Is Vitamin A an Antioxidant or a Pro-oxidant? - The Journal of Physical

Sep 22, 2017 - It is found that retinol may act in parallel as an effective antioxidant via H atom donating as well as a pro-oxidant in yielding react...
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Is Vitamin A an Antioxidant or a Pro-oxidant? Duy Quang Dao,*,† Thi Chinh Ngo,† Nguyen Minh Thong,‡ and Pham Cam Nam*,§ †

Institute of Research and Development, Duy Tan University, 03 Quang Trung, Danang 550000, Viet Nam Campus in Kon Tum, The University of Danang, 704 Phan Dinh Phung, Kon Tum 580000, Viet Nam § Department of Chemistry, The University of Da Nang−University of Science and Technology, 54 Nguyen Luong Bang, Danang 550000, Viet Nam ‡

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S Supporting Information *

ABSTRACT: Antioxidant efficiency of all-trans-retinol has been studied on the basis of characteristic thermochemical properties using density functional theory. The influence of the solvent polarity has also been evaluated. It is found that retinol may act in parallel as an effective antioxidant via H atom donating as well as a pro-oxidant in yielding reactive hydroxyl radical. In fact, the lowest values of bond dissociation enthalpy were found at the C18−H and C18−OH positions. Retinol was also determined to be a good electron donor but bad acceptor in the single electron transfer (ET) reaction with hydroperoxyl (HOO•) radical. In addition, potential energy surfaces of H atom transfer (HAT) and radical adduct formation (RAF) reactions between retinol and HOO• radical were also investigated in the gas phase and in the solvent. The results demonstrated that the RAF mechanism was generally more predominant than ET and HAT ones. The most favored radical addition position was found at the C2C3 double bond in the cyclohexenyl ring. Moreover, the radical scavenging reactivity via RAF reactions was strongly exergonic and thermodynamically feasible while the ET one was endergonic. Natural bond orbital analysis showed that the lone pairs of electrons on the oxygen atom of the HOO• radical were donated to the unoccupied antibonding orbital of transferred H atom in HAT reactions. In contrast, in the case of RAF reactions, strong interactions between 2p orbitals on oxygen atoms of the radical and the π orbital of the double bond on the retinol molecule were recognized. The results obtained in this work were in agreement with previous experimental observations.



hydrogen atom transfer (HAT) ones.9,10 The obtained radical product may undergo a decomposition reaction to form an alkoxyl radical (LO•) from the lipoperoxyl one (LOO•) and 2,3-retinoid epoxide compound (see Figure 1 for numbering of atomic sites). Another reaction pathway is that the RAF product radical reacts with singlet oxygen (O2) to form retinoid-derivative peroxyl radical (RetOO•), or it may undergo a second addition of the lipoperoxyl radical.10 It can be seen

INTRODUCTION Vitamin A (retinol) is a generic term referring to a form of retinoids (group of fat-soluble unsaturated hydrocarbons) including retinol, retinal, and retinoic acid. By using an in vitro peroxidation system, Das and co-workers demonstrated that antioxidant activities of retinoids have been ranked as retinol ≥ retinal > retinoic acid.1,2 The main sources of vitamin A in food are provitamin A carotenoids from vegetables and retinyl esters from animal tissues.3,4 Vitamin A is an important regulator of embryogenesis, cell growth and differentiation, vision, and reproduction.5 Deficiency of vitamin A leads to welldescribed defects in vision and fertility and, in animals, increased susceptibility to carcinogenesis.6 One of the most active forms of vitamin A is all-transretinol.7 The biological metabolites of retinol are unique. They contain five conjugated double bonds located at their cyclohexenyl ring as well as isoform specific side chains.8 This interesting structure has a significant effect on their reactivity like antioxidant actions. According to the literature, all-trans-retinol can act as a chainbreaking antioxidant in effectively scavenging the lypoperoxyl radical in solution.7 Additionally, the radical adduct formation (RAF) reaction to the cyclohexenyl ring on retinol has been experimentally indicated to be more predominant than © 2017 American Chemical Society

Figure 1. Optimized geometry with the numbered atomic sites of alltrans-retinol calculated at the BMK/6-31G level of theory. Received: July 18, 2017 Revised: September 22, 2017 Published: September 22, 2017 9348

DOI: 10.1021/acs.jpcb.7b07065 J. Phys. Chem. B 2017, 121, 9348−9357

Article

The Journal of Physical Chemistry B that the epoxide formation in consuming LOO• radical generates another radical, i.e., the LO• radical; thus, this does not tend to net radical scavenging. Vitamin A like retinol can act as a radical trapping antioxidant in adding a maximum of six LOO• radicals to its conjugated system. On the other hand, RetOO• radical could cause a self-oxidation by reacting with other retinoid compounds or could become a pro-oxidant for lipid system.10 Several computational studies on the provitamin A βcarotene suggest that the abstraction reaction is more predominantly to occur from the C4 position (as numbered in Figure 1) of the cyclohexenyl ring.11,12 As a result, the H atom abstraction from the C4 position results in a highly stabilized radical and the unpaired electron is delocalized over the polyene chain. Chen et al. investigated the reaction between β-carotene and HO•, HOO• radicals,13 as well as antioxidative activity of carotenes against the peroxidation of lipids initiated by nitrogen dioxide.14 In their works, hydrogen-atom transfer (HAT), radical adduct formation (RAF), and electron transfer (ET) mechanisms were investigated. Among these mechanisms, HAT and RAF were found to be thermodynamically more favorable than the SET one. Moreover, antioxidant action via the single electron transfer (SET) mechanism of vitamin A has also been studied in calculating its ionization energy (IE) quantity. Katsumata et al. studied experimentally the electronic structure of all-transretinol by means of gas phase HeI photoelectron spectroscopy, and the authors calculated the ionization energy (IE) of each compounds by using the HF/6-311G level of theory.15 As a result, experimental and calculated adiabatic IE values of vitamin A are 6.73 and 7.13 eV, respectively. The large deviation is due to the insufficiently high computational level of theory used. Similarly, Martinez et al. also calculated at the BPW91/D95V model chemistries the vertical IE and vertical EA values of the vitamin A equal to 6.22 and 0.54 eV, respectively.16 Recently, Abyar and Farrokhpour updated IE values and the main electronic configurations of the vitamin A ion states and the ones of its derivatives by performing calculations using direct SAC−C-CI theory considering electron correlations.17 The authors found that the IE value is around 7.11 eV. Thus, retinol may act as a strong antioxidant via the SET mechanism in comparing to the IE value of phenol (i.e., 8.49 eV or 195.8 kcal/mol18) which is a referenced phenolic antioxidant. On the basis of the above resumes, it is evident that the vitamin A plays an important role for human health; thus, it is important to analyze its viable antioxidant mechanism especially on the fact of free radical scavenging properties. Although there are different experimental data concerning the antioxidant activity of vitamin A as well as separated computational results related to its thermochemical parameters, there are no systematical theoretical works which determine all characterizing parameters of its free radical scavenging capacity as well as calculate the possible antioxidant reaction mechanisms. Regarding this purpose, the main goal of this work is to systematically evaluate five different mechanisms of antioxidant action including hydrogen atom transfer (HAT)/proton coupled electron transfer (PCET), radical adduct formation (RAF), single electron transfer followed by proton transfer (SETPT), and sequential proton loss electron transfer (SPLET). Several thermochemical properties characterizing these mechanisms have been first calculated in the gas phase,

chloroform, and diethyl ether solvents: bond dissociation enthalpy (BDE), ionization energy (IE), electron affinity (EA), proton dissociation enthalpy (PDE), proton affinity (PA), and electron transfer enthalpy (ETE). Second, in order to provide more insight into the competition between HAT and RAF mechanisms, the potential energy surface of the reactions between all-trans-retinol and hydroperoxyl (HOO•) radical on all possible sites was also performed. Moreover, the hydroxyl group (−OH) at the chain end of the retinol molecule which is affected by five conjugated double bonds could be dissociated to generate the hydroxyl radical (HO•). The pro-oxidant action of retinol was also elucidated. All calculations have been carried out at (RO)BMK/6-311++G(2d,2p)//BMK/6-31G model chemistries.



