Antiradical Activity and Mechanism of CoumarinâChalcone Hybrids

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A: Spectroscopy, Molecular Structure, and Quantum Chemistry

Antiradical Activity and Mechanism of CoumarinChalcone Hybrids:Theoretical Insights Yunsheng Xue, Yunping Liu, Qingquan Luo, Han Wang, Ran Chen, Yin Liu, and Ya Li J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.8b06787 • Publication Date (Web): 08 Oct 2018 Downloaded from http://pubs.acs.org on October 9, 2018

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The Journal of Physical Chemistry

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Antiradical Activity and Mechanism of Coumarin-Chalcone Hybrids:

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Theoretical Insights

3 4 5

Yunsheng Xue*, Yunping Liu, Qingquan Luo, Han Wang, Ran Chen, Yin Liu, Ya Li

6 7

Jiangsu Key Laboratory of New Drug Research and Clinical Pharmacy, School of

8

Pharmacy, Xuzhou Medical University, No.209, Tongshan Road, Xuzhou, Jiangsu

9

221004, China

10 11 12 13 14 15 16 17 18 19 20 21 22

Corresponding author:

23

Tel: +86-516-83262137; E-mail: [email protected]

24 25

1

ACS Paragon Plus Environment

The Journal of Physical Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

26

Abstract

27

In view of their multifunctional features of coumarins and chalcones, coumarin-chalcone

28

hybrids have attracted much attention in recent years. Herein, the free radical scavenging

29

activities of a series of coumarin-chalcone hybrids were investigated using the density

30

functional theory (DFT) method. Three main reaction mechanisms were explored:

31

hydrogen atom transfer (HAT), electron transfer followed by proton transfer (SET-PT) and

32

sequential proton loss electron transfer (SPLET). Thermodynamic descriptors associated

33

with these mechanisms were calculated in gas phase and solvents. The results demonstrate

34

that the predicted antioxidant efficiencies are generally in accordance with the

35

experimental results. HAT is proposed as the thermodynamically favored mechanism in

36

gas phase and non-polar solution, while SPLET is preferred in polar media. Our results

37

indicate that compound MPHCC possess potential for inactivating free radicals via double

38

HAT and double SPLET mechanisms depending upon polarity of environment. In addition,

39

SPLHAT mechanism provides an alternative pathway to HAT and SPLET for radical

40

scavenging by MPHCC and OPHCC. The results confirmed the crucial role of hydroxyl

41

groups on chalcone moiety in trapping radicals. 4′-OH in catechol group is proposed as the

42

primary target for radical attack.

43 44 45 46 47 48 49 50 51 52 2


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1. Introduction

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Free radicals induced oxidative stress (OS) is believed to be a contributor to various

55

human diseases like cancer, cardiovascular diseases, neurological disorders, diabetes and

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ageing.

57

importance. During the past decade, significant research efforts have been made for

58

discovering more effective antioxidants for treatment of these adverse conditions.3,4

59

Phenolic compounds are plant secondary metabolites commonly found in herbs and fruits,

60

which have been identified as efficient protectors against OS.5-7 In fact, natural and

61

synthetic phenols exhibit a fascinating array of biological activities, which can also

62

contribute to their beneficial health effects.

1,2

Therefore, identifying molecules for protection against OS is a matter of vital

63

Among the diverse phenolic compounds, chalcones and coumarins represent the two

64

typical examples with benefits to human health. Chalcones (1,3-diaryl-2-propen-1-ones,

65

Fig. 1) are a subfamily of flavonoids and are usually found in fruits, vegetables, teas, and

66

other plants. In addition, chalcones are considered as the precursors of flavonoids and

67

isoflavonoids.8 Over the past decades, chalcone and their derivatives have attracted much

68

interest due to their important spectral properties as well as a spectrum of biological

69

activities, such as antioxidant, antifungal, antimalarial, anticancer, anti-inflammatory and

70

antibacterial activities.8 Natural and synthetic chalcones have shown to possess strong

71

radical scavenging effects. 9-14

3



O

O

2 13 3 O1 O  12 C 9 1' 2' 3' 10 4 A 8  11  B 5 4' 6' 7 OH 5' 6

O

O

OH

CC

O

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OCH3

PMCC O

O

O

O

NO2

O OCH3

OH

OH

MNCC

OH

VCC

O

O O

O

OH

O

O

OH OHCC

OH

OH

OH

OPHCC

O O

O OH OH

OH

MPHCC

72 73

Fig.1 The molecular structures and atomic numbering of the studied coumarin-chalcone

74

hybrids.

