A DFT study on the mechanism and kinetics of reactions of pterostilbene with hydroxyl and hydroperoxyl radicals

Accepted Manuscript A DFT Study on the Mechanism and Kinetics of Reactions of Pterostilbene with Hydroxyl and Hydroperoxyl Radicals Juan J. Guardia, Mónica Moral, José M. Granadino-Roldán, Andrés Garzón PII: DOI: Reference:

S2210-271X(15)00444-2 http://dx.doi.org/10.1016/j.comptc.2015.11.004 COMPTC 1985

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Computational & Theoretical Chemistry

Received Date: Revised Date: Accepted Date:

18 September 2015 5 November 2015 5 November 2015

Please cite this article as: J.J. Guardia, M. Moral, J.M. Granadino-Roldán, A. Garzón, A DFT Study on the Mechanism and Kinetics of Reactions of Pterostilbene with Hydroxyl and Hydroperoxyl Radicals, Computational & Theoretical Chemistry (2015), doi: http://dx.doi.org/10.1016/j.comptc.2015.11.004

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A DFT Study on the Mechanism and Kinetics of Reactions of Pterostilbene with Hydroxyl and Hydroperoxyl Radicals

Juan J. Guardia,1 Mónica Moral,2,* José M. Granadino-Roldán,3 and Andrés Garzón4 1

Departamento de Química Orgánica, Facultad de Ciencias, Instituto de Biotecnología, Universidad de

Granada, C/ Severo Ochoa s/n, 18071, Granada, Spain 2

Instituto de Investigación de Energías Renovables, Universidad de Castilla−La Mancha, Paseo de los

Estudiantes s/n, 02071 Albacete, Spain 3

Departamento de Química Física y Analítica, Facultad de CC. Experimentales, Universidad de Jaén,

Campus Las Lagunillas, s/n, 23071, Jaén, Spain 4

Departamento de Química Física, Facultad de Farmacia, Universidad de Castilla−La Mancha, Paseo

de los estudiantes s/n, 02071 Albacete, Spain

Abstract The mechanism and kinetics of pterostilbene reactions with •OH and •OOH radicals were studied in gas and aqueous phases through Density Functional Theory (DFT). For the pterostilbene + •OH reaction in gas phase, the addition of •OH to unsaturated carbons is kinetically favored with respect to the direct hydrogen-abstraction from the hydroxyl group. In aqueous solution, •OH should react at diffusion controlled rate with pterostilbene via hydrogen abstraction or adduct formation. For pterostilbene + •OOH reaction in gas phase, the highest rate constant was obtained for hydrogen abstraction pathway in the hydroxyl group. In solution, only the hydrogen-abstraction mechanism is thermodynamically favored.

1. Introduction Hydroxyl (•OH) and peroxyl (•OOR) radicals are reactive oxygen species (ROS) which are constantly being formed in the human body, being the mitochondrion a major intracellular source of ROS. Those radicals can damage macromolecules essential to life such as proteins, lipids and DNA, and therefore their removal by antioxidant defenses is 1

needed [1–4]. Although there exists a causal relationship between intracellular ROS and aging, it has not been possible to distinguish whether a chronic oxidative stress is a result of an age-related increase in ROS production or whether the increase in ROS production hastens the aging process [3]. In any way, a relationship between ROS production, senescence and the pathogenesis of degenerative diseases is typically found in aged populations [5]. Phenolic compounds can be naturally found in some foods and medicinal plants, and beneficial properties such as antioxidant and radical scavenging activities are generally attributed to them [6–11]. It is generally assumed that the reactions between phenolic compounds and ROS proceed through five main mechanisms: direct hydrogen atom transfer (HAT) and proton-coupled electron transfer (PCET) from the antioxidant molecule (eq 1); single-electron transfer (SET, eq 2a), which can be followed by a subsequent proton transfer process (sequential electron-proton transfer or SEPT, eqs 2a and 2b); radical adduct formation (RAF, eq 3); and sequential proton loss electron transfer (SPLET) (eqs 4a and 4b) [12–20]: •OX + ArOH → XOH + ArO•

(1)

•OX + ArOH → XO– + ArOH•+

(2a)

XO– + ArOH•+ → XOH + ArO•

(2b)

•OX + ArOH → XO–ArOH•

(3)