COMPUTATIONAL DETAILS The Gaussian 09, revision E.01 program package was used.19 All calculations were performed by using the BMK functional (Boese and Martin’s τ-dependent hybrid functional).20 The optimized geometries of neutral molecules, respective radicals, radical anions and cations, and the vibrational frequencies of these species were calculated at the 6-31G basis set. Enthalpy values were evaluated from single-point calculations at the basis set of the 6-311++G(2d,2p) and taking into account thermal corrections to enthalpy from the respective 6-31G results. The restricted open shell formalism was used for the radicals. This computational scheme was chosen as the most reliable one based on the comparison of measured and computed BDE values of different small species which have reasonably similar molecular structures with a part of the vitamin A (see Figure S1 and Table S1 of the Supporting Information). Moreover, theoretical calculations have also indicated that the BMK functional significantly outperformed the other popular density functional theory methods for the calculation of bond dissociation enthalpies (BDEs). The accurate predictions depend on the type of the bonds. For example, BMK could reliably predict the C−H BDEs with a mean deviation of ca. 0.5 kcal/mol,21 +0.3 kcal/mol for C−C bond22 and +1.8 kcal/mol for C−H bond of N, O, and S-containing monoheterocyclic compounds.23 The three most common antioxidant mechanisms including HAT, SETPT, and SPLET which have been widely accepted were investigated in terms of their characteristic thermochemical properties:24−26 Hydrogen atom transfer (HAT) A − H → A• + H•,

(BDE)

(R1)

Single electron transfer followed by proton transfer (SETPT) A − H → AH+• + e−, AH+• → A• + H+,

(IE)

(R2)

(PDE)

(R3)

Sequential proton loss electron transfer (SPLET) A − H → A− + H+,

A− → A• + e−,

(PA)

(R4)

(ETE)

(R5)

The corresponding thermochemical properties which are characterized by the above mechanisms at 298.15 K and 1 atm are calculated as follows:27,28 BDE(A − H) = H(A•) + H(H•) − H(A − H) 9349

(1)

DOI: 10.1021/acs.jpcb.7b07065 J. Phys. Chem. B 2017, 121, 9348−9357

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The Journal of Physical Chemistry B

Table 1. Thermochemical Properties (BDE, PDE, PA, and ETE) of the Retinol in the Gas Phase (GAS) and in Diethyl Ether (DEE) Solvent Calculated at the (RO)BMK/6-311++G(2d,2p)//BMK/6-31G Model Chemistries, (Units in kcal/mol) PAa

ETEb

PDEc

BDEd

bonds

GAS

DEE

GAS

DEE

GAS

DEE

GAS

DEE

C4−H C5−H C6−H C7−H C9−H C10−H C11−H C13−H C14−H C15−H C17−H C18−H C19−H C20−H O−H C18−OH C3−CH3 C1−CH3

353.9 407.6 402.5 401.4 360.9 382.7 374.9 380.5 379.0 386.8 387.7 349.4 368.7 380.2 366.9

91.5 138.8 136.8 130.5 96.9 117.6 112.6 117.4 114.9 118.0 117.6 85.9 101.3 111.1 90.9

37.3 4.1 10.3 14.0 35.0 28.3 33.5 29.8 30.1 37.2 37.0 34.5 33.3 25.5 48.9

55.3 36.8 37.8 38.4 61.3 55.9 57.9 58.3 56.4 68.3 68.8 59.9 62.2 59.9 87.8

61.5 260.3 261.4 264.0 244.6 259.6 257.0 259.0 257.8 272.7 273.3 232.6 250.6 254.4 264.4

−200.6 −179.9 −178.9 −176.2 −195.4 −180.1 −183.1 −177.8 −182.3 −167.2 −167.2 −207.7 −190.1 −185.7 −174.9

77.2 97.7 98.8 101.4 82.0 97.0 94.4 96.3 95.2 110.1 110.7 70.0 88.0 91.7 101.8 69.4 97.5 73.8

76.7 97.4 98.4 101.1 81.9 97.2 94.2 99.5 95.0 110.1 110.1 69.6 87.2 91.6 102.4 68.1 97.0 73.5

a BDE(A−H) = H(A•) + H(H•) − H(A−H). bPDA = H(A•) + H(H+) − H(AH•+). cPA = H(A−) + H(H+) − H(A−H). dETE = H(A•) + H(e−) − H(A−).

IE = H(AH•+) + H(e−) − H(A − H)

(2)

PDE = H(A•) + H(H+) − H(AH•+)

(3)

PA = H(A−) + H(H+) − H(A − H)

(4)







ETE = H(A ) + H(e ) − H(A )

6-31G model chemistries in order to evaluate the HAT and RAF mechanisms. Natural bond orbital (NBO)33 analyses were also performed at transition states (TS) to provide more insight into the electron transfer between retinol and the free radical.



(5)

where H is the total enthalpy of the studied species at 298.15 K and is usually estimated from the following expression: H = E0 + ZPE + Htrans + Hrot + H vib + RT

RESULTS AND DISCUSSION

Optimized Molecular Structure of Retinol. The geometry of all-trans-retinol was first optimized in the gas phase at the BMK/6-31G level of theory. Figure 1 displays the optimized geometry with the numbered atomic sites of alltrans-retinol calculated in the gas phase at the BMK/6-31G model chemistry. As observed in Figure 1, there is generally a chain of five π(CC) orbitals in the molecular structure of retinol in which four of them are located in a polyene chain (i.e., C10C11, C12C13, C14C15, and C16C17) with bond lengths of around 1.36−1.37 Å, and one is found in the cyclohexenyl ring (i.e., C2C3 having a bond length of 1.36 Å). Moreover, the lengths of five single C−C bonds of the cyclohexenyl ring vary from 1.52 to 1.55 Å. These bond distances around 1.52−1.55 Å show that all of the carbon atoms C1, C6, C5, and C4 are in typical sp3 hybridization. The C2C3 equilibrium distance (i.e., 1.36 Å) implies that there is a formation of a localized double bond between these two atoms. The bond angles of C2−C1−C6 (110.9°), C1−C6−C5 (112.3°), C6−C5−C4 (109.3°), and C5−C4−C3 (113.7°) are slightly different. Moreover, the dihedral angle between C2C3 and C10 C11 is found to be 42.6°. This shows that the polyene chain that contains 4 π(CC) orbitals is inclined against the plane containing the cyclohexenyl ring and leads to a bent conformation. Thus, the π(CC) orbitals of the polyene chain and the one of cyclohexenyl ring are not completely conjugated. Moreover, the −OH group of the all-trans-retinol structure is turned down and creates a C17−C18−O−H dihedral angle of −56.6° (Figure 1). The C18−OH bond length of the conformer 1 is 1.45 Å.

