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J. Phys. Chem. A 2010, 114, 10081016

Theoretical Study of the Peripheral Disulde Bridge Substituent Effects on the Antioxidant Properties of Naphthyridine Diol Derivatives
Ao Yu,*, Jian Wang, Xiaosong Xue, and Yongjian Wang*,
Central Laboratory, College of Chemistry, Nankai UniVersity, Tianjin 300071, Peoples Republic of China, and Key Laboratory of BioactiVe Materials, Ministry of Education, College of Life Sciences, Nankai UniVersity, Tianjin 300071, Peoples Republic of China ReceiVed: September 8, 2009; ReVised Manuscript ReceiVed: NoVember 13, 2009

The effect of a peripheral disulde bridge substituent on the phenolic O-H bond dissociation energy (BDE) and the ionization potential (IP) of naphthyridine diol has been studied by density functional theory (DFT) calculation. Compared with naphthalene diol, the substituent of a peripheral disulde bridge group is very efcient in reducing the BDE, whereas the insertion of nitrogen atoms into the naphthalenic ring only slightly changes the BDE of O-H bond but dramatically enhances the IP. It is similar with the stereoelectronic effect of the heterocyclic ring for the well-known R-tocopherol antioxidant and leads to a highly delocalized spin distribution. With the incorporation of these two aspects, a potential antioxidant is expected to be more active and more stable than R-tocopherol.
1. Introduction Free radical chain oxidation is one of the most ubiquitous phenomena in nature. Some processes of oxidation reactions may result in the deterioration of foods and materials as well as various degenerative diseases.1-4 Consequently, to explore potential antioxidants which can efciently retard or prevent the radical chain oxidation reactions is always a very interesting research object.5-9 By far, natural and synthetic phenols are the most abundant and widely used antioxidants. When acting as radical inhibitors in autoxidation systems, they can easily transfer the H-atom to peroxyl or alkoxyl radicals in the degradation reactions for the low O-H bond dissociation energy (BDE) (eq 1).
CHART 1

ArOH + ROO f ArO + ROOH

(1)

Therefore, the lower the BDE(O-H) value is, the easier the dissociation of the O-H bond will be, and also the easier the phenols react with the radicals. Thus, the BDE of O-H bond is one of the most important parameters to start with while designing a potential antioxidant. Generally, electron-donating (ED) groups at the ortho- and para-positions relative to the phenolic O-H can weaken the O-H bond and thus enhance the reactivity of the O-H group to peroxyl radicals.10-17 This strategy has been proven to be the primary guideline for rational design of the novel and more effective antioxidants. Nevertheless, the efforts to increase the transferring rate of H-atom to peroxyl radical by ED substituent have not been thoroughly successful. The reason is that the substitution of phenols with strong ED groups decreases the BDE(O-H) values and also the ionization potentials (IPs) of molecules at the same time which in turn renders the direct reaction with oxygen through electron transfer of phenolic compounds (eq 2). For instance, because of the sensitivity to oxygen in the air, 1,8-napthalene
* Corresponding authors: Ao Yu (esr@nankai.edu.cn) and Yongjian Wang (yongjian_wang@nankai.edu.cn). Central Laboratory, College of Chemistry. Key Laboratory of Bioactive Materials, Ministry of Education, College of Life Sciences.

diol (1, Chart 1) was found to be useless as an antioxidant thought it was predicted to have a lower BDE(O-H) than R-tocopherol (R-TOH, 2, the best-known example of a phenolic antioxidant, Chart 1) by approximately 7 kcal/mol.18 So, the ionization potential of a molecule is assumed to be another crucial index for designing a novel potential antioxidant. Besides these, the other criteria, including solubility, bioavailability, and nontoxicity, must also be considered when designing an effective and safe antioxidant.19,20 However, considering the activity of a potential antioxidant, BDE(O-H) and IP, which directly determine if a phenolic compound could act as a radical inhibitor, are the two most signicant parameters.

