Computational and Theoretical Chemistry 982 (2012) 7483

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Computational and Theoretical Chemistry

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

A theoretical study of the structureradical scavenging activity of hydroxychalcones

Yunsheng Xue a,, Youguang Zheng a, Lin An a, Ling Zhang a, Yan Qian a, Ding Yu a, Xuedong Gong b,
Yi Liu a,
a
b

Chemical and Biological Pharmaceutical Engineering Research Center, School of Pharmacy, Xuzhou Medical College, No. 209, Tongshan Road, Xuzhou, Jiangsu 221004, China
Department of Chemistry, Nanjing University of Science and Technology, Nanjing, Jiangsu 210094, China

a r t i c l e

i n f o

Article history:
Received 11 November 2011
Received in revised form 27 December 2011
Accepted 27 December 2011
Available online 6 January 2012
Keywords:
Hydroxychalcones
Radical scavenging activity
DFT
OH bond dissociation enthalpy
Ionization potential

a b s t r a c t
The molecular structure and radical scavenging activity of six new synthesized hydroxychalcones have
been explored by using density functional theory (DFT) with the B3LYP exchange correlation functional.
The minimum energy conformations were obtained from the energy scan, then a further geometry optimization was performed at the B3LYP level with 6-31 + G basis set. For radicals and cations, the geometry optimizations and frequency calculations were also done at the UB3LYP/6-31 + G level. The
homolytic OH bond dissociation enthalpy (BDE) and the adiabatic ionization potential (IP) were determined both in gas phase and in solvents using PCM model. The geometry structure, radical, electron character and the frontier molecular orbital were analyzed to explore the key factors that inuence the radical
scavenging activity of the hydroxychalcones. Based on BDE and IP values, it was revealed that compound
3 is expected to be more efcient hydrogen atom and electron donors than others, B-ring of hydroxychalcones is the active center and the hydrogen atom transfer (HAT) appears as a major mechanism in antioxidant action. The calculated results are in good agreement with experimental values.
2012 Elsevier B.V. All rights reserved.

1. Introduction
Free radicals, reactive oxygen species (ROS), and reactive nitrogen species (RNS) are implicated in numerous pathological conditions such as inammation, metabolic disorders, cellular aging,
reperfusion damage, atherosclerosis, and carcinogenesis [15].
Therefore, there is increasing interest in the protective and preventive function of foods and their constituents against oxidative damage caused by free radicals.
Polyphenol compounds such as protocatechuic acid, caffeic acid
and a variety of avonoids are present in fruits and vegetables and
are an integral part of the human diet. It is already known that
dietary polyphenols show potent antiradical ability. The radical
scavenging abilities of these compounds depend greatly on the number and arrangement of phenolic hydroxyl groups. Recently, theoretical methods especially density functional theory (DFT) method,
have been successfully used to evaluate chemical properties, such
as bond dissociation enthalpy (BDE) and the adiabatic ionization
potential (IP) of polyphenol compounds and to elucidate the
structureactivity relationship (SAR) for phenolic antioxidants
[615]. Furthermore, the study of the electronic and molecular
properties is of great importance that helps to understand the mechanism of the antioxidant activity of these compounds.
Corresponding authors. Tel.: +86 516 83262137 (Y. Xue), +86 516 83262136 (Y.
Liu).
E-mail addresses: xzmcysxue@sina.com (Y. Xue), njuliuyi2003@gmail.com (Y.
Liu).
2210-271X/$ - see front matter 2012 Elsevier B.V. All rights reserved.
doi:10.1016/j.comptc.2011.12.020

Chalcones (or 1,3-diaryl-2-propen-1-ones) are natural compounds that are largely distributed in plants, fruits, and vegetables
(see Fig. 1). They are precursors in avonoid biosynthesis: the
enzymatic cyclization of the 6-hydroxychalcones leads to the formation of avanones, and subsequently to a large number of avonoid groups, including avones, avonols, dihydroavonols,
aurones, and isoavones [16]. The presence of a a,b-unsaturated
bond and the absence of the central C-ring are two specic characteristics of chalcones, making these compounds chemically different from the other avonoids. Chalcone derivatives generate strong
interest stemming from their broad spectrum of pharmacological
activities, such as anti-ulcer, anti-cancer, antimitotic, anti-inammatory, anti-malarial, anti-fungal, anti-HIV and antioxidant activities [1724].
Hydroxychalcones, as an important part of chalcones family, are
widespread among natural and synthesized chalcones and have
attracted an increased attention. In the last decade a large number
of reports have been published on the benecial effects of hydroxychalcones, especially the antioxidant activity [2529]. These experimental results have shown that hydroxychalcones are efcient for
the scavenging of various radicals including DPPH radical. Moreover, some of them, such as 2,3,4,6-tetrahydroxychalcone, exhibit
more potent radical-scavenging activity than vitamin C and
a-tocopherol [27].
Apart from the experimental studies, a few theoretical investigations mainly based on DFT have also been performed on the
antioxidant activity of hydroxychalcones to elucidate the SAR. Cotelle et al. [30] investigated the redox properties of a series of

