Theoretical calculations have been performed to predict antioxidant properties for phenolic compounds extracted from Artocarpus Altilis. The two-layer ONIOM method with the high layer treated with ROB3LYP/6-311++G(2df,2p) consists of only two atoms of the breaking bond as the core zone and is able to provide reliable evaluation for BDE(O–H) for phenolic compounds. An important property of antioxidants is determined via the homolytic O-H bond dissociation enthalpy (BDE) of those compounds extracted from Artocarpus Altilis. Based on BDE(O-H) values, compound 12 is considered as a potential antioxidant with the BDE value is estimated to be about 77.3 kcal/mol in the gas phase.

1. Chemical Physics Letters 613 (2014) 139–145
Contents lists available at ScienceDirect
Chemical Physics Letters
journal homepage: www.elsevier.com/locate/cplett
Theoretical investigation on the bond dissociation enthalpies of
phenolic compounds extracted from Artocarpus altilis using
ONIOM(ROB3LYP/6-311++G(2df,2p):PM6) method
Nguyen Minh Thonga
, Tran Duongb
, Linh Thuy Phamc
, Pham Cam Namd,∗
a
The University of Danang – Campus in Kon Tum, 704 Phan Dinh Phung, Kontum, Viet Nam
b
Department of Chemistry, Hue’s University College of Education, 34 Le Loi, Hue, Viet Nam
c
Department of Biochemistry, University of California, Los Angeles – UCLA, Los Angeles, CA 90095, United States
d
Department of Chemistry, The University of Danang, Danang University of Science and Technology, 54 Nguyen Luong Bang, Lien Chieu, Da Nang, Viet Nam
a r t i c l e i n f o
Article history:
Received 12 June 2014
In final form 29 August 2014
Available online 6 September 2014
a b s t r a c t
Theoretical calculations have been performed to predict the antioxidant property of phenolic com-
pounds extracted from Artocarpus altilis. The O H bond dissociation enthalpy (BDE), ionization
energy (IE), and proton dissociation enthalpy (PDE) of the phenolic compounds have been com-
puted. The ONIOM(ROB3LYP/6-311++G(2df,2p):PM6) method is able to provide reliable evaluation for
the BDE(O H) in phenolic compounds. An important property of antioxidants is determined via the
BDE(O H) of those compounds extracted from A. altilis. Based on the BDE(O H), compound 12 is con-
sidered as a potential antioxidant with the estimated BDE value of 77.3 kcal/mol in the gas phase.
© 2014 Elsevier B.V. All rights reserved.
1. Introduction
Natural antioxidants present in plants effectively scavenge
harmful free radicals from our body. Free radical is any species
that is capable of independent existence and contains one or more
unpaired electrons, which reacts with other molecules by donating
or accepting electrons and involves in many pathological conditions
[1].
It is possible to reduce the risk of chronic diseases and prevent
disease progression by either enhancing the natural antioxidant
defense of the body or by supplementing with proven dietary
antioxidants. All human cells protect themselves by multiple
mechanisms especially by the enzymatic and the non-enzymatic
antioxidant systems against free radical damages. However, these
protective mechanisms may not be enough for severe or con-
tinued oxidative stresses. Hence, certain amounts of antioxidant
supplements are constantly required to maintain an adequate
level of antioxidants in order to balance the reactive oxygen
species in human body [2]. Many natural organic compounds
extracted from leaves, seeds, and other parts of plants are con-
sidered as potential antioxidants [3,4]. The great advantages of
these compounds are in their high antioxidant activity, non-toxic
∗ Corresponding author.