ArOH + O2 f [ArOH]+ + O2-

(2)

The rapid development of quantum chemistry and computation methodologies allows the reliable BDEs and IPs of compounds to be calculated with equivalent or greater accuracy than those obtained from experiments. Theoretical calculations, therefore, could be used as a cogent tool for predicting the relationship between the structure and activity of a compound and also for designing novel potential antioxidants. To our pleasure, the strategy not only remarkably shortens the designing period but also reduces the blindness. Up to now, there are several successful examples in rational interpretation of

10.1021/jp908658z 2010 American Chemical Society Published on Web 12/11/2009

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structure-activity relation (SAR) of some natural antioxidants21-23 and design of novel antioxidants14-18,24 using the powerful and economical quantum chemical methods. Presently, in order to explore a potential antioxidant with more activity than R-TOH and more inert to oxygen, Pratt and co-workers14,16,17,25 have made great progress in investigating the effects of the incorporation of a nitrogen atom into phenolic ring on BDEs and IPs using both theoretical and experimental methods (4-6, Chart 2). The results show that the insertion of a nitrogen atom into the phenolic ring just slightly changes the BDE of the O-H bond but dramatically enhances the IP of the target molecule which could make the target molecule stable in the air. Subsequently, substituent 3-pyridinols and 5-pyrimidinols, such as compounds 7-10, were examined to be the excellent peroxyl radical scavengers in the process of autoxidation with the similar BDE but very high IP compared with corresponding no N-substitution compounds in organic solution. Unfortunately, although 88-fold more reactive toward peroxyl radical than R-TOH, compound 10 decomposes signicantly in air (ca. 30% in 6 h). Therefore, the lower BDE and much higher IP than R-TOH are two key factors to develop the novel antioxidants. Additionally, up to now, most of the above rationally designed antioxidants are the monophenolic compounds based on the R-TOH template, and the naphthols, especially naphthalene diols, catch little attention.18,26 Here, the 1,8-naphthalene diol and 2,7-naphthalene diol were selected as the targets to investigate the effects of the nitrogen atom insertion and hence to develop a new model system for antioxidant design. As an essential property of an antioxidant, it is well-known that antioxidant-derived radicals should not propagate the chain oxidation of a substance. However, Bowry and co-workers27,28 reported in the early 1990s that even R-TOH, the most famous bioactive antioxidant, could mediate the peroxidation of LDL lipids in the absence of coantioxidants, such as ascorbate, and render it a prooxidant. So, it is important to nd a new group which not only can provide a low BDE but can reduce the activity of an antioxidant-derived radical to substance. The ortho-substitution of bulky groups, such as tert-butyl, is regarded as the universal means to maintain the kinetic and thermodynamic stability of phenoxyl radicals.29,30 Nevertheless, this method may ultimately be counterproductive under certain conditions. BO-653 (3, Chart 1), another potential synthetic antioxidant with two tert-butyls in the ortho-position of phenolic O-H designed by Niki and co-workers,19 has low H-atom abstraction reactivity although its phenoxyl radical is more stable than that of R-TOH due to the steric hindrance of two bulky ortho groups.7 Accordingly, the strategy described as purely

electronic effects in origin should be taken into account here. It is well-known that delocalization of spin density of the phenoxyl radical is an efcient method to reduce its reactivity.31,32 In general, CH3O-, CH3S-, and (CH3)2N- at the othro or para position of phenolic hydroxyl could fully stabilize the phenoxyl radicals for the contribution of the p lone-pair electron conjugating with the aromatic ring plane. Interestingly, since the late 1970s, Haddon and co-workers33-35 had reported the substituent peripheral disulde bridge group could be effective in the delocalization of spin density and concomitant stabilization of radicals (Chart 3), and they reported in 2007 the rst radical, 11, based on a single phenalenyl unit which was stabilized against -dimerization in the solid state by electronic effects rather than by steric bulky substituents. Their studies also revealed that the disulde may not be the reactive center under general conditions. To the best of our knowledge, the disulde bond usually exists in many proteins (i.e., lysozyme and immunoglobulin). Therefore, we suggested the peripheral disulde bridge in novel potential antioxidants may not cause additional toxicity. Encouraged by these results, we introduced a disulde bridge group into our present system. As part of the continuing investigation for designing effective antioxidants using DFT calculation, rst, we systematically investigated the effects of the incorporation of nitrogen atoms into the naphtholic ring and the substituent of a peripheral disulde bridge group on the BDE(O-H) and IP values (Chart 4). Then we compared the effects of two other chalcogen atoms, O and Se, and the familiar strong electron-donating groups on the BDE and IP with the rst step result and, in turn, developed an optimum new strategy for antioxidant design. Finally, three original compounds with potential antioxidant activity were predicted. 2. Computational Methodology All of the theoretical calculations here were carried out using the GAUSSIAN 0336 packages mounted on the NK-Star Supercomputer. The geometries of the neutral molecules were fully optimized by the B3LYP method in conjunction with the 6-311G(d,p) basis set, and the UB3LYP procedure was used for the geometry optimization of the corresponding radicals. Frequency was computed on these geometries at the same level