75 76

On the other hand, coumarins (2H-1-benzopyran-2-ones, Fig.1) comprise a large class

77

of phenolic substances found in plants. Natural and synthetic molecules based on coumarin

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skeleton have been investigated as medicinal agents because of their diverse range of

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biological activities including antioxidant, antimicrobial, monoamine oxidase (MAO)

80

inhibition, antitumor and antiviral activities. 15-17

4


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Hybridization of two or more pharmacophores with different mechanisms of action in

82

the same molecule is a powerful strategy for drug design.18,19 In view of their

83

multifunctional features of coumarin and chalcone, a series of coumarin-chalcone hybrids

84

have been designed and synthesized in recent years. The coumarin-chalcone hybrids have

85

been proven to possess diverse and impressive pharmacological activities such as

86

anticancer, antimicrobial, antimalarial, antitubercular and antioxidant. 20-22

87

Among previous studies on coumarin-chalcone hybrids, researchers have paid special

88

attention on the free radical scavenging and antioxidant activities, which were believed to

89

be responsible for many other pharmacological activities. Hamdi and coworkers

90

synthesized a series of coumarin derivatives containing a chalcone moiety, and the

91

significant antibacterial and free radical scavenging activities of these compounds were

92

confirmed.

93

coumarin-chalcone hybrids possessing a benzoyl substituent at C-3, which were found

94

having better antioxidant properties than the well-known antioxidants such as catechin and

95

quercetin.24,25 Moreover, the results indicated that the position and number of hydroxyl

96

groups on coumarin and benzoyl rings play a key role in their antioxidant activity.

97

Sashidhara et al. reported the preparation of three series of novel biscoumarin-chalcone

98

hybrids. The scavenging efficiency against formation of O2• and •OH in non-enzymic

99

systems as well as lipid peroxidation inhibition activity in microsomes were investigated.

100

23

Vazquez-Rodriguez et al. disclosed the synthesis of a series of novel

26

5



101

More recently, Liu and Xi

27

synthesized several coumarin-chalcone hybrids

102

possessing a 3-phenylpropenal substituent at C-8 (Fig.1) to evaluate their antioxidant

103

properties. The inhibitory effects on Cu2+/GSH-, •OH-, and AAPH-induced oxidation of

104

DNA and activity on trapping ABTS+• and DPPH were tested. It was found that the

105

antioxidant activity of hydroxyl group on chalcone can be enhanced by coumarin even in

106

the absence of a conjugation system. The hydroxyl group at coumarin moiety has

107

significant influence on inhibiting •OH-induced oxidation of DNA.

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In light of the potent antioxidant property of coumarin-chalcone hybrids, it is

109

interesting to perform a theoretical study on the antioxidant activity to highlight their

110

structure-activity relationship. During the past decades, density functional theory (DFT)

111

have been successfully used to elucidate the structure-antioxidant activity of phenolic

112

compounds. 3,28-38 To the best of our knowledge, only two reports are available about the

113

theoretical studies on the antioxidant properties of coumarin-chalcone hybrids. Mazzone

114

and coworkers 39 theoretically studied the structural characteristics, antioxidant ability and

115

the spectral properties of a series of coumarin-chalcone hybrids synthesized in Vazquez-

116

Rodriguez's experiment.25 Three antioxidant mechanisms (HAT, SET-PT and SPLET)

117

have been investigated thermodynamically. Subsequently, the same group performed the

118

study on the kinetics and mechanism of two selected coumarin-chalcone hybrids with

119

peroxyl radical.40 It is worth noting that the coumarin-chalcone hybrids studied by

120

Mazzone et al. are structurally different from those reported by Liu and Xi in terms of the

6


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hybridization manner (C3 or C8 position on coumarin moiety) and the linker structure

122

(carbonyl or enone) connecting coumarin moiety and the benzene ring B (Fig.1).

