Computational and Theoretical Chemistry 1060 (2015) 58–65

Contents lists available at ScienceDirect

Computational and Theoretical Chemistry

journal homepage: www.elsevier.com/locate/comptc

Comparative antioxidant potency and solvent polarity effects on HAT

mechanisms of tocopherols
Kahina Bakhouche a,⇑, Zoubeida Dhaouadi b, Nejmeddine 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, Algeria
b
Laboratoire de Spectroscopie Atomique Moléculaire et Applications (LSAMA), Faculté des Sciences de Tunis, Université de Tunis El Manar, Campus Universitaire, 1060 Tunis, Tunisia

a r t i c l e i n f o a b s t r a c t

Article history: The antioxidant activity of the four forms of tocopherol has been investigated in gas phase and in differ-
Received 7 January 2015 ent solvents using PBE0/6-31+G(d) level of theory. The three main working mechanisms, homolytic
Received in revised form 7 February 2015 hydrogen atom transfer (HAT), single electron transfer-proton transfer (SET-PT) and sequential proton
Accepted 21 February 2015
loss electron transfer (SPLET) have been considered. The O–H bond dissociation free energy (BDFE), ion-
Available online 19 March 2015
ization 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
Keywords:
show the effect of the substituent position with respect to the phenolic O–H group on the reactivity.
Tocopherols
Antioxidant activity
The methyl group, in ortho position, lends additional inductive and steric stability to the tocopheroxyl
Inductive effect radical and therefore, increases antioxidant activity. a-tocopherol is shown to be the most reactive form
Solvent effect in gas phase with the lowest BDFE, IP, and PA values, whereas in all solvents, c-tocopherol has the lowest
Free energy 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.
Ó 2015 Elsevier B.V. All rights reserved.

1. Introduction each of them, for homologous members, labeled as a, b, c, and d

Vitamin E is a very important compound of biological mem-
branes, 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
⇑ Corresponding author. Tel.: +213 541 786 104.
E-mail address: kahinabak@yahoo.fr (K. Bakhouche).
(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 [9–18], the model chosen in the present work is
denoted TOH (Fig. 1(b)), where the side chain is assumed to be a
hydrogen atom. Previously, experimental [19–21] and theoretical
[12–17,22,23] investigations have been carried out on vitamin E
antioxidant properties. In other papers [18–24], the effect of vari-
ous substituents on reaction enthalpies related to antioxidant
mechanism action of chromanol (basic structure of vitamin E) in
gas phase and water, have been studied.
a-tocopherol (a-TOH) is known to be the most powerful lipid sol-
uble antioxidant [25], it traps peroxyl radical ROO and converts it to
hydroperoxyde product ROOH (a-TOH + ROO ? a-TO + ROOH),

http://dx.doi.org/10.1016/j.comptc.2015.02.018
2210-271X/Ó 2015 Elsevier B.V. All rights reserved.
 K. Bakhouche et al. / Computational and Theoretical Chemistry 1060 (2015) 58–65
Fig. 1. (a) Structure of tocopherols, a-tocopherol (R1 = R2 = R3 = CH3), b-tocopherol (R1 = R3 = CH3, R2 = H), c-tocopherol (R1 = H, R2 = R3 = CH3), d-tocopherol (R1 = R2 = H,
R3 = CH3). (b) Model of tocopherol used in this work.
the tocopheroxyl radical a-TO reacts with another peroxyl radical to
form non radical inactive product (a-TO + ROO ? inactive pro-
duct), or reacts with a coantioxidant molecule (CoAH) [26,27] to
reduce the tocopheroxyl radical a-TO and reconstitute a neutral
molecule a-TOH (a-TO + CoAH ? a-TOH + CoA). Similarly, the
radical derived from the coantioxidant CoA can either terminate
with ROO (CoA + ROO ? inactive product). Tocopherol can 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 hydro-
gen 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
(Eqs. (4) and (5)) named SPLET [33].
TOH ! TO þ H
TOH ! TOHþ þ e
TOHþ ! TO þ Hþ
 þ
TOH ! TO þ H
 program package [38]. The geometry optimization of all the mole-
TO ! TO þ e 
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 view-
point, the net result of the three mechanisms is the same, TO and H.
However, it is possible that under certain conditions, one of the pos-
sible 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
–TDS reach few tens of kJ mol1 [34–37], and all the free energies,
DG = DH  TDS, 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 ¼ DGðTO Þ þ DGðH Þ  DGðTOHÞ
The first step of the SET-PT mechanism is characterized by the
ionization potential (IP), which can be calculated as follows:
IP ¼ DGðTOHþ Þ þ DGðe Þ  DGðTOHÞ
The second step of the SET-PT mechanism is described by the
proton dissociation enthalpy (PDFE):
 þ þ
PDFE ¼ DGðTO Þ þ DGðH Þ  DGðTOH Þ
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:
59
PA ¼ DGðTO Þ þ DGðHþ Þ  DGðTOHÞ ð9Þ
ETFE ¼ DGðTO Þ þ DGðe Þ  DGðTO Þ ð10Þ
In this manuscript, our first aim is to calculate and compare the
antioxidant activity of a-, b-, c- and d-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 evalu-
ated 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 a-, b-, c- and d-TOH. Considered sol-
vents, in this theoretical investigation, are water, DMSO, methanol
as polar solvents and benzene, toluene as non-polar ones. We are
ð1Þ also interested to calculate the solvation free energy of electron
and proton in different media using a good model already used
ð2Þ by other authors [18,34].
ð3Þ
2. Computational details
ð4Þ Our computations have been carried out with the Gaussian03
ð5Þ
cules 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 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 accu-
rate than B3LYP for the determination of thermochemical parame-
ters 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
ð6Þ
Formalism of Polarizable Continuum Model (IEF-PCM) [42,43] 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
ð7Þ
DG = DH  TDS, without ZPE.
3. Results and discussion
ð8Þ
3.1. Gas phase
3.1.1. Energetic analysis
The gas phase free energies of proton DG(H+) and electron
DG(e–) are respectively 26.34 kJ mol1 [44] and 3.62 kJ mol1
60 K. Bakhouche et al. / Computational and Theoretical Chemistry 1060 (2015) 58–65