Y. Xue et al. / Computational and Theoretical Chemistry 982 (2012) 7483

R2
R1

5
4

A
3

6'

1'
9

O8

10

5'

B
2'

4'
3'

75

electron to the free radical. Again, the radical cation arising from
the electron transfer must be stable, so it does not react with substrate molecules. In this case, the adiabatic ionization potential (IP)
is the most signicant energetic factor for the scavenging activity
evaluation. Molecules with the low IP and BDE values are expected
to have high activity. Thus, in the present study BDE and IP values
were used as the main molecular descriptors to elucidate the radical scavenging activity of the investigated compounds.
The homolytic BDE values of the OH bond were calculated as
the differences in the enthalpy of the reactants at 298.15 K and
1.00 atm with the use of the following equation:

R4
R3

1 : R1=OH, R2=OH, R3=H, R4=H

: R1=H, R2=H, R3=OH, R4=OH

: R1=OH, R2=OH, R3=OH, R4=OH
: R1=H, R2=OH, R3=H, R4=H
: R1=H, R2=H, R3=H, R4=OH
6 : R1=H, R2=OH, R3=H, R4=OH

2
3
4
5

BDE OH H ArO H H  H ArOH:

Fig. 1. Structures of the hydroxychalcones studied.

hydroxychalcones by cyclic voltammetry and theoretical calculation. Kozlowski and co-workers [31] have reported a detailed study
of conformational, electronic and antioxidant properties of a series
of natural hydroxychalcones by B3P86/6-31 + G calculations.
Their results demonstrated the importance of the H atom transfer
mechanism to explain their capacity to scavenge the free radicals.
Furthermore, the active sites were identied as the 6-OH group
and the 3,4-dihydroxy-catechol. The calculated results obtained
by Chen et al. [32] shown that the 2,4,30 ,40 -tetrahydroxychalcone
(butein) can serve as a powerful antioxidant against DPPH radical.
Despite these advances in experimental and theoretical works,
an understanding of the relationship between the structure and
antioxidant activity and the antioxidant mechanism is still lacking.
Very recently, Zhou et al. [33] have synthesized six hydroxychalcones 16 (see Fig. 1) and evaluated their antioxidant activity by
several antioxidant assays. In the present work, the structural
and electronic properties of these hydroxychalcones and their
radicals were investigated at DFT level, with the aim to further
shed light on the structureradical scavenging activity relationship
of these compounds and provide new clue for antioxidant development. Specically, the homolytic bond dissociation enthalpy (BDE)
of OH bonds, adiabatic ionization potential (IP), HOMO orbital
distribution and spin density in free radicals were calculated. With
the current work we hope to add knowledge on the structureradical scavenging activity of hydroxychalcones and stimulate the
interest for further research and exploitation of such avonoids
for food or other applications.
2. Methods
In the literature, two main mechanisms by which antioxidants
can play their protective role were proposed and widely analyzed
[12]. The rst one is referred as H-atom transfer (HAT, Eq. (1)) from
the antioxidant ArOH that becomes itself a radical. The second one
is referred as one-electron transfer (ET, Eq. (2)) in which the antioxidant gives an electron to the free radical becoming a radical
cation.

R ArOH ! RH ArO

R ArOH ! R ArO

Both mechanisms are important for the scavenging activity of

reactive species by an ArOH in a certain chemical or biological system and may occur in parallel. In HAT, the reactivity of an ArOH
can be estimated by calculating the OH bond dissociation enthalpy (BDE), where the lower is the BDE value the higher is the
expected activity. In ET mechanism, the antioxidant can give an