123

Taking into consideration above facts and as a continuation of our research in

124

theoretical elucidation of the antioxidant activity of phenolics compounds, 41-43 herein, we

125

want to theoretically evaluate the antioxidant activity of the coumarin-chalcone hybrids

126

synthesized by Liu and Xi 27 (Fig. 1). The main aim of the present study was to get insight

127

into the contribution of the structural features to the radical scavenging potential and to

128

determine the preferred mechanism for trapping radicals. To this end, the physiochemical

129

parameters including bond dissociation enthalpy (BDE), ionization potential (IP), proton

130

dissociation enthalpy (PDE), proton affinity (PA) and the electron transfer enthalpy (ETE)

131

were calculated to explore the free radical scavenging mechanism. In addition, frontier

132

molecular orbital (FMO) and spin density of radicals were also analyzed.

133

2. Computational method

134

All the calculations were performed using the Gaussian09 program package.44

135

Geometrical optimization and frequency analysis were carried out at DFT level using the

136

B3LYP functional

137

reliability of DFT-B3LYP method in the calculation of thermodynamic parameters

138

governing antioxidant activity has been confirmed by previous studies on chalcones

139

and other phenolic compounds.33,42,47 Fully relaxed potential energy scan was performed

140

at the (U)B3LYP/6-31G(d) level to explore the possible conformational structures. Single

45,46

in conjunction with the 6-31G(d,p) basis set in gas phase. The

7


41,43


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141

point energy (SPE) calculations were performed at the (U)B3LYP/6-311++G(2d,2p) level

142

using the geometries optimized by (U)B3LYP/6-31G(d,p) method.

143

Solvent effects were simulated by employing the polarized continuum model (PCM).48

144

Benzene and water were used as solvents to mimic lipid and aqueous environments,

145

respectively, whereas ethanol was chosen to simulate the experimental environment. For

146

comparison with the data in solvents, the gas-phase calculations were also performed. The

147

distribution and energy of frontier orbitals HOMO and LUMO as well as the spin density

148

of the radicals were calculated at the (U)B3LYP/6-31G(d,p) level of theory in gas phase.

149

It has been recognized that the reaction of scavenging free radicals could proceed via

150

at least three different mechanisms:29,33 hydrogen atom transfer (HAT, eq.(1)), single

151

electron transfer followed by proton transfer (SET-PT, eq.(2)) and sequential proton loss

152

electron transfer (SPLET, eq.(3)).

153

ArOH + R• → ArO• + RH

(1)

154

ArOH + R• → ArOH+• + R−→ RH + ArO•

(2)

155

ArOH → ArO− + H+; ArO− + R• → ArO• + R−; R−+ H+→ RH

(3)

156

Based on the above equations, the same thermodynamic balance will be obtained due

157

to the identity of the reactants and products in all three mechanisms. To determine the most

158

thermodynamically favorable mechanism, the aforementioned parameters including BDE,

159

IP, PDE, PA and ETE were calculated using the calculated reaction enthalpies (H) of the

160

steps in the three mechanisms.

8


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161

For HAT mechanism, the proton and electron of phenolic hydroxyl on antioxidant

162

(ArOH) are transferred in one step to free radical (R•). The reactivity of ArOH was

163

measured by the O–H BDE (eq.(4)), where the lower the BDE value, the higher the

164

expected activity.

165

BDE = H (ArO • ) + H (H • ) – H (ArOH)

166

SET-PT is a two-step reaction mechanism initiated by electron transfer from ArOH,

167

and then followed by a proton release from the cation radical (ArOH+•). In this case, the

168

antioxidant activity was determined by the IP and PDE factors (eqs.(5) and (6)). Lower

169

values of IP and PDE mean higher activity.

