FAS Theses and Dissertations

Water is essential to the biological processes required for life. However, the same properties that make water so ubiquitous in biology—namely its polarity and ability to form stable hydrogen bonding networks—also make it a poor solvent for nonpolar gases relative to many organic solvents. As a result, increasing the gas capacity of aqueous systems could have crucial impacts in medicine or for technologies requiring efficient transport of gaseous reactants, such as fuel cells or bioreactors. This dissertation investigates aqueous porous liquids, termed microporous water, as a strategy for improving gas solubility in water. Specifically, it describes two approaches to synthesizing microporous materials for use in microporous water and evaluates the feasibility of using the resulting dispersions in biomedical applications.
Chapter One introduces the importance of solvating gases within a liquid medium for industrial applications. Zeolites and metal–organic frameworks are presented as ideal gas sorbents, and field of porous liquids is subsequently discussed to illustrate how these materials have been incorporated into a liquid medium to result in free-flowing liquids with permanent microporosity. Chapter Two proposes a thermodynamic strategy towards creating porous liquids in water whereby microporous nanocrystals with hydrophobic pores resistant to water intrusion and hydrophilic external surfaces can be stably dispersed in water while retaining the porosity of the solid-state porous material. Initial dispersions utilizing pure-silica zeolites and hydrophobic metal–organic frameworks are introduced. Next, we describe the synthesis and characterization of high-silica ZSM-5 nanoparticles for microporous water, yielding a dispersion with record-high oxygen capacities. Finally, we discuss efforts to reproducibly synthesize ZSM-5 with lower Si/Al ratios to probe the effects of framework composition on gas uptake and water intrusion behavior. Chapter Three introduces the utility of encapsulated microbubbles for ultrasound-based medical diagnostics and, in turn, the disadvantages of using these materials compared to more stable microporous frameworks. We discuss our collaborative efforts to quantify the nonlinear cavitation behavior of various microporous water samples and the potential towards using these materials as noninvasive pressure sensors. Afterwards, we describe additional investigations to examine the suitability of aqueous porous liquids as ultrasound contrast agents. Chapter Four addresses the challenge of improving biocompatibility in metal–organic framework nanoparticles. Factors influencing the biocompatibility and hydrophobicity of these materials are considered and we describe our synthetic efforts towards constructing frameworks with biocompatible components. Specifically, we explore strategies to introduce hydrophobicity in an existing magnesium-based framework by utilizing ligands with hydrophobic moieties.

Understanding and controlling heat transfer in solids is a fundamental challenge with broad implications for thermal management, energy efficiency, and the development of next-generation climate technologies. While the phonon gas model has long provided a framework for describing thermal conduction in crystalline solids, its applicability to many functional materials becomes limited by their chemical and structural complexity. In these systems, anharmonicity, large unit cells with anisotropic bonding environments, and stimuli-responsive behavior can give rise to transport regimes that even modern theoretical frameworks may struggle to predict or rationalize. This dissertation investigates the chemical factors that govern thermal transport, combining structural, thermophysical, spectroscopic, and mechanical characterization to examine the influence of molecular-level and extended structure. Through a series of structurally complex crystals that undergo solid-state phase transitions, we interrogate the elusive relationship between local dynamics and thermal conduction by tracking the evolution of vibrational mode character. This body of work ultimately seeks to leverage chemistry as a powerful lens to elucidate how structure shapes thermal transport in complex systems. To contextualize these studies, Chapter 1 surveys vibrational thermal transport models and introduces systems with alkyl chain bilayers that undergo phase transitions between ordered and dynamically disordered states. Chapter 2 establishes a methodological foundation for performing high-quality end-to-end thermal conductivity measurements, with particular emphasis on our development of single crystal deposition techniques to enable reliable thermophysical characterization across this family of layered materials. Building on this foundation, Chapter 3 examines thermal transport mechanisms in a two-dimensional metal–halide perovskite across its order–disorder phase transition. Our results reveal a crossover in energy transport from phonon propagation-dominated to wave-like tunneling regimes, demonstrating how the vibrational transport mechanism can abruptly shift even as the total thermal conductivity remains largely stable. Chapter 4 investigates the manipulation of thermal conductivity through systematic structural modification of layered perovskites, evaluating the roles of alkyl chain length, inorganic layer composition, and non-covalent chemical interactions at the organic–organic interfaces. Chapter 5 extends the transport picture to dialkylammonium halide salts as analogous bilayer systems with distinct chemical interaction networks, but comparable local chain environments and phase-change thermodynamics. Despite the similarities, we observe different thermal conductivity changes across their transitions, highlighting how the extended material framework directly impacts transport behavior in ways not fully captured by the molecular picture. Together, these results help us establish a conceptual framework for understanding thermal transport in chain-bilayer systems and point towards design rules for enhanced control over heat in complex phase-change crystals.

