Climate change due to greenhouse gas build up in the earth’s atmosphere is an existential threat to humanity. To mitigate climate change, a significant shift from fossil fuels is necessary. Over the years, several renewable energy sources like solar, wind, geothermal etc. have been explored with emphasis on discovering and developing new materials with better performance. In this work, we focus on using first principles computational methods to investigate key functional properties of materials of interest for applications in solar cells and catalytic conversion for energy generation. We show geometric effects of carboxylic acid binding on a transition metal surface to impact the deoxygenation reaction mechanism. Using insights from binding energy calculations and transition state theory, we elucidate the reaction pathway. From geometric study of organic ligands adsorbed on the perovskite surface, we show tuning of the work function by changing functional groups and observe a correlation with the bulk antibonding characteristics of the bond between metal and anion. Lastly, through first principles, we discover the geometric unfolding of the perylene diimide (PDI) chromophore due to change in the overall charge on the organometallic complex. With further investigation from time-dependent density functional theory, we discover the electron reservoir behavior of the PDI chromophore which is responsible for CO2 reduction.

As part of the ongoing effort to substitute finite fuel and chemical resources with renewable resources, biomass is emerging as one of the most promising sources. Biomass consists of three main components of cellulose, hemicellulose, and lignin. Traditionally, cellulose has been used extensively in pulping industry, while lignin has been considered waste and is burned to generate heat. Lignin, a complex aromatic polymer component of biomass, has the potential to be used as a source of aromatic chemicals and pharmaceutical synthons. The recalcitrant nature of lignin, the lack of effective lignin breakdown methods and analytical techniques to analyze it are the main obstacles to obtaining high-yield chemicals from lignin. Mass spectrometry has proven to be one of the most promising analytical techniques and it is widely used in the pharmaceutical and chemical industries.  The goal of this work is to develop analytical methods using mass spectrometry and lignin model compounds. Additionally, this work focused on the development and application of quantitative Derivatization Followed by Reductive Cleavage(q-DFRC) for the evaluation of various biomass pretreatment methods.  Since most commercially available lignin model compounds fail to mimic the structure of native lignin, it is necessary to develop compounds that more closely reflect the functionality of native lignin. The first project of this dissertation is focused on developing precursors for synthesizing ?-O-4 model compounds and modifying their functional groups. The precursors have been synthesized and analyzed using gas chromatography-mass spectrometry. These precursors were used to synthesize ?-O-4 model compounds that exhibit all characteristics of the native lignin.  The second project involved the synthesis and mass spectral analysis of a mixed linkage trimer containing both ?-O-4 and ?-5 bond types. A detailed analysis of the mass spectral fragmentation of lignin trimer with lithium adduct ionization is presented. The developed analysis of the lignin trimer facilitates the structural elucidation of lignin breakdown products.  The third project involved the application of q-DFRC as one of the lignin breakdown techniques to evaluate different biomass pretreatment methods. Ethanosolv, dioxosolv, co-solvent enhanced lignocellulosic fractionation (CELF), hydrotropic, and acetic acid/formic acid pretreatments were evaluated by q-DFRC with deuterium-labeled acylated monolignols internal standard. An evaluation and comparison of the quality of lignin obtained from each of these pretreatments was conducted.  This dissertation provides valuable information for the advancement of mass spectrometric analysis of lignin, and it can be applied to lignin oligomer analysis. Furthermore, the q-DFRC results provide insight into how various pretreatments are related to the extent of condensation in extracted lignin.

Organic semiconductors have gained attention recently due to their potential applications in flexible, low-cost, lightweight electronics and solar cells. However, developing new organic semiconductors with improved performance remains a significant challenge due to the vast space of possible molecular structures. Furthermore, the high cost and time-consuming nature of experimental synthesis and characterization hinder the rapid discovery of new materials. To overcome these challenges, this dissertation presents a novel data-driven approach. The primary focus of this work is the development of data-driven tools, namely machine learning models, to predict critical electronic and structural properties of molecular organic semiconductors. These models are trained on a large dataset of quantum chemical calculations, enabling the efficient screening of thousands of candidate molecules. In addition to developing the predictive models, this work includes creating a user-friendly web platform. The platform enables scientists and engineers to access the models and rapidly explore the chemical space to design new materials. The platform also includes visualization and analysis tools to guide the design process and facilitate collaboration between researchers. The data-driven tools developed in this research have the potential to significantly accelerate the discovery and development of new molecular organic semiconductors, paving the way for the next generation of flexible electronics and renewable energy technologies. Overall, this dissertation offers a practical and innovative framework for designing organic semiconductors, leveraging data-driven approaches to overcome the challenges of the traditional experimental trial-and-error process.

