Student Flash Talks – 2025 Jeannette Brown Lectureship

Cyanine-incorporated amorphous polymeric carbon dots for optical reactive oxygen species sensing 

Reactive oxygen species (ROS) are common cellular oxidants that, when overproduced by cellular stressors, cause harm to cells. Detection of ROS is of utmost importance to understand a wide variety of cellular function and toxicity mechanisms. Conventional ROS fluorescence assays involve using a single dye to visualize ROS quantity. Herein, we describe an ROS-sensitive fluorescent dye-incorporated carbon dot with dual fluorescence capabilities and good biocompatibility. Carbon dots (CDs) made of citric acid and urea were synthesized with incorporated cyanine-3-amine (Cy3), a bright red fluorescent dye, to create Cy3-CDs. To get Cy3 into the ROS-sensitive form, this work demonstrated that Cy3 alone and Cy3 within carbon dots can be electrochemically reduced to its colorless form. Cy3, CDs, and Cy3-CDs are all responsive to additions of superoxide, leading to an increase in fluorescence. Other oxidizers, such as hydrogen peroxide and potassium permanganate, quench CD, Cy3, and Cy3-CD fluorescence. This work examines how oxidizers interact with CDs, Cy3, and Cy3-CDs and molecular level hypothesis are explored that can aid in the design of future carbon dot-based ROS sensors. 

Designing Polymeric Micellar Nanoparticles for Organ-Selective mRNA Delivery

Genetic disorders like cystic fibrosis and thalassemia result from genetic mutations that disrupt essential protein production, leaving patients without definitive cures. Messenger RNA (mRNA) therapy offers a revolutionary approach, enabling cells to synthesize therapeutic proteins without permanently altering the genome. However, its clinical potential hinges on overcoming major challenges in precise and efficient delivery to target organs. To address these barriers, we developed an innovative mRNA delivery platform using cationic polymeric micelles—nanoscale carriers assembled from diblock amphiphilic polymers—to enable safe, targeted, and effective mRNA transport. Our strategy integrates high-throughput parallel synthesis with AI-driven design tools, including SHapley Additive exPlanations (SHAP), to systematically evaluate a diverse library of micelle formulations. By modifying nitrogen-based functional groups, we achieved fine-tuned control over micelle properties, optimizing stability, mRNA encapsulation, and cellular uptake. Comprehensive in vitro screening identified key chemical determinants—amine acidity, steric effects, and binding strength—that critically influence micelle performance. Among them, micelle A7 emerged as a top-performing candidate, demonstrating exceptional lung-specific targeting with minimal off-target distribution in vivo. Building on this success, we engineered binary and ternary mixed micelles, combining A7 with polymers of varying charge profiles to dynamically control organ specificity. This breakthrough enabled us to redirect biodistribution from the lungs to the spleen and, more recently, refine compositions for precise targeting of the liver. Moreover, we established a strong correlation between in vitro and in vivo performance using Multitask-Gaussian Process models, underscoring the predictive power of in vitro models for anticipating in vivo outcomes. Overall, this innovative study integrates advanced data science with experimental design demonstrating the pivotal role of chemical amine-dependent optimization for advancing targeted mRNA delivery to the lungs.

Label-free detection of virus-like particles with surface-enhanced Raman spectroscopy

Cassandra L. Wouters,¹ Mahmoud Matar Abed,¹ Timmy B. Nguyen,¹ Clarice E. Froehlich,² Punarbasu Roy,¹ Theresa M. Reineke,¹ Christy L. Haynes¹,*
¹Department of Chemistry, University of Minnesota, Minneapolis, MN 55455, United States
²Department of Chemical Engineering and Materials Science, University of Minnesota, Minneapolis, MN 55455, United States
[email protected]

Virus detection is highly important; the last several years, since the onset of the SARS-CoV-2 pandemic, have highlighted a weakness in the field: the need for highly specialized and complex methodology for sensitive virus detection, which also manifests as sacrifices in limits of detection made to achieve simple and rapid sensing. Surface-enhanced Raman spectroscopy (SERS) has the potential to fill this gap. In this study, the physical entrapment of vesicular stomatitis virus through substrate design to localize virus analytes into SERS hotspots is explored. Quantitative detection of the virus is achieved down to 101 genetic copies per milliliter with an R2 of 0.987 using the optimized physical entrapment method. This study shows great promise for further explorations of label-free virus detection methods involving thoughtful substrate design, as is briefly demonstrated by expanding the scope of virus-like particles detected. 
 

