Dominant Carbons in trans- and cis-Resveratrol Isomerization - The

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Dominant Carbons in Trans and Cis-Resveratrol Isomerization Feng Wang, and Subhojyoti Chatterjee J. Phys. Chem. B, Just Accepted Manuscript • DOI: 10.1021/acs.jpcb.7b02115 • Publication Date (Web): 12 Apr 2017 Downloaded from http://pubs.acs.org on April 13, 2017

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Dominant Carbons in Trans and Cis-resveratrol Isomerization Feng Wang* and Subhojyoti Chatterjee Molecular model Discovery Laboratory, Department of Chemistry and Biotechnology, Faculty of Science, Engineering and Technology, Swinburne University of Technology, Hawthorn, Melbourne, PO Box 218, Victoria, 3122, Australia Abstract A comprehensive analysis for isomerization of geometric isomers in case of resveratrol is been presented. As an important red wine molecule, only one geometric isomer of resveratrol, i.e., trans-R rather than cis-R is primarily associated with health benefit. In the present study, density function theory (DFT) provides accurate descriptions of isomerization of resveratrol. The nearly planar trans-R forms a relatively rigid and less flexible conjugate network but the non-planar cis-R favors a more flexible structure with steric through space interaction. The calculated carbon nuclear magnetic resonance (NMR) chemical shift indicates that all carbons are different in the isomers, it further reveals that four carbon sites, i.e., C(6), C(8)=C(9) and C(11) has significant response to the geometric isomerization. Here C(6) is related to steric effect in cis-R whereas C(11) may indicate the isomerization proton transfer on C(9) linking with the resorcinol ring. The excess orbital energy spectrum (EOES) confirms the NMR “bridge of interest” carbons and reveals that five valence orbitals of 34a, 35a, 46a, 55a and 60a respond to the isomerization most significantly. The highest occupied molecular orbital (HOMO), 60a of the isomer pair are further studied using dual space analysis (DSA) for its orbital momentum distributions, which exhibit p-electron dominance for trans-R but hybridized sp-electron dominance for cis-R. Finally, energy decomposition analysis (EDA) highlights that trans-R is preferred over the cis-R by ˗4.35 kcal⋅mol-1, due to small electrostatic energy enhancement of the attractive orbital energy with respect to the Pauli repulsive energy. 1. Introduction Although named as the red-wine molecule, resveratrol (trans-3,5,4′-trihydroxystilbene) is found in many plant species including those often consumed by humans such as grapes, peanuts, berries and tomato.1-7 Recent studies claimed that one tomato contains as much resveratrol as fifty bottles of red wine.8 The highest naturally contained level of resveratrol is believed to be in a Japanese knotweed called Polygonum cuspidatum.9,10

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Resveratrol has many applications in human physiology which includes cancer chemoprevention, antioxidant, anti-inflammatory, anti-viral and neuroprotective property; reducing obesity, preventing aging together with protection from ischemia and infection etc.1119

For example, trans-resveratrol is being used as a preventive agent against several important

pathologies; cardiovascular diseases, cancers, viral infection and neurodegenerative processes.20-23 Resveratrol is also known to mimic the antidiabetic effects of calorie restriction in rodents as well as in boosting life span in flies and worms. Whether resveratrol is beneficial to humans is not very clear, but a recent study suggests that it can also imitate the effects of calorie restriction in obese people,24 along with its antiaging mechanism through the involvement of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase SIRT1.25 In a recent review, Latruffe et. al., (2014)26 indicated that the intracellular biological effect, which can be finally produced through the molecular interaction of resveratrol with albumin, contributes to the transport of resveratrol through the blood circulation. Resveratrol plays an essential role for its further delivery at the cell surface and, consequently, for membrane uptake.26-28 A recent study of (trans) resveratrol29 also indicated on its antioxidant properties along with its ability to bind with organic compounds present in many organisms, such as hormone receptors and enzymes. The ability of resveratrol to interact with biological molecules provides multiple biological activities when studied in vitro.30,31 Molecular shape in three-dimensional (3D) space including chirality may connect to the bioactivity (potency) of a compound (drug). In organic chemistry, controlling molecular steric properties and/or chirality in photochemical reactions is one of the most intriguing topics because of the inherently challenging nature of the excited-state reactions, which involve weak interactions and short-lived excited species.32-34 As part of an ongoing effort to establish sensitive molecular properties in the development of theoretical tools, which are able to differentiate isomers such as conformers33,34 and enantiomers,35,36 the present study examines the properties associate to the geometrical isomers of resveratrol, trans-R and cis-R, in order to reveal how the properties of trans-R are related to its electronic structure for its bioactivity with respect to its cis-R isomer. Resveratrol is a polyphenol stilbene with a C=C double bond. It has two principal (geometric) isomers, trans (E) and cis (Z). The trans-R appears to be the more predominant and stable natural form but cis-R has never been found in grape extract.29,30,37 Cis-isomerisation can occur when the trans-R is exposed to solar38,39 or ultraviolet radiation40 etc. In the present study, we employed quantum mechanical calculations together with tools we developed, to explore the 2|Page ACS Paragon Plus Environment


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chemical shift of particular carbon sites, for the information of through space and through bond interactions in the trans-R and cis-R isomerization. The theoretical tools include dual space analysis (DSA)41 which reveals the cross sections of an orbital in momentum space hence sensitive to the shape of an isomer42-45, excess orbital energy spectrum (EOES)46,47 which extract the conformer structural information on individual orbitals and energy decomposition analysis (EDA).45,48 With the help of such tools developed for isomers, one is able to reveal physical connections of the energy terms in the isomers of resveratrol and NMR spectroscopy. 2. Computational details Density functional theory (DFT) based hybrid Becke three-parameter Lee-Yang-Parr (B3LYP) functional with 6-311++G(d,p) basis set, i.e., B3LYP/6-311++G(d,p) was employed for geometric optimization. This model is sufficient to produce reliable geometries for many organic and bio-molecules.49-52 As pointed by Lahiri et. al., (2014)53 that there exist serious incongruities between computations performed at comparable levels of DFT and coupled cluster (CC) theory for dispersive optical properties which is supported by polarimetric data of Stephens et. al. (2009).54 Our recent higher level study on IR spectroscopy of ferrocene also indicates that the performance of B3LYP with appropriate Fe basis set is significantly more accurate than a number of other quantum mechanical methods including CCSD.55 Based on the optimized geometries, potential energy scans (PES) for both trans-R and cis-R are performed through rotating the two C-C bonds connected to the stilbene C=C bond using a smaller basis set, B3LYP/6-31G(d). The