(6)

Htrans, Hrot, and Hvib are the translational, rotational, and vibrational contributions to the enthalpy, respectively. E0 is the total energy at 0 K, and ZPE is the zero-point vibrational energy. The influence of the solvents on the thermochemical properties was also studied. The calculation in solvents is based on integral equation formalism of the polarizable continuum model (IEF-PCM) at the same level of theory as in the gas phase.29 The enthalpy value for the hydrogen atom (H•) was calculated at the same level of theory. The enthalpies in the gas phase of proton (H+) being 1.4811 kcal/mol (5/ 2RT, the value of an ideal gas) and of electron (e−) being 0.7519 kcal/mol are commonly accepted.30 Solvation enthalpies of proton and electron in the DEE solvent was calculated using a recent approach31,32 in which it is proposed that a proton or an electron when surrounded by other solvent molecules will bind to a solvent molecule (DEEsol) to yield a charged particle DEE+sol or DEE−sol. These particles are embedded in a dielectric continuum. Cartesian coordinates of neutral and charged particles (e.g., anion and cation forms) of the diethyl ether (DEE) molecule in the same solvent optimized at the BMK/6-31G level of theory are shown in Table S2 of the Supporting Information. Furthermore, the potential energy surface (PES) of the reaction between retinol and the HOO• radical was investigated in the gas phase at the (RO)BMK/6-311++G(2d,2p)//BMK/ 9350

DOI: 10.1021/acs.jpcb.7b07065 J. Phys. Chem. B 2017, 121, 9348−9357

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The Journal of Physical Chemistry B Characteristic Thermochemical Properties for Antioxidant Activity. In order to evaluate the free radicalscavenging activity of retinol via the H atom transfer (HAT) mechanism and its possible pro-oxidant property, bond dissociation enthalpies (BDE) were calculated for either C− H bonds or C−OH, O−H, and C−CH3 ones. It was wellknown that vitamin A is preferably soluble in nonpolarized solvent. Indeed, Wilkie extracted vitamin A using chloroform (ε = 4.7113) and diethyl ether (ε = 4.2400) as solvents.34 In this experiment, the latter was found to have an appreciably higher absorption value than the former. Thus, in the actual study, diethyl ether (DEE) was evidently chosen to evaluate the influence of solvent on thermochemical properties including BDE. The results of all of the thermochemical properties (i.e., BDE, PDE, ETE, and PA) calculated in both the chloroform and diethyl ether solvent are resumed in Table S3 of the Supporting Information. Calculated BDE values in the gas phase as well as in DEE are presented in Table 1. As can be seen, the antioxidant capacity via the HAT mechanism of retinol is completely decided by C18−H donating site with BDE(C18−H) equal to 70.0 kcal/ mol in the gas phase. Thus, retinol may display as a strong antioxidant via the HAT mechanism with a ΔBDE of −18.3 kcal/mol35 in comparison with the experimental BDE(O−H) value of phenol (i.e., 88.3 ± 0.8 kcal/mol36), a referenced phenolic antioxidant. The other H-donating sites of retinol are located at the C4−H, C9−H, and C19−H positions with BDE equal to 77.2, 82.0, and 88.0 kcal/mol in the gas phase, respectively. The lower BDE values of C4−H, C9−H, and C18−H bonds result from the electron-withdrawing effect of the hydroxyl −OH group and the conjugated π system of the polyene chain. It is interesting to note that BDE(O−H) being of 101.8 kcal/mol is much higher than the one of almost BDE(C−H). So, the O−H bond cannot contribute to the H− donating capacity of retinol. Furthermore, the C1−CH3 bond also shows a significantly low BDE of 73.8 kcal/mol in the gas phase, and this leads to a high possibility to form the CH3• free radical from retinol. On the other hand, the lowest bond dissociation enthalpy in the entire retinol molecule is found at the C18−OH bond position. Indeed, BDE(C18−OH) is equal to 69.4 kcal/mol in the gas phase. This notably low BDE value can be explained by the negative inductive effect (−I) of four double bonds that are regularly distributed along the long polyene chain. The strong polarization of the C18−OH bond may result in the generation of reactive •OH radicals that can consequently react with biological molecules such as DNAs, lipids, and proteins, causing the oxidative stress.37 Regarding the effect of solvent, it is observed that the low polarity of the DEE solvent tends to inconsiderable effect on the BDE value. In fact, the BDE value is varied about 0.1−3.2 kcal/mol in DEE as compared to the one in the gas phase (Table 1). For example, BDE(C18−H) is 70.0 and 69.6 kcal/ mol in the gas phase and DEE solvent, while BDE(O−H) is equal to 101.8 and 102.4 kcal/mol, respectively. So, the order of bond dissociation enthalpies can be classified as follows: BDE(C18−OH) ≈ BDE(C18−H) < BDE(C1− CH3) < BDE(C4−H) < BDE(C9−H). The low BDE(C4−H) value which indicates a strong H atom donating capacity at the C4 position is quite coherent with the previous studies on the provitamin A β-carotene.11,12 On the basis of BDE evaluation, it is generally found that retinol can act in parallel as a strong antioxidant with high H atom donor capacity and a strong

reactive oxygen species donor (i.e., a pro-oxidant) in generating OH• reactive free radical. Electron transfer corresponds to the first step of a single electron transfer followed by proton transfer (SETPT) mechanism that is one of the most important actions of an antioxidant.27,28 Ionization energy (IE) is the required energy quantity that an isolated atom or molecule in the ground electronic state must absorb to discharge an electron in forming a cation. This quantity characterizes the electron donor capacity of the antioxidant molecule. The lower IE value represents the higher antioxidant activity. The adiabatic IE values in the gas phase and DEE solvent were calculated by applying eq 2. As a result, adiabatic IE in the gas phase is equal to 6.41 eV (or 147.81 kcal/mol). The error margin is of 0.32 eV in comparison with the experimental IE reported by Katsumata and Ikehata (i.e., 6.73 eV).15 Otherwise, the calculation of IE in DEE at the same level of theory shows a lower value of 5.28 eV due to the reason that the low polarity of DEE facilitates an electron-releasing process in forming the radical cation. On the other hand, by comparing to the standard IE value of phenol in the gas phase (i.e., 8.49 eV or 195.8 kcal/ mol18), the absolute difference (ΔIE) is equal to −47.98 kcal/ mol. Thus, retinol may be a strong antioxidant via the SETPT mechanism based on its electron-donating capacity with the ΔIE around −45 kcal/mol.35 The electron transfer mechanism is evaluated not only based on its electron-donor capacity but also electron-acceptor one which is characterized by the electron affinity (EA) quantity.38 The higher EA value represents the stronger electron acceptor capacity. Consequently, adiabatic EA values calculated in the gas phase and the DEE solvent at the (RO)BMK/6-311+ +G(2d,2p) model chemistries are equal to 0.61 and 1.76 eV, respectively. These results are coherent with the ones obtained by Martinez et al.16 Moreover, the adiabatic IE and EA of the HOO• radical, one of the representative reactive free radical, are also evaluated. As a result, the IE and EA values in the gas phase are 12.05 and 0.90 eV, respectively. Similarly, IE and EA in DEE solvent are equal to 9.53 and 3.43 eV, respectively. In applying a full electron donator acceptor map (FEDAM)38,39 which allows for a qualitative identification of the relative electron-donor/-acceptor capability among antioxidant molecules and free radicals, it can be seen that retinol seems to be a good electron donator but bad electron acceptor. In fact, retinol has a tendency to transfer one electron to the HOO• radical in both the gas phase and the DEE solvent. The FEDAM of retinol and HOO• radical can be found in Figure S2 of the Supporting Information. The second step of the SETPT mechanism consists of deprotonation of the formed radical cation which is described by proton dissociation enthalpy (PDE). The PDE quantity shows thermodynamically preferred C−H or O−H sites of the radical cation for deprotonation. The PDEs calculated in the gas phase and in the DEE solvents by BMK method are reported in Table 1. As a result, the most favorable deprotonation positions are found at C18, C4, C9, and C20 atoms with PDE value of 232.6, 239.8, 244.6, and 254.4 kcal/ mol, respectively. The order is in line with the one of BDE as shown previously. Moreover, the results demonstrated that PDEs calculated in the solvent are significantly lower than the corresponding values in the gas phase. For example, the PDE value at C18 reduces from 232.6 kcal/mol in the gas phase to −207.7 kcal/mol in DEE. The lower PDEs in the DEE solvent may result from high solvation enthalpy of proton (i.e., −235.7 9351