170

IP = H (ArOH•+) + H (e−) – H (ArOH)

(4)

(5)

171

PDE = H (ArO • ) + H (H + ) – H (ArOH •+ )

172

SPLET is the reverse mechanism with respect to SET-PT initiated by the proton loss.

173

Then, the formed phenoxy anion (ArO−) undergoes the electron transfer. The two

174

parameters PA and ETE (eqs.(7) and (8)) were chosen to describe the two steps,

175

respectively.

(6)

176

PA = H (ArO − ) + H (H + ) – H (ArOH)

(7)

177

ETE = H (ArO • ) + H (e − ) – H (ArO − )

(8)

178

According to these reaction mechanisms, DFT calculations were performed to obtain

179

the thermodynamic descriptors associated with the three mechanisms. The molecular

180

enthalpy (H) at 298.15 K is the sum of single point energy (SPE) value calculated at

9



181

B3LYP/6-311++G(2d,2p) level and the thermal contributions to enthalpy (TCE) at

182

B3LYP/6-31G(d,p) level. The gas phase and solvation enthalpies of hydrogen atom, proton,

183

and electron were taken from the literature. 47,49,50

184

3. Results and discussion

185

3.1. Conformational and geometrical structures

186

Conformational structure of an antioxidant is an important factor associated with their

187

antioxidant ability. To our knowledge, no conformational study has been reported on the

188

coumarin-chalcone hybrids studied here. Thus, a conformational study was first performed

189

to identify the most stable conformations of the studied compounds and then to properly

190

explore the structure-activity relationship. For the studied coumarin-chalcone hybrids,

191

conformational spaces mainly derive from rotation around the single bonds of C8-C10 (θ

192

angle in Fig.1), C10-C11 (ω) and C12-C1′ (φ). For trans configuration of chalcones, there

193

are two possible conformers, s-trans and s-cis forms in terms of the torsion angle C12-C11-

194

C10-O13 (ω). According to previous studies, the s-cis conformer was found to be more

195

stable than the s-trans one.11,41,51 Thus, only the s-cis conformers were considered in

196

following study.

197

As shown in Fig.1, the 7-OH group is present in all the studied coumarin-chalcone

198

hybrids. Thus, intramolecular hydrogen bonding (IHB) can occur between the 7-OH and

199

the neighboring C=O group, which are expected to favor coplanarity between the 3-

200

phenylpropenal and coumarin portion. Indeed, our calculations confirm the stabilization

10


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201

effect of the IHB on the compounds. Besides, the conformational spaces derived from

202

rotation of B ring around C12-C1′ (φ) and from possible orientation of the hydroxyl groups

203

were also explored for the compounds with substituent on B ring.

204

The optimized structures of the most stable coumarin-chalcone hybrids are presented

205

in Fig.S1. It was found that all the studied coumarin-chalcone hybrids adopt planar

206

structure due to the formation of IHB between 7-OH and the neighboring keto group, which

207

are helpful for the stabilization of the compounds. As expected, an intra-molecular

208

hydrogen bond was formed between the OH group and the adjacent OH or OCH3 groups

209

for compounds MPHCC and VCC bearing a catechol or guaiacol moiety in ring B.

210

The H-abstraction from OH groups at different position will result in different phenoxy

211

radicals. The optimized structures and the key dihedral angles of the most stable radicals

212

for each compound are given in Fig. S2 and Table S1. In comparison with neutral

213

molecules, no significant geometrical change was found in phenoxy radicals with exception

214

of the 7-OH radicals. As shown in Fig. S3, due to the steric repulsion between 7-O and the

215

keto group, the C9-C8-C10-C11 dihedral angle (θ) in the 7-OH radicals drifts from 0º to a

216

value that is dependent on the substitution in B-ring (Table S1). Consequently, nonplanar

217

structures were obtained for the 7-OH radicals. Similar phenomenon was found for the

218

anions (ArO-) generated from proton abstraction. In the case of cation radicals (ArOH+•)

219

generated from electron abstraction, the planarity is retained and thus the conjugation is

220

similar to the parent molecule.

