Mechanisms of Antioxidant Activities of Fullerenols from First

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A: Spectroscopy, Molecular Structure, and Quantum Chemistry

Mechanisms of Antioxidant Activities of Fullerenols from First Principles Calculation Zhenzhen Wang, Xingfa Gao, and Yuliang Zhao J. Phys. Chem. A, Just Accepted Manuscript • DOI: 10.1021/acs.jpca.8b06340 • Publication Date (Web): 23 Sep 2018 Downloaded from http://pubs.acs.org on September 25, 2018

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The Journal of Physical Chemistry

Mechanisms of Antioxidant Activities of Fullerenols from First Principles Calculation Zhenzhen Wang, †,§ Xingfa Gao,*,‡ and Yuliang Zhao*,† †

CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, Institute of

High Energy Physics, Chinese Academy of Sciences, Beijing, 100049, China. ‡

College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang,

330022, China. §

University of Chinese Academy of Sciences, Beijing, 100049, China.

ABSTRACT. Fullerenols possess excellent antioxidant activity, in which they can scavenge all of the major physiologically relevant reactive oxygen species (ROS). However, the underlying ROS-scavenging mechanisms of C60 fullerenols are not completely understood. Using density functional theory calculations, we investigated ·OH-, O2·−- and H2O2-scavenging mechanisms of C60 fullerenols and the correlations between hydroxyl distributions and radical-scavenging ability. For scavenging ·OH and O2·−, H· donation and electron transfer via hydrogen bonds, respectively, are the dominant mechanisms for C60 fullerenols. Although the obtained fullerenols simultaneously contain radicals and anions, there is an isolated OH anion, which possesses the activity of eliminating H2O2. The ·OH-scavenging activity depends on the distribution of hydroxyls, according to the calculations for ten C60(OH)24 isomers. Fullerenols, in which the

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distribution of hydroxyls leads to low redox potential (ε) values, possess high scavenging activity. For the nonmagnetic fullerenols, activity relies on the number of sp2 substructures, in which the greater their number is, the lower the activity of the fullerenols. The results will be of fundamental importance in understanding the antioxidant activities of fullerenols.

■ 1. Introduction

Reactive oxygen species (ROS) are a series of intermediates that are produced in the process of the reduction of O2. They mainly contain O2·−, ·OH and H2O2, which are strong oxidizing agents. Aerobic organisms generate ROS constantly. Normally, oxidation and antioxidation of living organisms maintain dynamic equilibrium, whereas when organisms are exposed to exogenous materials, the equilibrium is broken, and excess ROS are generated. They can attack almost all biological molecules, including DNA, thus leading to severe damage to organisms, such as senescence, cancer, cardiovascular disease, deformity, neurodegenerative disease, etc. Therefore, it is essential in biomedicine, especially for cancer chemotherapy, to develop a chemical species that can potentially scavenge ROS. Some fullerene derivatives, which mainly include tris-malonyl C60 (C3) and polyhydroxy fullerene (fullerenols), have excellent antioxidative activity via scavenging free radicals.1-11 Fullerenols, which have attached hydroxyl groups (-OH) on fullerene cages, have moderate water solubility and biocompatibility.12-14 L. Y. Chiang et al. first found that fullerenols have potential antioxidative properties by which they can scavenge superoxide radical anions (O2·−) generated by xanthine and the xanthine oxidase system.15 This is especially true for C60(OH)22, which can scavenge 1O2, O2·− and ·OH.16 The antioxidant properties and negligible toxicity of fullerenols have also been substantially described in some review papers.7,8,17-19 Investigations in


