Radical-Induced CisâTrans Isomerization of Fatty Acids: A

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Radical-Induced Cis-Trans Isomerization of Fatty Acids: A Theoretical Study Yu-Zan Tzeng, and Ching-Han Hu J. Phys. Chem. A, Just Accepted Manuscript • Publication Date (Web): 09 Jun 2014 Downloaded from http://pubs.acs.org on June 16, 2014

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The Journal of Physical Chemistry

Radical-Induced

Cis-Trans

Isomerization of

Fatty

Acids:

Theoretical Study

Yu-Zan Tzeng, Ching-Han Hu*

Department of Chemistry, National Changhua University of Education, Changhua 50058, Taiwan

ACS Paragon Plus Environment

A


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Abstract Trans fatty acids (TFAs) create deleterious effects, thus their existence in human is a great health concern. TFAs can be obtained through diet, or they can be formed endogenously by radical-induced cis to trans isomerization. The mechanism of .

isomerization of fatty acid catalyzed by radicals including nitrogen dioxide (NO2 ), .

.

thiyl (RS ), and peroxide (ROO ) radicals were investigated using density functional theory. With linoleic acid, a fatty acid consisting of two homoconjugated C=C bonds, we found that the radical addition mechanism is more favorable than the hydrogen abstraction mechanism. For all investigated radicals, the isomerization catalyzed by .

.

RS radical involves the smallest reaction barrier. We found that NO2 Reactions through the N-terminus are more favorable than reactions through the O-terminus. .

The reaction barriers for NO2 catalyzed isomerizations were found to be lowered to a larger extent in polar solvent. β-carotene and lycopene were shown to protect fatty acids from isomerization by intercepting the isomerization-causing radicals.

Keywords: lipid, thiyl, nitrogen dioxide, hydrogen abstraction, radical addition


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1. Introduction Saturated and unsaturated fatty acids are components of lipids. An important category of lipid is phospholipid, which constitutes biomembranes. Naturally occurring monounsaturated and polyunsaturated fatty acids contain alkenes with a cis configuration, despite the fact that trans isomers thermodynamically more stable. Trans fatty acids obtained via dietary sources have been demonstrated to alter the structure and fluidity of the phospholipid bilayer.1 Moreover, these trans fatty acids raise the ratio of low-density lipoprotein (LDL) cholesterol and lower the ratio of HDL cholesterol, thus increase the risk of coronary heart disease.2,3 In addition to dietary resources, trans fatty acids can be generated by .

endogenous radicals. Thiyl and NO2 radicals have been demonstrated to induce the isomerization of lipids in solutions, in lipid vesicles, and in vivo.4-8 The position of C=C bonds of endogenously produced trans fatty acids are different from those of trans fatty acids obtained through diet. The endogenous trans isomers have been recognized as important species involving in membrane damage, and have been implicated in certain related diseases.4-10 Fatty acid alkene isomerization can occur via two routes, namely reversible addition by a radical catalyst (radical addition) or hydrogen abstraction (HA) (Scheme 1). In radical addition, the catalytic radical species adds to one of the C=C bond and the radical adduct undergoes C-C bond rotation. Dissociation of the radical catalyst completes the isomerization. In the HA mechanism, an allylic or bis-allylic hydrogen is abstracted by the catalytic radical species. Following by C-C bond rotation, the fatty acid radical is quenched by hydrogen atom donation from the surrounding environment or from the neutralized catalytic radical. A distinguishing feature of these two mechanisms is that, radical addition may afford only geometrical isomers,



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whereas HA can result in both geometrical isomers and conjugated dienes. In the presence of the thiyl radical (both in homogeneous solution phases and in liposomes), a small amount of conjugated diene is observed, while the geometrical isomer is the major product.11 The presence of the conjugated diene product suggests that the HA mechanism is active, and the intermediacy of the pentadienyl radical has generated much research interest.4 High-level ab initio theories and DFT have been applied to study homoconjugated dienes and the bis-allylic radicals.12-16 Bond strength for the bis-allylic C-H and the rotational barriers for 1,4-pentadienyl radical have been investigated by Borden et al.12 Spin density of pentadienyl radicals of fatty acids, and the reactivity of these radicals toward oxygen molecule was reported by Pratt et al.13,15,16 Moreover, Viskolcz et al. have investigated the reactions of 1,4-pentadiene and arachidonic acid radicals with oxygen.14

Scheme 1. Possible reaction pathways for the radical-initiated isomerization of fatty acids. Radical addition and HA mechanisms are both present in the isomerization .

reactions catalyzed by NO2 in solution for mono- or polyunsaturated alkenes.17 For


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.

the reactions of NO2 with fatty acids consisting of bis-allylic hydrogens (methyl linoleate), the HA mechanism is suggested to be strongly preferred over the radical .

addition mechanism.18,19 However, in another example, NO2 was found to react with arachidonic acid, which contains four homoconjugated C=C double bonds, via the radical addition mechanism exclusively.5 Schöneich et al. revealed that in solution, thiyl radicals can abstract bis-allylic hydrogens from poly-unsaturated fatty acids (PUFAs).20 Sprinz et al. showed that in liposomes, thiyl radicals catalyze PUFA isomerization via the radical addition mechanism.21 Chatgilialoglu’s research group investigated thiyl radical catalyzed isomerizations in solution, micelle and liposome, within which addition and HA mechanisms are involved.4,10,11,22-25 Carotenoids (CARs) consist of extended terpene units and end groups which contain hydrocarbons (carotenes), or oxygenated hydrocarbons (xanthophylls). CARs are one of the most important type of phytochemicals as they protect biological tissues from the deleterious effects of singlet oxygen.26 CARs have also been demonstrated to exhibit radical chain-breaking function in defense against lipid peroxidation.27-30 Moreover, it was demonstrated that carotenes are capable of .