A novel genomic perturbation enables resistance to environmental toxins in Shewanella oneidensis

Alessandra G. Gavin, Stephanie L. Mitchell, Erin E. Carlson

Nanoscale lithiated nickel manganese cobalt oxide (NMC) is an optimal cathode material for electric vehicles due to high energy storage capacity and low cost. The growing demand for these materials has increased global mining for raw materials, and a lack of proper material handling protocols has led to greater environmental concentrations of NMC and associated metals. Previous work has shown that the ubiquitous gram-negative environmental bacterium, Shewanella oneidensis, rapidly evolves hereditable resistance to both metals and NMC nanomaterial. Current work demonstrates that the specific combination of cobalt and nickel ions released from NMC nanomaterial trigger a unique genomic perturbation that enables resistance. Genomic sequencing revealed a 10x to 20x duplication of 25 conserved genes in all metal- and NMC-resistant populations. To better understand this phenomenon, we monitored the accumulation and loss dynamics of the duplicated region in the presence and absence of cobalt and nickel. We found that the copy number of this region increases rapidly and equilibrates at 10x after ~1,200 bacterial generations of metal exposure.  In the absence of metals, copy number in resistant cells decreases from 6x to 3x over ~1,200 generations, but never returns to 1x over the time course of our experiments. We found that metal tolerance remained constant throughout DNA accumulation and loss, which indicates that DNA duplication is a mechanism of sustained resistance. These results indicate that duplication of this DNA segment is a dynamic and selective response that allows S. oneidensis to survive in toxic conditions. This work not only illuminates the broader ecological consequences associated with introducing nanomaterials into the environment, but also provides insight into the larger tapestry of bacterial resistance by identifying a novel genomic perturbation that enables survival in a hostile environment. 

Tumor necrosis factor-alpha (TNF-α) is a key proinflammatory cytokine involved in immune regulation, chronic inflammation, and various diseases, including autoimmune disorders, neurodegenerative diseases, and cancer. Real-time monitoring of TNF-α levels can provide valuable insights into inflammatory responses and disease progression, potentially informing early intervention strategies.

Current techniques for detecting and quantifying TNF-α, such as ELISA, are limited by their inability to provide continuous, real-time data. These methods require separate sample collection and processing, leading to delays in data acquisition and restricting their applicability to dynamic biological systems. As biological processes are inherently dynamic, fluctuating over time in response to various stimuli, there is a growing need for a method that can continuously track TNF-α levels without interrupting the studied biological system.

To address this limitation, we are developing an aptamer-based micro-freeflow electrophoresis (μFFE) assay for continuous TNF-α monitoring. This approach leverages the high specificity of aptamers and the continuous separation capability of μFFE to enable real-time detection of TNF-α dynamics in biological systems, offering new opportunities for studying TNF-α’s role in inflammation and disease progression.

Carbon Dot-Based Sensors for the Rapid Detection of Foodborne Pathogenic Bacteria

Abigail Stitgen, Alejandra Rodriguez-Nazario, Heather Muenter, Christy L. Haynes

Every year, approximately one in six people in the United States are infected with foodborne illnesses, with pathogenic bacteria causing most of these illnesses. Current methods for sensing bacteria contamination rely heavily on bacterial culturing, which can be time-consuming and labor-intensive. As such, novel methods for quickly detecting bacteria contamination are needed. This project outlines the use of carbon dots (CDs) as fluorescent sensors for the rapid detection of bacteria. CDs are carbon-based nanomaterials that have piqued interest for sensing applications due to their facile synthesis, nontoxicity, tunable surface chemistry, and bright fluorescence. Thus, they can be leveraged as a platform to develop a fast and cheap method for detecting pathogenic bacteria contamination.

This work focuses on the synthesis and functionalization of CDs with high affinity for bacteria. To this end, the fluorescence intensity and photoluminescence quantum yields of CDs made from cheap starting materials can be tuned as a function of reaction temperature. Preliminary experiments also demonstrated that CDs with a strong positive surface charge will electrostatically bind and label bacteria whereas neutrally charged CDs will not interact with the bacteria. In an effort to find alternatives for electrostatic interactions, boronic acid-functionalized CDs are being explored as a means to form diol bonds with lipopolysaccharides on Gram-negative bacteria membranes. Together, these studies will constitute a fast and cheap method for detecting foodborne pathogenic bacteria using fluorescent CDs.

