Scavenging Mechanism of Curcumin Toward the Hydroxyl Radical: A

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Scavenging Mechanism of Curcumin Toward the Hydroxyl Radical: A Theoretical Study of Reactions Producing Ferulic Acid and Vanillin Neha Agnihotri and P. C. Mishra* Department of Physics, Banaras Hindu University, Varanasi 221 005, India ABSTRACT: Curcumin is known to be an antioxidant, as it can scavenge free radicals from biological media. A sequence of H-abstraction and addition reactions involving up to eight OH radicals and curcumin or its degradation products leading to the formation of two other antioxidants, namely, ferulic acid and vanillin, was studied. Single electron transfer from curcumin to an OH radical was also studied. All relevant extrema on the potential energy surfaces were located by optimizing geometries of the reactant and product complexes, as well as those of the transition states, at the BHandHLYP/6-31G(d,p) level of density functional theory in the gas phase. Single-point energy calculations were also performed in the gas phase at the BHandHLYP/aug-cc-pVDZ and B3LYP/aug-cc-pVDZ levels of theory. Solvent effects in aqueous media were treated by performing single-point energy calculations at all of the above-mentioned levels of theory employing the polarizable continuum model and the geometries optimized at the BHandHLYP/6-31G(d,p) level in the gas phase. A few reaction steps were also studied by geometry optimization in aqueous media, and the thus-obtained Gibbs free energy barriers were similar to those obtained by corresponding single-point energy calculations. Our calculations show that the hydrogen atom of the OH group attached to the phenol moiety of curcumin would be most efficiently abstracted by an OH radical, in agreement with experimental observations. Further, our study shows that OH addition would be most favored at the C10 site of the heptadiene chain. It was found that curcumin can serve as an effective antioxidant.

1. INTRODUCTION Physical and mental stress, environmental pollution, and use of packaged food, among other factors, are responsible for enhanced levels of free radicals, which cause oxidative damage to the human body. Several free radicals that cause oxidative and nitrative damage to DNA by reacting with the bases are called reactive oxygen species (ROSs) and reactive nitrogen oxide species (RNOSs) respectively.14 ROSs and RNOSs are constantly formed in the human body, and to prevent the damage that they can cause, they must be scavenged. This job can be done effectively by certain antioxidants.58 Damage to DNA caused by different mechanisms and imbalances between oxidant and antioxidant activities are responsible for several health problems, including cancer, cardiovascular disorders, and Alzheimer’s and Parkinson’s diseases.915 An effective approach to prevent such disorders and diseases would be to scavenge the ROSs and RNOSs using antioxidants as components of food. Curcumin [1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptdiene-3, 5-dione], an extract of the plant Curcuma longa or turmeric, is known to be an antioxidant that can scavenge free radicals.16,17 It has been shown in various studies that curcumin has diverse biological and pharmacological properties, such as antioxidant, antitumor, antiinflammatory, antibacterial, antifungal, antiviral, and anticoagulant activities.1821 It contains a heptadiene chain with two terminal benzene rings, each of which has a hydroxyl group and a methoxy group attached symmetrically. Because of the important role of the hydroxyl groups attached to the benzene rings in the antioxidant activity, curcumin lies in the category of phenolic antioxidants.22 r 2011 American Chemical Society

The antioxidant properties of curcumin and its abilities to scavenge free radicals and to inhibit lipid peroxidation through electron donation from the phenolic group have been reported earlier.2329 Using laser flash and pulse radiolysis techniques, Jovanovic et al.30 proposed another antioxidant mechanism of curcumin that involves H-atom abstraction, mainly from the central CH2 group in the chain of the keto form. They also proposed that H-abstraction from the phenolic group accounted for only about 15% of the overall reaction. On the other hand, Barclay et al.31 studied the reaction of curcumin with peroxyl radicals and concluded that it is a phenolic chainbreaking antioxidant, donating H-atoms from the phenolic groups. In a recent study,32 Litwinienko and Ingold showed that the antioxidant activity of curcumin is enhanced in polar media. In the previous studies, different free radicals were considered.2332 Given the differing opinions on the mechanism of action of curcumin as an antioxidant, theoretical studies can prove valuable because they can reveal different possible reaction mechanisms along with associated barrier heights. On the basis of a theoretical study, Sun et al.33 concluded that the antioxidant action of curcumin involves H-abstraction from its phenolic groups, not from the central CH2 group, in agreement with the conclusion of Barclay et al.31 In that theoretical study,33 hydrogen-atom- and single-electron-transfer mechanisms were considered, and it was found that the former mechanism was more probable than the latter. In another recent theoretical study,18 Galano et al. found Received: September 27, 2011 Published: October 28, 2011 14221

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The Journal of Physical Chemistry A

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Figure 1. Structures of the four lowest-energy conformers of curcumin (Cur ICur IV). Relative Gibbs free energies (kcal/mol) of the four conformers obtained at the BHandHLYP/aug-cc-pVDZ level of theory in aqueous media are given with respect to that of Cur I.

that different mechanisms are favored in curcumin2,2-diphenyl1-picrylhydrazyl (DPPH) and curcuminCH3O• reactions. The OH radical is known to be a potent and commonly occurring ROS. It can react efficiently with a wide variety of chemical species in different ways, including H-abstraction and addition. To the best of our knowledge, such reactions between the OH radical and curcumin have not yet been studied theoretically. The main aim of the present work was to study systematically different mechanisms of reactions involving hydroxyl radicals and curcumin or its reaction products so as to be able to explain the formation of two major experimentally observed products, namely, ferulic acid and vanillin. This study, in turn, is expected to reveal how OH radicals are scavenged by curcumin.

