Spectroscopic and Electronic Analysis of Chelation Reactions of

Article pubs.acs.org/jced

Cite This: J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Spectroscopic and Electronic Analysis of Chelation Reactions of Galangin and Related Flavonoids with Nickel(II) Yamina A. Dávila,*,† Matías I. Sancho,‡ María C. Almandoz,‡ and Estela Gasull‡ INTEQUI−CONICET−Fac. de Química, Bioquímica y Farmacia, Á rea de Química Física, Universidad Nacional de San Luis, San Luis 5700, Argentina ‡ IMIBIO−CONICET−Fac. de Química, Bioquímica y Farmacia, Á rea de Química Física, Universidad Nacional de San Luis, San Luis 5700, Argentina †

S Supporting Information *

ABSTRACT: The stoichiometry and apparent stability constants (β) of the complexes formed between Ni2+ and four different hydroxyflavones (3-hydroxyflavone, 5-hydroxyflavone, chrysin, and galangin) were determined in methanolic solutions. A multivariate curve resolution methodology was applied to estimate the β values using UV−vis spectroscopic data. All the complexes exhibit 1:2 metal:ligand stoichiometry. The highest and lowest β values were obtained for the galangin and 5-hydroxyflavone complexes, respectively. The formation of the complexes was confirmed by Fourier transform infrared spectroscopy. Time-dependent density functional theory and natural transition orbital analysis were performed to describe the spectroscopic features of the studied compounds, and quantum theory of atoms in molecules was applied to evaluate different intermolecular interactions. Good correlations were obtained between the calculated UV−vis absorption spectra using the M06 functional and the experimental ones. The main absorption band of these Ni2+ complexes have an important metal-to-ligand charge transfer mixed with an intraligand charge transfer (ILCT). Two possible chelation sites were considered for the interaction of Ni2+ with galangin. The combination of spectroscopic and quantum chemistry calculations results indicate the existence of an equilibrium between the two carbonyl-hydroxyl sites of galangin in the Ni2+ complex formation.

1. INTRODUCTION Flavonoids are polyphenolic compounds of low molecular weight1 with a basic structure derived from the benzo-γ-pyrone or chromone. They are widely distributed in the vegetal kingdom and are important components of the human diet.2−4 Many relevant biological properties of these compounds like the antiviral,5 antibacterial,6 cytotoxic,7,8 antitumoral,9 and vascular protective activity, among others, are constantly under study. It is known that several biological and physicochemical properties of the flavonoids are strongly related to their structural features.10,11 For example, the antibacterial activity and the metal complexing ability of flavones are mainly affected by the presence of OH groups in C3 and/or C5, next to the carbonyl group.12−14 In the same way, the antioxidant activity and enzyme inhibitory effects are associated with the presence of a catechol group in the B ring of the molecule and a resorcinol group in the A ring.15 Wang et al. analyzed the antioxidant and anti-inflammatory activity of fisetin, kaempferol, morin, myricetin, and quercetin, and despite the fact that these flavones are structurally related, their biological activities varied considerably.16 For this reason, the structure−activity relationships of these compounds are of great interest. The ability of flavones to act as complexing agents of several metal cations is one the most relevant properties of these molecules. This ability is associated with the presence of the 4-carbonyl-5-hydroxyl and 4-carbonyl-3-hydroxyl groups in the flavones, as well as with catechol derivatives in B ring.14,17 © XXXX American Chemical Society

There are many studies regarding the preferential chelation site of polyhydroxylated flavones with biologically relevant metals. For example, it is known that the complexation of Al3+ with hydroxyflavones in the 4-carbonyl-3-hydroxyl site is favored in neutral and acidic media, while in alkaline solutions the catechol group (ring B) is the preferred site.18 In some cases, the metal−ligand interaction may affect the ligand properties, resulting in different biological effects.17,19,20 It was observed that inhibitory effects of many isoflavones against human cancer cell lines were enhanced through complexation with Ni2+ and Mn2+ ions. These complexes showed a higher activity and selectivity than other metallic complexes analyzed for the same cancer cell lines.21 Other examples for this enhanced biological activity are the complexes of Cu2+, Ni2+, Co2+, Zn2+, Fe3+, Cr3+, Cd2+, and Mn2+ with the natural product 5-hydroxy-7,4′-dimethoxyflavone. The antibacterial activity of these compounds was tested and appeared to be more active than that of the free ligand.22 Additionally, it has been reported that the Ni2+ complexes with quercetin and 3-hydroxyflavone with a 1:1 stoichiometry adopt a nonplanar conformation. Nonplanar structures display a lesser interaction with membrane components than planar structures. Therefore, the improvement in the biological activities of flavonoids on complexation may be due to their ability to alter membrane fluidity and permeability.22 Received: December 4, 2017 Accepted: April 16, 2018