Table 1 3.1.2. NBO analysis and correlation with structure reactivity

The BDFE, IP, PDFE, PA and ETFE (in kJ mol1) calculated values of a-, b-, c- and d-TOH The antioxidant activity of TOHs can be correlated with the
in gas phase at PBE0/6-31+G(d).
degree of stabilization of the tocopheroxyl radical (TO). In fact,
TOH BDE0 (exp)a BDE BDFE IP PDFE PA ETFE stabilization depends on the number of electron-donating charac-
a-TOH 327 (323) 313.5 246.8 639.8 921.3 1417.4 143.7 ter of the group bonded to the ortho oxygen atom. a-TOH is more
b-TOH 337 (336) 322.0 260.4 653.3 921.4 1423.8 150.9 reactive (antioxidant) than the other forms because these three
c-TOH 335 (335) 320.6 253.7 654.7 913.3 1420.9 147.1 TOHs lack one (b-, c-) or two (d-) ortho methyl groups and such
d-TOH 345 (344) 330.0 268.5 667.4 915.4 1425.8 157.0
electron-releasing groups stabilize tocopheroxyl radical (Fig. 2)
a
Calculated model of tocopherol (exp: experimental values of BDE) [15]. 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 stabiliza-
[45]. Free energy of hydrogen atom in gas phase, is calculated using
tion of the tocopheroxyl radical. Inductive effect operates at all the
DFT/PBE0/6-311++G(d,p) method, the obtained value is
three positions (ortho, meta and para).
1344.05 kJ mol1.
This is particularly useful because electron delocalization is
In Table 1, the BDFE, IP, PDFE, PA and ETFE of the four (a, b, c, d)
expected to correlate with antioxidant activity. That is, the greater
forms of TOH (which differ by the number and the position of
the electron delocalization the more stabilized will be the TO
methyl groups on the aromatic ring) are presented. The free ener-
radical relative to the parent TOH and, hence, the weaker will be
gies of these systems are calculated using DFT at the PBE0/6-
the O–H bond in the TOH and the greater will be reactivity.
31+G(d) level of theory.
Therefore, a-TOH is more reactive than d-TOH.
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 3.1.3. Hyperconjugation effects
chain was replaced by ethyl group. It is noticed that BDEs were Natural bond orbital (NBO) analysis is used to evaluate bond
approximated from the calculated total electronic energies, E0. order n (Fig. 2) in all the radical structure of a-, b-, c- and d-TOH
The main reason of this approach application was the effort to omit and the strongest bond order n = 38.63 is obtained with a-TOH.
any corrections. Our results are found to be in good agreement This parameter confirms the good delocalization in a-TOH contain-
with BDEs reported in previous theoretical and experimental ing three methyl groups comparatively to the other forms. The
works [9,15,19]. Results relevant free energies of our species, in bond order n is widely correlated with the number of methyl
gas phase, are available as Supporting Information. groups. In fact, when the number of CH3 decreases, the bond order
The BDFEs values listed in Table 1, grow in this order a- < c- decreases also, and at equal number of methyl groups as in b and
< b- < d-TOH. Together with BDEs values, it is shown that a-form c-TOH, the bond order value 35.71 is constant, while d-TOH with
of TOH is the most reactive compound. one methyl group have the lowest bond order (n = 32.79). The loss
On another hand, obtained reaction free energies related to the of each methyl group affect the bond order n decreasing it by
HAT, SET-PT and SPLET mechanisms confirm the highest antioxidant Dn = 2.92. Then, we can conclude that the conjugation effect in
effectiveness of a-TOH, because it has the lowest value of BDFE the chromanol is function of the number of methyl groups, and this
(246.8 kJ mol1), IP (639.8 kJ mol1) and PA (1417.4 kJ mol1) link between the structure and the electronic delocalization act on
(Table 1) comparatively to the other forms. For all TOHs, high values the reactivity or on the antioxidant potency of these molecules.
of PA show that the proton transfer from the neutral form TOH is Bigger is the number of methyl groups, more is the delocalization
disfavored. and hardy is the antioxidant reactivity.

