Computational Study of Hydrogen Atom Transfer in the Reaction of Quercetin with Hydroxyl Radical
Abstract
1. Introduction
2. Computational Methods
3. Results and Discussion
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
DFT | Density functional theory |
IBO | Intrinsic bond orbital |
HAT | Hydrogen atom transfer |
PCET | Proton-coupled electron transfer |
ET | Electron transfer |
PT | Proton transfer |
SPLET | Sequential proton-loss electron transfer |
IRC | Intrinsic reaction coordinate |
MD | Molecular dynamics |
References
- Mayer, J.M. Understanding Hydrogen Atom Transfer: From Bond Strengths to Marcus Theory. Acc. Chem. Res. 2011, 44, 36–46. [Google Scholar] [CrossRef] [PubMed]
- Mayer, J.M.; Hrovat, D.A.; Thomas, J.L.; Borden, W.T. Proton-Coupled Electron Transfer versus Hydrogen Atom Transfer in Benzyl/Toluene, Methoxyl/Methanol, and Phenoxyl/Phenol Self-Exchange Reactions. J. Am. Chem. Soc. 2002, 124, 11142–11147. [Google Scholar] [CrossRef] [PubMed]
- Meyer, T.J.; Huynh, M.H.V.; Thorp, H.H. The Possible Role of Proton-Coupled Electron Transfer (PCET) in Water Oxidation by Photosystem II. Angew. Chem. Int. Ed. 2007, 46, 5284–5304. [Google Scholar] [CrossRef] [PubMed]
- Klinman, J.P.; Offenbacher, A.R. Understanding Biological Hydrogen Transfer Through the Lens of Temperature Dependent Kinetic Isotope Effects. Acc. Chem. Res. 2018, 51, 1966–1974. [Google Scholar] [CrossRef]
- Ingold, K.U.; Pratt, D.A. Advances in Radical-Trapping Antioxidant Chemistry in the 21st Century: A Kinetics and Mechanisms Perspective. Chem. Rev. 2014, 114, 9022–9046. [Google Scholar] [CrossRef]
- Smith, L.M.; Aitken, H.M.; Coote, M.L. The Fate of the Peroxyl Radical in Autoxidation: How Does Polymer Degradation Really Occur? Acc. Chem. Res. 2018, 51, 2006–2013. [Google Scholar] [CrossRef]
- Capaldo, L.; Ravelli, D. Hydrogen Atom Transfer (HAT): A Versatile Strategy for Substrate Activation in Photocatalyzed Organic Synthesis. Eur. J. Org. Chem. 2017, 2017, 2056–2071. [Google Scholar] [CrossRef]
- Poon, J.-F.; Pratt, D.A. Recent Insights on Hydrogen Atom Transfer in the Inhibition of Hydrocarbon Autoxidation. Acc. Chem. Res. 2018, 51, 1996–2005. [Google Scholar] [CrossRef]
- Lushchak, V.I. Free Radicals, Reactive Oxygen Species, Oxidative Stress and Its Classification. Chem.-Biol. Interact. 2014, 224, 164–175. [Google Scholar] [CrossRef]
- Jomova, K.; Raptova, R.; Alomar, S.Y.; Alwasel, S.H.; Nepovimova, E.; Kuca, K.; Valko, M. Reactive Oxygen Species, Toxicity, Oxidative Stress, and Antioxidants: Chronic Diseases and Aging. Arch. Toxicol. 2023, 97, 2499–2574. [Google Scholar] [CrossRef]
- Losada-Barreiro, S.; Sezgin-Bayindir, Z.; Paiva-Martins, F.; Bravo-Díaz, C. Biochemistry of Antioxidants: Mechanisms and Pharmaceutical Applications. Biomedicines 2022, 10, 3051. [Google Scholar] [CrossRef] [PubMed]