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DOI: 10.1021/acs.jced.7b01058 J. Chem. Eng. Data XXXX, XXX, XXX−XXX

Journal of Chemical & Engineering Data

Article

β = [NiaLb]/([Ni]a [L]b )

In this context, the study of the chelation sites influence and the molecular geometry of flavonoid metallic complexes on biological properties is necessary. It must be noted that the molecular structure of the complexes strongly depends on the type of metal used and the general synthesis conditions. In the present study, a systematic analysis on the complexing ability of four hydroxyflavones was carried out. The complex formation of 3-hydroxyflavone (3OHF), 5-hydroxyflavone (5OHF), 5,7-dihydroxyflavone (chrysin, CRY), and 3,5,7-trihydroxyflavone (galangin, GAL) with Ni2+ in methanolic solutions was studied using spectroscopic methods. Moreover, density functional theory (DFT) calculations were employed to characterized the molecular structure of the complexes and identify the metal−ligand interactions that stabilized these compounds.

(1)

where L is the free ligand and NiaLb the metallic complex. 2.3. FTIR Spectroscopy. The infrared spectra of the free ligands and the metallic complexes were registered in the 4000− 400 cm−1 region using a Shimadzu IR Affinity-1 spectrophotometer with a spectral resolution of 2 cm−1. The spectra were registered after deposition of the sample solution on the surface of KBr pellets, following published recommendations for these kind of complexes.26 2.4. Computational Detail. The molecular geometries of 3OHF, 5OHF, CRY, GAL, and their Ni2+ complexes were fully optimized using the hybrid DFT functional B3LYP.27,28 For the nickel atom, the Los Alamos double-ξ (LANL2DZ) effective core potential was implemented, and for the rest, the 6-31+G(d,p) basis set was used. Stability check of the SCF solution was performed for all the complexes to evaluate possible spin contaminations. The harmonic vibrational frequencies of the free ligands and the complexes were performed to obtain the thermodynamic parameters and verify that the obtained molecular structures were true minima. An ultrafine integration grid was specified to reduce numerical integration errors, and the zero point vibrational energies were corrected using a scaling factor of 0.9825.29 The solvent effect on the gas-phase optimized structures was analyzed using polarizable continuum models (IEF-PCM and SMD),30,31 and the UAHF radii set was employed to build the solvent cavity. The vertical excitation energies and the corresponding absorption wavelengths of the complexes were calculated within the nonequilibrium time-dependent density functional theory (TD-DFT) framework.32 For this purpose, six functional were tested: the global hybrid functionals B3LYP,27,28 PBE0,33 and M06,34 and the long-range corrected functionals wB97XD,35 CAM-B3LYP,36 and LC-wPBE.37 These calculations were carried out with the same basis set employed for the optimizations and with the IEF-PCM model. The electronic transitions were analyzed using natural transition orbitals (NTO),38 which provides a good representation of the electronic transitions in terms of single particles. All of these calculations were performed with the Gaussian 09

2. EXPERIMENTAL DATA 2.1. Reagents. Flavonoid chemical structures studied in the present work are shown in Figure 1. 5OHF, CRY, and GAL were

Figure 1. Chemical structures, numbering system, and UV−vis absorption range of the studied flavonoids.