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to verify that they are real minima on the potential-energy surface without any imaginary frequency. The zero point energy (ZPE) and thermal corrections were also calculated using the same method (unscaled). For the molecules with more than one possibly stable conformation, the one with the lowest electronic energy was singled out for the following calculations except for special illustration. Single point energy calculations were then carried out with an extended basis set of 6-311++G(2df,2p). The B3LYP and restricted open shell formalism ROB3LYP with the large basis set were applied for the neutral molecules and open shell radicals at the (U)B3LYP/6-311G(d,p) optimized geometry. The enthalpy of a species at 298.15 K was obtained using the equation

H(298.15 K) ) E0 + ZPE + Htrans + Hrot + Hvib + RT (3)

The homolytic O-H bond dissociation enthalpy [BDE(O-H)] of each molecule (X-A-OH) was calculated as the enthalpy change in gas phase at 298.15 K of the following equation (eq 4), where the enthalpy of the H atom was estimated by taking its exact electronic energy of -0.5 hartree.

X-A-OH(g) f X-A-O(g) + H(g)

(4)

The gas-phase adiabatic ionization potential (IP) of X-A-OH is dened as the amount of energy required to remove an electron from a molecule at 0 K. It was computed as the energy change of the equation

X-A-OH(g) f X-A-OH+H(g) + e-(g)

(5)

For both the neutral molecule and its radical cation, the electronic energies and the unscaled zero point vibrational energies were taken at the (U)B3LYP/6-311G(d,p) level for IP calculation. The distribution of spin density of radicals was also calculated at the UB3LYP/6-311G(d,p) level. 3. Results and Discussion 3.1. Bond Dissociation Energies and Ionization Potentials of Compounds 14-17. The model (RO)B3LYP/6311++G(2df,2p)//(U)B3LYP/6-311G(d,p) was chosen to

estimate the BDE and IP values which were rst proposed by DiLabio and co-workers37 and had been demonstrated to be an optimum model for obtaining more reliable BDE values of various types of bonds, including X-H (X ) C, O, S, and P).38-42 The compounds investigated in this research are shown in Chart 4. The calculated values for compounds 14-17 are listed in Scheme 1. The results show that, compared with the parent molecule, the insertion of nitrogen atoms at the meta-positions of the naphtholic ring relative to hydroxyl increases the BDE(O-H) slightly by 2.18 kcal/mol and the substituent of a peripheral disulde bridge group decreases it dramatically by 13.17 kcal/ mol; with the two effects combined together, the apparent BDE value decreases 8.50 kcal/mol (Scheme 1). To explore how the insertion of nitrogen atoms and substitution of a peripheral disulde bridge group affect the BDE, the ground-state effect (GE), radical effect (RE), and total effect (TE ) RE - GE) were calculated based on the reaction enthalpies of the isodesmic reactions shown in Scheme 2. These calculation methods have been used successfully to investigate the substituent effect on the BDE values.25,43-45 Here, the GE elucidates how the ground-state stability of neutral molecule changes with the introduction of a substituent heteroatom or group, the RE provides the same effect on the stability of radical, and the GE and RE together determine the tendency of the BDE value to change. As indicated in Scheme 3, both the meta-position N-atom replacement and peripheral disulde bridge substitution cause a destabilizing effect on the neutral molecule (with a negative GE), but an inverse effect exists for the corresponding radical, that is, the meta-position N-atom replacement causes a destabilizing effect (RE ) -3.82 kcal/mol) while the peripheral disulde bridge substitution stabilizes the radical to a much larger extent (RE ) 9.99 kcal/mol). Moreover, we found the value changes for the GE and RE of the combination of the two effects are -4.64 and 3.86 kcal/mol, respectively. It should be noted that the total GE or RE cannot be attributed to the simple linear addition of the two separate effects but exhibits a cutdown effect (viz., for GE, 4.64 kcal/mol <3.17 + 1.63 ) 4.80 kcal/mol, and for RE, 3.86 kcal/mol <9.99 - 3.82 ) 6.17