The enthalpy of each species was calculated by the equation

H298 = E + ZPE + Htranst + Hrot + Hvib + RT, where Htranst, Hrot and Hvib
are the translational, rotational, and vibrational contributions to
enthalpy, respectively. The exact value of the electronic energy of
the H atom (0.5 hartree) was used instead of the prediction by
DFT methods. The enthalpy of the H-atom at 298.15 K, including
the translational and PV corrections, was 0.49764 hartree [12].
The IP values were obtained according to the formula IP = E0(ArO+)  E0(ArOH), in which E0 (ArOH) is the total energy of the parent molecule whereas E0 (ArO+) denotes the corresponding total
energy of the cation radical generated after the electron transfer.
ZPE was added to the electronic energy to obtain E0 at 0 K. In all
computations, cation radicals from the optimized neutral compounds in the global energy minimum were generated and further
fully optimized.
All computations were performed using the Gaussian 03 software package [34]. In the DFT calculations, the B3LPY functional
combined with the 6-31 + G basis set were used for geometry
optimization, computation of harmonic vibrational frequencies,
BDE and IP. The suitability of this level of theory for studies of bond
dissociation enthalpy of polyphenols has already been evidenced
elsewhere [3538].
To nd the best conformation, the neutral form of title compounds was subjected to potential energy surface scans at the
B3LYP/6-31G level of theory. At the minimum energy conformations obtained from the energy scan, further geometry optimization was performed with the B3LYP/6-31 + G basis set without
symmetry constraints. For the geometry optimization of the free
radicals and cation radicals, the unrestricted UB3LYP/6-31 + G level of theory was applied. The computations performed for the radicals were made for the optimized most stable structure of the
neutral molecules, after H atom is abstracted from OH groups. In
the process of optimization of the structure of radicals and cation
radicals, the spin contamination was monitored. For all optimized
structures, we calculated the harmonic vibrational frequencies to
ensure it to be a true local minimum.
The HOMO orbital distribution were determined by using the
B3LYP/6-31 + G level of theory for the fully optimized structure
of the compounds. Additionally, the spin density for each atom of
the radicals studied was computed using the unrestricted B3LYP/
6-31 + G level of theory in gas phase and solvent.
Since the free radical-scavenging action strongly depends on
polar solution in the real biological systems, solvent effect was taken into account in this study. The solvent effect was implicitly taken into consideration within the framework of self-consistent
reaction eld polarizable continuum model (SCRF-PCM) [3941],
which has been successfully applied in the investigations about
solvent effects on BDEs of chalcones [31] and other polyphenols
[79]. It is worthy to note that the effects of explicit water molecules in the surrounding of the OH group of phenol were investigated [42], and conrmed that the use of PCM gives a relatively
good description of BDEs. Kozlowski et al. also tested the use of a
hybrid model (i.e., one or two molecules surrounding the OH

76

Y. Xue et al. / Computational and Theoretical Chemistry 982 (2012) 7483

groups + PCM) for quercetin [43]. They observed only a slight difference in BDE as compared to a pure PCM calculation, while computational time was dramatically increased. Thus, in the present
paper, calculations were performed with the integral equation formalism polarized continuum model (IEFPCM) [44,45].

3. Results and discussion

3.1. Conformational analysis and optimized geometries
Conformational analysis is an important tool to characterize the
antioxidant capacity of hydroxychalcones since the behavior

of different OH groups is strongly inuenced by both the

neighboring groups and the geometry. To compute all the appropriate values of the selected parameters that may characterize
the radical scavenging activity, the conformational space of the
molecules under investigation has been explored by optimizing
all the possible conformers, in order to locate the one with the lowest energy.
The a,b-double bond of chalcones is always considered to exist in
the trans conguration, since the cis conguration is unstable due to
the strong steric effects between the B-ring and the carbonyl group.
Then two conformers arising from the torsion around C7C9 bond
must be taken into account: the s-cis and the s-trans compounds.
Our previous calculations [46,47] have indicated that the s-cis con-

Fig. 2. Potential energy curves of hydroxychalcones 16 calculated at the B3LYP/3-21G level in gas phase.

Y. Xue et al. / Computational and Theoretical Chemistry 982 (2012) 7483

former is more stable than the s-trans one, thus, we decided to focus
on the s-cis conformer for compounds 16. In order to analyze the
torsion around the C1C7 and C10C10 bonds, a fully relaxed torsional potential is computed for 16 at the B3LYP/3-21G level of
theory in vacuo. The potential energy surface scan was performed
around the two bonds (Fig. 1) in steps of 30 by varying the torsion
angles h [C6C1C7C9] and u [C9C10C10 C60 ] from 0 to 180.
The plots of the potential energy prole are shown in Fig. 2. It can
be observed that the PES exhibits two unique energy minima for
each hydroxychalcone studied. The pairs of torsional angle values
are h = 0, u = 0 for the global minimum and h = 0(180),
u = 180(0) for the local minimum (see Table 1). The energy difference between the two conformers of each hydroxychalcone is very
low, with the largest value of only 0.72 kcal/mol.
At the minimum energy conformations obtained from the energy scan, further geometry optimization was performed with
the B3LYP/6-31 + G basis set. Geometry optimizations on the radicals were performed, starting from the optimized structure of the
parent molecule, after the H atom was removed from the 3, 4, 30
and 40 positions. No geometrical parameter constraint was imposed during the optimization, except those favoring the stabilizing effects due to hydrogen bonding between two adjacent OH
groups. The optimized structures of the most stable conformers
of neutral form of hydroxychalcones are shown in Fig. 3 along with
the pattern of intramolecular hydrogen bonds (IHBs). It has been

Table 1
The energy as a function of torsional angle of the six hydroxychalcones at the B3LYP/
3-21G level.
Comp.