HIV is among the world’s most deadly infectious diseases. Recent therapeutic advancements have begun to increase the life expectancy of people living with this virus. The mechanisms that lead to neurobiological complications in HIV cases are not well understood. HIV infection in macrophages results in HIV-1 Tat proteins being released and impairing the function of monoamine transporters. HIV-infected patients have displayed unusual synaptic levels of neurotransmitters and led to reduced binding and function of monoamine transporters such as the norepinephrine transporter, vesicular monoamine transporter, and serotonin transporter.   Here we use different approaches to develop an accurate three-dimensional model of the HIV-1 Tat and NET binding complex which would help reveal how HIV-1 Tat causes toxicity in the neurons by affecting uptake. The modeling results show that HIV-1 Tat-hNET binding is highly dynamic and HIV-1 Tat preferentially binds to hNET in an outward-open state. VMAT2 is related to NET as it transports a wide range  of  substrates  including dopamine, norepinephrine, and serotonin. HIV-1 Tat affects VMAT2 similarly to NET, binding and inhibiting its function. VMAT2 is also inhibited by a number of small molecules and the binding modes are explored. The neurobiological mechanisms underlying HIV-associated depression are not well understood. Depression severity in HIV cases has been linked to acute and chronic markers of systemic inflammation and relates to serotonin levels. HIV-1 Tat affects the serotonin reuptake mechanism by inhibiting the serotonin transporter. Here we explore the possible binding modes of HIV-1 Tat and SERT. There are also a number of substrates that inhibit SERT normal function and the binding of HIV-1 Tat-SERT complex. The binding modes of these complexes are also explored here.   There is a significant need for new therapeutic compounds for the treatment of cognitive dysfunction. Current therapies provide minimal symptomatic relief, without curing or halting cognitive impairment. Preclinical data have shown that inhibitors of cyclic nucleotide phosphodiesterase 2 improve memory in Alzheimer’s disease mouse models and reverse some markers of neuropathology. Family members of PDE, notably PDE4 and PDE5, have been shown to be druggable targets and suggest the same can apply to PDE2. PDE2A is the most prevalent of the family and is expressed in the hippocampus and frontal/temporal cortex regions. PDE2 is a dual specific enzyme that hydrolyzes cGMP and cAMP, and is involved in memory and cognition and is susceptible to Alzheimer’s disease associated neuropathology. Clinical studies have not produced improved candidates due in part to suboptimal selectivity, poor metabolic stability, or limited brain penetrance. Currently there are no PDE2A inhibitors that are approved for clinical use. Here we utilize state-of-the-art drug discovery tools and techniques to discover, design, and optimize novel and drug-like inhibitors for PDE2A. The discovery schema for novel, potent and selective PDE2A inhibitors will use a proven, iterative process where outcomes of in vitro and in vivo testing informs and guides modeling and medicinal chemistry.

Pt(II)-based agents are used in approximately 50% of all cancers that are treated with chemotherapy. Unfortunately, the dose-limiting toxicity of these agents remains problematic for patients undergoing treatment. Additionally, Pt(II) therapeutics suffer from transporter-dependent uptake, limited chemical functionalization, and high susceptibility to inactivation by free thiols within the cytosol. Developing small molecules with non-canonical mechanisms of action is one strategy that can be employed to circumvent these limitations. Utilization of coordination complexes with Ru(II) metal centers is one attractive strategy. Ru(II) compounds are often octahedral, facilitating greater accessibility for chemical diversity; Ru(II) complexes use passive transport and transferrin-mediated transport for cellular uptake; Ru(II) is a harder Lewis acid than Pt(II), facilitating reduced thiol coordination, which results in reduced inactivation. Herein, we investigate several Ru(II) scaffolds that display non-canonical mechanisms. They are able to preferentially induce ribosome biogenesis stress and mitochondrial membrane uncoupling. Complementary to this work, we investigated the mechanism of action for photoactive chemotherapeutics (PACTs) and photodynamic therapeutics (PDTs). Despite the fact that reactive oxygen species (ROS) generated by PDTs can oxidize nucleobases, cellular bioenergetic pathways are effectively shut down before DNA damage could be recognized by DNA damage repair (DDR) machinery, suggesting that, unlike Pt(II) therapeutics, DNA damage is not the cause of cell death for these compounds.