E-mail address: camnamp@yahoo.com (P.C. Nam).
effects on human beings, and safety to the environment [5]. In
nature, Artocarpus altilis is known as a good source of pheno-
lic compounds including flavonoids, stilbenoids, arylbenzofurons,
and Jacalin [6–9] whose beneficial role in the digestive process
in humans is well established. The leaves, roots, and root bark
of this plant are used as traditional medicines for the treat-
ment of antioxidant, gout, hepatitis, hypertension, fever, liver
disorders, and diabetes [10]. Therefore, the study of antioxi-
dant compounds extracted from A. altilis is a matter of great
interest to researchers in different fields. Regarding the proper-
ties of its antioxidants, prenylflavones, cycloheterophyllin, and
artonins A and B inhibited iron-induced lipid peroxidation in
rat brain homogenate, scavenged 1,1-diphenyl-2-picrylhydrazyl
(DPPH), scavenged peroxyl radicals, hydroxyl radicals that were
generated by 2,2-azobis (2-amidinopropane) dihydrochloride and
the Fe3+–ascorbate–EDTA–H2O2 system, respectively [6]. There are
many phenolic compounds extracted from A. altilis, therefore in
our restricted aim, the chosen compounds for examining their
antioxidant properties are nine geranyl flavonoids [11] and three
new geranyl aurones [9] from the leaves of A. altilis as shown
in Figure 1.
The purpose of this study was to determine whether natu-
ral components from A. altilis act as antioxidants. Compounds
1–12 were identified as 1-(2,4-dihydroxyphenyl)-3-[8-hydro-
xy-2-methyl-2-(4-methyl-3-pentenyl)-2H-1-benzopyran-5-yl]-1-
propanone (1), 1-(2,4-dihydroxyphenyl)-3-{4-hydroxy-6,6,
http://dx.doi.org/10.1016/j.cplett.2014.08.067
0009-2614/© 2014 Elsevier B.V. All rights reserved.

2. 140 N.M. Thong et al. / Chemical Physics Letters 613 (2014) 139–145
OH
HO
O
OH
OH
OH
HO
O
OH
OH
OH
HO
O
OH
OH
O
OH
OH
OH
OHO
HO
OH
OHO
HO
O
OOH
HO
OH
A
B
C
1'
2'
4' 1
3
4
1''
1
A 1'
2'
4'
B
1
3
4
3
O
OOH
HO
OH
A
B
C
1'
2'
4' 1
3
4
3''
2
H
H
O
OOH
HO
OH
A
B
C
1'
2'
4' 1
3
4
1''
3''
4
HO
2'' O
OOH
HO
OH
A
B
C
1'
2'
4' 1
3
4
1''
3''
5O
A
B
1'
2'
4' 1
3
4
6
O
OOH
HO
OH
A
B
C
1'
2'
4' 1
3
4
1''
3''
8
A
B
1'
2'
4' 1
3
4
HO
5''
6''7''
A
BA'
B'
9
4
1'
1'
2'
2'
4'
4'
1
1
3
3
4
O
O
HO
O
OCH3
OH
O
O
HO
O
OH
OHO
O
OH
OH
A
B
A
B
1
2
3
4
5
6
81
2
3
4
5
6
1
2
3
4
5
6
81
2
3
4
5
6
1
2
4
1
2
3
4
5
6
A
B 3
10 11
12
Figure 1. Structures of twelve investigated compounds extracted from Artocarpus
altilis.
9-trimethyl-6a,7,8,10a-tetrahydro-6H-dibenzo[b,d] pyran-5-yl}-
1-propanone (2), 2-geranyl-2 ,3,4,4 -tetrahydroxydihydrochal-
cone (3), 1-(2,4-dihydroxyphenyl)-3-[3,4-dihydro-3,8-dihydr-
oxy-2-methyl-2-(4-methyl-3-pentenyl)-2H-1-benzopyran-5-yl]-
1-propanone (4), 1-(2,4-dihydroxyphenyl)-3-[8-hydroxy-2-
methyl-2-(3,4-epoxy-4-methyl-1-pentenyl)-2H-1-benzopyran-5-
yl]-1-propanone (5), 2 -geranyl-3 ,4 ,7-trihydroxyflavanone (6),
cycloaltilisin 6 (7), 1-(2,4-dihydroxyphenyl)-3-[8-hydroxy-2-
methyl-2-(4-hydroxy-4-methyl-2-pentenyl)-2H-1-benzopyran-
5-yl]-1-propanone (8), and 2-[6-hydroxy-3,7-dimethylocta-
2(E),7-dienyl]-2 ,3,4,4 -tetrahydroxydihydrochalcone (9), Altilisin
H (10), Altilisin I (11), and Altilisin J (12) [9,11].
