Antioxidant activity of the hazelnut plant determination by computational chemistry methods

Abstract

Nowadays, it is known that the species defined as free radicals in our body increase due to the change in our eating / drinking habits, physical activities and environmental conditions. Free radicals cause especially canser and diseases affecting many systems such as nervous system, cardiovascular system and digestive system. The formation of free radicals causes cell / tissue damage or cell deaths that occur as a result of oxidative balance disruption due to the insufficient antioxidants defined as oxidative stress.

The purpose of this study is to determine the activity ranking of the compounds that give antioxidant properties to hazelnut plants by using quantum chemistry methods and to determine which hydroxyl groups cause the activity. In the antioxidant activity calculations, HAT, SET-PT and SPLET mechanisms are optimized with DFT//M062X/6-311++G(d,p) method, and single point energy as well as the E_HOMO-E_LUMO values were obtained with the Gaussian09 program in three different phases: gas, ethanol and water. According to the results, Riboflavin compound has been found to have the highest antioxidant potential and it was found that the antioxidant capacity of the compound originated from OH group at O4 position.

Keywords

Hazelnut antioxidant activity riboflavin DFT M062X free radical

1 Introduction

Deficiency of antioxidant molecules leads to oxidative stress which is caused by deterioration of oxidative balance due to the exceeding of the free radical above optimum level results in cell / tissue damage or cell deaths [1 –3] which cause many diseases such as cardiovascular diseases, cancer, respiratory and excretory disorders, diabetes and aging [4, 5]. The substances that have such an important role and stand out with their antioxidant functions are vitamins E and C, carotenoids and phenolic substances. Phenolic antioxidant molecules are very effective in preventing autooxidation through free radical terminator and metal chelating mechanisms. Recently, phenolic compounds in some plant ingredients are accepted as antioxidants and are commercially produced [6, 7]. Flavonoids, which are commonly found in plants and plant-based fruits are estimated to be more than 4000, have attracted recently by especially in terms of their antioxidant capacities and known to have many biological activities such as anti-inflammatory, antiviral, antiallergic, antitronbotic antibacterial and anti cancer. Flavonoids, which are commonly found in plants and plant-based fruits are estimated to be more than 4000, have attracted recently by especially in terms of their antioxidant capacities and known to have many biological activities such as anti-inflammatory, antiviral, antiallergic, antitronbotic antibacterial and anti cancer. Flavonoid derivatives also play an important role in inhibitor design studies against Parkinson’s and Alzheimer’s disease [8].

The hazelnut (Corylus avellana L.) tree, which is the subject of this study, is the most popular tree species in the Betulaceae family, consists of more than one big branch and has a fruit called hazelnut [9]. Fourteen different types of hazelnuts grow: Foşa, incekara, kalınkara, kan, kargalak, kuş, palaz, sivri, tombul, uzun musa, yassı badem, yuvarlak badem, acı ve akıldak [10]. The hazelnut plant, which is grown in many regions of Europe and Asia, is one of the most important agricultural crops in the world. According to the international nuts and dried fruits statistical database in 2017/2018, Turkey is the main manufacturer and exporter with 73% share in the world with over 490,000 tons of hazelnut production. In the literature, while antioxidant capacity of hazelnut compound was experimentally examined by Masullo et al. [11], antioxidant activity of molecules derived from hazelnut shell extract, a phenolically rich byproduct [12]. This study aims to identify the antioxidant molecules of hazelnut plant: neutral, radical, cationic radical and anionic forms to explain the structure antioxidant relationship. which has a very important role in the world and to list the antioxidant capacities.

We had also been concerned with the calculation of antioxidant descriptors: BDE, AIP, PDE, PA, ETE, ΔH_acidity, ΔG_acidity for trans-p-coumaric and transsinapinic acids. The next step was the determination of the preferred mechanism of antioxidation and calculation of E_HOMO and E_LUMO and transition energy between those states. All calculations were performed in vacuum and water medium.