Fig. 2. Bond order n and NBO (u.e) charges of TOHs.

 K. Bakhouche et al. / Computational and Theoretical Chemistry 1060 (2015) 58–65
ortho1
ortho2
Fig. 3. Steric effect between ortho2 methyl and hydrogen atom of hydroxyl group
in c-TOH.
3.1.4. Inductive effects
The NBO charges on the phenoxyl radical are also shown in
Fig. 2. The presence of two electron–donors CH3 groups in ortho
positions increases the ionic character of C5–C6 and C6–C1 bonds
and then reinforces the inductive effects, for example, in a-TOH the
charges are C6(0.392) and C1(0.031) while in d-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 Dq = 0.023 coming from a-TOH to d-TOH
(0.552, 0.542, 0.540 and 0.529 on a-, b-, c-, and d-TOH
respectively) and then decrease the inductive effects, and therefore
the reactivity of these molecules. The oxygen partial charges of b-
and c-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 hydro-
xyl group in c-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 [46–49] and chromans
[18,28], where methylation especially of the chromanol ortho posi-
tions, lead to an additional inductive and steric stability to the
chromanoxyl state and therefore increase antioxidant activity. In
our case, BDFE between a-TOH (two ortho methyl) and b-TOH
(one ortho methyl) is 13.6 kJ mol1, whereas between a- and d-
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 a-,
b-, c- and d-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 calcu-
lated as in the case of TO (from geometry optimizations followed
Table 2
Free energies of hydrogen atom, solvation free energy of proton and electron
calculated (in kJ mol1) using IEF-PCM/PBE0/6-311++G(d,p) method.
DGsolv Benzene Toluene Methanol DMSO
e 2.25 2.38 32.63 46.70
DG (H) 1344.1 1344.1 1344.1 1344.1
DGsolv (H+) 857.5 883.2 1014.9 1094.0
DGsolv (e–) 1.6 5.5 77.6 129.0
61
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 DG(H) are presented in Table 2.
Solvation free energies of electron and proton are respectively
the free energies change of the reactions below:

SolventðsolvÞ þ eðgÞ ! solventðsolvÞ ð11Þ
SolventðsolvÞ þ HþðgÞ ! solvent  HþðsolvÞ ð12Þ
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 ener-
gies of solvent(solv) are obtained from geometry optimizations fol-
lowed by a frequency calculations using IEF-PCM/PBE0/6-
311++G(d,p) method, for example:
H2 OðwaterÞ þ eðgÞ ! H2 OðwaterÞ
H2 OðwaterÞ þ HþðgÞ ! H3 OþðwaterÞ
 

DGsolv ðe Þ ¼ DG H2 OðwaterÞ  DG H2 OðwaterÞ  DGðgÞ ðe Þ
 

DGsolv ðHþ Þ ¼ DG H3 OþðwaterÞ  DG H2 OðwaterÞ  DGðgÞ ðHþ Þ
In previous theoretical study [18], proton and electron solvation
free energies were determined according to Eqs. (11) and (12),
but solvation free energies of hydrogen atom were taken from pub-
lished solvation enthalpies and entropies [52–54]. 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 1097.6 kJ mol1 when the num-
ber of explicit solvents is larger than four. Zhan and Dixon [56]
obtained 1098.3 kJ mol1. Hwang et al. [57] calculated the solva-
tion free energy of the proton in methanol, they suggested that
the DGsolv(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 low-
est 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 d-TOH (hydrogen atom in ortho posi-
tions), whereas the lowest ones were obtained for a-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 sub-
stituents (NO2, COH and CF3) and electron donating groups
(NMe2, NH2, NHMe and OH), respectively.
Water In our results, the differences between the highest and the lowest
78.40 BDFE values of TOHs in gas phase, benzene, toluene, methanol,
1344.1 DMSO and water are 21.7, 22.5, 22.7, 21.7, 21.2 and 20.9 kJ mol1
1004.0
respectively. We also see, there is no big difference in BDFE of each
89.3
TOH in all used solvents (for a-TOH, BDFE in benzene is
62 K. Bakhouche et al. / Computational and Theoretical Chemistry 1060 (2015) 58–65