2. COMPUTATIONAL DETAILS To obtain the most stable conformer of curcumin for the study of its reactions of OH radicals, geometries of the four lowestenergy conformers reported in previous studies were fully optimized in the gas phase using the B3LYP and BHandHLYP functionals of density functional theory, along with the 6-31G (d,p) basis set.34,35 Single-point energy calculations were performed at the B3LYP/aug-cc-pVDZ and BHandHLYP/aug-ccpVDZ levels of theory in the gas phase using the geometries optimized at the B3LYP/6-31G(d,p) and BHandHLYP/6-31G (d,p) levels of theory, respectively. To treat the bulk solvent effect of aqueous media, single-point energy calculations were performed at all of the above-mentioned levels of theory using the polarizable continuum model (PCM)36,37 with the geometries optimized at the respective levels of theory in the gas phase. In this model, the solute

is placed in a cavity formed by interlocking spheres centered on the solute atoms in the continuum of the solvent medium. For the study of reactions, the geometries of all reactant, intermediate, and product complexes and transition states involved in reactions of hydroxyl radicals with curcumin were optimized in the gas phase at the BHandHLYP/6-31G(d,p) level of density functional theory. The BHandHLYP functional was employed here because it has been found to be reliable (in some cases, more so than the popular B3LYP functional), particularly for open-shell systems.6,38 Single-point energy calculations at the B3LYP/aug-cc-pVDZ and BHandHLYP/aug-cc-pVDZ levels of theory in the gas phase were carried out using the geometries optimized at the BHandHLYP/6-31G(d,p) level. Solvation in aqueous media was treated by employing single-point energy calculations at the BHandHLYP/6-31G(d,p), B3LYP/augcc-pVDZ, and BHandHLYP/aug-cc-pVDZ levels of theory using the PCM and the geometries optimized at the BHandHLYP/ 6-31G(d,p) level of theory in the gas phase. Geometry optimizations in aqueous media were also performed in a few cases at the BHandHLYP/6-31G(d,p) level of theory employing the PCM. Vibrational frequency analysis was carried out after each geometry optimization. Reactant, intermediate, and product complexes were characterized by all real vibrational frequencies, whereas transition states were characterized by one imaginary vibrational frequency each. To obtain Gibbs free energies, necessary thermal energy corrections to the total energy were applied at a temperature of 298.15 K. These corrections, as an approximation, were also taken to be valid for the corresponding single-point energy calculations in both the gas phase and aqueous media. Genuineness of the optimized transition states 14222

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Table 1. Relative Gibbs Free Energies (ΔG) at 298.15 K (kcal/mol) of the Four Lowest-Energy Conformers of Curcumin (Cur ICur IV) Obtained at Different Levels of Theory in the Gas Phase and in Aqueous Mediaa with Respect to Those of the Most Stable Conformer (Cur I) conformer

B3LYP/6-31G(d,p)

B3LYP/aug-cc-pVDZb

BHandHLYP/6-31G(d,p)

BHandHLYP/aug-cc-pVDZc

Cur I

0.0 (0.0)

0.0 (0.0)

0.0 (0.0)

0.0 (0.0)

Cur II

0.3 (1.8)

0.4 (0.5)

0.2 (0.6)

0.3 (1.4)

Cur III

0.1 (0.2)

0.1 (1.5)

0.1 (0.1)

0.1 (2.1)

Cur IV

5.3 (3.6)

6.3 (4.1)

3.7 (1.2)

4.8 (3.7)

a

In parentheses. b Results obtained by single-point energy calculations using the geometries optimized at the B3LYP/6-31G(d,p) level of theory in the gas phase. c Results obtained by single-point energy calculations using the geometries optimized at the BHandHLYP/6-31G(d,p) level of theory in the gas phase.

was ensured by visually examining the vibrational modes corresponding to the imaginary frequencies, and intrinsic reaction coordinate (IRC) calculations39 were not required for this purpose. All geometry optimization calculations were performed using the Windows versions of the Gaussian 98 (G98W),40 Gaussian 03 (G03W),41 and Gaussian 09 (G09W)42 suites of programs. Solvation in aqueous media was studied using the Gaussian 09 (G09W)42 and Gaussian 98 (G98W)40 suites of programs. For visualization of optimized structures and vibrational modes, the GaussView program43 was employed.

3. RESULTS AND DISCUSSION 3.1. Conformational Isomers of Curcumin. The atomic numbering scheme for curcumin employed here is shown in Figure 1. A comprehensive conformational analysis of curcumin was not the main aim of the present study. However, to ascertain its most stable structure for the study of reactions, some of its lowest-energy conformers were considered (Figure 1); three of them have the enol form, whereas the fourth has the keto form, as reported in a previous study by Kolev et al.44 The geometries of these four conformers were fully optimized at the BHandHLYP/ 6-31G(d,p) level of theory in the gas phase. The presence of intramolecular hydrogen bonds between the OH and OCH3 groups attached to the two benzene rings has a significant effect on the stability of the molecular structures. This type of hydrogen bonding exists in all of the conformations considered here (Cur I, Cur II, Cur III, Cur IV) (Figure 1). It was found that the keto structure of curcumin (Cur IV) is nonplanar, with an O11 C11C10C9 dihedral angle, corresponding to the central part of the heptadiene chain, of 114°. However, each methoxyphenol moiety was planar (except for the H atoms of the methyl group) in all four conformations. It is noted that the Gibbs free energy of Cur I, which has the enol form, was found to be 3.7 kcal/mol lower than that of Cur IV at the BHandHLYP/augcc-pVDZ level of theory in aqueous media. The other two enol conformers of curcumin, that is, Cur II and Cur III, were also found to be more stable than Cur IV (Figure 1). These Gibbs free energies suggest that the enol form of curcumin should be dominant in aqueous media, in agreement with the results obtained by Sun et al.33 Therefore, for further analysis, we considered only the enol isomers of curcumin. The positions of the hydroxyl groups attached to the C2 and C17 atoms are the same in all three enol conformers (Cur ICur III). In Cur I, the methoxy groups are attached at the C1 and C18 positions of the benzene rings, and the intramolecular hydrogenbond distances H2O1 and H17O18 are 2.08 Å each. In Cur II, the methoxy groups are attached to the C3 and C18 positions