High-Throughput Discovery of Antivirulence Therapeutic Leads for Bacterial Infection

Hannah Addis and Erin Carlson

It is estimated that antimicrobial-resistant pathogens were responsible for 1.27 million deaths and 4.95 million deaths globally in 2019. The need for novel strategies to combat this ongoing public health threat is critical. Inhibiting bacterial virulence mechanisms, which are required to harm the infected host, could provide an alternative therapeutic strategy to treating drug-resistant infections over traditional antibiotics that quickly evolve resistance. Two-component systems (TCSs), found ubiquitously in bacteria, are signal transduction pathways that respond to environmental stimuli and are commonly linked to bacterial virulence, making them attractive targets for antivirulence therapies. Within the TCS, the membrane bound sensory histidine kinase (HK) interacts with external stimuli to promote autophosphorylation of a conserved histidine residue using its native substrate, adenosine triphosphate (ATP), at the catalytic (CA) domain. Due to the highly conserved nature of the CA domain, designing small molecules to block the binding of ATP at the CA domain is a strong path towards pan-inhibition of multiple virulence mechanisms within an organism and between bacterial species. Additionally, as many HKs are not required for survival, targeting them may limit evolutionary pressure to develop resistance. By establishing and validating a fluorescence polarization assay targeting the CA domain of a model HK, we have investigated multiple large small molecule libraries to identify scaffolds within novel regions of chemical space. Work is ongoing to validate and further develop these leads into potent inhibitors of bacterial virulence therapeutics for the treatment of antimicrobial-resistant infections. 

dsRNA loading into silica nanoparticles for the plant pathogen management 

Wilanyi R. Alvarez Reyes¹, Rima Jamous¹, Juliana Milagres², Rania El-Tanbouly^2,3, Raja Muthuramalingam Thangavelu², Washington daSilva², Christy L. Haynes^1
1 Department of Chemistry, University of Minnesota, Minneapolis, Minnesota, 55455, US
² Department of Plant Pathology & Ecology, The Connecticut Agricultural Experiment Station, New Haven, Connecticut, 06511, US
³ Department of Floriculture, Ornamental Horticulture and Landscape Design, Faculty of Agriculture, Alexandria University, Egypt

A key strategy to eradicate global hunger is the promotion of a sustainable food system to ensure long-term food security. However, various factors hinder the promotion of sustainable agriculture, including plant pathogens. Potato Virus Y (PVY) stands out as one of the most economically impactful plant pathogens, causing significant food loss and reducing crop quality. Hence, there is an urgent need for innovative sustainable technology to combat PVY. One promising approach is dsRNA-mediated gene silencing technology, which activates a biological mechanism in the plant that specifically targets and silences the plant pathogen. However, like any technology, dsRNA silencing technology has limitations, such as instability and vulnerability to degradation during plant delivery. To address these challenges, I am focusing on loading dsRNA into silica-derived nanoparticles (SiO₂ NPs) for the delivery and suppression of PVY in potatoes.  The study investigates three types of SiO₂ NPs: fast-dissolving (FDS), mesoporous (MSN), and ultra-porous mesostructured (UMN) SiO₂ NPs, to analyze how their distinct physical properties influence dsRNA loading capabilities.  It was found that UMNs, functionalized with aminosilane to promote electrostatic interaction with dsRNA, exhibited the highest dsRNA loading capacity, followed by MSN and FDS, respectively. Subsequent greenhouse and field studies have shown that the delivery of dsRNA using SiO₂ NPs successfully suppresses PVY in potatoes. This project presents a novel, sustainable nano-enabled virus silencing tool that could play a significant role in combating plant pathogens and contribute to the effort to alleviate world hunger.