ArOH → ArO– + H+

(4a)

ArO– + •OX → ArO• + XO–

(4b)

Trans-resveratrol (trans-3,5,4-trihydroxystilbene) is a polyphenol found in a variety of plant species such as grapes, berries and peanuts [21,22]. The biological activity of this compound has been widely studied in the last years revealing potential 2

health benefits such as good antioxidant activity, free radical scavenging, as well as estrogenic, anti-inflammatory and anticancer activities [22–24]. Its antioxidant activity seems to be related to its hydroxyl groups, which can scavenge free radicals produced in vivo as it has been shown that if the hydroxyl groups are eliminated or replaced by methoxyl groups, the molecule can lose its activity [25–29]. On the contrary, Rossi et al. have reported that methoxylated derivatives of trans-resveratrol such as pterostilbene and 3,5,4-trimethoxystilbene can be more efficient antioxidants in reducing DNA damage than the pristine compound, being the highest protective activity that exerted by the compound with only one hydroxyl group (i.e. pterostilbene, see Chart 1) [30]. Therefore, additional insight into the molecular mechanism of the antioxidant activity of trans-resveratrol and pterostilbene is needed. Our aim in the present work is to study the reactions of •OH and •OOH radicals with pterostilbene by means of the Density Functional Theory (DFT). The results will be compared with those previously reported for the corresponding reactions of trans-resveratrol [31].

OH HO

trans-resveratrol

OH

OH H3CO

OCH 3

pterostilbene OCH 3

H3CO

OCH 3

3,5,4-trimethoxystilbene

Chart 1. Chemical structures of trans-resveratrol and methoxylated derivatives. 3

2. Computational Details Gaussian09 Rev. D.01 has been employed for all the calculations [32]. The reagent and transition state (TS) geometries were optimized at the M06-2X level [32], along with the 6-311+G** basis set. M06-2X is especially recommended for thermodynamic and kinetic calculations [32,33]. An initial conformational analysis was carried out for the reagents to obtain the lowest energy conformation. The nature of the stationary points was assessed by means of the normal vibration frequencies calculated from the analytical second derivatives of the energy. First-order saddle points, which are related to transition states, must show an imaginary value for the hessian eigenvector primarily describing the product formation step, whereas the real minima of the potential energy hypersurface, which are related to stable species, have to show positive real values for all of the vibrational frequencies. In addition, intrinsic reaction coordinate calculations at the M06-2X/6-311+G** level were carried out to assess each reaction pathway. Rate constants (k) were calculated through the thermodynamic formulation of the Transition State Theory (TST):  


=



 exp −

∆  



(5)

where kB and h are the Boltzmann and Planck constants, respectively. Gibbs free energy barriers (∆G⧧) were computed at 298.15 K. The tunneling effect along the reaction coordinate has been accounted for by means of the transmission coefficient χ(T) given by Wigner´s model ) = 1 +





| ∗| 



 



(6)

where ω* is the TS imaginary frequency [34−37]. Thus, the final expression for the rate constant (kW) becomes 4


 = )


(7)

As the mechanism involving SET processes is concerted, ∆G⧧ was calculated using the Marcus Theory [38-40]. The activation barrier is defined in terms of the free energy of reaction (∆G0) and the internal reorganization energy (λ) through the equation ∆

!

"

= 1 + 

# $ "



(8)

λ was estimated by using the so-called four-point method λ1 = E0(G*) – E0(G0)

(9)

λ2 = E*(G0) – E*(G*)

(10)

λ = λ1 + λ2

(11)

where E0(G0) and E*(G*) are the ground-state energies of the neutral and ionic states, respectively. E0(G*) is the energy of the neutral molecule at the optimal ionic geometry; E*(G0) is the energy of the charged state at the optimal geometry of the neutral molecule [41,42]. Solvent effects were included by using the SMD [43] continuum solvation model, which describes the quantum mechanical charge density of a solute molecule interacting with a continuum description of the solvent. The performance of SMD for the prediction of solvation free energies has been tested on a set of 61 small molecules with a reasonable level of accuracy [44]. In solution, some of the calculated k values can be close to diffusion-limit rate constants. For diffusion-controlled bimolecular reactions the apparent rate constant (kapp) can be obtained through [45,46]  