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vitro have shown that fullerenols can protect cells from oxidative stress induced by H2O2 and superoxide dismutase (SOD), prevent intervertebral disk degeneration and the oxidation of glutathione (GSH), decrease hepatic lipid peroxidation, and inhibit apoptosis induced by ionizing radiation.8,20-24 Thus, fullerenols could be used as a drug to treat diseases.25-29 Experiments in vivo have also demonstrated that fullerenols can reduce oxidative stress in dogs during small intestine transplantation.30 Injac, R. and coworkers found that pretreatment of Wistar rats with C60(OH)24 notably counteracts the harmful effect of doxorubicin (DOX), which is one of the most widely used drugs in chemotherapy. The possible protective role of fullerenols depends on scavenging of ROS induced by DOX.31-33 Nerve cells are lipid rich and vulnerable to ROS. Fullerenols can reduce excitotoxicity induced by neuronal death by up to 80% in mice via the elimination of ROS. Thus, fullerenols could be used to treat neurodegenerative diseases (such as Parkinson’s disease and Alzheimer’s disease34). Because of the presence of connecting polar groups (-OH) on the surface of fullerene, fullerenols can be used as “anchor” molecules interacting with erythrocyte cytoskeletal proteins, prolonging the residence time of drugs.35 Recently, Gd@C82(OH)22 nanoparticles developed by Zhao and co-workers,36 were found to not only exhibit strong MRI relaxivity but also inhibit the growth of hepatoma cells by reducing tumor-induced oxidative stress rather than directly killing tumor cells.37,38 Furthermore, Gd@C82(OH)22 nanoparticles exhibit very high anti-tumor activity but low toxicity,39,40 and their properties and biological effects have been reviewed by Meng and Zhao et al.41 Despite their great pharmacological potential, little is known about the mechanisms of their ROS-scavenging activities. The OH-scavenging mechanism could occur in one of two ways. Experiments have shown that fullerenols may donate the hydrogen atom of a hydroxyl group to interact with ·OH or donate the olefinic double bonds between carbon atoms to add ·OH.42,43 However, it is unclear


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which way is dominant. The O2·−- and H2O2-scavenging mechanisms by C60 fullerenols have not been investigated. Furthermore, Nel and co-workers considered that the nanoparticle structure has a significant effect on bioactivity.44 Fullerenols have different numbers and distributions of hydroxyl groups, which could noticeably affect their reactivity, stability and optical properties.45 Experiments have indicated that C60(OH)12-14 is insoluble in water and has no biological activity. However, fullerenols, which contain 18-24 or 30-38 hydroxyl groups, exhibit antiviral activity, and the activity of the former is higher than that of the latter.46 Thus, it is extremely important to understand the relationship between the configuration of fullerenols and their antioxidative properties for application in the field of biomedicine. In this work, we investigate ROS (O2·−, ·OH and H2O2)-scavenging mechanisms for C60 fullerenols and the relationship between fullerenol structure and radical-scavenging ability using density functional theory calculations. This work will provide atomic insights into the antioxidant properties of fullerenols. This is also a basis for the investigation of anticancer and antitumor drugs of fullerenols. ■ 2. Methods The Density Functional Theory (DFT) and B3LYP methods47 were employed to obtain all structures. The geometry optimizations and frequency analysis were performed using the 631G(d,p)48 basis set in the gas phase. To consider the solvent effects, single-point energy calculations were performed with the B3LYP/6-31+G(d,p) method and PCM solvent model on the basis of the optimized geometries. All values in the work are Gibbs free energies. All calculations were performed using the GAUSSIAN 09 package.49 Calculation of ε is similar to our previous work.11


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■ 3. Results and Discussion 3.1. The mechanism of ·OH scavenging by fullerenols. To understand the chemical origin of ·OH-scavenging activity by C60 fullerenols, the reactions via the direct-addition and H·-donation pathways are both studied (Figure 1). The addition of ·OH to C60 yields ·C60OH with ∆G = –43.1 kcal·mol-1. Because the abstraction of one electron from C60 is endothermic with ∆G = 36.6 kcal·mol-1 in water, direct addition should be the exclusively dominant pathway for C60 to scavenge ·OH. The subsequent reactions of ·OH with ·C60OH are exothermic via both pathways. The direct addition and H· donation afford C60 fullerenols (6,6-vic-diols in figure 1a) and C60 ether as the lowest-energy products, respectively. Interestingly, H· donation is more energetically favorable than direct addition by 11.0 kcal·mol-1 (Figure 1a). Next, C60 6,6-vic-diol donate H·, which yields C60-6,6-hemiacetal radicals. H· donation was also more favorable in the reactions of ·OH with C60-6,6-hemiacetal radicals (Figure 1b). Therefore, although both pathways principally work because of the extremely high reactivity of ·OH, for C60 fullerenols with many OH groups, the H·-donation pathway will prevail because the sp2 carbons of C60 cores are in the minority and shielded by the outer OH groups. Considering that fullerenols with few OH groups easily aggregate in water, their ability to accept direct additions will be dramatically lowered, and H· donation will be the dominant ·OHscavenging mechanism. This is consistent with our previous calculation that C60 fullerenols have reducibility and easily donate H· to O2.11