Scheme 1

Parts of the hazelnut plant: (A) tree, (B) nut, (C) male flowers, (D) skin, (E) leaf, (F) bark, (G) guard leaf, (H) tree bark [9].

2 Methods

There are three different mechanisms in the literature for determining antioxidant activity: Hydrogen Atom Transfer (HAT)[13 –16], Single Electron Transfer - Proton Transfer (SET -PT) and Sequential Proton Loss Electron Transfer (SPLET) mechanisms [17]. The HAT mechanism is responsible for calculating the bond dissociation energy (BDE) (Eq. 1).The low BDE value indicates high antioxidant properties as it facilitates the inactivation of free radicals [18]. The lower BDE parameter characterizes better antioxidant property. The lower BDE parameter characterizes better antioxidant property. $R + AntiOx : H \to R : H + AntiOx$ $BDE = H (Antiox) + H (R : H) - H (Antiox : H) - H (R)$ (1)

The SET-PT mechanism, which takes place in two steps, plays a role in calculating the ionization potential (IP) (Eq. 2) and the deprotonation energy (PDE) (Eq. 3) of the cation radical. Antioxidants with low IP values increase the likelihood of radical anion formation through direct $\bar{e}$ transfer. The ability of a phenolic compound to deliver $\bar{e}$ relates to an extended electronic delocalization over the entire molecule. Therefore, it can be said that a phenolic compound with high π-delocalization degree is more active [15 , 19]. $R + AntiOx : H \to R :^{-} + AntiOx H^{+}$ $R^{-} + H^{+} \to RH$ $IP = H (ArO H^{+}) + H (e -) - H (ArOH)$ (2) $PDE = H (ArO) + H (H^{+}) - H (ArO H^{+})$ (3)

Finally, the SPLET mechanism, which takes place in three steps, the first step is related to the calculation of the enthalpy of proton affinity (PA) (Equation 4), the second step is antioxidant anion switch to the radical form by giving an electron to the free radical and the electron transfer (ETE) is related to calculating the enthalpy (Equation 5) [14–16 , 19]. $AntiOx : H \to AntiO x^{-} + H^{+} (Proton affinity)$ $AntiO x^{-} + R \to AntiOx + R^{-} (\bar{e} transfer enthalpy)$ $R^{-} + H^{+} \to RH$ $PA = (Ar O^{-}) + H (H^{+}) - (ArOH)$ (4) $ETE = H (ArO) + H (e^{-}) - H (Ar O^{-})$ (5)

The physicochemical properties of the compounds are parameters expressed as molecular descriptive are electronegativity (χ), electron affinity (S), chemical hardness (η) and electrophilicity index (ω). According to Koopman’s theory [20, 21] χ, η, S and ω values were obtained with E_HOMO-E_LUMO values (IA=-E_HOMO and EA=-E_LUMO) (Equations 6–9) of neutral molecules [20]. $η \approx (IP - EA) / 2$ (6) $χ = - μ \approx (IP + EA) / - 2$ (7) $S \approx 1 / - 2 η$ (8) $ω \approx μ^{2} / - 2 η$ (9)

In this study, it was aimed to determine the ranking of the compounds that have the most antioxidant properties of hazelnut and to identify the –OH groups that contribute the most to being antioxidant. Candidate antioxidant molecules (ascorbic acid, isoquercetin, kaempferol, myricetin, myricitrin, quercetin, riboflavin and sucrose) were determined by selecting a molecule containing at least four hydroxyl (-OH) groups in the structure of the hazelnut plant from the Dr. Duke’s Phytochemical ve Ethonobatical Databases-USDA [22] database. The most stable conformers of the selected compounds were performed with the semi-experimental PM6 [23] method, Spartan’14 [24] program, and the geometry optimizations of the stable structures were carried out with the HF/6–31Gd [25] method. TD energy calculations for three different antioxidant mechanisms (HAT, SPLET, SET-PT) proposed in the literature and E_HOMO-E_LUMO are calculated using the DFT//M062X/6–311 + Gdp [26] method calculations were performed with Gaussian09 [27] in gas, ethanol and water phases using the HF/6-31++Gdp method and images were taken with GaussView5 [28]. Similar results were obtained with experimental data in antioxidant activity calculations made by Atalay and her group using the same approaches [29 –32]. Especially quercetin molecules M05-2X/6-311++G(d,p)