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C nuclear magnetic resonance (C-NMR) isotropic shielding values were calculated,

based on the obtained geometries of resveratrol isomers, using three models, i.e., B3LYP/6311++G**//B3LYP/6-311++G**, B3PW91/6-311++G**//B3LYP/6-311++G** and M06-2X/6311++G**//B3LYP/6-311++G**. The

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C NMR chemical shift for the resveratrol isomers is

calculated using the gauge invariant atomic orbital (GAIO) method56 in gas phase and in dimethyl sulfoxide (DMSO, ε = 46.7) solvent using polarizable continuum model (CPCM).57 The results obtained are compared with the internal reference standard i.e. tetra-methylsilane (TMS) for carbon C-NMR. Excess orbital energy spectrum (EOES)46 has been proven to be a very useful tool to identify particular orbital pairs of the isomers in response to the subtle orbital based differences between conformer pairs. EOES takes the excess orbital energies of the corresponding orbitals in two isomers such that (Eq. 1)46,47, 3|Page ACS Paragon Plus Environment

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∆εi = ∆εi,cis-R - ∆εi,trans-R

(1)

EOES of resveratrol identifies a group of orbitals which responses the local changes with respect to the geometric conformers. Among the group of orbitals identified by EOES between the trans-R and cis-R, the highest occupied molecular orbital (HOMO, 60a) of resveratrol is among the orbitals which experience significant isomeric changes. To further understand such significant orbital differences between trans-R and cis-R, dual space analysis (DSA)41 is employed. The HOMO electron densities in coordinate space is transformed into momentum space using Fourier transform (FT). The triple differential cross section of the orbital in momentum space,58 which is the theoretical orbital momentum distributions (TMDs) for the occupied orbitals in the system is given by (Eq. 2),59

σi ∝

∫

2

dΩ φ i (p) ,

(2)

where p is the momentum of the target electron at the instant of ionization. Here φi(p) is the molecular orbital (60a) in momentum space. The momentum cut-off for the calculations is 10 a.u.60, implying the Born-Oppenheimer approximation (for molecules) and the independentparticle (mean-field) approximation in the NEMS code.61 Dissection of the physical origins of intra and intermolecular interactions of molecules will further help in the understanding of the structural differences between trans-R and cis-R. As a result, energy decomposition analysis (EDA) is employed.62-73 The EDA is capable of bridging the gap between the conceptually simple interpretations of chemical bond nature and the elementary quantum mechanics.74 Morokuma75 and the extended transition state (ETS) of Ziegler and Rauk76 are the most well known EDA methods. In this present study, we have concentrated on the ADF based ETS scheme, where the total bonding energy of the fragments (atoms) is expressed as the sum of preparation energy and interaction energy (Eq. 3), using the B3LYP/TZ2P model.74,76 ∆E = ∆EPrep + ∆EInt

(3)

Where, ∆EPrep corresponds to the energy required to deform the separated fragments from their equilibrium geometry and ∆EInt the stabilizing energy term called interaction energy that includes the instantaneous interaction between the fragments. Gaussian 09 (G09)77 computational chemistry package and Amsterdam density functional (ADF) computational chemistry program78-80 are used for all the quantum mechanical calculations. 4|Page ACS Paragon Plus Environment


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3. Results and discussion 3.1 Geometric properties and stabilities of trans- and cis-resveratrol Geometries of the resveratrol isomers, i.e. Trans (trans-R) and Cis (cis-R) in the ground electronic states are obtained using B3LYP/6-311++G(d,p). Figure 1 gives the chemical structure and nomenclature of trans resveratrol (3,5,4'-trihydroxystilbene) with standard IUPAC labelling and the corresponding present single index system in parentheses in blue. In the structures, the phenol ring is labelled as R(1) which also presents the perimeter; whereas the resorcinol ring is labelled as R(2) which also defines the perimeter of the ring. The figure also displays the optimized 3D structures of trans-R (Figure 1(b)) and cis-R (Figure 1(c)). Both the optimised structures of trans-R and cis-R are obtained without imaginary frequencies, indicating that the 3D structures in Figure 1 are true minimum energy structures. The agreement between the measurement and the DFT calculations is excellent. Table 1 compares the selected geometric and other molecular properties of trans-R between crystal Xray diffraction measurement and other theoretical studies.81-83 Note that measurements are only available for trans-R in the literature. The calculated geometric properties agree well with the X-ray measurement of trans-R. Only small discrepancies is seen between the calculations due to the use of different models i.e., Guder et. al., (2014)82 used the B3PW91/6-311++G** model for the optimization and the present study uses the B3LYP/6-311++G** model for geometric optimization. Note that a request to the authors for the B3PW91/6-311++G** optimized geometry of trans-R was not successful as the authors did not keep the data after the article was published. Interestingly, both models predict shorter C-C bonds except for the single bonds C(9)-C(10) and C(5)-C(8) but with longer C-O bonds than the measurement. For example, all calculated C-O bond lengths in trans-R are shorter than 1.370 Å, whereas the corresponding measured C-O bond lengths are above 1.375 Å. The carbon-carbon bonds of trans-R reflect the chemical structure and conjugation. It is considered as the “bridge of interest” as marked in Figure 1(a). Inside the box of “bridge of interest”, it includes the stilbene bond C(8)=C(9); the two single C-C bonds on both sides of the stilbene bonds, C(5)-C(8) and C(9)-C(10), which connect the stilbene carbons with R(1) and R(2) rings as a conjugated carbon bridge, as well as six phenol carbons of C(5), C(4) and C(6) for R1 and C(10), C(11) and C(15) for R(2), connecting at C(5) and C(10) with “Y” shaped nodes, respectively. The rest of the carbons are outside the box representing bridge of interest concerning isomerism. The measured stilbene bond length, C(8)=C(9), is 1.333 Å which is 5|Page ACS Paragon Plus Environment