The ethyl acetate soluble fraction of the methanol extract of the
leaves of A. altilis was subjected to repeated silica gel column chro-
matography to yield compounds 1–9 [11]. Compounds 10–12 are
new aurones, which were identified in methanol solvent. Struc-
tural elucidation of new compounds has been reported with their
tyrosinase and (␣)-glucosidase inhibitory activities [9].
Previous researches have proposed and characterized two main
mechanisms by which the antioxidants can play their protective
roles being the hydrogen atomic transfer (HAT, Eq. (1)) and the
single electron transfer–proton transfer (SET–PT, Eq. (2)). The HAT
mechanism involves a hydrogen atom being abstracted from the
antioxidant, ArOH, turning ArOH into a free radical. The process
is dependent on the bond dissociation energy (BDE) of the O H
bond in ArOH. On the other hand, the first step of the SET–PT
mechanism is governed by the ionization energy (IE), which is the
electron transfer capacity of the antioxidant to donate an electron
to the free radical. As the result, the antioxidant becomes a radical
cation [12]. The second step of this mechanism, where a proton is
transferred to the formed ROO− anion, is governed by proton dis-
sociation enthalpy (PDE) from ArOH•+ radical cation formed in the
first step. However, low IE values also enhance the probability of
superoxide radical anion generation through the direct electron-
transfer to surrounding O2 [12,13].
ROO• + ArOH → ROOH + ArO• (1)
ROO• + ArOH → ROO−
+ ArOH•+ → ROOH + ArO• (2)
Recently, Nam and coworkers studied the thiophenol, 3-
pyridinethiol, phenylphosphine, toluene, benzenthioselenol, and
their derivatives using density functional theory (DFT) with the
(RO)B3LYP method to accurately determine the BDE of the S H,
P H, C H, and Se H bonds [14–18]. For the larger phenolic com-
pounds like vitamin E, enol curcumin, and epigallocatechin gallate,
the two-layer ONIOM method [19–23] with the high layer treated
with ROB3LYP/6-311++G(2df,2p) that consists of only the hydro-
gen and oxygen atoms was used to predict the BDE(O H) with the
accuracy within 1–2 kcal/mol [24]. In the present work, we contin-
ued to develop this partitioning scheme using the DFT restricted
open-shell (RO)B3LYP/6-311++G(2df,2p) for the high layer and the
semi-empirical PM6 method for the low layer with the aim to fur-
ther shed light on the electronic properties of phenolic compounds
extracted from A. altilis and their radicals. In addition, the other
reaction enthalpies such as IE and PDE were also calculated to eluci-
date the radical scavenging activity of the investigated compounds.
2. Computational methods
All computations were performed using the Gaussian 09 (ver-
sion A.02) suite of programs [25]. Geometry optimizations and
vibrational frequency calculations were conducted using the semi-
empirical PM6 method. Vibrational frequencies obtained at the
PM6 level were subsequently scaled by a factor of 1.078 for esti-
mating the zero-point vibrational energies (ZPE).
The reaction enthalpies values in gas phase at 298.15 K and
1.00 atm for the polyphenol compound (ArOH) were calculated
from the following expression:
BDE(O H) = H(ArO•) + H(H•) − H(ArOH) (3)
IE = H(ArOH•+) + H(e−
) − H(ArOH) (4)
PDE = H(ArO•) + H(H+
)–H(ArOH•+) (5)
where H’s are the enthalpies of different species at 298.15 K.
The enthalpies were estimated from the given expression:
H(T) = E0 + ZPE + Htrans + Hrot + Hvib + RT. The 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 enthalpy value for the hydrogen
atom in the gas phase was taken at its exact energy of −0.5 hartree.
The calculated gas-phase enthalpies of the proton (H+) and electron
(e−) were taken from the literature [26,27].