M1

M2

DE (kcal/mol)

E (hartree)

E (hartree)

1
2
3
4
5
6

0
0
0
0
0
0

0
0
0
0
0
0

800.04804
800.04574
949.65063
725.24378
725.2432
800.0437

0
0
0
180
180
0

30
180
180
0
180
180

800.04690
800.04572
949.65048
725.24344
725.24291
800.04345

0.72
0.01
0.09
0.21
0.18
0.16

77

found that the neutral species of molecules 1, 2 and 3 are characterized by IHB which contributes to the stability. The optimized
geometrical parameters for neutral molecules and its radicals are
shown in Table 2. From the data of bond distances and bond angles,
it can be seen that no signicant geometrical change has been observed when going from the neutral molecule to the phenoxy
(ArO) and the cation (ArOH+) radicals obtained after hydrogen
and electron abstraction, respectively. Most of the bond distances
are exhibiting double bond character and at the same time shorter
than single bonds. From the data of dihedral angle in Table 2, it can
also be seen that compounds 1 and 3 with o-dihydroxyl groups in
A-ring are completely planar, while others have some degree of
deviation from the planarity due to the torsion between A-ring
and the plane of enone system. The planarity of 1 and 3 is further
indication of possible extended conjugation and their stronger
antioxidant activities.
3.2. BDE computation. The inuence of solvents
The hydrogen donating ability of the wide class of polyphenols
and the ability of these compounds to form the radical forms are
characterized by BDE. The BDE corresponds to the OH bond
breaking (H 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 3 presents the
calculated BDE values in gas phase and solvents (ethanol and
water) by applying B3LYP/6-31 + G method.
For a compound possessing more than one phenolic hydroxyl,
its radical-scavenging activity is determined by the one with the
lowest OH BDE. On the basis of the calculated OH BDEs (Table
3), the hydrogen donating ability of hydroxychalcones follows
the order: 3 > 2 > 1 > 6 > 5 > 4, which is fully consistent with the
galvinoxyl radical (GO)-scavenging rate constant obtained from
experimentally kinetic measurement [33]. Moreover, among the
phenolic hydroxyls at different positions, the hydroxyl at position
40 in compound 3 has the lowest OH BDE, 72.9, 78.5 and
78.8 kcal/mol in gas phase, ethanol and water, respectively (Table
3). These results indicate that there are some correlations between

Fig. 3. Optimized structures of hydroxychalcones 16 calculated at the B3LYP/6-31 + G level in gas phase.

180.0
178.8
178.9
180.0
179.1
179.0
179.0
177.7
180.0
178.8
178.9
180.0
180.0
180.0
179.2
178.9
179.5
179.2
179.2
177.5
179.1
178.9
179.3
179.6
0.1
6.5
5.7
0.0
4.9
5.9
5.2
17.5
0.0
5.1
4.2
0.0
0.0
0.0
5.5
5.5
13.5
3.9
4.2
25.9
4.6
4.3
4.3
4.7
179.9
161.7
162.6
179.9
165.1
165.3
166.1
172.4
179.9
162.3
163.6
179.8
179.8
180.0
170.7
162.5
159.6
166.8
167.9
173.2
166.8
162.7
171.8
174.1
127.9
128.0
128.0
127.7
128.2
127.8
127.5
126.9
128.2
128.3
128.2
127.6
127.7
127.6
128.0
128.0
127.5
128.2
127.4
126.8
128.2
128.2
127.4
127.5
120.3
120.3
120.3
119.1
120.3
120.2
120.2
118.9
120.2
120.1
120.1
120.1
120.1
119.0
120.4
120.3
118.9
120.3
120.2
119.1
120.3
120.3
120.2
118.8
119.8
119.5
119.2
119.4
119.6
120.1
120.2
123.0
119.6
119.3
119.1
120.2
120.1
120.6
119.9
118.9
120.4
119.5
120.3
123.6
119.5
118.8
120.5
121.6
0.971
0.9667
0.9695

0.9715
0.9666
0.9668
0.9665

0.9662
0.9707

0.9746
0.9819
0.9678

0.9701
0.9702
0.9732
0.9666
0.9823
0.9659
0.9660
0.9685

0.9699
0.9835
0.9659

0.9693
0.9655
0.9655
0.9656

0.9698
0.9656
0.9843
0.9746
0.9823
0.9699

0.97
0.9834

1.4964
1.5067
1.5037
1.5024
1.5039
1.5009
1.4997
1.4776
1.4980
1.5079
1.5043
1.4931
1.4919
1.4907
1.4963
1.5008
1.4893
1.5047
1.4994
1.4715
1.5047
1.5017
1.4919
1.485
1
1-radical-a
1-radical-b
1-cation
2
2-radical-a
2-radical-b
2-cation
3
3-radical-a
3-radical-b
3-radical-c
3-radical-d
3-cation
4
4-radical
4-cation
5
5-radical
5-cation
6
6-radical-a
6-radical-b
6-cation