Table 3 the molecule lead to a decrease in IP comparatively to the presence

The BDFE, IP, PDFE, PA and ETFE (in kJ mol1) calculated values of a-, b-, c- and d-TOH of hydrogen atoms in these positions (d-TOH). Whereas the ten-
in different solvents.
dency of IP values in methanol, DMSO and water is quite different
Solvent BDFE IP PDFE PA ETFE and becomes b- < a- < d- < c-TOH. Consequently, polar solvent
a-TOH Benzene 245.4 557.4 173.1 482.0 248.5 changes the IP ordering of the TOHs comparing to gas phase order.
Toluene 245.2 548.6 152.1 451.5 249.2 We can also see a great influence of polar solvent on the electron
Methanol 250.4 419.3 82.7 233.5 268.5 solvation free energy; it passes from 1.6 in benzene to
DMSO 250.6 369.9 1.7 153.7 217.9
Water 251.9 405.7 97.0 239.5 263.2
129.0 kJ mol1 in DMSO. Less negative solvation free energy of
electron represents the major reason of higher IPs in benzene.
b-TOH Benzene 261.1 563.5 182.6 484.6 261.5
Toluene 261.2 555.1 161.6 455.8 260.9
The solvent medium involves a significant decrease in the abso-
Methanol 268.0 416.5 103.2 235.9 283.8 lute values of IP; the lowest ones are associated to DMSO. The dif-
DMSO 266.1 364.0 23.1 155.2 231.9 ferences between IP values in gas phase and DMSO of a-, b-, c- and
Water 266.9 401.6 116.1 241.8 275.9 d-TOH are respectively 269.9, 289.3, 278.2 and 296.7 kJ mol1. The
c-TOH Benzene 252.6 568.0 169.6 479.9 257.7 solvent influences the IPs drastically comparatively to solvent
Toluene 253.2 559.8 148.7 449.3 259.2 effect upon BDFEs. This is not unexpected, because it is well known
Methanol 255.5 427.8 79.3 226.7 280.4
that cation radicals are charged and they are quite sensitive to the
DMSO 256.5 376.5 1.1 146.8 230.8
Water 256.1 412.1 94.7 232.4 274.4 solvent. Our results agree well with those pointed out in the litera-
ture [35,58].
d-TOH Benzene 267.9 573.3 179.7 482.4 270.6
Toluene 267.9 564.8 158.5 451.6 271.7
Methanol 272.1 423.7 100.1 229.7 294.1 3.2.3. Proton dissociation free energy
DMSO 271.8 370.7 22.1 148.5 244.3 PDFE represents the reaction free energy of the second step of
Water 272.8 408.8 114.8 235.7 287.9 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
245.4 kJ mol1 and in water is 251.9 kJ mol1), this means that the water, they obtained 26 kJ mol1 for a-tocopherol model (phytyl
system (neutral, radical) has nearly the same free energy in all sol- tail was replaced by ethyl group), and 25 kJ mol1 for another
vents; the free energy of hydrogen atom is constant model of a-tocopherol (without the phytyl tail). In this paper,
(DG(H) = 1344.1 kJ mol1). The average sequence of BDFEs values PDFE values of all TOHs decease in solvents comparatively to gas
in the different solvents is the same that in the gas phase: a- < c- phase; these results are in good accordance with Najafi et al. study
< b- < d-TOH. We can then conclude that a-TOH remains the most [18].
reactive molecule and the solvent (polar or non-polar) does not Examination of the values in Table 3 shows that in water, DMSO
change the reactivity ordering of the TOHs comparing to gas phase. and methanol, PDFE values are lower than benzene and toluene
ones. Again, polar solvents cause larger attenuation of solvent effect.
3.2.2. Ionization potential For all TOHs (a-, b-, c- and d-TOH) forms, the difference between
According to SET-PT mechanism, IP (Eq. (7)) is another impor- PDFE values in DMSO and in benzene, reached between 157.6 and
tant physical criterion indicating the range of electron donation. 171.4 kJ mol1; exceptionally, low PDFE of TOHs in DMSO is attrib-
Low IP value is favorable to raise the electron-transfer reactivity uted to a very good solvation ability of proton in this aprotic solvent
while high IP value decreases the electron transfer rate between [59], the proton solvation free energy in this solvent is
antioxidant and free radical. The calculated IPs of TOHs in solvents 1094.0 kJ mol1. PDFEs in DMSO for a-, b-, c- and d-TOH are by
are presented in Table 3. respectively 919.6, 898.2, 912.2 and 893.3 kJ mol1 lower than the
IP values in non-polar solvents (benzene and toluene) grow in gas phase values mainly in a- and c-TOH (the presence of methyl
this order a- < b- < c- < d-TOH, however, methyl groups in ortho group in ortho2 position, which facilitates deprotonation of the
positions (a-TOH) have an opposite effect and their presence in hydroxyl group); this means that the solvent increases the departure