preventing lipid peroxidation induced by NO2 .31 However, adverse effects to supplemental β-carotene (β β -CAR) intake were also reported.32,33 Evidence was found for the fact that β-CAR becomes pro-oxidative at high concentrations.34,35 Conjugated dienes and all-trans retinol were shown to retard radical-induced cis-trans isomerization of lipids.11 In addition, it has been demonstrated in liposomes α-tocopherol, ascorbic acid and all-trans retinol are capable of scavenging thiyl radical (capacity in increasing order), thus preventing it from catalyzing cis-trans isomerization of fatty acids.36,37 As carotenes contain a more extended conjugated system, testing whether these compounds offer better protective functions against



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radical-induced isomerization in fatty acids is meritorious. The purpose of this study is to investigate radical-induced fatty acid isomerization at the theoretical level. Both radical addition and hydrogen abstraction mechanisms were explored. Investigation into the radical scavenging capacity of carotenes was performed by comparing their radical affinities with that of the fatty acid. It is noted, however, that the mechanisms investigated by our quantum chemistry approach are one-to-one, radical to fatty acid reaction. The model is very different from those in micelle, liposome, or membrane. In these systems, the assembly of lipids, the location of the C=C bond, and the diffusibility of radicals are all relevant factors.

2. Computational approach Computations were performed using the three-parameter hybrid, generalized gradient approximation (GGA) exchange and correlation functional B3LYP38,39 along with the 6-31G(d) basis set for geometry optimizations and vibrational frequency analysis. Transition states were verified with one imaginary vibrational frequency. Single-point energies were computed at the optimized geometries, using the kinetic energy density dependent meta-GGA functional MPWB1K,40 along with the 6-31++G(d,p) basis set. The choice is based on our previous study,41 in which the bond dissociation energies of model compounds obtained using various DFT functionals were compared with those obtained with the G3 theory.42 The MPWB1K/6-31++G(d,p)//B3LYP/6-31G(d) approach was shown to be the most accurate among all tested DFT methods. In addition, it was demonstrated that the accuracy is not affected by replacing the DFT optimized geometries with those obtained using B3LYP/6-31G(d).41 The solvent effects of benzene and water were included using the polarizable


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continuum

model

(PCM)

developed

by

Tomasi

and

Barone43,44

at

the

MPWB1K/6-31++G(d,p) level. Convergence difficulties were encountered with the United Atom approach of PCM, especially for the transition states of HAs. This difficulty was overcome by selecting individual spheres for hydrogen atoms. Linoleic acid (LAH), an essential fatty acid for humans, was chosen in our study. Moreover, we used a smaller molecule, namely (2Z,5Z)-hepta-2,5-diene (hep), to be our model species. Structure and numbering of LAH and hep are illustrated in .

.

.

Scheme 2. Reactions of RS , nitrogen dioxide (NO2 ), and CH3OO with LAH were .

.

investigated. CH3S and CH3OO were chosen to represent thiyl and peroxide radicals, respectively. The computations were performed with the Gaussian03 program series.45 O

HO

2

1 3

18

4 6

5

1

17

16

2 7

8

3

H

H 9

4

15

14

H

H

hep 13

11 12

10 LAH

Scheme 2. Structures of linoleic acid (LAH) and (2Z,5Z)-hepta-2,5-diene (hep).

3. Results and Discussion Radical addition mechanism for model diene. Radical additions to the model



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diene (hep) may occur at C2 or C3. Only one of the enantiomeric transition states and radical addition adducts were investigated. Figure 1(a) illustrates the potential energy . surface (PES, in Gibbs free energy at 298K) for the addition of CH3S to C2, which is

the location of the lower barrier. Isomerization commences with the addition of a radical via transition state TS1, forming the cis radical adduct. Rotation of the adduct leads to the trans adduct via TS2. Isomerization is completed by the departure of the catalytic radical (TS3) to form the trans product. The radical-diene adducts are endergonic by 3.3 kcal/mol, and TS1 and TS3 are 12.4 and 12.2 kcal/mol higher in free energy than the reactants, respectively. The free energy landscape of the lower barrier radical addition is shown in Figure 1(b). For nitrogen dioxide, additions by the .

.

N (referred to hereafter as -NO2 ) or O (-ONO ) terminus of the radical were investigated. For both additions, reactions via C2 involved the lowest barrier with .

.

values of 20.0 kcal/mol and is 22.9 kcal/mol for -NO2 and -ONO additions, .

respectively. For CH3OO addition, the lowest barrier path occurs through addition at C3, and the barrier (24.2 kcal/mol) is the highest among all investigated radicals. For all radicals, the addition adducts are endergonic. Detailed energetic data are summarized in Support Information. .

CH3S was found to be the most effect catalyst for the cis-trans isomerization. .

Our observation has important biological implications, because CH3S can be generated from methionine residues.6 In contrast, nitrogen dioxide is less effective in .

catalyzing the isomerization, while CH3OO is the least effective. Addition of nitrogen dioxide via the N-terminus involves a barrier that is lower than that via the .

.

O-terminus. Structures of the rate-determining TSs of -NO2 , -ONO , and CH3OO


.