purchased from Merck and used without further purification. 3OHF was synthesized based on the Algar−Flynn−Oyamada23 reaction and purified by successive crystallization from MeOHH2O. The purity control and characterization of the compound was performed according to a previously reported procedure.24 Anhydrous nickel chloride (NiCl2) was purchased from Fluka; sodium chloride (NaCl) and spectroscopic grade MeOH were purchased from Merck. 2.2. UV−Vis Spectroscopy. The UV−vis spectra were recorded on a Cary 50 UV−visible spectrophotometer in the 200−500 nm range. Methanolic solutions of 3OHF (7.02 × 10−5 mol·kg−1), 5OHF (7.77 × 10−5 mol·kg−1), CRY (4.58 × 10−5 mol·kg−1), and GAL (3.89 × 10−5 mol·kg−1) were prepared. Then, different volumes of the NiCl2 stock solution (5.47 × 10−3 mol·kg−1) were added to the flavonoids reaction mixture. All of these series of samples were placed in UV cells, hermetically closed, and thermostatized at 298.15 K for 15 min. The ionic strength was kept constant (0.01 mol·kg−1) by the addition of NaCl. The equilibrium data from the recorded spectra were analyzed using a multivariate curve resolution methodology with the ReactLab Equilibria 1.1 Software.25 The number of species that contribute to the absorption spectra were determined using a factor analysis procedure (EFA). The best fit between several complexation models and the experimental data was obtained. The apparent stability constant (β) derived from the fitting process can be defined as follows:

Table 1. Maximum Absorption Wavelengths (λmax) of the Studied Hydroxyflavones and the Corresponding Ni2+ Complexesa λ (nm) 3OHF complex 5OHF complex CRY complex GAL complex

305 343b 420b 372.54c 270.2 336b 409b 367.27c 267.46 312b 400b 366.1c 266.1 358.9b 424b 385c

εL (L mol−1cm−1)d 16954 152.68

εC (L mol−1cm−1)d 20205 17943

5965.2 149.28

8813.5 7578.8

16774 337.41

24438 6090.7

12604 243.72

14917 11054

a εL and εc are the molar absorptivity of the ligand and the complex at λmax, respectively. λ is wavelength. bMain absorption band. cIsosbestic point. dMolar absorptivity at λmax.

B



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Table 2. Apparent Formation Constants (as log β) of the Studied Complexes in MeOH at 25 °C Calculated with the ReactLab Equilibria Software log β 3OHF 5OHF CRY GAL a

9.759 9.031 9.135 9.891

± ± ± ±

σa 102

SSQb

1.11 2.52 1.18 1.26

0.623 0.355 0.435 0.322

9.35·10−3 1.74·10−2 9.71·10−3 1.91·10−2

Important shifts were observed in the main absorption bands of all the analyzed ligands. The Ni2+ complexation in methanol induces in band I a bathochromic shift of 73 nm for GAL, 67 nm for 5OHF, 77 nm for 3OHF, and 75 nm for CRY. The characteristic maximum absorption wavelengths of each complex and the corresponding molar absorptivities are reported in Table 1. The highest bathochromic shift was observed for the complex formation with 3OHF. The spectral analysis performed using the ReactLab Equilibria software revealed a 1:2 metal:ligand stoichiometry for all the studied complexes. The stability constants (β) calculated according to this model are shown in Table 2. It is important to note that the β values of these complexes are all fairly high. The Ni:GAL2 complex has the highest stability constant, followed by Ni:3OHF2, Ni:CRY2, and Ni:5OHF2. It can also be observed that the β values of the flavones with one OH group in C3 (α site) are higher than the corresponding values of the flavones with one OH in C5 (β site). This trend may suggest that in polyhydroxylated flavones, such as GAL, the coordination with the metal atom involves the α site, rather than the β site.44 A possible explanation for this behavior lies in the acid−base properties of the monohydroxylated flavones. The pKa of 5OHF (11.58) is higher than the pKa of 3OHF (8.51), and the intramolecular H-bond with the carbonyl group is stronger in 5OHF.45 For this reason, 3OHF can be ionized more easily to form the anionic species, which is the reactive form in the formation of the metallic complex.17 In addition, the β value in Ni:CRY2 is higher than that in Ni:5OHF2, suggesting that the OH in C7

σ, standard deviation. bSSQ, sum of squares.