Proteins function as integral components of complex molecular networks, orchestrating a wide array of biological processes, including signal transduction, gene regulation, and metabolic control. Pathogenic mutations frequently perturb these protein-protein interaction (PPI) networks, compromising biochemical function. Consequently, modulation of PPIs with small molecules provides a highly promising framework for the development of targeted strategies in disease treatment. In this thesis, I describe our efforts to develop a novel class of multicovalent PPI modulators called COUPLrs. Using mobility shift proteomics, we identified multiple COUPLrs capable of selectively oligomerizing lineage-specific cancer mutations including NPM1c and EML4-ALK. We further highlight that molecular COUPLrs can systematically and unbiasedly identify proteins amenable to chemical complexation, binding to a variety of protein classes classically considered “undruggable.”

In Chapter 1, I provide a brief outlook of the critical role PPIs play in biological systems and disease, outlining traditional approaches to discovering small-molecule PPI modulators. I then focus on PROTACs and molecular glues as emerging therapeutic strategies capable of modulating PPIs by recruiting E3 ligases to disease-relevant proteins, discussing the advantages and restrictions of rationally designing and screening for new scaffolds.

In Chapter 2, I discuss our usage of COUPLrs in tandem with CONNECT proteomics to streamline the identification of hundreds of proteins amenable to covalent complexation with other proteins. We profiled our library of COUPLrs in 13 cancer lines representative of 10 tissue lineages, discovering differentially essential proteins which are highly promising for coupling. Finally, we optimized an advanced COUPLr for the oncogene EML4-ALK which led to the formation of a dimer of trimers and subsequent degradation of EML4-ALK.

In Chapter 3, I describe our recent efforts to take highly specific and potent small molecule ligands of TEAD and convert them into COUPLrs capable of modifying TEAD’s native PPIs. I provide an overview of the design considerations and subsequent evaluations of TEAD COUPLr treatments in a YAP oncogenic cancer cell line. Finally, I discuss proteomic evaluation of TEAD COUPLrs to identify potential binding partners.

Collectively, this thesis defines a novel class of PPI modulators which seek to streamline screening readouts and enhance the probability of identifying small molecule modulators capable of coupling proteins together. These COUPLrs provide a unique advantage over PROTACs due to their favorable drug-like properties. Compared to molecular glues, COUPLrs can be more readily rationally designed and screened for through a combination of mobility shift assays and proteomics.

