Chemistry, 1926-2026

Compound identification is important in many fields, from medicine to legal. For the United States Pharmacopeia (USP) precise, accurate, and accessible compound identification methods help achieve its goal of uniformity in the creation of medicine. To this end USP worked with Mestrelab to develop USP-ID, a software that conducts quantitative analysis on NMR spectra. The software is still under development and this paper explores its efficacy in relation to metabolomic samples, specifically horse serum samples. While the calculated spectra show promise with average R-squared (R2) values over 0.8, there is more work to be done to elicit confidence in the results and prevent false positives.

Copper is an essential metal nutrient required by all cells to maintain proper homeostasis. Some cancer cells exhibit altered copper metabolism, which render then suspectable to a distinct form of cell death induced by excess copper known as cuproptosis. Thus, small molecules which can increase the amount of copper in cells, known as copper ionophores, have emerged as promising therapeutic agents to eliminate cancer cells via cuproptosis. While untargeted copper ionophores have some intrinsic selectivity towards cancer cells, they often cause detrimental off-target metal accumulation in unwanted tissues. Therefore, to fully realize the therapeutic potential of copper ionophores, strategies to direct these agents to specific cell types by targeting overexpressed cancer cell receptors are needed. Here, we report two novel targeted copper ionophores—an antibody-drug conjugate (HER2-GTSM(Cu)) and a small-molecule drug conjugate (FAP-GTSM(Cu))—that functionalize the copper ionophore Cu-GTSM. To evaluate our targeted ionophores, we utilized a combination of fluorescence imaging and inductively coupled plasma mass spectrometry assays that demonstrate Fibroblast Activation Protein (FAP)-dependent selective copper accumulation of FAP-GTSM(Cu) in FAP-overexpressing cancer cells. Taken together with cell viability data, these results indicate that Cu-GTSM exhibits higher toxicity at lower doses, whereas FAP-GTSM(Cu) enables controlled, targeted copper delivery. The designed platform is inherently modular and can be adapted to target any therapeutically actionable biomarker that is overexpressed on cancer cells, thereby broadening the translational potential of this work.

Within catalysis, transition-metal complexes are powerful due to their versatility and robustness, where modification of the ligand or metal can tweak catalytic activity and pathways. Redox-active ligands such as PDI are attractive as they facilitate metal-ligand cooperation and stabilize the compound. Over the years, a variety of PDI ligands have been investigated, where altering its electronics and steric bulk can increase activity or suppress undesired reaction pathways. In particular, the Chirik group has demonstrated how increasing steric bulk drives selectivity and catalytic activity in (PDI)Fe for [2+2] cycloaddition. [2+2] cycloaddition generates cyclobutane derivatives, which are building blocks for natural product and petrochemicals. Previous work in the group demonstrated that increasing steric bulk in PDI suppresses the undesired β-H elimination pathway in [2+2] cycloaddition. Since the group has not explored PDI ligands bulkier than iPrPDI , this work describes the synthesis of sBuPDI and i-PentPDI ligands and their metalation onto Fe. The reduced (PDI)Fe complexes were found to have lower catalytic activity than the parent (iPrPDI)Fe precatalyst in [2+2] cycloadditions.

As traditional semiconductor transistor models approach the physical limit of innovation, the synthesis and characterization of materials useful for quantum computing grow more significant. 2M-WS₂ is a topological superconductor synthesized using a two-step ‘top-down’ procedure similar to many other metallic-phase transition metal dichalcogenides. Because of its lower reagent costs relative to other materials, 2M-WS₂ represents an economically viable template for research into synthesis optimization and organic molecule intercalation. Reagent concentrations and temperature conditions are modified to study their effects on crystal size and phase purity, and halogenated amines are intercalated into the van der Waals gaps of the material to study the intermolecular forces driving intercalation. The results of these condition scans provide a clear direction for future transition metal dichalcogenide research, both for synthesis optimization as well as for studying low-dimensional material structure and properties.

Despite the decades of research into Alzheimer’s Disease (AD), a neurodegenerative disorder growing in prevalence, an effective treatment option has remained elusive. Previous studies which have analyzed the disorder from a metabolic perspective have treated brain regions shown to be structurally heterogenous as singular units. Two regions relevant to the ongoing discussion of AD whose sub-regional variation have been overlooked are the white matter fiber tracts and cerebellar layers. This thesis applies matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) at a spatial resolution of 10 μm to resolve the lipid and metabolite profiles of these sub-regions, and how they change with aging and AD. Three distinct datasets were analyzed: a base-line wild-type, an aging comparison (2-month vs 26-month C57BL/6J), and an AD comparison (age-matched 15-month-old control vs 5XFAD). A principal component analysis established variation between the anterior and posterior fiber tracts as well as the molecular and granular cerebellar layers. In the aging analysis, low NAD+/NADH ratios in posterior brain regions were mechanistically tied to energy state (ADP/ATP and AMP/ATP ratios) and reduced unsaturated fatty-acid (FA) decline via a compensatory pathway sustaining FA desaturation. When applying this pathway to the AD mouse model, sharp declines in FAs were observed in posterior regions despite low NAD+/NADH values. The dysfunction of the Electron Transport Chain (ETC) which causes a rapid accumulation of NADH and disrupts ATP production was suggested as the driver against the activation of the compensatory lipid metabolism pathway.