Persistent Toughness and Heat Triggered Plasticization in Polylactide Modified with Poly(ethylene oxide)-block-poly(butylene oxide)

Matthew C. Larson, Jonathan P. Coote, Frank S. Bates, Chirstopher J. Ellison

Poly(lactide) (PLA) is a promising biodegradable polymer with potential applications in single-use packaging. However, its use is limited by brittleness, and its biodegradability is restricted to industrial compost conditions due in part to an elevated glass transition temperature (Tg). We previously showed that addition of a poly(ethylene-oxide)-block-poly(butylene oxide) diblock copolymer (PEO–PBO) forms macrophase-separated rubbery domains in PLA that can impart significant toughness at only 5 wt %. This work demonstrates that PEO–PBO/PLA blends exhibit substantial toughness for at least nine months, beyond the average lifetime of single-use packaging, even amidst oxidative degradation of PEO–PBO into oligomeric products. Due to the glassy nature of the PLA matrix, these degradation products are confined to macrophase-separated domains, and the blend morphology is preserved. However, modest thermal annealing (∼60 °C) causes these domains to rapidly reduce in area fraction and size from migration and solubilization of the PEO–PBO degradation products into PLA, which plasticizes PLA and reduces the blend Tg. As a result, aged PEO–PBO/PLA blends degrade in just under half the time of similarly aged neat PLA when submerged in artificial seawater at 50 °C. This surprising combination of properties addresses two of PLA’s most significant limitations with a single additive by (1) toughening the PLA during its useful lifetime and then (2) accelerating its degradation rate by heat-triggered plasticization when exposed to elevated temperatures at end-of-life, such as those of industrial (or even home) compost.

https://pubs.acs.org/doi/full/10.1021/acsmacrolett.4c00678 

Robust Encapsulation of Reactive [4Fe–4S] Cluster Models Inside Synthetic Cages as Protein-like Hosts

Weak-field iron-sulfur clusters are highly versatile and ubiquitous cofactors that are central to a range of essential biological functions, including electron transfer, cell signaling, transcription, and catalysis. Their structural flexibility and tunability make them widely adaptable to various functions, including catalyzing such challenging multielectron, multiproton-driven reactions as N₂ fixation to ammonia and CO₂ reduction to CO and hydrocarbons efficiently and selectively under ambient conditions. The discovery of synthetic systems that reproduce these functions is highly desirable from a green energy perspective. However, doing so is challenged by the need to maintain both stability and synthetic flexibility in the adoption of tunable weak-field ligand environments. Herein, we describe synthetic analogs of [4Fe–4S] clusters encapsulated by synthetic metal-organic cages that enable both requirements to be met. Thus, we synthesized the host-guest complexes containing [M₄NDI₆](NTf₂)₈, M=Fe, Ni, Zn, tetrahedral cages hosting [Fe₄S₄(SR)₄](NMe₄)₂ clusters with R= -Ph, -CH₂CH₂OH, -^tBu ligands giving rise to different intermolecular interactions. Extensive study of the cages binding [4Fe-4S] cluster with Ph ligands reveals the unparalleled stability to the weak-field clusters that are manifested in weeks-long solution lifetimes at 120 °C reflecting the reduced propensity of the encapsulated clusters to aggregation. Moreover, in-depth characterization by ¹H NMR, ⁵⁷Fe Mössbauer spectroscopy, and electrochemistry reveals the ability to tune the electron-richness of the iron-sulfur core through π- π stacking interactions between the ligand Ph groups and the NDI panels. Despite their increased solution robustness, we demonstrate that the [4Fe–4S] guests remain reactive towards simple substrates and thus that the host-guest complex offers a unique route for exploiting both stability and reactivity in cluster-based models. 

Structure-Based Design of BPTF Bromodomain Inhibitors and Degraders as a Novel Approach for Anti-Cancer Therapy

Chun-Ju Tsou, Sourav Das, Kesavan Babu, Stanley Nithianantham, Tim Stachowski, Osama Alaidi, Marcus Fischer, Anang Shelat, William C. K. Pomerantz*
[email protected], [email protected] 