"Transition-metal catalyzed Suzuki-Miyaura (SM) cross coupling is a powerful synthetic method for constructing carbon-carbon and carbon-heteroatom bonds in designing organic compounds, agrochemicals, pharmaceuticals, and precursors for materials.  However, the nature of catalysis and identity of the transition metal catalysts used in these reactions remain under debate or unknown. This work reports the studies of three metals: Pd, Cu, and Ni. Pd-nanocluster catalysts and their formation in ligand-free SM reactions with Pd(II) nitrate as a precatalyst was investigated. The catalysts are water-soluble neutral Pd tetramer and trimer in their singlet electronic states as identified by UV-Vis absorption spectroscopy and are formed by leaching of spherical Pd(0) nanoparticles with an average diameter of about three nanometers. The Pd(0) nanoparticles are produced by reducing Pd(II) nitrate and characterized with transmission electron microscopy (TEM) and Pd-K edge extended x-ray fine structure spectroscopy (EXAFS). The Pd(II) reduction is induced by ethanol and enhanced by potassium hydroxide and monitored with x-ray photoelectron spectroscopy (XPS). For the Cu-catalyzed SM coupling, a water-soluble active molecular catalyst, and its formation in the ligand-free SM cross-coupling reactions with copper iodide as the precatalyst in aqueous solutions has been reported. The SM coupling is homogeneous in nature, and the molecular catalyst is Cu(OH) in its singlet electronic state also identified by experimental and computational UV-Vis absorption spectroscopy. The Cu(OH) catalyst is generated through the leaching of oval-shaped Cu₂O nanoparticles, which are characterized with X-ray Auger electron spectroscopy, X-ray absorption spectroscopy (XAS), and TEM. The soluble Cu(OH) species is stable for at least four weeks under ambient conditions. Similarly, for Ni-catalyzed ligand-free SM coupling, the active Ni catalyst is reported as Ni(0) species with Ni(0) powder as the precatalyst. The SM coupling is also homogeneous in nature. The water-soluble active Ni(0) catalyst is generated through the leaching of Ni(0) nanoparticles, which are characterized with XPS, XAS, and TEM. The water-soluble active Ni(0) catalyst species is stable for at least eight weeks under ambient conditions. Thus, this talk showcases the nature of catalysis and the identity of catalytically active species in ligand-free SM reactions catalyzed by Pd, Cu, and Ni transition metals."

Transition metals such as Fe, Cu, and Zn are micronutrients that have critical roles at the host-pathogen interface as both the host and pathogen need them for survival. The host has developed innate immune strategies to sequester metals such as Fe which pathogens need for survival as well as strategies to secrete certain metals such as Cu to exert toxic effects on the pathogen. In return, pathogens have evolved strategies to scavenge metals they need, as well as export or store excess metal. Candida albicans, is an opportunistic fungal pathogen that has the capacity to cause systemic infections that can lead to death in immunocompromised and immunosuppressed populations. Azoles, such as fluconazole, are one of the four classes of antifungals that are FDA approved and are a first line treatment for C. albicans infections.  Our lab has shown significant changes to metallohomeostasis of C. albicans as a result of fluconazole treatment. In this talk, I will discuss our work to determine how C. albicans overcomes azole treatment by modifying Cu homeostasis pathways. I will also discuss a potential strategy that focuses on metal dyshomeostasis and takes advantage of our innate immune system to develop a possible treatment for C. albicans infections.

