A density functional theory study of structure‐activity relationships in caffeic and dihydrocaffeic acids and related monophenols

Abstract

Structure-activity relationships in the antioxidants caffeic acid and dihydrocaffeic acid as well as in the monophenols isoeugenol, eugenol, and dihydroeugenol were investigated by using the density functional theory (DFT). The higher antioxidant activity of caffeic acid, among the rest, could be attributed to its lower difference in the heat of formation (∆HOF) value. Dihydrocaffeic acid exhibits less antioxidant activity than caffeic acid, owing to both its higher ∆HOF value and its limited spin delocalization. These two latter findings could also account for the lower antioxidant activity of both eugenol and dihydroeugenol as compared to isoeugenol. DFT calculations afford a good molecular descriptor, ∆HOF, that correlates well with the antioxidant activity in molecules exhibiting similar structural characteristics. The presence of a simple double bond in the side chain makes a difference in the antioxidant activity only if it leads to an extended conjugation. Calculated dipole moment values for both the parent molecules and the respective phenoxyl radicals correlate well with their antioxidant efficiency in some instances.The capacity to predict antioxidant activity is important, because it improves the selection of effective new compounds with low toxicity and saves experimental work. The interest in the relative evaluation of antioxidants (AH) through theoretical calculations is increasing, and several molecular descriptors have been used so far in an attempt to find suitable theoretical parameters characterizing the activity of the antioxidants (1-6). The main mechanism of action by phenolic antioxidants (AH) is considered to be the scavenging of free radicals by donation of their phenolic hydrogen atom (7). Parameters that characterize this ease of donation could be useful in estimating the ability of phenolic compounds to scavenge free radicals. A molecular descriptor that seems to correlate well with experimental results is the difference in the heat of formation (∆ΗΟF) values between the parent molecule (AH) and its corresponding radical (R • ) (2-4,8), also denoted as the phenolic O-H bond dissociation enthalpy (BDE).Calculations used for the determination of ∆ΗΟF and other theoretical parameters are mostly semiempirical. However, continuing improvements in computer technology and electronic structure calculation software allow us to compute modest-sized molecules at "state-of-the-art" ab initio and/or density functional theory (DFT) levels in reasonable times.In the present study, differences in the activity of the compounds examined in Reference 9 were studied on a theoretical basis. In particular, it was shown that the experimental differences found for caffeic acid and its saturated counterpart as well as for eugenol, isoeugenol, and dihydroeugenol were strongly dependent on conditions that influenced the order and size of this difference. Quantum-chemical calculations were used to examine whether molecular characteristics support the experimental findings (9). To the best of our knowledge, neithe...

A computational study of the structure‐activity relationships of some p‐hydroxybenzoic acid antioxidants

“…0.12 Å, as compared to those of the parent compounds. Values obtained range from 1.239 to 1.261 Å, and account well for a significant amount of double-bond character (1,3,13). All these features were also found (1) in the case of cinnamates and might account well for the correctness of our calculated radical structural parameters.…”

“…The nearly equal O-H bond-length values derived for all parent compounds (0.970-0.974 Å) could mean that, as expected (1,3,14), the O-H bond-length value is not a useful molecular descriptor by itself in comparing antioxidant activity of the phenolic antioxidants.…”

“…Details on the calculation of the ∆HOF values and on the geometries of all minimum-energy structures for the parent molecules-which were fully optimized by using DFT calculations (7) and the B3LYP functional (UB3LYP for the resulting radicals) with the 6-31+G(d) basis set-were given in previous papers (1,3). All calculations were carried out using the GAUSSIAN 98 program suite (8).…”

“…The degree of conjugation and the calculated spin delocalization values in the phenoxyl radicals also could explain the scavenging activity. Moreover, ∆HOF differences derived between antioxidants exhibiting either extended or minor molecular conjugations are small (2,3). However, the presence of one double bond in the side chain makes a difference in the antioxidant activity if it leads to an extended conjugation.…”

Application of Electrochemiluminescence for the Evaluation of the Antioxidant Capacity of Some Phenolic Compounds Against Superoxide Anion Radicals

“…6. 31 Rutin is a naturally occurring flavonol consisting of aglycone quercetin and a rutinoside moiety at position 3 of the C ring (Fig. 5).…”