%&& =  ( '

'

(12)

being kD the steady-state Smoluchowski rate constant for an irreversible bimolecular diffusion-controlled reaction [47] which can be calculated as follow: kD = 4π r DAB NA

5

(13)

where r, NA, and DAB are the reaction distance, the Avogadro number, and the mutual diffusion coefficient of reactants A (free radical) and B (antioxidant). DAB was calculated as the sum of the individual diffusion coefficient of the reagents (Di), which were in turn estimated from the Stokes−Einstein approach  

 )* = + , - %

(14)

where η corresponds to the viscosity of the solvent (η = 8.9 × 10 −4 Pa s for water) and a is the radius of the solute molecule [48−50]. If the studied compound can donate protons, experimental pKa values are useful to analyze the role of the SPLET mechanism. To the best of our knowledge there are no pKa values reported for pterostilbene. However, pKa can be estimated through the proton exchange method (also known as isodesmic method) [51,52]. Under this approach the pKa is estimated as ∆ $

./% 01) = 234) + ./% 05)

(15)

where pKa(HR) is an experimental pKa value reported for a reference compound, HR, which should be structurally similar to the studied system. In our case, phenol was chosen as reference compound (pKa(HR) = 10.09) [53]. ∆G0 must be also calculated for the following reaction: ( 016) → 06) + 186)

(16)

where HA(s) corresponds to the compound for which pKa is estimated (pterostilbene) in aqueous solution. As it is well known that computational methods poorly reproduce the solvation energies of the proton. A free energy of –270.28 kcal mol–1 in aqueous solution was used for it following the recommendation of Camaioni and Schwerdtfeger [54].

3. Results and Discussion 6

The gas phase optimized structure and atom numbering of pterostilbene are shown in Fig. 1. The twisted molecular structure of pterostilbene, with a dihedral angle τ(C1-C2-C5-C6) of –40.8º, contrasts with the near-planar structure computed in water solution (using SMD model) where τ(C1-C2-C5-C6) amounts to –5.7º. An optimized planar structure at the M05-2X/6-311G** level has been also reported for transresveratrol in water [30]. As discussed above, a large number of possible reactions can occur between phenolic compounds and free radicals. They can distinguish into two general kinds of mechanisms: radical addition (RAF) and hydrogen atom abstraction. The abstraction can occur in a direct way (HAT/PCET) or according to more complex mechanisms such as SEPT and SPLET. In a first approximation, we will study the reactions in gas phase and only RAF and HAT mechanisms will be considered due to ∆G⧧ barriers as high as 150 kcal mol-1 were obtained for the SET mechanism. In a second step, solvent effects will be taken into account. To simplify the study (there is a considerable number of chemically different hydrogen atoms in the studied molecule) we decided not to consider more H-abstraction pathways than those related to -OH and -C(3)H=C(4) Hgroups. The transition states corresponding to the addition pathways were computed in both sides of the reagent and distinguished as a and b (see Figure 1). Different transition states were named TSn(a/b), where n indicates the position attacked by the •OX species. Thus, TS1, TS2 and TS5 correspond to transition states in which •OX is involved in a HAT mechanism, whereas the RAF mechanism occurs through TS3a(b) and TS4a(b). Fig. 1 shows different transition states found for the reactions of pterostilbene with •OX, whereas their main geometrical parameters can be found in Table 1.

7

Fig. 1. Different transitions states found for pterostilbene + •OH reaction (in gas phase) and pterostilbene + •OOH reaction (in aqueous phase).

8

Table 1 Main geometrical parameters (r for bond lengths and α for angles) calculated for the predicted transition states. Data corresponding to reactions in aqueous solution appear within parentheses. Pathway Geometrical parameter •OH reactions •OOH reactions TS1HAT r[(>CH)O…H(•OH)] (Å) a 1.003 1.109 (1.082) r[(-O)H…•O(H)] (Å) b 1.497 1.270 (1.329) α[(>CH)O…H…•O(H)] (degrees) 151.4 163.2 (163.9) TS2HAT r[>C…H(•OH)] (Å) a 1.192 1.363 (1.320) r[(>C)H…•O(H)] (Å) b 1.344 1.158 (1.204) α[(>C…H…•O(H)] (degrees) 165.8 169.9 (171.8) TS3aRAF r[>(H)C…•O(H)] (Å) b 2.167 1.962 (2.022) RAF TS3b r[>(H)C…•O(H)] (Å) b 2.182 1.956 (2.007) TS4aRAF r[>(H)C…•O(H)] (Å) b 2.227 1.975 (2.041) TS4bRAF r[>(H)C…•O(H)] (Å) b 2.207 1.978 (2.041) TS5HAT r[>C…H(•OH)] (Å) a 1.197 1.375 (1.350) r[(>C)H…•O(H)] (Å) b 1.339 1.148 (1.178) α[(>C…H…•O(H)] (degrees) 160.9 163.7 (170.1) a

