Accepted Manuscript Comparative antioxidant potency and solvent polarity effects on HAT mechanisms of tocopherols Kahina Bakhouche, Zoubeida Dhaouadi, Nejemeddine Jaidane, Dalila Hammoutène PII: DOI: Reference:
S2210-271X(15)00097-3 http://dx.doi.org/10.1016/j.comptc.2015.02.018 COMPTC 1753
To appear in:
Computational & Theoretical Chemistry
Received Date: Revised Date: Accepted Date:
7 January 2015 7 February 2015 21 February 2015
Please cite this article as: K. Bakhouche, Z. Dhaouadi, N. Jaidane, D. Hammoutène, Comparative antioxidant potency and solvent polarity effects on HAT mechanisms of tocopherols, Computational & Theoretical Chemistry (2015), doi: http://dx.doi.org/10.1016/j.comptc.2015.02.018
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Comparative antioxidant potency and solvent polarity effects on HAT mechanisms of tocopherols Kahina Bakhouche a,*, Zoubeida Dhaouadi b, Nejemeddine Jaidane b, Dalila Hammoutène a a
Laboratoire de Thermodynamique et Modélisation Moléculaire (LTMM), Faculté de Chimie, USTHB BP 32, El Alia 16111 Bab Ezzouar,
Alger, Algerie b
Laboratoire de Spectroscopie Atomique Moléculaire et Applications (LSAMA), Faculté des Sciences de Tunis, Université de Tunis El
Manar, Campus Universitaire 1060, Tunis, Tunisie
* Corresponding author. Tel.: +213 541 786 104. E-mail address:
[email protected] (Kahina Bakhouche).
Abstract The antioxidant activity of the four forms of tocopherol has been investigated in gas phase and in different solvents using PBE0/6-31+G(d) level of theory. The three main working mechanisms, homolytic hydrogen atom transfer (HAT), single electron transfer-proton transfer (SET-PT) and sequential proton loss electron transfer (SPLET) have been considered. The O –H bond dissociation free energy (BDFE), ionization potential (IP), proton dissociation free energy (PDFE), proton affinity (PA) and electron transfer free energy (ETFE) parameters have been calculated in gas phase and solvents. The theoretical results show the effect of the substituent position with respect to the phenolic O–H group on the reactivity. The methyl group, in ortho position, lends additional inductive and steric stability to the tocopheroxyl radical and therefore, increases antioxidant activity. -tocopherol is shown to be the most reactive form in gas phase with the lowest BDFE, IP, and PA values, whereas in all solvents, -tocopherol has the lowest PA and PDFE values. The solvent effects are evaluated using an implicit solvation model (IEF-PCM). We have used a good model to calculate the solvation free energy of proton and electron in different media, where proton or electron was attached to one molecule of solvent and the obtained species were optimized using IEF-PCM approach in the same solvent. In gas phase, and non-polar solvents like benzene and toluene, BDFE value is lower than PA and IP, this suggested that HAT would be the most favorable mechanism for explaining the antioxidant activity of tocopherols, whereas SPLET mechanism is thermodynamically preferred in polar solvents like water, DMSO and methanol, where PA value of all forms of tocopherol is considerably lower than BDFE and IP.