Progress in the detection of molecules in interstellar environments is advanced by stateresolved laboratory spectroscopy of the candidate molecules. Gas-phase precision spectroscopy is challenged, however, by the size and complexity of the probed molecules. This paper outlines the construction, testing, and application of a mid-infrared (IR) cavity-enhanced frequency comb spectrometer for measurement of complex molecules cooled to cryogenic temperatures through collisions with helium buffer gas. The instrument sources 6-11 µm comb light, and spectra are measured using a Fourier transform spectrometer. The molecules here measured garner interest both as spectroscopic problems as is the case of ethanol, a model of the interactions between large-amplitude internal motions in a nonrigid molecule, and as astrochemical problems as is the case of naphthalene and acenaphthene, both polycyclic aromatic hydrocarbons (PAHs) that may be identified in interstellar environments. High-resolution mid-IR spectra of these molecules are presented and fit to model Hamiltonians.

The direct C(sp3)–H arylation of amino acid scaffolds offers a concise route to stereochemically defined unnatural amino acids, but the strong, polar, and densely functionalized C–H environment of these substrates is poorly suited to conventional hydrogen atom transfer. This thesis investigates whether excited-state proton-coupled electron transfer (PCET) at an iridium polypyridyl carboxylate, in which proton and electron transfer are partitioned between a pendant carboxylate and the iridium center, can be interfaced with nickel metallaphotoredox catalysis to arylate such substrates under visible-light irradiation. A library of twelve 2,2′-bipyridine (bpy) carboxylate ligands (L1–L12) spanning electron-withdrawing to electron-donating substituents was synthesized using Negishi and P(V)-mediated cross-couplings and coordinated to an Ir(dF(CF3)ppy)2 scaffold. Giese-trapping benchmarks against strained C–H substrates (cubane, cyclobutanes and cyclopropane) identified the CF3-substituted bpy as the most capable abstractor and established a threshold abstracting strength below which the electron-rich complexes were uniformly inactive. In the dual-catalytic arylation of Boc-Pro-OMe with an electron-deficient bromopyridine, systematic screening of base, solvent, nickel ligand, and ligation protocol identified K2HPO4, acetonitrile, and pyridyl carboxamidine (PyCam) as the productive combination, delivering up to 85% analytical yield. Two variables initially masked as reproducibility issues proved mechanistically central: water content in the heterogeneous K2HPO4 base, which is required for phase-transfer deprotonation of the Ir(II)-CO2H intermediate, and the equivalence of in situ and preformed Ni(PyCam)Br2 which rules out a Cl•-mediated HAT pathway and supports PCET as the operative radical-generation step. Preliminary scope on scale-up demonstrated that the optimized conditions extend to a second amino acid substrate (Boc-Met-OMe) while exposing a scale-dependent erosion of yield. Together, these results establish iridium carboxylate PCET as a viable radical-generation modality for nickel-mediated C(sp3)–H arylation in the amino acid regime and define the operational window within which the two cycles are compatible.

The circuits of the future will be optical, capable of transmitting information with larger bandwidths and more efficiency than the electronic circuits that currently connect our world. Photonic crystals (PhCs), synthetically fabricated materials with a periodically alternating dielectric lattice, can control the behavior of incident light based on their photonic band structure, or dispersion contour. The physical structure of PhCs can be tuned via dispersion engineering to selectively change their light guiding properties, an exciting phenomenon that will make optical circuits a reality. A process flow for the nanofabrication of polymer PhCs and a new spectroscopic setup to characterize their dispersion contours is presented. This setup will enable the first measurements of the full photonic band structure of polymer PhCs to better understand the link between chemical structure and photon dispersion.

Biomolecular condensates (condensates) are complex subcellular structures that emerge from the liquid-liquid phase separation of intrinsically disordered proteins (IDPs). Condensates have been implicated across both normal cellular function and disease. Given that the processes by which biomolecular condensates form are not fully understood, it is of interest to elucidate how the sequence composition of constituent IDPs influence their material properties and underlying physical behavior. However, modeling condensate systems via standard molecular dynamics (MD) techniques is challenging, as simulating under the canonical ensemble induces finite-size effects (FSE) which alter system thermodynamics and make accurately reproducing in vivo conditions difficult. In this thesis, I propose a methodology for predicting relevant kinetic and thermodynamic parameters of condensates in the macroscopic limit by applying the modified liquid droplet (MLD) framework to ensembles of finite-size MD simulation trajectories. To this end, I simulated three variants of heterogeneous nuclear ribonucleoprotein A1 low-complexity domain (HNRNPA1-LCD) across multiple system densities and volumes to calculate FSE-resolved nucleation barrier height, critical nucleus size, surface tension, and dilute phase density. I find that the emergent properties of HNRNPA1-LCD condensates are modulated by sequence variation, and that their observed behavior can be rationalized from the physicochemical properties of the introduced mutations. In addition, I find that the performance of the MLD framework is sensitive to simulation conditions, as high-density, low-volume regimes yield especially severe FSE that are difficult to resolve.