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additions are depicted in Figure 2. Hydrogen abstraction mechanism for model diene. Figure 3(a) illustrates .

the lowest energy mechanistic pathway for hydrogen abstraction of hep by CH3S . Initiation of the HA reaction may also occur through hepb, a local minimum being only 0.3 kcal/mol higher in energy than hep in the gas phase. HA commences with the abstraction of a bis-allylic hydrogen from C4 of hepb, resulting in a planar pentadienyl radical with C2v symmetry (hepr). The reaction barrier of 13.7 kcal/mol, is 1.3 kcal/mol higher than that of its barrier to radical addition (Figure 1(a)). Intermediate hepr undergoes rotation to form hepr23 or hepr34. It is observed that rotating a peripheral unconjugated (C2-C3) bond involves larger barrier (via hepr23ts) than rotating a central unconjugated (C3-C4) bond (via hepr34ts). However, hepr23 is lower in energy than hepr34. HA of hep results in hepr34, which has a smaller C3-C4 rotational barrier (7.4 kcal/mol) for resulting in hepr. Isomerization is completed by quenching of these radicals from a source of hydrogen. In this study, we calculated HA by these radicals from the neutralized radical catalysts CH3SH, HNO2, HONO, and CH3OOH. It is noted, however, that hydrogen donors are present, including the allylic or bis-allylic hydrogen from a second fatty acid. As shown in Figure 3(b), HA by hepr can also occur at C6 (via tsrto2) to form hep2, or at C4 (via tstor) to form hep. Hep2 is 5.3 kcal/mol lower in energy than hep because of its conjugated diene structure. HAs at C2, C4, and C6 of hepr23 result in hep2, hep3 and hep4, respectively. hep3 adopts an all-trans conformation and is the lowest energy isomer resulting from these isomerizations (6.5 kcal/mol lower in energy than hep). The highest energy product (hep4) is homoconjugated, and it differs from hep by one trans C=C bond. HA of hepr34 at C2 and C6 result in hep5



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and hep6 respectively. HA at C4 of hepr34 has a high energy barrier and results in the homoconjugated conformer hep (see Figure 3(a)). hep5 consists of a cis,cis conjugated structure and is higher in energy than hep2. hep6 consists of a cis,trans conjugated structure and is higher in energy than hep5, which can be attributed to its s-cis conformation. It can be seen that hep6 and hep2 are s-cis and s-trans isomers. The relative energies of all reaction species (including the TSs) in the gas phase, as well as energetics for reactions in benzene and in water, are summarized in Table 1. In the gas phase, HA of hepb involve barriers that are 3-4 kcal/mol smaller than those .

for the HA of hep. Barriers for HA by CH3S are significantly lower than those of the .

other radicals. For nitrogen dioxide, HA by the N-terminus (-NO2 ) involves smaller .

barrier than does HA by the O-terminus (-ONO ). The observation is interesting, .

.

considering the fact that HA by -NO2 is less endergonic than that by -ONO , which can be attributed to the larger bond dissociation energy of H-ONO than H-NO2. For each reaction pathway, the “reaction barrier” is obtained as the largest energy difference between the TSs and the lowest local minima at its left on the PES. We define the “critical reaction barrier” (∆Gc) as the smallest barrier of all reaction

pathways. The ∆G c values of all pathways are summarized in Table 2. .

For CH3S , the reaction leading to hep3 (via tsr23to3) is related to ∆Gc, which is 22.9 kcal/mol. However, we observe that barriers of other reactions are somewhat similar. For example, the barrier leading to hep2 via tsrto2 (from hepr) is only slightly higher, with a value of 23.9 kcal/mol. The most kinetically favorable product, and the TSs and intermediates leading to this product are depicted in bold face in .

.

.

Table 1. For CH3S , -ONO and CH3OO reactions, the most kinetically favorable product is hep3. Calculated ∆Gc values for these reaction were obtained from the


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energy difference between tsr23 and hepr23, which are 22.9, 25.3 and 28.1 kcal/mol, .

respectively. For NO2 , the critical barrier occurs in the first step of hydrogen abstraction of hepb and is attributed to the endergonic nature of this radical formation. .

∆Gc for the HA of -NO2 (21.0 kcal/mol) is 1.0 kcal/mol lower than that of addition; .

however, it is still 4.8 kcal/mol lower than HA by -ONO . ∆Gc is not noticeably affected by the inclusion of solvation effects of benzene and water. The most noticeable influence by the polarity of solvent is seen in -NO2

.

reaction, in which ∆Gc is lowered in polar solvents. Table 2 summarizes the critical barriers for isomerization induced by the radicals for both addition and HA mechanisms. In every instance, the addition mechanism is .

favored. For CH3S , the critical barrier for radical addition reaction is overwhelmingly .

smaller than that of HA. For nitrogen dioxide, -NO2 reactions involve smaller barriers .

.

than -ONO reactions. Furthermore, HA of -NO2 has a barrier that is only slightly higher than the barrier for addition. Despite the fact that the critical barrier for the HA mechanism is higher than those for the radical addition mechanism, it is noted however, that the barriers for the .

.

.

HA (tstor) initiated by CH3S , -ONO , and CH3OO are comparable with ∆Gc for .

radical addition. For example, HA of CH3S has a barrier (13.7 kcal/mol) that is only .

slightly higher than its ∆Gc for radical addition (12.4 kcal/mol). HA of CH3OO has a .

barrier that is lower than that of its ∆Gc for radical addition. For -NO2 , critical barrier is calculated from the initiation step of HA, and is ~1 kcal/mol higher than that for radical addition. In cases where reactive radicals are present, both mechanisms may



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be competitive. Radical addition mechanism for LAH.