1. Introduction Vitamin E is a very important compound of biological membranes, because of its multiple roles. Several studies suggest that vitamin E may contribute to lower the risks of specific chronic and degenerative diseases such as Alzheimer, age-related macular degeneration, some types of cancer [1], cataracts and ischemic heart disease [2]. Refat et al. [3] studied the complex of vitamin E and vanadyl(II) [VO(Vit E)2(H2O)2] which has a noticeable activity in decreasing glucose levels, it is a good complex against diabetes. The antioxidant activity of vitamin E [4] is due to its ability to donate phenolic hydrogen to lipid free radicals and to retard autocatalytic lipid peroxidation process [5]. Its efficiency is enhanced in carotenoids [6]. The fat soluble vitamin E is found naturally in two forms of tocopherols and tocotrienols [7] having each of them, for homologous members, labeled as , and (Fig. 1(a)) differing by methyl substitution on the aromatic ring. Tocopherol and tocotrienol have the same chromanol which represent the active antioxidant part of vitamin E. The function of the side chain is to enhance generally the solubility of vitamin E in lipids and not affects its antioxidant action [8]. Therefore, in many experimental and theoretical studies, models of tocopherols are employed [918], the model chosen in the present work is denoted TOH (Fig. 1(b)), where the side chain is
1
assumed to be a hydrogen atom. Previously, experimental [1921] and theoretical [1217, 22,23] investigations have been carried out on vitamin E antioxidant properties. In other papers [1824], the effect of various substituents on reaction enthalpies related to antioxidant mechanism action of chromanol (basic structure of vitamin E) in gas phase and water, have been studied. -tocopherol (-TOH) is known to be the most powerful lipid soluble antioxidant [25], it traps peroxyl radical ROO• and converts it to hydroperoxyde product ROOH (-TOH + ROO• -TO• + ROOH), the tocopheroxyl radical -TO• reacts with another peroxyl radical to form non radical inactive product (-TO• + ROO• inactive product), or reacts with a coantioxidant molecule (CoAH) [26,27] to reduce the tocopheroxyl radical -TO• and reconstitute a neutral molecule -TOH (-TO• + CoAH -TOH + CoA•). Similarly, the radical derived from the coantioxidant CoA• can either terminate with ROO• (CoA• + ROO• inactive product). Tocopherol cans react directly with free radicals like •O2, •OH, •OOH [22,23,28]. Many scavenging mechanisms are involved in the reaction of phenolic antioxidants (TOH) with free radicals [29,30]. Homolytic hydrogen atom transfer (HAT) (Eq. (1)) [31] or heterolytic hydrogen atom transfer which can be, a single electron transfer (Eq. (2)) [32] followed by a proton transfer (Eq. (3)) called SET-PT, or a sequential proton transfer followed by an electron transfer (Eq. (4), Eq. (5)) named SPLET [33]. TOH → TO• + H•
(1)
TOH → TOH+• + e–
(2)
TOH+• → TO• + H+
(3)
TOH → TO– + H+
(4)
TO– → TO• + e–
(5)
The hydrogen atom transfer (HAT), the single-electron transfer (SET), and the sequential proton loss (SPL) mechanisms must always occur in parallel, but with different rates. From the antioxidant action viewpoint, the net result of the three mechanisms is the same, TO• and H•. However, it is possible that under certain conditions one of the possible mechanisms may prevail. In general, free energy represents the criterion of the thermodynamically preferred process. In the case of the studied reactions, the absolute values of the entropic term –TΔS reach few tens of kJ mol1 [3437], and all the free energies, ΔG = ΔH – TΔS, are only shifted in comparison to the corresponding enthalpies. Therefore, in our study we calculate reaction free energies related to the three antioxidant scavenging process. The HAT mechanism is characterized by the homolytic bond dissociation free energy (BDFE) of the O–H bond. BDFE is calculated by the following equation: BDFE = ΔG(TO•) + ΔG(H•) – ΔG(TOH)
(6)
The first step of the SET-PT mechanism is characterized by the ionization potential (IP), which can be calculated as follows: IP = ΔG(TOH+•) + ΔG(e– ) – ΔG(TOH)
(7)
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The second step of the SET-PT mechanism is described by the proton dissociation enthalpy (PDFE): PDFE = ΔG(TO•) + ΔG(H+) – ΔG(TOH+•)
(8)
The first step of the SPLET mechanism is characterized by the proton affinity (PA), whereas electron transfer enthalpy (ETFE) refers to the second step. PA and ETFE can be calculated by the equations: PA = ΔG(TO–) + ΔG(H+) – ΔG(TOH)
(9)
ETFE = ΔG(TO•) + ΔG(e–) – ΔG(TO–)
(10)
In this manuscript, our first aim is to calculate and compare the antioxidant activity of -, -, - and TOH in gas phase and in a set of polar and non-polar solvents, which depends on the number and the position of electron-donating character of the methyl group with respect to the oxygen radical. The antioxidant activity of TOHs is evaluated thermodynamically through the BDFE, IP, PDFE, PA, and ETFE. Our second goal is to point out the influence of the solvent polarity on the nature of the scavenging mechanism (homolytic hydrogen atom transfer (BDFE) or heterolytic hydrogen atom transfer (SET-PT, SPLET)) of -, -, - and -TOH. Considered solvents, in this theoretical investigation, are water, DMSO, methanol as polar solvents and benzene, toluene as non-polar ones. We are also interested to calculate the solvation free energy of electron and proton in different media using a good model already used by other authors [18,34].