1.4838
1.4815
1.4796
1.4772
1.4811
1.4878
1.4853
1.5014
1.4805
1.4778
1.4762
1.4870
1.4845
1.4865
1.4857
1.4788
1.4822
1.4811
1.4846
1.4956
1.4811
1.4755
1.4861
1.4921

1.2346
1.2304
1.2325
1.2292
1.2331
1.2308
1.232
1.2313
1.2354
1.2314
1.2339
1.2342
1.2351
1.2304
1.2333
1.2337
1.2295
1.2329
1.2324
1.2343
1.2329
1.2348
1.2339
1.2301

1.3499
1.3512
1.3517
1.371
1.3518
1.35
1.3595
1.3713
1.3521
1.3539
1.354
1.3491
1.3601
1.3681
1.3495
1.3518
1.3745
1.3519
1.3633
1.3796
1.3519
1.3541
1.3629
1.3747

1.4636
1.4619
1.4615
1.4375
1.4584
1.4615
1.4439
1.4302
1.4579
1.4555
1.4557
1.4642
1.4433
1.4349
1.4638
1.4614
1.4334
1.4584
1.4376
1.4227
1.4584
1.4557
1.4379
1.4273

0.9659

0.982
0.9761
0.9697
0.9699
0.97
0.9843

119.4
118.8
119.0
118.8
119.0
119.1
119.2
120.1
119.4
118.9
119.0
119.4
119.4
119.1
119.2
119.1
118.9
119.2
119.4
121.0
119.2
119.1
119.4
118.9

D(7,9,10, 10 )
D(8,7,9,10)
D(6,1,7,8)
A(9,10, 10 )
A(7,9,10)
A(1,7,8)
A(1,7,9)
O(4)-H
O(3)-H
O(2)-H
O(1)-H
R(10,10 )
R(9,10)
R(7,8)
R(7,9)
R(1,7)
Parameters

Table 2
The selected geometrical parameters of the six hydroxychalcones and its radicals at the (U) B3LYP/6-31 + G level.

0.1
2.9
3.0
0.0
1.8
2.8
1.6
5.6
0.1
1.8
1.8
0.0
0.0
0.0
2.9
3.0
4.2
0.6
1.0
6.5
1.7
1.8
1.1
1.1

Y. Xue et al. / Computational and Theoretical Chemistry 982 (2012) 7483

D(9,10, 10 ,60 )

78

the two parameters, namely, the lower the OH BDE is, the more
active is the hydroxychalcones to scavenge galvinoxyl radical.
In the present study compounds 13, bearing o-dihydroxyl
groups on the two aromatic A and B rings, presented lower BDE
values (72.978.1 kcal/mol), in comparison to those of compounds
46 bearing no such groups (80.984.6 kcal/mol). Comparing 2
with 5, or 1 with 4, we nd that the presence of o-dihydroxyl group
on aromatic rings decreases the OH BDE by about 8 kcal/mol (Table 3). The reason can be found in the fact that the radical arising
from H-atom removal is stabilized by the formation of the IHB with
the vicinal hydroxyl, as evidenced from theoretical calculations
[12], suggesting that the BDE of catechol is 9.1 kcal/mol lower than
that of phenol. It is noteworthy that the very important role of odihydroxyl groups has previously been discussed for other polyphenol compounds, based on experimental data as well as theoretical calculations [4852]. In the 30 -OH and 40 -OH radicals of
compounds 1, 2 and 3, we also observe H-bonding between the
remaining OH group and the neighboring phenolic oxygen atom.
After the OH bond is broken in the parent compound, the radical
is able to rearrange to the more stable conformation, corresponding to the formation of a new H-bond, as shown in Fig. 4. A decrease of 8.7 kcal/mol in energy is observed between the
molecule without (Fig. 4a) and with (Fig. 4b) this new H-bond.
Moreover, the potential energy surface scan at B3LYP/6-31G level
of theory (Fig. 4c) shows that the barrier height for the rotation of
OH in the radical is only ca. 5.8 kcal/mol, so this rearrangement
can occur at room temperature. The IHB enthalpy in 2 is estimated
to be 8.5 kcal/mol, which is similar to that of phenolic radical of
catechol by theoretical calculations, 8.09.6 kcal/mol [12,52,53].
From the gas phase BDE values, it can be found that lesser
amount of energy is required for breaking the hydroxyl groups
on B-ring with respect to the corresponding hydroxyl groups on
A-ring. As exemplied in compounds 5 and 4, 40 -OH in the B-ring
had a lower BDE value than 4-OH in the A-ring in both gas phase
and solvents. This clearly conrms that HAT from the B-ring is easier than that of A-ring, which is congruent with experimental
results; i.e. compound 5 is more active in the GO-scavenging reaction than is compound 4 [33].
In compound 1, 4-OH had a lower BDE value than 3-OH, and
hence the HAT reaction should rst occur in 4-OH. Similarly, the
BDE value of 30 -OH for compound 2 was relatively high; thus, the
hydrogen abstraction from 40 -OH is more favorable than that from
30 -OH. Furthermore, the BDE values (Table 3) for all the radicals of
compound 3 give the following sequence for the present OH groups:
40 < 30 < 4 < 3. These results clearly show that p-hydroxyl group has
stranger radical-scavenging activity than m-hydroxyl group.
When the solvents were taken into consideration an increase in
the range of 2.15.9 kcal/mol was obtained for BDE values. A close
inspection on the BDE values in structurally related aurones [54]
revealed a similar phenomenon, i.e., an increasing of the BDE values in going from gas phase to solvent. This nding indicates that
in polar solvents, such as ethanol and water, the antioxidants studied have a lower ability to hydrogen transfer than in gas phase. It is
noticeable that the order of BDE values calculated for the solvent
phase is the same as that for the gas phase but small difference
is observed from the values of the radicals of 3. The hydrogen
abstraction from 4-OH in 3 is more favorable than that from 3OH in gas phase, while reversed case is found in water.
From Table 3, it can be seen that the BDE values of each of the
OH groups present in all radicals of hydroxychalcones are similar
to, or smaller than, those of phenol calculated at the same level
of theory. This indicates that most of the phenolic hydroxyls have
stronger hydrogen donating ability than phenol. It can also be seen
from Table 3 that the BDE of 40 -OH group in 3 (72.9 kcal/mol in gas
phase) is similar to that of the HPMC (72.3 kcal/mol), a model for
the antioxidant a-tocopherol lacking the phytl (C16H33) tail. This