of the benzene rings, and the intramolecular hydrogen-bond distances H2O3 and H17O16 are 2.07 Å each. In Cur III also, the methoxy groups are attached to the C3 and C18 positions of the benzene rings but the orientations of the hydroxyl and methoxy groups attached to the two benzene rings are opposite to each other, and the intramolecular hydrogen-bond distances H2O3 and H17O18 are somewhat different, at 2.07 and 2.08 Å, respectively (Figure 1). A previous study by Kolev et al.44 performed at the B3LYP/6-31G* level of theory found the same three enol structures as mentioned above to be most stable, although the stability order was different. The total relative energies of the three most stable conformers reported by Kolev et al.44 were within 0.7 kcal/mol, with Cur III being most stable and Cur I and Cur II having total energies that were 0.08 and 0.70 kcal/mol higher, respectively. The somewhat different stability orders for the three enol conformers in the two studies is not surprising, as better basis sets were used in the present study than in the previous case.44 The Gibbs free energies of all three conformers of curcumin (Cur ICur III) obtained at different levels of theory in the gas phase and in aqueous media are presented in Table 1. According to the Gibbs free energies obtained at the B3LYP/aug-cc-pVDZ and BHandHLYP/aug-cc-pVDZ levels of theory in aqueous media, conformer Cur I is more stable than conformers Cur II and Cur III by 0.5 kcal/mol or more. Thus, we conclude that Cur I is the most stable conformer of curcumin in aqueous media. However, because Cur I and Cur II differ in their Gibbs free energies by only 0.5 kcal/mol at the B3LYP/aug-cc-pVDZ and BHandHLYP/aug-cc-pVDZ levels of theory, these conformers coexist, with the abundance of the former being greater than that of the latter. Therefore, we studied reactions of curcumin with OH radicals considering conformer Cur I. However, we expect that similar results would also be found if Cur II were used in place of Cur I. In another recent study by Galano et al.,18 Cur I was also considered for calculations on reactions. Further, in an experimental NMR study by Payton et al.,45 conformer Cur I was found to predominate in solutions. 3.2. Single-Electron-Transfer Reactions. We considered single-electron transfer from curcumin (Cur I) to an OH radical. This reaction can be represented as AIP

Cur þ OH• f Cur•þ þ OH

ðiÞ

In this reaction, curcumin acts as an electron donor, and the OH radical acts as an electron acceptor. The adiabatic ionization potential (AIP) is a very important physical quantity that provides information about the process of single-electron transfer. It was calculated for the above reaction in both the gas phase and aqueous media, and the results are presented in Table 2. 14223



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These results show that the AIP values in water are much lower than those in the gas phase at all levels of theory employed here. Further, it was found that, in going from the gas phase to aqueous media, the viability of the single-electron-transfer process is strongly enhanced. 3.3. H-Abstraction Reactions. We considered hydrogenatom abstractions by an OH radical from all of the relevant sites of Cur I. This reaction can be represented as ΔGbn

ΔGrn

CurHx þ OH• f ½TSx f Cur• þ Hx OH

ðiiÞ

where x = 24 and 611 are the labels of hydrogen atoms of Cur I (Figure 1), ΔGbn is the barrier energy for the abstraction of the Hx atom, ΔGrn is the energy release corresponding to ΔGbn, n is a label for reaction step number, and [TS]x is the transition state involved in the reaction. Because the heptadiene chain is symmetrical Table 2. Adiabatic Ionization Potential for the Single-Electron-Transfer Process from Cur I to OH• Obtained at Different Levels of Theory in the Gas Phase and Aqueous Media medium gas phase aqueous media a

BHandHLYP/

BHandHLYP/

B3LYP/

6-31G(d,p)

aug-cc-pVDZa

aug-cc-pVDZa

160.0

127.2

110.9

47.2

15.5

4.5

Results obtained by single-point energy calculations using the geometries optimized at the BHandHLYP/6-31G(d,p) level of theory in the gas phase or aqueous media.

about the C10 atom, we considered reactions at sites lying on only one side of it. Thus, the possible sites for H-abstraction reactions would only be O2, C3, C4, C6, C7, C8, O9, C10, and C11 (Figures 2 and 3). The Gibbs free energy barriers and releases involved in abstraction reactions by an OH radical at different sites of Cur I calculated at different levels of theory in the gas phase and aqueous media are presented in Table 3. As it was not possible to locate separate reactant complexes for H-abstraction from the different sites of Cur I, Gibbs free energy barriers were calculated with respect to the sum of Gibbs free energies of Cur I and an OH radical. In this way, we obtained the relative Gibbs free energies for the various transition states (TS1TS9) and product complexes (PC1PC9) related to the abstractions of different H-atoms of Cur I by an OH radical (Figure 2). The optimized structures of all of the transition states along with the corresponding imaginary frequencies (ν) and some important interatomic distances are presented in Figure 3. At the BHandHLYP/aug-cc-pVDZ level of theory in aqueous media, the Gibbs free energy barriers for H-abstraction from the C11, O2, C3, C4, C6, C7, C8, O9, and C10 positions of Cur I, denoted by ΔGb1, ΔGb2, ΔGb3, ΔGb4, ΔGb5, ΔGb6, ΔGb7, ΔGb8, and ΔGb9, respectively, were found to be 18.3, 16.2, 20.9, 21.8, 24.6, 22.1, 22.2, 21.4, and 22.7 kcal/mol, respectively (Table 3). These Gibbs free energy barriers follow the order O2 > C11 > C3 > O9 > C4 > C7 > C8 > C10 > C6. Thus, the lowest Gibbs free energy barrier corresponds to H-abstraction from the OH group of curcumin attached to C2 (Figure 3, Table 3). Further, the most stable product (PC2) is also formed by H-abstraction

Figure 2. Relative Gibbs free energies of reactants (Cur I + OH•), different transition states (TS), and product complexes (PC) involved in hydrogen abstraction by an OH radical from various sites of Cur I obtained at the BHandHLYP/aug-cc-pVDZ level of theory in aqueous media. For structures of transition states, see Figure 3. 14224



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Figure 3. Optimized structures of transition states (TS1TS9) involved in hydrogen abstraction by an OH radical from the different sites of Cur I (Figure 2) obtained at the BHandHLYP/6-31G(d,p) level of theory in the gas phase. The imaginary vibrational frequencies (ν) associated with all of the transition states are given in cm1. Certain important optimized interatomic distances (Å) are also given.

