Chemistry
Computational investigation of the mechanism of HOCl-mediated cysteine oxidation in the conserved zinc-binding core of cytosolic chemoreceptor transducer-like protein D (TlpD)
Presenter(s): Lindsay Zumwalt
Advisor(s): Dr. O. Maduka Ogba
Helicobacter pylori, a gastric pathogen present in about 50% of the global population, is known to facilitate gastritis, stomach ulcers, and stomach cancer. Previous experimental studies show that local unfolding at the conserved chemoreceptor zinc-binding (CZB) domain within the transducer-like protein D (TlpD) cytoplasmic chemoreceptor upon contact with hypochlorite (a known biological oxidant), is implicated in the mode in which H. pylori effectively colonizes the stomach. However, the mechanism of oxidation at the conserved zinc-bound cysteine residue upon HOCl contact, the role of the zinc complex in modulating the reaction, and the origins of selective oxidation are unknown. Our work utilizes DFT computations to probe plausible mechanisms for the oxidation process, illuminates the role of ligand exchange equilibria at the zinc complex in modulating the reactivity and regioselectivity, and provides new hypotheses for the origin of the chemoattractant response. Insights from our computational study will be presented.
Computational Investigation Into the Origins of Reactivity for Metal-Thiolate Complexes in the activation of H-E bonds.
Presenter(s): Joshua Oommen, Zach Nelson
Advisor(s): Dr. O. Maduka Ogba,
Within the last decade, experimentalists have attempted to mimic the heterolytic bond cleavage of H-H bonds by [NiFe] hydrogenases by constructing synthetic metal-thiolate complexes using various transition metals for its potential applications in industrial reduction chemistry and alternative fuel sources. In their seminal work in 2008, Stradiotto and colleagues synthesized an iridium (III) and a rhodium (III) thiolate complex that was used for the successful cleavage of silane (Si-H) bonds, facilitating the hydrosilylation of ketones. Experiments reveal that stoichiometric amounts of the iridium (III) complex was needed for this transformation, while catalytic amounts were achieved for the rhodium (III) analog. The mechanism for the reactions using both metal-thiolate complexes and the origins of differing reactivity between the complexes have not been explored. Our research goal is to use quantum mechanical computations to (i) elucidate the plausible mechanism(s) for Si-H activation mediated by both metal-thiolate complexes, and (ii) uncover the factors affecting the difference in reactivity between these complexes i.e., stoichiometric for iridium(iii), catalytic for rhodium(iii). Furthermore, experimental attempts to heterolytically cleave dihydrogen (H-H) using these complexes failed, and results from our work will serve as a launch point for designing metal-thiolate variants for this important transformation. In this presentation, we will present the computed ground state complexes along the reaction pathway toward the hydrosilylation of acetophenone using both iridium (III), rhodium (III), and cobalt (III) metal thiolate complexes, and present our validation analysis with existing crystal structures. Our current hypothesis for the differing reactivity based on the ground state complexes will be discussed.
Computational Investigation of the Factors Precluding Catalytic Turnover in Ca(NTf2)2 Mediated Sulfur(VI) Fluoride Activation
Presenter(s): Brian Han, Matthew Nwerem
Advisor(s): Dr. O. Maduka Ogba
Nitrogen-containing sulfur(VI) compounds are commonly used in the pharmaceutical industry to combat bacterial infections. Synthesis of these compounds is typically facilitated by nucleophilic attack of a sulfur(VI) chloride pre-cursor by an amine nucleophile. However, the relative instability of sulfur(VI) chlorides makes selective synthesis challenging in the presence of competing nucleophiles, and hence precludes late-stage functionalization of complex natural products. Sulfur(VI) fluorides have become an attractive alternative to the chloride analogs given the increased selectivity that can be achieved with these precursors. Our collaborators succeeded in synthesizing nitrogen-containing sulfur(VI) compounds under mild condition using a myriad of sulfur(VI) fluorides in the presence of amine nucleophiles and mediated by calcium triflimide – Ca(NTf2)2. This contrasts conventional methods where strong base/nucleophiles with elongated heating process were required. However, the mechanism for sulfur(VI)-fluoride activation using Ca(NTf2)2 is not known, and in most cases, stoichiometric calcium triflimide is required for the transformation. In my research project, we used quantum mechanical calculations to shed light on the reaction mechanism for Ca(NTf2)2 mediated sulfonyl-fluoride activation and specifically, to elucidate the factors preventing the catalytic turnover of Ca(NTf2)2 in t-BuOH as solvent. In this talk, I will present the minimum energy pathway for Ca(NTf2)2 mediated sulfur(VI) fluoride activation, and our current hypothesis for the origins of inhibition in this reaction.