3 Results and discussion

In this study, which aims to detect and antioxidant compounds of hazelnut plants by quantum chemical methods, modeled four or more -OH groups containing eight chemical molecules including ascorbic acid, isoquercetin, kaempferol, myricetin, myricitrin, quercetin, riboflavin and sucrose, with the TD-DFT//M062X/6-311++Gdp method in the gas as well as in ethanol and water phases were compared by comparing the BDE, ETE, PA, ETE and PDE values (Table 1) obtained from the three main antioxidation mechanism models: HAT, SET-PT and SPLET.

Table 1
Calculated BDE, ETE, PDE, PA and IP values (kJmol^–1) with TD-DFT//M062X/6-311++G(d, p) method in gas, water and ethanol phases along with E_HOMO and E_LUMO as well as band gap energy values (eV) with HF/6-31++Gdp method

Compounds

ascorbic isoquercetin kaempferol myricetin myricitrin quercetin riboflavin sucrose

acid

gas BDE 406.26 439.25 428.24 411.08 394.98 425.73 475.46 469.23

ETE –1109.08 –1447.18 –1105.75 –1093.59 –1071.99 –1096.66 –1197.82 –1146.65

PDE 825.26 987.76 981.19 964.71 941.47 981.82 962.54 842.89

PA 1459.59 1497.04 1478.23 1448.91 1411.22 1466.63 1617.52 1560.13

IP –474.76 –604.27 –608.72 –609.38 –602.25 –611.84 –542.84 –429.42

ethanol BDE 398.62 424.52 412.72 402.13 393.93 412.49 473.35 471.25

ETE –1229.60 –1232.52 –1238.56 –1231.56 –1219.19 –1234.75 –1280.46 –1250.15

PDE 605.42 686.17 689.76 676.81 655.54 691.92 701.28 588.94

PA 828.80 857.62 851.86 834.26 813.69 847.82 954.39 921.98

IP –1006.22 –1061.06 –1075.33 –1074.09 –1061.03 –1078.86 –1027.35 –917.12

water BDE 398.11 423.75 411.84 401.61 393.91 411.77 473.27 471.29

ETE –1233.05 –1234.70 –1241.71 –1235.02 –1222.39 –1238.20 –1281.64 –1252.24

PDE 599.43 677.22 679.76 668.31 647.70 683.26 694.50 582.90

PA 809.78 837.07 832.17 815.24 794.94 828.59 933.52 902.14

IP –1022.70 –1074.86 –1089.29 –1088.08 –1075.15 –1092.87 –1042.61 –932.99

gas E_HOMO –798.83 –700.50 –693.63 –693.02 –706.78 –690.16 –767.35 –866.96

E_LUMO –48.67 –128.09 –127.15 –130.14 –137.26 –131.40 –248.58 –42.50

gap 750.15 572.41 566.47 562.88 569.52 558.75 518.77 824.45

ethanol E_HOMO –788.33 –722.24 –701.90 –701.48 –714.73 –697.88 –751.49 –874.31

E_LUMO –33.60 –136.68 –137.70 –140.59 –140.30 –139.86 –241.54 –15.51

gap 754.72 585.56 564.19 560.88 574.43 558.02 509.95 858.80

water E_HOMO –787.93 –723.56 –702.53 –702.11 –715.36 –698.51 –750.78 –873.97

E_LUMO –33.39 –137.18 –138.41 –141.25 –140.64 –140.43 –241.28 –14.75

gap 754.54 586.37 564.11 560.85 574.72 558.07 509.50 859.22

Compounds
gas	BDE	406.26	439.25	428.24	411.08	394.98	425.73	475.46	469.23
	ETE	–1109.08	–1447.18	–1105.75	–1093.59	–1071.99	–1096.66	–1197.82	–1146.65
