Actual Structure, Thermodynamic Driving Force, and Mechanism of

ARTICLE pubs.acs.org/JPCB

Actual Structure, Thermodynamic Driving Force, and Mechanism of Benzofuranone-Typical Compounds as Antioxidants in Solution Xiao-Qing Zhu,* Jian Zhou, Chun-Hua Wang, Xiu-Tao Li, and Sha Jing State Key Laboratory of Elemento-Organic Chemistry, Department of Chemistry, Nankai University, Tianjin 300071, China

bS Supporting Information ABSTRACT: 5,7-Ditert-butyl-3-(3,4-dimethylphenyl)benzofuran-2(3H)-one (HP-136) (1H) and its 30 analogues (2H5H) as benzofuranone-typical antioxidants were synthesized. The structures of the benzofuranones in solid and solution were examined by using experimental and theoretical methods. The results show that the dominant structure is the lactone form rather than the enol form both in solid and solution. The thermodynamic driving forces of the 31 benzofuranone-typical compounds to release protons [ΔGPD(XH)], hydrogen atoms [ΔGHD(XH)], and electrons [Eox(XH)] and the thermodynamic driving forces of the anions (X) of the benzofuranones to release electrons [Eox(X)] were determined for the first time in DMSO. The ΔGHD(XH) scale of these compounds in DMSO ranges from 65.2 to 74.1 (kcal/mol) for 1H4H and from 73.8 to 75.0 (kcal/mol) for 5H, respectively, which are all smaller than that of the most widely used commercial antioxidant BHT (2,6-ditert-butyl-4-methylphenol, 81.6 kcal/ mol), suggesting that the 31 XH could be used as good hydrogen-atom-donating antioxidants. The ΔGPD(XH) were observed to range from 11.5 to 16.0 (kcal/mol) for 1H4H and from 18.6 to 22.4 (kcal/mol) for 5H, indicating that benzofuranones (1H4H) are good proton donors, and their analogues (5H) should belong to middle-strong proton donors. Eox(XH) of the 31 XH to release an electron vary from 1.346 to 1.962 (V versus Fcþ/0), implying that the 31 XH are weak electron donors, whereas the quite negative Eox(X) show that X are good electron donors. The Gibbs free-energy changes of the radical cations (XHþ•) to release protons [ΔGPD(XHþ•)] were evaluated according to the corresponding thermodynamic cycle, and the results reveal that XHþ• are good proton donors. Further inspection of our experimental results showed the ΔGHD(XH), ΔGPD(XH), ΔGPD(XHþ•), Eox(XH), and Eox(X) of the five chemical and electrochemical processes are all linearly dependent on the sum of Hammett substituent parameters σ with very good correlation coefficients, indicating that for any one- or multisubstituted species at the para- and/or meta-position of benzofuranones and their various reaction intermediates, the five thermodynamic driving force parameters all can be easily and safely estimated from the corresponding Hammett substituent parameters. The rates of hydrogen atom transfer from XH to DPPH• were determined by using the UVvis absorption spectroscopy technique. Combining these important thermodynamic parameters and dynamic determination results, the mechanism of hydrogen transfer from HP-136 and its analogues to DPPH• was studied. The results suggest that the hydrogen transfer from HP-136 and its analogues 2H to DPPH• actually includes two steps, proton transfer and the following electron transfer, but the proton transfer is rate-determined.

’ INTRODUCTION Antioxidants are one class of very important compounds that can scavenge various harmful free radicals in chemical and biological process,1 such as food deterioration,2 chemical materials degradation,3 the oxidative damaging of DNA,4 amino acids,5 proteins and membrane lipids,6 aging,7 and some human disease.8 Due to their potential clinical significance, natural antioxidants, such as vitamin E,9,10 coenzyme Q,11 R-tocopherol12 and the related compounds, ascorbic acid,13 the flavonoids,14 stilbenes related to resveratrol,15 catechines16 which occur naturally in tea,17 glutathione and related thiols,18 and so forth have been widely studied by both experimental and theoretical methods. Recently, continual interest has been paid to the development of efficient manmade (synthetic) antioxidants, such as phenols,19 amines,20 benzenethiols,21 benzofuranones,22 naphthalene diols, and so on. Among the above-mentioned various manmade antioxidants, the r 2011 American Chemical Society

commercial 5,7-ditert-butyl-3-(3,4-dimethylphenyl)benzofuran2(3H)-one (HP-136) and its analogues as one type of very important carbon-centered radical antioxidant, due to their harmfulness to organic materials and high efficiency in inhibiting the degradation of oil and stabilizing the polymers at high temperature,22,23 have attracted much special attention of chemists, biochemists, and industrial chemists. By systematically examining the past publications on the chemistry of benzofuranone-typical compounds as antioxidants, it is found that although the structure of HP-136 and its analogues as antioxidants in solution, the reaction mechanism of HP-136 and its analogues with some radicals, the effect of solvent on the activity of benzofuranone-typical compounds as Received: January 5, 2011 Revised: February 21, 2011 Published: March 15, 2011 3588

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The Journal of Physical Chemistry B Scheme 1. Possible Antioxidation Mechanisms of HP-136 and Its Analogues

antioxidants, and the stability of the antioxidant-derived radicals in solution,24 as well as the application of benzofuranone-typical compounds as potential chain-breaking antioxidants25 have been extensively examined, there are many scientific problems about the chemistry of HP-136 and its analogues as antioxidants that are still unsolved, such as (1) the real structure of HP-136 and its analogues in solution as efficient antioxidants, that is, as the ketone form or enol form, (2) the mechanism of HP-136 and its analogues to release a hydrogen atom in antioxidation by one step or multiple steps, (3) how to scale the relative activity of various benzofuranonetypical compounds as chain-breaking antioxidants, (4) the effects of the position and nature of substituents at the benzofuranone benzene rings on the ability of benzofuranone-typical compounds as antioxidants, and so on. Especially, the most fundamental thermodynamic parameters, such as the thermodynamic driving forces of benzofuranone-typical compounds (XH) as antioxidants to release electrons, to release hydrogen atoms, and to release proton in solution, the thermodynamic driving force of the radical cations of benzofuranone-typical compounds (XHþ•) to release protons, and the thermodynamic driving force of the anion of benzofuranone-typical compounds (X) to release electrons in solution, are still quite rare to be systematically determined. Because the antioxidation process of benzofuranone-typical antioxidants could involve multistep mechanisms, such as Hþe and eHþ (Scheme 1) and the efficiency of the benzofuranone-typical antioxidants is not only dependent on their structures and thermodynamic driving forces but also on the antioxidation mechanism, it is clear that the lack of these fundamental thermodynamic parameters not only can cause difficulties to thoroughly elucidate the detailed mechanisms of HP-136 and its analogues in antioxidation reactions but also can induce a lot of difficulties to quantitatively scale the relative activities of HP-136 and its various analogues as benzofuranone-typical antioxidants and to design and synthesize novel benzofuranone-typical compounds as more efficient antioxidants with higher activity. Therefore, the determination of thermodynamic driving forces of HP-136 and its various analogues as well as their reaction intermediates to release an electron, to release a proton, and to release a hydrogen atom in solution has been a strategic goal in our research program for a long time. In this paper, six contributions can be provided: (1) 24 benzofuranones (1H4H) and 7 analogues (5H) (Scheme 2) were designed and synthesized according to convenient synthetic strategies. (2) The real structures of benzofuranone-typical compounds in solid and in

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Scheme 2. Structures and Numbers of HP-136 and Its Analogues Investigated in This Work

Figure 1. Absorption changes of methyl-9H-fluorene-9-carboxylate anion (ln) during the reaction with HP-136 in DMSO: (a) [ln] = 3.3 104 mol/L; (b) [ln] = 2.6 104 mol/L, with 8.0 108 mol/ L HP-136 added; (c) [ln] = 1.9 104 mol/L, with 1.6 107 mol/L HP-136 added; (d) [ln] = 1.2 104 mol/L, with 2.4 107 mol/L HP-136 added; (e) [ln] = 0.5 104 mol/L, with 3.2 107 mol/L HP-136 added; (f) [ln] = 3.1 107 mol/L, with 4.0 105 mol/L HP-136 added.