For ONIOM method, the enthalpy values at higher level method
were evaluated from the calculated single-point electronic energy
based on PM6 optimized structures. In Figure 2, we describe seven
ways of choosing the layer in our proposed ONIOM scheme. In the
proposed ONIOM treatment, each molecule is divided into two lay-
ers: the atoms at the breaking bond are treated as a high layer while
the leftover atoms of the molecule belong to the second layer, which
are treated as a low layer. The (RO)B3LYP/6-311++G(2df,2p) and
PM6 methods are applied to the atoms in the high layer and low
layer, respectively.
In addition, we consider some different ways of selecting the
ONIOM model denoted as 1A, 3A and 5A. For the 1A, the model
has only one oxygen atom and one hydrogen atom related to the

3. N.M. Thong et al. / Chemical Physics Letters 613 (2014) 139–145 141
OH
R5 R1
R2
R3
R4
High layer
low layer
MODEL 3A-1
OH
R5 R1
R2
R3
R4
High layer
low layer
MODEL 3A-2
OH
R5 R1
R2
R3
R4
High layerlow layer
MODEL 1A
OH
R5 R1
R2
R3
R4
High layer
low layer
MODEL 5A-1
OH
R5 R1
R2
R3
R4
High layer
low layer
OH
R5 R1
R2
R3
R4
High layer
low layer
MODEL 5A-2
OH
R5 R1
R2
R3
R4
High layer
low layer
MODEL 5A-3 MODEL 5A-4
Figure 2. Schematic description of two-layer proposed ONIOM model.
target bond for estimating BDE at the higher level of theory. The
rest are defined as the low layer calculated using the PM6 method.
The 3A ONIOM model has three heavy atoms including oxygen and
two carbon atoms at the high layer. We have two ways to choose
three heavy atoms in the high level, namely the 3A-1 and the 3A-
2. Similarly, the 5A ONIOM model has five heavy atoms including
oxygen and four carbon atoms at the high layer. There are four
ways to build up the high layer in the 5A model, denoted as the
5A-1, 5A-2, 5A-3 and 5A-4.
3. Results and discussion
3.1. The reliability of the two layer ONIOM model for BDEs
calculation
In this part, a series of substituted phenols, X-C6H4OH with
X = H, F, CH3, NH2, NO2, and OH, was chosen to benchmark the cal-
culated BDE(O H) values with the experimental data and to assess
the partitioning scheme for the two-layer-ONIOM as described in
Figure 2. It should be noted that the substituent is in turn placed at
the ortho, meta, and para positions of the aromatic ring (except for
o-NH2 and o-NO2). The calculated BDE(O H) of these substituted
phenol are summarized in Figure 3.
From the calculated results for a series of substituted phenols
shown in Figure 3, the largest deviation between our calculated
BDE(O H) using model 1A and the experimental values of the
corresponding molecules is 1.3 kcal/mol in the case of o-CH3-
C6H4OH. For the other substituted compounds of phenol, the
differences between the theoretical calculation and the experimen-
tal data of BDE(O H) are small and in the range of 0.5–1.0 kcal/mol.
However, when we apply models 3A-1 and 3A-2 with three heavy
atoms (one oxygen and two carbons) at the high layer, the dif-
ference between our calculated and the experimental BDE(O H)
significantly increases with the averaged deviation is 5.2 kcal/mol.
The largest deviation of 8 kcal/mol is observed with o-CH3-C6H4OH
using model 3A-1. For models 5A-1, 5A-2, 5A-3 and 5A-4 with five
heavy atoms (one oxygen and four carbons) at the high layer, the
difference between our calculated and the experimental BDE(O H)
is the largest. The average deviation using these models ranges
between 5.6 and 11.2 kcal/mol.