Proteins are molecular machines that control nearly all cellular processes and physiological functions in the body, and their activity is tightly regulated by post-translational modifications (PTMs). O-Linked β-N-acetylglucosamine (O-GlcNAc) is an essential and dynamic, nutrient-responsive monosaccharide PTM that decorates serine and threonine residues on nuclear and cytoplasmic proteins. The addition and removal of O-GlcNAc are mediated by a single pair of enzymes, the writer O-GlcNAc transferase (OGT) and the eraser O-GlcNAcase (OGA). Although O-GlcNAc is broadly involved in diverse cellular processes and disease states, many protein- and site-specific functions of O-GlcNAc remain poorly characterized. Induced proximity strategies that selectively install or remove O-GlcNAc from desired protein targets offer a powerful approach to accelerate functional annotation and uncover therapeutic opportunities for O-GlcNAc. Here, I present work describing the development and application of a generalizable induced-proximity method using a destabilized nanobody-OGT fusion that enables targeted protein O-GlcNAcylation and direct investigation of protein-specific O-GlcNAc functions, uncovering regulatory roles in transcriptional activation and immune signaling. In Chapter 1, I provide a comprehensive review of the O-GlcNAc field. This chapter highlights the discovery of O-GlcNAc, the foundational studies that established its biological significance, and summarizes the biochemical and cellular biology of the O-GlcNAc cycling enzymes, OGT and OGA, and current understanding of protein- and site-specific functions of O-GlcNAc across biological pathways implicated in various human diseases. Efforts to therapeutically modulate O-GlcNAc are also discussed, with particular emphasis on neurodegenerative disorders. Finally, emerging technologies and future opportunities for investigating O-GlcNAc biology and translating mechanistic insights into therapeutic strategies are outlined. Chapter 2 details my efforts to develop a next-generation induced-proximity approach using a destabilized nanobody-OGT fusion (dnGFP-OGT) to selectively install O-GlcNAc on target proteins. This chapter outlines the design principles, optimization, and validation of this method. The generalizability of this strategy is demonstrated across diverse classes of O-GlcNAc-modified proteins, revealing which substrates can be efficiently O-GlcNAcylated through induced proximity. This strategy facilitates precise, target-specific modulation of O-GlcNAc and establishes a platform for investigating the functional consequences of O-GlcNAc across multiple cellular contexts, as explored in subsequent chapters. In Chapter 3, I describe the application of dnGFP-OGT to directly investigate the effects of protein-specific O-GlcNAcylation on seven transcription factors. Coupling this approach with luciferase reporter systems enables quantitative assessment of changes in transcriptional activation as a direct effect of O-GlcNAcylation. Using this strategy, I uncovered a nutrient-sensing inhibitory role for O-GlcNAc on the AP-1 transcriptional complex. This chapter further discusses the mechanistic impact of O-GlcNAc on AP-1 proteins, c-Fos and c-Jun, through protein- and glycosite-level analyses and highlights downstream implications for immune signaling. In Chapter 4, I examine the roles of O-GlcNAc in cellular stress response, transcriptional signaling, and circadian rhythm. Using targeted protein O-GlcNAc approaches in combination with glycosite mapping, this chapter explores how O-GlcNAc modulates these complex biological processes at the protein- and site-levels. Collectively, these studies highlight the contextual complexity of O-GlcNAc regulation and provide a framework for future investigations into how O-GlcNAc regulates dynamic pathways in mammalian systems. In Chapter 5, I investigate the regulation of OGT protein stability and alternative splicing. OGA inhibition and nutrient supplementation were found to trigger proteasome-dependent degradation of OGT, and the potential contributions of previously implicated E3 ligases were assessed. I describe mechanistic studies using systematic OGT tetratricopeptide repeat (TPR) domain truncations to identify determinants of OGT alternative splicing, and quantitative proteomics experiments were performed to identify candidate splicing factors that may be O-GlcNAc-modified to signal OGT splicing. Together, these studies provide further insight into cellular mechanisms controlling OGT abundance and expression.