Unlike hep, LAH is asymmetric

(Scheme 2). The number of reactions pathways to be considered is greater for both radical addition and HA. Radical addition could occur at C9, C10, C12 and C13; thus there are four reaction pathways for each radical addition. The structures of the .

reaction species involved in CH3S addition are depicted in Figure 4(a). PESs for all addition reactions are illustrated in Figure 4(b) (only the data for minimum barrier path are shown, and the complete results are summarized in Support Information). Energy barriers for radical additions at different sites of LAH were found to be very .

similar. For example, in gas phase the barriers of CH3S additions at C9, C10 and C12 are only 0.5, 0.5 and 0.6 kcal/mol higher in energy than that of C13. In gas phase, ∆G

.

c

of CH3S addition (11.1 kcal/mol) is obtained via the

addition pathway at C13 reaction route. The barrier is slightly lower than that of

.

.

.

addition for hep (12.4 kcal/mol). The ∆G c values for -NO2 , -ONO and CH3OO are 17.8 (addition at C12), 20.9 (addition at C10) and 22.9 (addition at C9) kcal/mol, respectively. These barriers are ~2 kcal/mol lower in energy than their counterparts in .

.

.

the model diene. Structures of the rate-determining TSs for -NO2 , -ONO and CH3OO additions are illustrated in Support Information.


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Scheme 3. Reaction schemes for the radical-initiated HA of LAH.



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Hydrogen abstraction mechanism for LAH. Based on our experience with the model diene system, we adopted the following strategy to simplify the investigation. First, HA of LAH involving higher reaction barrier (tstor34 in Figure 3(a)) was omitted. Second, for the HAs by these radicals, only reactions leading to conjugated dienes were investigated. LAH leads to the formation of LAr, from which two further radicals may be formed by rotating the peripheral bonds (C9-C10 and C12-C13) of the pentadienyl radical (LAr9 and LAr12, respectively). HAs of these radicals from the quenched radical catalysts (RH) on both ends result in the four conjugated dienes; LAHb, LAHc, LAHd and LAHe. The critical barriers of HA and addition mechanisms, and the most kinetically favored HA products are summarized in Table 3 (the overall results can be found in the Support Information). The critical barriers of HAs for LAH are comparable to their counterparts in the model diene. .

For HA, ∆Gc of CH3S is the energy difference of the TS leading to LAHb (tsr9tob). For nitrogen dioxide, HA of nitrogen dioxide on the N-terminus is also more energetically favorable than HA on the O-terminus. Similar to the finding in mode system, the addition mechanism is more favorable .

than the HA mechanism for all investigated radicals. CH3S is the most effective catalyst in the cis to trans isomerization of LAH. The HA mechanism, which leads to conjugated diene products, is not favored. LAHe adopts all-trans structures, and is the lowest energy conjugated isomer. However, LAHe is not a kinetically favored product. The most noticeable solvation effect was observed for nitrogen dioxide. In water, ∆Gc .

of -NO2 addition is reduced by ~3 kcal/mol. Moreover, reaction barriers for the initiation step of HA were included in Table 3. .

HA of CH3S has a barrier (13.2 kcal/mol) that is slightly higher than its ∆Gc for .

radical addition (11.1 kcal/mol). In contrast, HA of CH3OO has an initiation barrier (20.4 kcal/mol) that is lower than that of its ∆Gc for radical addition (22.9 kcal/mol). .

The critical barrier for the HA of CH3S (21.9 kcal/mol) is taken from the energy difference between tsr9tob and LAr + RH (see Scheme 3). Other species, such as an unsaturated fatty acid or a radical, may compete with the thiol for the LAr radical. Energy barriers for the addition of O2 to LAr were computed. In gas phase and in


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benzene the barriers are 18.1 and 11.8 kcal/mol, respectively (refer to the Support Information for the complete energy surfaces). Moreover, the reactions are exergonic. These data suggest that LAr radical undergoes O2 binding more efficiently than hydrogen abstraction from the thiol. The results are consistent with the experimental observation, that the presence of O2 enhances peroxidation via hydrogen abstraction by thiyl radical, while retarding thiyl radical catalyzed isomerizations.25 Protective capability of carotene species. Two carotene species, β-carotene and lycopene (β β -CAR and LYC, see Scheme 4), were investigated in this study. The extended conjugated system of carotene compounds provides multiple reaction sites for radical addition. As indicated by previous theoretical studies, the lowest barrier reaction occurs at C5,46,47 and we investigated addition at C5 only. The reaction barrier and reaction free energy for the addition of radicals to β -CAR and LYC are summarized in Table 4. The TSs for the addition of radicals to LYC are depicted in Figure 5. Relative activity of the addition of radicals to carotenes are shown to occur in the same order as those observed in the reactions with LAH. The lowest barrier is .

.

.

observed by CH3S addition, followed by -NO2 , then by CH3OO . Additions to LYC yield smaller barriers than those of additions to β -CAR.

Scheme 4. β-carotene (β β-CAR) and lycopene (LYC). Comparing with ∆Gc of radical reactions with LAH (Table 3), β-CAR and LYC



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are capable of offering protection against lipid isomerization by reacting faster with .

the isomerization-causing radicals. An exception is seen in the reaction of CH3S and .

β-CAR. The barrier for the addition of CH3S to β-CAR (12.7 kcal/mol, gas phase) is .

.

found to be higher than for the addition of CH3S to LAH (11.1 kcal/mol). For -NO2 .

and CH3OO , both carotenes could prevent isomerization by intercepting the isomerization-causing radicals. When solvent effects are included in the calculations, .

the barriers of -NO2 and carotene reactions are further reduced. In contrast, ∆Gc of .

the radical addition of -NO2 are lowered to a larger extent in benzene and in water .

than those of CH3S . Another feature of radical reaction to carotene is that unlike additions to LAH, all radical additions are exergonic (Table 4). The thermodynamic stability of the carotene radical may render them lower reactivity, and thus the radical adducts are more likely to be terminated.

4. Conclusion In this study, we investigated the radical addition and HA mechanisms involved in the radical-induced cis to trans isomerizations of fatty acids using density functional theory. We investigated these reactions using nitrogen dioxide, and radicals .

