Synthesis and characterization of RPy2N2 pyridinophane ligands and transition metal complexes as therapeutics and catalysts

Abstract

The pyridinophane family of macrocycles has been studied for decades as ligand scaffolds for metals towards a wide variety of applications including biological mimics, catalysts, and therapeutics A newer ligand scaffold to join the library, RPy2N2, introduces a second pyridine ring to the long-standing PyN3 scaffold. This work explores the effect of 4 position modification of the two pyridine rings of RPy2N2 on the characteristics of the ligand and the complexes of Cu(II) and Fe(III) for application as a SOD1 mimic and catalyst respectively. This work found that the modulation of the electronics of the 4-position substitution tuned the electronics of the ligand overall, as evidenced in 1H NMR shifts and protonation constants. This mirrored the trends seen with the 4-position substituted RPyN3 series, but beyond that the exchange of one secondary nitrogen atom for a pyridine ring vastly changed the behavior of the ligand scaffold, more than the electronics of the 4-position did. The pyridine ring is less electron-rich than a secondary amine nitrogen atom, the effects of which can be seen throughout the rest of this work. When metalated with Cu(II), the RPy2N2 series vastly outperformed the previously studied RPyN3 series as functional SOD1 mimics, resulting in the most active copper-based small molecule functional SOD mimic to date. The electron-withdrawing groups improved the activity, but the change in the ligand scaffold allowed for more drastic changes that greatly increased the activity of the [CuII(RPy2N2)]2+ complexes as SOD1 mimics. Similarly, the RPy2N2 ligand scaffold had such a great effect on the catalytic yields of the complex formed in situ between FeIII(OTf)3 and RPy2N2, that no difference could be seen between the different electronic substitutions. The ligand scaffold change increased the catalytic yield to the maximum possible yield for the model reaction in use, an improvement of at least 10% over the RPyN3 series. Additionally, it was seen that the RPy2N2 ligand series is capable of forming two distict species in solution with Fe(III), posited to be the monomeric and µ-oxo dimeric complexes, and that these complexes can interchange with each other with simple pH control. Altogether, this work focused on the functionalization of pyridine rings in RPy2N2 ligands and studying the effect of that functionalization on the activity of the ligands and the metal complexes.