Post-translational histone modification is one of the most common epigenetic regulatory mechanisms that modifies chromatin structure and affects gene expression. BPTF (Bromodomain PHD Finger Transcription Factor), the largest subunit of NURF (Nucleosome remodeling complex), is an epigenetic reader protein that recognizes histone acetylation on H4K16ac through its bromodomain. Overexpression of BPTF is associated with several human cancers and has been correlated with poor patient prognosis. While mechanisms vary based on cancer type, many involve protein-protein interactions (PPI) with transcription factors such as c-MYC and MITF. In the pediatric cancer, neuroblastoma, we found that knockdown of the BPTF protein also affects c-MYC and MYCN expression. To study its biological functions and molecular mechanisms within protein complexes, several BPTF bromodomain inhibitors have been developed in the Pomerantz lab, including BZ1, and now our newest inhibitor, BZ2. BZ2 has significant improvements over BZ1 with high affinity towards BPTF (Kd = 34 nM) and >10-fold selectivity over other class I bromodomain-containing proteins, CECR2, GCN5, and PCAF, and was found to impact the growth of both MYC and MYCN neuroblastoma cell lines but at low micromolar levels. To improve cellular uptake in cell-based assays, a series of new analogs have been designed to optimize drug-like properties. BPTF bromodomain inhibitor-based degraders are also being developed in parallel to evaluate the effect of BPTF modulation. Preliminary progress will also be disclosed.

Molecular Insights into Electrolyte & Solvent Effects: Selectivity for Electrochemical Reductive Bond Homolysis

Authors: Nhu H. Quach,¹ Mayank Tanwar,² Zach A. Nguyen,³ Dylan G. Boucher,³ Shelley D. Minteer,³ Matthew Neurock ^1,2 
1Department of Chemistry, University of Minnesota, Minneapolis, MN, 55455, USA
²Department of Chemical Engineering and Material Sciences, University of Minnesota, Minneapolis, MN, 55455, USA
³Department of Chemistry, University of Utah, Salt Lake City, UT, 84112, USA 

Electrochemistry offers a promising alternative to traditional organic synthesis, providing enhanced tunability, selectivity, and yields under milder conditions. While progress has been made in electrode and catalyst design, the role of electrolytes remains understudied.  Understanding how electrolytes interact with different components of an electro-organic reaction will provide an additional handle for efficient reaction design. This work employs first-principles density functional theory (DFT) calculations and Ab-initio molecular dynamics (AIMD) simulations, along with classical molecular dynamics (MD) simulations, to unravel the influence of electrolyte species on the reaction mechanism of an electrochemical reductive bond homolysis reaction. Insights from simulations show that small inorganic cations interact more strongly with polar aprotic solvents than organic cations, which can significantly alter the microenvironment of intermediate species, thus driving the selectivity of the reaction. The understanding from this work would provide a better rational platform to improve the control over yields and selectivity in electrochemical systems.

Multimetallic Cu-chalcogenide clusters as molecular platforms for next generation catalysis

Kallumkal, M.; Bailey, G. A.*
Department of Chemistry, University of Minnesota – Twin Cities, Minneapolis, MN 55455

Earth abundant copper-chalcogenide materials are known catalysts for small activation in heterogeneous catalysis. Nature also utilizes atomically precise Cu-S core in their enzymes such as N₂O reductase. Even though they are highly active for small molecule conversion, their atomic level chemistry is under explored relative to the bulk material properties. Understanding the molecular level reaction mechanism would help us to formulate design principles for next generation catalysts with high product specificity and selectivity. Atomically precise nanoclusters have the advantage of multimetallic cooperativity and molecular precision which enables us to leverage their potential to be explored as platforms to understand multielectron driven reactivity at molecular level. The present work shows efforts to understand fundamental structural transformations and reactivities of previously reported atomically precise Cu-S cluster stabilized by strongly coordinating carbene ligands. This study reveals novel solution stability and unprecedented structural changes in the cluster scaffolding upon reaction with a variety of hydrogen ion donating agents. The electrochemical behavior of this cluster at varying reaction conditions are under investigation. A promising electrochemical activity will extend the caliber of this cluster platforms to be employed as catalyst for electrochemical reduction of small molecules such as CO₂ and N₂O.