DOI: 10.1021/acs.jpcb.7b07065 J. Phys. Chem. B 2017, 121, 9348−9357

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The Journal of Physical Chemistry B

were also performed to evaluate the electron transfer mechanism during these reactions. Electron Transfer Reactions. Adiabatic reaction enthalpies (ΔH) and Gibbs free energies (ΔG) of the single electron transfer reaction between retinol and the HOO• radical are considered in order to study the associated energy evolution. The electron-donating/-accepting process between retinol (Ret) and the HOO• radical may occur as follows:38

kcal/mol) in such a nonpolar solvent like DEE. The similar results are obtained with the chloroform solvent as presented in Table S4 of the Supporting Information. This phenomenon was also confirmed by different works in literature.28,40 Thus, it indicates that the deprotonation ability of retinol is more preferable in solvent than in the gas phase. The sequential proton loss electron transfer (SPLET) also displays as an important antioxidant mechanism which is initiated by the first step of proton loss in forming retinol anion (R4). This important step is characterized by proton affinity (PA) value (eq 4). The lower the PA value is, the higher the antioxidant activity via the SPLET mechanism is. The PAs at different carbon atoms calculated in the gas phase and the DEE solvent are presented in Table 1. It is observed that the PAs at different carbon positions follow an increasing order: C18−H < C4−H < C9−H < O−H < C19−H with values equal to 349.4, 353.9, 360.9, 366.9, and 368.7 kcal/mol, respectively. This trend is quite coherent with the one of BDE. Additionally, a remarkable effect of the solvent on PAs is noted due to the higher solvation enthalpy of proton in the solvent compared to that in the gas phase. In fact, PAs at the C18−H position reduce significantly from 349.4 in the gas phase to 85.9 kcal/ mol in DEE. In comparing PAs with IE and BDEs in both phases, it is clearly observed that the BDEs are always lower than the corresponding values of PAs and IE. This indicates that the HAT mechanism is more preferred than both SPLET and SETPT ones. The single electron releasing process from the retinol anion which is symbolized by electron transfer enthalpies (ETE; eq 5) consists of the second step of the SPLET mechanism. Note that, in both the gas phase and the DEE, ETE values are always lower than that of IE. For example, the lowest ETEs obtained in the gas phase and the DEE are 4.1 and 36.8 kcal/mol, respectively, while the IEs are equal to 6.41 (148.8 kcal/mol) and 5.28 eV (121.8 kcal/mol). It means that single electron donation from the anionic form is more preferable than from its neutral one. Moreover, the solvent effect tends to a significant increase of ETE which indicates that the DEE solvent is unfavorable for the electron transfer process. Thus, on the basis of all of the thermochemical properties considered in this section, the HAT mechanism is thermodynamically preferred in both gas phase and solvent media. The most favorable H atom donor sites are located at C18, C4, and C9 carbon atoms. However, the antioxidant capacity via HAT and the pro-oxidant capacities of retinol in yielding the HO• radical may be in concurrence owing to the quasiequal values of BDE (C18−OH; 69.4 kcal/mol) and BDE (C18−H; 70.0 kcal/ mol). Interaction of Retinol with the HOO• Radical. In order to provide more insight into the free radical quenching capacity of retinol, its interaction with the HOO• radical which consists of a representative reactive radical is evaluated in the gas phase. Three types of reactions are considered: electron transfer (ET), H atom transfer (HAT), and radical adduct formation (RAF). The relative importance of these reaction pathways depends on several factors such as nature of free radical, structural features of antioxidant molecule, and, in biological systems, its locations and orientations with membrane.41 Potential energy surface (PES), transition state structures, and singly occupied molecular orbital (SOMO) were systematically investigated for HAT and RAF mechanisms. Natural bond orbital (NBO) analyses realized at transition states (TSs)

Ret + HOO• → Ret•+ + HOO−

(R6)

Ret + HOO• → Ret•+ + HOO+

(R7)

For reaction R6, the adiabatic reaction enthalpy and Gibbs energy are calculated as follows: 0 ΔHdonor = [H(Ret(•+)) + H(HOO−)]

− [H(Ret) + H(HOO•)]

(7)

0 ΔGdonor = [G(Ret(•+)) + G(HOO−)]

− [G(Ret) + H(HOO•)]

(8)

Whereas for reaction R7, the calculations correspond to 0 ΔHacceptor = [H(Ret(•−)) + H(HOO+)]

− [H(Ret) + H(HOO•)]

(9)

0 ΔGacceptor = [G(Ret(•−)) + G(HOO+)]

− [G(Ret) + G(HOO•)]

(10)

As a result, ΔH0donor and ΔG0donor values of the electrondonnating process in the gas phase are equal to 125.7 and 125.5 kcal/mol, respectively. These values in the DEE solvent are 46.2 and 61.9 kcal/mol, respectively. In addition, ΔH0acceptor and ΔG0acceptor values of the electron-accepting process in the gas phase are 264.0 and 266.3 kcal/mol, respectively, while these values in the DEE solvent are 178.6 and 195.2 kcal/mol, in turn. On the basis of these results, it can be noted that (i) the electron-donating process is thermodynamically more favorable than the electron-accepting one in both media with two times lower values of ΔH and ΔG; (ii) the electron-donating and -accepting processes are more feasible in the DEE solvent than in the gas phase; and (iii) the electron transfer processes are strongly endogenic with high positive values of reaction enthalpies and Gibbs energies. Hydrogen Atom Transfer Reactions. On the basis of BDE calculations, it is observed that the three weakest C−H bonds are found at the position of C4−H (BDE = 77.2 kcal/mol), C9−H (BDE = 82.0 kcal/mol), and C18−H (BDE = 70.0 kcal/ mol). Thus, the reactions of retinol with the HOO• radical were investigated at these three positions to evaluate the H atom donation process. All structural optimizations were first performed in the gas phase at the BMK/6-31G level of theory and single-point energy calculations were both obtained in the gas phase and the DEE solvent at the (RO)BMK/6-311+ +G(2d,2p). The PES of these reactions in the gas phase is displayed in Figure 2. Cartesian coordinates and molecular enthalpies of all transition states of HAT reactions are presented in Table S4 of the Supporting Information. IRC plots for these transition states at the BMK/6-31G level of theory are also shown in Figure S3 of the Supporting Information. 9352

DOI: 10.1021/acs.jpcb.7b07065 J. Phys. Chem. B 2017, 121, 9348−9357

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Passing through the transition states, the formation of the HOOH molecule and of the Ret• radical is recognized in a product intermediate (INT-2; Figure 2) with relative energies of −9.42, −5.25, and −16.90 kcal/mol below the reactants for C4−H, C9−H, and C18−H, respectively. Finally, these product intermediates are taken away to form separated products (PROD) with relative energies equal to −7.87, −3.48, and −14.83 kcal/mol below the reactants, respectively. Table 2 summarizes reaction enthalpies and Gibbs energies (in kcal/mol, at 298 K) for HAT and RAF reactions of the Table 2. Relative Reaction Enthalpies (ΔH) and Relative Gibbs Free Energies (ΔG; at T = 298 K) for HAT and RAF of the Retinol with the HOO• Radical in the Gas Phase and the DEE Solvent

Figure 2. PES of HAT reactions between retinol and HOO• radical calculated in the gas phase at the (RO)BMK/6-311++G(2d,2p)// BMK/6-31G model chemistries.