1400
Values of thermodynamic parameters (kJ mol )
−1

BDFE
IP
PA
1200

1000

800

600

400

200

0
methanol

DMSO

water
gas
toluene
benzene

Media in increasing relative permittivity

Fig. 4. BDFE, IP, and PA of a-TOH in different media.

 K. Bakhouche et al. / Computational and Theoretical Chemistry 1060 (2015) 58–65
of proton from the radical cations. In the studied environments,
PDFEs grow in this order: DMSO < methanol < water < toluene <
benzene < gas phase.
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, DG(a-TOH) = 655.699 a.u., DG(a-TO–) = 655.189 a.u.
and in DMSO, DG(TOH) = 655.708 a.u., DG(a-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 c-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 a-, b-, c- and d-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 c-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 a-TOH in Fig. 4. Therefore, HAT represents the most
probable mechanism in gas phase and non-polar solvents. The
TOHs (a-, b-, c-, and d-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 favor-
able mechanism for a-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 radi-
cal, 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 a-, b-, c- and d-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.
63
In all environments, a-TOH has the lowest values of ETFEs and
d-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 dissocia-
tion free energy (BDFE), ionization potential (IP), proton dissocia-
tion 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/PBE0/6-311++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 a-TOH, which has the lowest O–H bond dissociation free
energy, ionization potential, and proton affinity values compared
to the other forms of TOH (b-, c-, and d-). 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 sol-
vents (benzene and toluene), a-TOH has the lowest BDFE, IP and
ETFE values, whereas in polar solvents (methanol, DMSO, water),
c-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.
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.comptc.2015.02.
018.
References
[1] E.-S.A.M. Al-Sherbini, A.H. El Noury, M.N. El Rouby, T. Ibrahim, Vitamin E (a-
tocopherol) enhances the PDT action of hematoporphyrin derivatives on
cervical cancer cells, Med. Laser Appl. 24 (2009) 65–73.
[2] J.N. Hathcock, A. Azzi, J. Blumberg, T. Bray, A. Dickinson, B. Frei, I. Jialal, C.S.
Johnston, F.J. Kelly, K. Kraemer, L. Packer, S. Parthasarathy, H. Sies, M.G. Traber,
Vitamins E and C are safe across a broad range of intakes, Am. J. Clin. Nutr. 81
(2005) 736–745.
64 K. Bakhouche et al. / Computational and Theoretical Chemistry 1060 (2015) 58–65
[3] M.S. Refat, S.A. El-Shazly, Identification of a new anti-diabetic agent by
combining VOSO4 and vitamin E in a single molecule: studies on its spectral,
thermal and pharmacological properties, Eur. J. Med. Chem. 45 (2010) 3070–
3079.
[4] Y. Ohkatsu, T. Kajiyama, Y. Arai, Antioxidant activities of tocopherols, Polym.
Degrad. Stab. 72 (2001) 303–311.
[5] G.W. Burton, M.G. Traber, Vitamin E: antioxidant activity, biokinetics, and
bioavailability, Annu. Rev. Nutr. 10 (1990) 357–382.
[6] F. Bhm, R. Edge, E.J. Land, D.J. McGarvey, T.G. Truscott, Carotenoids enhance
vitamin E antioxidant efficiency, J. Am. Chem. Soc. 119 (1997) 621–622.
[7] C.M. Seppanen, Q.H. Song, A.S. Csallany, The antioxidant functions of
tocopherol and tocotrienol homologues in oils, fats, and food systems, J. Am.
Oil Chem. Soc. 87 (2010) 469–481.
[8] G.W. Burton, K.U. Ingold, Vitamin E: application of the principles of physical
organic chemistry to the exploration of its structure and function, Acc. Chem.
Res. 19 (1986) 194–201.
[9] M. Lucarini, P. Pedrielli, G.F. Pedulli, Bond dissociation energies of O–H bonds
