A Theoretical Study of the Structure–Radical Scavenging Activity of Hydroxychalcones

7/21/2019 A Theoretical Study of the StructureRadical Scavenging Activity of Hydroxychalcones

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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 Chemical and Biological Pharmaceutical Engineering Research Center, School of Pharmacy, Xuzhou Medical College, No. 209, Tongshan Road, Xuzhou, Jiangsu 221004, Chinab 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 havebeen 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 opti-

mization was performed at the B3LYP level with 6-31 + G basis set. For radicals and cations, the geom-

etry 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 deter-

mined both in gas phase and in solvents using PCM model. The geometry structure, radical, electron char-

acter and thefrontier molecular orbital were analyzed to explore thekey factors that influence theradical

scavenging activity of the hydroxychalcones. Based on BDE and IP values, it was revealed that compound

3 is expected to be more efficient hydrogen atom and electron donors than others, B-ring of hydroxychal-

cones is the active center and the hydrogen atom transfer (HAT) appears as a major mechanism in anti-

oxidant 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 nitro-

gen species (RNS) are implicated in numerous pathological condi-

tions such as inflammation, metabolic disorders, cellular aging,

reperfusion damage, atherosclerosis, and carcinogenesis [15].

Therefore, there is increasing interest in the protective and preven-

tive function of foods and their constituents against oxidative dam-

age caused by free radicals.

Polyphenol compounds such as protocatechuic acid, caffeic acid

and a variety of flavonoids 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

scavengingabilitiesof thesecompounds dependgreatlyonthe num-

ber andarrangement of phenolic hydroxyl groups. Recently, theoret-

ical 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

propertiesis of great importance that helps to understandthe mech-

anism of the antioxidant activity of these compounds.

Chalcones (or 1,3-diaryl-2-propen-1-ones) are natural com-pounds that are largely distributed in plants, fruits, and vegetables

(see Fig. 1). They are precursors in flavonoid biosynthesis: the

enzymatic cyclization of the 6-hydroxychalcones leads to the for-

mation of flavanones, and subsequently to a large number of flavo-

noid groups, including flavones, flavonols, dihydroflavonols,

aurones, and isoflavones [16]. The presence of a a,b-unsaturatedbond and the absence of the central C-ring are two specific charac-

teristics of chalcones, making these compounds chemically differ-

ent fromthe other flavonoids. Chalcone derivatives generate strong

interest stemming from their broad spectrum of pharmacological

activities, such as anti-ulcer, anti-cancer, antimitotic, anti-inflam-

matory, anti-malarial, anti-fungal, anti-HIV and antioxidant activi-

ties[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 beneficial effects of hydroxy-

chalcones, especially the antioxidant activity [2529]. These exper-

imental results have shown that hydroxychalcones are efficient for

the scavenging of various radicals including DPPH radical. More-

over, 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 investi-

gations mainly based on DFT have also been performed on the

antioxidant activity of hydroxychalcones to elucidate the SAR. Co-

telle et al. [30] investigated the redox properties of a series of

2210-271X/$ - see front matter 2012 Elsevier B.V. All rights reserved.doi:10.1016/j.comptc.2011.12.020

Corresponding authors. Tel.: +86 516 83262137 (Y. Xue), +86 516 83262136 (Y.

Liu).

E-mail addresses: [email protected] (Y. Xue), [email protected] (Y.

Liu).

Computational and Theoretical Chemistry 982 (2012) 7483

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Computational and Theoretical Chemistry

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hydroxychalcones by cyclic voltammetry and theoretical calcula-

tion. 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 identified 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 hydroxychal-

cones16 (seeFig. 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 furthershed light on the structureradical scavenging activity relationship

of these compounds and provide new clue for antioxidant develop-

ment. Specifically, 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 structurerad-

ical scavenging activity of hydroxychalcones and stimulate the

interest for further research and exploitation of such flavonoids

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 first 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 anti-

oxidant gives an electron to the free radical becoming a radical

cation.