The installation of a C–X bond (where X = F, Cl, Br, or I) modifies the physiochemical properties of molecules, often granting them improved bioactivity. Thus, halogenation reactions are highly valued in synthetic chemistry, particularly in the agricultural and pharmaceutical industries. However, synthetic halogenation often encounters significant challenges in achieving chemo and regioselectivity. Halogenation is also a prominent transformation in biology, present in all domains of life; to date, there have been over 5000 halogenated metabolites identified in the scientific literature. Nature has evolved halogenases, enzymes that perform C–X bond formation with remarkable efficiency and selectivity. While multiple classes of halogenases have been characterized in the past few decades, there are still halogenated metabolites biosynthesized via unknown C–X bond formation strategies, leading to gaps in our understanding of this important class of enzymatic transformations. In this thesis, we describe the characterization of diiron halogenases, an emerging subfamily of halogenase enzymes capable of radical-based halogenation. We use sequence-based information to determine and identify conserved features of these halogenases. Using information we gathered from our bioinformatic studies, we then biochemically characterize a new member of this halogenase subfamily, providing experimental evidence for the presence of a diiron cofactor. Together, these approaches expand our knowledge of enzymatic C–X bond formation and the reactivities of metal cofactors in biology. In Chapter 1, I provide a review of the current state of knowledge regarding enzymatic C–X bond formation. This chapter explores the three halogenase families: electrophilic, nucleophilic, and radical halogenases. This section provides an overview of the C–X bond formation strategies utilized by each family along with their substrate scope, accepted mechanisms, and structural bases for halogenation. This section ends with a discussion of the discovery of the first putative dimetal halogenase, CylC, and previous efforts to further our understanding of this new halogenase subfamily. Chapter 2 describes bioinformatic efforts to gain an understanding of key features of the protein sequences of the dimetal halogenase subfamily. By analyzing multiple sequence alignments, we identify distinct sequence motifs in dimetal halogenases that differentiate them from diiron N-oxygenases, their closest structurally characterized homologs. Prediction of the structures of dimetal halogenases suggests a basis for metallocofactor and halide binding, something previously obscured in older homology models. These findings provide an improved understanding of this enzyme subfamily and hypotheses to guide in vitro biochemistry. Chapter 3 describes the in vitro characterization of a CylC homolog and dimetal halogenase, NocO from nocuolactylate biosynthesis. We describe the purification of NocO with its cognate acyl carrier protein (ACP), NocM, and describe our initial efforts to characterize this protein alongside CylC. This section also discusses the difficulties associated with working with this halogenase subfamily, especially on preparative scales. We then detail the development of a coupled enzyme assay to generate ACP-tethered intermediates for the reconstitution of NocO’s chlorination activity and an exploration into its ability to use other anions for C–H functionalization. This chapter establishes important methods and a platform to guide work for metallocofactor characterization. In Chapter 4, we leverage the information we obtained from bioinformatics and the in vitro reconstitution of NocO’s chlorination activity to further characterize the nature of NocO’s metallocofactor. We discuss our efforts to optimize a platform for the expression of several unstable active site variants, as well as new insights gained into the residues responsible for metal binding. Finally, we present the first direct spectroscopic evidence of a diiron cofactor in this halogenase subfamily, thus confirming NocO’s identity as a non-heme diiron halogenase and the first diiron enzyme known to perform halogenation. Collectively, this thesis expands our knowledge of enzymatic C–X bond formation through bioinformatic analyses of the diiron halogenase family and the characterization of the first confirmed diiron halogenase. These findings could be used as a basis to further mechanistic studies of these enzymes and to ultimately expand enzymatic toolboxes for C–H functionalization.

Fibrous structures are among nature's most ancient and ubiquitous design motifs, recurring across length scales from nanometer-level protein filaments to centimeter-scale tendons and engineered textiles. In engineering these structures, the manufacturing process itself is not merely an intermediate step but an active determinant of molecular orientation, phase separation, and geometric form, factors that collectively govern the mechanical and functional performance of the resulting material. Across nearly all fiber fabrication platforms, solvents serve as a central yet often underexamined mediator linking molecular interactions to macroscopic structure. This thesis places solvent control at the forefront of fiber manufacturing and investigates how solvent-mediated processes can be exploited as active design parameters across three progressively larger length scales. At the molecular scale, the role of inorganic ions in restructuring the water network is harnessed to achieve sustainable protein denaturation and regeneration. At the single-fiber scale, a fiber spinning platform harnessing solvent-induced precipitation is designed to fabricate hierarchically aligned hydrogel microfibers with robust mechanical performance. At the scaffold scale, solvent-mediated spinning and removal of sacrificial fibers facilitates cell infiltration for thicker, more contractile cardiac ventricle models with programmable architecture. Together, these studies demonstrate that treating solvents as deliberate control variables, rather than passive carriers, provides a unifying framework for rational fiber manufacturing from the control of molecular conformation to organ-level function. Chapter 1 begins by reviewing common fiber fabrication platforms, their mechanisms, and structural design strategies, with an emphasis on how solvents influence fiber properties across scales. Building on this framework, Chapter 2 initiates this multiscale study at the molecular level, combining experimental, computational, and theoretical approaches to reveal that concentrated lithium bromide denatures proteins through an entropy-driven disruption of the surrounding water network rather than direct binding. Guided by this indirect mechanism, a closed-loop regeneration process is designed that yields a keratin gel capable of rapid solidification upon immersion in water, enabling sustainable protein manufacturing. Chapter 3 then moves to the single-fiber scale, introducing the wet rotary jet spinning (WRJS) system in which solvent-induced precipitation and a salting-out process produce hierarchically aligned hydrogel microfibers with flaw insensitivity, fracture resistance, and high mechanical strength. Extending to the macroscopic scaffold scale, Chapter 4 develops focused rotary jet co-spinning (FRJcS), a strategy that incorporates sacrificial fibers to increase scaffold porosity and promote cell infiltration in tissue-engineered cardiac ventricle models, and unveils that the heart's contra-rotating helical fiber architecture plays a critical functional role for pumping efficiency. Finally, Chapter 5 summarizes the findings, discusses limitations in cross-scale modeling and platform-specific transferability, and outlines future directions toward generalizable frameworks for solvent-guided fiber manufacturing.