in substituted phenols from equilibration studies, J. Org. Chem. 61 (1996)
9259–9263.
[10] J.S. Wright, D.J. Carpenter, D.J. McKay, K.U. Ingold, Theoretical calculation of
substituent effects on the O–H bond strength of phenolic antioxidants related
to vitamin E, J. Am. Chem. Soc. 119 (1997) 4245–4252.
[11] D.H. Setiadi, G.A. Chass, L.L. Torday, A. Varro, J.G. Papp, Vitamin E models.
Shortened side chain models of a, b, c and d tocopherol and tocotrienol-A
density functional study, J. Mol. Struct. (Theochem). 637 (2003) 11–26.
[12] M. Leopoldini, T. Marino, M. Toscano, Antioxidant properties of phenolic
compounds: H-atom versus electron transfer mechanism, J. Phys. Chem. A 108
(2004) 4916–4922.
[13] J. Espinosa-García, Theoretical enthalpies of formation and O–H bond
dissociation enthalpy of an a-tocopherol model and its free radical, Chem.
Phys. Lett. 338 (2004) 274–278.
[14] X.-Y. Li, C.-X. Hu, M.-L. Li, Z.-G. Liu, A study on photoinduced electronic
transition in complex of vitamin E and benzoquinone, J. Mol. Struct.
(Theochem.) 674 (2004) 257–266.
[15] E. Klein, V. Lukeš, M. Ilčin, DFT/B3LYP study of tocopherols and chromans
antioxidant action energetic, Chem. Phys. 336 (2007) 51–57.
[16] N.K. Singh, P.J. O’Malley, P.L.A. Popelier, Electronic structure calculations of
vitamin E analogues: a model for calculated geometries, hyperfine coupling
constants, reaction enthalpies (DHr) and relative bond dissociation enthalpies
(DBDE), J. Mol. Struct. (Theochem.) 811 (2007) 249–254.
[17] A. Mohajeri, S.S. Asemani, Theoretical investigation on antioxidant activity of
vitamins and phenolic acids for designing a novel antioxidant, J. Mol. Struct.
(Theochem.) 930 (2009) 15–20.
[18] M. Najafi, M. Zahedi, E. Klein, DFT/B3LYP study of the solvent effect on the
reaction enthalpies of homolytic and heterolytic O–H bond cleavage in mono-
substituted chromans, Comput. Theor. Chem. 978 (2011) 16–28.
[19] D.D.M. Wayner, E. Lusztyk, K.U. Ingold, P. Mulder, Application of photoacoustic
calorimetry to the measurement of the O–H bond strength in Vitamin E (a-
and d-tocopherol) and related phenolic antioxidants, J. Org. Chem. 61 (1996)
6430–6433.
[20] E.T. Denisov, A new semiempirical method of estimation of activity and bond
dissociation energies of antioxidants, Polym. Degard. Stab. 49 (1995) 71–75.
[21] S. Tafazoli, J.S. Wright, P.J. O’Brien, Prooxidant and antioxidant activity of
vitamin E analogues and troglitazone, Chem. Res. Toxicol. 18 (2005) 1567–
1574.
[22] M. Navarrete, C. Rangel, J.C. Corchado, J. Espinosa-García, Trapping of the OH
radical by a-tocopherol: a theoretical study, J. Phys. Chem. A 109 (2005) 4777–
4784.
[23] M. Navarrete, C. Rangel, J. Espinosa-García, J.C. Corchado, Theoretical study of
the antioxidant activity of vitamin E: reactions of a-tocopherol with the
hydroperoxy radical, J. Chem. Theory Comput. 1 (2005) 337–344.
[24] M. Najafi, K.H. Mood, M. Zahedi, E. Klein, DFT/B3LYP study of the substituent
effect on the reaction enthalpies of the individual steps of single electron
transfer–proton transfer and sequential proton loss electron transfer
mechanisms of chroman derivatives antioxidant action, Comput. Theor.
Chem. 969 (2011) 1–12.
[25] M. Wijtmans, D.A. Pratt, L. Valgimigli, G.A. DiLabio, G.F. Pedulli, N.A. Porter, 6-
Amini-3-Pyridinols: toward diffusion controlled chain-breaking antioxidants,
Angew. Chem. Int. Ed. Engl. 42 (2003) 4370–4373.
[26] V.W. Bowry, K.U. Ingold, The unexpected role of vitamin E (a-Tocopherol) in the
peroxidation of human low-density lipoprotein, Acc. Chem. Res. 32 (1999) 27–34.
[27] R. Amorati, F. Ferroni, M. Lucarini, G.F. Pedulli, L. Valgimigli, A quantitative
approach to the recycling of a-tocopherol by coantioxidants, J. Org. Chem. 67