All computed results shown in Figure 3 (see also Table S1 in
supporting data) show that the BDE(O H) values obtained from
the model 1A are reasonably accurate and comparable with the best
experimental data. To assess the performance of this partitioning
scheme in model 1A, we also performed to obtain the S value,
which is defined as the error of the ONIOM energy related to the
correct target energy, [E(high,real)] [29]. The equation of S is as
followed:
S = BDE(ONIOM) − BDE(high, real)
= [BDE(low, real) − BDE(low, model)]
− [BDE(high, real) − BDE(high, model)] = S(low) − S(high)
where S(level) = BDE(level,real) − BDE(level,model) is the “sub-
stituent effect” for the dissociation energy evaluated at the given
level. If the substituent effect evaluated at the low level, S(low),
is the same as that evaluated at the high level, S(high), the ONIOM
error S is zero, and the ONIOM reproduces the exact target energy
[29].

4. 142 N.M. Thong et al. / Chemical Physics Letters 613 (2014) 139–145
Figure 3. Comparisons of the calculated BDE(O H) values of phenolic systems using seven ONIOM models with the experimental data taken from Ref. [28].
Table 1 shows the substituent effect (S) evaluated at the PM6
method and those at the ROB3LYP/6-311++G(2df,2p) for a system of
XC6H4OH. It is clear that the calculated absolute errors (| S|) based
on a series of substituted phenols are within 0.2–2.3 kcal/mol. The
standard deviation ( ) of the ONIOM error is of 1.3 kcal/mol.
All computed results shown in Figure 3 and Table 1 emphasize
that the ONIOM(ROB3LYP/6-311++G(2df,2p):PM6) and the parti-
tioning scheme of model 1A in Figure 2 are actually the reasonable
ONIOM combinations. Hence we choose model 1A as our method
of choice for further study of BDE(O H). However, the reliabil-
ity of model 1A needs to be checked further for larger molecules,
like ubiquinol-2, ubiquinol-6, and ubiquinol-10 (ubiquinol-10 is
known as a strong antioxidant). Figure 4 depicts the structure of
ubiquinols and the chosen model 1A. The high layer is displayed in
the bond type format and the low layer is in the wire frame for-
mat. The calculated BDE(O H) of ubiquinols are given in Table 2.
It can be observed that our calculated BDE(O H) values are in very
good agreement with the corresponding experimental values for
ubiquinols, with the deviation of only ±1.0 kcal/mol.
Our calculations using two-layer ONIOM combined with the
partitioning scheme 1A described above predict the BDE(O H) of
substituted phenol, uniquinol-2, uniquinol-6, and ubiquinol-10 to
be stable and reliable. In the next part we will use this method to
compute the BDE(O H) of twelve phenolic compounds extracted
from A. altilis as shown in Figure 1.
3.2. BDE(O H) values of studied compounds extracted from A.
altilis
3.2.1. Finding the position of the weakest O H bond
For a compound possessing more than one phenolic hydroxyl,
its radical-scavenging activity is determined by the one with the

5. N.M. Thong et al. / Chemical Physics Letters 613 (2014) 139–145 143
Table 1
S values between the real and the model system at the ONIOM(ROB3LYP/6-
311++G(2df,2p):PM6) for model 1A.
Molecule S value
kcal/mol
S = S(Low) − S(High)
S(Low) S(High)
C6H5OH −44.6 −43.5 −1.1
o-F-C6H4OH −45.8 −44.1 −1.7
m-F-C6H4OH −42.5 −42.8 +0.3
p-F-C6H4OH −45.8 −46.1 +0.3
o-CH3-C6H4OH −46.8 −49.1 +2.3
m-CH3-C6H4OH −44.3 −44.0 −0.3
p-CH3-C6H4OH −47.1 −46.1 −1.0
o-NH2-C6H4OH −54.9 −55.9 +1.0
m-NH2-C6H4OH −43.0 −44.0 +1.0
p-NH2-C6H4OH −51.7 −53.8 +2.1
o-NO2-C6H4OH −30.1 −28.6 −1.5
m-NO2-C6H4OH −41.8 −40.3 −1.5
p-NO2-C6H4OH −39.1 −39.3 +0.2
o-OH-C6H4OH −51.5 −52.6 +1.1
m-OH-C6H4OH −41.2 −42.5 +1.3
p-OH-C6H4OH −49.1 −50.2 +1.1
Figure 4. Structures and two layer ONIOM model of ubiquinol-n (n = 2, 6, 10).
