Abstract
Equilibrium structures of all derivatized systems of p-hydroxybenzoic acid, 3,4-dihydroxybenzoic acid, 3-methoxy-4-hydroxybenzoic acid, and 3,5-dimethoxy-4-hydroxybenzoic acid and calculated structural and energetic molecular descriptors were determined at the B3LYP/6-31+G(d) density functional theoretical level in an attempt to study their structure-activity relationships (SAR). The theoretical antioxidant activity trend, derived in terms of hydrogen-donating capacity against radicals in lipid systems, is in excellent agreement with the experimental one. The lower antioxidant activity of benzoates, experimentally found relative to the homologous cinnamates, could be due to (i) their lower spin delocalization, (ii) their higher calculated heats of formation values in forming radicals (ΔHOF), and (iii) the much stronger electron-withdrawing effect of the-COOH group than-CH=CHCOOH. The low calculated dipole moment values of the global minimum structures of the antioxidants could facilitate their solubilities in nonpolar solvents, hence the ease of hydrogen abstraction. However, highest occupied molecular orbital (HOMO) eigenvalues can neither predict antioxidant activity nor differentiate the same activity between two series of structurally related compounds. Again, density functional theory calculations provide a good molecular descriptor, ΔHOF, to correlate with the antioxidant activity in molecules showing similar structural characteristics.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Bakalbassis E.G., A. Chatzopoulou, V.S. Melissas, M. Tsimidou, M. Tsolaki, and A. Vafiadis, An ab initio and a DFT Study for the Explanation of the Antioxidant Activity of Four p-Hydroxycinnamic Acid Derivatives, Lipids 36:181–190 (2001).
Nenadis, N., S. Boyle, E.G. Bakalbassis, and M. Tsimidou, An Experimental Approach to Structure-Activity Relationships of Caffeic and Dihydrocaffeic Acids and Related Monophenols, J. Am. Oil Chem. Soc. 80:451–458 (2003).
Bakalbassis E.G., N. Nenadis, and M. Tsimidou, A Density Functional Theory Study of Structure-Activity Relationships in Caffeic and Dihydrocaffeic Acids and Related Monophenols, 80:459–466 (2003).
Tyrakowska, B., A.E.M.F. Soffers, H. Szymusiak, S. Boeren, M.G. Boersma, K. Lemanska, J. Vervoort, and I.M.C.M. Rietjens, TEAC Antioxidant Activity of 4-Hydroxybenzoates, Free Rad. Biol. Med. 27:1427–1436 (1999).
Colapietro, M., A. Domenicano, and C. Marciante, Structural Studies of Benzene Derivatives. VI. Refinement of the Crystal Structure of p-Hydroxybenzoic Acid Monohydrate, Acta Cryst. B 35:2177–2180 (1979).
Heath, E.A., P. Singh, and Y. Ebisuzaki, Structure of p-Hydroxybenzoic Acid and Acid-Acetone Complex (2/1), Acta Cryst. C 48:1960–1965 (1992).
Parr, R.G., and W. Yang, Density Functional Theory of Atoms and Molecules, Oxford University Press, New York, 1989.
Frisch, M.J., G.W. Trucks, H.B. Schlegel, G.E. Scuseria, M.A. Robb, J.R. Cheeseman, V.G. Zakrzewski, J.A. Montgomery, Jr., R.E. Stratmann, J.C. Burant, et al., Gaussian 98, Revision A.11, Gaussian, Inc., Pittsburgh, PA, 2001.
Tewari, Y.B., J. Chen, M.J. Holden, K.N. Houk, and R.N. Goldberg, Thermodynamic and Quantum Chemical Study of the Conversion of Chorismate to (pyruvate + 4-hydroxybenzoate), J. Phys. Chem. B 102:8634–8639 (1998).
Wiberg, K.B., Substituent Effects on the Acidity of Weak Acids. 2. Calculated Gas-Phase Acidities of Substituted Benzoic Acids, J. Org. Chem. 67:4787–4794 (2002).
Fabian, W.M.F., AM1 Calculations of Rotation Around Essential Single Bonds and Preferred Conformations in Conjugated Molecules, J. Comput. Chem. 9:369–377 (1988).
Nelson, M.R., and R.F. Borkman, Internal Rotation Barriers: Ab initio Calculations on Substituted Ethyl Benzoates and Benzoic Acids as Models for Polyester Flexibility, J. Mol. Struct. THEOCHEM 432:247–255 (1998).
Wright, J.S., D.J. Carpenter, D.J. McKay, and K.U. Ingold, Theoretical Calculation of Substituent Effects on the O-H Bond Strength of Phenolic Antioxidants Related to Vitamin E, J. Am. Chem. Soc. 119:4245–4252 (1997).
Zhang, H.Y., Selection of Theoretical Parameters Characterizing Scavenging Activity of Antioxidants on Free Radicals, J. Am. Oil Chem. Soc. 75:1705–1709 (1998).
Bors, W., W. Heller, C. Michel, and M. Saran, Flavonoids as Antioxidants: Determination of Radical-Scavenging Efficiencies, Methods Enzymol. 186:345–355 (1990).
Rice-Evans, C.A., N.J. Miller, and G. Pagana, Structure-Antioxidant Activity Relationships of Flavonoids and Phenolic Acids, Free Rad. Biol. Med. 20:933–956 (1996).
Natella, F., M. Nardini, M. Di Felice, and C. Scaccini, Benzoic and Cinnamic Acid Derivatives as Antioxidants: Structure-Activity Relation, J. Agric. Food Chem. 47:1453–1459 (1999).
Wright, J.S., E.R. Jonson, and G.A. DiLabio, Predicting the Activity of Phenolic Antioxidants: Theoretical Method, Analysis of Substituent Effects, and Application to Major Families of Antioxidants, J. Am. Chem. Soc. 123:1173–1183 (2001).
Zhang, H.-Y., Y.-M. Sun, and X.-L. Wang, Substituent Effects on O-H Bond Dissociation Enthalpies and Ionization Potentials of Catechols: A DFT Study and Its Implications in the Rational Design of Phenolic Antoixidants and Elucidation of Structure-Activity Relationships for Flavonoid Antioxidants, Chem. Eur. J. 9:502–508 (2003).
Hansch, C., A. Leo, and R.W. Taft, A Survey of Hammett Substituent Constants and Resonance and Field Parameters, Chem. Rev. 91:165–195 (1991).
Van Acker, S.A.B.E., M.J. de Groot, D.J. van den Berg, M.N.J.L. Tromp, G.D.O. den Kelder, W.J.F. van der Vijgh, and A. Bast, A Quantum Chemical Explanation of the Antioxidant Activity of Flavonoids, Chem. Res. Toxicol. 9:1305–1312 (1996).
Author information
Authors and Affiliations
Corresponding author
About this article
Cite this article
Vafiadis, A.P., Bakalbassis, E.G. A computational study of the structure-activity relationships of some p-hydroxybenzoic acid antioxidants. J Amer Oil Chem Soc 80, 1217–1223 (2003). https://doi.org/10.1007/s11746-003-0845-3
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/s11746-003-0845-3