Cereblon (CRBN) is the target of thalidomide derivatives that achieve therapeutic efficacy against some hematologic neoplasias by recruiting neosubstrates for degradation. These findings have motivated scientists in the field of targeted protein degradation to hijack CRBN by designing small molecules that bind to CRBN’s orthosteric thalidomide binding site to induce degradation of neosubstrates implicated in diseases. Despite the success of these orthosteric ligands, challenges remain in broadening the repertoire of proteins degradable by CRBN and enhancing the efficacy and selectivity of these drugs. Furthermore, efforts in the field have vastly focused on designing ligands to target the thalidomide binding site, leaving other regions of CRBN largely understudied. Allosteric ligands are significant contributors to key therapeutic protein targets, providing mechanisms to enhance efficacy of orthosteric ligands, overcome resistance mutations, and circumvent off-target toxicities. Here I present the identification and characterization of a cryptic allosteric site on the E3 ligase adapter protein CRBN that is ligandable by small molecule SB-405483 and its derivatives. In Chapter 1, I introduce allostery and the implementation of allosteric ligands in representative cancer targets. I then detail the discovery and development of orthosteric CRBN molecular glues that degrade G-loop containing proteins. Finally, I discuss the role of CRBN allostery for targeted protein degradation modalities as well as the identification of orthosteric ligands that degrade CRBN neosubstrates that lack the canonical G-loop motif. In Chapter 2, I describe the discovery of the cryptic allosteric site and allosteric ligand SB-405483 as well as subsequent in vitro validation and crystal structure studies. I then discuss cellular experiments that reveal SB-405483 enhances orthosteric ligand engagement with CRBN and subsequently potentiates the degradation of neosubstrate CK1α. In Chapter 3, I investigate the therapeutic implications of allosteric modulation of CRBN by SB-405483. I first demonstrate SB-405483 can be used to accelerate the discovery of CRBN neosubstrates by global proteomics. I then elucidate that SB-405483 alters the degradation landscape of orthosteric ligands, potentiating the degradation of some neosubstrates while inhibiting the degradation of others. I finally discuss cryo-EM efforts which establishes the mechanism by which SB-405483 elicits its allosteric effects. In Chapter 4, I discuss ongoing biological testing of SB-405483 analogues with the goal of developing superior allosteric CRBN ligands. I first describe biological assays used to assess allosteric CRBN ligands, testing their affinity for CRBN, impact on orthosteric ligand binding, and influence on protein degradation. I then perform analysis on correlations between different biological assays and their implications. Finally, I shortlist superior allosteric CRBN ligands for future investigation. Throughout the chapter I draw from concepts and findings from allosteric ligands in the GPCR field, establishing these concepts in the framework of CRBN allostery.