ΔH, kcal/mol reactions HAT reactions C4−H + OOH C9−H + OOH C18−H + OOH RAF reactions C2C3 + OOH C10C11 + OOH C12C13 + OOH C14C15 + OOH C16C17 + OOH

In general, the reaction occurs as follows (R8): Ret( −H) + HOO• → Ret ··· H ··· OOH → Ret• + HOOH

(R8)

At the initiation step of the H-atom abstraction reaction, the O2 atom of the HOO• free radical approaches the H atom of the weak C−H bonds of retinol to form a hydrogen bond in a reactant intermediate (INT-1) with energy lying below the separated reactants by −0.30, −4.42, and −7.21 kcal/mol corresponding to C4−H, C9−H, and C18−H, respectively. Then, the weak H atom is separated from the retinol molecule in forming a chemical bond with the HOO• radical via transition state (TS) lying energy barrier above reactants by 12.94, 13.38, and 9.16 kcal/mol for reaction at the C4−H, C9− H, and C18−H positions, respectively. The studied C−H bonds are elongated in this state with the bond distances of 1.27, 1.28, and 1.26 Å assigned to C4···H, C9···H, and C18···H bonds, respectively (Figure 3). At the same time, the O2···H bond length is equal to 1.31, 1.30, and 1.32 Å, in sequence.

ΔG, kcal/mol

GAS

DEE

GAS

DEE

−7.87 −3.48 −14.83

−8.61 −4.01 −15.77

−7.67 −3.86 −14.54

−8.41 −4.39 −15.48

−27.89 −15.40 −17.00 −16.97 −21.78

−27.91 −15.49 −17.68 −17.30 −22.33

−24.46 −13.72 −14.54 −14.68 −19.14

−24.75 −13.95 −15.39 −15.18 −19.91

retinol with the HOO• radical in the gas phase and the DEE solvent. It is shown that all of the HAT reactions are exergonic and thermodynamically favorable. Indeed, the Gibbs energy (ΔG) of HAT reactions at C4−H, C9−H, and C18−H positions are of −7.67, −3.86, and −14.54 kcal/mol, respectively (Table 2). Thus, retinol can scavenge the HOO• radical through this mechanism with an increasing reactivity as follows: C9−H < C4−H < C18−H. The nonpolar diethyl ether solvent slightly lowers the reaction enthalpies and Gibbs free energies of the HAT reactions (Table 2). Relative energies of all of the reaction states during HAT reactions calculated in the gas phase and the DEE solvent are shown in Table S5 of the Supporting Information. As can be seen in Table 2, the relative enthalpies (ΔH) of the HAT reactions are slightly lowered in the DEE solvent. For example, the ΔH value for the reaction at C4−H is reduced from −7.87 to −8.61 kcal/mol in the gas phase and the DEE solvent, respectively. Moreover, the HAT reactions are more exergonic in the DEE than in the gas phase. The ΔG value for reaction at C4−H is decreased from −7.67 to −8.41 kcal/mol, in sequence. Radical Adduct Formation Reactions. The addition reaction of the HOO• radical to the CC double bond on the polyene chain of the retinol occurs generally through two steps (R9 and R10):

In the first step, the HOO• free radical is added to the α or β positions of the double CC bond to form a C−OOH bond.

Figure 3. Optimized TS structure and SOMO distribution of TSs of H-atom abstraction reactions between retinol and the HOO• radical. 9353

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The Journal of Physical Chemistry B The epoxidation reaction then takes place in the second step in which the oxygen atom closes the epoxide ring in separating the HO• radical. So, the whole reaction process takes place via two transition states (TS-1 and TS-2) and three intermediate states (INT-1, INT-2, and INT-3) before arriving at the product (PROD; Figure 4).

Figure 4. PES of addition reactions of the HOO• radical to π bonds on the retinol molecule calculated in the gas phase at the (RO)BMK/ 6-311++G(2d,2p)//BMK/6-31G model chemistries.

Figure 4 displays PES of all RAF reactions between the HOO• radical and the retinol calculated in the gas phase at the (RO)BMK/6-311++G(2d,2p)//BMK/6-31G model chemistries. Cartesian coordinates and molecular enthalpies of all transition states of RAF reactions are shown in Table S7 of the Supporting Information. IRC plots for these transition states at the BMK/6-31G level of theory in the gas phase are also displayed in Figure S4 of the Supporting Information. As can be seen, the reaction pathways are initiated by an approach of the free radical to the carbon center of the retinol to form the first intermediate complex (INT-1) with an energy lying below the separated reactants from −2.41 kcal/mol for the reaction at C14C15 to −6.62 kcal/mol in the case of C16C17. The HOO• radical then forms a chemical bond with the carbon center of the retinol via the first transition state (TS-1) which is characterized by an energy barrier varied from 7.12 to 15.49 kcal/mol for the reaction at C16C17 and C10C11 bonds, respectively (Figure 4). The C···O2 bond distance is equal to 2.12 and 2.03 Å, respectively, whereas the bond angle ∠C16−C17−O2 is 99.1° and ∠C10−C11−O2 is equal to 98.8° (Figure 5). The molecular systems are then stabilized by passing the second intermediate state (INT-2) with relative energy lying between −21.27 and −2.77 kcal/mol below the initial reactants for the reaction at C2C3 and C10C11 bonds, respectively. In the second transition state of the reaction pathway (TS-2), the O2 atom tends to form a chemical bond with the remaining carbon center of the CC double bond in establishing an epoxide bridge. The TS-2 states are described by energy barriers of 0.45−13.55 kcal/mol for the reactions at C16C17 and C10C11 bonds, respectively. The bond distances of C16···O2 and C10···O2 are equal to 1.93 and 1.96 Å, whereas bond angles ∠C16−C17−O2 and ∠C10−C11−O2 are now reduced to 82.0 and 83.8°, respectively. Moreover, the O2···O3 bond of the HOO• radical is elongated and the HO• radical is released at the same time with the closure of the epoxide ring. The molecular system is stabilized at the third intermediate

Figure 5. Optimized TS structures of all RAF reactions between the retinol and the HOO• radical calculated in the gas phase at the BMK/ 6-31G level of theory.