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Figure 1. Nomenclature and optimized structures i.e., (a) The IUPAC nomenclature is given and the labels in blue is employed in the present study. The red dotted line box in the structure is the “bridge of interest” for resveratrol. Three dimensional (3D) structures for trans (b) and (c) cis – resveratrol are obtained using B3LYP/6-311++G** model. 6|Page ACS Paragon Plus Environment


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slightly shorter than isolated C=C bond length of 1.337 Å in ethene (gas phase), whereas the calculated C=C bond length using different models are the same as 1.346 Å in Table 1. It indicates that the stilbene bond in resveratrol can be shorter in solid (the measurement) than in gas phase (Table 1 colored in red). The conjugation is enhanced by two aromatic rings. The two single C-C bonds, C(5)-C(8) and C(9)-C(10), which connect the stilbene carbons C(8)=C(9) with R(1) and R(2) rings, are 1.463 Å and 1.466 Å, respectively (Table 1 coloured in blue), in excellent agreement with the measurement of 1.460 Å and 1.468 Å.82 It is seen that the single C-C bond lengths in trans-R are between the C-C and C=C bond lengths in isolation. The uneven bond lengths, C(5)-C(8) and C(9)-C(10), is an indicator of different rings (phenol ring and resorcinol ring) of resveratrol. Finally, the fact that stilbene C=C bond is longer than isolated C=C and the C-C bonds are shorter than isolated single C-C bond suggests conjugation nature of “Z”shaped bridge of interest, C(6)-(C(4))-C(5)-C(8)=C(9)-C(10)-(C(11))-C(15) in resveratrol. The other CC bonds in the box, C(6)-(C(4))-C(5) and C(10)-(C(11))-C(15) are part of the R(1) and R(2) rings and connect to the stilbene bond forming a two “Y”-shaped structures. That is, C(4)-C(5), C(6)-C(5); C(11)-C(10) and C(15)-C(10). The carbons outside the box are the least affected group in the resveratrol carbons (the black coloured carbons in the table). The CC bond lengths of these carbons in trans-R show certain aromaticity although not perfect conjugation as in benzene. It is also noted that the measured ring perimeters R(1) for phenol, and R(2) for resorcinol in the trans-R are not the same, i.e., R(1) is given by 8.285 Å but R(2) is given by 8.311 Å.84 The present study gives 8.380 Å for R(1) and 8.379 Å for R(2) using the B3LYP/6-311++G** model, whereas the same perimeters of 8.369 Å for both R(1) and R(2) using the B3PW91/6-311++G** model.82 It may indicate that phenol and resorcinol perimeters of the trans-R is more different in crystal solid but very similar in gas phase. The angles also exhibit minor discrepancies between theory and measurements at the regions either related to the local carbons in the box or with the hydroxyl groups (-OH). It needs to note that the measurement is in solid state whereas the calculations are in free gas phase. Therefore, it will be of no surprise that the same angles of the compound between solid state and gas phase do not align perfectly. As a result, the discrepancies between angles will not be over stated here. As geometric isomers, trans-R and cis-R cannot be produced through rotation of the rigid double stilbene C=C bond. The cis-R isomer has not been studied as extensively as trans-R in the literature. Fortunately, Table 1 indicates that the present theoretical model is accurate and hence will be employed in the present study. Although it is unlikely to rotate the C=C bond to 7|Page ACS Paragon Plus Environment

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Table 1: Comparison of selected geometrical parameters and other properties of trans and cis – resveratrol. Parameters

8.380 8.379

Trans Guder et. al.,a Theo. Expt. (B) (C) 8.369 8.285 8.369 8.311

1.368 1.370 1.369 1.398 1.394 1.388 1.388 1.405 1.407 1.463 1.346 1.466 1.406 1.402 1.393 1.393 1.395 1.391

1.361 1.363 1.363 1.393 1.397 1.386 1.386 1.404 1.403 1.459 1.346 1.463 1.399 1.404 1.390 1.394 1.391 1.391

1.385 1.379 1.392 1.371 1.377 1.373 1.372 1.396 1.396 1.460 1.333 1.468 1.398 1.399 1.366 1.391 1.383 1.374

0.017 0.009 0.023 -0.027 -0.017 -0.015 -0.016 -0.009 -0.011 -0.003 -0.013 0.002 -0.008 -0.003 -0.027 -0.002 -0.012 -0.017

122.7 117.7 119.7 120.2 121.4 117.2 123.8 119.1 122.1 119.6 127.4 126.7 118.2 123.1 118.8 120.4 116.8 122.4 120.8 118.7 121.7 117.0 121.3

117.8 122.7 119.6 119.6 122.1 117.2 123.8 119.1 121.4 120.2 127.2 126.5 118.1 122.9 118.9 119.9 117.1 121.7 121.2 118.8 122.5 116.9 120.6

120.2 119.6 120.2 119.3 122.3 116.7 123.9 119.3 121.2 120.2 128.5 126.5 119.3 122.0 118.7 120.3 118.8 119.8 121.5 117.9 120.4 117.8 121.8

-2.5 1.9 0.5 -0.9 0.9 -0.5 0.1 0.2 -0.9 0.6 1.1 -0.2 1.1 -1.1 -0.1 -0.1 2.0 -2.6 0.7 -0.8 -1.3 0.8 0.5

Present work (A) R(1)c R(2)c Bond length (Å) O(1) – C(2) C(14) – O(17) C(12) – O(16) C(2) – C(7) C(2) – C(3) C(3) – C(4) C(6) – C(7) C(5) – C(6) C(4) – C(5) C(5) – C(8) C(8) – C(9) (stilbene bond) C(9) – C(10) C(10) – C(15) C(10) – C(11) C(14) – C(15) C(13) – C(14) C(12) – C(13) C(11) – C(12) Bond angles (˚) O(1) – C(2) – C(7) O(1) – C(2) – C(3) C(7) – C(2) – C(3) C(2) – C(7) – C(6) C(5) – C(6) – C(7) C(4) – C(5) – C(6) C(6) – C(5) – C(8) C(4) – C(5) – C(8) C(3) – C(4) – C(5) C(2) – C(3) – C(4) C(5) – C(8) – C(9) C(8) – C(9) – C(10) C(9) – C(10) – C(15) C(9) – C(10) – C(11) C(11) – C(10) – C(15) C(10) – C(15) – C(14) C(13) – C(14) – O(17) C(15) – C(14) – O(17) C(13) – C(14) – C(15) C(12) – C(13) – C(14) C(13) – C(12) – O(16) C(11) – C(12) – O(16) C(11) – C(12) – C(13) Dihedral angles (˚) C(5) – C(8) – C(9) – C(10) C(8) – C(9) – C(10) – C(11)

