H bond dissociation

Computational and Theoretical Chemistry 1077 (2016) 87–91

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Monohydroxy flavones. Part IV: Ehthalpies of different ways of O–H bond dissociation Maria H. Vakarelska-Popovska, Zhivko Velkov ⇑ Department of Chemistry, South-West University ‘‘Neofit Rilski”, Blagoevgrad, Bulgaria

a r t i c l e

i n f o

Article history: Received 22 August 2015 Received in revised form 12 October 2015 Accepted 31 October 2015 Available online 12 November 2015 Keywords: Antioxidant activity Enthalpies Flavones

a b s t r a c t The flavonoids with antioxidant properties are polyfunctional compounds in general but their activity is associated with a specific hydroxyl group. In this study we present the enthalpy of all ten monohydroxy flavones calculated by a quantum-chemical method. The optimization of the geometry has been performed with the B3LYP functional and the standard 6-311++G(d,p) basis set. The objective is to estimate the effect of the position of a hydroxyl group on the radical-scavenging activity of these compounds. The results have shown that the most expected mechanism for the reaction of monohydroxy flavones with active radicals in water is SPLET. Ó 2015 Elsevier B.V. All rights reserved.

1. Introduction The nutritive value of fruits and vegetables is due mainly to the various phenolic antioxidants, and especially to the flavonoids [1]. The daily intake of flavonoids is significantly higher compared to other phenolic antioxidants and carotenoids [2]. The modern man is exposed to drugs, air pollution, increased UV radiation and toxic substances that are contained in food and water. These factors and different chronic diseases increase the concentration of active radicals in the human body. This makes the intake of antioxidants mandatory. The flavones are a class of flavonoids possessing a 2-phenylchromen-4-one (2-phenyl-1,4-benzopyrone) structure. A double bond between atoms 2 and 3 in ring C combines the p-electron system of the molecule, and enhances the radicalscavenging activity and as a consequence their antioxidant activity [3]. The two terms do not overlap completely and we are conscious of it. Flavones are the subject of many quantum-chemical studies in the recent years [4–10]. This is why thermodynamic functions, energies of highest occupied orbitals, spin densities, and more, are being calculated. Flavonoids and, in particular, flavones possess a variety of biological activities. Therefore, the object of most quantum-chemical studies is natural or synthetic flavonoids, with biological activity [1,3–7]. Articles of this type are widely quoted. These molecules, however, own several different hydroxyl, methoxyl and other

⇑ Corresponding author. http://dx.doi.org/10.1016/j.comptc.2015.10.033 2210-271X/Ó 2015 Elsevier B.V. All rights reserved.

groups. In such articles, the contribution of every separate hydroxyl group in the mechanism of reaction with active radicals cannot be precisely evaluated. The object of this study is the isomeric monohydroxy flavones. What we will try to compare is the reactivity of monohydroxy flavones toward radicals, according to the position of the hydroxyl group therein. Here we will stress on the particular role of the position of the hydroxyl group on the reactivity in all ten isomers. Undoubtedly, the number and positions of the hydroxyl groups have strong influence on the radical-scavenging activity [11]. The various flavones react with active radicals following different mechanisms. This study should give a clear answer to the question which hydroxyl groups are more likely to react with radicals and by what mechanism the reaction would proceed. The reaction between the phenolic antioxidants and radicals can occur by several mechanisms (Fig. 1) [12–16]: (i) An electron transfer from the antioxidant to the active radical, which produces a cation–radical and an anion. The electron transfer is followed by proton transfer from the cation–radical to the anion (SET–PT). (ii) Direct hydrogen atom transfer between the antioxidant and the active radical (HAT). (iii) Deprotonation of the antioxidant followed by electron transfer from the resulting anion to the active radical. The next step is a protonation of the anion produced by the active radical (SPLET). Some authors differentiate fourth way for phenolic type antioxidants: proton-coupled electron-transfer (PCET) [13,17]. In the PCET mechanism, a radical (R) possesses one, or two, lone pairs of electrons on the atom that bears the unpaired electron, a hydrogen-bond complex is formed between the –OH and a lone pair on R. The proton is then transferred from its two bonding electrons to the radical’s lone pair with the