from the same site (Table 3, Figure 2). At the BHandHLYP/ 6-31G(d,p) and B3LYP/aug-cc-pVDZ levels of theory in aqueous media, the same site was also found to be most favored for H-abstraction (Table 3). Therefore, H-abstraction from the OH group attached to C2 is most preferred. At the B3LYP/augcc-pVDZ level of theory in aqueous media, the Gibbs free energy barrier, ΔGb2, was found to be zero, showing that the corresponding reaction step would be barrierless (Table 3). However, this conclusion is not corroborated by the results obtained at the BHandHLYP/6-31G(d,p) and BHandHLYP/aug-cc-pVDZ levels of theory (Table 3). It should be mentioned that the B3LYP functional sometimes does not yield reliable results, particularly for open-shell systems, as reported earlier.6 Therefore, in this situation, we would consider the results obtained at the BH andHLYP/aug-cc-pVDZ level of theory to be more reliable (Table 3). The H-abstraction barrier energy from C11 (i.e., from the OCH3 group) in aqueous media lies next to that corresponding to H-abstraction from the OH group attached to C2 at the different levels of theory (Table 3). To evaluate the effects of possible geometry relaxations in aqueous media on the reaction barrier energies, geometry

optimization in aqueous media was attempted using the PCM at the BHandHLYP/6-31G(d,p) level of theory for the different transition states. Because of convergence problems, reactions could be successfully studied for only three sites, namely, C11, C3, and C10. The corresponding Gibbs free energy barriers were found to be 13.3 kcal/mol (ΔGb1), 19.0 kcal/mol (ΔGb3), and 19.0 kcal/mol (ΔGb9), respectively. No significant changes were found in the geometrical parameters of the species involved in the reactions in going from the gas phase to aqueous media. The Gibbs free energy barriers for these reactions were found by single-point energy calculations in aqueous media using the geometries optimized at the BHandHLYP/6-31G(d,p) level of theory in the gas phase to be 16.0, 21.0, and 21.9 kcal/mol respectively. A comparison of the two sets of barrier energies shows that there is not much difference between them. Thus, the barrier energies obtained by single-point energy solvation calculations in aqueous media, particularly their relative values, are quite reliable. 3.4. Addition Reactions. We considered addition reactions of an OH radical at different sites of Cur I. If the site where the addition of an OH radical would occur is denoted as Cn, the 14225



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Table 3. Gibbs Free Energy Barriers (ΔGbi ) and Releases (ΔGri ) (i = 19) at 298.15 K (kcal/mol) Involved in Hydrogen Abstraction Reactions by an OH Radical from Different Sites of Curcumin (Cur I) (Figures 2 and 3) Obtained at Different Levels of Theory in the Gas Phase and in Aqueous Mediaa free energy barrier

BHandHLYP/

BHandHLYP/

B3LYP/

H-abstraction site

or release

6-31G(d,p)

aug-cc-pVDZb

aug-cc-pVDZb

C11 (C1)

ΔGb1

12.1 (16.0)

12.5 (18.3)

2.4 (6.0)

ΔGr1

20.5 (21.5)

22.2 (24.8)

16.6 (17.1)

O2 (C2)

ΔGb2

11.0 (15.8)

12.4 (16.2)

2.3 (0.0)

C3

ΔGr2 ΔGb3

40.4 (43.2) 17.5 (21.0)

42.4 (43.2) 17.1 (20.9)

33.1 (32.3) 8.1 (11.4)

ΔGr3

10.0 (11.8)

10.7 (13.6)

6.0 (8.7)

ΔGb4

17.5 (21.0)

18.2 (21.8)

9.2 (12.2)

ΔGr4

11.8 (13.3)

12.7 (14.8)

8.0 (10.0)

ΔGb5

18.0 (22.4)

19.5 (24.6)

10.5 (15.2)

ΔGr5

13.3 (13.8)

15.0 (15.0)

10.4 (10.3)

C7

ΔGb6

14.7 (20.9)

15.7 (22.1)

6.5 (13.7)

C8

ΔGr6 ΔGb7

18.8 (20.0) 16.9 (20.9)

19.6 (20.2) 18.4 (22.2)

15.0 (16.9) 9.3 (12.7)

ΔGr7

11.9 (13.2)

12.6 (13.5)

8.3 (9.0)

ΔGb8

15.6 (18.5)

18.6 (21.4)

5.7 (8.5)

ΔGr8

29.0 (32.9)

31.3 (31.7)

22.4 (23.0)

ΔGb9

17.5 (21.9)

18.5 (22.7)

8.6 (12.5)

ΔGr9

8.3 (8.8)

9.6 (9.9)

5.2 (5.6)

C4 C6

O9 (C9) C10

a In parentheses. b Results obtained by single-point energy calculations using the geometries optimized at the BHandHLYP/6-31G(d,p) level of theory in the gas phase.

Table 4. Gibbs Free Energy Barriers (ΔG0i b) and Releases (ΔG0i r) (i = 111) at 298.15 K (kcal/mol) Involved in the Addition Reactions of an OH Radical at Different Sites of Curcumin (Cur I) (Figures 4 and 5) Obtained at Different Levels of Theory in the Gas Phase and in Aqueous Mediaa free energy

BHandHLYP/

BHandHLYP/

B3LYP/

OH-addition site

barrier or release

6-31G(d,p)

aug-cc-pVDZb

aug-cc-pVDZb

C1

ΔG01b

11.7 (14.1)

11.8 (15.1)

4.2 (7.3)

ΔG01r

20.6 (20.7)

19.3 (19.7)

12.9 (13.3)

C2

ΔG02b

11.5 (10.5)

11.2 (12.4)

3.5 (4.3)

ΔG02r

26.0 (24.3)

24.8 (24.1)

18.5 (17.7)

C3

ΔG03b

14.3 (14.9)

14.1 (14.7)

6.5 (6.6)

C4

ΔG03r ΔG04b

17.7 (16.1) 11.1 (13.6)

16.8 (17.4) 11.7 (13.6)