software package.39 As additional support to molecular analysis, Fukui functions were evaluated over GAL to identify the possible sites of electrophilic attack using Hirshfield charges.40 Finally, quantum theory of atoms in molecules (QTAIM) was employed to describe the strength and characteristics of various inter- and intramolecular interactions.41 Specifically, the value of the electronic charge density (ρ) evaluated at the point between two atoms (BCP) is related to the bond strength, and corresponding Laplacian (∇2ρ), total energy density (Hb), and the ratio between the potential and kinetic energy densities, |Vb|/Gb are employed to characterize the covalent or ionic nature of bonds. Reactivity descriptors and topologic studies were performed with Multiwfn 3.3.8 software.42,43

3. RESULTS AND DISCUSSION 3.1. Stoichiometry and Apparent Formation Constants of the Complexes. The interactions between the hydroxyflavones and Ni2+ were studied by means of UV−vis spectroscopy.

Figure 2. UV−vis absorption spectra of hydroxyflavones free and complexed with NiCl2 in methanol at 25 °C. The insets show an enlarged view of band II. (a) 5-hydroxyflavone, (b) 5,7-dihydroxyflavone, (c) 3-hydroxyflavone, and (d) 3,5,7-trihydroxyflavone. C



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Figure 3. Optimized molecular geometries of the cis and trans hydroxyflavones complexes with Ni2+.

In the above scheme, ΔGgas and ΔGsol are the Gibbs energy changes of the reaction in gas phase and in methanol, respectively. The Gibbs energy change of solvation is denoted as ΔGsolv. All ΔG values were calculated following a known procedure.47 No internal instabilities were found for singlet states in the Ni2+ complexes. Because the stoichiometry of these complexes was 1:2 M:L, two possible orientations were considered for the ligands, the cis and the trans. Moreover, GAL exhibits two chelating sites for the Ni2+ atom, the α and β site. For this reason, four different structures were calculated for Ni:(GAL)2 complex, the cis and the trans forms for the two chelating sites. In Figure 3, the molecular structures of the studied complexes obtained with the B3LYP/6-31+G(d,p) and LANL2DZ level of theory are shown, and the corresponding ΔG values are listed in Table 3. The equilibrium constants of the complexes formation derived from DFT results (KCT) are also listed in this

improves the complex formation. The observed shifts in the UV−vis spectra of the free flavonoids and the Ni2+ complexes are in good agreement with this hypothesis. A high intensity band II and a low intensity band I (and shifted to higher wavelengths like 5OHF and CRY) are characteristic of flavonoids with OH groups in A-ring (benzoyl moiety). However, when the OH groups are in the cinnamoyl moiety (like 3OHF), the intensity of both bands (I and II) is high. An enlarged view of band II for each complex is depicted in Figure 2. The UV−vis spectra of 5OHF and CRY show a small bathochromic shift on this band (between 240 and 280 nm) when the Ni complexes are formed. On the other hand, this shift is not observed in the 3OHF spectra; the nickel complexation only induces a minor hypochromic shift in band II. The spectra of GAL and Ni: (GAL)2 show a similar behavior to 3OHF, suggesting that the chelation is favored in the 4-carbonyl-3-hydroxyl site. 3.2. Infrared Spectral Analysis. The Fourier transform infrared (FTIR) spectra of the studied hydroxyflavones and the corresponding nickel complexes were registered (Support Information). The vibrational analysis presents evidence supporting the formation of the metallic complexes. The free flavonoids are characterized by the sharp absorption band of the CO stretching vibration (νCO), appearing at 1613 cm−1 (3OHF), 1651 cm−1 (5OHF), 1654 cm−1 (CRY), and 1653 cm−1 (GAL). The Ni2+ complex formation induces a broadening and a relative intensity reduction of this band in the studied flavones. Also, a small shift to 1606 cm−1 is observed in the Ni:(3OHF)2 complex. The intensity of a sharp band located between 1446 and 1452 cm−1 attributed to a δ(OH) vibration for the free ligands is notably reduced when the complex is formed. These results suggest that the carbonyl and OH group are involved in the complex formation.46,47 In addition, IR spectra of the complexes exhibit a new band in the region of low wavenumber, which is not present in the spectra of the free ligands. This band is located at 465 cm−1 (Ni:(3OHF)2), 466 cm−1 (Ni:(5OHF)2), 452 cm−1 (Ni:(CRY)2), and 465 cm−1 (Ni:(GAL)2) and can be attributed to the ν(Ni−O) stretching vibration. These values are consistent with the wavenumbers reported for square planar NiO4-type compounds.48 3.3. Quantum Chemistry Results. 3.3.1. Spectroscopic and Thermodynamic analysis. The stability constants of the flavonoids-Ni complexes were also calculated by means of the DFT results (KCT). These KCT values were derived from the ΔG° in methanolic solution of the following reaction scheme:

Table 3. Gibbs Energy Change (kJ/mol) and Formation Constants (KCT) for the Flavonoid−Nickel Complexes in Gas Phase and in Solution Obtained from B3LYP/631+G(d,p) and LANL2DZ Calculations IEF-PCM complex

ΔG°

Ni:(3OHF)2 −121.23 Ni:(5OHF)2 −103.34 Ni:(CRY)2 −96.08 Ni:(GAL)2-α site −97.01 Ni:(GAL)2-β site −83.62 Ni:(3OHF)2 Ni:(5OHF)2 Ni:(CRY)2 Ni:(GAL)2-α site Ni:(GAL)2-β site

−121.46 −104.99 −106.65 −100.47 −98.87

ΔGs cis −74.11 −66.22 −63.70 −55.91 −45.29 trans −75.67 −66.53 −66.08 −52.70 −49.25

SMD

log KCT

ΔGs

log KCT

log KC (exp)

12.98 11.60 11.16 9.80 7.94

−58.42 −57.14 −55.31 −47.94 −42.91

10.24 10.01 9.69 8.40 7.52

9.76 9.03 9.13 9.89

13.26 11.58 11.66 9.23 8.63

−59.21 −56.19 −57.52 −51.18 −30.75

10.37 9.84 10.08 8.97 5.39

9.76 9.03 9.13 9.89

table (as log KCT). These results indicate that the trans orientation is the most stable conformation for the studied complexes, although the energy differences are very small. It can be seen that the KCT values calculated in methanol with the SMD model are in better agreement with the experimental values (differences of ∼1 log KC unit) compared with the IEF-PCM results. The ordering in the stability of the complexes is well reproduced, except for the Ni:(GAL)2 complex. According to the KCT calculated with both solvation models, this complex should have the smallest stability constant; however, the experimental measurements indicate that the Ni:(GAL)2 is the most stable complex. This discrepancy may be due to a competition of both chelating sites of GAL. The data reported in Table 3 indicate that the α-form is the preferred site for the D



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Table 4. Calculated (λTD‑DFT) Wavelengths (in nm) for the Flavonoid−nickel Complexes from TD-DFT Simulations Employing Different Functionalsa B3LYP

PBE0

complex

λ (exp)

λTD‑DFT

f

Δλ

λTD‑DFT

f

Δλ

Ni:(3OHF)2 Ni:(5OHF)2 Ni:(CRY)2 Ni:(GAL)2-α site Ni:(GAL)2-β site

419.72 403.42 387.06

478.68 440.41 422.71 472.16 443.97 M06

0.369 0.166 0.171 0.382 0.408

58.96 36.99 35.65 40.58 12.39

450.48 416.92 400.41 446.07 424.35

0.493 0.232 0.244 0.545 0.539

30.46 13.50 13.35 14.49 7.23

431.58

wB97XD

complex

λ (exp)

λTD‑DFT

f

Δλ

λTD‑DFT

f

Δλ


419.72 403.42 387.06

448.08 412.68 396.00 442.34 420.02 CAM-B3LYP

0.583 0.279 0.269 0.681 0.682

28.36 9.26 8.94 10.76 11.56

391.73 357.65 344.68 395.34 376.65

1.023 0.663 0.719 1.035 1.0486

27.99 45.77 42.38 36.24 54.93

431.58

LC-wPBE

complex

λ (exp)