Antioxidant Properties of Naphthyridine Diol Derivatives

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J. Phys. Chem. A, Vol. 114, No. 2, 2010 1011

kcal/mol). This might be due to the extra mutually attenuated interaction on BDE between N-atom and disulde group. It is clear that the peripheral disulde bridge substitution dramatically reduces the BDE(O-H) value through stabilizing the radical mainly because the disulde substituent leads to a highly delocalized spin distribution, while the meta-position N-atom replacement increases slightly the BDE(O-H) values because the N-atom destabilizes the radical more than the ground-state molecule. When the two effects coexistent, the contribution of the disulde substitution is larger than that of the N-atom replacement, and the total effect is to reduce the BDE(O-H) effectively. The ionization potential is also of signicance for an antioxidant through an H-atom transfer (HAT) mechanism. Nguyens study had shown that the (U)B3LYP/6-311G(d,p) method together with the calibrated equation (IP ) 0.9902IPCalc + 7.7552 (in kcal/mol)) brought IP values in excellent agreement with the experimental results.42 With the method, the IP values of compound 14-17 were calculated and are shown in Scheme 1. The results show that the replacing of N-atoms at the metapositions dramatically increases the IP value by 16.83 kcal/mol,

while the peripheral disulde substitution produces opposite effect by decreasing the IP value by 21.24 kcal/mol, and combining these two effects together only decreases the IP with a small value of 3.00 kcal/mol. Comparing the BDE(O-H) and IP values of compounds 14-17, we can conclude that the peripheral disulde bridge substituent is effective in reducing the BDE and the metaposition N-atom replacement is effective in increasing the IP. Thus the compound incorporating the two effects together may be a potential effective air-stable chain-breaking antioxidant. 3.2. Substituent Effect of Peripheral Chalcogen Element Bridge on BDE(O-H) and IP Values of 1,8-Naphthyridine3,6-diols. According to the discussion above, the peripheral disulde bridge group in conjunction with the introduction of N-atoms is considered to be a good strategy to reduce the BDE(O-H) value to a great extent (8.50 kcal/mol from our calculation) but reduce the IP value to a relatively small extent (3.00 kcal/mol) for 2,7-naphthalene-diol. It encourages us to investigate whether other chalcogen elements (O and Se) could do the same or perform better than sulfur. To address this

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CHART 5

SCHEME 4

TABLE 1: Calculated BDE(O-H) (298.15 K) and IP (0 K) Values of Peripheral Chalcogen Bridge Substituted 1,8-Naphthyridine-3,6-diols (kcal/mol)
compd 18 17 19 X O S Se BDE 78.89 76.66 76.79 IP a 188.14 175.35 171.47

TABLE 2: The HOMO Energies of Compounds 17-19 (hartree)