11



221

3.2. HAT mechanism

222

O-H BDE is generally regarded as a major descriptor in evaluating the free radical

223

scavenging activity of antioxidants. The calculated O-H BDEs for the studied coumarin-

224

chalcone hybrids in gas phase and in solvents (benzene, ethanol and water) are listed in

225

Table 1.

226

Due to the formation of IHB between 7-OH and the adjacent C=O, abstracting the H

227

atom from 7-OH implies the breaking of IHB, which will increase the value of BDE for 7-

228

OH. Indeed, the BDE values of 7-OH in gas phase are in the range of 95.6-97.1 kcal/mol,

229

significantly larger than that of other OH groups (75.0–83.1 kcal/mol). This indicates that

230

the hydroxyl group at coumarin moiety (7-OH) is unfavorable to donate H atom compared

231

to OH groups at chalcone moiety, and thus the coumarin moiety is not active group for

232

trapping radicals via HAT. These results are in line with the experimental observation, i.e.,

233

compounds CC, PMCC and MNCC having only one 7-OH at coumarin moiety cannot trap

234

ABTS+· and DPPH radicals 27. It was found that the BDE values of 7-OH are very similar

235

with each other for the studied compounds, indicating that the introduction of substituents

236

(OCH3 or NO2 or OH) on B-ring merely exert slight effect on the 7-OH BDE.

237

For compounds VCC and OHCC having only one OH group on B-ring, the BDEs of

238

4′-OH and 2′-OH are in the range of 83.6-77.2 kcal/mol, which are significantly smaller

239

than those of 7-OH groups. This indicates that the hydroxyl group on chalcone moiety

240

plays the major role in trapping radicals, which is consistent with the experimental

12


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241

observation showing that compounds CC, PMCC and MNCC with one hydroxyl group

242

attaching to coumarin cannot trap DPPH27. Moreover, the BDEs of 4′-OH in VCC are

243

smaller than the corresponding data of 2′-OH in OHCC in all the four media, indicating

244

that the OH group at para-position tends to donate hydrogen atom more easily than that at

245

ortho-position. This is in line with the experimental result showing that the rate constant

246

of VCC (k =5.72 mM-1S-1) is larger than that of OHCC (4.23 mM-1S-1).

247

For compounds OPHCC and MPHCC with two OH groups on the B-ring, the 4′-OH

248

in MPHCC presents the lowest BDE value among the OH groups on B-ring. Compared to

249

MPHCC, the BDE value of 4′-OH in OPHCC is significantly larger, and even larger than

250

that of 3′-OH in MPHCC. Hence, the dihydroxyl groups at adjacent position (3′,4′-diOH)

251

in chalcone moiety is expected to possess higher abilities to donate hydrogen atom, and 4′-

252

OH in catechol moiety is regarded as the primary target for radical attack. Therefore, hybrid

253

compound MPHCC, which exhibits the lowest BDE value, is proposed as a better

254

antioxidant candidate, via HAT.

255

Table 1. The calculated BDE values of the studied coumarin-chalcone hybrids in gas

256

phase and solvents. The experimental rate constant (k) are also included for comparison. Comp. Gas CC 7-OH MNCC 7-OH PMCC 7-OH

k (mM-1s-1) a　

BDE Benzene

Ethanol

Water -

95.7

94.7

91.0

88.5 -

95.6

94.6

90.9

88.4 -

96.1

95.0

91.1 13


88.5


VCC 4'-OH 7-OH OHCC 2'-OH 7-OH MPHCC 3'-OH 4'-OH 7-OH (4',3')-OHb OPHCC 2'-OH 4'-OH 7-OH (4',2')-OHc

Page 14 of 37

5.72 81.4 97.1

81.6 95.4

79.6 90.7

77.2 88.1 4.23

83.1 96.0

83.6 94.4

81.9 90.1

79.6 87.5 10.70

78.5 75.0 97.1 77.0

79.7 76.3 95.5 76.9

78.7 75.6 90.9 74.4

76.4 73.3 88.2 72.0 7.81

82.2 80.8 96.4 100.9

82.9 82.2 94.7 100.8

81.6 82.2 90.2 98.1

79.3 80.0 87.6 95.6

257

a

rate constant in trapping DPPH radical, see Liu & Xi27.