.

that model thiyl (CH3S ) and peroxide (CH3OO ) radicals. Our results show that for all investigated radicals, radical additions are more favorable than HA reactions. The thiyl radical was found to be the most effective catalyst for the isomerization. Isomerization catalyzed by nitrogen dioxide is not as effective as those catalyzed by thiyl radical; its isomerization would occur through the N-terminus. Our computations .

reveal that -NO2 catalyzed isomerization is more efficient in the more polar environments. The protective capacity of carotene species against radical-induced cis-trans isomerization of lipids was also investigated. Carotenes β-CAR and LYC were confirmed to offer protection by forming exergonic addition adducts with the isomerization-causing radicals at faster rates than does the fatty acid. In polar .

environments, the protective ability against -NO2 catalyzed isomerization is


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significantly enhanced. LYC intercepts the isomerization-causing radicals at a higher rate than β-CAR.

Acknowledgement. The authors acknowledge that the National Science Council of Taiwan, Republic of China, supported this work under Grant No. NSC101-2113-M-018 -004.

Supporting Information Available: Reaction free energetics of radical additions on various reaction sites, and energetics for the HA of LAH are summarized. The materials are available, free of charge, via Internet at http://pubs.acs.org.



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References: (1) Diefenbach, R.; Heipieper, H.-J.; Keweloh, H.: The Conversion of Cis Into Trans Unsaturated Fatty Acids in Pseudomonas Putita P8: Evidence for a Role in the Regulation of Membrane Fluidity. Appl. Microbiol. Biotechnol. 1992, 38, 382-387. (2) Sun, Q.; Ma, J.; Campos, H.; Hankinson, S. E.; Manson, J. E.; Stampfer, M. J.; Rexrode, K. M.; Willett, W. C.; Hu, F. B.: A Prospective Study of Trans Fatty Acids in Erythrocytes and Risk of Coronary Heart Disease. Circulation 2007, 115, 1858-1865. (3) Brouwer, I. A.; Wanders, A. J.; Katan, M. B.: Effect of Animal and Industrial Trans Fatty Acids on HDL and LDL Cholesterol Levels in Humans – A Quantitative Review. PLoS ONE 2010, 5, e9434. (4) Chatgilialoglu, C.; Ferreri, C.: Trans Lipids: the Free Radical Path. Acc. Chem. Res. 2005, 38, 441-448. (5) Jiang, H.; Kruger, N.; Lahiri, D. R.; Wang, D.; Vatèle, J.-M.; Balazy, M.: NO2 Induces Cis-Trans Isomerization of Archidonic Acid Within Cellular Phospholipids. J. Biol. Chem. 1999, 274, 16235-16241. (6) Chatgilialoglu, C.; Ferreri, C.; Lykakis, I. N.; Wardman, P.: Trans-Fatty Acids and Radical Stress: What are the Real Culprits? Bioorg. Med. Chem. 2006, 14, 6144-6148. (7) Chatgilialoglu, C.; Ferreri, C.; Melchiorre, M.; Sansone, A.; Torreggiani, A.: Lipid Geometrical Isomerism: From Chemistry to Biology and Diagnostics. Chem. Rev. 2014, 114, 255-284. (8) Balazy, M.; Chemtob, S.: Trans-arachidonic Acids: new Mediators of Nitro-Oxidative Stress. Pharmacol Ther 2008, 119, 275-290. (9) Schwinn, H.; Sprinz, K.; Dröβler, S.; Leistner, O.; Brede, J.: Thiyl Radical-Induced Cis/Trans Isomerization of Methyl Linoleate in Methanol and of Linoleic Acid Residues in Liposomes. Int. J. Rad. Biol. 1998, 74, 359-365. (10) Ferreri, C.; Costantino, C.; Landi, L.; Mulazzani, Q. G.; Chatgilialoglu, C.: Thiyl Radical-Mediated Cis-Trans Isomerization of Fatty Acids in Phospholipids. Chem. Commun. 1999, 407-408. (11) Ferreri, C.; Costantino, C.; Perrotta, L.; Landi, L.; Mulazzani, Q. G.; Chatgilialoglu, C.: Cis−Trans Isomerization of Polyunsaturated Fatty Acid Residues in Phospholipids Catalyzed by Thiyl Radicals. J. Am. Chem. Soc. 2001, 123, 4459-4468. (12) Fort, R. C.; Hrovat, D. A.; Borden, W. T.: Ab Initio Calculations of the Stabilization Energy of Pentadienyl Radical from Rotational Barriers and from Lowering of Bond Dissociation Energies. J. Org. Chem. 1993, 58, 211-216. (13) Pratt, D. A.; Mills, J. H.; Porter, N. A.: Theoretical Calculations of Carbon−Oxygen Bond Dissociation Enthalpies of Peroxyl Radicals Formed in the Autoxidation of Lipids. J. Am. Chem. Soc. 2003, 125, 5801-5810. (14) Szori, M.; Csizmadia, I. G.; Viskolcz, B.: Nonenzymatic Pathway of PUFA Oxidation. A First-Principles Study of the Reactions of OH Radical with 1,4-Pentadiene and Arachidonic Acid. J. Chem. Theo. Comput. 2008, 4, 1472-1479. (15) Hu, D.; Pratt, D. A.: Secondary Orbital Interactions in the Propagation Steps of Lipid Peroxidation. Chem. Commun. 2010, 46, 3711-3713. (16) Pratt, D. A.; Tallman, K. A.; Porter, N. A.: Free Radical Oxidation of Polyunsaturated Lipids: New Mechanistic Insights and the Development of Peroxyl Radical Clocks. Acc. Chem. Res. 2011, 44, 458-467. (17) Giamalva, D. H.; Kenion, G. B.; Church, D. F.; Pryor, W. A.: Rates and Mechanisms of Reactionof Nitrogen Dioxide with Alkenes in Solution. J. Am. Chem.