∆ (C – A)

-179.572 8.074

∆ (C – B)

Present work Cis ∆b

8.379 8.377

0.001 0.002

0.024 0.016 0.029 -0.022 -0.020 -0.013 -0.014 -0.008 -0.007 0.001 -0.013 0.005 -0.001 -0.005 -0.024 -0.003 -0.008 -0.017

1.368 1.370 1.369 1.397 1.368 1.389 1.390 1.403 1.406 1.473 1.346 (1.345)d 1.477 1.404 1.399 1.391 1.396 1.392 1.395

0.000 0.000 0.000 0.001 0.026 -0.001 -0.002 0.002 0.001 -0.010 0.000 -0.011 0.002 0.003 0.002 -0.003 0.003 -0.004

2.4 -3.1 0.6 -0.3 0.2 -0.5 0.1 0.2 -0.2 0.0 1.3 0.0 1.2 -0.9 -0.2 0.4 1.7 -1.9 0.3 -0.9 -2.1 0.9 1.2

122.7 117.6 119.7 120.1 121.3 117.4 123.2 119.3 121.9 119.6 130.6 130.2 121.9 118.7 119.3 119.9 116.6 122.3 121.0 118.8 122.1 117.1 120.9

0.0 0.1 0.0 0.1 0.1 -0.2 0.6 -0.2 0.2 0.0 -3.2 -3.5 -3.7 4.4 -0.5 0.5 0.2 0.1 -0.2 -0.1 -0.4 -0.1 0.4

-6.9197 145.1578 8|Page

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-179.654 C(3) – C(2) – O(1) – H(18) -171.941 C8) – C(9) – C(10) – C(15) 6.563 C(6) – C(5) – C(8) – C(9) Geometrical parameters 7061.3711 (a.u.) 2.64 µ (D) 0 ∆E (kcal⋅⋅mol-1)* 141.61230 ZPE (kcal⋅⋅mol-1) -766.36390 E + ZPE (a.u.) 3.96 HOMO – LUMO gap (eV) Rotational Constants (GHz) 1.35456 RA 0.15617 RB 0.14038 RC a 86 Guder et. al., (2014) using the B3PW91/6-311++G(d,p) model. b

∆ = trans - cis.

c

Perimeters of the phenol rings.84

d

D. Mikulski et. al.,(2010) - Previous theo. work88

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178.7686 -38.3631 -34.8952 5114.7036 1.48 4.29510 141.90988 -766.35658 4.37 0.90907 0.23623 0.20823

*

Eh = -481042.19856 kcal⋅mol-1.

produce cis-R as the energy is as high as 67 kcal⋅mol-1,87 the total electronic energy difference between cis-R and trans-R is quite small, i.e., ∆E = 4.30 kcal⋅mol-1, which is slightly smaller than the energy difference of 5.1 kcal⋅mol-1 for stilbene (1,2-diphenylethylene) using the B3LYP/6-31G* model.85 In addition to significant planar or dihedral angle differences between trans-R and cis-R, other properties such as dipole moment, HOMO-LUMO energy gap and electron extent also show apparent differences. For example, there is a large reduction of dipole moment from trans-R to cis-R. The dipole moment of trans-R is given by 2.64 Debye using the B3LYP/6-311++G(d,p) model, which is reduce to 1.48 Debye for cis-R using the same DFT model. The changes in 3D orientations of trans-R and cis-R also significantly affect other anisotropic properties such as significantly decreased electric spatial extent , from approximately 7061 a.u. to approximately 5114 a.u. which is also reflected by the reduction of rotational constants of RA, RB and RC in the same table. Such changes in the shape of resveratrol affect the electronic structures such as the HOMO-LUMO energy gap, which increases from 3.96 eV in trans-R to 4.37 eV in cis-R. Resveratrol can be seen as a connection of the phenol (R(1)) and the resorcinol (R(2)) rings through a stilbene double bond, C(8)=C(9). The optimized trans-R is, in general, almost planar in 3D space. The torsion angle of δ (C(8)-C(9)-C(5)-C(6)) is given by 6.58°, for co-planarity 9|Page ACS Paragon Plus Environment

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Figure 2. Potential Energy Scan (PES) curve of (a) trans and (b) cis resveratrol through rotation of φ=∠C(8)-C(9)-C(10)-C(11) at the B3LYP/6-31+G* level of theory.