solution were discovered according to the crystal structure and IR of 3H (G = H) as well as the state Gibbs energy difference between the enol form and lactone form of the benzofuranones (XH) in solution. (3) Standard electrochemical characterization of the 31 benzofuranones (XH) and their corresponding anions (X) were examined by using the electrochemical methods of CV (cyclic votammetry) and OSWV (Osteryoung square-wave voltammetry), respectively. (4) The thermodynamic driving force of the 31 benzofuranones (XH) to release protons in DMSO was determined according to the proton exchange reaction thermodynamics of the 31 benzofuranones with a proton acceptor as a reference. (5) Thermodynamic driving forces of the 31 benzofuranones (XH) to release hydrogen atoms and the thermodynamic driving forces of the 31 XHþ• to release protons in DMSO were estimated quantitatively by using the thermodynamic cycle method according to Hess’ law. (6) The 3589

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The Journal of Physical Chemistry B

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Table 1. pKas of XH and Oxidation Potentials of XH and X in DMSO (V versus Fcþ/0) Eox(X)b

Eox(XH)b compounds

pKa(XH)a

CV

OSWV

CV

OSWV

HP-136 (1H)

9.56

1.541

1.518

0.585

0.626

10.72 9.82

1.372 1.501

1.346 1.487

0.789 0.633

0.826 0.670

2H (an) p-NMe2 p-OCH3 p-CH3

9.58

1.547

1.524

0.583

0.622

p-H

9.50

1.683

1.578

0.545

0.573

p-Cl

9.06

1.710

1.694

0.467

0.489

p-CF3

8.42

1.824

1.806

0.362

0.405

m-OCH3

9.23

1.668

1.659

0.510

0.556

m-CH3

9.50

1.549

1.531

0.522

0.598

m-Cl m-CF3

8.80 8.71

1.746 1.798

1.725 1.785

0.413 0.375

0.452 0.443

o-OCH3

11.67

1.522

1.505

0.576

0.617

o-CH3

10.55

1.562

1.552

0.475

0.554

o-Cl

9.95

1.729

1.713

0.480

0.509

o-CF3

9.76

1.857

1.849

0.364

0.428

OCH3

9.31

1.540

1.520

0.562

0.563

CH3

9.28

1.628

1.616

0.501

0.501

H Cl

9.10 8.88

1.685 1.874

1.668 1.869

0.450 0.391

0.439 0.347

Br

8.51

1.893

1.882

0.323

0.311

OCH3

8.79

1.815

1.807

0.440

0.434

CH3

9.02

1.659

1.648

0.492

0.490

Cl

8.65

1.927

1.917

0.341

0.337

Br

8.43

1.976

1.962

0.354

0.308

16.32 16.24

1.421 1.472

1.415 1.457

0.757 0.746

0.734 0.753

Figure 2. Cyclic voltammetry (CV) (solid line) and Osteryoung square wave voltammetry (OSWV) (dash line) of HP-136 (1H) for its electronchemical oxidation in DMSO (M = 2.4 103 mol/L).

3H (ae)

4H (ad)

Figure 3. CV (solid line) and OSWV (dash line) of the anion of HP136 (1) for its electrochemical oxidation in DMSO (M = 1.2 103 mol/L); the anion is formed in situ from the reaction of HP-136 with KH in DMSO.

5H (ag) p-OCH3 p-CH3 p-H

15.15

1.479

1.469

0.672

0.696

p-Cl

14.07

1.703

1.684

0.615

0.628

m-OCH3

14.49

1.598

1.582

0.677

0.681

m-CH3

15.77

1.479

1.462

0.703

0.716

m-Cl

13.61

1.740

1.722

0.598

0.607

a

pKas were measured in DMSO at 298 K, and the indicators (HIn) were FH, 9-nitrile-FH, and 9-methyl formate FH. b Measured by CV and OSWV methods in DMSO at 298K; the unit in volts versus Fcþ/0 and reproducible to 5 mV or better.

detailed mechanistic steps of hydrogen atom transfer from the benzofuranones to DPPH•, a well-known radical, in solution were elucidated according to the determined thermodynamic driving forces together with some kinetic parameters of the relative reactions.

Figure 4. UV spectral changes of DPPH• (519 nm) (1 104 mol/L) for the reaction of DPPH• (519 nm) (1 104 mol/L) with HP-136 (2 103 mol/L) in DMSO and under the aid of Mg(ClO4)2 (1.0 103 mol/L) at 298 K.

’ RESULTS HP-136 (1H) and its 30 analogues (2H5H) shown in Scheme 2 were synthesized according to the literature methods,26,27 and the structures were identified by 1H NMR and MS (Supporting Information). The pKa values of XH (1H5H) in

DMSO were measured by using the overlapping indicator method at 25 °C,28 which is based on the proton exchange equilibrium between XH and a proton acceptor as indicators. Figure 1 is an example to show the UV/vis absorption changes of the methyl-9Hfluorene-9-carboxylate anion (ln) as an indicator in DMSO when the different amounts of HP-136 were added into the reaction 3590



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Table 2. Thermodynamic Driving Forces of HP-136 and Its Analogues (XH) to Release Hydrogen Atoms and Protons, Thermodynamic Driving Forces of XHþ• to Release Protons in DMSO (kcal/mol), and Redox Potentials of XH and X in DMSO (V versus Fcþ/0) ΔGHD

ΔGPD

a

b

ΔGPD þ• c

Eoox

Eoox d

(X)d

compounds

(XH)

(XH)

(XH )

(XH)

HP-136 (1H)

68.2

13.1

36.3

1.518

0.626

p-NMe2

65.2

14.7

35.4

1.346

0.826

p-OCH3

67.6

13.5

36.2

1.487

0.670

p-CH3

68.3

13.1

36.4

1.524

0.622

p-H

69.4

13.0

36.6

1.578

0.573

p-Cl

70.7

12.4

37.9

1.694

0.489

p-CF3

71.7

11.5

39.5

1.806

0.405

m-OCH3 m-CH3

69.4 68.8

12.6 13.0

38.5 36.1

1.659 1.531

0.556 0.598

m-Cl

71.2

12.1

38.1

1.725

0.452

2H (an)

m-CF3

71.4

12.0

39.4

1.785

0.443

o-OCH3

71.3

16.0

32.9

1.505

0.617

o-CH3

71.3

14.5

34.1

1.552

0.554

o-Cl

71.4

13.6

37.6

1.713

0.509

o-CF3

73.1

13.4

39.1

1.849

0.428

OCH3 CH3

69.4 70.7

12.8 12.7

35.2 36.1

1.520 1.616

0.563 0.501

H

71.9

12.5

36.1

1.668

0.439

Cl

73.8

12.2

38.9

1.869

0.347

Br

74.1

11.7

38.9

1.882

0.311

OCH3

71.6

12.0

39.7

1.807

0.434

CH3

70.7

12.4

36.9

1.648

0.490

Cl Br

73.7 74.0

11.9 11.5

40.1 40.8

1.917 1.962

0.337 0.308

p-OCH3

75.0

22.4

27.2

1.415

0.734

p-CH3

74.4

22.2

28.8

1.457

0.753

p-H

74.3

20.8

29.1

1.469

0.696

p-Cl

74.4

19.3

34.0

1.684

0.628

m-OCH3

73.8

19.9

32.3

1.582

0.681

m-CH3

74.7

21.6

28.6

1.462

0.716

m-Cl

74.2

18.6

35.1

1.722

0.607

3H (ae)

4H (ad)

respectively (Figures 24). The detailed results are also summarized in Table 1. The thermodynamic driving forces of XH to release protons and to release hydrogen atoms and the thermodynamic driving forces of XHþ• to release protons in this work are all defined as the Gibbs free-energy changes of the corresponding dissociation processes in DMSO, which can be obtained from the pKa values of XH and the redox potentials of relative species according to the corresponding eqs 13, respectively; eqs 13 were all derived from the related thermodynamic cycles according to Hess’s law. The detailed results of the three thermodynamic parameters are listed in Table 2. ΔGPD ðXHÞ ¼ 1:37pKa ðXHÞ

ð1Þ

ΔGHD ðXHÞ ¼ ΔGPD ðXHÞ 23:06½Ered ðHþ Þ Eox ðX Þ ð2Þ ΔGPD ðXHþ• Þ ¼ ΔGHD ðXHÞ þ 23:06½Ered ðHþ Þ Eox ðXHÞ ð3Þ The reactions of HP-136 and its analogues (XH) with DPPH•, a well-known radical, in dry DMSO solution were examined; the result yields two products, DPPHH and the dimer of X• (X2) (eq 4). From eq 4, it is clear that the reaction was carried out by a formal hydrogen atom transfer from XH to DPPH•; the formed radical X• then became X2 by dimerization. The rate of the hydrogen atom transfer was determined by monitoring the spectra change of DPPH• at λmax = 519 nm (Figure 5), and the second-order rate constants (k2) are summarized in Table 3.