Dissertation Advisor: Professor Daniel G. Nocera

Kristopher Glen Reynolds

Time-Resolved Spectroscopic Detection of High Energy Intermediates in Energy Conversion and Photoredox Reactions

Abstract All reactions of interest to the chemist occur via high energy transient intermediates. Understanding the nature and dynamics of these transient species is a key step in elucidating relevant reaction mechanisms. However, due to the often extremely short lifetime of those intermediates, their detection requires spectroscopic tools which are commensurate with the timescale of their formation and consumption. Herein, I employ transient absorption spectroscopy across a wide variety of timescales and spectral ranges to uncover the nature and dynamics of, elusive and sought after, high energy transient intermediates in both energy conversion and photoredox transformations. In Chapter 1, I provide a general overview of photochemistry and transient spectroscopy which is intended to set the broader context in which the remainder of this work exists. In Chapter 2, I briefly cover the theoretical foundations upon which this work rests. The aim of this chapter is to familiarize the reader with the key concepts of electronic spectroscopy as well as the photophysical and photochemical phenomena which will be used to interpret the spectroscopic data in the chapters to follow. In Chapter 3, I discuss the use of transient infrared spectroscopy to uncover the mechanism of the photochemical oxidation of bicarbonate. These studies reveal the first known spectroscopic evidence of the bicarbonate radical as a result of single electron oxidation and its subsequent evolution of CO2 and O2. The work presented here conclusively shows that the single electron oxidation of bicarbonate can serve as a means to clearing bicarbonate in CO2 electrolytic cells addressing the carbonate problem, a key bottleneck toward the realization of efficient low temperature CO2 reduction. In Chapter 4, ultrafast transient absorption spectroscopy is employed to uncover the mechanisms by which open-shell photoreagents engage redox recalcitrant substrates despite both thermodynamic and kinetic limitations. Transient absorption spectroscopy reveals that all radical ions studied herein exhibit extremely short excited state lifetimes when excited at their lowest energy optical transition in the red, too short in fact to engage in diffusion limited chemistry with substrates. However, blue light excitation of these radical ions revealed the universal formation of long lived (>6 ns) solvated electrons in the NIR, the lifetime of which was quenched by extremely hard to reduce substrates such as fluorobenzene. Furthermore, the formation of closed shell decomposition products originating from the radical ions under certain conditions leads to the formation of long lived and closed-shell photoreagents competent of driving challenging redox chemistry. Together this work demonstrates that the observed reactivity from radical ions to drive extremely challenging reactions originates from both the generation of solvated electrons and/or photodecomposition of the radicals to a closed shell species. In Chapter 5, ultrafast transient absorption spectroscopy in conjunction with high level quantum chemical calculations are employed to determine the origins of the ultra-short excited state lifetimes of radical ions. Ultrafast transient absorption spectroscopy on the radical anions of a series of structurally related dicyanoacenes as well as select radical cations reveal that the ground electronic state is repopulated in a few picoseconds after excitation. In such cases quantum chemical calculations reveal the presence of low-lying conical intersections between the lowest energy doublet excited state and the ground state which are responsible for the ultrashort lifetimes measured by transient absorption spectroscopy. Furthermore, this work provides general classifications of the types of structural distortions that are responsible for the conical intersections. In Chapter 6, additional studies of the dynamics of photo-induced reactivity of select photoredox platforms are discussed. Examples of both intramolecular transformations arising from LMCT or intramolecular energy transfer as well as intermolecular reactivity arising from the interaction of an excited state or photo-induced species with another are presented. Lastly, possible project directions for future students in the Nocera lab toward the generation and detection of the CO2 radical anion are discussed.

Enzymes, as paragons of efficient and selective homogeneous catalysis, are an enduring source of inspiration for chemists. Decades of biochemical studies have elucidated fundamental principles underlying enzymatic catalysis, raising the enticing prospect that small molecules designed in accordance with these principles might begin to approximate the catalytic performance of their macromolecular counterparts. Here, we report efforts at the interfaces of organic chemistry, computational chemistry, and combinatorial mathematics to harness three enzymatic principles— geometric preorganization, mechanistic generality, and cooperativity—in reactions catalyzed by organic small molecules.