	PDE	825.26	987.76	981.19	964.71	941.47	981.82	962.54	842.89
	PA	1459.59	1497.04	1478.23	1448.91	1411.22	1466.63	1617.52	1560.13
	IP	–474.76	–604.27	–608.72	–609.38	–602.25	–611.84	–542.84	–429.42
ethanol	BDE	398.62	424.52	412.72	402.13	393.93	412.49	473.35	471.25
	ETE	–1229.60	–1232.52	–1238.56	–1231.56	–1219.19	–1234.75	–1280.46	–1250.15
	PDE	605.42	686.17	689.76	676.81	655.54	691.92	701.28	588.94
	PA	828.80	857.62	851.86	834.26	813.69	847.82	954.39	921.98
	IP	–1006.22	–1061.06	–1075.33	–1074.09	–1061.03	–1078.86	–1027.35	–917.12
water	BDE	398.11	423.75	411.84	401.61	393.91	411.77	473.27	471.29
	ETE	–1233.05	–1234.70	–1241.71	–1235.02	–1222.39	–1238.20	–1281.64	–1252.24
	PDE	599.43	677.22	679.76	668.31	647.70	683.26	694.50	582.90
	PA	809.78	837.07	832.17	815.24	794.94	828.59	933.52	902.14
	IP	–1022.70	–1074.86	–1089.29	–1088.08	–1075.15	–1092.87	–1042.61	–932.99
gas	E_HOMO	–798.83	–700.50	–693.63	–693.02	–706.78	–690.16	–767.35	–866.96
	E_LUMO	–48.67	–128.09	–127.15	–130.14	–137.26	–131.40	–248.58	–42.50
	gap	750.15	572.41	566.47	562.88	569.52	558.75	518.77	824.45
ethanol	E_HOMO	–788.33	–722.24	–701.90	–701.48	–714.73	–697.88	–751.49	–874.31
	E_LUMO	–33.60	–136.68	–137.70	–140.59	–140.30	–139.86	–241.54	–15.51
	gap	754.72	585.56	564.19	560.88	574.43	558.02	509.95	858.80
water	E_HOMO	–787.93	–723.56	–702.53	–702.11	–715.36	–698.51	–750.78	–873.97
	E_LUMO	–33.39	–137.18	–138.41	–141.25	–140.64	–140.43	–241.28	–14.75
	gap	754.54	586.37	564.11	560.85	574.72	558.07	509.50	859.22

In the calculations, BDE, ETE, PDE, PA and IP values were determined separately for all -OH groups in the molecule. In addition, E_HOMO-E_LUMO and bandgap values, which are very important criteria for molecular stability, were calculated for the same method and phase, and distribution maps of molecular orbitals were drawn. In the light of these results, -OH groups determined for each molecule were determined as O5, O12, O2, O8, O10, O2, O4 and O5 for ascorbic acid, isoquercetin, kaempferol, myricetin, myricitrin, quercetin, riboflavin, sucrose molecules, respectively. The values obtained are given in Table 1 and Scheme 3.

When Table 1 is analyzed, it was found that the BDE values calculated from Eq. 1 are high with 1–15 kJmol^–1 differences in the gas phase for all the molecules studied except the sucrose compound.

As in previous studies by Atalay and his group, in this study, an inverse relationship was found between ethanol and water phases between the solvent’s dipole moment (μ_water = 1.87> μ_et = 1.69 debye) and BDE, The values though the differences are neglectable (the values are between 0.9 kJ mol^–1 and 0.2 kJ mol ^–1) decreased by increased dipole moment of the solvents [29, 31].