(2002) 9295–9303.
[28] G.W. Burton, T. Doba, E.J. Gabe, L. Hughes, F.L. Lee, L. Prasad, K.U. Ingold,
Autoxidation of biological molecules. 4. Maximizing the antioxidant activity of
phenols, J. Am. Chem. Soc. 107 (1985) 7053–7095.
[29] H.Y. Zhang, Y.M. Sun, X.L. Wang, Substituent effects on O–H bond dissociation
enthalpies and ionization potentials of catechols: a DFT study and its
implications in the rational design of phenolic antioxidant and elucidation of
structure-activity relationships for flavonoid antioxidants, Chem. Eur. J. 9
(2003) 502–508.
[30] H.-Y. Zhang, H.-F. Ji, How vitamin E scavenges DPPH radicals in polar protic
media, New J. Chem. 30 (2006) 503–504.
[31] V.B. Luzhkov, Mechanisms of antioxidant activity: the DFT study of hydrogen
abstraction from phenol and toluene by the hydroperoxyl radical, Chem. Phys.
314 (2005) 211–217.
[32] B. Rojano, J. Saez, G. Schinella, J. Quijano, E. Vélez, A. Gil, R. Notario,
Experimental and theoretical determination of the antioxidant properties of
isoespintanol (2-isopropyl-3,6-dimethoxy-5-methylphenol), J. Mol. Struct.
(Theochem.) 877 (2008) 1–6.
[33] L. Estévez, R.A. Mosquera, Molecular structure and antioxidant properties of
delphinidin, J. Phys. Chem. A 112 (2008) 10614–10623.
[34] J. Rimarčik, V. Lukeš, E. Klein, M. Ilčin, Study of the solvent effect on the
enthalpies of homolytic and heterolytic N–H bond cleavage in p-
phenylenediamine and tetracyano-p-phenylenediamine, J. Mol. Struct.
(Theochem.) 952 (2010) 25–30.
[35] E. Klein, V. Lukeš, Study of gas-phase O–H bond dissociation enthalpies and
ionization potentials of substituted phenols – applicability of ab initio and
DFT/B3LYP methods, Chem. Phys. 330 (2006) 515–525.
[36] A.N. Pankratov, A.V. Shalabai, Quantum-chemical evaluation of the protolytic
properties of tocopherols, J. Struct. Chem. 45 (2004) 756–761.
[37] J. Rimarčik, V. Lukeš, E. Klein, L. Rottmannová, On the enthalpies of homolytic
and heterolytic S–H bond cleavage in para and meta substituted thiophenols,
Comput. Theor. Chem. 967 (2011) 273–283.
[38] Gaussian 03, Revision B.05, M.J. Frisch, G.W. Trucks, H.B. Schlegel, G.E.
Scuseria, M.A. Robb, J.R. Cheeseman, J.A. Montgomery Jr., T. Vreven, K. N.
Kudin, J.C. Burant, J.M. Millam, S.S. Iyengar, J. Tomasi, V. Barone, B. Mennucci,
M. Cossi, G. Scalmani, N. Rega, G.A. Petersson, H. Nakatsuji, M. Hada, M. Ehara,
K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H.
Nakai, M. Klene, X. Li, J.E. Knox, H.P. Hratchian, J.B. Cross, C. Adamo, J. Jaramillo,
R. Gomperts, R.E. Stratmann, O. Yazyev, A.J. Austin, R. Cammi, C. Pomelli, J.W.
Ochterski, P.Y. Ayala, K. Morokuma, G.A. Voth, P. Salvador, J.J. Dannenberg, V.G.
Zakrzewski, S. Dapprich, A.D. Daniels, M.C. Strain, O. Farkas, D.K. Malick, A.D.
Rabuck, K. Raghavachari, J.B. Foresman, J.V. Ortiz, Q. Cui, A.G. Baboul, S.
Clifford, J. Cioslowski, B.B. Stefanov, G. Liu, A. Liashenko, P. Piskorz, I.
Komaromi, R.L. Martin, D.J. Fox, T. Keith, M.A. Al-Laham, C.Y. Peng, A.
Nanayakkara, M. Challacombe, P.M. W. Gill, B. Johnson, W. Chen, M.W.
Wong, C. Gonzalez, J.A. Pople, Gaussian Inc, Pittsburgh PA, 2003.
[39] C. Adamo, V. Barone, Toward reliable density functional methods without
adjustable parameters: the PBE0 model, J. Chem. Phys. 110 (1999) 6158–6170.
[40] A.M. Mendoza-Wilson, D. Lardizabal-Gutiérrez, E. Torres-Moye, L. Fuentes-
Cobas, R.R. Balandrán-Quintana, A. Camacho-Dávila, A. Quintero-Ramos, D.
Glossman-Mitnik, Optimized structure and thermochemical properties of
flavonoids determined by the CHIH(medium)–DFT model chemistry versus
experimental techniques, J. Mol. Struct. 871 (2007) 114–130.
[41] A.M. Mendoza-Wilson, R.R. Sotelo-Mundo, R.R. Balandrán-Quintana, D.
Glossman-Mitnik, M.A. Sántiz-Gómez, K.D. García-Orozco, Exploration of the