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HO

OH

∆G = −43.1

C 60

∆G = −60.3 C 60-6,6-vic-diols C 60OH

OH H 2O

O HO

(b)

HO

O

OH

∆G = −49.3

HO

OH

(a)

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OH

O

C60 ether

OH ∆G = −52.6 ∆G = −61.9

C60-6,6-hemiacetal OH radical

C 60O(OH)2 O

O

H 2O

C 60O 2

Figure 1. Reactions energies of C60 species with ·OH via the direct-addition and H·-abstraction mechanisms. Unit in kcal·mol-1. Gao et al. proposed a principle that regulates the band gap of graphene via hydrogenation. They concluded that the band gap of graphene will increase with an increase in the number of nonmagnetic sp2 substructures.50 For fullerenols, hydroxyl radical-scavenging activity has a direct relationship with the band gap. Thus, according to this principle, C60 is divided into ten different electronic states, which are divided into three groups, i.e., a-c contain four single electrons, d-f contain two single electrons and g-j have no single electrons (Figure 2). The unit cells of sp2 substructures for every configuration are also given in Figure 2. The total number of sp2 substructures is listed in Table 1. To obtain the change in the Gibbs free energy of ·OH scavenging using the H·-extraction mechanism, their corresponding radical structures were also calculated, in which one H· is seized from the site of high spin density for a-f and the site of high negative charge for g-j. The corresponding radical structures are depicted in Figure S1, in which a, d, f, h and i form 5,6-hemiacetal, b forms epoxy, c and e form ether, g forms 6,6-hemiacetal and j forms an oxygen radical. The relative Gibbs free energy of C60(OH)24 and its corresponding


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radical are given in Table S1. In general, the lower the number of single electrons in fullerenols is, the more stable their structures.

Figure 2. Skeletal structures of unit cells of C60(OH)24. Dark spots and blue spots show the site of hydroxyls and single electrons, respectively. Red, green and pink display sp2-substructures isolated by hydroxyl, which are benzenoid-, ethene- and other π-conjugate units, respectively. Words below the figure depict names and numbers of sp2-substructures of every configuration. The calculated free energies of reactions are listed in Table 1. Apparently, all ten fullerenols have negative reaction energies, with ·OH-scavenging activity. Furthermore, the reaction energies strongly depend on the number of single electrons of C60(OH)24. That is, the hydroxyl radical-scavenging activity of C60(OH)24 increases with an increase in the number of single electrons. In nonmagnetic C60(OH)24 (g-j), the ·OH-scavenging activity decreases with an increase in the number of sp2 substructures. This is because the band gap of C60(OH)24 increases with the increase in the number of sp2 substructures, similar to graphene46, weakening the electron-losing ability of C60(OH)24. However, the principle is not applicable for ferromagnetic C60(OH)24 due to its special electronic structure.


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Table 1. Ground Electronic States, Numbers of Unpaired Electrons (Nu.e.), Numbers of sp2substructures (Ns), and Changes in Gibbs Free Energy (∆G) for the C60(OH)24 Isomers to Scavenge ·OH Species Statea Nu.e. Ns ∆G (kcal·mol−1) FM 4 10 −87.2 a FM 4 4 −78.7 b FM 4 14 −75.8 c FM 2 17 −75.2 d FM 2 2 −63.6 e FM 2 11 −62.5 f NM 0 6 −51.2 g NM 0 7 −49.0 h NM 0 8 −39.9 i NM 0 18 −24.9 j a NM and FM mean nonmagnetic and ferromagnetic, respectively.