R ArOH! RH ArO

1

R ArOH! R ArO

2

Both mechanisms are important for the scavenging activity of

reactive species by an ArOH in a certain chemical or biological sys-

tem and may occur in parallel. In HAT, the reactivity of an ArOH

can be estimated by calculating the OH bond dissociation enthal-

py (BDE), where the lower is the BDE value the higher is theexpected activity. In ET mechanism, the antioxidant can give an

electron to the free radical. Again, the radical cation arising from

the electron transfer must be stable, so it does not react with sub-

strate molecules. In this case, the adiabatic ionization potential (IP)

is the most significant 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 rad-

ical 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:

BDEOH HArO

H H HArOH:

The enthalpy of each species was calculated by the equation

H298= E+ ZPE + Htranst + Hrot+ Hvib+ RT, whereHtranst, Hrot andHvibare 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(Ar-

O+) E0(ArOH), in whichE0 (ArOH) is the total energy of the par-

ent 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 com-

pounds in the global energy minimum were generated and further

fully optimized.

All computations were performed using the Gaussian 03 soft-

ware 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 find the best conformation, the neutral form of title com-

pounds was subjected to potential energy surface scans at theB3LYP/6-31G level of theory. At the minimum energy conforma-

tions obtained from the energy scan, further geometry optimiza-

tion 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 le-

vel of theory was applied. The computations performed for the rad-

icals 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 structureof 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 ta-

ken into account in this study. The solvent effect was implicitly ta-

ken into consideration within the framework of self-consistent

reaction field 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 mole-

cules in the surrounding of the OH group of phenol were investi-

gated [42], and confirmed that the use of PCM gives a relatively

good description of BDEs. Kozlowski et al. also tested the use of ahybrid model (i.e., one or two molecules surrounding the OH

O

R2 R4

R1 R3

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

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

3 R1=OH, R2=OH, R3=OH, R4=OH

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

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

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

2

3

4

56

17

8

910

1 '

6 '

5'

4 '

3 '2 '

A B

::

:

:

:

:

Fig. 1. Structures of the hydroxychalcones studied.

Y. Xue et al. / Computational and Theoretical Chemistry 982 (2012) 7483 75


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groups + PCM) for quercetin[43]. They observed only a slight dif-

ference in BDE as compared to a pure PCM calculation, while com-

putational time was dramatically increased. Thus, in the present

paper, calculations were performed with the integral equation for-

malism 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 influenced by both the

neighboring groups and the geometry. To compute all the appro-

priate 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 low-

est energy.

Thea

,b-doublebond of chalcones is alwaysconsidered to exist in

thetrans configuration, since thecis configuration is unstable dueto

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 hydroxychalcones16calculated at the B3LYP/3-21G level in gas phase.

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


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former is more stablethanthe s-trans one, thus, wedecided to focus

on the s-cis conformer for compounds16. In order to analyze the

torsion around the C1C7 and C10C10 bonds, a fully relaxed tor-

sional 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 30by varying the torsion

anglesh [C6C1C7C9] andu [C9C10C10C60] from 0to 180.The plots of the potential energy profile are shown inFig. 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) forthe local minimum (see Table 1). The energy differ-ence 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 en-

ergy scan, further geometry optimization was performed with

the B3LYP/6-31 + G basis set. Geometry optimizations on the rad-

icals were performed, starting from the optimized structure of the

parent molecule, after the H atom was removed from the 3, 4, 3 0

and 40 positions. No geometrical parameter constraint was im-

posed during the optimization, except those favoring the stabiliz-

ing 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

found that the neutral species of molecules 1,2 and3 are charac-

terized 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 significant geometrical change has been ob-

served 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 compounds1 and3 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 of1 and3 is further

indication of possible extended conjugation and their stronger

antioxidant activities.