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M.H. Vakarelska-Popovska, Z. Velkov / Computational and Theoretical Chemistry 1077 (2016) 87–91

3'

H

2' 1 O

8

4'

1'

7

5'

2

6'

+

R +H

R (ii)

R

Ao + R-H

R

+H

-H

4

5

Ao-H

Ao-H

3

6

(i)

e-

(iii)

O

Ao

+

R

e-

Fig. 1. General structure of a flavone.

kJ/mol

Scheme 1. The main reaction mechanisms of radical-scavenging.

450 400 350 300 250 200 150 100 50 0 -50 F-6’* F-3 -100

IP PDE PA ETE BDE

F-5ʹ F-4ʹ

F-5

F-3ʹ

F-6

F-2ʹ

F-7

F-8

Monohydroxy flavones

Fig. 2. Chart of the calculated enthaplies.

accompanying electron moving from the lone pair on the phenol’s oxygen atom to the radical’s singly occupied molecular orbital. The formation of a complex with a hydrogen bond between Ao–H and R causes the reaction to be entropically disfavored. However, a formation of a hydrogen bond complex also has effects that strongly favor a reaction, whether by the HAT or PCET mechanism. Thus, the formation of the complex causes the O atom in AoH and the radical center to approach each other more closely than they would if a hydrogen bond was not formed. The mechanisms shown in Fig. 1 address only the formation of the final stable radical Ao and do not account for any subsequent transformations of this radical. (Scheme 1). The first step of mechanism (i) Single Electron Transfer–Proton Transfer (SET–PT) is described by the ionization potential (IP) or sometimes by energy of highest molecular orbital according to Koopman theorem [18,19]. The second step as a rule is faster and can be described by proton dissociation enthalpy (PDE) defined by Eq. (4). Mechanism (ii) (HAT) dominates when Bond Dissociation Enthalpy (BDE) is low (Eq. (2)). Mechanism (iii) (SPLET) is expected to occur in antioxidants with easily deprotonated functional group as phenolics. SPLET is feasible when a hydroxyl group is acidic: low proton affinity (PA) and low electron transfer enthalpy (ETE) as they are defined (Eqs. (5) and (6)) (see Fig. 2). Normally, the free energy represents a criterion of the thermodynamically preferred process. Klein and co-authors have found for the investigated reaction that the absolute values of the entropic term (TDrS) is much smaller than the enthalpic therm [20]. Therefore, comparison of BDEs, IPs, PDEs, PAs and ETEs can show which mechanism is thermodynamically preferred. 2. Computational details The calculations were carried out using the DFT, as implemented in the Gaussian09 program package [21]. The optimization of the geometry was performed with the Becke 3-parameter hybrid

exchange functional combined with the Lee–Yang–Parr correlation functional (B3LYP) with the standard 6-311++G(d,p) basis set [22]. The optimization was achieved without any geometry constraints. For all structures the harmonic vibrational frequencies were computed to confirm the true minima on the calculated potential surface. All possible intramolecular interactions were taken into account in the initial geometries. Solvent effects on the calculated structures were investigated with the self-consistent reaction field (SCRF) method, via the polarized continuum method (PCM) [23]. The total enthalpies of the species X are usually estimated from the equation:

HðXÞ ¼ E0 þ ZPE þ DHtrans þ DHrot þ DHvib þ RT

ð1Þ

where E0 is the calculated total electronic energy, ZPE stands for zero-point energy, DHtrans, DHrot, and DHvib are the translational, rotational and vibrational contributions to the enthalpy. Finally, RT represents pV-work term and is added to convert the energy to the enthalpy. Total enthalpies were calculated at T = 298 K. ZPE values were not scaled [24]. From the calculated total enthalpies, we have determined the following descriptors:

BDE ¼ HðArO Þ þ HðH Þ  HðArOHÞ

ð2Þ

IP ¼ HðArOH þÞ þ Hðe Þ  HðArOHÞ

ð3Þ

PDE ¼ HðArO Þ þ HðHþÞ  HðArOH þÞ

ð4Þ

PA ¼ HðArOÞ þ HðHþÞ  HðArOHÞ

ð5Þ

ETE ¼ HðArO Þ þ Hðe Þ þ HðArOÞ

ð6Þ

3. Results and discussions 3.1. O–H bond dissociation enthalpies (BDE) Calculated O–H BDE values are compiled in Table 1. The lowest BDE in vacuo has the hydroxyl group in 6-hydroxyflavone (338.754 kJ/mol) and 60 -hydroxyflavone (339.920 kJ/mol). Six isomers are close to them – F-8 (342.057 kJ/mol), F-40 (344.535 kJ/mol), F-50 (352.932 kJ/mol), F-7 (355.807 kJ/mol), F-30 (356.844 kJ/mol) and F-20 (359.989 kJ/mol). It is more difficult to dissociate two hydroxyl groups – F-3 (410.070 kJ/mol) F-5 (411.406 kJ/mol). These BDE values are indicative for the propensity of the isomers to react by HAT mechanism in nonpolar solvents.

M.H. Vakarelska-Popovska, Z. Velkov / Computational and Theoretical Chemistry 1077 (2016) 87–91 Table 1 O–H bond dissociation enthalpies. Flavone

BDE/vac (kJ/mol)

BDE/PCM

F-60 a F-50 F-40 F-30 F-20 F-3 F-5 F-6 F-7 F-8

339.920 352.932 344.535 356.844 359.989 410.070 411.406 338.754 355.807 342.057

341.787 350.613 345.066 396.037 352.029 358.429 384.808 344.099 360.115 340.784

a The digits in the first column correspond to the place of the hydroxyl group in the flavones (see Fig. 1).

Table 2 Calculated ionization potential, proton dissociation enthalpy, proton affinity and electron transfer enthalpy. Flavone 0a

F-6 F-3 F-50 F-40 F-5 F-30 F-6 F-20 F-7 F-8

IP (kJ/mol)

PDE (kJ/mol)

PA (kJ/mol)

ETE (kJ/mol)

378.574 347.814 392.332 365.190 369.658 381.365 371.738 379.341 392.692 381.872

40.715 18.540 45.646 24.052 11.222 34.430 31.566 31.240 36.504 45.016

104.267 127.960 127.117 108.668 152.742 127.267 123.880 123.160 106.436 115.683

233.592 201.314 219.569 232.471 228.139 219.669 216.292 224.941 249.752 221.173

a The digits in the first column correspond to the place of the hydroxyl group in the flavones. H(e) = 232.676 kJ/mol; H(H+) = 1083.803 kJ/mol according [22].

It can be seen from the formula in the previous section, all structural factors which stabilize the radical and destabilize the hydroxyflavone reduce BDE. As we have concluded in earlier studies [25], important stabilizing factor in hydroxyflavones is the effective electron density transfer from the hydroxyl group to the carbonyl oxygen at 4th position. It is not possible to draw out electoron density from the hydroxyl group at position 6. Therefore, the isomer F-6 is not sufficiently stable and as a result the O–H BDE is the lowest. The reason for the small O–H BDE in the 60 -hydroxyflavone is different. There is an orbital interaction between the hydroxyl oxygen and the hydrogen at 3th position. This orbital interaction stabilizes well the resulting radical and, hence, decreases O–H BDE. The isomers with the highest O–H BDE are F-3 and F-5. The hydroxyl group of the F-3 isomer is not a typical phenolic hydroxyl group, and the resulting radical is very unstable. For homolytic cleavage of O–H bond in the isomer F-5, it is necessary to also tear a very strong hydrogen bond with the carbonyl oxygen, which greatly increases the BDE. In water medium, four isomers have low BDE: F-8 (340.784 kJ/ mol), F20 (341.787 kJ/mol), F-6 (344.100 kJ/mol) b F-40 (345.066 kJ/ mol). Other four have average BDE: F30 (350.614 kJ/mol), F-60 (352.029 kJ/mol), F3 (358.430 kJ/mol) b F-7 (360.115 kJ/mol) and two isomers have very high BDE – F-5 (384.808 kJ/mol) and F-50 (396.037 kJ/mol). Obviously, the polarizing effect of the water is a factor which affects BDE with the same force as the intramolecular factors. Isomers F-60 , F-50 , F-40 , and F-8 amend their BDE with nearly 2 kJ/mol in water, but F-20 , F-30 , F-3, F-5, F-6 and F-7 amend more. The reasons for these changes are various. BDE reduces in isomers F-20 , F-3 and F-5 possessing intramolecular H-bond, but in isomers F-30 , F-6 and F-7 BDE increases. Obviously, aqueous environment