X)O HOMO -0.23334 X)S -0.21273 X ) Se -0.20821

a IP is calibrated by the equation IP ) 0.9902IPCalc + 7.7552 (in kcal/mol).42

problem, we calculated the BDE and IP of compounds 18 and 19 shown in Chart 5. First of all, it should be noted that there are two representative stable conformers for compounds 17-19, namely, both hydroxyl groups pointing toward or away from the heteroatom (O, S, and Se). The toward conformers have higher single point energies than the away conformers. Therefore, in our calculation, the latter conformer is taken into account and the results are listed in Table 1. It is found that for the substitution with different chalcogen elements, the IP values decrease with O, S, and Se, but the BDE values of 17 and 19 are almost the same, and 18 is the highest. The difference in BDEs can be interpreted by the different conjugational abilities of O-atom and S-, Se-atom with the -system. The disulde group in 17 and diselenium group in 19 are better electron-donating groups than the peroxide group in 18 because of the electron-richness and large atom radii. Furthermore, our calculated results (see Supporting Information, Table S3) show the angle values for OOC4, SSC4, and SeSeC4 are ca. 105 (very close to the value of HOH in H2O), 94, and 91, respectively, in both molecules and radicals. This manifests that O has nearly a sp3 hybridized orbital in 18,

and S, Se have little hybridization in 17 and 19.46 As a consequence, the lone-pair electrons on oxygen are equivalent and display the tetrahedral directions, while those on sulfur and selenium are nonequivalent, namely, one lone-pair of electrons is mainly in the 3s or 4s orbital and the other pair is mainly in the 3p or 4p orbital. As shown in Scheme 4, the nearly equivalent tetrahedral sp3 orbitals of O (Scheme 4, a) are symmetrical with the direction away from the ring plane, but the mainly 3p and 4p orbitals of S and Se (Scheme 4, b) are nearly perpendicular to the ring plane. Thus, the 3p or 4p orbitals can more effectively conjugate with the -system than sp3 orbitals, rendering a more stable radical (consistent with the calculated result of spin density distribution, see Figure S1 in Supporting Information) and thus lower BDE value. The differences in IPs for compounds 17-19 can be explained by the frontier orbital. The ionization potential, which is dened as the amount of energy required to remove an electron from a parent molecule, should have the opposite change trend with the energy of the highest occupied molecular orbital (HOMO), that is the lower the HOMO, the weaker the molecular donating electron ability and then the higher the IP (Table 2). For compounds 18, 17, and 19, the enhancement of the donating electron ability benets from the energy increase of HOMO from O to S to Se, which comes from the conjugation of the lone pair on the chalcogen atom with the -system.47 In summary, on the basis of the calculated results, we can conclude that the peripheral disulde substitution does have a

Antioxidant Properties of Naphthyridine Diol Derivatives

CHART 6

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TABLE 3: Calculated BDE(O-H) (298.15 K) and IP (0 K) Values of 1,8-Naphthyridine-3,6-diol Derivatives (kcal/mol)

compd 15 20 21 22 23 17 R H CH3 CH3O (CH3)2N CH3S -S-SBDE 87.35 83.68 81.37 73.42 84.74 76.66 BDEa 0 -3.67 -5.98 -13.93 -2.61 -10.69 IP b 195.18 185.09 185.46 158.09 186.90 175.35 IP a 0 -10.09 -9.62 -37.09 -8.28 -19.83

a BDE or IP is the difference of BDE or IP value between the derivative and the parent molecule 15. b IP is calibrated by the equation IP ) 0.9902IPCalc + 7.7552 (in kcal/mol).42