3.2. BDE computation. The influence 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 stabil-

ity of the hydroxyl bonds. The molecules with lower values of BDE

are endowed with higher antioxidant activity.Table 3presents 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

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)

h u E(hartree) h u E(hartree)

1 0 0 800.04804 0 30 800.04690 0.72

2 0 0 800.04574 0 180 800.04572 0.01

3 0 0 949.65063 0 180 949.65048 0.09

4 0 0 725.24378 180 0 725.24344 0.21

5 0 0 725.2432 180 180 725.24291 0.186 0 0 800.0437 0 180 800.04345 0.16

Fig. 3. Optimized structures of hydroxychalcones16calculated at the B3LYP/6-31 + G level in gas phase.



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-20 0 20 40 60 80 100 120 140 160 180 200

-803.855

-803.850

-803.845

-803.840

-803.835

-803.830

B3LYP/6-31G*(b)

(a)

Energy(h

artree)

Dihedral angle (degree)

(a) (b)

(c)

Fig. 4. Optimized structures without (a) and with (b) IHB and potential energy curve (c) of the 40-OH radical of2 in gas phase.

1 2 3

4 5 6

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

Table 3

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

Compound BDE (kcal/mol) IP (kcal/mol) K(M1s1)a

Radicals Gas Ethanol Water Gas Water

1 3-OH 78.1 81.3 81.6 176.2 134.5 29.8 0.9

4-OH 77.3 81.0 81.3

2 30-OH 75.9 79.8 80.0 172.9 128.9 69.5 3.3

40-OH 73.2 77.3 77.6

3 3-OH 78.0 81.8 82.0 168.7 128.3 93.2 2.2

4-OH 77.1 81.7 82.1

30-OH 76.1 81.4 81.8

40-OH 72.9 78.5 78.8

4 4-OH 84.6 87.7 87.9 180.1 140.7 0.13 0.01

5 40-OH 81.1 83.4 83.4 175.9 133.0 0.30 0.01

6 4-OH 84.3 87.1 87.4 172.9 131.9 0.32 0.01

40-OH 80.9 83.0 83.0

Phenol 83.4 85.4 85.7 190.7 136.8

Vit.C analogueb 75.1 202.1

HPMCc 72.3 154.2

a Rate constant[33].b Vitamin C model lacking the lateral chain.c 6-hydroxy-2,2,5,7,8-pentamethylchroman (HPMC), a model for the antioxidanta-tocopherol lacking the phytl (C16H33) tail.



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means that hydroxychalcone 3 should be of comparable antioxi-dant activity with a-tocopherol, which is a biological reference compound for the antioxidant activity and a major lipid-solublechain-breaking antioxidant normally in human blood plasma[55].

HO

O

O

-0.15

0.02

0.33

-0.11

0.23

0.28

0.37

1r-a

0.07 O

O

HO

0.30

-0.01

0.20

-0.12

0.34

-0.16

0.09

0.32

1r-b

OH

O

O

-0.06

0.34

-0.14

0.31

0.02

0.130.34

0.08

2r-a

O

OH

O

0.27

-0.15

0.33

-0.09

0.17

-0.01

0.27

-0.180.08

0.28

2r-b

OH

OH

HO

O

O

0.02

0.28

-0.15

0.33

-0.11

0.23

0.07

0.37

3r-a

OH

OH

O

HO

O

0.30

0.20

-0.12

0.34

-0.16

0.32

0.09

3r-b

OHHO

HO

O

-0.07

0.19

-0.13

0.29

0.30

0.34

0.080.02

3r-c

O

OHO

HO

O

0.29

-0.16

0.35

-0.17

0.24

-0.02

0.21

-0.13

0.28

3r-d

0.06 OH

O

0.33

-0.13

0.36

-0.23

0.44

-0.21

O

0.39

4r

O

O

0.33

-0.18

0.40

-0.19

0.28

-0.11

0.33

-0.22

0.32

5r

O

O OH

0.33

-0.12

0.36

-0.23

0.44

-0.21

0.39

6r-a

O

HO O

0.33

-0.17

0.40

-0.18

0.26

-0.10

0.31

-0.21

0.32

6r-b

Fig. 6. Spin density distribution in the phenoxy radicals of hydroxychalcones16in gas phase calculated at the B3LYP/6-31 + G level.



