Remote Stereoelectronic Effects in Pyrrolidone- and Caprolactam-Substituted Phenols: Discrepancies in Antioxidant Properties Evaluated by Electrochemical Oxidation and H-Atom Transfer Reactivity

Abstract

New antioxidants are commonly evaluated via two main approaches, i.e., the ability to donate an electron and the ability to intercept free radicals. We compared these approaches by evaluating the properties of 11 compounds containing both antioxidant moieties (mono- and polyphenols) and auxiliary pharmacophores (pyrrolidone and caprolactam). Several common antioxidants, such as butylated hydroxytoluene (BHT), 2,3,5-trimethylphenol (TMP), quercetin, and dihydroquercetin, were added for comparison. The antioxidant properties of these compounds were determined by their rates of reaction with 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical and their oxidation potentials from cyclic voltammetry. Although these methods test different chemical properties, their results correlate reasonably well. However, several exceptions exist where the two methods give opposite predictions! One of them is the different behavior of mono- and polyphenols: polyphenols can react with DPPH more than an order of magnitude faster than monophenols of a similar oxidation potential. The second exception stems from the size of a “bystander” lactam ring at the benzylic position. Although the phenols with a seven-membered lactam ring are harder to oxidize, the sterically nonhindered compounds react with DPPH about 2× faster than the analogous five-membered lactams. The limitations of computational methods, especially those based on a single parameter, are also evaluated and discussed.

The Role of Ligands in Oxidative Addition Chemistry of Low-Valent Main Group Derivatives: Not Only Stabilization but Also Activation

“…Thus, it has recently been shown that, within certain classes of antioxidants, their oxidative potentials correlate with the rate constants of their interaction with the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH). 31 Figure 5 shows that, in general, there is a semiquantitative correlation of "the lower the oxidation potential, the higher the rate of oxidative addition", despite some exceptions that strongly distort it. The cases of thiophene and triethylamine are the most striking, showing kinetics relatively lower than what would be expected from the oxidation potentials of their complexes with 1.…”

“…In particular, the reactivity can be predicted on the basis of the oxidation potential, which is determined quickly and easily. Thus, it has recently been shown that, within certain classes of antioxidants, their oxidative potentials correlate with the rate constants of their interaction with the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) …”

Hybrids of Sterically Hindered Phenols and Diaryl Ureas: Synthesis, Switch from Antioxidant Activity to ROS Generation and Induction of Apoptosis

“…Generally, there is a correlation between antioxidant and pro-oxidant activity and oxidation potential. However, the connection between the ability to donate an electron and the ability to intercept radicals is not always straightforward and exceptions do exist [ 42 ], especially when multiple redox-active groups are present.…”