state (INT-3) before passing the final separated products (PROD) including the retinol epoxide and the hydroxyl radical. The INT-3 state is characterized by relative energies lying from −32.76 to −19.29 kcal/mol underneath reactants for the reactions at C2C3 and C10C11 bonds, respectively. Similarly, the relative energy of products is equal to −27.89 to −15.41 kcal/mol. It is noted that the HOO• radical addition to the C2C3 double bond on the cyclohexenyl ring of the retinol is the most favorable with the lowest values of ΔH and ΔG, i.e., −27.89 and −24.46 kcal/mol, respectively (Table 2). This theoretical observation is quite coherent with the one experimentally obtained on β-carotene.9 Moreover, as observed for the HAT process, all of the RAF reactions are slightly more feasible and exergonic in the DEE solvent than in the gas phase with the lower ΔH and ΔG values. Furthermore, the RAF reactions are more strongly exergonic than the HAT ones (Table 2), where the relative Gibbs free energy (ΔG) in the gas phase varies from −24.46 to −13.72 kcal/mol for the reactions at C2C3 and C10C11 bonds, respectively. Whereas, the ΔG values calculated in the DEE solvent vary from −24.75 to −13.95 kcal/mol for similar reactions. This leads to the conclusion that the free radical scavenging activity of the retinol based on the RAF reactions is thermodynamically more feasible. SOMO and NBO Analyses of HAT and RAF Reactions. In this section, singly occupied molecular orbital (SOMO) and natural bond orbital (NBO) analyses are investigated to provide more insight into the mechanism of HAT and RAF reactions between the retinol and the HOO• radical. Figures 3 and 6 display SOMO density surfaces of HAT and RAF transition states, respectively. Table 3 displays NBO analysis results of the transition states for both types of reactions. 9354

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Table 3. NBO Analysis of Transition States of Reactions between Retinol and the HOO• Radical reactions C4−H + HOO•

C9−H + HOO•

C18−H + HOO•

C2C3 + HOO• (TS-1)

C2C3 + HOO• (TS-2) C10C11 + HOO• (TS-1)

C10C11 + HOO• (TS-2) C12C13 + HOO• (TS-1)

Figure 6. SOMO distribution of TSs of all RAF reactions between the retinol and the HOO• radical.

C12C13 + HOO• (TS-2)

It is widely accepted that the hydrogen atom transfer (HAT) and the proton coupled electron transfer (PCET) consist in two distinct mechanisms in which an electron and a proton are transferred in a single step.42 The electron and the proton are transferred together in the HAT mechanism as a hydrogen atom, while they are transferred between different sets of orbitals in the PCET mechanism.43 It is predicted that PCET reactions can occur in a prereaction hydrogen-bonded complex but also in lone pair−π and π−π interactions.43−46 Since reactants and products of both reactions are similar, analysis of their transition state is necessary to distinguish between them. Martinez et al. proposed that the analysis of SOMO of TS seems to be a reliable criterion to differentiate between HAT and PCET processes.47 It is observed that SOMO of HAT TS has significant atomic orbitals density that is distributed along, or nearly along, the H-transition vector. Conversely, SOMO of PCET TS involves p orbitals that are orthogonal to the transition vector.43 As can be seen in Figure 3, the SOMO in all transition states has a node plane at shifting H atom, and it is mostly localized at C···H···O2 transition vectors which is corresponding to HAT transition states. NBO analysis at TS indicates that two lone pairs of electrons on the O2 atom of the HOO• radical are transferred to the vacant orbital on the donated H atom during the HAT process. For example, the second and third lone pairs of electrons on the O2 atom, LP(2) O2 and LP(3) O2, are transferred to the unoccupied antibonding orbital on the H atom, LP*(1) H, with stabilization energies of 21.63 and 132.07 kcal/mol, respectively, during the reaction of the HOO• radical with the retinol at the C18−H position. On the reverse trend, the unoccupied antibonding orbital on C18, LP*(1) C18, interacts with the one on the H atom, LP*(1) H, with a

C14C15 + HOO• (TS-1)

C14C15 + HOO• (TS-2)

C16C17 + HOO• (TS-1)

C16C17 + HOO• (TS-2)

E(2), kcal/mol

donor NBO (i)

acceptor NBO (j)

LP*(1) C4 LP (2) O2 LP (3) O2 LP*(1) C9 LP (3) O2 LP (2) O2 LP*(1) C18 LP (3) O2 LP (2) O2 σ(1) C3 - O2

LP*(1) LP*(1) LP*(1) LP*(1) LP*(1) LP*(1) LP*(1) LP*(1) LP*(1) LP*(1)

LP*(1) C2 LP(2) O3 LP*(1) C2

σ*(1) C3 - O2 σ*(1) C3 - O2 σ*(1) O2 - O3

38.94 14.09 10.11

σ(1) O2 - O3 σ(1) C11 - O2

LP*(1) C2 LP*(1) C10

6.90 36.79

LP*(1) C10 LP (2) O3 LP*(1) C10

σ*(1) C11 - O2 σ*(1) C11 - O2 σ*(1) O2 - O3

26.47 13.08 7.08

LP (2) O2 σ (1) C13 - O2

LP*(1) C10 LP*(1) C12

7.68 39.13

LP*(1) C12 LP (2) O3 LP*(1) C12

σ*(1) C13 - O2 σ*(1) C13 - O2 σ*(1) O2 - O3

29.58 12.54 8.54

σ(1) O2 - O3 σ(1) C13- O2 LP(2) O3

LP*(1) C12 LP*(1) C12 LP*(3) O2

8.33 9.98 31.04

σ (2) C12 - C13 LP*(1) C14 LP (1) C15 LP (1) C15 LP (2) O2

LP*(1) C14 σ*(2) C12 - C13 LP*(1) C14 σ*(2) C16 - C17 LP*(1) C14

37.58 16.95 244.47 14.96 5.87

LP (1) O2 σ (1) O2 - O3 LP (2) O3

LP*(1) C14 LP*(1) C14 σ*(1) C17 - O2

5.04 11.12 17.20

LP*(1) C16 σ*(1) C17 - O2 LP*(1) C16

σ*(1) C17 - O2 LP*(1) C16 σ *(1) O2 - O3

49.60 43.06 9.04

σ (1) O2 - O3 σ (1) C17 - O2 LP (2) O2 LP (1) O2

LP*(1) LP*(1) LP*(1) LP*(1)

11.96 9.87 4.37 5.32

H H H H H H H H H C2

C16 C16 C16 C16

313.78 23.31 126.16 307.30 133.09 23.10 345.14 132.07 21.63 42.25

stabilization energy equal to 345.14 kcal/mol. This indicates a degeneration of the H atom from the C18−H bond toward the O2 atom to form a new O2−H bond. The orbital interaction is quite similar to the other studied HAT reactions. Regarding RAF reactions, the observation on SOMO shows that 2p orbitals on O2 and O3 atoms have a high tendency to overlap with the π orbital on the C2C3 double bond. NBO analysis demonstrates that the σ bonding orbital of the formed C3−O2 bond, σ(1) C3−O2, donates electrons to the 9355

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The addition reaction of the HOO• radical to double bonds in the cyclohexenyl ring (at the C2C3 position) is the most favored, and this is coherent with the result reported in literature.9 The RAF reaction at the C16C17 position being next to the HO group at the chain end is also preferred. Moreover, the RAF mechanism is more predominant than the ET and HAT ones, and all of the radical scavenging reactivity via RAF reactions is strongly exergonic and thermodynamically feasible. NBO analyses at TSs show that different lone pairs of electrons on the O2 atom of the HOO• radical are donated to the unoccupied antibonding orbital of the transferred H atom during the HAT process. Additionally, the strong overlapping between 2p orbitals on O atoms of the radical with the π orbital on the double bond of retinol is recognized during RAF reactions. The obtained results contribute to a better understanding of the antioxidant actions of all-trans-retinol which might potentially allow preventing oxidative damage in living systems.