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3.3. IP computation. The influence 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 inTable 3, the lowest IP value in gas phase is found

for3 (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 substitu-

ents, whereas IP value is affected by the structure of the whole

molecule[12]. In other words, within the mechanism of the elec-

tron transfer, the main factors affecting the value of IP are the ex-

tended delocalization and conjugation of thep-electrons, ratherthan the presence of particular functional groups such as addi-

tional hydroxyls.

Contrary to BDE values, where the solvent effect was not great,

IP values were severely affected because the charge separation pro-

cess 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 3that 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 com-

parison to those reported for other flavonoids 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 pre-

dominates for the scavenging of free radicals, hydroxychalcones

16are not expected to be as efficient as other flavonoids. In addi-tion, as seen fromTable 3, the IP values of hydroxychalcones16

are slightly lower than that of the Vitamin C model, but these val-

ues are higher than that of HPMC. The antioxidant mechanism of

a-tocopherol was testified to be H-atom transfer because it is dif-ficult to donate electrons [58], thus the hydroxychalcones act as

thea-tocopherol, and they are also difficult to donate electrons.Therefore, the dominant antioxidant mechanism of the hydroxy-

chalcones should correspond to the H-atom transfer (HAT).

3.4. HOMO orbital distribution

Free radical-scavenging activity of various phenolic antioxi-

dants is also strictly related to the distribution of the HOMO orbi-

tal. The molecules with a lower energy of the HOMO orbital haveweaker electron donating ability. Besides, the electronic density

distribution in these orbitals permits prediction of the most prob-

able sites in the molecules investigated which can be easily at-

tacked by free radicals and other reactive agents. More active

redox sites of these molecules are characterized by high density

of the HOMO orbital. Analysis ofFig. 5shows that HOMO orbitals

of the six compounds present different distribution that depend

on the position and number of substituted OH groups. For com-

pounds 1and 4, which are bearing OH groups on A-ring, the HOMO

orbitals are almost delocalized on the whole molecule, whereas in

compounds2 and5 bearing OH groups on B-ring, the HOMO orbi-

tals are mainly localized on 3-phenylpropenal and phenolic oxygen

atom. As far as compounds3 and6 are concerned, the HOMOs are

essentially outspreaded on 3-phenylpropenal and OH groups on B-ring with a smaller contribution on A-ring. The contribution to the

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 suit-

able 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 den-

sities 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 inFig. 6,thespin 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 fromFig. 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 exam-

ple, the spin population is 0.28 on the O-atom in 40-OH radical of3

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 A-ring. The relation between BDE and spin density follows the same

trend in gas phase and in solvents. Comparing radicals2r-b with

3r-d or 5r with 6r-b, we find that the radicals have almost the

same spin density distribution with each other, indicating the pres-

ence of additional hydroxyl or o-dihydroxyl group on another ring

has almost no influence on the spin density distribution. This can

explain why these radicals have very similar BDE values and exper-

imental results with each other.

4. Conclusions

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

B3LYP functional to the study of SAR for a series of hydroxychal-

ones. The OH BDE and the adiabatic IP have been computed bothin the gas phase and in solutions. In addition, the electronic fea-

tures 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 and3 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 estab-

lish 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 confirmed, i.e., themost efficient systems acting as hydrogen donors are those charac-



9/10

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 Develop-

ment of Jiangsu Higher Education Institutions, Laboratory of Bio-

logical 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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A Theoretical Study of the Structure–Radical Scavenging Activity of Hydroxychalcones