11.1 (11.8) 4.1 (5.0)

ΔG04r

19.9 (21.8)

19.9 (21.7)

15.2 (16.6)

ΔG05b

16.6 (18.7)

16.4 (17.9)

9.2 (9.8)

ΔG05r

14.8 (14.5)

14.1 (14.7)

8.7 (8.6)

C5 C6

ΔG06b

11.4 (14.0)

12.0 (14.8)

4.2 (4.8)

ΔG06r

17.2 (18.3)

16.5 (18.6)

11.6 (12.1)

C7

ΔG07b

10.2 (12.9)

11.1 (14.7)

4.7 (8.1)

C8

ΔG07r ΔG08b

29.9 (31.1) 8.5 (12.2)

28.8 (31.2) 9.6 (13.7)

23.3 (25.8) 3.1 (6.3)

ΔG08r

28.5 (31.6)

27.6 (30.9)

21.8 (24.3)

ΔG09b

14.1 (13.1)

14.0 (12.8)

6.2 (4.8)

ΔG09r

24.6 (20.9)

23.0 (17.2)

14.2 (9.3)

C9 C10 C90

ΔG010b

8.0 (10.2)

8.2 (10.3)

0.2 (1.5)

r ΔG010

29.5 (29.5)

27.9 (28.7)

20.7 (20.7)

ΔG011b

17.0 (19.1)

18.1 (21.0)

8.2 (10.9)

r ΔG011

27.2 (26.8)

26.3 (26.1)

16.0 (16.2)


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Figure 4. Relative Gibbs free energies of reactants (Cur I + OH•), different transition states (TS0 ), and product complexes (PC0 ) involved in the addition of an OH radical at various sites of Cur I obtained at the BHandHLYP/aug-cc-pVDZ level of theory in aqueous media. For structures of transition states, see Figure 5.

reaction can be expressed as 0 ΔGnb

0 ΔGnr

Cn þ OH• f ½TS0 n f Cn OH•

ðiiiÞ

where n = 111 corresponds to the different carbon atoms of Cur I (Figure 1), ΔG0nb is the Gibbs free energy barrier of the addition reaction at atom n, ΔG0nr is the corresponding energy release, and [TS0 ]n is the transition state involved in the reaction. As it was not possible to locate separate reactant complexes for addition at the different carbon atoms, the Gibbs free energy barriers were calculated with respect to the sum of Gibbs free energies of Cur I and an OH radical. The calculated Gibbs free energy barriers and releases involved in the addition reactions of an OH radical at the different sites of Cur I at various levels of theory in the gas phase and aqueous media are presented in Table 4. The relative Gibbs free energies of the different transition states and product complexes with respect to that of the common reactant (sum of Gibbs free energies of Cur I and an OH radical) obtained at the BHandHLYP/aug-cc-pVDZ level of theory in aqueous media are presented in Figure 4, whereas the optimized structures of all of the transition states along with the corresponding imaginary frequencies are presented in Figure 5. The COH (O13H13) interatomic distances at the different transition states follow the order C8 > C7 > C10 > C2 > C4 > C1 > C6 ≈ C9 > C5 > C3 > C90 . At the BHandHLYP/aug-cc-pVDZ level

of theory in aqueous media, the Gibbs free energy barriers for OH radical additions at the C1, C2, C3, C4, C5, C6, C7, C8, C9, C10, and C90 positions of Cur I, denoted by ΔG01b, ΔG02b, ΔG03b, ΔG04b, ΔG05b, ΔG06b, ΔG07b, ΔG08b, ΔG09b, ΔG010b , and ΔG011b, respectively, were found to be 15.1, 12.4, 14.7, 13.6, 17.9, 14.8, 14.7, 13.7, 12.8, 10.3, and 21.0 kcal/mol, respectively (Table 4). These barrier energies follow the order C10 > C2 > C9 > C4 > C8 > C7 ≈ C3 > C6 > C1 > C5 > C90 . Thus, the addition reaction would be most favored at the C10 site of the heptadiene chain. This site was also found to be most favored at all of the other levels of theory employed here (Table 4). From the Gibbs free energies of the adducts, it was found that the most stable adduct wais also formed at the C10 site, followed by those at the C8 and C7 sites. This finding establishes that the most favored site for the addition reaction would be C10. Galano et al.18 also found C10 to be the most favored site for addition of the •OCH3 radical. To validate the results on Gibbs free energy barriers discussed above, we attempted to optimize all of the transition states (TS10 TS110 ) at the BHandHLYP/6-31G(d,p) level of theory in aqueous media using the PCM. However, convergence could be achieved and Gibbs free energy barriers obtained in only six of these cases, corresponding to addition reactions at the C1, C3, C4, C5, C7, and C9 sites. Thus, the Gibbs free energy barriers in aqueous media were found to be 13.6 kcal/mol (ΔG01b), 14.8 kcal/mol (ΔG03b), 11.8 kcal/mol (ΔG04b), 17.1 kcal/mol (ΔG05b), 12.4 kcal/mol 14227



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Figure 5. Optimized structures of transition states (TS10 TS110 ) involved in the addition of an OH radical to the different sites of Cur I (Figure 4) obtained at the BHandHLYP/6-31G(d,p) level of theory in the gas phase. The imaginary vibrational frequencies (ν0 ) associated with all of the transition states are given in cm1. Certain important optimized interatomic distances (Å) are also given.