λTD‑DFT

f

Δλ

λTD‑DFT

f

Δλ


419.72 403.42 387.06

394.39 361.24 347.83 397.34 378.84

1.016 0.623 0.681 1.038 1.023

25.33 42.18 39.23 34.24 52.74

373.08 332.66 319.94 374.99 352.47

1.111 0.941 1.001 1.127 1.280

46.64 70.76 67.12 56.59 79.11

431.58

λ(exp) is the experimental wavelength of the complex, f the oscillator strength, and Δλ the difference between the calculated and experimental wavelengths in absolute value. a

chelation with Ni2+ ions in methanol (a higher relative stability is obtained with the SMD model). The same trend is observed in the UV−vis spectroscopic results. However, there might be significant amounts of the β-form in solution, contributing both to the experimental log β value. The coexistence of α-form and β-form in solution for a structurally related complex (Mg(II)quercetin) has been previously reported.49 The UV−vis spectra recorded in methanol of the studied complexes were also simulated by means of PCM/TD-DFT calculations. The comparison between the experimental and theoretical UV−vis spectra of flavonoid−metal complexes for the elucidation of their structure was performed with satisfactory results.14,49 The calculated absorption wavelengths (λTD‑DFT)

and oscillator strengths (f) involved in the lower energy transitions are reported in Table 4. From these λTD‑DFT values, the mean unsigned error (MUE) of each functional was calculated, and the following results were obtained: M06 (MUE = 14.3 nm) < PBE0 (MUE = 18 nm) < CAM-B3LYP (MUE = 35.2 nm) < wB97XD (MUE = 38.1 nm) < B3LYP (MUE = 43 nm) < LC-wPBE (MUE = 60.3 nm). It can be observed that M06 presents the lowest MUE followed closely by the functional PBE0. The results obtained with the CAMB3LYP and wB97XD functional present an intermediate accuracy, and the B3LYP and LC-wPBE functional yields the worst excitation energies. Because the M06 results are in good agreement with the experimental UV−vis spectra of the hydroxyflavones−nickel

Figure 4. Experimental and theoretical UV−vis spectra of Ni:(GAL)2 complex in methanol and positions of electronic transitions calculated with the TD-DFT/PCM.

Figure 5. UV−vis spectra of Ni:(GAL)2 complex in methanol registered in a temperature range of 10−50 °C. E



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complexes, further discussion of spectroscopic properties are based in these results. In Figure 4, the simulated UV−vis spectra of the Ni:(GAL)2 complex (α and β forms) are shown and compared with the experimental one. The absorption wavelength of the complex (band I 431 nm) is overestimated in the α-form and underestimated in the β-form (approximately 11 nm in both cases), and the two structures present similar calculated oscillator strengths. The other maximum absorption wavelength of the complex (band II 362 nm) is also overestimated in the α-form and underestimated in the β-form.

Moreover, the oscillator strength of this band is lower than the f value of band I for the α-form and slightly higher for the β-form. From these TD-DFT results, it is not possible to propose a preferential chelating site of GAL toward nickel ion. The calculated UV−vis spectra suggest that the two structures, which would be in equilibrium, contribute to the experimental UV−vis spectrum of the Ni:(GAL)2 complex. In a recent study, Moncomble and Cornard were able to identify the equilibrium between the α-form and the β-form of a Mg(II)-Quercetin by registering the UV−vis spectra of the complex at increasing

Figure 6. NTOs for the hydroxyflavones−Ni(II) complexes for the two main absorption bands. For each state, the calculated wavelength (λTD-DFT) and the oscillator strength f are listed. F