Abstract: The human cytochrome P450 1B1 (CYP1B1) is an emerging target for small- molecule therapeutics. Several solid tumors overexpress CYP1B1 to the degree that it has been referred to as a universal tumor antigen. Conversely, its expression is low in healthy tissues. CYP1B1 may drive tumorigenesis through promoting the formation of reactive toxins from environmental pollutants or from endogenous hormone substrates. Additionally, the expression of CYP1B1 in tumors is associated with resistance to several common chemotherapies and with poor prognoses in cancer patients. However, inhibiting CYP1B1 with small molecules has been demonstrated in cellular and murine model systems to reverse this resistance phenotype. Thus, an approved CYP1B1 inhibitor may be of immense benefit to cancer patients struggling against chemotherapy-resistant disease.

However, developing selective inhibitors of CYP1B1 is challenging due to the existence of approximately fifty related cytochromes P450 found in humans which share similar structural features. Confounding this fact, CYP1B1 preferentially binds substrates of low three-dimensional complexity and with high lipophilicity, which from a synthetic viewpoint are relatively nondescript, making rational inhibitor design difficult.

This work offers new synthetic approaches toward the solution to the challenge of developing selective CYP1B1 inhibitors. The first part of the work describes the discovery and mode of action of a previously unknown inhibitor of CYP1B1 active at sub-nanomolar concentrations, and with unprecedented selectivity compared to existing inhibitors. Next, the pharmacokinetic optimization of this lead compound was undertaken resulting in an improved lead with excellent metabolic stability for future applications in disease models, and with the long-term goal of translation into the clinic for use in human patients. Together, the development of a series of new molecular entities is described which enable the exquisite control of the activity of this medically relevant enzyme and is an important step toward the development of drug candidates.

Abstract: In this seminar, we will focus on our recent work on two different thin film systems – metal halide perovskites and organic semiconductors.For one, through proper control of processing, we are able to realize pinhole free organic semiconductor films with single crystal grains with mm dimensions. We have found that transport in these films is considerably improved compared to disordered films, and that organic solar cells incorporating these long-range-ordered films exhibit highly delocalized, and band-like charge transfer (CT) states, contributing to noticeably lower energy losses. We will discuss these aspects and our understanding to-date of which molecules are amenable to the formation of such films, and how to propagate their growth. Also, organic hole transport materials (HTMs) are ubiquitous in halide perovskite solar cells, but what is less well known is that shallow HTMs that facilitate hole extraction from the perovskite also enable halogen transport. We will present our understanding of this phenomenon, as well as impacts to devices with regard to Au diffusion.

Bio: Barry Rand earned a BE in electrical engineering from The Cooper Union in 2001. Then he received MA and PhD degrees in electrical engineering from Princeton University, in 2003 and 2007, respectively. From 2007 to 2013, he was at imec in Leuven, Belgium, ultimately as a principal scientist, researching the understanding, optimization, and manufacturability of thin-film solar cells. Since 2013, he is in the Department of Electrical Engineering and Andlinger Center for Energy and the Environment at Princeton University, currently as a Professor. Prof. Rand’s research interests highlight the border between electrical engineering, materials science, chemistry, and applied physics, covering electronic and optoelectronic thin-films and devices. He has authored over 160 refereed journal publications, has 25 issued US patents, and has received the 3M Nontenured Faculty Award (2014), DuPont Young Professor Award (2015), DARPA Young Faculty Award (2015), and ONR Young Investigator Program Award (2016).

Dr. Shanina Sanders Johnson
Ph.D., Hampton University
B.S., University of North Carolina at Chapel Hill
At Spelman since 2011, promoted to Associate Professor recently

Abstract: Dr. Johnson's work has involved implementing culturally relevant pedagogies into organic chemistry lecture and laboratories. Activities that provide context to chemistry have been created and implemented to allow for incorporation of student background, interests, and experiences into the curriculum. These strategies allow students to see the relevance of science, reflect on their science identity, and connect their personal experiences and knowledge to their learning. Additionally, allowing for cultural context in the curriculum supports diversity within the classroom on multiple levels. This type of strategy is ultimately aimed at not only diversifying chemistry but also ushering in social change that provides for a more equitable field.  

This event is cosponsored by the College of A&S Dean’s Office and the Office for Institutional Diversity.