better performance than the other two chalcogen elements. Although compound 18 has the highest IP among the three compounds, it also has the highest BDE, whereas compound 17 has the similar scale of BDE with compound 19 but higher IP. On the other hand, compared with R-TOH (BDECalc ) 74.8 kcal/mol, BDEexpt ) 78.3 kcal/mol; IPCalc ) 159.3 kcal/mol16,17), compound 17 still has similar scale BDE and higher IP and could be regarded as a potential antioxidant. 3.3. Comparison of the Substituent Effect of Peripheral Disulde Bridge on BDE(O-H) and IP with Other ElectronDonating Groups of 1,8-Naphthyridine-3,6-diol. It is beyond any question now that the substituent peripheral disulde bridge group can lower the BDE value excellently and still keep the relatively high IP of 1,8-naphthyridine-3,6-diol. Nevertheless, previous studies indicate many strong electron-donating groups, such as CH3O-, CH3S-, and (CH3)2N-, are frequently selected to weaken the phenolic hydroxyl. And some recent works by Pedulli and co-workers deal with the effect of sulfur substituents on the BDE of phenolic OH bonds.48-50 In order to understand if the peripheral disulde bridge could exhibit a unique or better function than other donating groups due to its specic rigid construction, we calculated the BDEs and IPs of some electrondonating compounds shown in Chart 6, and the results are presented in Table 3. The BDEs of compounds 15 and 20-22 decrease from 87.35 to 73.42 kcal/mol in the order of R ) H, CH3, CH3O, (CH3)2N with the increasing ability of electron donating, as shown in Table 3. Although the decrease of BDE(O-H) by dimethylamino is the largest one (13.93 kcal/mol), the decrease of IP is 37.09 kcal/mol, which is much larger than 19.83 kcal/mol decreased by a peripheral disulde group in compound 17. On the other hand, although compound 23 also has two sulfur substituted in 4, 5 positions as compound 17, it has a higher BDE than the latter. So we can conclude that the rigid peripheral disulde bridge group is a very important factor in lowering the BDE of 1,8-naphthyridine-3,6-diol derivatives and keeping a high IP. For the possible origins of the differences above, we would try to give a compendious interpretation from two aspects, spin density distribution of phenoxyl radical and intramolecular hydrogen bonding (IHB). As illuminated in the calculation method section, the O-H bond homolytic dissociation enthalpy [BDE(O-H)] of each molecule is calculated as the enthalpy

Figure 1. The spin density distributions of the corresponding radicals of 15, 17, and 20-23.

change of the eq 4 in the gas phase at 298.15 K, which indicates the BDE value is determined by both the absolute enthalpy of neutral molecule and corresponding radical. Therefore, all efforts based on the SAR to increase the absolute enthalpy of parent molecule and to reduce that of corresponding phenoxyl radical are benecial to lower the BDE value. However, in general, for phenolic antioxidant, the strength of O-H bond has a more close connection with the stability of phenoxyl radical. The more stable the phenoxyl radical is, the lower BDE value will be. The spin density distribution might indirectly reect the stability of a phenoxyl radical in a sense. With the spreading of it, the amount of spin on any atom is diluted and the reactivity lowers. Therefore, in order to get insight into the effect of substitution on the BDE and stability of radicals, the spin density distributions of the corresponding radicals of 15, 17, and 20-23 were calculated and the results are shown in Figure 1. The spin densities on the phenoxyl radical O-atom in substituent compounds are all lower than that on compound 15, and 17 and 22 are the lowest. Meanwhile, on the other positions of phenolic hydroxyl radical, the spin densities have almost the same tendency. Therefore, we can conclude here that the delocalization of spin density is more sufcient with the electron-donating group substituted in the ring of naphthyridine diol, which is favorable to stabilize these radicals and lower BDE values. Then why does the compound 23 have a higher BDE than 17? In order to nd out the possible reasons, the optimized molecular structures of compounds 17, 21, and 23 with lowest electronic energy were investigated and are shown in Figure 2. The CH3-O and CH3-S bonds in 21 and 23 lie in a plane which is nearly perpendicular to the ring skeleton and the adjacent hydroxyl prefers to orient toward the heteroatom X (O or S) as a consequence of the steric repulsion of the two CH3- and the lone-pair stereospecic IHB of oxygen and sulfur. According to Schaefers investigations,46,51,52 the stereospecicity for IHB to oxygen can be interpreted in terms of nearly equivalent lone pairs, while that to sulfur are best discussed in terms of nearly

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TABLE 4: Calculated BDE(O-H) (298.15 K) and IP (0 K) Values of Compounds 24-27 (kcal/mol)

24 BDE IP d Figure 2. The optimized molecular structures of compounds 17, 21, and 23. 74.84 170.55 25 66.15 73.33b 166.29a 164.16b
a