258

b The

BDE of 3'-OH in the phenoxyl radical formed by the hydrogen loss from 4'-OH.

259

c The

BDE of 2'-OH in the phenoxyl radical formed by the hydrogen loss from 4'-OH.

260 261

It should be noted that the phenoxyl radical of MPHCC and OPHCC generated from

262

the first HAT from 4′-OH site may scavenge second free radical by H-atom donation from

263

the 3′-OH or 2′-OH site.52 Previous studies have revealed that the BDE value of the second

264

HAT (BDED) showing a good correlation with the radical scavenging activity of phenolic

265

compounds.28,53 To explore the possibility of the second HAT mechanism, the BDED

266

values in all four media were calculated for MPHCC and OPHCC (Table 1).

267

As seen from Table 1, the BDED values of MPHCC are 77.0, 76.9, 74.4 and 72.0

268

kcal/mol in gas phase, benzene, ethanol and water, respectively. Clearly, these BDEDs are

269

significantly lower than the corresponding BDEs of 3′-OH, even lower than those of 4′-OH

14


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270

in polar solvents. This indicates that the second HAT action is possible for MPHCC when

271

trapping radicals, giving ortho-quinone of MPHCC. Therefore, the double HAT action with

272

considerable low BDEs should be an important factor responsible for the higher rate

273

constants of MPHCC. On the contrary, the BDEDs of OPHCC are significantly larger than

274

the corresponding BDEs of OH groups, which denies the possibility of second HAT from

275

2′-OH in OPHCC.

276

In order to explain the differences in BDEs, the spin densities of phenoxyl radicals for

277

the studied coumarin-chalcone hybrids were calculated and presented in Fig. 2. As shown

278

in Fig. 2, for 7-OH radicals, the spin densities mainly distribute on the coumarinic portion

279

of the hybrids molecules. By contrast, the spin densities of other radicals are centered on

280

the B-ring and enone moiety. The spin densities on the O-atom of the 7-OH radicals are

281

almost the same of 0.37 for all the compounds, notablely larger than that in other radicals.

282

This implies poor stability for the 7-OH radicals, which explain the higher BDE values of

283

7-OH. The spin densities on O-atom of the 4′-OH radicals are 0.29, 0.32 and 0.30 for

284

MPHCC, OPHCC and VCC, respectively, significantly lower than that of 2′- and 3′-OH

285

radicals. This means smaller BDEs for the 4′-OH groups, especially for that on MPHCC,

286

which is in good agreement with the BDE results.

287

0.06 O -0.03 0.03 0.26 O-0.01O -0.14 -0.14 -0.03 0.29 0.01 0.34 -0.10 -0.16 O 0.27 0.37 CC-R7

0.06 O -0.03 -0.01 0.03 O 0.27 O 0.14 -0.14 -0.03 0.01 0.35 0.28 -0.10 -0.16 O 0.28 0.37 MNCC-R7

0.05 O -0.03 -0.01 0.03 0.26 O O -0.14 -0.14 -0.03 NO2 0.01 0.30 0.34 -0.10 -0.15 O 0.26 0.37

15


PMCC-R7

OCH3


O

288

O0.05 -0.03 -0.01 0.03 0.08 O O 0.26 O O 0.07 -0.15 -0.13 OCH -0.01 -0.14 -0.14 -0.03 3 0.30 0.33 0.21 0.01 0.34 0.27 -0.10 -0.07 -0.15 OH -0.13 O O 0.24 0.30 0.26 0.37 0.01 VCC-R4' VCC-R7