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Y. Xue et al. / Computational and Theoretical Chemistry 982 (2012) 7483

Table 3
The BDE and IP (in kcal/mol) values of hydroxychalcones 16 at the B3LYP/6-31 + G level.
Compound

1
2
3

4
5
6

BDE (kcal/mol)
Radicals

Gas

Ethanol

Water

Gas

Water

3-OH
4-OH
30 -OH
40 -OH
3-OH
4-OH
30 -OH
40 -OH
4-OH
40 -OH
4-OH
40 -OH

78.1
77.3
75.9
73.2
78.0
77.1
76.1
72.9
84.6
81.1
84.3
80.9
83.4
75.1
72.3

81.3
81.0
79.8
77.3
81.8
81.7
81.4
78.5
87.7
83.4
87.1
83.0
85.4

81.6
81.3
80.0
77.6
82.0
82.1
81.8
78.8
87.9
83.4
87.4
83.0
85.7

176.2

134.5

29.8 0.9

172.9

128.9

69.5 3.3

168.7

128.3

93.2 2.2

180.1
175.9
172.9

140.7
133.0
131.9

0.13 0.01
0.30 0.01
0.32 0.01

190.7
202.1
154.2

136.8

Phenol
Vit.C analogueb
HPMCc

Rate constant [33].

Vitamin C model lacking the lateral chain.
6-hydroxy-2,2,5,7,8-pentamethylchroman (HPMC), a model for the antioxidant a-tocopherol lacking the phytl (C16H33) tail.

(a)

(b)

(c)
-803.830

Energy (hartree)

a
b

K (M1s1)a

IP (kcal/mol)

-803.835
-803.840

(a)

-803.845
-803.850

(b)

B3LYP/6-31G*

-803.855
-20

20

40

60

80 100 120 140 160 180 200

Dihedral angle (degree)

Fig. 4. Optimized structures without (a) and with (b) IHB and potential energy curve (c) of the 40 -OH radical of 2 in gas phase.

Fig. 5. HOMO shapes of hydroxychalcones 16 in gas phase calculated at the B3LYP/6-31 + G level.