Figure 3. The calculated redox potential (ε) and change in Gibbs free energy of scavenging ·OH using H·-extraction mechanism for ten different C60(OH)24. To find a method that can explain the correlation between all C60(OH)24 and ·OH-scavenging activity, the redox potential (ε) of ten different C60(OH)24 were calculated and are shown in Figure 3. Surprisingly, the ·OH-scavenging activity of fullerenols directly depends on the redox potential (ε). Fullerenols, which have low values of ε, simultaneously have low values of ∆G. Reducibility depends on the hydroxyl distributions of fullerenols. Fullerenols with unstable π-


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electron configurations on C60 cores have high reducibilities, i.e., high ·OH-scavenging activities. Fullerenol a, which contains 4 single electrons, has the lowest value of ε, possessing the strongest activity. However, the most feasible synthesis in this experiment, fullerenol g, which has the symmetry of D3, is the most appropriate configuration due to the stable electronic structure and strong ·OH-scavenging ability. 3.2. The mechanism of scavenging O2·− by fullerenols. C60 fullerenols, which contain π bonds, have the ability to accept electrons. Forró51, Gao, and the coworkers

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found that fullerenols also have acidity. Thus, these two properties of C60

fullerenols will be considered as relevant for O2·− scavenging. The scavenging mechanism of O2·− was studied for four simple but typical C60 fullerenols, k, l, m and n (Figure 4). k and l are vicdiols with OH groups located at the 6,6- and 5,6-ring junctions of C60 (6,6- and 5,6-vic-diols). m and n are diols with OH groups located -meta and -para in the 6-ring (m- and p-diols). k−, l−, m− and n− are formally conjugate bases. k− is a deprotonated vic-diol, l− is a hemiacetal, and m− and n− have an open-bonded ether. In our previous work, we found that k is the most thermodynamically stable compared to the others. The preference of the 6,6-adduct has been ascribed to the shorter bond length and thus higher reactivity of the 6,6-bond.52-54 k− is also the most thermodynamically stable of the corresponding conjugate bases. However, l− has nearly the same energy as k− in water. This could be because deprotonation induces the formation of an open-bonded hemiacetal, which releases the strain energy of the C60 core.


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Figure 4. Skeletal structures for C60 fullerenols (top) and the corresponding conjugated bases (bottom). 3.2.1. The C60 fullerenols scavenge O2·− via the acid ionization mechanism. The mechanism of O2·− scavenging was proposed (Table 2). The reactions mainly undergo three steps. (i) C60 fullerenols (FOHs) first afford H+ to O2·−, forming corresponding conjugate bases (FO−) and HOO·. (ii) Subsequently, FO− captures H+ from solvent to form FOH. (iii) The mutual collision of two HOO· yields O2 and H2O2. The first and second steps could easily be conducted at room temperature for the four FOHs (Table S2). The common result of these two steps is the generation of HOO· and H2O with a reaction energy of −52.6 kcal·mol-1. Then, as the reaction proceeds, the mutual collision of two HOO· yields O2 and H2O2 with a heat release of −27.1 kcal·mol-1. The overall reaction has a barrier of 33.3 kcal·mol-1, with ∆G = −139.6 kcal/mol (Table 2). This indicates that fullerenols could act as catalysts to eliminate O2·−, in which the reaction passes over a barrier of 33.3 kcal·mol-1. Table 2. Reactions via the Acid Ionization Mechanism and Their Gibbs Free Energy Changes ∆G (kcal·mol-1)

Reactions

1 FOH + O ∙ → FO + HOO ∙

∆G1a

2 FO + H O → FOH + H O

∆G2a


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∙ 3 O∙ + H O → HOO + H O

─56.2

4 2HOO ∙ → O + H O

─27.1

5 2O∙ + 2H O → O + H O + 2H O a

─139.6

Data present in the supporting information. 3.2.2. The C60 fullerenols accept electrons for O2·−-scavenging-addition reaction. Liu et al.

have demonstrated that the SOD activity of water-soluble fullerene depends on the first reduction potentials, charge and molecule structure based on experiments. The higher the first reduction potentials of fullerenols are, the stronger their SOD activity. The reduction potential corresponds to the ability to accept electrons, thus showing that electron transfer plays a crucial role in the process of O2·− scavenging. The measured first reduction potentials of some dendritic C60 monoadducts range from −0.585 to −0.077 V according to experiments.55 These values are among the range of the first reduction potentials of C60 fullerenols calculated in our previous investigation.11 Thus, for C60 diols, electron transfer from O2·− to C60 diols should be considered for SOD activity. The process of electron transfer may be conducted more than once. Furthermore, it should be considered that the transfer proceeds via carbon cage and hydrogen bond networks. The mechanism of transfer of electrons via carbon cage is depicted in Scheme 1. The process contains five steps: (i) electron transfer from O2·− to C60 diols to form O2 and C60 diol radical anions (int1), (ii) electron transfer from another O2·− to int1 to generate int2 with two negative charges, in which O2·− interacts with carbon cages, (iii) int2 captures one H+ from H3O+ such that int3 is formed, (iv) the isomerization of int3 releases H2O2 and FO− (int4), and (v) int4 seizes one H+ from H3O+ back to FOH. The changes of free energy in the first step are −1.9, −14.3, −16.1 and −6.2 kcal·mol-1 for the four FOHs (Table 3). The geometrical changes of