2. Computational details Our computations have been carried out with the Gaussian03 program package [38]. The geometry optimization of all the molecules and radicals, are performed using the density functional theory DFT approach with the PBE0 functional [39] and the basis set 6-31+G(d). The complete set of optimized Cartesian geometries is available in the supporting information. The PBE0 functional employed in this study was selected because through diverse investigations [12-18, 22-25, 35,37] the B3LYP functional has been used as the best functional, for DFT thermochemical calculations, which consume much more computational time. Nevertheless in Mendoza-wilson et al. results, they showed that PBE0 functional is much more accurate than B3LYP for the determination of thermochemical parameters of flavonoids [40] and quercetin [41]. Therefore, in this work we use PBE0 to show that, as B3LYP [15,18], this functional (PBE0) can give a good result to study the antioxidant activity of tocopherol. Frequency calculations are also carried out at this level to verify the existence of a true minimum. Natural bond orbital (NBO) analysis was used to evaluate bond order, in radical systems. Solvent is treated implicitly using the Integral Equation Formalism of Polarizable Continuum Model (IEF-PCM) [4243] at the same level of theory as in the gas phase. The total free energies of all particles (electron, proton, hydrogen atom, TOHs) in gas phase and in solvent are calculated according the equation ΔG = ΔH –TΔS, without ZPE.
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3. Results and discussion 3.1. Gas phase 3.1.1. Energetic analysis The gas phase free energies of proton ΔG(H+) and electron ΔG(e–) are respectively 26.34 kJ mol1 [44] and 3.62 kJ mol1 [45]. Free energy of hydrogen atom in gas phase, is calculated using DFT/PBE0/6311++G(d,p) method, the obtained value is 1344.05 kJ mol1. In Table 1, the BDFE, IP, PDFE, PA and ETFE of the four () forms of TOH (which differ by the number and the position of methyl groups on the aromatic ring) are presented. The free energies of these systems are calculated using DFT at the PBE0/6-31+G(d) level of theory. Our calculated BDEs (bond dissociation enthalpies) values are compared with those computed at the B3LYP/6-311++G(d,p) level by Klein et al. [15] for another model of tocopherol, where the side chain was replaced by ethyl group. It is noticed that BDEs were approximated from the calculated total electronic energies, E0. The main reason of this approach application was the effort to omit any corrections. Our results are found to be in good agreement with BDEs reported in previous theoretical and experimental works [9,15,19]. Results relevant free energies of our species, in gas phase, are available as supporting information. The BDFEs values listed in Table 1, grow in this order ----TOH. Together with BDEs values, it is shown that -form of TOH is the most reactive compound. On another hand, obtained reaction free energies related to the HAT, SET-PT and SPLET mechanisms confirm the highest antioxidant effectiveness of -TOH, because it has the lowest value of BDFE (246.8 kJ mol1), IP (639.8 kJ mol1) and PA (1417.4 kJ mol1) (Table 1) comparatively to the other forms. For all TOHs, high values of PA show that the proton transfer from the neutral form TOH is disfavored. 