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between the stilbene bond and phenol (R(1)) ring whereas φ (C(8)-C(9)-C(10)-C(11)) is given by 8.21°, indicating approximately co-planarity between the stilbene bond and the resorcinol (R(2)) ring, as φ is small. This torsional angle pair is measured as δ = -3° and φ = 8°, respectively, by crystal X-ray diffraction,81 but were calculated89 as δ = 2.9° and φ = 7.2° using the PWC/NNP model in DMol3 as well as δ = 9.5° and φ = 7.5° using B3PW91/6-311++G**.82 It is noted that the planar structure of trans-stilbene was somehow artificial as the structure was forced on the planar structure which led to an imaginary frequency of trans-stilbene but was ignored in the study.85 The cis-R also possesses the C1 point group symmetry, with the torsional angles between the stilbene C=C double bond and the phenol ring and resorcinol ring are δ = 33.29° and φ = 40.16°, respectively. The angles are close to the same torsional angle of 34.08° obtained for cis-stilbene (1,2-diphenylethylene) using the B3LYP/6-31G* model.85 It is discovered that the cis-R is more flexible than the trans-R isomer with smaller energy barriers for rotations. Figure 2 presents the potential energy scans (PES) of trans-R (a) and cisR (b), by rotating the C-C bonds which is connected with the stilbene bond C(8)=C(9) of the isomers, either the C(9)-C(10) (i.e., C=C-R(2), Figure 2) or the C(5)-C(8) (C=C-R(1), Figure S1) bonds. Figure 2 shows the PES for trans-R (upper panel, (a)) and cis-R (lower panel, (b)) with rotations of the C(9)-C(10) bond, i.e., the dihedral angle of φ=∠C(8)-C(9)-C(10)-C(11). Almost symmetric energy barriers of the trans-R have been located at approximately φ=80° and φ=250°, respectively, with the barrier heights of ∆E = 4.5 Kcal⋅mol-1 (Figure 2(a)). On the other hand, rotation of the same φ angle of cis-R produces multiple energy barriers separating local energy minimum structures. The energy barrier heights with respect to the minima range are from approximately 1.0-2.5 Kcal⋅mol-1 (Figure 2(b)), apparently lower than the energy barriers of trans-R. Rotation of the other ring, R(1) in Figure 1, i.e., the C(5)-C(8) bond (the dihedral angle δ=∠C(6)C(5)-C(8)-C(9)) also produces the similar PES for trans-R and cis-R, respectively, which are presented in Figure S1. The potential energy scans show, again, that the cis-R is also more flexible with respect to rotation of the δ angle than the trans-R isomer, for the same reasons. However, rotations of this bond, i.e., the R(1) ring with a single hydroxyl group (δ) requires larger energy than rotations of the R(2) ring with two hydroxyl groups (φ). The energy barriers of upper panel in Figure S1(a) is approximately 5.0 Kcal⋅mol-1 by rotating the δ angle in transR. Although the other energy barriers in cis-R have similar heights with those when rotating 11 | P a g e ACS Paragon Plus Environment

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the φ angle in Figure 2(b) with approximately 2.0 Kcal⋅mol-1 for the barrier heights, the energy barriers of cis-R at δ = 120° and δ=300° in Figure S1(b) are apparently higher when rotating the dihedral angle δ. As a result, the relatively more rigid and flat geometry of trans-R prevents the resveratrol from the unwanted flexibility and shape as in cis-R. Rotation of the resorcinol ring (R(2)), i.e., φ, is easier than rotation of the phenol ring (R(1)), δ, in trans-R, which is the same trend in cis-R. Such structural advantages may contribute to the reasons why trans-R has significant potentials for food and pharmaceutical applications than its cis-R isomer.

3.2 Carbon NMR spectrum of trans-Resveratrol: the measured and the calculated In order to understand the structure of trans-R and to validate the theoretical models, we calculated the carbon NMR chemical shift using a number of DFT models and compared with available NMR measurements.82,86,88 Table 2 compares the calculated C-NMR chemical shift of trans-R in dimethyl sulfoxide (DMSO) solution using different models with the measured and calculated,82 as well as an earlier carbon NMR measurement in DMSO-d6 solution. In the same table, the measurement of carbon NMR chemical shift of the unsubstituted transstilbene88 are also given. The measurements agree well. For example, the carbon sites in the resorcinol ring R(2), such as C(11) and C(15) have nearly identical chemical shift in the measurements. Note that the chemical shift of C(5) =125.4 ppm and C(9)=128.0 ppm in trans-R might be transposed,82 and the correct chemical shift ought to be C(5)=128.0 ppm and C(9)=125.4 ppm, as revealed by all calculations and the earlier measurement.86 The 13C-NMR measurements of trans-R and cis-R in CD3OD solution confirmed that C(5)=130.0 ppm and C(9)=129.5 ppm.87 It is discovered that the chemical shift obtained using the B3PW91/6-311++G(d,p) model agrees well with the measurements, followed by the B3LYP/6-311++G(d,p) model. However, the more recent M06-2X functional, which produced excellent NMR chemical shift to other molecules such as β-lactam and alanine89 or diazine molecules45 etc., generates large errors and is not suitable for the C-NMR calculations of resveratrol, as shown in 4th column in Table 2. This is in agreement with previous study of resveratrol.82 The excellent agreement between the measurement and calculations is achieved using the present B3PW91/6-311++G(d,p). The calculated mean signed error (MSE) is given by -1.4 when the B3PW91/6-311++G(d,p) model is used; whereas this MSE for the M06-2X/6-311++G(d,p) model is as large as -15.5 which is significantly larger than the B3LYP/6-311++G(d,p) model with the MSE of -5.4. The 12 | P a g e ACS Paragon Plus Environment


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calculations using the B3PW91/6-311++G(d,p) model has a slightly larger error than the same model of Guder et. al., (2014)82 with an MSE of -0.7. It is noted that the present study is based on the optimised geometry of trans-R but the previous study was based on the same model of B3PW91/6-311++G(d,p). The calculated carbon NMR chemical shift of trans-R agrees well, in general, with the measurements in DMSO solution, indicating that the models employed are sufficiently accurate in the structural calculations. Table 2. Comparison of the measured and calculated 13C NMR (in ppm) chemical shifts (with respect to TMS) for trans resveratrol in DMSO solution using different DFT models*. Present work* Ref 82 (2014) B3PW91 B3LYP M06-2X B3PW91 Expt.a 159.0 163.6 173.0 158.6 157.0 C(2) 115.8 119.2 129.5 114.9 115.4 C(3) 134.1 137.8 149.8 133.6 127.7 C(4) 129.8 134.4 143.8 129.0 125.4c C(5) 125.9 129.3 140.8 125.5 127.7 C(6) 115.4 118.9 128.6 114.7 115.4 C(7) 132.6 136.4 147.6 130.7 127.4 C(8) 127.7 131.3 141.3 126.2 128.0d C(9) 141.3 146.1 156.6 140.9 138.1 C(10) 100.0 103.3 113.2 99.4 104.2 C(11) 160.4 165.2 174.3 159.9 158.3 C(12) 99.6 102.8 112.4 98.9 101.7 C(13) 159.8 164.6 174.2 159.6 158.3 C(14) 107.9 111.3 120.8 106.2 104.2 C(15) * All theory based on the 6-311++G(d,p) basis set. Site

a

Ref 86 (2005) Ref 87 (2003) Expt.b Expt.e 157.2 158.5 115.4 129.0 127.8 116.6 128.1 130.6 127.8 129.0 115.4 116.6 128.0 127.1 125.6 129.5 139.2 141.5 104.2 105.9 158.3 159.8 101.7 102.8 158.3 159.8 104.2 105.9