lowest BDE(O H). To reduce computation time, we used the PM6
method to calculate preliminarily the BDE(O H) at any position to
find out the weakest bond. Then, the weakest bond was continued
to be calculated at higher level of calculation using model 1A. The
calculated results are given in Table 3. In compound 12, 2-OH had
the lowest BDE value, 65.0 kcal/mol. The lowest BDE(O H) is at
position 3 of ring B for compounds 3 and 9, which are estimated
to be about 68.9 and 68.4 kcal/mol, respectively. The BDE values
of 4-OH for compounds 1, 2, 4, 5, 6, 7, 8, which are lower than
other positions are estimated to be about 70.7, 71.2, 71.8, 70.6, 67.7,
66.7 and 70.4 kcal/mol, respectively. Similarly, in compound 10 and
11, the BDE values of 8-OH are the lowest BDE values, 66.8 and
69.2 kcal/mol, respectively.
Table 2
Calculated BDE(O H) of ubiquinols (data are in kcal/mol).
Molecule BDE(O H) Experimental valuea
BDE(O H)b
Ubiquinol-2 81.9 82.3 −0.4
Ubiquinol-6 81.9 82.3 −0.4
Ubiquinol-10 77.8 78.5 −0.7
a
Experimental values from Ref. [28].
b
BDE(O H) = BDE(O H)calc − BDE(O H)expt.
Table 3
The O H bond dissociation enthalpies and the proton dissociation enthalpies using
the PM6 method, kcal/mol.
Compounds Active sitea
BDEb
PDEc
1 2 (ring A) 83.8 190.9
4 (ring A) 82.7 172.0
4 (ring B) 70.7 158.1
2 2 (ring A) 83.4 171.8
4 (ring A) 82.8 171.2
4 (ring B) 71.2 159.7
3 2 (ring A) 83.8 170.7
4 (ring A) 82.8 158.5
3 (ring B) 68.9 156.0
4 (ring B) 83.8 169.7
4 2 (ring A) 101.9 189.1
4 (ring A) 83.1 170.2
4 (ring B) 71.8 158.9
2 (ring C) 100.2 187.3
5 2 (ring A) 84.3 169.5
4 (ring A) 82.3 167.4
4 (ring B) 70.6 155.9
6 4 (ring A) 80.2 156.7
3 (ring B) 71.9 148.4
4 (ring B) 67.7 144.2
7 2 (ring A) 85.1 171.8
4 (ring A) 81.6 168.4
3 (ring B) 70.9 157.8
4 (ring B) 66.7 153.6
2 (ring A ) 81.2 167.9
4 (ring A ) 81.9 168.7
3 (ring B ) 68.9 155.8
4 (ring B ) 71.8 158.7
8 2 (ring A) 83.2 166.7
4 (ring A) 82.6 166.1
4 (ring B) 70.4 153.9
7 100.6 184.1
9 2 (ring A) 83.8 174.0
4 (ring A) 82.7 172.8
3 (ring B) 68.4 158.7
4 (ring B) 70.5 160.7
6 99.9 190.2
10 6 (ring A) 79.3 174.9
8 (ring B) 66.8 162.6
11 6 (ring A) 79.9 167.0
8 (ring B) 69.2 156.3
12 6 (ring A) 79.9 160.5
2 (ring B) 65.0 145.7
3 (ring B) 71.2 151.8
a
See Figure 1 for definition of atom numbering.
b
BDE(O H) for the phenolic compounds.
c
PDE for the radical cations of phenolic compounds.
Table 4
ONIOM(ROB3LYP/6-311++G(2df,2p):PM6)-computed BDE(O H) of twelve pheno-
lic compounds extracted from Artocarpus altilis.