3.1.2. NBO analysis and correlation with structure reactivity The antioxidant activity of TOHs can be correlated with the degree of stabilization of the tocopheroxyl radical (TO•). In fact, stabilization depends on the number of electron-donating character of the group bonded to the ortho oxygen atom. -TOH is more reactive (antioxidant) than the other forms because these three TOHs lack one (-, -) or two (-) ortho methyl groups and such electron-releasing groups stabilize tocopheroxyl radical (Fig. 2) and therefore increase reactivity values. The methyl group has an inductive and hyperconjugation effects which participates in the electron delocalization of the aromatic ring and hence in stabilization of the tocopheroxyl radical. Inductive effect operates at all the three positions (ortho, meta and para). This is particularly useful because electron delocalization is expected to correlate with antioxidant activity. That is, the greater the electron delocalization the more stabilized will be the TO • radical relative to the parent TOH and, hence, the weaker will be the O–H bond in the TOH and the greater will be reactivity. Therefore, -TOH is more reactive than -TOH. 3.1.3. Hyperconjugation effects Natural bond orbital (NBO) analysis is used to evaluate bond order n (Fig. 2) in all the radical structure of
-, -, - and -TOH and the strongest bond order n=38.63 is obtained with -TOH. This parameter confirms the good delocalization in -TOH containing three methyl groups comparatively to the other forms. The bond order
4
n is widely correlated with the number of methyl groups. In fact, when the number of CH3 decreases, the bond order decreases also, and at equal number of methyl groups as in and -TOH, the bond order value 35.71 is constant, while -TOH with one methyl group have the lowest bond order (n=32.79). The loss of each methyl group affect the bond order n decreasing it by n = 2.92. Then, we can conclude that the conjugation effect in the chromanol is function of the number of methyl groups, and this link between the structure and the electronic delocalization act on the reactivity or on the antioxidant potency of these molecules. Bigger is the number of methyl groups, more is the delocalization and hardy is the antioxidant reactivity. 3.1.4. Inductive effects The NBO charges on the phenoxyl radical are also shown in Fig. 2. The presence of two electrondonors CH3 groups in ortho positions increases the ionic character of C5C6 and C6C1 bonds and then reinforces the inductive effects, for example, in -TOH the charges are C6(0.392) and C1(0.031) while in TOH their values become C6(0.364) and C1(0.239). The decrease of the number of methyl groups induces a decrease in the negative partial charge of oxygen radical by q = 0.023 coming from - TOH to - TOH (0.552, 0.542, 0.540 and 0.529 on -, -, -, and -TOH respectively) and then decrease the inductive effects, and therefore the reactivity of these molecules . The oxygen partial charges of - and - TOH (where the two methyl groups are in ortho and para positions) are very similar. The little difference can be attributed to the steric repulsion between the ortho2 methyl and the hydroxyl group in -TOH (Fig. 3). We can then conclude that as well the number as the position of the methyl groups act on the reactivity and then on the antioxidant potency of these molecules. This is in accordance with previous studies on the substituted phenols [4649] and chromans [18,28], where methylation especially of the chromanol ortho positions, lead to an additional inductive and steric stability to the chromanoxyl state and therefore increase antioxidant activity. In our case, BDFE between -TOH (two ortho methyl) and -TOH (one ortho methyl) is 13.6 kJ mol1, whereas between - and -TOH (no ortho methyl) is 21.7 kJ mol1. In our results, the difference between the homolytic hydrogen atom transfer HAT (BDFE) and the heterolytic atom transfer SET-PT (IP+PDFE) or SPLET (PA+ETFE) of all TOHs reached 1314.3 kJ mol1, meanings that the HAT is the most favorable mechanism in the gas phase.