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Soc. 1987, 109, 7059-7063. (18) Pryor, W. A.; Lightsey, J. W.: Mechanisms of Nitrogen Dioxide Reactions: Initiation of Lipid Peroxidation and the Production of Nitrous Acid. Science 1981, 214, 435-437. (19) Gallon, A. A.; Pryor, W. A.: The Reaction of Low Levels of Nitrogen Dioxide with Methyl Linoleate in the Presence and Absence of Oxygen. Lipids 1994, 29, 171-176. (20) Schöneich, C.; Dillinger, U.; von Bruchhausen, F.; Asmus, K.-D.: Oxidation of Polyunsaturated Fatty Acids and Lipids Through Thiyl and Sulfonyl Radicals: Reaction Kinetics, and Influence of Oxygen and Structure of Thiyl Radicals. Arch. Biochem. Biophy. 1992, 292, 456-467. (21) Sprinz, H.; Schwinn, J.; S., N.; Brede, O.: Mechanism of Thiyl Radical-Catalyzed Isomerization of Unsaturated Fatty Acid Residues in Homogeneous Solution and in Liposomes. Biochim. Biophys. Acta 2000, 1483, 91-100. (22) Ferreri, C.; Samadi, A.; Sassatelli, F.; Landi, L.; Chatgilialoglu, C.: Regioselective Cis−Trans Isomerization of Arachidonic Double Bonds by Thiyl Radicals: The Influence of Phospholipid Supramolecular Organization. J. Am. Chem. Soc. 2004, 126, 1063-1072. (23) Chatgilialoglu, C.; Altieri, A.; Fischer, H.: The Kinetics of Thiyl Radical-Induced Reactions of Monounsaturated Fatty Acid Esters. J. Am. Chem. Soc. 2002, 124, 12816-12823. (24) Chatgilialoglu, C.; Ferreri, C.; Ballestri, M.; Mulazzani, Q. G.; Landi, L.: cis−trans Isomerization of Monounsaturated Fatty Acid Residues in Phospholipids by Thiyl Radicals. J. Am. Chem. Soc. 2000, 122, 4593-4601. (25) Mihaljević, B.; Tartaro, I.; Ferreri, C.; Chatgilialoglu, C.: Linoleic Acid Peroxidation vs. Isomerization: a Biomimetic Model of Free Radical Reactivity in the Presence of Thiols. Org. Biomol. Chem. 2011, 9, 3541-3548. (26) Di Mascio, P.; Murphy, M. E.; Sies, H.: Lycopene as the Most Efficient Biological Carotenoid Singlet Oxygen Quencher. Arch. Biochem. Biophys. 1989, 274, 532-538. (27) Edge, R.; McGarvey, D. J.; Truscott, T. G.: The Carotenoids as Anti-Oxidants -- a Review. J. Photochem. Photobio. B: Biol. 1997, 41, 189-200. (28) Burton, G. W.; Ingold, K. U.: Beta-Carotene: an Unusual Type of Lipid Antioxidant. Science 1984, 224, 569-573. (29) Terao, J.: Anitoxidant Activity of Beta-Carotene-Related Carotenoids in Solution. Lipids 1989, 7, 659-661. (30) Martin, H. D.; Ruck, C.; Schmidt, M.; Sell, S.; Beutner, S.; Mayer, B.; Walsh, R.: Chemistry of Carotenoid Oxidation and Free Radical Reactions. Pure Appl. Chem. 1999, 71, 2253-2262. (31) Böhm, F.; Tinkler, J.; Truscott, T.: Carotenoids Protect Against Cell Membrane Damage by the Nitrogen Dioxide Radical. Nat. Med. 1995, 1, 98-99. (32) Mayne, S. T.: Beta-Carotene, Carotenoids, and Disease Prevention in Humans. FASEB J. 1996, 10, 690-701. (33) Omenn, G. S.; Goodman, G. E.; Thornquist, M. D.; Balmes, J.; Cullen, M. R.; Glass, A.; Keogh, J. P.; Meyskens, F. L., Jr.; Valanis, B.; Williams, J. H., Jr.; et al.: Risk Factors for Lung Cancer and for Intervention Effects in CARET, the Beta-Carotene and Retinol Efficacy Trial. J. Natl. Cancer Inst. 1996, 88, 1550-1559. (34) El-Agamey, A.; Cantrell, A.; Land, E. J.; McGarvey, D. J.; Truscott, T. G.: Are Dietary Carotenoids Beneficial ? Photochem. Photobiol. Sci. 2004, 3, 802-811.