- Brunetti, C.; Di Ferdinando, M.; Fini, A.; Pollastri, S.; Tattini, M. Flavonoids as Antioxidants and Developmental Regulators: Relative Significance in Plants and Humans. Int. J. Mol. Sci. 2013, 14, 3540–3555. [Google Scholar] [CrossRef] [PubMed]
- Brewer, M.S. Natural Antioxidants: Sources, Compounds, Mechanisms of Action, and Potential Applications. Compr. Rev. Food Sci. Food Saf. 2011, 10, 221–247. [Google Scholar] [CrossRef]
- Romano, B.; Pagano, E.; Montanaro, V.; Fortunato, A.L.; Milic, N.; Borrelli, F. Novel Insights into the Pharmacology of Flavonoids. Phytother. Res. 2013, 27, 1588–1596. [Google Scholar] [CrossRef]
- Agati, G.; Azzarello, E.; Pollastri, S.; Tattini, M. Flavonoids as Antioxidants in Plants: Location and Functional Significance. Plant Sci. 2012, 196, 67–76. [Google Scholar] [CrossRef]
- Wang, W.; Sun, C.; Mao, L.; Ma, P.; Liu, F.; Yang, J.; Gao, Y. The Biological Activities, Chemical Stability, Metabolism and Delivery Systems of Quercetin: A Review. Trends Food Sci. Technol. 2016, 56, 21–38. [Google Scholar] [CrossRef]
- Zou, H.; Ye, H.; Kamaraj, R.; Zhang, T.; Zhang, J.; Pavek, P. A Review on Pharmacological Activities and Synergistic Effect of Quercetin with Small Molecule Agents. Phytomedicine 2021, 92, 153736. [Google Scholar] [CrossRef]
- Xiong, F.; Zhang, Y.; Li, T.; Tang, Y.; Song, S.-Y.; Zhou, Q.; Wang, Y. A Detailed Overview of Quercetin: Implications for Cell Death and Liver Fibrosis Mechanisms. Front. Pharmacol. 2024, 15, 1389179. [Google Scholar] [CrossRef]
- Ishizawa, K.; Yoshizumi, M.; Kawai, Y.; Terao, J.; Kihira, Y.; Ikeda, Y.; Tomita, S.; Minakuchi, K.; Tsuchiya, K.; Tamaki, T. Pharmacology in Health Food: Metabolism of Quercetin In Vivo and Its Protective Effect Against Arteriosclerosis. J. Pharmacol. Sci. 2011, 115, 466–470. [Google Scholar] [CrossRef]
- Kee, J.-Y.; Han, Y.-H.; Kim, D.-S.; Mun, J.-G.; Park, J.; Jeong, M.-Y.; Um, J.-Y.; Hong, S.-H. Inhibitory Effect of Quercetin on Colorectal Lung Metastasis through Inducing Apoptosis, and Suppression of Metastatic Ability. Phytomedicine 2016, 23, 1680–1690. [Google Scholar] [CrossRef]
- Caddeo, C.; Nacher, A.; Vassallo, A.; Armentano, M.F.; Pons, R.; Fernàndez-Busquets, X.; Carbone, C.; Valenti, D.; Fadda, A.M.; Manconi, M. Effect of Quercetin and Resveratrol Co-Incorporated in Liposomes against Inflammatory/Oxidative Response Associated with Skin Cancer. Int. J. Pharm. 2016, 513, 153–163. [Google Scholar] [CrossRef] [PubMed]
- Ramešová, Š.; Sokolová, R.; Degano, I.; Bulíčková, J.; Žabka, J.; Gál, M. On the Stability of the Bioactive Flavonoids Quercetin and Luteolin under Oxygen-Free Conditions. Anal. Bioanal. Chem. 2012, 402, 975–982. [Google Scholar] [CrossRef] [PubMed]
- Escandar, G.M.; Sala, L.F. Complexing Behavior of Rutin and Quercetin. Can. J. Chem. 1991, 69, 1994–2001. [Google Scholar] [CrossRef]
- Sokolová, R.; Ramešová, Š.; Degano, I.; Hromadová, M.; Gál, M.; Žabka, J. The Oxidation of Natural Flavonoid Quercetin. Chem. Commun. 2012, 48, 3433–3435. [Google Scholar] [CrossRef]