Compounds O H position BDE(O H)
kcal/mol
Gas phase Methanol Water
1 4-OH (ring B) 83.2 83.5 82.8
2 4-OH (ring B) 84.5 83.2 83.1
3 3-OH (ring B) 80.8 82.4 82.2
4 4-OH (ring B) 85.1 83.7 83.1
5 4-OH (ring B) 83.9 83.8 83.1
6 4-OH (ring B) 80.3 83.9 83.1
7 4-OH (ring B) 79.3 82.9 82.1
8 4-OH (ring B) 83.7 82.8 81.4
9 3-OH (ring B) 79.3 81.3 80.5
10 8-OH (ring B) 80.3 82.7 81.6
11 8-OH (ring B) 82.5 83.9 83.2
12 2-OH (ring B) 77.3 79.0 78.3

6. 144 N.M. Thong et al. / Chemical Physics Letters 613 (2014) 139–145
Table 5
The calculated ionization energies (eV) using the PM6 method and the available experimental value of some phenolic compounds and twelve compounds extracted from
Artocarpus altilis.
Compound IE IEb
Compounds from Artocarpus altilis IE
Calc. Expt.a
Phenol 8.38 (8.61) 8.49 ± 0.02 (8.70) 0.11 (0.09) 1 7.30 (7.87)
1,4-Benzenediol 8.00 (8.28) 7.94 ± 0.01 (8.44) −0.06 (0.16) 2 7.36 (7.77)
1,3-Benzenediol 8.29 (8.56) 8.20 (8.63) −0.09 (0.07) 3 7.45 (8.03)
1,2-Benzenediol 8.10 (8.44) 8.15 (8.56) 0.05 (0.12) 4 7.41 (8.06)
BHT 7.39 (7.74) N/A (7.80) N/A (0.06) 5 7.50 (7.98)
6 7.87 (8.20)
7 7.44 (7.80)
8 7.57 (7.98)
9 7.28 (7.83)
10 7.04 (7.56)
11 7.42 (7.85)
12 7.66 (8.08)
Data in parentheses are vertical values.
a
Experimental values are taken from the NIST Chemistry web book, number 69, http://webbook.nist.gov/chemistry/.
b
IE = IEexpt − IEcalc.
3.2.2. BDE(O H) of twelve phenolic compounds extracted from A.
altilis using ONIOM and the influence of solvents
The abilities of donating a hydrogen and forming the radical
form of a wide class of phenolic compounds are characterized by
the BDE values. The BDE corresponds to the O H bond breaking
(hydrogen abstraction), thus this parameter describes the stability
of the hydroxyl bonds. The molecules with lower values of BDE
are endowed with higher antioxidant activity. Table 4 presents
the calculated BDE values in the gas phase and in the solvents
(methanol and water) using ONIOM with our partitioning model.
On the basis of the calculated BDE(O H) values in Table 4, the
hydrogen donating ability of phenolic compounds follows the
order: 12 > 9 ≈ 7 > 10 ≈ 6 > 3 > 11 > 1 > 8 > 5 > 2 > 4. Moreover, among
the phenolic hydroxyls at different positions, the hydroxyl at posi-
tion 2 in compound 12 has the lowest BDE(O H), 77.3, 79.0 and
78.3 kcal/mol in the gas phase, methanol, and water, respectively.
From Table 4, it can be seen that the BDE values of each of
the O H groups present in all radicals of phenolic compounds
are smaller than those of phenols calculated at the same level of
theory. This indicates that most of the phenolic hydroxyls have
stronger hydrogen donating ability than phenols. It can also be
seen from Table 4 that the BDE of the 2-OH group in compound 12
(77.3 kcal/mol in gas phase) is similar to that of the ubiquinol-10
(78.5 kcal/mol).
3.3. Ionization energy (IE) of studied compounds extracted from
A. altilis
As discussed in the electron transfer–proton transfer mech-
anism (Eq. (2)), the IE is also the important parameter to be
considered while studying the antioxidant activity of a compound.
In this part, we first evaluated the accuracy of PM6 method for
calculating the IE value. The IE values of the following species
were calculated and compared with the experimental values: phe-
nol (C6H5OH), 1,4-benzenediol (pOH-C6H4OH), 1,3-benzenediol
(mOH-C6H4OH), 1,2-benzenediol (oOH-C6H4OH), and butylated
hydroxyl toluene (BHT, C15H24O).