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reduces the strength of the intramolecular hydrogen bonds. Thereby, this destabilizes the hydroxyflavone and thus reduces the BDE. On the other hand, aqueous environment assists distribution of p-electron density, stabilizes molecules (without intramolecular H-bonds) and this leads to an increase in the BDE. In reaction with the radicals, even in polar solvents, the first four compounds react by bimolecular mechanism (HAT). For the latter two compounds (F-30 and F-5), they cannot be expected to react with radicals in the same way. Our BDE values are lightly higher than those found in the literature on bioactive flavones. It is reasonable to expect flavonoids with second or third hydroxyl group to have lower BDE. Our BDE values are lightly lower than those found in the literature on 3-hydroxy flavone (376.1416) and 7-hydroxy flavone (385.3464) which probably due to different orbital basis [26]. The comparison of BDE with five OH groups of quercetin would give the evaluation of other hydroxyl groups influences. The difference between our results (358.429 and 360.115) and those of hydroxyl groups at position 3 and 7 in quercetine (350.200 and 370.7024) are less than 3%. The difference between BDE of OH group at 30 -position of quercetin (322.168) and our 30 -hydroxy flavone (396.037) is 18.6%. For hydroxyl group at 40 -position in quercetine (312.1264) and our monohydroxy flavone (345.066) the difference is 9%, and for hydroxyl group at position 5 in quercetin (415.4712) and our result (384.808) differs with 7.9% [27]. The presence of other hydroxyl groups in ring B and C decreases BDEs of hydroxyl groups at position 30 , 40 and 3, but increases BDEs of hydroxyl groups at position 5 and 7 in ring A. Comparing these results with our earlier results obtained with lower orbital basis (6-31G⁄⁄), it can be seen that the values of BDE are very similar [25], except those of F-5. Clearly, the addition of the diffuse functions greatly strengthen the hydrogen bond in this isomer.

3.2. Ionization potential (IP) IP is indicative for the propensity of the investigated compounds to participate in the SET–PT mechanism (Scheme 1(i)). Realization of SET–PT and SPLET in a nonpolar environment is not expected because of the formation of charged species. Therefore, we will comment only on thermodynamic functions calculated by taking into account the polarizing effect of the water. BDE and IP have close values. The comparison of the two tables (Tables 1 and 2) demonstrates the propensity of each of the isomers to take part in BDE or SET–PT mechanism. This comparison will show which of the isomers is more prone to react and why. The row of decreasing activity of monohydroxy flavonoids is as follows: F-3 > F-40 > F-5 > F-6 > F-60 > F-20 > F-30 > F-8 > F-50 > F-7. The most active isomer in this row is F-3 – it is the only monohydroxy flavon in which the hydroxyl group is not a typical phenolic. The difference between IPs of this isomer and the following one in this row is more than 17 kJ/mol. This monohydroxy flavon in the aquatic environment will react mainly by SET–PT mechanism. Its enthalpy of dissociation of the O–H bond (BDE) is 10.615 kJ/mol higher than its IP. The difference between second and seventh compound in the IP row (F-40 , F-5, F-6, F-60 , F-20 , F-3, F-8) is not significant. Only F-6 and F-60 in this group differ by 6.836 kJ/mol. The monohydroxy flavones F-50 and F-7 have the highest IP. They are characterized by more than 10 kJ/mol in comparison with the last isomer in the group of seven isomers mentioned above. Its propensity to lose an electron is significantly lower than to give a hydrogen.