80

Y. Xue et al. / Computational and Theoretical Chemistry 982 (2012) 7483

-0.15

HO
0.07

0.02
0.37
O

O
0.32

0.33

0.28

-0.11
0.09
HO

0.23

0.20
-0.01

-0.12

0.30

0.34

-0.16

1r-a

1r-b

0.34

0.31

-0.06

O
0.34

-0.18

OH
O
0.32

0.28

0.33

0.02

-0.11
OH

0.23

0.09
HO

0.20

OH
-0.12

0.30

0.34
OH

-0.16

3r-b

3r-a

0.06 OH

O 0.34
0.02

HO

0.19

0.08
OH

0.24

HO

-0.17

0.29
0.29

-0.07
-0.13

HO

3r-d
0.28

0.36
-0.23

0.33

0.44
-0.18

-0.21

4r
0.36
-0.23

0.33

0.44

-0.19

-0.11

0.40

0.33

-0.22

5r

OH

-0.12

0.32
O

0.39
O

-0.13

3r-c

0.33

-0.02

0.35
-0.16

0.30

-0.13

0.28
O

0.21
HO

0.39
O

OH
0.08

2r-b

-0.15

0.27

2r-a

0.37

-0.01

0.33
-0.15

HO
0.07

-0.09
0.27

0.02

0.13

0.28
O

0.17

0.08
OH

-0.14

0.26
HO
0.33

-0.21

-0.17
O

6r-a

0.32
O

-0.18

-0.10

0.40

0.31

-0.21

6r-b

Fig. 6. Spin density distribution in the phenoxy radicals of hydroxychalcones 16 in gas phase calculated at the B3LYP/6-31 + G level.

means that hydroxychalcone 3 should be of comparable antioxidant activity with a-tocopherol, which is a biological reference

compound for the antioxidant activity and a major lipid-soluble

chain-breaking antioxidant normally in human blood plasma [55].

Y. Xue et al. / Computational and Theoretical Chemistry 982 (2012) 7483

3.3. IP computation. The inuence of solvents

As stated above, scavenging of free radicals by polyphenols may
also be achieved via donation of a single electron. In this case, IP is
an important physical factor indicating the range of electron
donation. The molecules with lower values of IP are endowed with
higher antioxidant activity. The values for the IP of hydroxy
chalcones in the gas phase as well as in water are given in Table
3. As shown in Table 3, the lowest IP value in gas phase is found
for 3 (168.7 kcal/mol), which is largely lower than that of phenol
(190.7 kcal/mol), followed by 2 (172.9 kcal/mol), 6 (172.9 kcal/
mol), 5 (175.9 kcal/mol), 1 (176.2 kcal/mol) and 4 (180.1 kcal/
mol). Similar order is found in water phase. By comparison, we
found that the trend for calculated IP values is different from that
of BDE values. This discrepancy can be attributed to the fact that
BDE is affected by the local phenomena induced by the substituents, whereas IP value is affected by the structure of the whole
molecule [12]. In other words, within the mechanism of the electron transfer, the main factors affecting the value of IP are the extended delocalization and conjugation of the p-electrons, rather
than the presence of particular functional groups such as additional hydroxyls.
Contrary to BDE values, where the solvent effect was not great,
IP values were severely affected because the charge separation process is quite sensitive to the polarity of solvent [56]. As expected,
the presence of water medium involves a decrease of the IP values.
For instance, IP value of compound 3 that is one of the most active,
changes from 168.7 to 128.3 kcal/mol, in going from the gas-phase
to the water medium.
A close look at the IP values in gas phase of hydroxychalcones
16 shows that they are about 1022 kcal/mol lower than that of
phenol (190.7 kcal/mol). Such a difference is rather small in comparison to those reported for other avonoids which usually have
3040 kcal/mol lower IP value than that of phenol [57]. The latter
is an indication that when the electron transfer mechanism predominates for the scavenging of free radicals, hydroxychalcones
16 are not expected to be as efcient as other avonoids. In addition, as seen from Table 3, the IP values of hydroxychalcones 16
are slightly lower than that of the Vitamin C model, but these values are higher than that of HPMC. The antioxidant mechanism of
a-tocopherol was testied to be H-atom transfer because it is difcult to donate electrons [58], thus the hydroxychalcones act as
the a-tocopherol, and they are also difcult to donate electrons.
Therefore, the dominant antioxidant mechanism of the hydroxychalcones should correspond to the H-atom transfer (HAT).

