as M pro inhibitors, where the imine group in the compound forms hydrogen bonds with aspartic acid moieties of M pro as our current DC2H compound with histidine. 48 Furthermore, a semiquantitative comparison of binding energies of DC2H and DM4H, so-called standard drug molecules, shows that the binding energy with M pro is better than the previously calculated value of chloroquine (−5.20 kcal/mol) and hydroxyl chloroquine (−5.60 kcal/mol) and comparable to that of Remdesivir (−7.00 kcal/mol), 49 which is a recently used drug against SARS-CoV-2.

4.2. Details of Intermolecular Interactions. The M pro and NSP9 proteins show various intermolecular interactions, including H-bonds and hydrophobic and electrostatic interactions. All these interactions with amino acid residues and their bond lengths are given in Table 4 and Figure 9 . Figure 9 shows 3D orientations, while an overview of 2D interactions is provided in Figure S6 of the Supporting Information for ligand−protein interactions where both types of visualizations are commonly used in molecular docking studies. DC2H exhibited two conventional H-bond interactions with His41 (2.41 Å) and Gln189 (2.22 Å) amino acid residues of M pro . It also shows two electrostatic interactions with His41 (2.90 Å) and Cys145 (4.99 Å) amino acid residues. DC2H exhibits three hydrophobic interactions, which are alkyl, π-alkyl, and π···π stacking interactions with Met49 (5.12 Å), Met165 (4.82 Å), and His41 (4.83 Å) amino acid residues, respectively. In interactions of DC2H with M pro , the amino acid residue His41 has an active role as it revealed all H-bonds and hydrophobic and electrostatic interactions. DC2H with NSP9 showed two types of interactions: conventional H-bonding and hydrophobic interactions. The conventional H-bonding interactions are with Gly38 (2.36 Å) and Gly39 (2.54 Å) amino acid residues. The hydrophobic interactions are with Phe41 (4.06 Å), Phe57 (4.20 Å, 5.18 Å), Ile92 (4.34 Å), Ile66 (4.21 Å), and Val42 (3.90 Å, 3.70 Å, and 5.43 Å). Figure 9 shows the 3D interactions of DC2H with M pro and NSP9 proteins. Interestingly, as all the interactions between ligands and proteins can be broadly divided as polar and nonpolar, we have presented the density surface representations of polar and nonpolar interacting residues of the binding pockets as shown in Figure S7 . The interactions of DC2H and DM4H with the M pro protein are represented in Figure S7a ,b, respectively, where the total density surface of the protein is illustrated in cyan, polar areas are symbolized in magenta, and nonpolar areas are illustrated in yellow. The Nsp9 interactions with DC2H and DM4H are illustrated in Figure  S7c ,d, where the total density surface of the protein is shown in a warm-pink color, the polar area is denoted in green, and the nonpolar area are shown in yellow. An overview of polar and nonpolar surfaces signifies their respective contributions to assessing the nature of interactions in a semiquantitative way.

Two crystalline imine compounds, DC2H and DM4H, are synthesized efficiently, and their crystal structures are confirmed using the single-crystal X-ray diffraction technique. The crystal structures of these compounds are fully explored in terms of molecular configuration, intramolecular Hbonding, and intermolecular H-bonding. Moreover, a Cambridge Structural Database (CSD) search is carried out to find closely related crystal structures, and then, these crystal structures are compared with those of DC2H and DM4H. Intermolecular interactions that are the main aspect of the crystal packing of both compounds are further explored by Hirshfeld surface analysis. The quantum chemical and molecular docking calculations were performed to study the optoelectronic and antiviral potential of the synthesized compounds. The possible inhibition properties against two very crucial proteins (M pro and NSP9) of SARS-CoV-2 were studied through molecular docking. The calculated binding energies of DC2H and DM4H with M pro are found to be -6.3 and -6.6 kcal/mol, respectively, where negative energies indicate the favorable interactions of the synthesized compounds with the above-studied proteins of SARS-CoV-2. Thus, we have successfully not only synthesized these compounds but also investigated their potential functional properties.

6. EXPERIMENTAL SECTION 6.1. Material and Methods. The different solvents and precursors employed in the present experimental work were highly pure and purchased from Acros Organics, Alfa Aesar, and Sigma-Aldrich/Merck and were used as received.

6.2. Synthesis of Schiff Bases DC2H and DM4H. The precursors, 2,4-dimethylaniline or 3,4-dichloroaniline (5 mmol), were dissolved in 25 mL of ethanol, to which an ethanolic solution (25 mL) of equimolar quantities (5 mmol) of 2-hydroxybenzaldehyde or 4-hydroxybenzaldehyde was added dropwise. The reactants were refluxed for 2 h, and then, the clear solution was left for crystallization until the light-yellow needle-shaped crystals of DC2H and colorless rod-like crystals of DM4H were grown at the bottom and along the sidewall of the container. The crystals were separated by decantation and then dried gently under the folds of filter paper (Scheme 1). 

ACS Omega http://pubs.acs.org/journal/acsodf Article 6.3. X-ray Data Collection and Refinement Details. We collected the X-ray data of DC2H and DM4H on a Bruker Kappa Apex-II CCD diffractometer. The diffractometer contains an X-ray tube to generate monochromatic rays (λ = 0.71073 Å). Bruker APEX-II, 50 SHELXS-97, 51 and SHELXL 2018/3 52 are employed for data collection, structure solution, and refinement, respectively. Refinement of all nonhydrogen atoms is performed using ADP (anisotropic displacement parameters), while the refinement of H-atoms is performed using isotropic displacement parameters and using the riding model. The H-atoms are inspected by the keen observation of residual peaks using refinement of data. Mercury 4.0 53 and Platon 54 software tools are employed for the sake of graphics related to XRD.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.1c06325.

PXRD stick-like patterns of the simulation by singlecrystal analysis of DC2H and DM4H using Xpert High Score Plus software ( Figure S1 ); HS over d norm with the neighboring molecules for DC2H and DM4H ( Figure S2) ; HS plotted over curvedness in the range from −0.4 to 4 a.u. for DC2H and DM4H ( Figure  S3 ); interaction energies based on unperturbed electron distributions computed at the B3LYP level of theory employing the 6−31G basis set and scaled appropriately for DC2H and DM4H ( Figure S4) ; energy frameworks of E ele (coulomb energy), E dis (dispersion energy), and E tot total energy diagrams of DC2H and DM4H ( Figure S5 ); 2D interactions of DC2H and DM4H with amino acid residues of M pro (green ligands) and Nsp9 (red ligands) proteins, 2D interactions of DC2H and DM4H with the M pro protein, 2D interactions of DC2H and DM4H with the Nsp9 protein ( Figure S6 ); density surface representation of polar and nonpolar interactions of M pro and Nsp9 proteins in their binding pockets, and interactions of DC2H and DM4H with the M pro protein ( Figure S7 ); hydrogen-bond geometry (Å, deg) for DC2H and DM4H (Table S1 ); interaction energies of DC2H using Crystal Explorer 21 (in kJ/ mol) (Table S2) ; interaction energies of DM4H using Crystal Explorer 21 (in kJ/mol) ( 

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The authors declare no competing financial interest.