b

Corresponding to the bond being broken in the transition state Corresponding to the bond being formed in the transition state

For pterostilbene + •OH reaction in gas phase, TS1 HAT shows a geometry close to the reagents in which the breaking O···H bond length is 1.003 Å, whereas the forming H···O bond is significantly longer (1.497 Å). The geometry found for the rest of transition states involving H-abstraction pathways (TS2 HAT and TS5 HAT) is intermediate between the geometries of reagents and products (the breaking C···H bond length and the forming H···O bond length are around 1.19 – 1.20 and 1.34 Å, respectively). For the RAF mechanism (TS3 RAF and TS4RAF), •OH interacts with unsaturated carbons through an O···C bond length which lines in the range 2.17 − 2.23 Å. Table 2 summarizes activation (∆G⧧) and reaction (∆rG) Gibbs free energies and kinetic rate constants (k and kW) calculated for the HAT and RAF reaction pathways corresponding to the pterostilbene + •OH reaction. As can be seen, the most exergonic pathway corresponds to TS1 HAT followed by the RAF mechanisms. On the other hand, the lowest free energy barriers were calculated for TS4RAF, while near energy values were also found for TS1HAT and TS3 RAF (∆∆G⧧ ≤ 0.83 kcal mol-1). Consequently, the highest k was obtained for the addition mechanism through TS4 RAF which is about three times higher than the value calculated for the abstraction pathway TS1HAT. 9

Table 2

Activation (∆G⧧) and reaction (∆rG) Gibbs free energies calculated for the most relevant HAT and RAF pathways of pterostilbene + •OH reaction Pathway ∆rG (kcal k (L mol−1 v* χ(T) kW (L mol−1 ∆G⧧ (kcal −1 −1 −1 −1 mol ) s ) (cm ) s−1) mol ) HAT 8 TS1 5.44 –33.32 6.39×10 –1787.5 4.10 2.62×109 HAT 5 TS2 9.76 –14.65 4.36×10 –1124.4 2.23 9.72×105 RAF 8 TS3a 5.50 –25.43 5.79×10 –329.1 1.11 6.40×108 RAF 8 TS3b 5.56 –25.19 5.22×10 –318.6 1.10 5.73×108 RAF 9 TS4a 4.75 –26.13 2.03×10 –260.3 1.07 2.17×109 RAF 9 TS4b 4.73 –25.10 2.11×10 –315.4 1.10 2.31×109 HAT 5 TS5 10.04 –14.82 2.71×10 –1143.3 2.27 6.15×105

In the case of phenols + •OH reactions in aqueous solution, the hydrogen abstraction mechanism is barrierless and it occurs preferentially via PCET [30]. The optimization in solution of TS1 HAT produces an increase of the -OH…•OH distance and a corresponding decrease of the imaginary frequency and of the gradient, resulting in an optimized system with both reactants separated. This fact has been previously observed for other phenolic compounds such as coumaric acids and trans-resveratrol [30,55]. Iuga et al. assumed that, for the reaction of trans-resveratrol + •OH, the individual rate constants of PCET mechanism are diffusion controlled and equal to the diffusion rate constant (1.98 × 109 L mol−1 s−1) [30]. Hence, the total PCET rate constant was obtained as the sum of the individual rates of the PCET pathways for the three hydroxyl groups of trans-resveratrol (5.94 × 109 L mol−1 s−1) while the highest rate constant was calculated for the SET mechanism (7.95 × 10 9 L mol−1 s−1) [30]. Consequently, we may also assume that the PCET mechanism is also diffusion controlled for the pterostilbene + •OH reaction. On the other hand, the SET mechanism is not thermodynamically favored (∆rG = 2.18 kcal mol-1) (see Table 3). For this mechanism, a kapp value 1.6 times smaller than that reported for the pristine compound was obtained. Its product, ArOH•+, is an acid radical cation which can react according to eqn (2b) to give an equivalent product to that obtained through the direct hydrogen-abstraction from the 10