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M.H. Vakarelska-Popovska, Z. Velkov / Computational and Theoretical Chemistry 1077 (2016) 87–91

In a series of molecules with different substituents, the compounds with electron-donor substituents have lower IP, and with electron-acceptor – the IP is higher [28]. Within our group of ten isomeric monohydroxy flavons, we haven’t found structural reasons for the differences in IP – there is no correlation between BDE and IP. 3.3. Proton dissociation enthalpies (PDE) According to the SET–PT mechanism, the initial detachment of an electron and the formation of a cation–radical is followed by proton separation. The final product is the same as in a HAT mechanism. (Scheme 1). The PDE shows the thermodynamic tendency of individual hydroxyl groups to dissociate in radical–cations. Therefore, IP is a global descriptor for the investigated molecules, and PDE is a local descriptor for the hydroxyl groups. There is not much data in the literature for PDE of phenols [4,29]. All obtained results show that the dissociation of a proton is a process with lower energetic cost in the SET–PT mechanism. So it is in our case (see Table 2). As it can be expected, there is a significant linear correlation between PA and PDE. 3.4. Proton affinity (PA) PA represents the reaction enthalpy of proton dissociation from the hydroxyl group (the first step in the SPLET mechanism). F-60 , F-7 and F-40 are the most acidic isomers (Table 2). A reason for the high acidity of the three isomers is the transfer of electron density to the carbonyl oxygen. In addition, the stabilization of the anion, by means of an orbital interaction with hydrogen at position 3, is decisive for the highest acidity of F-60 . Those six isomers have an average acidity – F-8, F-20 , F-6, F-50 , F-30 and F-3. There is not an effective electron density transfer to the carbonyl oxygen in F-8, F-20 , F-6, F-50 . The lowest in acidity isomers are F-3 and F-5. The reason for this is that the hydroxyl group in F-3 is not a typical phenolic and the OH group of F-5 is involved in a very strong hydrogen bond which is the determinging factor for the reduction of acidity. The proton dissociation, however, is the step with low energetic cost in SPLET mechanism. More important is how the considered isomers are sorted according to their leaning of corresponding anion to give an electron. 3.5. Electron transfer enthalpies (ETE) ETEs demonstrate the propensity of the corresponding anions to donate electrons. The detachment of an electron from the anion of 3-hydroxy flavone is the process with the lowest energetic cost. Removal of an electron from eight anions (F-6, F-50 , F-30 , F-8, F-20 , F-5, F-40 , and F-60 ) is not so difficult. The detachement of an electron from F-7 is the most costly. This is no surprise. Usually the detachment of an electron from the most stable anion is the most difficult one. Obviously, the separation of an electron from an anion is more difficult than the dissociation of a proton from a monohydroxy flavone. Therefore, the process with high energetic cost in SPLET mechanism in the electron abstraction for the investigated compounds. The discussed row consequently demonstrates the tendency of the different isomers to participate in reaction with radicals by SPLET mechanism. 4. Conclusion Different enthalpies have been calculated for the ten isomeric monohydroxy flavones.

The data reported here reveals that SPLET is the preferred mechanism of a reaction with active radicals, independently of the position of the hydroxyl group in an aqueous medium. The enthalpies of dissociation of O–H bond and electron separation from molecules (HAT and SET–PT mechanisms) are more than 100 kJ/mol higher than the entalpies of electron separation from the anions (SPLET mechanism). The detachment of an electron from the anion of 3-hydroxy flavone is the process with the lowest energetic cost Fig. 2.

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