5H (ag)

The data were calculated from eq 2, taking E(Hþ/0) = 3.017 in DMSO (V versus Fc), which was derived from the literature.29 Relative uncertainties were estimated to be smaller than or close to 1 kcal/mol in each case. b The data were calculated from eq 1. c The data were calculated from eq 3, taking E(Hþ/0) = 3.017 in DMSO (V versus Fc).29 Relative uncertainties were estimated to be smaller than or close to 1 kcal/mol in each case. d The values derived by OSWV were chosen as the standard redox potentials of XH and X in DMSO because the values from OSWV were identified to be closer to the corresponding standard redox potentials than the values from CV.30 a

system. The pKa values of 31 benzofuranone-typical compounds in DMSO are summarized in Table 1. The oxidation potentials of XH and X in DMSO were determined by using CV and OSWV,

’ DISCUSSION 1. Actual Structure of Benzofuranones in Solid and in DMSO. From the previous reports on the structure of the

solvated HP-136 series, there seems to be two mutually conflicting views; one view thinks that the dominant structure of the HP136 series is a lactone form,31 but the other view thinks that the dominant structure of HP-136 series compounds should be an enol form (see Scheme 3).24,3234 To discover the real structure of the benzofuranone-typical compounds, the crystal structure of 3H (G = H) is examined for the first time (Scheme 4). From the crystal graph of 3H (G = H), 3591



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it is clear that the bond length between C8 and O2 is 1.1965 Å, which is close to that of the CdO double bond (1.23 Å) but quite smaller than that of the CO single bond (1.36 Å). Meanwhile, the bond length between C7 and C8 is 1.5244 Å, quite close to that of the general CC single bond (1.54 Å) but far longer than that of the general CdC double bond.32 These results strongly suggest that the real structure of HP136 series compounds in solid should be the lactone form rather than the enol form. To further support this conclusion, the IR of the parent compound was examined also. From the IR graph (Scheme 4), it is clear that the strong signal at Table 3. Reaction Rate Constants s of HP-136 and Its Analogues (2H) with DPPH• in DMSO XH

k2 (M1 s1)

k2 (M1 s1) (Mg2þ)

HP-136

0.696

0.009

p-NMe2

0.213

0.010

p-OCH3

0.542

0.012

p-CH3

0.752

0.045

p-H p-Cl

1.352 2.225

0.099 0.265

p-CF3

2.730

0.485

m-OCH3

1.747

0.082

m-CH3

1.167

0.129

m-Cl

2.614

0.475

m-CF3

2.534

0.331

o-OCH3

0.351

0.028

o-CH3 o-Cl

0.526 1.474

0.036 0.089

o-CF3

1.890

0.117

2H

Scheme 3. Tautomerism of Benzofuranone in DMSO

1600 cm1 is due to the CdO bond, and there is no obvious signal between 3400 and 3600 cm1, implying no OH bond in 3H (G = H) in the solid state. Because the real structure of the benzofuranones in crystals has been verified to be a lactone form rather than an enol form, it should be beyond doubt that the real structure of the benzofuranones in solution, such as in acetonitrile solution that the crystal of 3H (G = H) was formed, is also the lactone form rather than the enol form. The reason is that during the growing process of the crystal of 3H (G = H), the structure of 3H (G = H) is impossible to change. In order to further support our view, the Gibbs free-energy changes of benzofuranones (XH) and their corresponding radical cations (XHþ•) for the tautomerization from the lactone form to the enol form in DMSO were estimated by using DFT method and the PCM cluster continuum model; the calculated results are summarized in Table 4. From Table 4, it is clear that in DMSO, the Gibbs statement energy of HP-136 with the enol form is higher than that with lactone form by 9.0 kcal/mol, that is, the equilibrium constant for the tautomerization of HP-136 from the lactone form to the enol form is 2.53 107. In usual experiments on the kinetics of HP-136 as an antioxidant, the concentrations of HP-136 were generally smaller than 1 104 M, which means that the actual concentration of HP-136 with the enol form in the kinetic experiments was smaller than 2.53 1011 M. Such a low concentration of HP-136 with the enol form in solution could not be detected by any UV instrument until now. It is evident that as in the crystal state, the real structure of benzofuranone-typical compounds in solution is also the lactone form rather than the enol form. However, in the previous papers,24 Scaiano and co-workers thought that the efficient structure of lactone antioxidants should be attributed to the enol form rather than to the lactone form. We think that this view is incorrect. However, if the Gibbs statement energy of the radical cation of HP-136 in DMSO were examined (Scheme 5), it would have been found that the Gibbs statement energy of the enol form was lower than that of the corresponding lactone form by 14.0 kcal/mol, which means that the dominant structure of radical cation of HP-136 in DMSO should be the enol form rather than the lactone form. This result indicates that if the antioxidation of HP-136 were initiated by electron transfer, the enol structure of HP-136 could be involved. However, for most antioxidation reactions with HP-136, it was found that no reaction is initiated by electron transfer because the oxidation potential of HP-136 is too high (1.514 V versus Fc).

Scheme 4. Crystal Structure and IR of 3H (G = H)

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Table 4. Gibbs Free-Energy Changes of Benzofuranones (XH) and Their Corresponding Radical Cations (XHþ•) for the Tautomerization from the Lactone Form to the Enol Form in DMSO compounds

ΔΔG(XH)a

ΔΔG(XHþ•)b

HP-136 (1H)

9.0

14.0

p-NMe2

9.6

14.4

p-OCH3

9.8

13.5

10.2

13.1

p-H

8.8

13.0

p-Cl

8.8

12.6

p-CF3 m-OCH3

6.8 9.0

11.6 11.9

m-CH3

8.1

12.7

m-Cl

8.1

12.2

m-CF3

8.1

11.7

o-OCH3

8.5

11.6

o-CH3

8.7

11.8

Scheme 5. Comparison of the Gibbs State Energy between the Enol Form and Lactone Form of HP-136 and Its Radical Cation in DMSO

2H (an)

p-CH3

o-Cl o-CF3

10.4

8.3

8.9

10.0

9.7

13.5

3H (ae) OCH3

10.2

9.7

8.5

18.0

Cl

8.0

18.4

Br

7.9

17.8

CH3 H

4H (ad) 8.4

5.0

10.9 7.6

8.7 14.4

8.6

9.3

p-OCH3

11.1

10.4

p-CH3

10.2

9.7

p-H

10.7

8.4

OCH3 CH3 Cl Br 5H (ag)

p-Cl

10.6

8.4

m-OCH3

10.6

8.7

m-CH3 m-Cl

10.3 10.7

7.8 7.5

ΔΔG(XH) = ΔG°enol(XH) ΔG°ketone(XH), in units of kcal/mol. ΔΔG(XHþ•) = ΔG°enol(XHþ•) ΔG°ketone(XHþ•), in units of kcal/ mol, unit in kcal/mol. a b

2. Thermodynamic Driving Forces of HP-136 and Its Analogues to Release Hydrogen Atoms in DMSO. As it is

well known, the hydrogen-atom-donating ability of antioxidants is a crucial thermodynamic parameter for evaluating their antioxidation activity. In this work, we define the Gibbs free-energy change of HP-136 and its analogues to release hydrogen atoms in DMSO (ΔGHD, step a in Scheme 1) as their thermodynamic driving forces to release hydrogen atoms in DMSO and use this parameter to describe their hydrogen-atom-donating ability. From the second column in Table 2, it is clear that the ΔGHD scale of HP-136 and its 30 analogues (2H5H) in DMSO ranges from 65.2 kcal/mol for 2H (G = p-NMe2) to 75.0 kcal/mol for 5H