Stilbeneh Expt. 128.0 128.1 129.1 137.8 129.1 128.1 129.2 129.2 137.8 129.1 128.1 128.0 128.1 129.1

Guder et. al., (2014)82

b

Commodari et. al.,(2005)86

c,d

Comparison of two carbon NMR measurements and theoretical calculations including the calculations in Ref

86, this pair of carbons in trans-R may be an error, i.e., C(5)=128.0 ppm and C(9)=125.4 ppm. e

Deak et. al., (2003)87 The 13C-NMR in CD3OD solution.

f

Amini et. al., (2012)88

Chemical shift in C-NMR reflects the chemical environment away from the reference TMS. All twelve carbons of the unsubstituted trans-stilbene88 split into five carbon groups (last column in Table 2) as measured by the C-NMR. However, three hydroxyl groups in resveratrol largely reduced the symmetry from stilbene. In the carbon NMR measurements, four pairs of carbons in trans-R show identical carbon chemical shift, that is, C(3) and C(7) (δ=115.4 ppm), C(4) and C(6) (δ=127.7 ppm) in the phenol ring, R(1), and C(12) and C(14) (δ= 158.3 ppm), C(11) 13 | P a g e ACS Paragon Plus Environment

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and C(15) (δ=104.2 ppm) in the resorcinol ring, R(2). The measurements indicated that the chemical environment of these carbon pairs were equivalent (coloured in Table 2).82,86,88 However, the 3D structure of trans-R possesses a C1 point group symmetry as shown in Figure 1(b), as a result, none of the carbon atomic sites in trans-R is, in fact, strictly chemically equivalent. Only two pairs of carbon atoms which are away from the stilbene bond, i.e., C(3) and C(7) in the phenol ring R(1), exhibit similarities as δC(3) = 115.8 ppm and δC(7) =115.4 ppm. In the resorcinol ring R(2), i.e., C(12) and C(14), show similarities as δC(12) = 160.2 ppm and δC(14) =159.8 ppm, obtained using the present B3PW91 model (see Table 2). Other pair of carbons, C(4) and C(6) (δC(4) = 134.1 ppm and δC(6) =125.9 ppm), C(11) and C(15) (δC(11) = 100.0 ppm and δC(15) =107.9 ppm) are significantly different in their chemical shift. The differences between the carbons pairs are as large as 8 ppm! However, the time scales of the NMR spectrum are in the range of milliseconds to microseconds and rotational spectrum from nanoseconds to picoseconds. It is likely that the significantly faster phenyl ring flipping makes the corresponding carbon pairs, such as C(12) and C(14), C(15) and C(11), as well as C(6) and C(4), and C(7) and C(3) with averaged chemical shift in the measured NMR spectra. As a result, it is important for NMR measurements and analysis to be supported by quantum mechanics for more insight.

3.3 C-sites responsible for the isomers revealed by calculated NMR spectra It is well known that the trans-R and cis-R are geometric isomers, differing in 3D space orientation and chemical bonding. Their structures, including the geometric structures in 3D as well as the electronic structures, contribute to their property and functionality differences. The previous geometric structure information reveals that: Firstly, the trans-R is slightly more stable than the cis-R isomer with lower total electronic energy (Table 1). The nearly planar shape of trans-R may be the preferred shape in biophysical environment. Its lower energy will ensure that the trans-R isomer is populated with a larger number. Secondly, the trans-R is less flexible compared to the cis-R when rotating the bridge C-C single bonds, i.e., φ or δ angles, since trans-R has higher energy barriers with respect to rotations. The relative rigidity of transR warrants that the trans-R is potentially more capable of keeping the preferred shape than the flexible cis-R. Finally, rotation of the resorcinol ring, R(2), is slightly less difficult than rotation of the phenol ring R(1) in trans-R, which also apply to cis-R.



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Table 3. Comparison of the calculated

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C NMR (in ppm) isotropic chemical shifts (with

respect to TMS) of trans with cis resveratrola in gas phase. Site

B3PW91 Trans Cis ∆δ(T-C) C(2) 158.3 157.8 0.5 C(3) 115.7 115.7 0.0 C(4) 134.0 133.6 0.4 130.5 130.5 0.0 C(5) C(6) 124.8 131.1 -6.3 C(7) 113.7 112.2 1.5 C(8) 129.9 132.6 -2.7 C(9) 126.8 131.1 -4.3 C(10) 141.5 142.0 -0.5 C(11) 101.5 109.5 -6.0 C(12) 160.3 160.4 -0.2 C(13) 99.0 98.4 0.6 C(14) 159.3 158.2 1.2 105.9 104.7 1.2 C(15) a basis set 6-311++G(p,d).

Trans 163.0 119.3 137.7 135.1 128.2 117.1 133.2 130.3 146.2 104.8 165.2 102.3 164.2 109.3

B3LYP Cis 162.5 119.1 137.4 135.1 135.0 115.6 136.3 134.7 146.7 113.1 165.2 101.6 162.9 108.4

∆δ(T-C) 0.4 0.2 0.3 0.0 -6.8 1.6 -3.1 -4.4 -0.5 -8.3 -0.1 0.7 1.3 0.9

Trans 172.4 130.1 150.0 144.9 139.3 126.5 144.9 140.0 156.7 114.5 174.1 111.4 173.0 119.3

M06-2X Cis 171.2 130.5 148.5 145.4 130.5 125.6 147.9 144.0 159.1 122.9 174.9 110.9 173.0 118.0