3.2. Solvent effect The SET-PT and SPLET mechanisms are of capital importance in solvent media; previous studies on phenolic acids [50,51] showed that the free radical scavenging mechanism of these molecules and their antioxidant potency are solvent dependent. In this section, the nature of hydrogen atom transfer mechanisms of -, -, - and - TOH is studied using the IEF-PCM model at the PBE0/6-31+G(d) level of theory. Chosen solvents are going from the non-polar solvents like benzene, toluene to the most polar ones like methanol, DMSO, and water; their dielectric constants are presented in Table 2. Here, free energies of hydrogen atom H• in solvents were calculated as in the case of TO• (from geometry optimizations followed by a frequency calculations using PBE0/6-311++G(d,p) method), the solvent effect was evaluated using an implicit solvation model (IEF-PCM), the obtained values ΔG(H•) are presented in Table 2. Solvation free energies of electron and proton are respectively the free energies change of the reactions below:
5
Solvent(solv) + e–(g) → solvent(solv)
(11)
Solvent(solv) + H+(g) → solventH+(solv)
(12)
We employed the model: proton or electron was attached to one molecule of solvent, where solvent(solv) represents a molecule of solvent in its cavity, this means that the molecule of solvent is solvated in the same solvent ‘solv’ and it may be one of those used in this work: benzene, toluene, methanol, DMSO, water. Free energies of solvent(solv) are obtained from geometry optimizations followed by a frequency calculations using IEF-PCM/PBE0/6-311++G(d,p) method, for example: H2O(water) + e–(g) → H2O–(water) H2O(water) + H+(g) → H3O+(water) ΔGsolv(e–) = ΔG(H2O–(water)) ΔG(H2O(water)) ΔG(g)(e–) ΔGsolv(H+) = ΔG(H3O+(water)) ΔG(H2O(water)) ΔG(g)( H+) In previous theoretical study [18], proton and electron solvation free energies were determined according to Eq. (11) and Eq. (12), but solvation free energies of hydrogen atom were taken from published solvation enthalpies and entropies [5254]. Tawa and coworkers calculated the solvation free energy of proton in water [55], using the hybrid representation of the solvent. They showed that the free energy converged to kJ mol1 when the number of explicit solvents is larger than four. Zhan and Dixon [56] obtained kJ mol1. Hwang et al. [57] calculated the solvation free energy of the proton in methanol, they suggested that the ΔGsolv(H+) converged when the number of explicit methanol was greater than 3. The converged value is 1102.5 kJ mol1. 3.2.1. Bond Dissociation Free Energy BDFE In Table 3 we present the thermodynamic parameters for the four TOHs in different solvents, using the IEF-PCM/PBE0/6-31+G(d,p) method. Calculated BDFE values (Table 3) of TOHs according to Eq. (6) in solvents with different polarity are compared to the corresponding gas phase values in order to understand solvent effect on O–H bond dissociation. In accordance to gas phase data, the highest and lowest BDFEs of TOHs depend on the number and the position of methyl groups on the aromatic ring. In all solvents, the highest BDFE values were found for -TOH (hydrogen atom in ortho positions), whereas the lowest ones were obtained for -TOH (methyl groups in ortho positions). Therefore, solution and gas phase BDFE values always follow the same trends. Najafi et al. [18] have shown that, in solvents, the substituents in ortho position on chromans exert stronger influence upon BDE when compared with same substituents in meta position. They have obtained the highest and the lowest BDEs for groups in ortho and meta positions, in the case of electron-withdrawing substituents (NO2, COH and CF3) and electron donating groups (NMe2, NH2, NHMe and OH), respectively. In our results, the differences between the highest and the lowest BDFE values of TOHs in gas phase, benzene, toluene, methanol, DMSO and water are 21.7, 22.5, 22.7, 21.7, 21.2 and 20.9 kJ mol1 respectively. We also see, there is no big difference in BDFE of each TOH in all used solvents (for -TOH, BDFE in benzene is 245.4 kJ mol1 and in water is 251.9 kJ mol1), this means that the system (neutral, radical) has nearly the same
6