In Chapter 1, we report that a hydrogen-bond-donor (HBD) catalyst accelerates the SN2 step of an enantioselective Michaelis–Arbuzov reaction by recapitulating the enzymatic principle of geometric preorganization. Mechanistic and computational investigations show that the catalyst attenuates the reactivity of the chloride nucleophile but still accelerates the rate-determining dealkylation step by organizing the phosphonium cation and chloride anion into a geometry poised for entry into the SN2 transition state. This work constitutes the first demonstration of catalytic enantiocontrol over phosphonium dealkylation, establishing a new platform for the synthesis of P-stereogenic compounds.

In Chapter 2, we present the development of a chiral HBD catalyst that exhibits mechanistic generality by inducing high selectivities across two distinct steps in the synthesis of P- and C-stereogenic α-aminophosphonates. The same chiral scaffold engenders effective stereoinduction across two catalytic transition states that not only present antipodal electronic demands of the catalyst-bound anion, but also proceed through different catalyst molecularity. Computational modeling reveals that the catalyst must adopt at least three distinct conformations along the reaction coordinate, repurposing its catalytic residues in each to scaffold rich networks of attractive noncovalent interactions that selectively stabilize the transition states in each selectivity-determining event leading to the major product.

In Chapter 3, we describe an effort to accelerate the discovery of cooperative catalysis, wherein multiple catalytic units operate synergistically. We disclose a pooling–deconvolution algorithm, inspired by group testing, that identifies cooperative catalyst behavior at low experimental cost while accommodating potential inhibitory effects among catalyst candidates. The workflow was validated first on simulated cooperativity data and then by experimentally recovering previously documented cooperativity between organocatalysts in an enantioselective oxetane-opening reaction. The workflow was then applied in a discovery setting to a Pd-catalyzed decarbonylative cross-coupling reaction, identifying several ligand pairs that promote the target transformation at substantially lower catalyst loadings and temperatures than had previously been achieved with single-ligand systems.

In Chapter 4, we report the development of general Pd-catalyzed decarbonylative Suzuki–Miyaura cross-couplings between (hetero)aroyl chlorides and (hetero)arylboronic acids under mild conditions, leveraging cooperativity between a pair of phosphine ligands. Experimental and computational studies support a ligand-relay mechanism in which each phosphine preferentially promotes different elementary steps. These results validate empirical, mechanism-agnostic screening through pooling−deconvolution as a means of identifying synthetically enabling catalytic methods.

Atomically thin semiconducting transition metal dichalcogendides (TMDs) provide a versatile platform towards the realization and study of correlated electronic and excitonic phenomena. Stacking these two-dimensional materials into van der Waals heterostructures with control over the composition of the devices down to individual atomic layers enables the exploration of electronic and excitonic interactions, facilitating experimental investigations of quantum many-body phenomena. This dissertation focuses on the realization and characterization of interacting electrons and excitons in layer-engineered TMD heterostructures. In a monolayer TMD device, we demonstrate the formation of a zero-field quantum Wigner crystal, a hallmark correlated electronic phase, and characterize its melting into a Fermi liquid through an intermediate microemulsion phase using optical spectroscopy. Beyond the monolayer, we investigate bilayer Wigner crystals in the weak-coupling limit by inserting a thin hexagonal boron nitride (h-BN) spacer layer between two TMD layers. These bilayer Wigner crystals are stabilized at specific commensurate electron density ratios between the two layers (1:1, 3:1, 4:1, and 7:1) and are stabilized to higher densities than the monolayer due to the interlayer interactions. Additionally, we explore exciton-charge interactions in a bilayer TMD device with a monolayer h-BN spacer via a solid-state Feshbach resonance. By adjusting the charge and exciton densities, we probe the resulting exciton-exciton interactions mediated by exciton-charge interactions, observing both repulsive and attractive interaction regimes. We also characterize interlayer excitons in the same device structure, observing large Stark shifts, selective hybridization with intralayer excitons, and long lifetimes. Furthermore, we investigate a novel contact-engineering approach employing charge-transfer doping with another proximal atomically thin material towards achieving efficient electrical contacts to a monolayer TMD. Lastly, we provide an outlook on potential future directions, emphasizing the opportunities for engineering correlated excitons and exploring further quantum many-body electronic and optical phenomena. These results emphasize the potential of layer-engineered TMD devices for exploring fundamental quantum phenomena and opens pathways toward their use in quantum optoelectronic technologies.