single hydroxyl group, ArO• (∆rG = –38.81 kcal mol-1). The most exergonic pathway of the second step in the SEPT mechanism of trans-resveratrol + •OH reaction (∆rG = – 10.60 kcal mol-1) leads to the loss of a proton from the hydroxyl group at an equivalent position [30]. A pKa of 10.09 was estimated for pterostilbene according eq 17 (∆G0 = 17.51 kcal mol–1 was calculated for the process corresponding to eq 16). As could be expected, this value is higher than those previously estimated by the same method for trans-resveratrol (9.16) and piceatannol (7.86), which have three and four hydroxyl groups, respectively [52]. For a physiological pH of 7.4, a ratio of [PO‒]/[POH] = 2.04×10‒3 was calculated for pterostilbene by using the Henderson-Hasselbalch equation (where [POH] and [PO‒] correspond to the pterostilbene concentration and anionic pterostilbene concentration, respectively). Because of the low expected [PO‒]/[POH] ratio, the SPLET mechanism for pterostilbene + •OH reaction can be neglected. Nevertheless, this mechanism could play a role in the pterostilbene + •OOH reaction, as reported for related compounds [52], and it will be discussed below. Table 3 Reorganization energy (λ), Gibbs free energy of activation (∆G⧧), diffusion rate constant (kD), rate constant (k), and apparent rate constant (kapp) calculated for SET and SPLET mechanisms

λ (kcal kD (L mol−1 kapp (L ∆G⧧ (kcal ∆rG (kcal k (L mol−1 −1 −1 −1 mol−1) mol ) s ) s−1) mol−1 s−1) mol ) 10 9 SET •OH 10.18 3.75 2.18 1.11×10 8.67×10 4.86×109 –6 9 SET •OOH 32.04 24.67 24.19 5.14×10 8.15×10 5.14×10–6 a 7 9 SET(SPLET) •OH 6.63 7.38 -20.62 2.40×10 8.65×10 2.40×107 SET(SPLET)a •OOH 28.49 7.83 1.38 1.13×107 8.13×109 1.13×107 a SET reaction involving pterostilbene anion (corresponding to the second step of the SPLET mechanism, eq 4b) Mechanism

Radical

As concerns pterostilbene + •OOH reaction, the molecular structure and main geometrical parameters of the calculated transition states for HAT and RAF mechanisms are shown in Fig. 1 and Table 1. For the HAT mechanism, the breaking O/C···H bond lengths and the forming H···O bond lengths increase and decrease, respectively, with respect to the corresponding transition states of pterostilbene + •OH 11

reaction. The forming O···C bond lengths for the RAF pathways (TS3RAF and TS4RAF) decrease up to ~2.0 Å with respect to the corresponding transition states of pterostilbene + •OH reaction. Table 4 summarizes ∆G⧧, ∆rG, k and kW calculated for HAT and RAF mechanisms both in gas phase and in aqueous solution. In general, the rate constant calculated for the different pathways of this reaction are several orders of magnitude lower than those calculated for the reaction with •OH. Nevertheless, it must be considered that the relative concentration of •OOH radicals in tissues is considerably higher than that of •OH, being sometimes the reaction of •OOH radicals even faster than with •OH. In gas phase, the highest kW (1.17×102 L mol−1 s−1) was obtained for the reaction pathway through TS1 HAT. On the contrary, the kW values (4.62×10–1 and 3.72×10–1 L mol−1 s−1) calculated for TS4RAF pathways in solution are about 3 – 4 times higher than the corresponding value obtained for TS1HAT (1.12×10 –1 L mol−1 s−1). Nevertheless, all the addition channels are endergonic (∆rG = 3.06 – 3.60 kcal mol−1) while TS1HAT pathway is exergonic (∆rG = –4.89 kcal mol−1). Even if TS4RAF pathways took place at significant rates, products would not be observed due to the reversibility of the reactions. The high ∆rG values and low kapp values calculated for the SET mechanism do not suggests that this mechanism can compete with the HAT one. The highest kapp (1.13×107 L mol−1 s−1) in aqueous solution was calculated for the SET reaction involving pterostilbene anion (corresponding to the second step of the SPLET mechanism, eq 4b). Despite the low expected [PO‒]/[POH], the rate of the SPLET reaction pathway should be higher than the rate of the TS1HAT pathway since both rates differ by five orders of magnitude. Nevertheless, the SET reaction of pterostilbene anion is not thermodynamically favored (∆rG = 1.38 kcal mol−1) in contrast to the TS1 HAT reaction pathway of pterostilbene. Hence, the product of the hydrogen abstraction from the hydroxyl group (TS1HAT mechanism) would also the main product of the global reaction of pterostilbene with •OOH radical. 12