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temperatures.49 Following this procedure, the UV−vis spectra of a solution containing GAL and Ni2+ in a large excess were registered at increasing temperatures, in a 10−50 °C range (Figure 5). Two interesting features can be observed in this figure. First, band I experience a small bathochromic shift and its intensity raises at increasing temperatures. Band II also undergoes a small bathochromic shift and a decrease in the intensity at increasing temperatures. The conversion of the β-form into α-form by an endothermic process could be responsible for the observed spectral changes. The α-form presents a higher calculated absorption wavelength for band I and a lower oscillator strength for band II than the corresponding values of the β-form. The nature of the electronic transitions involved in the absorption bands of the complexes were analyzed using the NTO formalism38 instead of the classical treatment with canonical molecular orbitals. NTO calculations provide the most compact representation of the transition density between the ground and a given excited state. This treatment considers a single-particle transition between the hole (occupied) and electron (unoccupied) transition orbitals, which are different of the virtual and occupied canonical MO pairs from ground state calculation. The calculated NTO isosurfaces for the flavonoid− nickel complexes are shown in Figure 6. The two most intense and lowest energy transitions in the calculated spectrum of Ni: (3OHF)2 correspond to the excited states 7 and 10. The lowest energy transition (λ = 419.7 nm) can be identified as a metalto-ligand charge transfer (MLCT) mixed with intraligand charge transfer (ILCT). This ILCT takes place from the ring B to the ring A of 3OHF. The second lowest energy transition (λ = 339.6 nm) is a typical π → π* transition. In the case of Ni:5OHF2 complex, the NTO orbitals of band I (λ = 403.4 nm) are very similar to the corresponding orbitals for the same band in Ni:(3OHF)2; that is, a MLCT transition mixed with ILCT. It is important to note that in this case the ILCT takes place from the ring A to rings B and C of 5OHF. Band II (λ = 273 nm) and the shoulder (λ ≈ 329 nm), which are characteristic of the free ligand, correspond to a MLCT/ILCT mixture and a combination of MLCT with ligand-to-ligand charge transfer (LLCT), respectively. The NTO orbitals of Ni:(CRY)2 complex are very similar to the corresponding ones of the Ni:5OHF2 complex, suggesting that the OH group in position 7 has little effect in the nature of the electronic transitions in these complexes. Band I (λ = 387 nm) and band II (λ = 273 nm) are mainly MLCT/ILCT transitions. Moreover, many similarities can be observed between the NTO of the Ni:(GAL)2 complexes (α-form and β-form) and the transition orbitals of the complexes with monohydroxilated flavones. For example, the NTOs of α-form are almost identical to the orbitals of Ni:(3OHF)2 complex; a mixed MLCT/ILCT transition is obtained for band I (λ = 431 nm), although the ILCT character is lower in the GAL complex, and band II (λ = 362 nm) is mainly a π → π* transition. In the same way, the NTOs of the β-form are similar to the orbitals of Ni:(5OHF)2 complex. The same mixed MLCT/ILCT transition is obtained for band I, where the ILCT also takes place from the ring A to rings B and C of GAL. 3.3.2. Reactivity Descriptors and Topological Characterization of Chemical Bonds in Ni:GAL2 Complexes. Analysis of Fukui functions over GAL specifies two possible sites of electrophilic attack on O3 and O5. Quantitative study of dual descriptors using Hirshfeld charges shows different values to each site, f−O3 = 0.0732 and f−O5 = 0.0578, respectively. These

results denote a higher probability of electrophilic attack to O3, suggesting this site is preferred by nickel. QTAIM theory was employed in the Ni:(GAL)2 complex coordinated through α site and β site to evaluate and compare the inter- and intramolecular interactions. Figure 7 shows

Figure 7. Molecular graph of the Ni:(GAL)2 complexes calculated in the α and β forms. Gray lines, bond paths (BP); blue dots, nuclear critical points (NCP); red dots, bond critical points (BCP); gray dots, ring critical points (RCP).

molecular graphs with bond path (BP), bond critical points (BCP), and ring critical points (RCP) of two conformers. The complexation of each ligand with nickel induces the formation of three rings with two intramolecular hydrogen bonds (HB) and two Ni−O bonds, increasing the molecular stability. Espinosa et al.50 proposed for HB the relationship between bond energy EHB and potential energy density at corresponding BCP as EHB = V(rBCP)/2. Taken into account this equation the bond energy of both HB are −49.78 kJ/mol (O4−H5 and O3−H2′) in α form and −42.04 kJ/mol (O4−H3 and O3−H2′) in β form. According to the topological parameters the nature of these HB can be classified as weak with a main electrostatic contribution (Table 5).51 In addition, the ρ values in Ni−O4 BCP are very similar and exhibit a mixed ionic/covalent character for both chelating forms, in agreement with other flavonoids metallic complexes.52,53 Moreover, the ρ of Ni−O3 is higher than the corresponding value of Ni−O5 BCP, and the total electronic energy density is negative for both BCP. It can be observed in Table 5 a higher absolute value of Hb in Ni−O3 than Ni−O5, suggesting a lower covalence degree in the latter bond. Finally, it is important to note that these topological parameters may have a strong dependence with the basis set employed in the calculations, leading to different quantitative results when relatively small basis are used.54