26 72.19 160.15

27 75.07 74.8c 159.67 159.3c

a This BDE(O-H) is for the non-IHB hydroxyl hydrogen. b No H-bonding condition. c Data taken from ref 17. d IP is calibrated by the equation IP ) 0.9902IPCalc + 7.7552 (in kcal/mol).42

nonequivalent lone pairs. Early study53 indicates 3s and 3p orbitals have different r values and 3p valence orbitals extend signicantly beyond the 3s valence orbitals, which may render the less effective hybridization of S-atom and result in the lone pairs on the sulfur nonequivalent. Therefore, there is a strong IHB between the adjacent OH and the directional 3p lone-pair of sulfur in this perpendicular conformation of 23, which is proved by our calculation. The strength of IHBs in 23 is 4.54 kcal/mol, which is higher than that in 21 (see Supporting Information). As we all know, the stronger the IHB forms in the parent molecule, the higher the BDE value of O-H will be (vide infra). Therefore, there is no doubt that 23 has a higher BDE(O-H). Contrary to 23, 17 has the stable conformer with hydroxyl point away from the S-atom. As discussed above, in compound 23, the adjacent polar hydroxyl groups can interact with the nonequivalent 3p lone-pair electrons on pointing to S-atom through the electrostatic attraction and thus twist the 3p lonepair electrons into the ring plane to form intramolecular hydrogen bonding. But, the S-S bond in 17 will prevent the rotation of the 3p orbital round the Csp2-S bond, and the only change is the extending direction of the 3p electron cloud to a small extent. Thus, the most stable conformation taken by 17 is that all the atoms stay in a plane and the hydroxyl is away from heteroatom. With this structure, the 3p orbital on a disulfur group could conjugate with the -system more efciently and render in turn a much lower BDE(O-H). The stereoelectronic effect of the peripheral disulde bridge is similar to that of the heterocyclic ring for R-TOH, which ensures that the 2p-type lone-pair electrons on the ring oxygen adopts an orientation perpendicular to the plane of the aromatic ring and stabilizes the developed phenoxyl radical.54,55 3.4. Novel Class of Antioxidant. The above investigation conrms that the peripheral disulde bridge group could effectively stabilize the naphthalene diol radical and lower the BDE(O-H). Moreover, the meta-position N-atom gives rise to relatively high IP value and in turn could stabilize the neutral molecule in the oxygen-rich environment. Both characteristics

are benecial to a potential antioxidant which acts through the HAT mechanism. Thus a new strategy for antioxidant designing based on the peripheral disulde substitution and the inserting of N-atom into the molecule skeleton is explored. In this section, as a part of the continuing investigation of designing a promising phenolic antioxidant, three special compounds (24-26, Chart 7) are proposed as a new class of potential antioxidants. Table 4 shows the calculated BDE(O-H) and adiabatic IP values of compounds 24-26 and the R-TOH analogue HPMC (27, 6-hydroxy-2,2,5,7,8-pentamethylchroman, its BDE is almost the same as that of R-TOH). The results indicate that the proposed compounds possess lower BDE values than that of HPMC and compound 25 has the lowest value (8.92 kcal/mol lower than HPMC), while the IPs are all greater than that of HPMC. It conrms that these compounds do have a higher activity and stability than that of R-TOH. All these interesting ndings from the calculation data lead us to believe compounds 24-26 could be considered as excellent and promising antioxidants, at least the precursors. The spin density distributions of these three radicals, as well as the reference compound HPMC, were calculated at the UB3LYP/6-311G(d,p) level. The results are shown in Figure 3. The spin densities on the phenolic hydroxyl O-atom in 24, 25, and 26 are 29.23, 21.04, and 26.94%, respectively, while that in HPMC is the largest up to 35.34%. A further observation suggests that the total spin densities on the disulde bridge group are all in excess of 20% in compounds 24-26, and those on the ortho- and para-position of phenoxyl radical are also lower than that of the responding positions in HPMC. Therefore, we can conclude that the high delocalization of spin population due to the peripheral disulde bridge substitution and the planar -system might be more favorable to stabilize these radicals, and which could be considered to be the reason of low BDE values for compounds 24-26. On the other hand, the high delocalization of spin density also reduces the reactivity of phenolic radicals and may retard them from propagating the chain oxidation of a substance.

