The thermodynamic stability of twenty-nine Fe(III) complexes with various deprotonated forms of lipoic (LA) and dihydrolipoic (DHLA) acids, 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. Even though the complexes with LA- are more stable than those with DHLA−, the most thermodynamically stable Fe(III) complexes involve DHLA2−. 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 O2•− and ascorbate. 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 •OH radicals, but not by reaction with O2•−. Relative to the Cu(II)/Cu(I) reduction with ascorbate, the effects of DHLA are moderate/high, and with O2•− they are minor. LA has minor to negligible inhibition effects in all the cases considered.
Predictive catalysis was applied to the reaction of pyridinium 1,4‐zwitterionic thiolates with a copper carbene. Theoretical calculations were first performed to determine the suitability of their annulation reaction and to make predictions about the performance of different copper salts, diazo species, and pyridinium derivatives. With calculations in hand, the experimental conditions were optimized, the scope of the reaction was assessed, and the precision of the predictions was evaluated. Yields up to 90% were obtained for the synthesis of indolizine scaffolds in the reactivity of pyridinium 1,4‐zwitterionic thiolates with a metal carbene.
The thermodynamic stability of 11 complexes of Cu(II) and 26 complexes of Fe(III) is studied, comprising the ligands pyridoxamine (PM), ascorbic acid (ASC), and a model Amadori compound (AMD). In addition, the secondary antioxidant activity of PM is analyzed when chelating both Cu(II) and Fe(III), relative to the rate constant of the first step of the Haber-Weiss cycle, in the presence of the superoxide radical anion (O2•−) or ascorbate (ASC−). Calculations are performed at the M05(SMD)/6-311+G(d,p) level of theory. The aqueous environment is modeled by making use of the SMD solvation method in all calculations. This level of theory accurately reproduces the experimental data available. When put in perspective with the stability of various complexes of aminoguanidine (AG) (which we have previously studied), the following stability trends can be found for the Cu(II) and Fe(III) complexes, respectively: ASC < AG < AMD < PM and AG < ASC < AMD < PM. The most stable complex of Cu(II) with PM (with two bidentate ligands) presents a ΔGf0 value of −35.8 kcal/mol, whereas the Fe(III) complex with the highest stability (with three bidentate ligands) possesses a ΔGf0 of −58.9 kcal/mol. These complexes can significantly reduce the rate constant of the first step of the Haber-Weiss cycle with both O2•− and ASC−. In the case of the copper-containing reaction, the rates are reduced up to 9.70 × 103 and 4.09 × 1013 times, respectively. With iron, the rates become 1.78 × 103 and 4.45 × 1015 times smaller, respectively. Thus, PM presents significant secondary antioxidant activity since it is able to inhibit the production of ·OH radicals. This work concludes a series of studies on secondary antioxidant activity and allows potentially new glycation inhibitors to be investigated and compared relative to both PM and AG.
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