(G = p-CH3O). Because ΔGHD values of HP-136 and its 30 analogues (Scheme 2) are generally much smaller than or close to those of vitamin E (80.9 kcal/mol33), commercial widely used antioxidant BHT (2,6-ditert-butyl-4-methylphenol, 81.6 kcal/ mol34), and penothiazine (79.7 kcal/mol35), these compounds should belong to good or excellent hydrogen atom donors, which can be used as good antioxidants to quench some well-known radicals, such as HO•, NH2•, O•, (CH3)3Si•, HOO•, PhNH•, NH2NH•, PhO•, i-C3H7OO•, PhS•, (CH3)3Ge•, and (CH3)3Sn•. However, for the other radicals, such as TEMPO•, i-ASC•, O2•, and so on, HP-136 and its 30 analogues (2H5H) cannot quench them (Table 5). To intuitively compare the hydrogen-atom-donating abilities of benzofuranone-typical compounds as antioxidants with the common organic antioxidants, some typical benzofuranonetypical antioxidants are ranked together with some well-known natural or manmade important antioxidants in Figure 5 according to their Gibbs free energies to release hydrogen atoms. From the second column in Table 2, it is clear that ΔGHD of benzofuranones are not only strongly dependent on the nature of substituents but also dependent on the position of substituents. Herein, the remote substituents at the m- and p-positions were systematically examined, and the results are summarized in Figure 6. Figure 6 shows that the bond dissociation energies are linearly dependent on the sum of Hammett substituent parameters σp and σm with very good correlation coefficients, which indicates that the Hammett linear free-energy relationship holds in the hydrogen-abstraction process. From the slopes and the intercepts of the straight lines, the corresponding mathematical formula can be easily derived (eqs 57), according to which it is not difficult to estimate ΔGHD of benzofuranones. ΔGHD ð2HÞ ¼ 4:92

∑σ þ 69:23

ð5Þ

ΔGHD ð3HÞ ¼ 8:72

∑σ þ 71:96

ð6Þ

ΔGHD ð4HÞ ¼ 7:21

∑σ þ 71:04

ð7Þ

By investigation of these equations, it is clear that benzofuranones with electron-donating groups have lower bond dissociation energies 3593



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Figure 5. Comparison of ΔGHD between HP-136 as well as its analogues and some well-known antioxidants.

Table 5. Hydrogen Atom Affinities of Some Typical Carbon Atom and Heteroatom Radicals (kcal/mol) ΔGHA(R•)a

radicals CHtC•

radicals

ΔGHA(R•)a

123.2

HO•

109.1

Ph

103.4

NH2•

98.6

CHdCH•

101.4

O•

93.1

•

CF3•

97.9

(CH3)3Si•

80.6

cC3H5•

96.7

HOO•

78.5

CH3•

92.8

PhNH•

78.2

C2H5•

91.4

NH2NH•

77.8

i-C3H7• t-C4H9•

88.0 86.9

PhO• i-C3H7OO•

76.8 75.4

80.2

PhS•

73.7

CH2dCdCH

78.9

(CH3)3Ge•

71.3

OdCH•

78.5

(CH3)3Sn•

63.9

CH2dCHCH2•

76.8

TEMPO•

61.4

Ph2CH•

74.9

i-ASC•

60.5

Ph3C•

71.3

O2•

38.5

PhCH2• •

ΔGHA(R•) = ΔHHA(R•) 4.9 kcal/mol;36 the values of ΔHHA(R•) for the radicals listed in this table are all derived from the literature.37 a

than those of benzofuranones with electron-withdrawing groups, indicating that the electron-donating group can improve the stability of the carbon radical, which further hints that this radical has some positive charge densities on the radical carbon atom. Compared with some other carbon radicals, these radicals studied in this work should belong to class O.38 On the other hand, the bond dissociation

energies of 5H do not depend on the Hammett substituent parameters, implying that the 5• has less positive charge densities on the radical carbon atom. From these equations, it is interesting to find that the slope of the dependence of ΔGHD of 2H on the sum of the Hammett substituent constants (4.92) is much smaller than that of 3H (8.72) and 4H (7.21), implying the substituents on benzo-ring A has smaller effect than the substituents on benzo-ring B, and the reason could be the different structural characters of these two rings. From our theoretical results of 2H (G = H, radical), the dihedral angle of CC and CC is 26.3° (Table S1 in Supporting Information), indicating that the plane of benzoring A is not parallel to that of benzo-ring B, according to which it is reasonable to predict that substituent benzo-ring A has an inductive effect (σ = 0.08) whereas substituent benzo-ring B has a conjugation effect (σ = 0.15).39 As is well-known, the inductive effects decrease a lot with the increasing length, but conjugation effects do not. Therefore, the effect on ΔGHD from the substituent on benzo-ring A is smaller than that from benzo-ring B. This explanation also addressed why the substituent effects on ΔGHD of 5H are very also small [the ΔGHD difference between 5H (G = p-OCH3) and 5H (G = p-Cl) is only 0.6 kcal/mol, within the uncertainty of the experimental determinations]. These equations also show that with the same substituents, the ΔGHD value of 2H is smaller than that of 3H by about 14 kcal/ mol, which means that 2H• is usually more stable than the corresponding 3H•. One reason could be that the radical is an electron-deficient radical (this character also supports the fact that the speculation that the stability of the radical plays a more 3594



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Table 6. Comparison of ΔGHD, ΔGPD, and Eox of OrthoSubstituted 2H with the Corresponding Para-Substituted Isomers G ΔGHP(XH)

a

ΔGPD(XH)

c

Eox(XH)

Figure 6. Dependences of ΔGHD(2H) (9), ΔGHD(3H) (b), and ΔGHD(4H) (2) in DMSO on the sum of the Hammett substituent constants (∑σ).

Scheme 6. Effect from Ring A and Ring B of the Radical of Benzofuranone

important role than the stability of the neutral compounds in the hydrogen release process is reliable40), and the ditert-butyl substituent would increase the stability of the radical. Besides, dipoledipole interactions may also contribute to this. From our above discussion, we know that substituent rings A and B have an electron-withdrawing inductive effect and an electron-donating conjugative effect, respectively; therefore, dipole m is smaller than dipole n (Scheme 6). The smaller the dipole, the more stable the radical. Herein, 2H usually has smaller ΔGHD than 3H and 4H when the same substituents are introduced. The vacant ortho-postions of 2H permit their further modification to systematically extend the range of structureactivity space that can be accessed by studies employing these analogues (Table 6). Compared to the para-position, the introduction of OCH3, CH3, Cl, and CF3 in the ortho-position makes the ΔGHD(2H) increase by about 3.7, 3.0, 0.8, and 1.4 kcal/mol, respectively. Interestingly, the ΔGHD(2H) differences between the ortho- and para-positions [ΔGHD(2H)] do not have a large correlation with the electronic nature of the substituents but the volume of them. Actually, the larger the volume of the substituents, the larger ΔΔGHD(2H) (Table 6). The importance of steric repulsion is indicated by the calculated bond lengths and angles (Table S1 in Supporting Information). For example, in the hydrogen transfer

a

OCH3

CH3

Cl

CF3

o-

71.3

71.3

71.5

73.1

p-

67.6

68.3

70.7

71.7

Δb

3.7

3.0

0.8

1.4

op-

16.0 13.5

14.5 13.1

13.6 12.4

13.4 11.5

Δb

2.5

1.4

1.2

1.9

o-

1.505

1.552

1.713

1.849

p-

1.487

1.524

1.694

1.806

Δd

0.4

0.7

0.4

1.0

Unit is kcal/mol. b Δ = ΔG(o-isomer) ΔG(p-isomer). c Units in volts versus Fcþ/0. d Δ = 23.06(Eox(o-isomer) Eox(p-isomer)); the units are kcal/mol. a