The weaker OH bond and lower BDE values are favoring possibility of antioxidant activity, since they enable the reaction of free radical inactivation. According to the calculated BDE values, the ascorbic acid compound exhibits lower energy values in gas phase, while the Myricitrin compound possess lower energy than the other investigated compounds in studied liquid phases for all calculation compounds. The result shows that the most antioxidative compound is found, as Myricitrin has been promoted by the HAT mechanism.

The calculated IPs by Eq. 2 for selected candidate antioxidant molecules in the gas phase as well as in solvent phases are given in Table 1. The IP values in liquid phases would meaningfully change with respect to the values in the gas phase as the values are dramatically lower in solvent phases compared to the gas phase. In generally for the all mlecules, the IP energies drop in the solvent environment varies from about 460 to 530 kJ mol^–1, so this data shows that the polar solvent obtained by increasing the dipole moment promoted electron donating (IP_gas > IP_et>IP_water). The similar results in the literature were determined by Zheng et al.(2017) for the quercetin compound [16] and our pervious studies [29, 31]. According to IP values, the structure of Quercetin stands out as the compound with the highest antioxidant capacity in gas and liquid phases.

PA values calculated from modeling of gas, ethanol and water phases for SPLET mechanism related compounds are given in Table 1. When Table 1 is examined, it is determined that PA values decrease in the range of 600–670 kJmol^–1 when changing from gas phase to ethanol phase, and it shows a decrease of 20 kJmol^–1 when changing from ethanol phase to water phase. When the obtained PA values are examined, it means that for the myricitrin compound in gas, ethanol and water phases with the lowest energy values of 1411.22 kJ mol^–1, 813.69 kJ mol^–1 and 794.94 kJ mol^–1, the anion formation may be easier than the other investigated molecules. Myricitrin displayed the highest antioxidant activity according to the PA values obtained from the SPLET mechanism modeling.

PDE values calculated from the second step of SET-PT mechanism modeling are listed in Table 1. As can be seen in Table 1, when the transition from gas phase to ethanol phase for each studied compound, PDE values decrease approximately 220–310 kJmol^–1 energy value, while it showed a decrease of 6–10 kJmol^–1 in transition from ethanol phase to water phase. Calculated PDE values were calculated as the lowest for Ascorbic Acid with values of 825.26 kJmol^–1 and 599.43 kJmol^–1 in gas and water phase, and for Sucrose compounds with a value of 588.94 kJmol^–1 in ethanol phase. When Table 1 is examined, it was observed that ETE values increased in polar phases in accordance with the literature [32, 33]. When the ETE values in Table 1 are analyzed, lower ETE values were calculated in the ethanol and water phases of approximately 140 kJ mol^–1 compared to the gas phase for all the molecules studied except the isoquercetin compound (–1447.18 kJ mol^–1). On the other hand, the lowest ETE value was obtained for the Riboflavin compound in ethanol and water phases (–1280.46 and –1281.64 kJ mol^–1, respectively). When band gap values (Table 1), which is an important value for stability and e transfer, and Scheme 3 are examined, the gas, ethanol and water phases of Riboflavin compound have the lowest band gap value with values of 518.77 eV, 509.95 eV and 509.50 eV respectively. The stability order obtained in the water phase is determined as Riboflavin >quercetin >myricetin >kaempferol >myricitrin >isoquercetin >ascorbic acid >sucrose.

On the other hand, HOMO-LUMO maps and energy values which are used in computational methods for determining the physicochemical properties as well as structural stability of the molecules are examined for examined compounds. The orbital maps and obtained energy value for the water phase are given in Scheme 3 below. Previous studies have shown that the concentration of the orbital distribution of a molecule in certain regions has higher antioxidant capacity of that compound [29 , 32]. Looking at Scheme 3, the HOMO-LUMO distribution of the riboflavin compound has been found to be the most concentrated in certain atoms in the molecule.

