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Dimerization of quercetin, Diels-Alder vs. radical-coupling approach: a joint thermodynamics, kinetics, and topological study

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Abstract

Quercetin is a prototypical antioxidant and prominent member of flavonoids, a large group of natural polyphenols. The oxidation of quercetin may lead to its dimerization, which is a paradigm of the more general polyphenol oligomerization. There exist two opposing mechanisms to describe the dimerization process, namely radical-coupling or Diels-Alder reactions. This work presents a comprehensive rationalization of this dimerization process, acquired from density functional theory (DFT) calculations. It is found that the two-step radical-coupling pathway is thermodynamically and kinetically preferred over the Diels-Alder reaction. This is in agreement with the experimental results showing the formation of only one isomer, whereas the Diels-Alder mechanism would yield two isomers. The evolution in bonding, occurring during these two processes, is investigated using the atoms in molecules (AIM) and electron localization function (ELF) topological approaches. It is shown that some electron density is accumulated between the fragments in the transition state of the radical-coupling reaction, but not in the transition state of the Diels-Alder process.

Quantum chemistry calculations of the dimerization process of quercetin show that a radical coupling approach is preferred to a Diels-Alder type reaction, in agreement with experimental results. Analysis of the bonding evolution highlights the reaction mechanism.

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Notes

  1. The TopMod package is freely available on: http://www.lct.jussieu.fr/pagesperso/silvi/topmod.html

  2. Here we observed that the AIM spin density, which is non-zero in the B ring at C2’, C4’, and C6’, is shared between the different neighboring bonding ELF basins. As a consequence the spin density in the ELF basins is more diluted and appears very low.

  3. As expected, the V(C2,O1), V(C3,O3), and V(C9,O1) disynaptic basins have rather low populations (around 1.5-1.6 electrons). They are attributed to the polarization of the C-O bond by the electronegative oxygen atom (V(O1) and Vi=1,2(O3) are populated by about 4.5 electrons).

  4. Indeed the separation between both fragment domains occurs at ELF= 0.41, a value at which the core and valence domains are already separated. The 0.41 value reflects a rather large concentration of electron density between interacting atoms compared to the much smaller values usually found for the valence domain separation of non-covalent complexes, such as hydrogen bonded complexes (up to 0.2) [59].

  5. The 0.8 e decrease of the V1∪2(C2,C3) population is actually greater than the net transfer due to flow of population into the adjacent basins, mainly V(C2,C1’) and V(C2,O1).

  6. For 3-OH_fragment, this loss mainly corresponds to the V(C2,C3) population decrease (−0.8 e), which enhances the single bond character of C2,C3. Strong electronic reorganization is observed in the surrounding, e.g., electron transfer from V(O1,C9) and V(O1,C2) (0.5 e loss from both basins) toward the lone pair basin of O1. Concerning 4’OH_fragment, the population of the new V(O4’*,C2) basin mainly originates from the decrease of the Vi(O4’*)i=1,2 population (0.6 e). The total valence population of the B* ring significantly increases by 0.8 e, mainly due to a transfer from the V(C4,O4’*) basin (0.7 e) and from the V(C1’,C2) basin (0.1 e), so as to provide an aromatic character.

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Acknowledgments

The authors thank ‘Conseil Régional du Limousin’ for financial support and IDRIS (Institute du Développement et des Ressources Informatiques Scientifiques, Orsay, Paris) and Cali (Calcul en Limousin) for computing facilities. Support from the COST Chemistry CMST0804 project is acknowledged. This work was also supported by the Ministry of Education, Youth and Sports (LO1305) and by the Grant agency of the Czech Republic (P208/12/G016).

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Correspondence to Isabelle Fourré.

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ESM 1

Electronic supplementary information (ESI) available: additional ELF parameters (Tables S1, S2, S3), M06-2X/6-31+G(d,p)//M06-2X/6-31G(d) Gibbs energies of all reaction steps and of activation barriers for both Diels-Alder and radical-coupling reactions (Table S4), 3D structures of the intermediate state (radical coupling approach), and of the dimers (Fig. S1), 3D structure of the transition state of the Diels-Alder type reaction (Fig. S2), potential energy curves for the intermediate dimer formation in the radical coupling approach (Figs. S3) (DOC 705 kb)

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Fourré, I., Di Meo, F., Podloucká, P. et al. Dimerization of quercetin, Diels-Alder vs. radical-coupling approach: a joint thermodynamics, kinetics, and topological study. J Mol Model 22, 190 (2016). https://doi.org/10.1007/s00894-016-3051-8

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