4. CONCLUSIONS A systematic analysis on the complexing ability of four hydroxyflavones was carried out. The complex formation of 3OHF, 5OHF, CRY, and GAL with Ni2+ in methanolic solutions was studied using spectroscopic and DFT methods. The spectral analysis reveals a 1:2 metal:ligand stochiometry for all the studied complexes. Vibrational study confirms the complex formation in all cases. The Ni:(GAL)2 complex has the highest stability constant, followed by Ni:(3OHF)2 > Ni:(CRY)2 > Ni: (5OHF)2. The β values of the flavones with an OH group in C3 (α site) are higher than the corresponding values of the flavones with a OH in C5 (β site). Molecular simulations were carried out to obtain structural and thermodynamic insight of the Ni2+ complexes. TD-DFT G



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Table 5. Main Topological Parameters (in au) of Relevant Interactions Calculated with Bader’s Theory for the Ni:(GAL)2 Complexes (α and β Sites) topological parameters compound

BCP

ρb

∇2ρc

G/ρ

V × 102a

H × 103d

V/G val abs

Ni:(GAL)2 -α site

Ni−O3

89.3261 89.3255 83.6998 83.6997 32.0902 32.0904 17.5874 17.5873 87.5078 87.5065 84.3198 84.3208 23.3878 23.3882 15.8105 15.8104

73.0783 73.0778 67.4957 67.4957 11.1011 11.1012 66.9493 66.9488 74.6862 74.6852 71.5909 71.5900 95.5762 95.5766 64.5493 64.5491

0.0021 0.0021 0.0021 0.0021 0.0008 0.0008 0.0009 0.0009 0.0022 0.0022 0.0022 0.0022 0.0009 0.0009 0.0009 0.0009

−0.1955 −0.1955 −0.1756 −0.1756 −0.2449 −0.2449 −0.1343 −0.1343 −0.1949 −0.1949 −0.1839 −0.1839 −0.2012 −0.2012 −0.1191 −0.1191

−6.4006 −6.4003 −3.4206 −3.4206 1.6548 1.6298 1.6548 1.6548 −4.1031 −4.1024 −2.4713 −2.4708 1.8875 1.8874 2.1155 2.1155

10.3384 10.3384 10.1986 10.1986 93.7611 93.7610 89.0286 89.0285 10.2149 10.2149 10.1363 10.1360 91.4231 91.4234 84.9128 84.9128

Ni−O4 O4−H5 O3−H2′ Ni:(GAL)2 -β site

Ni−O5 Ni−O4 O4−H3 O3−H2′

Potential energy density (V) in au. bElectron density (ρ) in au. cLaplacian of the electron density (∇2ρ) in au. dTotal electron energy density (H) in au.

a

Notes

results indicate that M06 is a suitable functional to describe the UV−vis spectra of these compounds. The KCT values calculated in methanol using B3LYP/6-31+G(d,p) and LANL2DZ level of theory in combination with the SMD model are in good agreement with the experimental values (differences of ∼1 log β unit). The ordering in the stability of the complexes is well reproduced, except for the Ni:(GAL)2 complex. NTO analysis reveals a mixed MLCT/ILCT character for band I in all studied complexes. Although computational results show the α site as the preferred one by Ni2+ in GAL complex, the stability and reactivity differences between the two sites are small. For this reason, the two Ni:(GAL)2 calculated complexes could be simultaneously found. This is in very good agreement with experimental results. Because of the high thermodynamic stability and the planar structure observed, the analyzed nickel complexes could improve the biological activity of the free ligands. For this reason, the information reported in the present work could be helpful to the development of new therapeutic reagents for some diseases.

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The authors declare no competing financial interest.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jced.7b01058. FTIR spectra of 3OHF, 5OHF, CRY, GAL, and the corresponding nickel complexes (PDF)

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]; Phone: +54-0266-4520300. ORCID

Yamina A. Dávila: 0000-0001-6708-4980 Funding

Financial support from Universidad Nacional de San Luis, Argentina (Proico 2-1614) is gratefully acknowledged. Y.A.D. ́ thanks Concejo Nacional de Investigaciones Cientificas y Técnicas (CONICET) for a fellowship. H



Article

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