The calculated IE values given in Table 5 show that the PM6
method can predict the adiabatic IE values within an error margin
less than 0.11 eV. In the case of butylated hydroxyl toluene (BHT),
which does not have the available experimental adiabatic IE value,
the vertical IE value indicates the deviation between the calculated
and experimental data being only 0.06 eV. The calculated adiabatic
and vertical IE values of twelve phenolic compounds extracted from
A. altilis are also presented in Table 5. The sequence of IE values in
gas-phase is 10 < 9 < 1 < 2 < 4 < 11 < 7 < 3 < 5 < 8 < 12 < 6.
3.4. Proton dissociation enthalpy (PDE) of radical cation from
studied compounds
The calculated proton dissociation enthalpies of the radical
cation species formed in the first step of the SET-PT mechanism
are also given in Table 3. Each radical cation species may have
several positions for the deprotonization. On the basis of data in
Table 3, lowest gas-phase PDEs increase in the following order:
6 < 12 < 7 < 8 < 5 < 3 < 11 < 1 < 9 < 4 < 2 < 10.
However, in the SET–PT mechanism, the preferred site of antiox-
idant action may be estimated from the minimal sum of enthalpies
involved in a particular free radical scavenging mechanism [30].
This sum includes the adiabatic IE plus the PDE from Tables 3 and 5.
These values given in Table S2 of supporting information show that
the minimal energy requirements for the HAT and SET–PT mecha-
nism are associated with the same O H group of twelve studied
compounds and the final product of all free radical scavenging
mechanisms is the same. This indicates that the BDE and (IE + PDE)
are perfectly correlated. From data in Table S2, the sequence of
lowest gas-phase minimal sum of ionization energy and proton
dissociation enthalpies is 12 < 10 ≈ 7 < 6 < 9 < 3 < 11 < 1 < 8 < 5 < 2 < 4.
Therefore, it is concluded that formation of phenoxy radical
from a phenolic radical cation and a corresponding neutral phe-
nolic molecule is favored at the same position. It turned out that
the first mechanism has a greater impact on terminating the oxi-
dation process. Hence, the BDE is the key parameter to evaluate the
activity of antioxidants.
4. Conclusions
In this article, the ONIOM(ROB3LYP/6-311++G(2df,2p):PM6)
and partitioning model 1A, in which the core layer has only one
oxygen atom and one hydrogen atom related to the target bond
for estimating the BDE at the high level are actually the reason-
able ONIOM combinations for accurately predicting the BDE(O H)
values of a series of substituted phenols, ubiquinols, and twelve
selective gernaryl flavanoids extract from A. altilis. The BDE(O H)s
of compounds 3, 6, 7, 9, 10, and 12 amount to 80.8, 80.3, 79.3,
79.3, 80.3, and 77.3 kcal/mol, respectively and they are consid-
ered as the antioxidants. Compound 12 is a genaryl flavanoid with
BDE(O H) of 77.3, 79.0 and 78.3 kcal/mol in gas phase, methanol
and water, respectively. The adiabatic ionization energy of pheno-
lic compounds can be predicted using the PM6 method with the
accuracy within 0.11 eV. Formation of phenoxy radical from a phe-
nolic radical cation and a corresponding neutral phenolic molecule
is favored at the same position. On the basis of the results obtained,

7. N.M. Thong et al. / Chemical Physics Letters 613 (2014) 139–145 145
conclusions can be drawn regarding the potency of the BDE as
a major physicochemical parameter that correlates with the free
radical scavenging activity of phenolic compounds.
To sum up, this study will contribute to the ongoing interest on
the antioxidant activity of phenolic compounds from A. altilis and
their future exploitation for food or pharmaceutical applications.
Acknowledgements
This research is funded by Vietnam National Foundation for
Science and Technology Development (NAFOSTED) under grant
number 104.06-2013.21. We would also like to thank the Institute
for Computational Science and Technology at HoChiMinh City, Viet
Nam for permission to use computing systems for calculations in
this research.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.cplett.2014.08.067.
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