kinetic and thermochemical abilities for the free radical scavenging of two
quercetin conformers, J. Mol. Struct. 981 (2010) 187–193.
[42] E. Cancès, B. Mennucci, J. Tomasi, A new integral equation formalism for the
polarizable continuum model: theoretical background and applications to
isotropic and anisotropic dielectrics, J. Chem. Phys. 107 (1997) 3032–3041.
[43] J. Tomasia, B. Mennuccia, E. Cancès, The IEF version of the PCM solvation
method: an overview of a new method addressed to study molecular solutes at
the QM ab initio level, J. Mol. Struct. (Theochem.) 464 (1999) 211–226.
[44] J.J. Fifen, Z. Dhaouadi, M. Nsangou, Revision of the thermodynamics of the
proton in gas phase, J. Phys. Chem. A 118 (2014) 11090–11097.
[45] J.J. Fifen, Thermodynamics of the electron revisited and generalized, J. Chem.
Theory Comput. 9 (2013) 3165–3169.
[46] A.L.A. Bentes, R.S. Borges, W.R. Monteiro, L.G.M. de Macedo, C.N. Alves,
Structure of dihydrochalcones and related derivatives and their scavenging
and antioxidant activity against oxygen and nitrogen radical species,
Molecules 16 (2011) 1749–1760.
[47] J.S. Wright, E.R. Johnson, G.A. Dilabio, Predicting the activity of phenolic
antioxidants: theoretical method, analysis of substituent effects, and
application to major families of antioxidants, J. Am. Chem. Soc. 123 (2001)
1173–1183.
[48] E. Klein, V. Lukeš, DFT/B3LYP study of the substituent effect on the reaction
enthalpies of the individual steps of single electron transfer-proton transfer
and sequential proton loss electron transfer mechanisms of phenols
antioxidant action, J. Phys. Chem. A 110 (2006) 12312–12320.
[49] R. Bosque, J. Sales, A QSPR study of O–H bond dissociation energy in phenols, J.
Chem. Inf. Comp. Sci. 43 (2003) 637–642.
[50] O. Holtomo, M. Nsangou, J.J. Fifen, O. Motapon, DFT Study of the solvent effects
on the structure, UV–Vis spectra and the antioxidant activity of caffeic acid
phenethyl ester and some of its derivatives, J. Chem. Chem. Eng. 7 (2013) 910–
923.
[51] J.J. Fifen, M. Nsangou, Z. Dhaouadi, O. Motapon, N. Jaidane, Solvent effects on
the antioxidant activity of 3,4-dihydroxyphenylpyruvic acid: DFT and TD-DFT
studies, Comp. Theor. Chem. 966 (2011) 232–243.
[52] M.M. Bizarro, B.J.C. Carbal, R.M.B. dos Santos, J.A.M. Simõns, Substituent effects
on the O–H bond dissociation enthalpies in phenolic compounds: agreements
and controversies, Pure Appl. Chem. 71 (1999) 1249–1256.
[53] V.D. Parker, Applications of the standard potential of the (H+/H) couple, J. Am.
Chem. Soc. 114 (1992) 7458–7462.
[54] E. Wilhelm, R. Battino, Thermodynamic functions of the solubilities of gases in
liquids at 25 °C, Chem. Rev. 73 (1973) 1–9.
 K. Bakhouche et al. / Computational and Theoretical Chemistry 1060 (2015) 58–65 65

[55] G.J. Tawa, I.A. Topol, S.K. Burt, R.A. Caldwell, A.A. Rashin, Calculation of the
aqueous solvation free energy of the proton, J. Chem. Phys. 109 (1998) 4852–
4863.
[56] C.-G. Zhan, D.A. David, Absolute hydration free energy of the proton from first-
principles electronic structure calculations, J. Phys. Chem. A 105 (2001)
11534–11540.
[57] S. Hwang, D.S. Chung, Calculation of the solvation free energy of the proton in
methanol, B. Kor. Chem. Soc. 26 (2005) 589–593.
[58] M. Leopoldini, F. Rondinelli, N. Russo, M. Toscano, Pyranoanthocyanins: a
theoretical investigation on their antioxidant activity, J. Agric. Food Chem. 58
(2010) 8862–8871.
[59] E. Buncel, H. Wilson, Physical organic chemistry of reactions in dimethyl
sulphoxide, Adv. Phys. Org. Chem. 14 (1977) 133–202.
[60] A.P. Vafiadis, E.G. Bakalbassis, A DFT study on the deprotonation antioxidant
mechanistic step of ortho-substituted phenolic cation radicals, Chem. Phys.
316 (2005) 195–204.