- Lemańska, K.; Szymusiak, H.; Tyrakowska, B.; Zieliński, R.; Soffers, A.E.M.F.; Rietjens, I.M.C.M. The Influence of pH on Antioxidant Properties and the Mechanism of Antioxidant Action of Hydroxyflavones. Free. Radic. Biol. Med. 2001, 31, 869–881. [Google Scholar] [CrossRef]
- Musialik, M.; Kuzmicz, R.; Pawłowski, T.S.; Litwinienko, G. Acidity of Hydroxyl Groups: An Overlooked Influence on Antiradical Properties of Flavonoids. J. Org. Chem. 2009, 74, 2699–2709. [Google Scholar] [CrossRef]
- Álvarez-Diduk, R.; Ramírez-Silva, M.T.; Galano, A.; Merkoçi, A. Deprotonation Mechanism and Acidity Constants in Aqueous Solution of Flavonols: A Combined Experimental and Theoretical Study. J. Phys. Chem. B 2013, 117, 12347–12359. [Google Scholar] [CrossRef]
- Zenkevich, I.G.; Guschina, S.V. Determination of Dissociation Constants of Species Oxidizable in Aqueous Solution by Air Oxygen on an Example of Quercetin. J. Anal. Chem. 2010, 65, 371–375. [Google Scholar] [CrossRef]
- Yazdanshenas, R.; Gharib, F. Protonation Equilibria Studies of Quercetin in Aqueous Solutions of Ethanol and Dimethyl Sulphoxide. J. Mol. Liq. 2016, 224, 1227–1232. [Google Scholar] [CrossRef]
- Litwinienko, G.; Ingold, K.U. Solvent Effects on the Rates and Mechanisms of Reaction of Phenols with Free Radicals. Acc. Chem. Res. 2007, 40, 222–230. [Google Scholar] [CrossRef]
- Foti, M.C.; Daquino, C.; Mackie, I.D.; DiLabio, G.A.; Ingold, K.U. Reaction of Phenols with the 2,2-Diphenyl-1-Picrylhydrazyl Radical. Kinetics and DFT Calculations Applied To Determine ArO-H Bond Dissociation Enthalpies and Reaction Mechanism. J. Org. Chem. 2008, 73, 9270–9282. [Google Scholar] [CrossRef] [PubMed]
- Jovanovic, S.V.; Steenken, S.; Tosic, M.; Marjanovic, B.; Simic, M.G. Flavonoids as Antioxidants. J. Am. Chem. Soc. 1994, 116, 4846–4851. [Google Scholar] [CrossRef]
- Jovanovic, S.V.; Steenken, S.; Hara, Y.; Simic, M.G. Reduction Potentials of Flavonoid and Model Phenoxyl Radicals. Which Ring in Flavonoids Is Responsible for Antioxidant Activity? J. Chem. Soc. Perkin Trans. 2 1996, 11, 2497–2504. [Google Scholar] [CrossRef]
- Torić, J.; Karković Marković, A.; Mustać, S.; Pulitika, A.; Jakobušić Brala, C.; Pilepić, V. Proton-Coupled Electron Transfer and Hydrogen Tunneling in Olive Oil Phenol Reactions. Int. J. Mol. Sci. 2024, 25, 6341. [Google Scholar] [CrossRef]
- La Rocca, M.V.; Rutkowski, M.; Ringeissen, S.; Gomar, J.; Frantz, M.-C.; Ngom, S.; Adamo, C. Benchmarking the DFT Methodology for Assessing Antioxidant-Related Properties: Quercetin and Edaravone as Case Studies. J. Mol. Model. 2016, 22, 250. [Google Scholar] [CrossRef]
- Zhang, D.; Liu, Y.; Chu, L.; Wei, Y.; Wang, D.; Cai, S.; Zhou, F.; Ji, B. Relationship Between the Structures of Flavonoids and Oxygen Radical Absorbance Capacity Values: A Quantum Chemical Analysis. J. Phys. Chem. A 2013, 117, 1784–1794. [Google Scholar] [CrossRef]