process, the C9C7C8 angle of 2H (G = H) increased by 11.2° (112.3248123.5283°), and the dihedron angle decreased by 55.2° (81.529926.2556°), whereas the C9C7C8 angle of 2H (G = o-OCH3) increased by 9.2° (112.4161121.6867°), and the dihedron angle decreased by 42.9° (79.243636.3117°). The smaller increase of the C9C7C8 angle and the smaller decrease of the dihedron angle in 2H (G = o-OCH3), compared with 2H (G = H), together with the greater expansions of the angles upon forming 2H, indicate a considerably greater relief of steric strain for 2H (G = H) to release a hydrogen atom than for 2H (G = o-OCH3), a result consistent with the weaker bond in 2H (G = H). 3. Acidity Scale of the 31 Benzofuranone-Type Compounds in DMSO. As it is well-known, the hydrogen atom transfer can also be initiated by proton transfer; therefore, the acidities of these antioxidants are very important thermodynamic parameters. From the third column in Table 2, it is noticed that the ΔGPD(XH) of HP-136 and its analogues changes from 11.5 kcal/mol for 4H (G = Br) to 22.4 kcal/ mol for 5H (G = p-OCH3). To intuitively compare the protondonating abilities of HP-136 with those of common organic acid and conveniently examine the effect of the substituents and the structure on the electron-donating ability, nine organic acids and HP-136 as well as its analogues are ranked in Figure 7 according to their Gibbs free energies to release protons. From Figure 7, it is clear that the ΔGPD of HP-136 is 13.1 kcal/mol, greater than those of acetic acid (pKa = 12.6, ΔGPD = 17.3 kcal/ mol41) and benzoic acid (pKa = 11.1, ΔGPD = 15.2 kcal/ mol41). Similar to phenol antioxidation mechanism (pKa = 18.0, ΔGPD = 24.7 kcal/mol41), the strong acidity also suggests that these antioxidants could very easily release protons in the antioxidation process. Compared with ordinary benzyl methyl ester (ethyl-2-phenylacetate, pKa = 22.7, ΔGPD = 31.1 kcal/ mol42) and indanone (2-indanone, pKa = 16.9, ΔGPD = 23.2 kcal/mol43), whose structures are similar to that of benzofuranone, the acidity of HP-136 is much stronger. The strong proton-donating ability of HP-136 can be explained by the aromatic property of its anion. The anions of benzofuranones with (4n þ 2) π-electrons display aromatic properties and show special aromatic stabilization; therefore, it is very easy for benzofuranones to convert into their anions by releasing a proton. In addition, the phenyl ring can stabilize the anion very efficiently. 3595



Figure 7. Comparison of the proton-donating ability between HP-136 and some structure-related proton donors.

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(G = H), meaning that 5H should belong to middle-strong acid. The disparity between 5H (G = H) and 3H (G = H) in acidity should be caused by the electron negativity of heteroatom as their anions are all aromatic anions with (4n þ 2) π-electrons. The N(Me)2 on the 1 position of 5H has stronger electrondonating ability than oxygen on the 1 position of 3H; therefore, the stability of the anions of 5H is weaker. From Table 2, it is also noticed that the acidity was enhanced as the substituent on the benzo-ring was going from the electrondonating group to the electron-withdrawing group. The ΔGPD are linearly dependent on the sum of Hammett substituent parameters σp and σm, with very good correlation coefficients (Supporting Information), which indicates that the Hammett linear free-energy relationship holds in the hydrogen-abstraction process. For any of the one- or multisubstituted species at the para- and/or meta-positions of benzofuranones, the ΔGPD(XH) can be easily and safely estimated from the corresponding Hammett substituent parameters by using eqs 811. The slopes of the dependence of ΔGPD of 2H and 5H on the sum of the Hammett substituent constants are much smaller than those of 3H and 4H, implying that the substituents on 3H and 4H have a larger effect than the substituents on 2H and 5H. Compared to that at the para-position, the introduction of OCH3, CH3, Cl, and CF3 at the ortho-position makes the ΔGPD(2H) increase by about 2.5, 1.4, 1.2, and 1.9 kcal/mol, respectively. Similarly, the larger the volume of the substituents, the larger ΔΔGPD(2H) (Table 6). The reason could be that the departure of the proton causes a large steric repulsion for 2H (G = OCH3) but not for 2H (G = Cl) (Table 6). ΔGPD ð2HÞ ¼ 2:17

∑σ þ 12:84

ð8Þ

ΔGPD ð3HÞ ¼ 1:81

∑σ þ 12:36

ð9Þ


∑σ þ 12:24

ð10Þ


∑σ þ 20:87

ð11Þ

4. Electron-Donating Abilities of the Benzofuranone-Type Compounds in DMSO. Because it is possible that the antioxida-

Figure 8. Comparison of the electron-donating ability between HP-136 and some structure-related electron donors.

Further inspection of the ΔGPD(XH) in Table 2 shows that the ΔGPD of 2H (G = H) are much smaller than those of 3H (G = H), indicating the tert-butyls on the benzo-ring reduce the ability of 2H (G = H) to release a proton. As shown in Table 2, the ΔGPD of 5H (G = H) are larger than those of acetic acid and 3H

tion process of benzofuranone-type compounds is involved in an electron-induced mechanism (steps de in Scheme 1), it is necessary to examine electron-donating abilities of the benzofuranone-type compounds and the acidity of their corresponding radical cations in DMSO. From the fifth column in Table 2, it is clear that the oneelectron oxidation potentials of 1H5H (Eox) range from 1.346 (V versus Fcþ/0) for 2H (G = p-NMe2) to 1.962 (V versus Fcþ/ 0 ) for 4H (G = Br). Because the one-electron oxidation potentials of the1H5H all are quite positive (generally more positive than that of ferrocene), all of these antioxidants are quite weak oneelectron donors, and it is hard to convert all of these antioxidants into the corresponding radical cations. In order to intuitively compare the electron-donating abilities of HP-136 with common electron donors and conveniently examine the effect of the substituents and the structure on the electron-donating ability, seven electron donors and HP-136 and its analogues are ranked in Figure 8 according to their oxidation potentials. From Figure 8, it is clear that the electron-donating abilities of aniline (0.445 V44) and 1-methylpyrrolidine (0.455 3596



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Scheme 7. Three Possible Pathways of Hydrogen Transfer from XH to DPPH•

V44) are very strong. This may originate from the lone pair electrons on the nitrogen atom. Although oxygen atom also has a lone pair electron, the electronegativity of oxygen is much larger than that of the carbon atom; therefore, it is very difficult to compare the electron-donating ability of carbon-centered molecules and those of oxygen-centered molecules. The oxidation potentials of 1H, 2H (G = H), and 3H (G = H) are all smaller than that of phenol (2.10 V45), and the reason could be that the large plane can scatter the radical and charge density in these antioxidants. Further inspection of the fifth column in Table 2 found that the electron-withdrawing group weakens the electron-donation ability of 1H5H and the electron-donating group enhances the electron-donation ability of these antioxidants, and the Eox(XH) are linearly dependent on the sum of Hammett substituent parameters σp and σm, with very good correlation coefficients (Supporting Information). This result indicates that the Hammett

linear free-energy relationship holds in the electron-abstraction process. For any of the one- or multisubstituted species at the paraand/or meta-position benzofuranones, the Eox(XH) can be easily and safely estimated from the corresponding Hammett substituent parameters by using eqs 1215. Eox ð2HÞ ¼ 0:355

∑σ þ 1:604

ð12Þ

Eox ð3HÞ ¼ 0:693

∑σ þ 1:708

ð13Þ

Eox ð4HÞ ¼ 0:662

∑σ þ 1:707

ð14Þ

Eox ð5HÞ ¼ 0:520

∑σ þ 1:526

ð15Þ

The slopes of the dependence of Eox of 2H and the dependence of Eox of 5H on the sum of the Hammett substituent 3597



