Following the theoretical study of the secondary antioxidant activity of the deprotonated forms of lipoic (LA) and dihydrolipoic (DHLA) acids through their formation of complexes with Cu(II),[1] the present work focuses on the complexes that these species can form with Fe(III).[2] To this effect, the thermodynamic stability of twenty‐nine Fe(III) complexes with various deprotonated forms of LA and DHLA, with coordination numbers 4, 5 and 6, is studied at the M06(SMD)/6‐31++G(d,p) level of theory in water under physiological pH conditions at 298.15 K. The twenty‐four exergonic complexes are used to evaluate the secondary antioxidant activity of DHLA and LA relative to the Fe(III)/Fe(II) reduction by \(O_{2}^{\bullet -}\) and ascorbate, the first step of the Haber-Weiss cycle (see eq (1)). The second step of this cycle (called the Fenton reaction, see eq (2)), leads to the formation of biochemically harmful \(_{ }^{\bullet }\textrm{OH}\) radicals. A compound is found to have secondary antioxidant activity if its complex with Fe(III) (or with Cu(II)) is able to significantly slow down the first step of the Haber-Weiss cycle.

\(\left (1 \right )\left [ Fe(H_2O)_6) \right ]^{3+} + O_{2}^{\bullet -} \rightarrow \left [ Fe(H_2O)_6) \right ]^{2+} + O_{2}\)
\(\left (2 \right )\left [ Fe(H_2O)_6) \right ]^{2+} + H_{2}O_{2} \rightarrow \left [ Fe(H_2O)_6) \right ]^{3+} + OH^{-} + _{ }^{\bullet }\textrm{OH}\)

Rate constants for the single‐electron transfer (SET) reactions are calculated. The thermodynamic stability of the Fe(III) complexes does not fully correlate with the rate constant of their SET reactions, but more exergonic complexes usually exhibit smaller SET rate constants. Some Cu(II) complexes and their reduction to Cu(I) are also studied at the same level of theory for comparison. The Fe(III) complexes appear to be more stable than their Cu(II) counterparts. Relative to the Fe(III)/Fe(II) reduction with ascorbate, DHLA can fully inhibit the formation of \(_{ }^{\bullet }\textrm{OH}\) radicals, but not by reaction with \(O_{2}^{\bullet -}\). Relative to the Cu(II)/Cu(I) reduction with ascorbate, the effects of DHLA are moderate/high, and with \(O_{2}^{\bullet -}\) they are minor. LA has minor to negligible inhibition effects in all the cases considered.

[1] R. Castañeda-Arriaga, J. R. Alvarez-Idaboy, N. Mora-Diez, RCS Adv., 2016, 6, 107924-107932. [2] R. Monreal-Corona, J. Biddlecombe, A. Ippolito N. Mora-Diez, Antioxidants 2020, 9, 674.