∆δ(T-C) 1.2 -0.3 1.5 -0.5 8.9 0.9 -3.0 -4.0 -2.4 -8.5 -0.8 0.6 0.0 1.3

Table 3 compares the calculated C-NMR chemical shift of trans-R with cis-R using the three models in gas phase. To study properties of a molecule, gas phase provide information of the systems in isolation, without any environment effects. In this table, four carbon sites, C(6), C(8), C(9) and C(11), represent large C-NMR chemical shift (|∆δ| larger than 2.5 ppm) between transR and cis-R (highlighted in the table 3). Interestingly, the carbons with large chemical shift include the stilbene carbons C(8), C(9) and carbons C(6) and C(11). The latter, C(6) and C(11), do not directly bond to the stilbene C=C carbons. In this regards, all the three models, B3PW91/6311++G(d,p), B3LYP/6-311++G(d,p) and M06-2X/6-311++G(d,p) produce consistent results for these four carbons. It is noted that the chemical shift of C(6) predicted in the M06-2X/6311++G(d,p) model is opposite to those predicted by other models. That is, the other models calculated the chemical shift of C(6), C(8), C(9) and C(11) in trans-R significantly upfield (smaller δ) with respect to these carbons in cis-R, except C(6) from the M06-2X model, as shown in Table 3 (highlighted in green). Three of the four carbons in the resveratrol isomerization identified by the C-NMR are not difficult to understand, except for C(11). Site C(11) may imply that the isomerization from transR to cis-R involves the proton transfer on C(9) rather than C(8). First, the chemical environment of C(9) changes more than that of C(8) as indicated in Table 3. The isomerisation shifts C(9) upfield by 4.3 ppm, whereas C(8) shifts upfield by 2.7 ppm in the B3PW91/6-311++G(d,p) 15 | P a g e ACS Paragon Plus Environment

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calculations. Next, a very small chemical environment changes on C(4) with respect to the isomerisation indicates that the local chemical environment of C(4) changes little and it is unlikely that the proton (H(23)) on C(8) transfers when trans-R becomes cis-R. The proton on C(9), i.e., C(9)-H(24), is more likely to exchange with C(9)-C(10) to form cis-R, as all the local chemical environment, such as C(14), C(15), C(6) and C(11), responds accordingly, as shown in Table 3. 3.3 Orbitals responsible to the trans-R and cis-R isomerization The four carbon sites identified by the NMR chemical shift, C(6), C(8), C(9) and C(11), may be responsible for the trans-R and cis-R isomerization. All the carbons are contained in the “bridge of interest”. However, there are eight carbons sites in the bridge, why only four carbons are significant to the isomerisation? It is not difficult to understand that the stilbene C=C bond carbons, C(8) and C(9) play a significant role in trans-R and cis-R isomerization. However, the other carbons, C(6) and C(11) are not directly connected to the stilbene bond C(8)=C(9) in resveratrol. To explore orbital based information between the isomers, the recently developed excess orbital energy spectrum (EOES)46 is employed.

Figure 3. Excess orbital energy spectrum (EOES) of cis and trans resveratrol (∆=εcis – εtrans) at the B3LYP/6-311++G** level of theory.



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Figure 3 displays the excess orbital energy spectrum (EOES) of cis-R with respect to trans-R given in Eq.(1).46 The 3 oxygen and 14 carbon core orbital excess energies of the resveratrol isomer pair (4th to 17th) is present in the left side of the vertical line in Figure 3. As can be seen, the core electrons of both oxygen’s and carbons in the isomers change their energies to accommodate the geometrical changes between trans-R and cis-R. Such changes reveal atomic site-specific chemical environment information with different mechanisms from the C-NMR in the previous section. The largest excess orbital energies in the core region are C(6) and C(15) above the x-axis marked by green and purple circles, respectively, and C(4) (green) and C(11) (purple) below the x-axis as marked in Figure 3, in consistent with the sites determined from NMR. The EOES further indicates that C(15) and C(4) in the bridge of interest are important after the four NMR carbons. Here C(15) and C(6) have apparent steric through space interaction in the cis-R isomer (Figure 1(c)).

Figure 4. Comparison of theoretical momentum distributions of the highest occupied molecular orbital 60a for both trans-R and cis-R.


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Large excess orbitals energies are displayed in the valence space, as indicated in the EOES in Figure 3. A number of valence orbitals experience significant changes in orbital energies between trans-R and cis-R. Valence orbitals outside of the parallel blue lines at ∆ε = ±4.0 Kcal⋅mol-1 in Figure 3 are 34a, 35a, 46a, 55a and 60a (HOMO), and these orbitals are most likely responsible for the the trans-R and cis-R configurations.46,82 In order to understand the orbital difference between trans-R and cis-R quantitatively, we employ dual space analysis (DSA)41 to the highest occupied molecular orbital (HOMO). Figure 4 exhibits the theoretical momentum distributions (TMDs) of the HOMO (60a) of trans-R and of cis-R. Clearly, the HOMO of trans-R are dominated by p-electrons distributing on both sides of the molecular plane (trans-R is nearly planar), so that the orbital TMDs exhibit a bell shape.41-44 On the other hand, the HOMO of the non-planar cis-R exhibits quite different features in the stilbene region of C(8)=C(9), and the electron densities of the HOMO of cis-R loses the nodal plane as it is in the trans-R. As a result, the orbital TMDs exhibit a significant sxpy hybridized distribution such that the region of p 0.25 a.u. is for p-like region. Such significant natures of the HOMOs for trans-R and cis-R influences their molecular properties, chemical bonding and chemical reactions.

3.4 Energy decomposition analysis (EDA) Previous sections employed a number of properties to reveal the isomerization between the trans-R and cis-R using molecular orbital theory. In fact, the methods of understanding the isomerisation are not unique and molecular orbital theory is one of the most well known and efficient methods.48 Extended transition state (ETS) of Ziegler and Rauk65,66,76 are employed to calculate the interaction energy ∆EInt that includes the instantaneous interaction between the fragments for stabilization. The ∆EInt include Pauli energy term, ∆EPauli, the electrostatic term, ∆EEstat, as well as orbital energy term, ∆EOrb.48,62,90,91 Superposition of ∆EPauli and ∆EEstat gives the steric energy ∆ESter.68-71 The last term is the orbital energy, ∆EOrb, which represents relaxation of the ortho-normalized density to the fully optimized electron density of the entire supermolecule. We previously employed EDA to study ferrocene conformers with impressive success.48 In Figure 4, the excess energy of the decomposed components, ∆(∆E), are largely the balance between positive Pauli energy of 72.50 Kcal⋅mol-1 and negative orbital energy of –69.17 18 | P a g e ACS Paragon Plus Environment


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Kcal⋅mol-1, with a small negative residual of electrostatic energy of -7.78 Kcal⋅mol-1. As a result, a small negative interaction energy of -4.45 Kcal⋅mol-1 indicates a slightly more stable trans-R isomer over its cis-R form. The same figure indicates that the cis-R is unstabilized by a large steric energy of 64.71 Kcal⋅mol-1 (sum of Pauli and electrostatic energy). The calculated energy components of the trans-R and cis-R isomers are given in Supplementary materials Table S2.