Establishing Molecular Targets of Acetylated H2A.Z Using Photoaffinity Probes

Kerstin E. Peterson, William C. K. Pomerantz*

There are an estimated 650,000 protein-protein interactions (PPIs) that are responsible for a variety of processes in human biology, yet many are still unknown largely due to their dynamic and transient nature. Transient interactions are observed among proteins involved in transcription such as the bromodomain (BD) of the epigenetic regulatory protein Bromodomain PHD Finger-containing Transcription Factor (BPTF) and histone variant, H2A.Z. BPTF BD recognizes acetylated histones and subsequently recruits transcriptional regulators, and H2A.Z is often found at gene promoter regions where its hyper-acetylation is linked to an oncogenic role. We have identified the first BPTF BD interaction with acetylated H2A.Z via NMR analyses, but this work seeks to confirm the interaction under more physiologically relevant conditions. Transient PPIs are difficult to capture with current affinity-based tools relying on noncovalent interactions which makes identifying them challenging. To overcome this barrier and complement our previously reported NMR analyses, my work is focused on capturing PPIs with a covalent bond through photocrosslinking chemistry. This approach involves putting a photoreactive diazirine on N-terminal histone tails to covalently capture their protein interactors in addition to a biotin tag for streptavidin affinity enrichment. Photocrosslinking conditions were first optimized with the isolated BPTF BD and interactions with endogenous BPTF were subsequently verified through western blot. Evidence from anti-biotin western blots indicate a variety of proteins are also captured, some of which are other bromodomain-containing proteins BRD4 and BRD2. Initial bottom-up proteomics has been attempted but has further highlighted limitations for detecting low abundant proteins such as BPTF. While this study focuses on a specific acetylation pattern, to more fully address the H2A.Z acetylome collaborative work with the Garcia lab at Washington University is ongoing to elucidate which patterns of acetylation on H2A.Z exist in small-cell lung cancer cells, a BPTF and H2A.Z dependent cancer.

Figure 1. A) BPTF uses its bromodomain (BD) to bind an H2A.Z acetylated histone tail. B) Histone peptide probe design. Following probe development, histone peptide probe is incubated with protein interactors and UV light irradiation subsequently activates the diazirine to photocrosslink the probe with the proximal protein. Purple circles represent lysine acetylation (Ac), and the dark blue (B) circle indicates a biotin tag.

Unlocking the Untapped Potential of Atomically Precise Metal Chalcogenides

Shatha Alabbad, Gwendolyn Bailey

Platinum remains the benchmark catalyst for the Hydrogen Evolution Reaction (HER) in acidic electrolytes due to its low overpotential; however, its high cost and scarcity restrict large-scale applications, prompting the search for viable non-precious metal alternatives. Inspired by biological enzymes such as hydrogenases and nitrogenases, which employ metal clusters for hydrogen production and nitrogen fixation, molybdenum sulfide has emerged as a promising candidate for HER. To enhance its catalytic performance, strategies including nanoscale engineering, post-synthesis modifications, and high-surface-area supports have been explored. Nonetheless, elucidating structure-activity relationships in bulk materials continues to pose significant challenges. This work posits that atomically precise clusters offer a robust framework for probing reaction mechanisms, facilitating the discovery of new catalytic pathways, and enhancing both reactivity and selectivity. These tunable clusters leverage two key features: (i) delocalized electron clouds that enable efficient multi-electron transformations, and (ii) metal–ligand interactions that enable the metal to oscillate between oxidation states, thereby promoting selective substrate binding and stabilizing transition states and intermediates. In this presentation, we will discuss our synthetic approach, characterization techniques, and future research directions.

Magnetic Biochar: Investigation, Intervention, and Integration

AJ Castillo, Ian Roback, Brian Barry, Emilie Snell-Rood, Lee Penn

Biochar, derived from heating organic matter such as wood or food waste in the absence of oxygen, is an effective adsorbent for environmental contaminants like heavy metals and organic pollutants. Increasingly prominent as a soil amendment, biochar not only immobilizes contaminants but also enhances agricultural yields and serves as a primary method for carbon sequestration.

Though charcoal production is an ancient technique, modern biochar experiments continue to uncover new insights as competing pyrolytic pathways, diverse feedstocks, and heat-and-mass transport effects conspire to complicate the basic chemistry of biochar production and use. These insights help us optimize how we use chars and engineer chars with novel properties.

In our study, wood chips of invasive Buckthorn were pyrolyzed in a kiln, and magnetic response was imbued by decorating the biochar with iron oxide particles. We investigated the relationship between magnetic response, contaminant adsorption, material properties, and the effect of biochar on water chemistry. We then developed a novel one-pot synthesis method based on solution combustion to replicate the magnetic biochar, and we compared properties of the two char types. 