- Klein, E.; Rimarčík, J.; Senajová, E.; Vagánek, A.; Lengyel, J. Deprotonation of Flavonoids Severely Alters the Thermodynamics of the Hydrogen Atom Transfer. Comput. Theor. Chem. 2016, 1085, 7–17. [Google Scholar] [CrossRef]
- Chiodo, S.G.; Leopoldini, M.; Russo, N.; Toscano, M. The Inactivation of Lipid Peroxide Radical by Quercetin. A Theoretical Insight. Phys. Chem. Chem. Phys. 2010, 12, 7662–7670. [Google Scholar] [CrossRef]
- Leopoldini, M.; Marino, T.; Russo, N.; Toscano, M. Antioxidant Properties of Phenolic Compounds: H-Atom versus Electron Transfer Mechanism. J. Phys. Chem. A 2004, 108, 4916–4922. [Google Scholar] [CrossRef]
- Leopoldini, M.; Marino, T.; Russo, N.; Toscano, M. Density Functional Computations of the Energetic and Spectroscopic Parameters of Quercetin and Its Radicals in the Gas Phase and in Solvent. Theor. Chem. Acc. 2004, 111, 210–216. [Google Scholar] [CrossRef]
- Dimić, D.; Milenković, D.; Dimitrić Marković, J.; Marković, Z. Antiradical Activity of Catecholamines and Metabolites of Dopamine: Theoretical and Experimental Study. Phys. Chem. Chem. Phys. 2017, 19, 12970–12980. [Google Scholar] [CrossRef] [PubMed]
- Amić, A.; Marković, Z.; Dimitrić Marković, J.M.; Stepanić, V.; Lučić, B.; Amić, D. Towards an Improved Prediction of the Free Radical Scavenging Potency of Flavonoids: The Significance of Double PCET Mechanisms. Food Chem. 2014, 152, 578–585. [Google Scholar] [CrossRef] [PubMed]
- Mayer, J.M. Proton-Coupled Electron Transfer: A Reaction Chemist’s View. Annu. Rev. Phys. Chem. 2004, 55, 363–390. [Google Scholar] [CrossRef] [PubMed]
- Weinberg, D.R.; Gagliardi, C.J.; Hull, J.F.; Murphy, C.F.; Kent, C.A.; Westlake, B.C.; Paul, A.; Ess, D.H.; McCafferty, D.G.; Meyer, T.J. Proton-Coupled Electron Transfer. Chem. Rev. 2012, 112, 4016–4093. [Google Scholar] [CrossRef]
- Truhlar, D.G. Tunneling in Enzymatic and Nonenzymatic Hydrogen Transfer Reactions. J. Phys. Org. Chem. 2010, 23, 660–676. [Google Scholar] [CrossRef]
- Klein, J.E.M.N.; Knizia, G. cPCET versus HAT: A Direct Theoretical Method for Distinguishing X–H Bond-Activation Mechanisms. Angew. Chem. Int. Ed. 2018, 57, 11913–11917. [Google Scholar] [CrossRef]
- Knizia, G. Intrinsic Atomic Orbitals: An Unbiased Bridge between Quantum Theory and Chemical Concepts. J. Chem. Theory Comput. 2013, 9, 4834–4843. [Google Scholar] [CrossRef]
- Knizia, G.; Klein, J.E.M.N. Electron Flow in Reaction Mechanisms—Revealed from First Principles. Angew. Chem. Int. Ed. 2015, 54, 5518–5522. [Google Scholar] [CrossRef]
- Kühne, T.D.; Iannuzzi, M.; Del Ben, M.; Rybkin, V.V.; Seewald, P.; Stein, F.; Laino, T.; Khaliullin, R.Z.; Schütt, O.; Schiffmann, F.; et al. CP2K: An Electronic Structure and Molecular Dynamics Software Package—Quickstep: Efficient and Accurate Electronic Structure Calculations. J. Chem. Phys. 2020, 152, 194103. [Google Scholar] [CrossRef]
- Perdew, J.P.; Burke, K.; Ernzerhof, M. Generalized Gradient Approximation Made Simple. Phys. Rev. Lett. 1996, 77, 3865–3868. [Google Scholar] [CrossRef]