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(35) El-Agamey, A.; Lowe, G. M.; McGarvey, D. J.; Mortensen, A.; Phillip, D. M.; Truscott, T. G.; Young, A. J.: Carotenoid Radical Chemistry and Antioxidant/Pro-oxidant Properties. Arch. Biochem. Biophys. 2004, 430, 37-48. (36) Chatgilialoglu, C.; Zambonin, L.; Altieri, A.; Ferreri, C.; Mulazzani, Q. G.; Landi, L.: Geometrical Isomerism of Monounsaturated Fatty Acids: Thiyl Radical Catalysis and Influence of Antioxidant Vitamins. Free Radical Bio. Med. 2002, 33, 1681-1692. (37) Chatgilialoglu, C.; Ferreri, C.; Lykakis, I. N.; Mihaljević, B.: Biomimetic Thiyl Radical Chemistry by γ-Irradiation of Micelles and Vesicles Containing Unsaturated Fatty Acids. Isr. J. Chem. 2014, 54, 242-247. (38) Becke, A. D.: Density-Functional Thermochemistry. III. The Role of Exact Exchange. J. Chem. Phys. 1993, 98, 5648-5652. (39) Lee, C.; Yang, W.; Parr, R. G.: Development of the Colle-Salvetti Correlation Energy Formula Into a Functional of Electron Density. Phys. Rev. B 1988, 37, 785-789. (40) Zhao, Y.; Truhlar, D. G.: Hybrid Meta Density Functional Theory Methods for Thermochemistry, Thermochemical Kinetics, and Noncovalent Interactions: The MPW1B95 and MPWB1K Models and Comparative Assessments for Hydrogen Bonding and van der Waals Interactions. J. Phys. Chem. A 2004, 108, 6908-6918. (41) Guo, J.-J.; Hsieh, H.-Y.; Hu, C.-H.: Chain-Breaking Activity of Carotenes in Lipid Peroxidation: A Theoretical Study. J. Phys. Chem. B 2009, 113, 15699-15708. (42) Curtiss, L. A.; Raghavachari, K.; Redfern, P. C.; Rassolov, V.; Pople, J. A.: Gaussian-3 (G3) Theory for Molecules Containing First and Second-Row Atoms. J. Chem. Phys. 1998, 109, 7764-7776. (43) Cossi, M.; Scalmani, G.; Rega, N.; Barone, V.: Energies, Structures, and Electronic Properties of Molecules in Solution with the C-PCM Solvation Model. J. Chem. Phys 2002, 117, 43-54. (44) Mennucci, B.; Tomasi, J.: Continuum solvation models: A New Approach to the Problem of Solute’s Charge Distribution and Cavity Boundaries. J. Chem. Phys 1997, 106, 5151-5158. (45) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.; Cheeseman, J. R.; Montgomery Jr., J. A.; Vreven, T.; Kudin, K. N.; Burant, J. C.; et al. G03. Revision B.05 ed.; Gaussian, Inc.: Pittsburgh PA, 2003. (46) Cerón-Carrasco, J. P.; Bastida, A.; Requena, A.; Zúñiga, J.; Miguel, B.: A Theoretical Study of the Reaction of Beta-Carotene with the Nitrogen Dioxide Radical in Solution. J. Phys. Chem. B 2010, 114, 4366-4372. (47) Guo, J.-J.; Hu, C.-H.: Mechanism of Chain-Termination in Lipid Peroxidation by Carotenes: A Theoretical Study. J. Phys. Chem. B 2010, 114, 16948-16958.


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Table 1. Relative Free Energies (in kcal/mol, at 298 K) of Species Involved in the Hydrogen Abstractions by Radicals with Respect to R. + (2Z,5Z)-hepta-2,5-diene. The Energetics were Computed at the MPWB1K/6-31++G(d,p)//B3LYP/6-31G(d) Level of Theory, Results in Benzene and Water were Computed using PCM Model. Energetics for Species Involved in the Most Kinetically Favorable Reaction Path were Depicted in Bold Face. .

CH3S gas phase hepb tsrtor hepr tstor34 hepr34ts hepr34 hepr23ts hepr23 tsrto2 hep2 tsr23to2 tsr23to3 hep3 tsr23to4 hep4 tsr34to5 hep5 tsr34to6

0.3 13.7 -13.4 16.5 -2.0 -9.4 8.1 -13.9 10.5 -5.3 10.2 9.5 -6.5 12.9 -1.3 15.2 -3.9 14.5

NO2

benzene

water

0.4 14.4 -14.1 17.2 -1.9 -10.3 8.0 -14.5 10.7 -5.3 10.6 9.7 -6.2 13.7 -1.1 15.1 -4.1 14.9

0.2 13.6 -14.8 16.5 -2.2 -11.0 7.7 -15.1 9.8 -5.3 9.8 8.8 -6.2 12.9 -1.0 14.1 -4.2 14.1

gas phase 0.3 21.0 1.4 25.2 12.7 5.3 22.8 0.8 19.6 -5.3 19.1 17.5 -6.5 24.4 -1.3 20.5 -3.9 19.1

.

ONO

benzene

water

0.4 20.2 -2.3 23.9 9.9 1.6 19.9 -2.6 17.7 -5.3 17.3 15.8 -6.2 23.1 -1.1 18.6 -4.1 17.2

0.2 17.8 -6.4 21.7 6.2 -2.6 16.1 -6.7 14.7 -5.3 14.2 12.8 -6.2 20.7 -1.0 15.7 -4.2 14.2

gas phase 0.3 22.9 -6.4 25.9 5.0 -2.4 15.1 -6.9 20.2 -5.3 19.6 18.9 -6.5 21.7 -1.3 24.7 -3.9 24.4


.

CH3OO

benzene

water

0.4 21.6 -8.1 24.4 4.1 -4.3 14.0 -8.5 18.5 -5.3 18.3 17.3 -6.2 20.5 -1.1 22.6 -4.1 23.0

0.2 19.7 -9.9 22.6 2.8 -6.0 12.6 -10.2 16.1 -5.3 16.0 14.9 -6.2 18.5 -1.0 20.1 -4.2 20.8

gas phase 0.3 21.9 -10.4 24.7 1.0 -6.4 11.1 -10.9 19.0 -5.3 18.4 17.7 -6.5 20.9 -1.3 23.4 -3.9 23.0

.

benzene

water

0.4 22.7 -11.5 25.8 0.7 -7.7 10.6 -11.9 19.6 -5.3 19.0 18.4 -6.2 21.7 -1.1 23.4 -4.1 23.6