Finally, we will deploy these magnetic biochars in contaminated soils at a former dump site, assessing their performance in real-world conditions and validating our findings on biochar activity and magnetic response.
 

Asymmetric hydroacylation has tremendous potential for the preparation of valuable chiral ketones from simple aldehyde and alkene building blocks. However, decarbonylation of the aldehyde starting material siginificantly limits its scope, as most hydroacylation methodologies rely on embedded directing groups to enable efficient reactivity. Our work aims to provide an alternative approach to relieve the current constraints for substrates. This talk will discuss the development of chiral 2-aminopyridines as transient directing groups in hydroacylation, which relieve the need for embedded chelating groups in contexts where they were previous required. We demonstrate the advantages of our methodology in intramolecular contexts to form 7-membered-ketones, in intermolecular contexts of unstrained alkenes, and in complex molecule synthesis.

Energy-Activated and Diversifiable Aryne Precursors from Carboxylic Acids

Authors: Chia-Ling (Felicia) Yu^1†, Chris M. Seong^1†, Sallu S. Kargbo^1†, Daniel Gibney¹, Jan-Niklas Boyn^1*, Courtney C. Roberts^1*
† These authors contributed equally to this work

Densely substituted arene rings are ubiquitous in pharmaceuticals and agrochemicals which support human health and wellbeing. Arynes–a triple bond in a benzene ring–are an intriguing solution to the problem of generating decorated arenes. State-of-the-art aryne precursors are plagued by two issues: 1) the additives required for activation are incompatible with many desirable functional groups intrinsic to the aryne itself as well as the coupling partners which limits the scope, and 2) derivatization of the precursors requires lengthy linear sequences often using harsh conditions rendering them impractical for discovery chemists. Here, we show the design of an aryne precursor made in a single step from a commercially available carboxylic acid and then derivatized in a single SNAr step. Unprecedented aryne activation proceeds using blue light or mild heat, avoiding the use of additives. The model system for this precursor incorporates an ortho-amino group in the final stage because anilines are found in 40% of medicinal chemistry patents and are highly underrepresented in aryne methodology. These precursors have the potential to supersede existing precursors and enable broad access to this desirable synthon.

Domino Reactions of Free Carbenes with Alkynes: Synthesis of Polycyclic Heteroaromatic Hydrocarbons

Sangjun Lee and Thomas R. Hoye
[email protected] and [email protected]

Alkynes are well-recognized for their high energy potential, rendering them versatile substrates for a variety of transformations in organic synthesis. Notable examples include the hexadehydro-Diels-Alder (HDDA) reaction, which generates arynes, and the formation of free carbene from 2-alkynyl iminoheterocycles with electron-deficient alkynes. Those methodologies have provided a variety of opportunities to construct the complex polycyclic system.
In this talk, I will present the free carbenes generated from 2-alkynyl iminoheterocycles can react with tethered alkynes, resulting in the generation of a second free carbene and leading to the formation of intriguing polycyclic heteroaromatic hydrocarbons. 

Acidic Alkalis: Assessing Lewis Acidity of Group 1 Metal Cations

Alkali metal salts such as LiClO₄ are well-known as Lewis acidic promoters for the Diels-Alder reaction, the Mukaiyama-Michael reaction, and other notable organic transformations. More recent studies have enhanced the reactivity of lithium and sodium metal cations further by pairing them with more weakly coordinating anions such as tetrakis(3,5-bis(trifluoromethyl)- phenyl)borate (BAr^F₄).

Previous work in our group to assess the catalytic activity of Lewis and Brønsted-acidic BAr^F₄ salts led us to inquire into the reactivity of simple alkali metal cations. To that end, pseudo-first-order kinetic studies of Friedel-Crafts and Stork reactions were undertaken using alkali BAr^F₄ salts as catalysts, and the resulting trends were analyzed. Interestingly, catalytic activity is directly correlated with various fundamental properties of the cation, including ionic radius and ionization energy. Work to assess potential divergences in reactivity trends between oxygen-based and sulfur-based Michael acceptors, as a method of experimentally assessing hard-soft interaction ability and gauging relative oxophilicity/thiophilicity, is ongoing.