81

HOMO from OH groups on B-ring is greater than that from OH

groups on A-ring. This reveals that 40 -OH and 30 -OH are more suitable for the formation of stable radical forms than 4-OH and 3-OH,
respectively. Thus, the OH groups on B-ring can be easily attacked
by the free radicals and other reactive agents in the real biological
systems. This assumption is in agreement with the calculated BDE
values, especially with the lowest one, obtained for the formation
of the 40 -OH radical, because the greatest contribution to the
HOMO comes from this oxygen atom.
3.5. Spin density distribution
The spin density is often considered to be a more realistic
parameter which provides a better representation of the reactivity.
The stability of free radicals and the antioxidant potency are
mainly determined by this factor [7,10,59]. Therefore, the spin densities on the various radical forms of hydroxychalcones 16 are
also analyzed to help understand the differences in reactivity of
the various OH groups, and consequently the differences in BDE
values. It should be pointed out that the more delocalized the spin
density in the radical form is, the easier the radical is formed, and
thus the lower the BDE value is [11]. As can be noted in Fig. 6, the
spin densities of 30 -OH, 3-OH and 4-OH radicals mainly distribute
on the phenolic oxygen atom and the phenyl ring, whereas in 40 OH radicals the spin densities delocalize not only on the phenolic
oxygen and B-ring, but also on central double bond. This indicates
that the spin densities in 40 -OH radicals are more delocalized and
thus the 40 -OH radicals are more stable than other radicals. This
is consistent with the BDE results; i.e., 40 -OH group has the lowest
BDE value among all the phenolic hydroxyls in each molecule. It
can also be seen from Fig. 6, the spin density appears to be more
delocalized for the radicals originating from the B-ring (40 - and
30 -OH) than those located on the A-ring (4- and 3-OH). As an example, the spin population is 0.28 on the O-atom in 40 -OH radical of 3
and it is 0.32 for the same compound in the 4-OH position. This in
turn results in lower BDE value of the B-ring than that of the Aring. The relation between BDE and spin density follows the same
trend in gas phase and in solvents. Comparing radicals 2r-b with
3r-d or 5r with 6r-b, we nd that the radicals have almost the
same spin density distribution with each other, indicating the presence of additional hydroxyl or o-dihydroxyl group on another ring
has almost no inuence on the spin density distribution. This can
explain why these radicals have very similar BDE values and experimental results with each other.

3.4. HOMO orbital distribution

4. Conclusions

Free radical-scavenging activity of various phenolic antioxidants is also strictly related to the distribution of the HOMO orbital. The molecules with a lower energy of the HOMO orbital have
weaker electron donating ability. Besides, the electronic density
distribution in these orbitals permits prediction of the most probable sites in the molecules investigated which can be easily attacked by free radicals and other reactive agents. More active
redox sites of these molecules are characterized by high density
of the HOMO orbital. Analysis of Fig. 5 shows that HOMO orbitals
of the six compounds present different distribution that depend
on the position and number of substituted OH groups. For compounds 1 and 4, which are bearing OH groups on A-ring, the HOMO
orbitals are almost delocalized on the whole molecule, whereas in
compounds 2 and 5 bearing OH groups on B-ring, the HOMO orbitals are mainly localized on 3-phenylpropenal and phenolic oxygen
atom. As far as compounds 3 and 6 are concerned, the HOMOs are
essentially outspreaded on 3-phenylpropenal and OH groups on Bring with a smaller contribution on A-ring. The contribution to the

In this article, we have applied a DFT method employing the

B3LYP functional to the study of SAR for a series of hydroxychalones. The OH BDE and the adiabatic IP have been computed both
in the gas phase and in solutions. In addition, the electronic features such as HOMO orbital distribution and spin density of neutral
and radical species have also been presented. On the basis of our
investigation, we can outline the following conclusions:
Hydroxychalones 1 and 3 with o-dihydroxyl groups in A-ring
are completely planar, while others have some degree of deviation
from the planarity due to the torsion between A-ring and the plane
of enone system. As far as the HAT mechanism is concerned, the
stability of radicals is enhanced by the possibility that they establish intramolecular H bonds between the radical oxygen atom and
adjacent hydroxyl. BDE values are within a range of 72.984.6 kcal/
mol in the gas phase, whereas solutions show an increase in the
values of around 3 kcal/mol. For these compounds, the important
role of the o-dihydroxy (catechol) moiety is conrmed, i.e., the
most efcient systems acting as hydrogen donors are those charac-

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Y. Xue et al. / Computational and Theoretical Chemistry 982 (2012) 7483

terized by the o-dihydroxy functionality. Solution- and gas-phase

BDE values follow the same trend, 3 > 2 > 1 > 6 > 5 > 4, which is
fully consistent with the GO-scavenging rate constant obtained
from kinetic measurement. The results reveal that the trend for
calculated IP values is different from that of BDE values and the
dominant antioxidant mechanism of the hydroxychalcones should
correspond to the HAT. To sum up, this study will contributes to
the ongoing interest on the antioxidant activity of chalcones and
their future exploitation for food or pharmaceutical applications.

Acknowledgements
Financial support for this work was provided by Natural Science
Foundation of Jiangsu Province (No. BK2009523), Natural Science
Foundation of Education Ministry of Jiangsu Province (No.
09KJB350003, 11KJB350005), Priority Academic Program Development of Jiangsu Higher Education Institutions, Laboratory of Biological Therapy for Cancer of Xuzhou Medical College (C0903),
the Special Fund for the Presidents Project of School of Pharmacy
(2010YKJ003), Innovative Practice Training Program for Students
of Jiangsu Higher Education Institutions and Innovative Practice
Training Program for Students of School of Pharmacy.

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