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reactants and products are relatively minor, and the reaction barrier is expected to be similar to the reaction energy. H 2O H 3O

O2

(v) [int4] H2 O2

O2

FOH

R

(i)

FO −

FHO

(iv)

[int1] O2

(ii)

(FO⋅⋅⋅⋅ OOH) − [int3]

(FO⋅⋅⋅⋅ OOH) 2− [int2]

(iii)

H2 O

H 3O

Scheme 1. C60 fullerenols mimic SOD enzyme via the electron transfer-O2·−-addition mechanism. Furthermore, as seen in Table 3, the LUMOs of C60 fullerenols are 0.97, 0.49, 0.38 and 0.88 eV higher in energy than the HOMO of O2·− (Table 3), in which fullerenols have a similar range of LUMO as tris-malonyl C60.56 Thus, reducibility and the difference between the LUMO of C60 fullerenols and the HOMO of O2·− are the main reason for electron transfer from O2·− to C60 fullerenols. After that, C60 fullerenols obtain one negative charge and one single electron. The Table 3. Changes in Gibbs free Energies Calculated in Gas Phase and Water (in Parentheses) for Reactions of Scheme 1. Species

∆G1a

∆G2a

∆G3a

∆G4a

Ts2

Ts4

Gaps

ε

(kcal·mol-1)

(kcal·mol-1)

(kcal·mol-1)

(kcal·mol-1)

(kcal·mol-1)

(kcal·mol-1)

(eV)b

(V)

−62.7

−4.7

−224.2

6.6

29.7

6.9 0.97

0.53

(−1.9)

(−10.0)

(−59.7)

(−8.2)

(18.4)

(3.1)

−75.0

−7.0

−228.3

−1.6

22.6

22.7 0.49

−0.39

(−14.3)

(−11.3)

(−62.0)

(−7.8)

(16.0)

(16.4)

−76.4

4.5

−230.5

−11.6

31.0

24.2 0.38

−0.23

(−16.1)

(2.2)

(−66.4)

(−16.2)

(28.1)

(20.8)

−66.2

5.5

−234.7

6.0 (2.1)

32.1

10.9

0.88

0.59

k

l

m

n


12

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(−6.2) a

(−1.1)

(−66.1)

(22.4)

(18.2)

∆G1 through ∆G4 are for reactions (i) through (iv) of Scheme 1, respectively; Ts2 and Ts4 are energy barriers of

reactions (ii) and (iv) of scheme 1. b

Energy differences between the LUMO of FOH and the HOMO of O2·−.

b)

a) + H2O2

OOH HO

+ H2O2

H

HO

O

O

16.4

ts3-2

int3-1

9.5

16.3

ts3-3

OH

ts3-4

O

int3-5

int3-4

0.0

−8.2

+ H2O2

26.9

16.4

3.1 ts3-1

+ H2O2

O

HO

0.0

O

H

OOH

OH

OH

O

int3-3

int3-2

−7.9 int3-6

c)

d)