free energy in all solvents; the free energy of hydrogen atom is constant (ΔG(H•) = 1344.1 kJ mol1). The average sequence of BDFEs values in the different solvents is the same that in the gas phase: ---TOH. We can then conclude that -TOH remains the most reactive molecule and the solvent (polar or non-polar) doesn’t change the reactivity ordering of the TOHs comparing to gas phase. 3.2.2. Ionization Potential According to SET-PT mechanism, IP (Eq. (7)) is another important physical criterion indicating the range of electron donation. Low IP value is favorable to raise the electron-transfer reactivity while high IP value decreases the electron transfer rate between antioxidant and free radical. The calculated IPs of TOHs in solvents are presented in Table 3. IP values in non-polar solvents (benzene and toluene) grow in this order ----TOH, however, methyl groups in ortho positions (-TOH) have an opposite effect and their presence in the molecule lead to a decrease in IP comparatively to the presence of hydrogen atoms in these positions (-TOH). Whereas the tendency of IP values in methanol, DMSO and water is quite different and becomes ----TOH. Consequently, polar solvent changes the IP ordering of the TOHs comparing to gas phase order. We can also see a great influence of polar solvent on the electron solvation free energy; it passes from 1.6 in benzene to 129.0 kJ mol1 in DMSO. Less negative solvation free energy of electron represents the major reason of higher IPs in benzene. The solvent medium involves a significant decrease in the absolute values of IP; the lowest ones are associated to DMSO. The differences between IP values in gas phase and DMSO of --- and -TOH are respectively 269.9, 289.3, 278.2 and 296.7 kJ mol1. The solvent influences the IPs drastically comparatively to solvent effect upon BDFEs. This is not unexpected, because it is well known that cation radicals are charged and they are quite sensitive to the solvent. Our results agree well with those pointed out in the literature [35,58]. 3.2.3. Proton Dissociation Free Energy PDFE represents the reaction free energy of the second step of SET-PT mechanism (Eq. (8)). It is also important to study PDFEs and to investigate the solvent effects on reaction free energies. Klein et al. [15] calculated PDE (Proton Dissociation Enthalpy) in water, they obtained 26 kJ mol1 for -tocopherol model (phytyl tail was replaced by ethyl group), and 25 kJ mol1 for another model of -tocopherol (without the phytyl tail). In this paper, PDFE values of all TOHs decease in solvents comparatively to gas phase; these results are in good accordance with Najafi et al. study [18]. Examination of the values in Table 3 shows that in water, DMSO and methanol, PDFE values are lower than benzene and toluene ones. Again, polar solvents cause larger attenuation of solvent effect. For all TOHs (, -, - and -TOH) forms, the difference between PDFE values in DMSO and in benzene, reached between 157.6 and 171.4 kJ mol1; exceptionally, low PDFE of TOHs in DMSO is attributed to a very good solvation ability of proton in this aprotic solvent [59], the proton solvation free energy in this solvent is 1094.0 kJ mol1. PDFEs in DMSO for ---and -TOH are by respectively 919.6, 898.2, 912.2 and 893.3 kJ mol1 lower than the gas phase values mainly in - and -TOH (the presence of methyl group in ortho2 position, which facilitates deprotonation of the hydroxyl group); this means that the solvent increases the departure of proton from the radical cations. In the studied environments, PDFEs grow in this order: DMSO < methanol < water < toluene < benzene < gas phase.
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3.2.4. Proton affinity PA represents the reaction enthalpy of the first step in SPLET mechanism (Eq. (9)). The calculated gas phase PAs of all molecules are significantly higher than BDFEs and IPs values. The solvent favors the deprotonation process, that’s why the PA values obtained in solvents are far away lower than those in the gas phase, due to the large solvation free energy of proton (Table 2). We observed that PAs obtained in polar solvents, especially in DMSO, are lower than those in non-polar solvents (toluene, benzene). There is little difference of our system (TOH, TO–) free energies in solvents, mainly for neutral molecules, for example, in benzene, ΔG(-TOH) = 655.699 a.u., ΔG(-TO–) = 655.189 a.u. and in DMSO, ΔG(TOH) = 655.708 a.u., ΔG(-TO–) = 655.233 a.u. Therefore, solvation free energy of proton represents the major reason of higher PAs in non-polar solvents compared to polar solvents values. For the four forms of TOH, lowest PAs in non-polar and polar solvents were found for -TOH. The calculated PAs in DMSO are by 1263.7, 1268.6, 1274.1 and 1277.3 kJ mol1 lower than the corresponding gas phase value, for -, -, - and -TOH respectively. In the studied environments, for the four TOHs, PAs grow in the order below: DMSO < methanol < water < toluene < benzene ˂ gas phase. The parameters listed in Table 3 indicate that, for the four forms of TOH, in polar solvents, the