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Scheme 8. Thermodynamic Analysis Platform on the Mechanism of Hydrogen Transfer from HP-136 to DPPH•

constants are much smaller than those of 3H and 4H, implying the substituents on 2H and 5H have a smaller effect than the substituents on 3H and 4H. The main reason causing this should be the small inductive effects of the substituents in 2H and 5H and the large conjugative effects in 3H and 4H. By examining the effect of substitients at the ortho-positions, it can be found that Eox of ortho-substituted 2H are 0.4, 0.7, 0.4, and 1.0 kcal/mol for the substituents OCH3, CH3, Cl, and CF3, respectively, which are slightly larger than those of the substituents at the corresponding para-positions in 2H, indicating that for the same substituent at different positions, the potential differences are very small, which further hints that the steric effect has little effect in these electron-transfer processes. Theoretical calculations also support this (Table 4).46 5. Acidity of Radical Cations of the 31 BenzofuranoneType Compounds in DMSO. From the fourth column in Table 2, it is clear that the scale of ΔGPD of 1Hþ•5Hþ• changes from 27.2 to 40.8 kcal/mol, indicating these radical cations belong to very strong proton donors; the acidities of them in DMSO are not only much greater than those of some typical organic acids, such as PhOH (pKa = 18, equivalent to 24.6 kcal/mol47) and PhCOOH (pKa = 11, equivalent to 15.0 kcal/mol47), but they are

also larger than those of some inorganic acids in DMSO, such as HONO (pKa = 7.5, equivalent to 10.23 kcal/mol43), CF3COOH (pKa = 3.45, equivalent to 4.7 kcal/mol48), and HCl (pKa = 1.8, equivalent to 2.5 kcal/mol48). Figure 9 shows a comparison of proton-donating abilities between the radical cation of HP-136 and some structure-related radical cations in DMSO. Because ΔGPD of 1Hþ•5Hþ• all are quite smaller than zero, it is conceived that all of these radical cations should be relatively unstable, which implies that 1Hþ•5Hþ• in DMSO could not be directly detected and characterized by ESR spectroscopy under normal experimental conditions. Because the values of Eox and ΔGPD for 1H5H and 1Hþ•5Hþ• are so positive and negative, respectively, it is reasonable to conclude that when the hydrogen atom transfer is initiated by electron transfer, the electron-transfer step (step d) should be the ratedetermining step. By further inspection, it is found that the ΔGPD of 2Hþ• (G = H) to release a proton is only 0.5 kcal/mol smaller than that of 3Hþ• (G = H), suggesting that the ditert-butyls have little effect on the proton-donating ability of 3Hþ•. The ΔGPD of 5Hþ• (G = H) to release a proton is only 0.7 kcal/mol larger than that of 3Hþ• (G = H), indicating the N(Me)2 on 5Hþ• weakens its 3598



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Table 7. Energetics of Each Mechanistic Step of Hydrogen Transfer from XH to DPPH in DMSO Shown in Scheme 8 (kcal/mol)a ΔGa hydrogen donors

step a

step b

step c

step d

step e

HP-136 (1H)

37.1

48.9

11.6

23.4

11.8

p-NMe2

33.2

48.0

13.2

28.0

14.8

p-OCH3

36.5

48.8

12.0

24.4

12.4

p-CH3

37.3

49.0

11.6

23.3

11.7

p-H p-Cl

38.6 41.2

49.2 50.5

11.5 10.9

22.1 20.2

10.6 9.3

p-CF3

43.8

52.1

10.0

18.3

8.3

m-OCH3

40.4

51.1

11.1

21.7

10.6

m-CH3

37.5

48.7

11.5

22.7

11.2

m-Cl

41.9

50.7

10.6

19.3

8.8

m-CF3

43.3

52.0

10.5

19.1

8.6

o-OCH3

36.9

45.5

14.5

23.2

8.7

o-CH3 o-Cl

38.0 41.7

46.7 50.2

13.0 12.1

21.7 20.7

8.7 8.6

o-CF3

44.8

51.7

11.9

18.8

6.9

2H

Figure 9. Comparison of proton-donating abilities between the radical cation of HP-136 and some structure-related radical cations in DMSO. a

ability to release a proton; the reason could be that 5Hþ• is more stable than 3Hþ•. Further inspection found that the ΔGPD(XHþ•) of benzofuranones are linearly dependent on the sum of Hammett substituent parameters σp and σm, with very good correlation coefficients (Supporting Information), which indicates that the Hammett linear free-energy relationship holds in the proton-abstraction process. For any of the one- or multisubstituted species at the para- and/or meta-position benzofuranones, the ΔGPD(XHþ•) can be easily and safely estimated from the corresponding Hammett substituent parameters by using eqs 1619. The slope of the dependence of ΔGPD(2Hþ•) on the sum of the Hammett substituent constants is much smaller than that of 3H and 4H, implying that the substituents on ring A have a smaller influence on ΔGPD (2Hþ•) than substituents on ring B. ΔGPD ð2Hþ• Þ ¼ 3:26

∑σ 37:28

ð16Þ

ΔGPD ð3Hþ• Þ ¼ 7:31

∑σ 37:01

ð17Þ


∑σ 37:94

ð18Þ


∑σ 30:34

ð19Þ

In the calculations of the energetics of each mechansitic step, we used pKa(DPPH2) = 5.9 (in DMSO), pKa(DPPH2þ•) = 1.9 (in DMSO), Eox(DPPH2) = 0.371 V versus Fc, Eox(DPPH) = 0.093 V versus Fc, and BDE(DPPH2) = 80.0 kcal/mol; the values were all derived from the literature.53 Eox(DPPH•) = 0.161 V versus Fc (determined in this work). The other thermodynamic parameters about the hydrogen donors all were directly derived from Tables 1 and 2.

As for Eox of 5 (G = H, 0.696 V), the electron-donating ability is also stronger than that of 3 (G = H), suggesting that the NMe on 5 has a strong electron-donating effect that could enhance the ability of 5 to donate an electron. From Table 2, we also noticed that the Eox of X attached to an electron-withdrawing group is larger than that of X attached to an electron-donating group, indicating that the electron-withdrawing group weakens the electron-donating ability of X, and the electron-donating groups show the opposite effect. If Eox(X) are plotted against the sum of Hammett substituent parameters σp and σm, a straight line can be available with very good correlation coefficients (Supporting Information), which indicates that the Hammett linear free-energy relationship holds in the electron-accepting process. For any radical of a one- or multisubstituted species at the para- and/or meta-position benzofuranones, the Eox(X) can be easily and safely estimated from the corresponding Hammett substituent parameters by using eqs 2023.

6. Redox Potentials of the Anions (X) in DMSO. From the

last column in Table 2, it can be seen that Eox(X ) changed from 0.308 to 0.826 V, suggesting these anions are not strong electron donors; the electron-donating abilities are much smaller than that of the diphenylmethane anion (1.540 V49) and the triphenylmethane anion (1.486 V49) and even smaller than that of the fluorine anion (1.069 V49). With comparison of the Eox of 3 (G = H, 0.439 V) with those of 2 (G = H, 0.573 V), it is found that the electron-donating ability of 3 (G = H) is weaker than that of 2 (G = H), indicating the tert-butyl on the benzoring could increase the electron-donating ability of 2 (G = H).

Eox ð2 Þ ¼ 0:308

∑σ 0:572

ð20Þ

Eox ð3 Þ ¼ 0:457

∑σ 0:434

ð21Þ

Eox ð4 Þ ¼ 0:379

∑σ 0:469

ð22Þ

Eox ð5 Þ ¼ 0:230

∑σ 0:694

ð23Þ

Herein it is worth pointing out that although the electrondonating ability of X is not great, X still is a good electron donor 3599



Figure 10. Dependences of the reaction rates of hydrogen atom transfer from 2H to DPPH• on ΔGo of the hydrogen atom transfer in step e.