HOO

20.8

HO OH

ts3-5

+ H2O2

HOO

O

+ H2O2

O

HO

OH

OH OH

0.0

4.6

int3-7

0.0 −16.2

O

19.0

int3-9

ts3-6

OH

ts3-7

0.8

2.1

int3-10

int3-11

+ H2O 2

int3-8

Figure 5. Reaction energy profiles for step iv of Scheme 1 for k, l m and n. Unit in kcal·mol-1. second step of the reaction is also electron transfer, in which another O2·− transfers an electron to C60 fullerenols to form int2 (FO ⋯ OOH via addition of oxygen to the surface of the carbon cage. The barriers of 18.4, 16.0, 28.1 and 22.4 kcal·mol-1 demonstrate that reactions can easily proceed in solution at 300 K. Next, int2 can easily obtain one H+ from the solvent to form int3 (Table 3). The rearrangement reaction of int3 generates H2O2 and FO−. (Figure 5) The barriers of rate-determining steps for the forward reactions for the four C60(OH)2 are 3.1, 16.4, 20.8 and 18.2 kcal·mol-1. However, the barriers of those of the reverse reactions are 11.3, 34.8, 37.0 and 16.9 kcal·mol-1, respectively. This indicates that isomerization for k and n is reversible, whereas it is irreversible for l and m. In reversible processes, the reaction maintains dynamic equilibrium.


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However, a forward reaction is expected, i.e., k and n are not the appropriate configurations for elimination of O2·−. l and m are in favorable configurations for scavenging O2·−. However, C605,6-sharing-H (int3-4 in Figure 5), formed in the fourth step of the reaction for l, is easily oxidized by H2O2 (Figure S2), which prevents the release of H2O2. Thus, m is the most effective structure for scavenging O2·− via this mechanism. 3.2.3. The C60 fullerenols accept electrons for O2·−-scavenging by hydrogen bond networks. The O2·−-scavenging mechanism is shown in Figure 6, in which C60-6,6-diol is an example. As O2·− interacts with hydroxyl to better form a H-bond network, four water molecules are added to the system. The reaction undergoes six steps: (i) and (ii) Electron transfer occurs from O2·− to fullerenols to form int5-2, and O2 is subsequently released via int5-2. (iii) The second O2·− transfers an electron to fullerenol to generate int5-4 by forming hydrogen bonds with hydroxyls. (iv) and (v) Fullerenol continuously transfers two H+ to O2·− via hydrogen bonds to form fullerenol anions and H2O2. (vi) Fullerenol anions capture two H+ from solvent, returning back to a pristine state (Figure 6). Because fullerenols can form hydrogen bonds with four water molecules (int5-1), the energy of reaction is an energy addition that contains int5-1 and two O2·−.


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Figure 6. Reaction energy profiles for C60-6,6-diol scavenges O2·− by hydrogen bond networks. Unit in kcal·mol-1. In the first step, fullerenols interact with O2·− via hydrogen bonds. The formed configuration of the intermediate is shown in Figure S3 for C60-6,6-diol with a slight energy increase of 1.1 kcal·mol-1 (Figure 6). The bond lengths among O2·−, four water molecules and fullerenol are also given in Figure S3, demonstrating that the interaction among them via formation of hydrogen bonds and electron transfer has not occurred. In the second step, electron transfer from O2·− to fullerenol forms O2 and another intermediate (int5-3). The step is endothermic by 3.3 (i.e., 4.41.1) kcal·mol-1, which is obviously lower than the reaction energy of electron transfer from O2·− to tris-malonyl C60.56 This demonstrates that fullerenols have a stronger ability to accept electrons than tris-malonyl C60. The barrier of electron transfer is considered to be similar to the reaction energy, as we discussed for the second mechanism. In the third step, another O2·− could interact again with int5-3 via a hydrogen bond. Electron transfer has not occurred. This step has a heat absorption of 13.0 (17.4-4.4) kcal·mol-1. The formed configuration of the intermediate (int5-4) is similar to int5-2, and the ground spin state is considered to be singlet, similar to the reaction of tris-malonyl C60. Then, proton transfer from fullerenol to O2·− could occur successively via two steps, finally forming H2O2. However, the energy convergence of the transition state becomes difficult due to the formation of many hydrogen bonds. Thus, the convergence criteria is reduced from 10-8 to 10-5. The obtained energy of the transition state is an approximate actual value, although there is always a small imaginary frequency. For the whole reaction, the barrier of the rate-determining step is no more than 21.5 kcal·mol-1, meaning that the mechanism is very feasible for C60-6,6-diol. In addition, the calculated energy profiles for the four fullerenols are shown in Figure S4. It is obvious that these reactions have low barriers for