- Goedecker, S.; Teter, M.; Hutter, J. Separable Dual-Space Gaussian Pseudopotentials. Phys. Rev. B 1996, 54, 1703–1710. [Google Scholar] [CrossRef] [PubMed]
- Grimme, S.; Hansen, A.; Brandenburg, J.G.; Bannwarth, C. Dispersion-Corrected Mean-Field Electronic Structure Methods. Chem. Rev. 2016, 116, 5105–5154. [Google Scholar] [CrossRef] [PubMed]
- VandeVondele, J.; Hutter, J. Gaussian Basis Sets for Accurate Calculations on Molecular Systems in Gas and Condensed Phases. J. Chem. Phys. 2007, 127, 114105. [Google Scholar] [CrossRef] [PubMed]
- Frisch, M.J.; Trucks, G.W.; Schlegel, H.B.; Scuseria, G.E.; Robb, M.A.; Cheeseman, J.R.; Scalmani, G.; Barone, V.; Petersson, G.A.; Nakatsuji, H.; et al. Gaussian 16, Revision C.01; Gaussian Inc.: Wallingford, CT, USA, 2016. [Google Scholar]
- Campo, M.G.; Corral, G.M. Structural, Dynamic, and Hydration Properties of Quercetin and Its Aggregates in Solution. J. Phys. Condens. Matter 2022, 34, 294001. [Google Scholar] [CrossRef]
- Lespade, L. Ab Initio Molecular Dynamics of the Reaction of Quercetin with Superoxide Radical. Chem. Phys. 2016, 475, 32–38. [Google Scholar] [CrossRef]
- Lespade, L. Ab Initio Molecular Dynamics of Electron Transfer from Gallic Acid to Small Radicals: A Comparative Study between Hydroxyl and Nitrogen Dioxide Radicals. Comput. Theor. Chem. 2018, 1135, 6–10. [Google Scholar] [CrossRef]
- Lespade, L. Ab Initio Molecular Dynamics of the Reactivity of Vitamin C toward Hydroxyl and HO2/O2− radicals. J. Mol. Model. 2017, 23, 347. [Google Scholar] [CrossRef]
- Milovanović, B.; Ilić, J.; Stanković, I.M.; Popara, M.; Petković, M.; Etinski, M. A Simulation of Free Radicals Induced Oxidation of Dopamine in Aqueous Solution. Chem. Phys. 2019, 524, 26–30. [Google Scholar] [CrossRef]
- Zeppilli, D.; Orian, L. Concerted Proton Electron Transfer or Hydrogen Atom Transfer? An Unequivocal Strategy to Discriminate These Mechanisms in Model Systems. Phys. Chem. Chem. Phys. 2025, 27, 6312–6324. [Google Scholar] [CrossRef]
- Kohlmann, T.; Goez, M. Laser Access to Quercetin Radicals and Their Repair by Co-Antioxidants. Chem. A Eur. J. 2020, 26, 17428–17436. [Google Scholar] [CrossRef]
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Vuzem, D.; Pilepić, V. Computational Study of Hydrogen Atom Transfer in the Reaction of Quercetin with Hydroxyl Radical. Hydrogen 2025, 6, 39. https://doi.org/10.3390/hydrogen6020039
Vuzem D, Pilepić V. Computational Study of Hydrogen Atom Transfer in the Reaction of Quercetin with Hydroxyl Radical. Hydrogen. 2025; 6(2):39. https://doi.org/10.3390/hydrogen6020039
Chicago/Turabian StyleVuzem, David, and Viktor Pilepić. 2025. "Computational Study of Hydrogen Atom Transfer in the Reaction of Quercetin with Hydroxyl Radical" Hydrogen 6, no. 2: 39. https://doi.org/10.3390/hydrogen6020039
APA StyleVuzem, D., & Pilepić, V. (2025). Computational Study of Hydrogen Atom Transfer in the Reaction of Quercetin with Hydroxyl Radical. Hydrogen, 6(2), 39. https://doi.org/10.3390/hydrogen6020039