Carnegie Mellon University
Experimental and Theoretical Studies of TAML\xae Activators : Pharma.pdf (10.03 MB)

Experimental and Theoretical Studies of TAML® Activators : Pharmaceuticals Degradation, Nuclear Tunneling and Electronic Structure Analysis

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posted on 2013-05-06, 00:00 authored by Longzhu Q. Shen

Green chemistry concerns the scientific disciplines that support sustainability as their zenith. Sustainability has both temporal and spacial dimensions. The addition of the spacial dimension to it has significantly enhanced its visibility and horizon. Green chemistry, as an important subset of sustainability, radiates broadly and this entails a pursuer to choose their spectrum of interest. Therefore, I defined the technical domain of green chemistry from my perspective. Through projecting green chemistry onto the primary basis composed by the principle domain defined by Prof. Anastas and challenges domain interpreted by Prof. Collins and the technical domain by my definition, I mapped out my green chemistry trajectory. In a word, my Ph.D. training can be summarized as a research journey of combating persistent organic pollutants, characterizing the electronic signature of catalysts for renewable energy generation and catalytically oxidizing active pharmaceutical ingredients and hydrocarbons via a combinatorial avenues of computation, analysis and scientific inference. In view of the problem space of green chemistry, seeking renewable energies and eliminating persistent, disrupting or toxic compounds appear on the higher levels according to Prof. Collins. I attempted to tackle all the four problems to certain degrees during my Ph.D.

Energy has propelled the engine of human civilization for hundreds of years. Today, the fossil fuels, the natural reserves we rely upon in the past, have approached their limit. More significantly, their continuing use shadows the sustainable future of human beings as well as the lives of all forms on this planet. An urgent need horizons for better ways to capture and convert solar energy to carbon neutral forms of chemical energy. The lesson from photosynthesis provides a promising answer — water splitting. To mimic this process, developing catalysts for water cleavage becomes the central theme. Among all the earth abundant and inexpensive elements, Co stands out for its high efficiency and dual capability of water reduction and oxidation. Between the two, water oxidation presents the major challenge. Co(IV) was shown to be the active intermediate in this chemical conversion. This highlights the importance of precise characterization of the electronic structure Co containing catalysts. To this end, I combined the spectroscopic information and DFT calculation to clarify the literature ambiguity in the diagnosis of Co containing complexes, and theoretically projects the avenue to acquire a Co(IV) electronic state in coordination complexes.

The study of eliminating persistent organic pollutants was performed in the United Nations in the summer 2011. Apart from a technical summary of my research, I also identified two important causes that impasse on many environmental issues between nations. This signifies a global leadership that can unify and usher the international strength toward the sustainable summit.

The research experience in the United Nations showed hydrocarbons and their halogenated derivatives are very resistant to natural attenuation. Then I started my fervent pursuit of hydrocarbon hydroxylation study via theoretical modeling. Comparing theoretical with experimental studies, the reaction rates of [FeV(O)(B*)]–1 with ethylbenzene (EtBZ) and its isotope labeled species EtBZ-d10 differ in three respects: (i) the initial[FeV(O)(B*)]–1 decay rate for the substrate EtBZ-d10 is slower than that for EtBZ, (ii) the slope of the ln (k/T) vs. 1/T plot of EtBZ-d10 is smaller than that for EtBZ over the experimental temperature range, and (iii) the extrapolated tangents of the kinetic curves give a large, negative intercept difference, Int(EtBZ) - Int(EtBZ-d10) < 0 at the limit 1/T → 0. Theoretical analysis, based on density functional theory calculations of thermodynamic parameters of the reaction species and Bell’s model for tunneling through quadratic barriers, shows that (i) and (ii) result from isotope-induced changes in both the zero-point energies and nuclear tunneling, whereas (iii) is exclusively an isotope mass effect on tunneling. The research result points out nuclear tunneling has a significant contribution to the hydrocarbon hydroxylation process. A theoretical model was proposed that can be used to predict absolute rate constants outside the experimental fathomable range

In addition to persistent molecules, endocrine disrupting chemicals also deserve special attention. Active Pharmaceutical Ingredients (APIs) have been recognized as a hot-spot environmental pollutants largely due to their high disrupting potency. These anthropocentric synthetics compounds are mostly designed to aim at evolutionarily conserved targets to trigger biological responses at minute levels and optimized for extra degradation resistance for stable shelf lives. All these therapeutic benefits translate into ecotoxicity concerns when the parent compounds or their metabolites are released to the environment. A large body of literature has linked the exposure to APIs to Biological disasters. Under such a context, I applied TAML activators to treat to highly prescribed antidepressant drugs, Zoloft and Prozaic. The API for each is sertraline and fluoxetine.

In the sertraline degradation study, I demonstrated that TAML activators at nanomolar concentrations in water activate hydrogen peroxide to rapidly degrade this persistent API. While all the API is readily consumed, degradation slows significantly at one intermediate, sertraline ketone. The process occurs from neutral to basic pH. The pathway has been characterized through four early intermediates which reflect the metabolism of sertraline, providing further evidence that TAML activator/peroxide reactive intermediates mimic those of cytochrome P450 enzymes. TAML catalysts have been designed to exhibit considerable variability in reactivity and this provides an excellent tool for observing degradation intermediates of widely differing stabilities. Two elusive, hydrolytically sensitive intermediates and likely human metabolites, sertraline imine and N-desmethylsertraline imine, could be identified only by using a fast-acting catalyst. The more stable intermediates and known human metabolites, desmethylsertraline and sertraline ketone, were most easily detected and studied using a slow-acting catalyst. The resistance of sertraline ketone to aggressive TAML activator/ peroxide treatment marks it as likely to be environmentally persistent and signals that its environmental effects are important components of the full implications of sertraline use.

Fluoxetine, represents the first member of the serotonin receptor reuptake inhibitors (SSRIs) family and is one of the most successful among all members. Its top prescription record among SSRIs and extra stability leads to prevalent occurrence in the environment. Environmental studies showed that FLX can be toxic to aquatic species at trace level of exposure and disruptive to their neurosystems. Therefore, it is urgent to seek an environmentally friendly solution to diminish the harm FLX can potentially bring to the environment. Treatment with TAML activators and hydrogen peroxide, fluoxetine was shown to be rapidly degraded to harmless endpoints. An elusive intermediate along the degradation pathway was proposed and its fleet fate was studied using DFT calculations. The cascade breakdown feature of FLX under TAML®/H2O2 treatment inspires green pharmaceutical design.




Degree Type

  • Dissertation


  • Chemistry

Degree Name

  • Doctor of Philosophy (PhD)


Terrence J. Collins

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