My research at NMSU has evolved due to my changing interests and due to the pressures of funding. At present I have four programs underway. These are (1) electron transfer reactions of encapsulated metal complexes; (2) the binding of fatty acids to cytochrome c, (3) the exploration of the fundamental chemistry of the ferrate ion, FeO42-, and (4) the environmental chemistry of the ferrate ion. The first two projects have been marginally supported by grant monies while the latter two constitute the primary focus of my funding to date.
While at NMSU I have had four university faculty come to NMSU to spend their sabbaticals conducting research in my laboratory. I have also continued a collaborative effort with Dr. Robert J. Balahura from the University of Guelph.
Electron in Encapsulated Complexes
Unlike inner-sphere electron transfer mechanisms, where the bridging ligands control the spatial arrangement of reactants, the detailed nature of ligand mediation of outer-sphere processes remains unclear. We propose to investigate the intimate role(s) that ligands play in the structural organization of outer-sphere ion pairs and, in particular, their function in mediating electron transfer reactions between metal complexes by acting as orbital pathways or by controlling the spatial orientation between the metal redox partners. This goal will be realized in a novel fashion using the guest/host capabilities of cyclodextrins to shield selected portions of a metal complex from interaction with their redox congeners or by using hydrogen bonding to restructure the ion pair formed prior to electron transfer. This allows “control” of outer-sphere processes for the first time. Encapsulation also permits the evaluation of outer-sphere reorganizational terms induced by differential solvation of two halves of a metal complex. Initial results with pentammine(4,4'-bipyridine)ruthenium(II) complexes showed only marginal decreases (50% decreases) in the bimolecular rates of electron transfer for monoencapsulated complexes. We interpreted this to mean that collisions on the “free amine” side of the complex, see publications. In recent unpublished work however, we have found that biencapsulated complexes, e.g., trans-(4-tert-buylpyridine)tetramineruthenium(II), are reduced 102-103 times more slowly! We are attempting to relate these decreases to changes in the outer-sphere reorganizational energies as well as distance separations. In addition, the studies of cyclodextrin modified electron transport between simple metal complexes should mimic the "supramolecular assemblies" found in biological processes. One novelty of our approach is that it does not require extensive, expensive, and difficult organic synthesis described by other workers.
Finally, important kinetic and thermodynamic contributions in the study of cyclodextrin encapsulation of metallocomplexes will result from these investigations, an area where little work has been done to date, but where other researchers are beginning to enter after our initial publications. A recent publication from our group has described the influence of hydrogen bonding between the 2' hydroxyl groups on the cyclodextrin and the primary coordination sphere of the metal. The mediation of buffers to form ternary complexes was also proposed. These studies also have important application in the use of cyclodextrins as pharmacological delivery vehicles for metallodrugs, such as cis-platin, used in cancer treatment, or gold complexes (Aurofin® ) used in arthritis therapy.
Fatty Acid Binding to Cytochromes c
This represents a new area of investigation for my group, and one of the most exciting. We have obtained preliminary evidence that fatty acids bind strongly to cytochromes c and alter the structure of these proteins. In view of cytochrome's importance in the terminal steps of cellular respiration, i.e., the electron transport system, this observation may provide a new and novel insight into a regulatory pathway heretofore unknown. The presence of elevated fatty acid levels in certain disease states, principly diabetes and stroke victims, indicates that elevated levels may be one mechanism for cell damage. The hypothesis to be tested is that fatty acids are able to bind to cytochromes c at physiological concentrations and alter the protein's capacity to transport electrons and may even alter its function.
In order to study this hypothesis, the following three specific goals for this research program are: (1) To understand the precise mechanism and site of fatty acid binding to cytochrome c. From a detailed determination of what structural and solution medium effects (such as pH) have on the binding kinetics, the elucidation of the probable binding mode may be achieved. NMR, MCD, stopped-flow kinetics and rapid scanning spectroscopy are primary techniques to be used in these studies. The MCD studies will be carried out at U of S. Carolina. In addition, we will use site-specific variants of cytochromes c to probe the precise nature of the cytochrome c-fatty acid (cyt c/FA) adduct. Although these variants are currently produced outside this laboratory the present plans are to acquire these techniques with the help of Dr. Peter Lammers, who is in the Department of Chemistry and Biochemistry, NMSU and from Dr. Wong at Oxford University. (2) To define the alteration of electron transport capabilities incurred by binding fatty acids to cytochromes c. Using the similar instrumental approaches for studying the binding of FAs, the student will investigate changes in the adduct's capacity to transfer electrons from both simple inorganic metal complexes as well as biochemical partners such as cytochrome c oxidase. Preliminary cyclic voltammetry experiments indicate that the redox properties fatty acids adducts decrease by at least 10mV. (3) To determine whether a cyt c/FA adduct is capable of oxidizing the bound fatty acid. Although this is a rather speculative proposition, if true, it would provide a very novel pathway for fatty acid metabolism. Oxidation of the adduct with hydrogen peroxide, molecular oxygen, or small inorganic reagents such as ferricyanide will be carried out and the followed by HPLC analysis of the resulting matrix to look for fatty acid oxidation products. One publication has arisen from this work and another is anticipated based on work by Aaron Rowland at NMSU.
Hypervalent Iron Chemistry (Ferrate Chemistry)
Bioinorganic Applications
The study of iron in its high oxidation states has recently been shown to be of significance in the understanding of organic oxidations as well as biological transformation of molecules. For example, in the function of methane monooxygenase (MMO) or ribonucleotide reductase (RNR), the production of non-heme iron(IV) complexes has been proposed to the active to carry out oxidative processes. In addition, the ferrous ion catalysis of epoxidation reactions involving either hydrogen peroxide (Fenton’s Reagent) or molecular oxygen apparently involves the production of an iron(IV) or iron(V) species.
In order to understand these important processes, a knowledge of iron in its higher oxidation states (>+3) is necessary. To date few complexes of hypervalent iron have been synthesized and characterized. Some examples of these include [Fe(dtc)3+ and Fe(diars)3]. The oldest, and perhaps most important hypervalent iron complex is potassium ferrate, K2FeO4, where iron is in the +6 oxidation state. Although this species has been known for over 150 years, relatively little is known regarding its chemistry.
Recently my group has studied the oxidation of hydrazine and monomethylhydrazine with ferrate. In each system, the oxidation process proceeded via 2e- steps to form diazene and azomethane, respectively. Using this pathway to diazenes, we were able to reduce C=C bonds, perhaps a somewhat unexpected result considering the oxidative strength of ferrate! We have also finished studies with hydroxlamines and thiosulfate where 2e- steps were again invoked in the reaction mechanisms.
Most recently we have published a preliminary study on the selective oxidation of anilines to either nitrobenzenes or azobenzenes. It is our belief that the reactions of this long neglected ion will provide a plethora of interesting chemistry. Two reactions were observed using rapid scanning spectrophotometry and are shown below.
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