O0.05 -0.03 -0.01 0.03 O O 0.26 -0.03 -0.14 -0.15 0.30 0.01 0.34 -0.11 -0.16 O 0.38 0.26

289

290

MPHCC-R7

O

OCH3 OH

O

O

0.37 O -0.02 -0.06 0.25 OH 0.30 OH -0.13 0.08 0.22

O 0.31 O O -0.17 -0.02 -0.09 0.18 0.37 0.29 -0.11 OH -0.19 OH 0.38 -0.01 0.01 OPHCC-R2' O 0.07

OH

0.36 O -0.10 -0.02 0.23 0.32 0.28 -0.16 OH -0.18 0.37

-0.14

OHCC-R2'

MPHCC-R3'

OH

0.05 O

O

OHCC-R7

0.05 O -0.03 -0.01 0.03 0.26 O O -0.14 -0.14 -0.03 0.01 0.34 0.30 -0.10 -0.15 O 0.37 0.26

O

O OH

Page 16 of 37

0.05 O -0.03 -0.01 0.03 O O 0.25 -0.15 -0.03 -0.14 0.33 0.31 -0.11 -0.15 O 0.26 0.38

0.07 O O 0.08 -0.01 -0.15 -0.13 OH 0.22 0.260.30 -0.02 -0.08 OH O 0.18 0.29 MPHCC-R4' O -0.01 O O 0.08 OH -0.19 -0.12 -0.02 0.21 0.38 0.32 -0.10 OH -0.17 O 0.30 0.32 0.01 OPHCC-R4'

OH

OH

291

OPHCC-R7

292

Fig. 2 Spin density distribution of phenoxy radicals of the studied coumarin-chalcone

293

hybrids computed at the B3LYP/6-31G(d,p) level in gas phase.

294 295

As seen in Table1, the BDEs of 7-OH tend to decrease stepwise from gas phase to

296

water, but the extent of solvents impact is small. The average deviation of BDEs between

297

gas phase and water is only about 8.2 kcal/mol for 7-OH, suggesting that solvents can

298

slightly improve the H-donating ability of the 7-OH groups. This observation may be

299

attributed to the IHB between 7-OH and the C=O group that tends to weaken with the

300

increasing of solvent polarity. Similar phenomenon was found in previous studies.11,41,43 16


Page 17 of 37 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


301

By contrast, different solvent effects were observed for the OH groups on B ring, for

302

which the highest BDEs were found in benzene medium. With the increasing of solvent

303

polarity, BDEs tend to decrease slightly from benzene to water. As an example, the BDEs

304

of 4′-OH on MPHCC change from 76.3 kcal/mol in benzene to 73.3 kcal/mol in water. This

305

trend may be attributed to better stabilization of the radicals in the presence of polar media,

306

as evidenced from the spin density distribution of MPHCC-R4′ in benzene and in water

307

(Fig.S4). Similar trend was found in previous studies on p-phenylenediamine

308

isoflavones. 31

47

and

309

For coumarin-chalcone hybrids with two or more OH groups, the activity is determined

310

by the one with the lowest BDE value. It can be seen from Table 1 that the BDEs decrease

311

in the order of PMCC>CC>MNCC>OHCC>VCC>OPHCC> MPHCC in gas phase and

312

benzene,

313

VCC >OHCC>MNCC>CC>PMCC. For ethanol and water solvents, the BDE values obey

314

the same order of PMCC>CC>MNCC>OHCC>OPHCC>VCC>MPHCC. Clearly,

315

MPHCC is the most active one among the studied coumarin-chalcone hybrids independent

316

of the media, while PMCC is the poorest one. From the experimental study by Liu and

317

Xi,27 MPHCC presents the highest rate constant (10.70 mM-1s-1) in DPPH assay, while