The calculations of the molecular identifiers calculated in gas, water and ethanol phases are obtained by TD-DFT//M062X/6-311++G(d,p) method for ascorbic acid, isoquercetin, kaempferol, myricetin, myricitrin, quercetin, riboflavin and sucrose compounds values are given in Table 2 below. The calculated χ, η, S and ω molecular properties clearly show that the examined molecules have chosen to act as e-transmitters rather than e-receptors in the studied environments. This is an indication of the examined molecules antioxidative activities[28, 32].

Table 2

Physicochemical identifier property values of the studied compounds in gas, ethanol and water phases calculated by TD-DFT // M062X / 6-311++G (d, p) method

Phase	Parameter	ascorbic	isoquercetin	kaempferol	myricetin	myricitrin	quercetin	riboflavin	sucrose
		acid
Gas	χ	0.1614	0.1578	0.1563	0.1567	0.1607	0.1564	0.1934	0.1732
	μ	–0.1614	–0.1578	–0.1563	–0.1567	–0.1607	–0.1564	–0.1934	–0.1732
	η	0.1428	0.109	0.1078	0.1071	0.1084	0.1064	0.0987	0.157
	S	3.4999	4.5867	4.6347	4.6643	4.6099	4.6988	5.0609	3.1845
	ω	0.0911	0.1142	0.1132	0.1146	0.1191	0.115	0.1894	0.0955
Ethanol	χ	0.1565	0.1635	0.1598	0.1603	0.1628	0.1595	0.1891	0.1694
	μ	–0.1565	–0.1635	–0.1598	–0.1603	–0.1628	–0.1595	–0.1891	–0.1694
	η	0.1437	0.1115	0.1074	0.1068	0.1093	0.1062	0.0971	0.1635
	S	3.4787	4.4837	4.6535	4.6809	4.5705	4.7049	5.1485	3.0571
	ω	0.0852	0.1199	0.1189	0.1203	0.1211	0.1197	0.1841	0.0877
Water	χ	0.1564	0.1639	0.1601	0.1606	0.163	0.1597	0.1889	0.1692
	μ	–0.1564	–0.1639	–0.1601	–0.1606	–0.163	–0.1597	–0.1889	–0.1692
	η	0.1436	0.1116	0.1074	0.1068	0.1094	0.1062	0.097	0.1636
	S	3.4795	4.4774	4.6541	4.6812	4.5682	4.7045	5.153	3.0556
	ω	0.0851	0.1203	0.1193	0.1207	0.1214	0.12	0.1839	0.0875

Scheme 2

2D structures of the Ascorbic Acid, ısoquercetin, kaempferol, Myricetin, Myricitrin, Quercetin, Riboflavin and Sucrose molecules, investigated -OH groups with numbered for each molecules.

Scheme 3

HOMO-LUMO maps, E_HOMO and E_LUMO’s along with bandgap values (eV) in the water phase obtained by TD-DFT//M062X/6-311++G(d, p) method of the studied compounds.

The theoretical approach we made in this study and the results we obtained are consistent with the theoretical determination of antioxidant activity both published by our group and by different groups in the literature [27–29 , 32–36].

4 Conclusions

In order to spot which of the compound gives the most antioxidant property to the hazelnut plant, results obtained with one of the computational chemistry approach TD-DFT//M062X/ 6-311++G(d,p) method used along with HAT, SET-PT and SPLET mechanisms for modelling. According to the acquired results, the BDE value obtained from the HAT mechanism along with the PA value obtained from the SPLET mechanism determined the Myricitrin compound as the most antioxidant compound, while the SET-PT mechanism with the calculated IP value suggest the Quercetin compound, and the PDE value determined the Ascorbic acid compound, the ETE value obtained from the SPLET mechanism together with band gap values calculated from E_HOMO-E_LUMO difference determined Riboflavin as the most antioxidant compound.

When all the results were examined, it was determined that Riboflavin and Myricitrin compounds, respectively, contributed to the antioxidant properties of the hazelnut plant.

Conflicts of interest

There are no competing interests to declare.

Footnotes

Acknowledgments

Our group thanks Prof. Dr. Safiye Sağ Erdem for software support.

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