(ΔG07b), and 13.9 kcal/mol (ΔG09b), respectively. The corresponding values of Gibbs free energy barriers were found by single-point energy calculations in aqueous media using the geometries optimized at the BHandHLYP/6-31G(d,p) level of theory in the gas phase to be 14.1, 14.9, 13.6, 18.7, 12.9, and 13.1 kcal/mol, respectively (Table 4). A comparison of the two sets of values shows that there is not much difference between them. Thus, we found that the Gibbs free energy barriers obtained from single-point energy calculations in aqueous media employing gas-phaseoptimized geometries, particularly their relative values, are quite reliable. 3.5. Successive H-Abstraction and Addition Reactions. Separate addition and H-abstractions reactions involving Cur I and an OH radical were discussed in sections 3.3 and 3.4. In this section, we consider a series of reactions of both addition and H-abstraction types. The adduct of an OH radical with Cur I

formed at the most favored site (i.e., C10) was considered for further reactions with other OH radicals. Gibbs free energy barriers were calculated with respect to the sum of total Gibbs free energies of the individual reactants. In the product PC100 , there are two OH groups, one each attached to C9 and C10. When another OH (O14H14) radical is placed near the OH groups attached to C9 and C10 (O9H9 and O13H13, respectively), it abstracts the H13 atom from O13 attached to C10, forming a water molecule. This process involves the transition state TSa, yields the product Pa along with a water molecule, and is accompanied by transfer of the H9 atom of the O9H9 group to O13. Thus, the attack of the second OH radical on Cur I is associated with a double H-atom transfer. The Gibbs free energy barrier associated with this reaction step, denoted by ΔGba , was found to be negative (4.6 kcal/mol) at all levels of theory employed here in both the gas phase and aqueous media 14228



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Table 5. Gibbs Free Energy Barriers (ΔGbi ) and Releases (ΔGir) (i = ag) at 298.15 K (kcal/mol) Corresponding to Different Addition and Abstraction Reactions Starting with the Adduct (PC100 ) and Involving up to Seven OH Radicals Leading to the Formation of Ferulic Acid and Vanillin (Figure 6) Obtained at Different Levels of Theory in the Gas Phase and in Aqueous Mediaa BHandHLYP/aug-cc-pVDZb

B3LYP/aug-cc-pVDZb

free energy barrier or release

BHandHLYP/6-31G(d,p)

ΔGba

7.8 (14.0)

3.9 (4.6)

13.2 (13.4)

ΔGra

48.2 (39.7)

50.7 (45.6)

47.7 (43.0)

ΔGbb

9.1 (19.3)

13.6 (17.5)

1.6 (10.5)

ΔGrb

20.1 (20.2)

20.3 (20.3)

15.6 (14.7)

ΔGbc ΔGrc

6.4 (6.7) 96.9 (91.9)

7.0 (5.9) 94.6 (86.7)

10.5 (10.2) 82.1 (75.1)

ΔGbd

8.0 (9.4)

8.7 (10.2)

1.8 (2.6)

ΔGrd

26.4 (24.9)

25.0 (25.1)

18.0 (17.4)

ΔGbe

9.8 (14.4)

9.6 (10.5)

20.5 (20.4)

ΔGre

51.4 (44.6)

49.1 (45.5)

41.5 (38.8)

ΔGbf

12.5 (16.3)

15.9 (16.9)

4.4 (10.7)

ΔGrf

20.9 (18.3)

21.8 (20.8)

14.8 (13.4)

ΔGbg ΔGrg

7.5 (7.8) 86.7 (78.3)

8.1 (6.7) 84.6 (70.7)

9.9 (9.3) 77.7 (65.0)


(Table 5). Therefore, this reaction step would be barrierless. When the third OH (O15H15) radical attacks the product formed in the previous step (i.e., Pa), it abstracts H9 from O13, producing a water molecule and the product Pb through the transition state TSb. The Gibbs free energy barrier (ΔGbb) associated with this reaction step was found at the BHandHLYP/augcc-pVDZ level of theory to be 13.6 and 17.5 kcal/mol in the gas phase and aqueous media, respectively. The corresponding values found at the B3LYP/aug-cc-pVDZ level of theory were 1.6 and 10.5 kcal/mol in the gas phase and aqueous media, respectively. We note that use of the BHandHLYP functional in place of B3LYP along with the aug-cc-pVDZ basis set yields appreciably higher Gibbs free energy barriers and also the Gibbs free energy barriers in aqueous media are appreciably higher than those in the gas phase. The B3LYP functional is known to be less reliable than the BHandHLYP functional for open-shell systems. Therefore, in this situation, the results obtained using the BHandHLYP functional appear to be more reliable than those obtained using the B3LYP functional. Further, it is likely that the calculated barrier energies in aqueous media are somewhat overestimated, as biological media are complex and cannot be exactly represented by aqueous media. The product Pb is attacked by a fourth OH (O16H16) radical at the C9 or the C90 site, with the same product being formed in both cases. We considered the C9 site for addition of the fourth OH radical. This reaction is followed by dissociation of both the C9C10 and C10C90 bonds and binding of the CHO group formed through dissociation of the C9C10 and C10C90 bonds at C90 through the transition state (TSc) (Figure 6). The product formed at this step consists of ferulic acid and another component having four carbon atoms in the chain which is denoted by Pc. The Gibbs free energy barrier (ΔGbc ) associated with this reaction step was found at the BHandHLYP/aug-cc-pVDZ level in aqueous media to be 5.9 kcal/mol and this step was highly exergonic, the energy release (ΔGrc) being 86.7 kcal/mol. Similar results were also found at the other levels of theory (Table 5). The product Pc was considered for attack by a fifth OH (O17H17) radical. The fifth OH radical would attack one of the