unoccupied antibonding orbital on the C2 atom, LP*(1) C2, with a stabilization energy equal to 42.25 kcal/mol. Moreover, the electron is also transferred from the second lone pair of the electron on the O3 atom of the radical, LP(2) O3, to the σ antibonding orbital on the C3−O2 bond, σ*(1) C3−O2, with a stabilization energy of 14.09 kcal/mol. The interaction between two unoccupied orbitals, LP*(1) C2 and σ*(1) C3−O2, is also recognized with a stabilization energy of 38.94 kcal/mol (Table 3). Thus, the electron transfer between the 2p orbital on O2 and O3 atoms with the π orbital of the C2C3 double bond tends to form a new C3−O2 σ bond after passing the first transition state TS-1. At the second TS of the reaction (TS-2) between the HOO• radical with retinol at the C2C3 bond, an overlap between the σ orbital of O2−O3, σ(1) O2−O3, with unoccupied orbital on the C2 atom, LP*(1) C2, is observed with a stabilization energy of 6.90 kcal/mol. Furthermore, the σ antibonding orbital of O2−O3, σ*(1) O2−O3, is also overlapped with LP*(1) C2 with an energy of 10.11 kcal/mol (Table 3). This process can also be observed on SOMO density surfaces (Figure 6). It is the overlapping between the orbital on O2−O3 with the unoccupied one on the C2 atom that results in the formation of a new bond C2−O2 to complete the epoxidation process as the second step of RAF reactions. The reactions at other π bonds on the polyene chain of retinol take place in a quite similar manner.



ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jpcb.7b07065. Validation of the used DFT/BMK methods; Cartesian coordinates of neutral, anion, and cations forms of DEE in the same solvent; thermochemical properties of the retinol in CHLO, DEE, and the gas phase; FEDAM of the retinol and HOO• radical; Cartesian coordinates, enthalpies, and IRC of the TS of all HAT reactions and RAF ones. (PDF)



CONCLUDING REMARKS The radical scavenging properties of all-trans-retinol have been evaluated in the gas phase and diethyl ether solvent. The different thermochemical properties (BDE, IE, EA, PDE, PA, and ETE) which characterize the antioxidant mechanisms (HAT, SETPT, and SPLET) were calculated. The potential energy surfaces of HAT and RAF reactions between retinol and the hydroperoxyl radical were also investigated. Several findings can be noted. The HAT mechanism is more predominant than SETPT and SPLET ones in both the gas phase and the DEE solvent. The H atom donor capacity of retinol is the most preferred at C18−H, C4−H, and C9−H positions with the BDEs of 70.0, 77.2, and 82.0 kcal/mol in the gas phase, in turn. In addition to being a strong antioxidant via HAT, retinol also displays as a prooxidant in yielding a hydroxyl radical owing to the lowest BDE of the C18−OH bond being 69.4 kcal/mol in the gas phase. The nonpolar DEE solvent slightly lowers the BDEs of the retinol. Retinol acts as a good electron donor but a bad electron acceptor in interacting with the HOO• radical. The electrondonating and -accepting processes are more preferred in the DEE solvent than in the gas phase. The electron transfer (ET) processes are strongly endogenic with highly positive values of reaction enthalpy and Gibbs free energy. The PA evaluated along the retinol molecule follows the same tendency with BDE with an increasing order of C18−H, C4−H, and C9−H. It means that, at these carbon positions, retinol may act as an antioxidant by donating an H atom (HAT) or proton (SPLET). All of the HAT reactions of the retinol and the HOO• radical are exergonic and thermodynamically favorable with negative Gibbs free energy. This type of reaction is more exergonic in the DEE than in the gas phase. The singly occupied molecular orbitals evaluated at TSs confirm that the H atom transfer process really takes place.



AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Duy Quang Dao: 0000-0003-0896-5168 Notes

The authors declare no competing financial interest.



ACKNOWLEDGMENTS This research is funded by Vietnam National Foundation for Science and Technology Development (NAFOSTED) under Grant No. 104.06-2015.09.



REFERENCES

(1) Das, N. P. Effects of Vitamin A and Its Analogs on Nonenzymatic Lipid Peroxidation in Rat Brain Mitochondria. J. Neurochem. 1989, 52, 585−588. (2) Palace, V. P.; Khaper, N.; Qin, Q.; Singal, P. K. Antioxidant Potentials of Vitamin A and Carotenoids and Their Relevance to Heart Disease. Free Radical Biol. Med. 1999, 26, 746−761. (3) Debier, C.; Larondelle, Y. Vitamins A and E: Metabolism, Roles and Transfer to Offspring. Br. J. Nutr. 2005, 93, 153−174. (4) Blomhoff, R.; Green, M. H.; Berg, T.; Norum, K. R. Transport and Storage of Vitamin A. Science 1990, 250, 399−404. (5) Fat-Soluble Vitamins (Subcellular Biochemistry); Quinn, P. J., Kagan, Va. E., Eds.; Springer Science+Business Media: New York, 1998; Vol 30. (6) Kolata, G. Vitamin A and Cancer. Science 1984, 224, 338−340. (7) Tesoriere, L.; Ciaccio, M.; Bongiorno, A.; Riccio, A.; Pintaudi, A. M.; Livrea, M. A. Antioxidant Activity of All-Trans-Retinol in