Table 4 Activation (∆G⧧) and reaction (∆rG) Gibbs free energies calculated for the most relevant HAT and RAF pathways of pterostilbene + •OOH reaction. Data corresponding to reactions in aqueous solution appear within parentheses. ∆G⧧ ∆rG k v* kW Pathway χ(T) (kcal mol−1) (L mol−1 s−1 ) (cm−1) (L mol−1 s−1) a (kcal mol−1) 15.63 –2.00 2.17×101 –2125.3 5.38 1.17×102 TS1HAT –2 (20.18) (–4.89) (1.00×10 ) (–3244.9) (11.22) (1.12×10–1) –11 31.10 16.67 9.97×10 –1883.1 4.44 4.43×10–10 TS2HAT –11 (32.02) (15.19) (2.08×10 ) (–2002.6) (4.89) (1.02×10–10) –2 19.09 1.59 6.36×10 –658.7 1.42 9.03×10–2 TS3aRAF –2 (19.43) (3.60) (3.55×10 ) (–593.5) (1.34) (4.76×10–2) –2 19.73 0.74 2.14×10 –690.6 1.46 3.13×10–2 TS3bRAF –2 (19.43) (3.60) (3.53×10 ) (–582.8) (1.33) (4.69×10–2) –2 19.26 –0.98 4.71×10 –619.9 1.37 6.47×10–2 TS4aRAF –1 (18.19) (3.24) (2.89×10 ) (–545.3) (1.29) (3.72×10–1) –2 19.06 0.70 6.63×10 –647.8 1.41 9.32×10–2 TS4bRAF –1 (18.06) (3.06) (3.58×10 ) (–545.3) (1.29) (4.62×10–1) –9 29.43 16.50 1.66×10 –1797.2 4.13 6.87×10–9 TS5HAT –11 (32.43) (16.42) (1.05×10 ) (–1918.5) (4.57) (4.81×10–11) a

The rate constant calculated in solution corresponds to an apparent rate constant (kapp) including Wigner´s corrections.

4. Conclusion In the present work, we have carried out a study on the reactivity of pterostilbene against hydroxyl (•OH) and hydroperoxyl (•OOH) radicals in gas and aqueous phases by means of the DFT calculations. For the pterostilbene + •OH reaction in gas phase, the addition mechanism through TS4RAF is kinetically favored while the k value calculated for the abstraction pathway TS1 HAT is about three times smaller than that calculated for TS4RAF. In aqueous solution, •OH reacts at diffusion controlled rate with pterostilbene via HAT (PCET) or RAF. As concerns pterostilbene + •OOH reaction in gas phase, the highest rate constant was obtained for the reaction pathway through TS1 HAT. In solution, only the TS1 HAT pathway is predicted to be thermodynamically favored and the product of the hydrogen abstraction from the hydroxyl group would be the main reaction product of the global reaction. The phenoxy radical formed from TS1 could react with •OOH or alkyl peroxyl radicals in subsequent reactions.

13

ACKNOWLEDGMENTS We gratefully thank the Centro Informático Científico de Andalucía (CICA) and the Supercomputing Service of the University of Castilla−La Mancha for allocation of computational resources. Mónica Moral Muñoz thanks to the E2TP-CYTEMASANTANDER program for their financial support.

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Antioxidants and Reactive Oxygen Species Reactions

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21

Hydrogen Abstraction vs. Radical Addition