Antioxidant Properties of Naphthyridine Diol Derivatives

J. Phys. Chem. A, Vol. 114, No. 2, 2010 1015 Compound 26, another conjugative structure compound with only one phenolic OH and one nitrogen atom inserting into the phenolic ring, has an analogous structure to R-tocopherol, but a lower BDE and similar IP with HPMC. This means that the phenyl ring and the peripheral disulde bridge substitution affect more the activity of antioxidant. In summary, on the basis of our theoretical calculation results, three promising compounds were proposed as novel antioxidants or precursors of antioxidants. Despite the fact that the simple predictors (BDE and IP) cannot be the whole story, it is the beginning to design an optimum synthetic antioxidant for a special role in chemical or biological systems, the molecule then can be tuned by attaching a side chain to modify other factors such as solubility and toxicity and so on. 4. Conclusion

Figure 3. Spin density distributions of corresponding radicals of compounds 24-26 and reference compound HPMC.

SCHEME 5

Compound 24 is a typical one among the naphthyridine diols discussed above, and it is not surprising that it has low BDE and high IP. But, as an isomer of 24, the BDE value for compound 25 is much lower. The reason could attribute to the intramolecular hydrogen bonding between two hydroxyl groups. Generally, in an adjacent two hydroxyl group system, the IHB effect is much complicated because it exists both in a parent molecule and corresponding radical.18,56 The formation of IHB in a radical is favorable to reduce the BDE value, while in a molecule that will give rise to an opposite effect. Thus the net result is determined by the total effect of these two aspects. Here, the energy of IHB is dened as the difference for an OH group coplanar with the aromatic ring pointing away from and toward an H-bonding acceptor. The calculated results manifest IHB enthalpies in a parent molecule and corresponding radical are estimated to be 5.40 and 12.58 kcal/mol, respectively (Scheme 5). The higher moiety (12.58 - 5.40 ) 7.18 kcal/ mol) would be additional contribution to lower the BDE value. From the molecule structure of compound 25, we can also nd the IHB in a radical is stronger than that in a molecule. The hydrogen bond length in a radical, 1.7948 , is obviously shorter than that in a parent molecule, 1.9137 (Scheme 5). Thus, the IHB must be considered to be another important factor to design the HAT activity of antioxidant.

In this work, the naphthyridine diols as a novel antioxidant were studied in detail by DFT calculation. Compared with naphthalene diol, the insertion of nitrogen atoms into the naphthalenic ring can only slightly change the BDE of O-H bond but dramatically enhance the IP of the parent molecule, whereas the substituent of a peripheral disulde bridge group is very efcient in reducing the BDE. With the incorporation of these two aspects, a novel antioxidant was developed which was expected to be more active and more stable than the wellknown R-tocopherol antioxidant. Compared with other strong electron-donating substituents, the peripheral disulde bridge dramatically reduces the BDE(O-H) values through stabilizing the developed radical mainly. It is similar with the stereoelectronic effect of the heterocyclic ring for R-TOH and leads to a highly delocalized spin distribution. The unique function of the specic rigid disulde bridge construction is of signicance for antioxidant design. All these interesting ndings from the calculation lead us to believe compounds 24-26 could be considered as promising antioxidants. They all have the lower BDE and higher IP than R-TOH. We think the strategy proposed in this research would provide a novel way for designing an effective antioxidant, and we are currently attempting to synthesize these compounds. Results of this investigation will be reported in a future publication. Acknowledgment. The authors gratefully acknowledge nancial support from National Natural Science Foundation of China (No. 20574039) and the General Foundation of Tianjin Science Committee for Applied Basic Research (No. 07JCYBJC02700). We also acknowledge support from Nankai University ISC. A. Yu thanks Dr. P. Cheng for a discussion and some help with the English. Supporting Information Available: Calculated gas-phase thermodynamic data of the molecules and their corresponding species of compounds 14-27, spin density distribution of radicals 18 and 19, detailed discussion of two representative stable conformers for compounds 17-19, and the IHB strenghts of compounds 21 and 23. This material is available free of charge via the Internet at http://pubs.acs.org. References and Notes
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