0.2 22.1 -12.8 25.6 -0.1 -9.0 9.7 -13.1 18.6 -5.3 17.8 17.4 -6.2 21.1 -1.0 22.4 -4.2 22.8


1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

hep6 ∆Gc

-1.8 22.9

-1.5 23.8

-1.4 23.6

-1.8 21.0

-1.5 20.2

-1.4 17.8

-1.8 25.3


Page 22 of 35

-1.5 25.4

-1.4 24.8

-1.8 28.1

-1.5 29.9

-1.4 30.2

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Table 2. Critical Barriers (∆Gc, in kcal/mol) for the Hydrogen Abstraction and Radical Addition Reactions of radicals with hep. For HA the Barriers of the Initiation Step are Shown in Parentheses, and the Kinetically Favored Products are Specified, for Addition the Sites of Lowest Barrier Reaction are Shown in Parentheses. The Energetics were Computed at the MPWB1K/6-31++G(d,p)//B3LYP/6-31G(d) Level of Theory, Results in Benzene and Water were Computed using the PCM Model. HA .

CH3S . NO2

.

ONO

.

CH3OO

.

addition

gas phase

benzene

water

gas phase

benzene

water

23.4 (13.7)

24.2 (14.4)

23.9 (13.6)

12.4 (C2)

13.0 (C2)

12.5 (C2)

hep3

hep3

hep3

21.0 (21.0)

20.2 (20.2)

17.8 (17.8)

20.0 (C2)

18.3 (C2)

16.1 (C2)

hep6

hep6

hep6

25.8 (22.9)

25.8 (21.6)

25.1 (19.7)

22.9 (C2)

21.4 (C2)

19.6 (C2)

hep3

hep3

hep3

28.6 (21.9)

30.3 (22.7)

30.5 (22.1)

24.2 (C3)

25.0 (C2)

24.4 (C2)

hep3

hep3

hep3



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

Page 24 of 35

Table 3. Critical Barriers (∆Gc, in kcal/mol) for the Hydrogen Abstraction and Radical Addition Reactions of radicals with LAH. For HA the Barriers of the Initiation Step are Shown in Parentheses, and the Kinetically Favored Products are Specified, for Addition the Sites of Lowest Barrier Reaction are Shown in Parentheses. The Energetics were Computed at the MPWB1K/6-31++G(d,p)//B3LYP/6-31G(d) Level of Theory, Results in Benzene and Water were Computed using the PCM Model. HA .

CH3S . NO2

.

ONO

.

CH3OO

.

addition

gas phase

benzene

water

gas phase

benzene

water

21.9 (13.2)

22.9 (14.5)

22.7 (13.7)

11.1 (C13)

11.8 (C13)

10.8 (C13)

LAHb

LAHb

LAHb

21.7 (21.7)

21.1 (21.1)

20.9 (18.8)

17.8 (C12)

16.5 (C12)

14.6 (C12)

LAHd

LAHd

LAHd

24.1 (21.3)

24.0 (21.4)

23.5 (19.9)

20.9 (C10)

19.6 (C10)

18.0 (C10)

LAHb

LAHb

LAHb

28.4 (20.4)

30.8 (22.2)

31.1 (21.9)

22.9 (C9)

23.9 (C9)

22.9 (C10)

LAHc

LAHc

LAHc


Page 25 of 35

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Table 4. Reaction Barrier (∆G ) and Reaction Free Energy (∆G) for the Addition of Radicals to β-carotene and Lycopene. The Energetics were Computed at the MPWB1K/6-31++G(d,p)//B3LYP/6-31G(d) Level of Theory, Results in Benzene and Water were Computed using PCM Model. ∆G‡

∆G

gas phase benzene water

gas phase benzene water

10.3

11.4

10.9

-15.8

-15.1

-14.9

11.3

9.8

6.2

-10.6

-12.0

-13.8

19.2

20.4

20.6

-10.9

-11.2

-10.6

12.7

13.1

12.3

-9.3

-9.7

-10.1

14.0

10.9

6.7

-6.7

-9.8

-12.3

21.4

21.8

21.4

-12.9

-12.7

-10.4

lycopene .

CH3S . NO2

.

CH3OO

.

β-carotene .

CH3S NO2

.

CH3OO

.



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Page 26 of 35

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1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48




1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48

Page 28 of 35

.

Figure 1. (a) The structures and selected geometrical parameters (bond lengths in Å ) for species involved in the addition of CH3S to C2 of hep; relative free energies are in kcal/mol. (b) Free energy landscapes of radical additions, only the lowest barrier path is shown; the reaction sites of lowest barrier are shown in parentheses.


Page 29 of 35

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


imag =

1.98

405 i cm-1

1.40

imag =

466 i cm-1

1.90 1.41

imag =

471 i cm-1

1.92 1.39

Figure 2. Structures and selected geometrical parameters (bond lengths in Å) of the .

.

.

rate-determining TSs for -NO2 , -ONO , and CH3OO additions to hep.


imag

= 1372 i cm-1

20 1.63

10

hepb 0

0.0 hep

hepr34 -10

hepr23

Page 31 of 35

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.

Figure 3. (a) Free energy landscapes for the HA of hep by CH3S . (b) Free energy landscapes for the HA of CH3SH by the radicals.


Page 33 of 35

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.

Figure 4. (a) The structures for species involved in the addition of CH3S to LAH via C13. (b) Free energy landscapes of radical additions, only the lowest barrier path is shown.



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Page 34 of 35

.

.

.

Figure 5. Structures and selected geometrical parameters of the TSs for the additions of CH3S , -NO2 , and CH3OO to lycopene.


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Radical-Induced CisâTrans Isomerization of Fatty Acids: A

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