PA parameter requires lower energy than BDFE and IP. For example, the energy of PA (146.8 kJ mol1), BDFE (256.5 kJ mol1) and IP (376.5 kJ mol1) of -TOH in DMSO, means that the PA is more favorable because it needs less energy. Lower PA implies that SPLET mechanism should dominate in water, DMSO and methanol, and hence that SPLET represents the most probable mechanism from the thermodynamic point of view. Moreover, for each form of TOHs values of PA and IP in gas phase, toluene, and benzene are higher than those of BDFE as showing for -TOH in Fig. 4. Therefore, HAT represents the most probable mechanism in gas phase and non-polar solvents. The TOHs (-, -, -, and -TOH) have the same behavior in gas phase, polar and non-polar solvents but with different values (Supporting information). We have chosen to present the variation of the favorable mechanism for -TOH in different environments (Fig. 4). According to this Fig. 4, the low PA values of TOHs in DMSO may be ascribed to a very good solvation ability of proton in this solvent [59]. Due to the polarity of the sulfoxide bond and the electron density at the oxygen, cations are much more solvated by DMSO than anions. Conversely, the aprotic nature of DMSO precludes the solvation of anions by hydrogen bonding so that these are solvated only by dipolar attraction and thereby, are more reactive. Aforementioned DMSO behavior is in good accord to previous studies where DMSO was employed in order to investigate the solvent effect on PDEs of antioxidant species [34, 60]. 3.2.5. Electron Transfer Free Energy Electron Transfer Free Energy ETFE represents the reaction free energy of the second step in SPLET mechanism (Eq. (10)). It shows the reduction of the anion TO to donate tocopheroxyl radical, its value in all media is lower than IP (in this case we have a reduction of the neutral molecule). Therefore, the formation of TO• is favorite comparatively to TOH+•. Our calculated ETFE are higher in solvent than in gas phase, especially in methanol. Thereby, solvent does not facilitate the electron transfer from anionic system. The difference between ETFE values in gas phase and methanol, for --- and -TOH are: 124.8, 132.8, 133.3, and 137.1 kJ mol1 respectively. The ETFE values in DMSO are lower than those in the other solvents.
8
In all environments, -TOH has the lowest values of ETFEs and -TOH has the highest ones. This trend corroborates to that one observed in the case of BDFEs. Electron-donating groups (CH3) cause a decrease in the electron transfer free energy (ETFE).
4. Conclusion In this paper, a density functional theory has been applied to study naturally occurring antioxidant compounds. Bond dissociation free energy (BDFE), ionization potential (IP), proton dissociation free energy (PDFE), proton affinity (PA), and electron transfer free energy (ETFE) are determined at the PBE0/6-31+G(d) level of calculations in gas phase and in various solvents by IEF-PCM model. We are interested to calculate solvation free energies of proton and electron in different media, through a good model using IEF-PCM/PBE0/6311++G(d,p) method. Obtained results of free energies related to the HAT, SET-PT and SPLET mechanisms in gas phase show the highest antioxidant activity of -TOH, which has the lowest O–H bond dissociation free energy, ionization potential, and proton affinity values compared to the other forms of TOH (-, -, and -). The antioxidant activity of TOHs compounds depends on the methyl groups at different positions to the phenolic group. The methyl in ortho position leads to additional inductive and steric stability to the tocopheroxyl state and therefore increases antioxidant activity. In non-polar solvents (benzene and toluene), -TOH has the lowest BDFE, IP and ETFE values, whereas in polar solvents (methanol, DMSO, water), -TOH has the lowest PA and PDFE values. The solvent polarity has an important influence in the ordering activity of the four TOHs. For all forms, free energies of radical and neutral systems, in all used solvents, change lightly BDFE values. Whereas non-polar solvents give high IP, PDFE and PA values comparatively to polar solvents, this due to a good solvation free energy of electron and proton in polar medium. From the thermodynamic point of view, homolytic hydrogen atom transfer (HAT) is the most favored scavenging free radical process in gas phase and non-polar solvents, where BDFEs values are lower than PAs and IPs values for all forms of TOH. However, in polar solvents, PAs values are considerably lower than BDFEs and IPs, and the SPLET mechanism represents the most plausible process.