C80 and C70 sites of the four-carbon atom chain of Pc. The C80 and C70 sites are the positions equivalent to the C8 and C7 sites, respectively, in Cur I (Figure 1). We considered the fifth OH radical attack at each of the sites C80 and C70 separately. At the BHandHLYP/aug-cc-pVDZ level of theory in aqueous media, we found the barrier energy (ΔGbd) involved in addition of the fifth OH radical at C80 to be 10.2 kcal/mol, whereas that involved in addition at C70 was found to be 12.2 kcal/mol (Table 5). Further, at the BHandHLYP/aug-cc-pVDZ level of theory in aqueous media, the adduct formed by reaction of the fifth OH radical at C80 was found to be more stable than that formed by addition at C70 by about 1.2 kcal/mol. Therefore, we considered the fifth OH radical addition to take place preferentially at the C12 site, and the structures and energies relevant to this reaction are presented in Table 5 and Figure 6. The Gibbs free energy barriers involved in this reaction were found to be similar, in the range of ∼810 kcal/mol at the BHandHLYP/6-31G(d,p) and BHandHLYP/aug-cc-pVDZ levels of theory in the gas phase and aqueous media, whereas the corresponding Gibbs free energies obtained at the B3LYP/aug-cc-pVDZ level of theory were much smaller (Table 5). In this situation, as discussed earlier, the results obtained using the BHandHLYP functional appear to be more reliable. The adduct formed by the fifth OH radical attack through the transition state TSd is denoted as Pd (Figure 6). The sixth OH (O18H18) radical attack was considered to take place at the C70 site. This adduct, formed through transition state TSe, is denoted by Pe (Figure 6). The Gibbs free energy barrier (ΔGbe ) for addition of the sixth OH radical at C70 as obtained at the BHandHLYP/aug-cc-pVDZ level of theory in aqueous media was found to 10.5 kcal/mol. Thus, this reaction step would be barrierless. This reaction step was also found to be barrierless at the other levels of theory employed here in both the gas phase and aqueous media (Table 5). The seventh OH (O19H19) radical attack was allowed to take place on Pe. The most appropriate reaction in this case appeared to be H-abstraction from any of the OH groups attached to C80 and C70 . The Gibbs free energy barrier (ΔGbf ) for H-abstraction from the OH group attached to C70 at the BHandHLYP/aug-cc-pVDZ 14229



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Figure 6. Optimized structures of transition states (TSaTSg) and products (Pa-Pg) occurring in the different abstraction and addition reactions involving up to seven OH radicals starting with the most stable radical adduct (PC100 ) obtained by OH addition at the C10 site of Cur I leading to the formation of ferulic acid and vanillin. The Gibbs free energy barriers and releases shown here were obtained at the BHandHLYP/aug-cc-pVDZ level of theory in aqueous media. The imaginary vibrational frequencies (ν) associated with the different transition states are given in cm1. Certain important optimized interatomic distances (Å) are also given.

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The Journal of Physical Chemistry A level in aqueous media was found to be 16.9 kcal/mol, whereas that from the OH group attached to C80 was found to be 18.7 kcal/mol. Further, the product formed after H-abstraction from the OH group attached to C70 was found to be more stable than that formed through H-abstraction from the OH group attached to C80 by about 1 kcal/mol. Therefore, the H-abstraction by the seventh OH group was allowed to take place from the OH group attached to C70 , and the corresponding product formed through transition state TSf is denoted by Pf (Figure 6). The next H-abstraction by the eighth OH group was allowed to occur from the OH group attached to C80 . This H-abstraction was accompanied by dissociation of the C80 C70 bond. The product formed at this stage through transition state TSg, consisting of a water molecule, CHO COCHO, and vanillin, is denoted by Pg. The Gibbs free energy barrier (ΔGbg) corresponding to the transition state TSg was found to be 6.7 kcal/mol at the BHandHLYP/aug-cc-pVDZ level of theory in aqueous media, whereas at the B3LYP/aug-cc-pVDZ level, this reaction was predicted to be barrierless. This reaction step was found to be highly exergonic, as the corresponding Gibbs free energy release was 70.7 kcal/mol at the BHandHLYP/ aug-cc-pVDZ level of theory in aqueous media. In a sense, the present study simulated the formation of two important experimentally observed products, namely, ferulic acid and vanillin through sequential reactions involving OH radicals, curcumin, and various intermediates produced during the successive reactions. Both ferulic acid and vanillin can react with additional OH radicals, so that they are themselves known to be antioxidants. The reactions studied here establish a high OH scavenging ability of curcumin. Thus, we have shown how, as a consequence of reactions involving OH radicals and curcumin or its degradation products, vanillin and ferulic acid would be formed. Both vanillin and ferulic acid also lie in the category of phenolic antioxidants. We also studied H-abstraction reactions from the phenolic groups of vanillin and ferulic acid by OH radicals and found the Gibbs free energy barriers at the BHandHLYP/6-31G(d,p) level of theory in the gas phase to be 10.1 and 9.3 kcal/mol respectively. In aqueous media, these barrier energies were found by single-point energy solvation calculations at the BHandHLYP/6-31G(d,p) level of theory employing the PCM to be 6.8 and 5.4 kcal/mol, respectively. In the case of H-abstraction from the OH group of phenol at the same level of theory in the gas phase and aqueous media, the Gibbs free energy barriers were found to be 8.2 and 10.3 kcal/mol, respectively, the latter of which corresponds to a rate constant of 0.4 1010 g mol1 s1compared to the experimental value of 1.0 1010 g mol1 s1.46 These results show that vanillin and ferulic acid can act as efficient phenolic antioxidants and that the theoretical calculations provide quite reasonable results in this regard.

4. CONCLUSIONS The present study leads to the following conclusions: (i) Single-electron transfer from curcumin to an OH radical should occur much more efficiently in water than in the gas phase. (ii) The formation of vanillin and ferulic acid could take place as a consequence of reactions involving OH radicals and curcumin or its degradation products. The reactions studied here include H-abstraction by OH radicals from curcumin or its degradation products and addition of OH radicals to curcumin or its degradation products at

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different stages. The most favored H-abstraction from curcumin by an OH radical would occur from the OH group attached to the C2 site of the molecule, whereas addition of an OH radical would be most favored at the C10 site of the heptadiene chain. Our theoretical findings in this regard are in agreement with experimental observations. (iii) On the whole, these reactions show how scavenging of eight OH radicals by curcumin or its degradation products, leading to the formation of two other antioxidants, namely, ferulic acid and vanillin, takes place. Thus, we found that curcumin should act as an efficient OH radical scavenger.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