Figure 11. Dependences of the reaction rates of hydrogen atom transfer from 2H to DPPH• on ΔGo of the proton transfer in step c.

in many chemical and biochemical reactions. The reason is that the formed radical X• can easily become dimer X2 to release a lot of heat (∼23 kcal/mol);24 the released heat can promote X to further release an electron. The CV graph of X in DMSO (Figure 3) shows that the oxidation of X is irreversible, which supports that the neutral radical X• is quite unstable. 7. Thermodynamic Analysis on the Mechanism of Hydrogen Transfer from HP-136 and Its Analogues (XH) to DPPH•. Because the hydrogen transfer reaction with HP-136 and its analogues as antioxidants could involve a complex mechanism (Scheme 1), an interesting controversy is whether the formal hydrogen atom transfer from XH to the surrounding substrates occurs in a one-step or multistep sequence involving electron transfer as the initial step and proton transfer as the initial step. In fact, the mechanism of hydrogen transfer has been a strategic goal in many famous groups for a long time.50 To clarify the hydrogen transfer mechanism of HP-136 and its analogues, in this work, we select DPPH• as a hydrogen acceptor, which is a very stable radical widely used in estimating the activity of the antioxidant and judging the hydrogen transfer mechanism.51 For the mechanism of hydrogen transfer from XH to DPPH•, there are three possible pathways that can be proposed (Scheme 7). In path I, the reaction was initiated by proton transfer and then followed by electron transfer to yield DPPH2

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and the corresponding neutral radical of XH (X•); the formed radical X• finally became the dimer. In path II, the reaction was initiated by electron transfer and then followed by proton transfer to form DPPH2 and X•; the formed X• finally became the dimer. In path III, the reaction was initiated by hydrogen atom transfer, and then, the formed X• became the dimer by dimerization. Obviously, an interesting but difficult question remained, that is, which one is the practical pathway of the hydrogen atom transfer from XH to DPPH•. To thoroughly elucidate the most likely mechanisms of the hydrogen atom transfer from XH to DPPH•, a thermodynamic analysis platform (TAP) on the possible mechanism of hydrogen transfer from HP-136 to DPPH• was constructed according to the thermodynamic relation chart (defined as Molecule ID Card in our previous work52) of the hydrogen-donor family (XH, XHþ•, X, and X•) and the thermodynamic relation chart of the hydrogen-acceptor family (DPPH•, DPPH, DPPHHþ• and DPPHH) (Scheme 8). From Scheme 8, it is clear that if the thermodynamic parameters of Eox(XH), ΔGPD(XHþ•), ΔGPD(XH), Eox(X), and ΔGHD(XH) and the thermodynamic parameters Ered(DPPH•), ΔGPA(DPPHHþ•), ΔGPA(DPPH•), Ered(DPPHHþ•) and ΔGHA(DPPH•) are available, the change of the standard-state free energy of each elementary step for the hydrogen atom transfer can be calculated. In fact, the values of Eox(XH), ΔGPD(XH), ΔGHD(XH), ΔGPD(XHþ•) and Eox(X) can be obtained from Table 2; the values of Ered(DPPH), ΔGPA(DPPH•), ΔGHA(DPPH•), ΔGPA(DPPH), and Ered(DPPHHþ•) can be obtained from the literature53 or from the determination in this work. The detailed results for the change of the standard-state free energy of each elementary step are summarized in Table 7. From Table 7, it is clear to find that the value scale of the standard free-energy changes for the three initial steps (steps a, c, and e) in the three possible pathways (Scheme 7) range from 33.2 to 44.8 kcal for path I, from 10.0 to 14.5 kcal/mol for path. II, and from 6.9 to 14.8 kcal/mol for path III. Because the state free-energy change for the reaction step a is quite positive (greater than 33 kcal/mol), it is impossible that the hydrogen atom transfer was initiated by electron transfer, that is, path I as the hydrogen transfer mechanism may be ruled out. As to path. III, because the state free-energy changes of the initial step all are negative values, path III should be the most likely mechanism of the hydrogen transfer. However, for path II, although the values of the state free-energy change of the initial step all are positive (10.014.5 kcal/mol), the magnitudes of the values are not quite great, which can be surmounted by molecule thermal motion at room temperature; this result indicates that even though the first reaction step is endothermic, it is also likely that the hydrogen atom transfer was initiated by proton transfer, even if the following electron transfer can release heat enough to remedy the heat that the first step took in. Therefore, both pathways II and III are likely mechanisms for the hydrogen atom transfer. In order to further dig out the real mechanism of the hydrogen atom transfer, the dependence of log k2 of the hydrogen atom transfer on the thermodynamic driving force of hydrogen atom transfer in step e (Figure 10) and the thermodynamic driving force of proton transfer in step c (Figure 11) as well as the effect of the Mg2þ ion on the rate of the hydrogen atom transfer (Figure 4) were examined. From Figure 10, it is clear that log k2 is not directly dependent on the thermodynamic driving force of the hydrogen atom transfer in step e, which means that the process of the hydrogen atom transfer is not completed by one step. However, 3600



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Scheme 9. Most Likely Mechanism of Hydrogen Transfer from HP-136 to DPPH in DMSO

from Figure 11, we can clearly find that in general, log k2 of the hydrogen atom transfer is in direct proportion to the thermodynamic driving force of the proton transfer in step c, indicating that the rate of the hydrogen transfer from XH to DPPH in DMSO was initiated by proton transfer and that the initial step c is the rate-determining step. Figure 4 shows that the addition of Mg2þ into the reaction system can significantly block the hydrogen atom transfer; the reason could be that Mg2þ can combine with the center N atom in DPPH•, which makes the proton-obtaining ability of the center N atom of DPPH• decrease (eq 24). Because the basicity of the radical N atom could be smaller than that of the N atom of the tertiary amine and the intramolecular 1,2-transfer of the proton is forbidden, the real mechanism of the hydrogen transfer from HP-136 to DPPH• in DMSO should be described as shown in Scheme 9.

’ CONCLUSIONS In this work, 15 substituted 5,7-ditert-butyl-3-phenylbenzofuran-2(3H)-ones (1H and 2H), 9 substituted 3-phenylbenzofuran-2(3H)-ones (3H and 4H), and 7 substituted 1-methyl-3phenylindolin-2-ones (5H) were designed and synthesized as types of very important carbon-centered radical antioxidants. After the real structure and the thermodynamic driving forces of the 31 benzofuranone-typical compounds (XH) in solution were examined, the following conclusions could be made: (1) The actual structure of benzofuranone-typical compounds in solution as antioxidants should be the lactone form rather than the enol form. However, for the radical cations of benzofuranone-typical compounds, the enol form is much more stable than the corresponding lactone form. (2) Because the ΔGHD(XH) values of XH (65.274.1 kcal/ mol for 1H4H and 73.875.0 kcal/mol for 5H) are all smaller than that of the most widely used antioxidants, the 31 XH should be good hydrogen-atom-donating antioxidants. (3) The scale of ΔGPD(XH) of the 31 benzofuranones ranges from 11.5 to 16.0 (kcal/mol) for 1H4H and from 18.6 to 22.4 (kcal/mol) for 5H, indicating that benzofuranones (1H4H) are good proton donors and their analogues (5H) should belong to middle-strong proton donors. If

1H4H are used as antioxidants, in most cases, the most likely mechanism should contain two isolated step, proton transfer in the first step and then electron transfer. (4) Because the oxidation potentials of the 31 XH [Eox(XH)] in DMSO are all quite positively high (1.3461.962 V versus Fcþ/0), the 31 XH are all due to very electron deficient compounds and are somewhat electrophilic. If XH are used as antioxidants, in general, the electronsufficient radicals, such as carbon-centered radicals, can be easier to be scavenged. (5) The ΔGPD(XH), ΔGHD(XH), ΔGPD(XHþ•), Eox(XH), and Eox(X) of the five chemical and electrochemical processes are all linearly dependent on the sum of substituent parameters σ, with very good correlation coefficients, indicating that for any one- or multisubstituted species at the para- and/or meta-position benzofuranones and their various reaction intermediates, the five thermodynamic driving forces all can be easily and safely estimated from the corresponding Hammett substituent parameters. (6) Because the reaction rates of hydrogen atom transfer from XH to DPPH• are, in general, positively dependent on the ΔGo of the initial proton transfer but negatively dependent on the ΔGo of hydrogen atom transfer, and the reaction can be significantly blocked by Mg(ClO4)2, the mechanism of the hydrogen atom transfer from 2H to DPPH• should be proton-initiated electron transfer rather than hydrogen atom one-step transfer. The most salient contribution of this paper is that not only the thermodynamic driving forces of 31 benzofuranonetypical compounds as antioxidants to release protons, hydrogen atoms, and electrons in solution were determined for the first time, but also the prevalent literature view on the real structure of benzofuranones as antioxidants in solution was corrected.