Understanding the Structure and Reactivity of Rare–Earth Metal Complexes Bearing a Redox–Active Ligand

Rana B. Abdu, Nick A. Garcia, Victoria T. Tafuri, Courtney C. Roberts

Rare earth metal complexes (i.e. early transition metal and lanthanide complexes), have been underutilized in organic synthesis as they lack the d electrons necessary for various traditional organometallic steps. The Roberts group addresses this challenge by employing a redox–active tris(amido) ligand which can act as an electron reservoir to provide the necessary electrons for organometallic transformations. Improving our understanding of how these complexes react provides complimentary reactivity to late transition metal chemistry. For instance, our group previously reported an early transition metal catalyzed alkyl–alkyl cross–coupling reaction. This filled a crucial gap in the literature of catalytic alkyl–alkyl cross–coupling reactions as late transition metal complexes (such as Pd) yielded low cross–coupled product as deleterious side reactions such as β–hydride elimination were prevalent. Therefore, further exploration of the complexes’ structures as well as their reactivity provides ways to overcome these challenges.

In this work, the synthesis and characterization of early transition metal (Sc, Y) and lanthanide (La, Tb–Lu) complexes bearing a tris(amido) redox–active ligand will be discussed. In addition to the complexes’ ability to catalyze alkyl–alkyl cross–coupling, their ability to form new C–C and C–heteroatom bonds via C–H activation of alkynes through sigma bond metathesis will also be described. These new reactions as well as the complexes’ unique reactivity with HB(pin) show how little is understood about the behavior of these complexes and demonstrate the need for further investigation. 

Exploring Defluorination Reactions Using ^tBuOK

Serena L. DiLiberti, Dr. Sangyun Kim, Professor Chris Douglas*

During an exploratory study, my former lab mate, Dr. Sangyun Kim, fortuitously discovered that ortho-substituted trifluoromethyl arenes could undergo complete defluorination upon treatment with ^tBuOK. However, there was an unknown major product formed that we could not easily identify, with conflicting NMR and MS data. Based on the ¹H and ¹³C NMR spectra, we originally suspected that the -CF₃ was being substituted by -O^tBu. However, direct substitution of a trifluoromethyl group with a t-butyl ether was unknown in the literature. Upon reflection, a more likely product was the t-butyl ester, where the fluorines acted as leaving groups and the carbon of the trifluoromethyl group was transformed into the carbon of the t-butyl ester. Based on this hypothesis, I synthesized the t-butyl ester via an alternative pathway, confirming that this was indeed the product from the defluorination reaction. Currently, we are exploring the scope of this reaction. I have successfully synthesized and tested 3 successful substrates in this defluorination. I plan to pursue mechanistic studies, such as kinetics and rates of defluorination, with the hopes of isolating an intermediate.

Aniline Decoration Via Energy Activated Arynes

Authors: Sallu Kargbo, Chris Seong, Felicia Yu

Anilines are important motifs in pharmaceuticals. In fact, aromatic C-N bonds are found in 40% of medicinal chemistry patents. While the development of Buchwald-Hartwig C-N coupling has drastically simplified the construction of anilines, the decoration of their aromatic rings still proves to be challenging. Current methods rely on electrophilic aromatic substitutions which are limited to ortho/para positions and mono-functionalization due to the deactivation of the arene core. In 2014, Garg and Houk demonstrated that arynes could be implemented in the synthesis of complex aminobenzenoids through a tandem o-chloroaryne-trapping/cross-coupling sequence. However, because the aryne chemistry is placed early in the synthesis, the implementation of this technology for the rapid development of a library of anilines with different aromatic substitutions is time and resource intensive. Here, we demonstrate a reversal of this logic by forming the C-N bond directly on the aryne precursor, enabling the divergent synthesis of medicinally relevant decorated anilines for SAR studies. By developing soluble, thermally activated, additive-free aryne precursors that can be aminated in the step before aryne formation, the late-stage derivatization of the arene core can be achieved through mono- or difunctionalization of their o-aminobenzynes. These precursors can be activated thermally without commonly used additives such as fluorides or strong base, allowing for broad functional group tolerance. Furthermore, these aryne precursors can all be stored in a bottle indefinitely until it is weighed out and heated, drastically simplifying access to this technology. This will allow for modular construction of highly decorated amine substituted arenes which are essential components of pharmaceuticals. We anticipate these new aryne precursors will be a paradigm shifting building block in synthesis with applications beyond just the pharmaceutical industry but also to agrochemicals and materials.