Figure 4. Excess energies of the decomposed energy of trans-R and cis-R based on the EDA.

4. Conclusions The present study has explored the isomerization of geometric isomers of resveratrol, trans-R and cis-R. Density functional theory (DFT) based quantum mechanical calculations indicate that trans-R is more stable and less flexible with respect to rotations of the single C-C(=C) bonds in resveratrol. Rotation of the resorcinol ring, R(2), is slightly less difficult than rotation of the phenol ring, R(1), for both trans-R and cis–R isomers as less energy is required. The nearly planar structure of trans-R ensures the conjugated electronic structure for the through 19 | P a g e ACS Paragon Plus Environment

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bond interaction and the rigidity, which is evidenced by the site dependent C-NMR chemical shift with respect to cis-R. The C-NMR four carbons sites, the stilbene carbons, i.e., C(8) and C(9), and C(11) and C(6) respond most significantly to the isomerization. Although excellent agreement with C-NMR measurements, present quantum mechanical calculations indicate that none of the carbons in resveratrol is strictly chemically equivalent, which is very different from the stilbene isomers. The slow C-NMR process contributes to the rotational “equivalence” of the four carbon pairs in the NMR measurements. The large chemical shift of C(11) upon isomerization suggests that the proton transfer on C(9) (which bond the resorcinol ring) rather than C(8) in resveratrol. On the other hand, C(6) may result in through space steric interaction in the cis-R. The carbon sites determined from the 13C-NMR is also been conformed using the excess orbital energy spectrum (EOES) of resveratrol, which further indicates that C(4), C(6), C(11) and C(15) sites experience the largest core electron energy changes, in agreement with the NMR information. The EOES also reveals that a group of five valence orbitals, 34a, 35a, 46a, 55a and 60a (HOMO) are the most significantly changed orbitals in the isomerization. Applying dual space analysis (DSA), the bonding character in the HOMO of trans-R with pdominance changes to sp-dominance in cis-R. Finally, energy decomposition analysis (EDA) shows that the small electrostatic energy ∆EEstat changes the balance of positive Pauli energy and attractive orbitals energy and makes the trans-R more stable. Associated Content Potential energy scan (PES) for tarns and cis resveratrol have been reported for δ = ∠C(6)-C(5)C(8)-C(9) (Figure S1) Comparison between calculated NMR using different DFT models i.e. B3PW91, B3LYP and M06-2X, in DMSO and gas phase has been illustrated for 13C, 1H and 17O atoms (Table S1) Comparison of energy terms for the trans and cis – resveratrol (Table S2) Author information *

Corresponding author - E-mail addresses [email protected]; Tel: +61 3 9214 5056; fax:

+61-3-9214-5921 Notes The authors declare no competing financial interest.



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Acknowledgements FW acknowledges Australia Research Council (ARC) through the Discovery Project (DP) for funding and PhD scholarship for SC. The authors also acknowledge the merit based supercomputing time from National Computational Infrastructure (NCI) and Swinburne University Supercomputing Facility. FW thanks Dr S. Olsen for useful discussions. SC thanks Minh Quoc Tran, Shiang Shan and Qudsia Arooj for their preliminary information. References (1) Jasinski, M.; Jasinska, L.; Ogrodowczyk, M.; Ogrodowczyk, J. Resveratrol in prostate diseases - a short review. Cent European J Urol. 2013, 66, 144 – 149. (2) Rimando, A. M.; Kalt, W.; Magee, J. B.; Dewey, J.; Ballington, J. R. Resveratrol, pterostilbene, and piceatannol in vaccinium berries. J. Agric. Food Chem. 2004, 52, 4713 – 4719. (3) Fremont, L. Biological effects of resveratrol. Life Sci. 2000, 66, 663-673. (4) Favaron, F.; Lucchetta, M.; Odorizzi, S.; da Cunha, A. P.; Sella, L. The role of grape polyphenols on trans-resveratrol activity against botrytis cinerea and of fungal laccase on the solubility of putative grape pr proteins. J. Plant Pathol. 2009, 91, 579-588. (5) Gatto, P.; Vrhovsek, U.; Muth, J.; Segala, C.; Romualdi, C.; Fontana, P.; Pruefer, D.; Stefanini, M.; Moser, C.; Mattivi, F.; Velasco, R. Ripening and genotype control stilbene accumulation in healthy grapes. J. Agric. Food Chem. 2008, 56, 11773 − 11785. (6) Simkovitch, R.; Huppert, D. Excited-state proton transfer in resveratrol and proposed mechanism for plant resistance to fungal infection. J. Phys. Chem. B. 2015, 119, 11684 – 11694. (7) Dekic, S.; Milosavljevic, S.; Vajs, V.; Jovic, S.; Petrovic, A.; Nikicevic, N.; Manojlovic, V.; Nedovic, V.; Tesevic, V. Trans- and cis-resveratrol concentration in wines produced in serbia. J. Serb. Chem. Soc. 2008, 73, 1027 – 1037. (8) Zhang, Y.; Butelli, E.; Alseekh, S.; Tohge, T.; Rallapalli, G.; Luo, J.; Kawar, P. G.; Hill, L.; Santino, A.; Fernie, A. R.; Martin, C. Multi-level engineering facilitates the production of phenylpropanoid compounds in tomato. Nat. Commun. 2015, 6, 8635 – 8646.


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TOC Graphics


Dominant Carbons in trans- and cis-Resveratrol Isomerization - The

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