’ EXPERIMENTAL SECTION 1. Materials. All reagents were of commercial quality from freshly opened containers or were purified before use. All of the benzofuranone-typical compounds studied were prepared in this laboratory following literature procedures and were already reported in the preceding paper.26,27 The commercial tetrabutylammonium hexafluorophosphate (Bu4NPF6, Aldrich) was recrystallized from CH2Cl2 and was vacuum-dried at 110 °C overnight before preparation of the supporting electrolyte solution. The 3601


The Journal of Physical Chemistry B purification of dimethyl sulfoxide solvent and the preparation of potassium dimsyl (CH3SOCH2Kþ) were carried out according to the standard procedures in the literature. 2. Determination of pKa. The procedures for purification and preparation of the DMSO solvent, the potassium dimsyl base, the solutions of the indicator, and the ionic liquids, as well as the overlapping indicator method for pKa determination as described in details by Bordwell and co-workers, were closely followed in the present work. The concentrations of the indicator and lactone solutions were about 50 mmol/L. The concentration of the potassium dimsyl solution was determined internally as a part of the manipulation during each run. 3. Electrochemical Measurements. The electrochemical experiments were carried out by cyclic voltammetry (CV) and osteryoung square wave voltammetry (OSWV) using a BAS-100B electrochemical apparatus in deaerated acetonitrile under an argon atmosphere at 298 K, as described previously. n-Bu4NPF6 (0.1M) in DMSO was employed as the supporting electrolyte. A standard three-electrode cell consists of a glassy carbon disk as the working electrode, a platinum wire as a counter electrode, and 0.1 M AgNO3/Ag (in 0.1 M n-Bu4NPF6DMSO) as the reference electrode. The ferrocenium/ferrocene redox couple (Fcþ/0) was taken as the internal standard. The reproducibilities of the potentials were usually e5 mV for anions. 4. Kinetic Measurements. Kinetic measurements were carried out in DMSO using a UV/vis spectrophotometer (HITACHI U-3000) connected to a superthermostat circulating bath to regulate the temperature of cell compartments. The rate of hydrogen atom transfer from XH to DPPH in DMSO was measured at 25 °C by monitoring the changes of absorption of DPPH at λmax = 518 nm under pseudo-first-order conditions (XH in over 20-fold excess). The pseudo-first-order rate constants were then converted to k2 by linear correlation of pseudo-first-order rate constants against the concentrations of XH. 5. Theoretical Calculations. All of the theoretical calculations were conducted with the Gaussian 03 programs. The geometry of each species was optimized by using the B3LYP/631þG(d) method. For the molecules that have more than one possible conformation, the conformation with the lowest electronic energy was singled out and used in the ensuing calculations. Each final optimized geometry was confirmed by the B3LYP/6-31þG(d) frequency calculation to be a real minimum on the potential energy surface without any imaginary frequency. Single-point electronic energies were then calculated at the B3LYP/6-311þþG(2df, 2p) levels. The free energy was obtained by combining the B3LYP/6-311þþG(2df, 2p) single-point electronic energies with ZPE, thermal corrections (298 K), and the entropy terms obtained at the B3LYP/6-31þG(d) level. Free energy of solvation values were calculated by using the integral equation formalism version of PCM (IEF-PCM),54 as implemented in Gaussian 03. PCM methods used here represent the solute as a cavity made up of a set of interlocking spheres. The cavity was built by the United Atom model (UA0). Hydrogen atoms were enclosed in the sphere of the atom to which they were bonded. All of the IEF-PCM calculations were performed at the B3LYP/6-31þG(d, p) level. Both the electrostatic and nonelectrostatic contributions were included for the total solvation energies.55

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’ ASSOCIATED CONTENT

bS

Supporting Information. Plots of some thermodynamic parameters of XH on the sum of the Hammett substituent constants, the standard orientation of HP-136 and its various analogues, and the crystallographic data as well as 1H NMR, MS, and IR spectra of some typical benzofuranone compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

’ AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected].

’ ACKNOWLEDGMENT Financial support from the National Natural Science Foundation of China (Grant Nos. 21072104, 20921120403, and 20832004), the Ministry of Science and Technology of China (Grant No. 2004CB719905), and the 111 Project (B06005) is gratefully acknowledged. The calculations were performed on a Nankai Stars supercomputer at Nankai University. ’ REFERENCES (1) (a) Wright, J. S.; Carpenter, D. J.; McKay, D. J.; Ingold, K. U. J. Am. Chem. Soc. 1997, 119, 4245. (b) Danesi, F.; Elementi, S.; Neri, R.; Maranesi, M.; D’Antuono, L. F.; Bordoni, A. J. Agric. Food Chem. 2008, 56, 9911–9917. (c) Ferreres, F.; Pereira, D. M.; Valent~ao, P.; Andrade, P. B.; Seabra, R. M.; Sottomayor, M. J. Agric. Food Chem. 2008, 56, 9967. (d) Niki, E.; Omata, Y.; Fukuhara, A.; Saito, Y.; Yoshida, Y. J. Agric. Food Chem. 2008, 56, 8255. (e) Zhao, L.; Zhang, C.; Zhuo, L.; Zhang, Y.; Ying, J. Y. J. Am. Chem. Soc. 2008, 130, 12586. (f) Kimata, A.; Nakagawa, H.; Ohyama, R.; Fukuuchi, T.; Ohta, S.; Suzuki, T.; Miyata, N. J. Med. Chem. 2007, 50, 5053. (g) Samaras, T. S.; Gordon, M. H.; Ames, J. M. J. Agric. Food Chem. 2005, 53, 4938. (h) Tsao, R.; Yang, R.; Xie, S.; Sockovie, E.; Khanizadeh, S. J. Agric. Food Chem. 2005, 53, 4989. (i) Pinelo, M.; Manzocco, L.; Nunez, M. J.; Nicoli, M. C. J. Agric. Food Chem. 2004, 52, 1177. (2) Miller, N. J.; Diplock, A. T.; Rice-Evans, C. A. J. Agric. Food Chem. 1995, 43, 1794. (3) Talcott, S. T.; Howard, L. R. J. Agric. Food Chem. 1999, 47, 2109. (4) Susan, J. D.; Aiguo Ma, , M. R.; Andrew, R. C. Cancer Res. 1996, 56, 1291. (5) Paresh, D.; Rajaram, K.; Husam, G.; Wael, H.; Ahmad, A.; Cesar, H. M., Jr. Circulation 2000, 101, 122. (6) Chauhan, A.; Chauhan, Ved.; Brown, W. T.; Cohen, I. Life Sci. 2004, 75, 2539. (7) (a) Ames, B. N.; Shigenaga, M. K.; Hagen, T. M. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 7915. (b) Cutler, R. G. Am. J. Clin. Nutr. 1991, 53, 373S. (8) Mates, J. M.; Perez-G omez, C.; Nunez de Castro, I. Clin. Biochem. 1999, 32, 595. (9) For a review, see: Burton, G. W.; Ingold, K. U. Acc. Chem. Res. 1986, 19, 194. (10) (a) Burton, G. W.; Joyce, A.; Ingold, K. U. Lancet 1982, 751. (b) Burton, G. W.; Joyce, A.; Ingold, K. U. Arch. Biochem. Biophys. 1983, 221, 281. (c) Ingold, K. U.; Webb, A. C.; Witter, D.; Burton, G. W.; Metcalf, T. A.; Muller, D. P. R. Arch. Biochem. Biophys. 1987, 259, 224. (11) Beyer, R. E. Biochem. Cell Biol. 1992, 70, 390. (12) Stocker, R.; Yamamoto, Y.; McDonagh, A. F.; Glazer, A. N.; Ames, B. N. Science 1987, 235, 1043. (13) Benzie, I. F. F.; Strain, J. J. Methods Enzymol. 1999, 299, 15. 3602


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