’ ACKNOWLEDGMENT The authors are thankful to the University Grants Commission (New Delhi, India) and the Council of Scientific and Industrial Research (New Delhi, India) for financial support. ’ REFERENCES (1) Wiseman, H.; Halliwell, B. Biochem. J. 1996, 313, 17. (2) Jena, N. R.; Mishra, P. C. J. Phys. Chem. B 2005, 109, 14205. (3) Agnihotri, N.; Mishra, P. C. J. Phys. Chem. B 2009, 113, 3129. (4) Agnihotri, N.; Mishra, P. C. J. Phys. Chem. B 2010, 114, 7391. (5) Shukla, M. K.; Mishra, P. C. Spectrochim. Acta A 1995, 51, 831. (6) Agnihotri, N.; Mishra, P. C. J. Phys. Chem. B 2009, 113, 12096. (7) Tiwari, S.; Mishra, P. C. J. Mol. Model. 2011, 17, 59. (8) Shukla, M. K.; Mishra, P. C. J. Mol. Struct. (THEOCHEM) 1996, 377, 247. (9) Srivastava, S. K.; Mishra, P. C. Int. J. Quantum Chem. 1979, 16, 1051. (10) Kumar, A.; Mishra, P. C.; Suhai, S. J. Phys. Chem. A 2006, 110, 7719. (11) Nelson, R. L. Free Radical Biol. Med. 1992, 12, 161. (12) Omenn, G. S.; Goodman, G. E.; Thornquist, M. D. N. Engl. J. Med. 1996, 334, 1150. (13) Janero, D. R. Free Radical Biol. Med. 1991, 11, 129. (14) Butterfield, D. A. Chem. Res. Toxicol. 1997, 10, 495. (15) Fay, D. S.; Fluet, A.; Johnson, C. J.; Link, C. D. J. Neurochem. 1998, 71, 1616. (16) Feng, J.-Y.; Liu, Z.-Q. J. Agric. Food Chem. 2009, 57, 11041. (17) Surh, Y.-J. Nat. Rev. Cancer 2003, 3, 768. lvarez-Diduk, R.; Ramírez-Silva, M. T.; Alarcon-A (18) Galano, A.; A ngeles, G.; Rojas-Hernandez, A. Chem. Phys. 2009, 363, 13. (19) Sreejayan, N.; Priyadarshini, K. I.; Devasagayam, T. P. A.; Rao, M. N. A. Int. J. Pharmacol. 1997, 151, 125. (20) Egan, M. E.; Pearson, M.; Weiner, S. A.; Rajendran, V.; Rubin, D.; Glookner-Pagel, J.; Canny, S.; Du, K.; Lukacs, G. L.; Caplan, M. J. Science 2004, 304, 600. (21) Dickinson, D. A.; Levonen, A. L.; Moellering, D. R.; Arnold, E.; Zhang, K. H.; Darley-Usmar, V. M.; Forman, H. J. Free Radical Biol. Med. 2004, 37, 1152. (22) Wright, J. S. J. Mol. Struct. (THEOCHEM) 2002, 591, 207. (23) Gorman, A. A.; Hamblett, I.; Srinavasan, V. S.; Wood, P. D. Photochem. Photobiol. 1994, 59, 389. (24) Chignell, C. F.; Bilski, P.; Reszka, K. J.; Motlen, A. G.; Sik, R. H.; Dahl, T. A. Photochem. Photobiol. 1994, 59, 295. (25) Unnikrishnan, M. K.; Rao, M. N. A. Mol. Cell. Biochem. 1995, 146, 35. 14231


The Journal of Physical Chemistry A (26) Anto, R. J.; Kuttan, G.; Babu, K. V. D.; Rajasekharan, K. N. Int. J. Pharm. 1996, 131, 1. (27) Priyadarshini, K. I. Free Radical Biol. Med. 1997, 23, 1997. (28) Sreejayan, N.; Rao, M. N. A. J. Pharm. Pharmacol. 1997, 49, 105. (29) Venkatesan, N. Br. J. Pharmacol. 1998, 124, 425. (30) Jovanovic, S. V.; Steenken, S.; Boone, C. W.; Simic, M. G. J. Am. Chem. Soc. 1999, 121, 9677. (31) Barclay, L. R. C.; Vinqvist, M. R.; Mukai, K.; Goto, H.; Hashimoto, Y.; Tokunaga, A.; Uno, H. Org. Lett. 2000, 2, 2841. (32) Litwinienko, G.; Ingold, K. U. J. Org. Chem. 2004, 69, 5888. (33) Sun, Y.-M.; Zhang, H.-Y.; Chen, D.-Z.; Liu, C.-B. Org. Lett. 2002, 4, 2909. (34) Lee, C.; Yang, W.; Parr, R. G. Phys. Rev. B 1988, 37, 785. (35) Becke, A. D. J. Chem. Phys. 1993, 98, 5648. (36) Miertus, S.; Scrocco, E.; Tomasi, J. Chem. Phys. 1981, 55, 117. (37) Cossi, M.; Scalmani, G.; Rega, N.; Barone, V. J. Chem. Phys. 2002, 117, 43. (38) Szori, M.; Fittschen, M. C.; Csizmadia, I. G.; Viskolcz, B. J. Chem. Theor. Comput. 2006, 2, 1575. (39) Gonzalez, C.; Schlegel, H. B. J. Chem. Phys. 1989, 90, 2154. (40) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.11.2; Gaussian, Inc.: Pittsburgh, PA, 2001. (41) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K. N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.; Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian 03, revision D.01; Gaussian, Inc.: Wallingford CT, 2004. (42) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N. ; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C; Jaramillo, J.; Gomperts, R. E.; Stratmann, O.; Yazyev, A. J.; Austin, R.; Cammi, C.; Pomelli, J. W.; Ochterski, R.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas, O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09, revision A.1; Gaussian, Inc.: Wallingford CT, 2009. (43) Frisch, A. E.; Dennington, R. D.; Keith, T. A.; Neilsen, A. B.; Holder, A. J. GaussView, revision 3.9; Gaussian, Inc.: Pittsburgh, PA, 2003.

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(44) Kolev, T. M.; Velcheva, E. A.; Stamboliyska, B. A.; Spiteller, M. Int. J. Quantum Chem. 2005, 102, 1069. (45) Pyton, F.; Sandusky, P.; Alworth, W. L. J. Nat. Prod. 2007 70, 143. (46) De, A. K.; Bhattacharjee, S.; Dutta, B. K. J. Hazard. Mater. 1999, 64, 91.

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Scavenging Mechanism of Curcumin Toward the Hydroxyl Radical: A

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