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their rate-determining steps, in which the barriers are from 14.6 to 22.5 kcal·mol-1. Therefore, the four fullerenols could scavenge O2·− via the third mechanism, in which C60-6,6-diol is the most favorable configuration. For the three mechanisms of scavenging O2·−, the first mechanism has a relatively high barrier and is not considered to be favorable. Because the surfaces of fullerenols are occupied by many hydroxyls, the addition of O2·− to the carbon cage is difficult. Thus, the second mechanism is also not favorable. The third mechanism has a relatively low barrier and could occur for the four fullerenols. Thus, it is considered to be the most probable among the three mechanisms. 3.3. The mechanism of scavenging H2O2 by fullerenols 3.3.1. Model for C60 fullerenol-anions. These investigations demonstrated that C60 fullerenols exist in the form of radical anions in solution,55 in which deprotonated vic-diol, 5,6hemiacetal, 6,6-diols and some isolated OH are the dominant groups.11 Thus, the forms of anions or radicals of these groups should be considered as structures for scavenging H2O2. C60OH− and C60-5,6-hemiacetal anion were selected to be models for the reaction. The H2O2-scavenging mechanism of C60OH− is shown in Scheme 2. The reaction mainly undergoes three steps: (i) the substitution reaction, i.e., HOO of H2O2 substitutes OH of C60OH− to form C60OOH−, (ii) C60OOH− capture of one H+ from another H2O2 to give C60O (epoxy), H2O, and HOO−, and (iii) the interaction of C60O (epoxy) with HOO− to release O2 and C60OH−. The total reaction is as follows: 2H O → O + 2H O, in which C60OH− acts as a catalyst. The calculated energy profile is shown in Figure 7. The first step is the rate-determining step with a barrier of 21.1 kcal·mol-1. Thus, C60-isolated OH has H2O2-scavenging activity. The addition of H2O2 to C605,6-hemiacetal anions has a barrier of 35.2 kcal·mol-1, which demonstrates that C60-5,6hemiacetal anions have low H2O2-scavenging activity (Figure S5).


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Scheme 2. The proposed mechanism for H2O2-scavenging by C60 fullerenol-anion in alkaline condition. 3.3.2. Model for C60 fullerenol-radical. The H2O2-scavenging mechanism of C60OH· and the C60-5,6-hemiacetal radical is proposed in Scheme S1. C60OH· could seize ·OH via H2O2, forming C60, H2O and HOO· (i). The calculated barrier of free energy is 32.4 kcal·mol-1, demonstrating that the reaction is difficult at 300 K. C60-5,6-hemiacetal radicals have similar processes of reaction with C60OH·, in which C60O (epoxy) is generated with a barrier of 43.6 kcal·mol-1 (ii). Then, C60O could interact with HOO·, and C60OH· is formed with a barrier of 22.4 kcal·mol-1. Thus, the barrier of the rate-determining step is 43.6 kcal·mol-1, indicating that C60-5,6hemiacetal radicals do not scavenge H2O2. Thus, in alkaline media, only isolated OH among C60 fullerenols has H2O2-scavenging activity. Both anions and radicals of 5,6-hemiacetal could not eliminate H2O2.


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21.1 ts6-1 0.0 int6-1 + 2H2O2 HO

16.7

13.8 ts6-2

int6-2 + H2O + H2O2 OOH

32.0 ts6-3

50.9 int6-3 + 2H2O + HOO O

81.7 int6-1 + 2H2O + O2

Figure 7. The proposed mechanism for H2O2-scavenging by C60 fullerenol-anion in alkaline condition. Unit in kcal·mol-1. ■ 4. Conclusions Fullerenols have excellent ROS-scavenging activity. The ·OH-scavenging mechanism has two pathways, i.e., ·OH addition and H· donation. Considering that fullerenols with few OH groups easily aggregate in water, their abilities to accept direct additions will be dramatically lowered, and H· donation will be the practically dominant ·OH-scavenging mechanism for C60 fullerenols. The ·OH-scavenging activity depends on the distribution of hydroxyls for ten C60(OH)24. Fullerenols, which have low redox potential (ε) values, possess high scavenging activity. For the nonmagnetic fullerenols, the activity relies on the number of sp2 substrates, in which the more there are, the lower the activity of fullerenols. The O2·−-scavenging may occur via three different mechanisms, i.e., (i) the acidity of fullerenols leads to elimination of O2·−, although the process has a high barrier; (ii) electron transfer occurs from O2·− to fullerenols, in which the second step transfer occurs via addition reaction of O2·− to fullerenols; and (iii) electron transfer occurs from O2·− to fullerenols via