Acknowledgements Authors thank the Abdus Salam ICTP (International centre for Theoretical Physics) for their financial support to this work through the OEA-NET 45 project. K.B would like to thank Prof. Souad Chekir Lahmar (University of Carthage, Tunisia), Prof. Samia Kaddour (University of Houari Boumediene Algiers, Algeria), for theirs material and moral supports, and Jean Jules Fifen for his help discussion.
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Figure captions Fig. 1. (a) Structure of tocopherols, -tocopherol (R1=R2=R3=CH3), -tocopherol (R1=R3=CH3, R2=H), -tocopherol (R1=H, R2=R3=CH3), tocopherol (R1=R2=H, R3=CH3). (b) Model of tocopherol used in this work.
Fig. 2. Bond order n and NBO (u.e) charges of TOHs. Fig. 3. Steric effect between ortho2 methyl and hydrogen atom of hydroxyl group in -TOH. Fig. 4. BDFE, IP, and PA of -TOH in deferent media.
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Table 1. The BDFE, IP, PDFE, PA and ETFE (in kJ mol1) calculated values of -, -, - and -TOH in gas phase at PBE0/6-31+G(d). TOH
BDE′(exp) a
BDE
BDFE
IP
PDFE
PA
ETFE
-TOH
327 (323)
313.5
246.8
639.8
921.3
1417.4
143.7
-TOH
337 (336)
322.0
260.4
653.3
921.4
1423.8
150.9
-TOH
335 (335)
320.6
253.7
654.7
913.3
1420.9
147.1
-TOH
345 (344)
330.0
268.5
667.4
915.4
1425.8
157.0
a
Calculated model of tocopherol (exp : experimental values of BDE) [15].
Table 2. Free energies of hydrogen atom, solvation free energy of proton and electron calculated (in kJ mol1) using IEF-PCM/PBE0/6311++G(d,p) method. ΔGsolv
Benzene
Toluene
Methanol
DMSO
Water
2.25
2.38
32.63
46.70
78.40
ΔG(H )
1344.1
1344.1
1344.1
1344.1
1344.1
ΔGsolv(H+)
857.5
883.2
1014.9
1094.0
1004.0
ΔGsolv(e–)
1.6
5.5
77.6
129.0
89.3
•
Table 3. The BDFE, IP, PDFE, PA and ETFE (in kJ mol1) calculated values of -,-, - and -TOH in different solvents.
-TOH
-TOH
-TOH
-TOH
Solvent
BDFE
IP
PDFE
PA
ETFE
Benzene Toluene Methanol DMSO
245.4 245.2 250.4 250.6
557.4 548.6 419.3 369.9
173.1 152.1 82.7 1.7
482.0 451.5 233.5 153.7
248.5 249.2 268.5 217.9
Water Benzene Toluene Methanol DMSO Water Benzene Toluene Methanol DMSO Water Benzene Toluene Methanol DMSO
251.9 261.1 261.2 268.0 266.1 266.9 252.6 253.2 255.5 256.5 256.1 267.9 267.9 272.1 271.8
405.7 563.5 555.1 416.5 364.0 401.6 568.0 559.8 427.8 376.5 412.1 573.3 564.8 423.7 370.7
97.0 182.6 161.6 103.2 23.1 116.1 169.6 148.7 79.3 1.1 94.7 179.7 158.5 100.1 22.1
239.5 484.6 455.8 235.9 155.2 241.8 479.9 449.3 226.7 146.8 232.4 482.4 451.6 229.7 148.5
263.2 261.5 260.9 283.8 231.9 275.9 257.7 259.2 280.4 230.8 274.4 270.6 271.7 294.1 244.3
Water
272.8
408.8
114.8
235.7
287.9
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Graphical abstract
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Highlights
Three mechanisms for hydrogen atom transfer are proposed.
The antioxidant descriptors: BDFE, IP, PDFE, PA and ETFE are calculated.
The most probable mechanism relies on the environment.
The antioxidant activity of tocopherols depends on the substituents upon the chromanol ring.
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