9356

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Article

The Journal of Physical Chemistry B Homogeneous Solution and in Phosphatidylcholine Liposomes. Arch. Biochem. Biophys. 1993, 307, 217−223. (8) Ross, A. Vitamin A. In Modern Nutrition in Health and Disease; Williams & Wilkins: Baltimore, MD, 1999; pp 305−313. (9) Burton, G. W.; Ingold, K. U. Beta-Carotene: An Unusual Type of Lipid Antioxidant. Science 1984, 224, 569−573. (10) Tesoriere, L.; D’Arpa, D.; Re, R.; Livrea, M. A. Antioxidant Reactions of All-transRetinol in Phospholipid Bilayers: Effect of Oxygen Partial Pressure, Radical Fluxes, and Retinol Concentration. Arch. Biochem. Biophys. 1997, 343, 13−18. (11) Krinsky, N. I. Carotenoids as Antioxidants. Nutrition 2001, 17, 815−817. (12) Krinsky, N. I.; Yeum, K.-J. Carotenoid−radical Interactions. Biochem. Biophys. Res. Commun. 2003, 305, 754−760. (13) Chen, C.-H.; Han, R.-M.; Liang, R.; Fu, L.-M.; Wang, P.; Ai, X.C.; Zhang, J.-P.; Skibsted, L. H. Direct Observation of the β-Carotene Reaction with Hydroxyl Radical. J. Phys. Chem. B 2011, 115, 2082− 2089. (14) Chen, S.-J.; Huang, L.-Y.; Hu, C.-H. Antioxidative Reaction of Carotenes against Peroxidation of Fatty Acids Initiated by Nitrogen Dioxide: A Theoretical Study. J. Phys. Chem. B 2015, 119, 9640−9650. (15) Katsumata, S.; Ikehata, N. HeI Photoelectron Spectroscopic Study of Vitamin A and Its Derivatives. J. Electron Spectrosc. Relat. Phenom. 2000, 107, 139−145. (16) Martínez, A.; Rodriguez-Girones, M. A.; Barbosa, A.; Costas, M. Donator Acceptor Map for Carotenoids, Melatonin and Vitamins. J. Phys. Chem. A 2008, 112, 9037−9042. (17) Abyar, F.; Farrokhpour, H. Ionization Energies and Photoelectron Spectra of Fat-Soluble Vitamins in the Gas Phase: A Theoretical Study. RSC Adv. 2014, 4, 35975−35987. (18) NIST Chemistry WebBook; http://webbook.nist.gov/ chemistry/ (accessed Apr 8, 2017). (19) Frisch, M. J.; et al. Gaussian 09, revision E.01; Gaussian, Inc.: Wallingford, CT, 2013. (20) Boese, A. D.; Martin, J. M. L. Development of Density Functionals for Thermochemical Kinetics. J. Chem. Phys. 2004, 121, 3405−3416. (21) Van Speybroeck, V.; Marin, G. B.; Waroquier, M. Hydrocarbon Bond Dissociation Enthalpies: From Substituted Aromatics to Large Polyaromatics. ChemPhysChem 2006, 7, 2205−2214. (22) Zheng, W.-R.; Fu, Y.; Guo, Q.-X. G3//BMK and Its Application to Calculation of Bond Dissociation Enthalpies. J. Chem. Theory Comput. 2008, 4, 1324−1331. (23) Wang, Y.-X.; Zheng, W.-R. A Comparison of the C−H Bond Dissociation Enthalpies of Sulfur-Containing Fused Heterocyclic Compounds to the C−H Bond Dissociation Enthalpies in Other Heterocycles. J. Sulfur Chem. 2015, 36, 155−169. (24) Galano, A. Free Radicals Induced Oxidative Stress at a Molecular Level: The Current Status, Challenges and Perspectives of Computational Chemistry Based Protocols. J. Mex. Chem. Soc. 2015, 59, 231−262. (25) Galano, A.; Mazzone, G.; Marino, T.; Alvarez-Idaboy, J. R.; Russo, N.; Alvarez-Diduk, R. Food Antioxidants: Chemical Insights at the Molecular Level. Annu. Rev. Food Sci. Technol. 2016, 7, 335−352. (26) Leopoldini, M.; Russo, N.; Toscano, M. The Molecular Basis of Working Mechanism of Natural Polyphenolic Antioxidants. Food Chem. 2011, 125, 288−306. (27) Thong, N. M.; Duong, T.; Pham, L. T.; Nam, P. C. Theoretical Investigation on the Bond Dissociation Enthalpies of Phenolic Compounds Extracted from Artocarpus Altilis Using ONIOM(ROB3LYP/6-311++G(2df,2p):PM6) Method. Chem. Phys. Lett. 2014, 613, 139−145. (28) Thong, N. M.; Quang, D. T.; Bui, N. H. T.; Dao, D. Q.; Nam, P. C. Antioxidant Properties of Xanthones Extracted from the Pericarp of Garcinia Mangostana (Mangosteen): A Theoretical Study. Chem. Phys. Lett. 2015, 625, 30−35. (29) Cancès, E.; Mennucci, B.; Tomasi, J. A New Integral Equation Formalism for the Polarizable Continuum Model: Theoretical

Background and Applications to Isotropic and Anisotropic Dielectrics. J. Chem. Phys. 1997, 107, 3032−3041. (30) Bartmess, J. E. Thermodynamics of the Electron and the Proton. J. Phys. Chem. 1994, 98, 6420−6424. (31) Markovic, Z.; Tošovic, J.; Milenkovic, D.; Markovic, S. Revisiting the Solvation Enthalpies and Free Energies of the Proton and Electron in Various Solvents. Comput. Theor. Chem. 2016, 1077, 11−17. (32) Fifen, J. J.; Nsangou, M.; Dhaouadi, Z.; Motapon, O.; Jaidane, N. Solvation Energies of the Proton in Methanol. J. Chem. Theory Comput. 2013, 9, 1173−1181. (33) Glendening, E. D.; Landis, C. R.; Weinhold, F. Natural Bond Orbital Methods. Wiley Interdiscip. Rev. Comput. Mol. Sci. 2012, 2, 1− 42. (34) Wilkie, J. Physical and Chemical Determination of Vitamin A. Ind. Eng. Chem., Anal. Ed. 1941, 13, 209−211. (35) Prior, R.; Wu, X.; Schaich, K. Standardized Methods for the Determination of Antioxidant Capacity and Phenolics in Foods and Dietary Supplements. J. Agric. Food Chem. 2005, 53, 4290−4302. (36) Wright, J. S.; Johnson, E. R.; DiLabio, G. A. Predicting the Activity of Phenolic Antioxidants: Theoretical Method, Analysis of Substituent Effects, and Application to Major Families of Antioxidants. J. Am. Chem. Soc. 2001, 123, 1173−1183. (37) Nimse, S. B.; Pal, D. Free Radicals, Natural Antioxidants, and Their Reaction Mechanisms. RSC Adv. 2015, 5, 27986−28006. (38) Martínez, A.; Vargas, R.; Galano, A. What Is Important to Prevent Oxidative Stress? A Theoretical Study on Electron-Transfer Reactions between Carotenoids and Free Radicals. J. Phys. Chem. B 2009, 113, 12113−12120. (39) Hernandez-marin, E.; Galano, A.; Martínez, A. Cis Carotenoids: Colorful Molecules and Free Radical Quenchers. J. Phys. Chem. B 2013, 117, 4050−4061. (40) Stepanić, V.; Gall Trošelj, K.; Lučić, B.; Marković, Z.; Amić, D. Bond Dissociation Free Energy as a General Parameter for Flavonoid Radical Scavenging Activity. Food Chem. 2013, 141, 1562−1570. (41) Galano, A. Relative Antioxidant Efficiency of a Large Series of Carotenoids in Terms of One Electron Transfer Reactions. J. Phys. Chem. B 2007, 111, 12898−12908. (42) Weinberg, D. R.; Gagliardi, C. J.; Hull, J. F.; Murphy, C. F.; Kent, C. A.; Westlake, B. C.; Paul, A.; Ess, D. H.; McCafferty, D. G.; Meyer, T. J. Proton-Coupled Electron Transfer. Chem. Rev. 2012, 112, 4016−4093. (43) Mayer, J. M.; Hrovat, D. A.; Thomas, J. L.; Borden, W. T. Proton-Coupled Electron Transfer versus Hydrogen Atom Transfer in Benzyl/Toluene, Methoxyl/Methanol, and Phenoxyl/Phenol SelfExchange Reactions. J. Am. Chem. Soc. 2002, 124, 11142−11147. (44) DiLabio, G. A.; Johnson, E. R. Lone Pair−π and π−π Interactions Play an Important Role in Proton-Coupled Electron Transfer Reactions. J. Am. Chem. Soc. 2007, 129, 6199−6203. (45) DiLabio, G. A.; Ingold, K. U. A Theoretical Study of the Iminoxyl/Oxime Self-Exchange Reaction. A Five-Center, Cyclic Proton-Coupled Electron Transfer. J. Am. Chem. Soc. 2005, 127, 6693−6699. (46) Munoz-Rugeles, L.; Galano, A.; Raul Alvarez-Idaboy, J. NonCovalent π−π Stacking Interactions Turn off Non-Adiabatic Effects in Proton-Coupled Electron Transfer Reactions. Phys. Chem. Chem. Phys. 2017, 19, 6969−6972. (47) Martínez, A.; Galano, A.; Vargas, R. Free Radical Scavenger Properties of α-Mangostin: Thermodynamics and Kinetics of HAT and RAF Mechanisms. J. Phys. Chem. B 2011, 115, 12591−12598.

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DOI: 10.1021/acs.jpcb.7b07065 J. Phys. Chem. B 2017, 121, 9348−9357