318

PMCC, CC and MNCC cannot quench radicals effectively. Moreover, the order of

319

scavenging ability against DPPH radical is MPHCC>OPHCC>VCC>OHCC. By

so

the

sequence

of

H-donating

ability

17


is

MPHCC>OPHCC>


320

comparison, the predicted trend of H-donating ability based on BDEs is generally in

321

agreement with the experimental results from DPPH assay. 27

322

3.3. SET-PT mechanism

323

Besides HAT mechanism, phenolic compounds can also trap free radicals through

324

donating a single electron. Table 2 presents the calculated IPs and PDEs associated with

325

the SET-PT mechanism in different media. Despite the fact that ionization and electron

326

transfer is not expected in non-polar media (such as benzene), computed values in benzene

327

were given just for comparison. As shown in Table 2, the sequence of IPs in gas-phase is

328

VCCbenzene>water>ethanol, with average largest deviation of about 219

352

kcal/mol.

353

It is observed that the BDEs are always lower than the IPs regardless of the media,

354

indicating that the HAT rather than the SET-PT represents the thermodynamically

355

preferred pathway for the examined cases.

356

3.4

357 358

SPLET mechanism Another possible pathway to radical scavenging is the SPLET mechanism

30,56,57.

Analogue to SET-PT, SPLET mechanism also involves two steps: deprotonation of

20


Page 21 of 37 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


359

phenolic OH group and the subsequent electron transfer. Table 3 summarized the

360

calculated PΑs and ETEs associated with SPLET mechanism in different media. As can be

361

seen in Table 3, the PAs of 7-OH are always larger than the corresponding data of 2′-OH,

362

3′-OH and 4′-OH in all four media, indicating that deprotonation from 7-OH is more

363

difficult than from others. This can be attributed to the existence of IHB between 7-OH and

364

the adjacent C=O group as well as the less stability of the 7-OH anion generated from

365

deprotonation. Among the OH groups at different positions, the 4′-OH is characterized with

366

lower PA value, especially in catechol group on MPHCC. These results indicate that 4′-

367

OH is likely to be most reactive within SPLET mechanism.

368

Table 3. The calculated PAs and ETEs of the studied coumarin-chalcone hybrids in gas

369

phase and solvents. Comp. CC 7-OH MNCC 7-OH PMCC 7-OH VCC 4'-OH 7-OH OHCC 2'-OH 7-OH MPHCC 3'-OH 4'-OH 7-OH

Gas

PA Benzen Ethano e l

Water

Gas

ETE Benzen Ethano e l

Water

333.6

98.1

44.5

46.8

78.0

96.5

93.6

90.2

329.1

95.3

43.1

45.6

82.4

99.2

94.9

91.3

335.6

99.7

45.6

47.9

76.4

95.1

92.6

89.1

324.9 335.7

91.7 99.7

41.0 45.6

43.6 47.9

72.4 77.0

89.7 95.6

85.7 92.3

82.1 88.7

327.3 336.8

93.5 99.8

41.2 44.3

43.6 46.5

71.8 75.1

90 94.6

87.8 92.9

84.5 89.6

325.0 315.6 334.9

91.2 84.0 99.4

39.6 34.9 45.5

42.1 37.7 47.8

69.5 75.3 78.1

88.4 92.2 96.1

86.2 87.8 92.5

82.8 84.2 88.9

21



(4', 3')OHa OPHCC

35.3

37.7

Page 22 of 37

84.8

81.4

2'-OH

325.0

91.6

39.9

42.3

73.1

91.2

88.8

85.5

4'-OH 7-OH (4', 2')OHb

320.5 338.2

88.4 101.0

39.4 45.2

42.2 47.4

76.2 74.1

93.7 93.6

89.9 92.0

86.3 88.7

39.8

42.4

105.4

101.7

370

a

371

SPLET process; b The second SPLET process occurred at 2'-OH in the 4'-O phenoxyl radical formed

372

through the first SPLET process.

The second SPLET process occurred at 3'-OH in the 4'-O phenoxyl radical formed through the first

373

Data in Table 3 shows that the lowest PAs in each compounds obey the same order of

374

MPHCC

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