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hydrogen bond networks. Because many hydroxyls occupy the surface of carbon cages, the addition of O2·− will become difficult. Elimination via hydrogen bonds (the third mechanism) will become the primary mechanism, in which fullerenols a-d have low barriers, possessing scavenging activity. Fullerenols, which were obtained in alkali and oxidizing conditions, simultaneously contain radicals and anions, in which hydroxyls and 5,6-hemiacetals are the dominant groups. The radical and anion forms of these two groups are considered to eliminate H2O2. However, there is an isolated OH anion, which possesses the activity of eliminating H2O2. This work will provide atomic level insights into the antioxidative activity of fullerenols.

■ ASSOCIATED CONTENT

Supporting Information. The Supporting Information is available free of charge on the ACS Publications website. Figures S1-S5, Tables S1 and S2, Schemes S1 and optimized structure for C60(OH)2 [k-l] and C60(OH)24 [a-j] (file type, i.e., PDF)

■ AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]; [email protected]. ORCID


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Xingfa Gao: 0000-0002-1636-6336 Notes The authors declare no competing financial interest. ■ ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (NSFC) Project (21373226) ■ REFERENCES (1) Zhou, Y.; Zhen, M.; Ma, H.; Li, J.; Shu, C.; Wang, C. Inhalable gadofullerenol/[70] fullerenol as high-efficiency ROS scavengers for pulmonary fibrosis therapy. Nanomednanotechnol. 2018, 14, 1361-1369. (2) Sachkova, A. S.; Kovel, E. S.; Vorobeva, A. A.; Kudryasheva, N. S. Antioxidant Activity of Fullerenols. Bioluminescent Monitoring in vitro. Proc. Tech. 2017, 27, 230-231. (3) Kudryasheva, N. S.; Kovel, E. S.; Sachkova, A. S.; Vorobeva, A. A.; Isakova, V. G.; Churilov, G. N. Bioluminescent Enzymatic Assay as a Tool for Studying Antioxidant Activity and Toxicity of Bioactive Compounds. Photochem. Photobiol. 2017, 93, 536-540. (4) Dubinina, I. A.; Kuzmina, E. M.; Dudnik, A. I.; Vnukova, N. G.; Churilov, G. N.; Samoylova, N. A. Study of antioxidant activity of fullerenols by inhibition of adrenaline autoxidation. Nanosyst-Phys. Chem. M 2016, 7, 153-157. (5) Sachkova, A. S.; Kovel, E. S.; Churilov, G. N.; Guseynov, O. A.; Bondar, A. A.; Dubinina, I. A.; Kudryasheva, N. S. On mechanism of antioxidant effect of fullerenols. Biochem. Biophys. Rep. 2017, 9, 1-8. (6) Wang, Z. Z.; Wang, S. K.; Lu, Z. H.; Gao, X. F. Syntheses, Structures and Antioxidant Activities of Fullerenols: Knowledge Learned at the Atomistic Level. J. Clust. Sci. 2015, 26, 375-388. (7) Grebowski, J.; Kazmierska, P.; Krokosz, A. Fullerenols as a New Therapeutic Approach in Nanomedicine. BioMed Res. Int. 2013. 751913. (8) Rade Injac, M. P., and Borut Strukelj: In Oxidative Stress and Nanotechnology: Methods and Protocols; Armstrong, D., Bharali, Dhruba J Ed.; Springer Science+Business Media: New York, 2013; Vol. 1028; pp 75-100. (9) Djordjevic, A.; Srdjenovic, B.; Seke, M.; Petrovic, D.; Injac, R.; Mrdjanovic, J. Review of Synthesis and Antioxidant Potential of Fullerenol Nanoparticles. J. Nanomater. 2015. Article ID 567073. (10) Sun, T.; Xu, Z. D. Radical scavenging activities of alpha-alanine C60 adduct. Bioorg. Med. Chem. Lett. 2006, 16, 3731-3734. (11) Wang, Z. Z.; Chang, X. L.; Lu, Z. H.; Gu, M.; Zhao, Y. L.; Gao, X. F. A precision structural model for fullerenols. Chem. Sci. 2014, 5, 2940-2948.


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Mechanisms of Antioxidant Activities of Fullerenols from First

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