|Abstract:||The activation of small molecules is crucial to the function of biological systems’ metabolic processes, detoxification, and cellular signaling. Metallocofactors and protein scaffolds often work in conjunction to attract and bind the small molecules, stabilize reactive intermediates, and shuttle protons and electrons to and from the active site. However, due to the size and dynamic nature of the protein scaffold it can be difficult to understand the mechanisms of these small molecule activation processes, as well as how the metal and protein scaffold work together to enable these transformations. The isolation and characterization of synthetic complexes can help to identify analogous reactive intermediates in enzymatic systems, as well as model the reactivity observed in enzymes. This thesis reports on the synthesis and characterization of tetrapodal metal-ligand complexes containing non-covalent interactions that model biologically relevant intermediates and reactivity towards small molecules.
Early work focused on the synthesis of a new tetrapodal ligand platform, Py2Py(piCy)2, which was accomplished in seven steps from commercially available materials. The ligand provides a contrast to the tripodal ligand N(piCy)3, that has been previously studied by Fout, et al. for the reduction of oxyanions and isolation of high valent iron species.
Py2Py(piCy)2 was complexed with the iron salt Fe(OTf)2(MeCN)2 and five unique iron complexes were able to be synthesized using the ligand framework. Characterization by NMR, infrared (IR), UV-visible, electron paramagnetic resonance (EPR), and Mössbauer spectroscopies was accomplished. Interestingly, the two ferric species isolated presented as iron(III)-hydroxo complexes, representing a functionality that has been proposed in non-heme 2- oxogluterate dependent (iron-2OG) enzymes, but has not been observed in the enzymatic systems. The majority of these iron-2OG dioxygenases will hydroxylate organic substrates through a radical rebound reaction after H-atom abstraction (HAA) from the substrate forms an iron(III)-hydroxo and caged substrate radical. Recent studies have also proposed that the iron(III)-hydroxo that is formed from the HAA is capable of other reactivity patterns towards substrate such as desaturation, epimerization, cyclization, or halogenation.
A study was conducted to determine if either of the synthetic iron(III)-hydroxo complexes were capable of performing the radical rebound hydroxylation observed in iron-2OG enzymes through the use of the stable C-centered radical, triphenylmethyl radical (Gomberg’s dimer). It was found that one of the iron(III)-hydroxo complexes was capable of performing a rapid hydroxylation of the radical substrate, while the other required the presence of adventitious water for hydroxylation to occur. It was also found that both iron(III)-hydroxo complexes had similar oxidative potency with BDFE values between 70-71 kcal/mole.
Further work with iron ligated tetrapodal ([Py2Py(afaCy)2Fe]2+), and tripodal ([N(afaCy)3Fe]2+) systems examining the catalytic reduction of perchlorate (ClO4-) to chloride (Cl-) was explored. It was found that the poisoning of each catalyst could be avoided through the use of an analogous zinc complex ([N(afaCy)3Zn]2+), which had a higher affinity for Cl- then either iron catalyst. Furthermore, the use of the zinc reagent allowed for a quantification of the turnover number (TON) for each catalyst. It was found the tetrapodal catalyst produced a TON of 48(2) while the tripodal system achieved a TON of 76(5), both of which represent order an order of magnitude improvement over the previously published values for iron catalysts.
In addition to the work done with the iron complexes, cobalt complexes were also synthesized from Py2Py(piCy)2. Two of the cobalt(II) complexes presented as high-spin systems while one presented as low-spin by EPR spectroscopy, but high-spin by SQUID magnetometry. It was also found that a cobalt complex could activate O2 to form a terminal cobalt(III)-hydroxo.