Theoretical studies of reaction rates in a magnetic field have gained renewed interest due to recent experimental observations of magnetic effects and the development of frameworks for chemical dynamics that include pseudomagnetic forces. In this thesis, I estimate the contribution from a magnetic field to the transmission factor for a reaction associated with a double-well potential constructed under the Empirical Valence Bond (EVB) model and analyze the low-friction phenomenon of rate increase in a magnetic field. By studying the dynamics around the transition state saddle point, a correction to the rate constant is obtained. The correction is given by the ratio of the positive roots of the characteristic polynomial with and without the magnetic field and may be considered the magnetic analogy to the Grote-Hynes transmission coefficient for friction. The work on this magnetic correction is concluded with a derivation of a closed-form expression for weaker fields. For this adiabatic reaction model problem, I find that above a threshold field, the field universally slows reactions. Below this threshold, I observe that for a symmetric potential, the field may appreciably increase the rate in the low friction regime. The mechanism of this rate increase is analyzed through a position autocorrelation function, and ultimately a promising connection is found between the field dependence of the orientational decorrelation and the field dependence of the rate. A compelling continuation of this work would be the extension of the presented analysis of rates in a magnetic field to nonadiabatic reactions, where magnetic field effects are strongest.

Industrial catalysis is reliant on transition metal catalysts, which are often scarce, expensive, environmentally detrimental, and toxic. Though traditionally viewed as not well-suited for catalysis, research in the past several decades has illuminated the potential for main group elements to facilitate catalytic transformations. Silicon, the second most abundant element in the Earth’s crust, would represent a sustainable, cheap, and nontoxic replacement for transition metals. In particular, silylenes are of interest due to their amphoteric site which resembles the partially filled d-orbitals of transition metals, however, the body of work on isolable silylenes is small. This work targeted the synthesis of a novel silylene supported by an LX2 (O,O,O) xanthene-based pincer ligand, which would represent the first oxygen-substituted monosilylene and the first neutral silylene within a pincer ligand framework. Dichlorosilane and hydridochlorosilane complexes within the novel ligand scaffold were synthesized. Attempts to access the corresponding silylene revealed that these silanes are highly robust, and are exceptionally privileged for substitution reactivity due to steric accessibility and electronic deficiency at the silicon center.

Two-dimensional (2D) materials exhibit tunable properties, high surface-to-volume ratios, and high mechanical strength, making them attractive for applications in electronics, catalysis, and energy storage. However, conventional methods like mechanical exfoliation or high-temperature synthesis are limited in scalability and restrict the range of accessible 2D materials, motivating the development of alternative synthetic approaches. Among these, chemical deintercalation of layered compounds containing interlayer alkali ions offers a potential method of producing tunable, high quality, and ultrathin sheets. Still, the role of the intercalated cation in determining exfoliation outcomes remains incompletely understood.

Here, ACrO2 (A = Li, Na, K) is investigated as a model system and undergoes three chemical deintercalation and exfoliation methods: solvent reaction, proton exchange, and oxidative extraction with acid treatment. Powder X-ray diffraction was used to characterize the structural changes of products located at the bottom of the vial after chemical processing, alongside transmission electron microscopy to track the structural and morphological changes of the exfoliated nanosheets found in the supernatant. It is shown that all alkali metals allow the formation of exfoliated nanosheets that adopt a crystalline Cr2O3 structure. Still, bulk LiCrO2 remains largely unchanged, while NaCrO2 and KCrO2 undergo significant deintercalation and structural transformations following various chemical treatments to form crystalline CrOOH. These findings highlight the crucial role of interlayer cations in determining exfoliation outcomes and could potentially pave the path for controlled nanosheet synthesis in layered oxides for scalable 2D material production.

Per- and polyfluoroalkyl substances (PFAS) are a highly stable and environmentally persistent class of compound that humans are frequently exposed to by contaminated wastewater sludge as fertilizer in agriculture. Current methods of detecting and processing PFAS in wastewater treatment plants are costly and require niche expertise, motivating the need to turn to protein-based biosensors as a quick, accessible, and on-site form of reliable testing. To detect and remediate PFAS types rapidly using an optical biosensor, this thesis seeks to screen varying proteins known to interact with PFAS as potential sensing modules for a biosensor in silico and study Acidimicrobium TMED77’s reductive dehalogenase (T7RdhA) in vivo as a potential fluorescent biosensor that can both detect and remediate varying PFAS types. Through screening, it was determined that peroxisome proliferated activated receptor  (PPAR-), T7RdhA, and Acidimicrobium Sp. 6 RdhA (A6RdhA) were proteins with the highest potential to serve as a sensing module for a biosensor. When circularly permuted green fluorescent protein (cp.GFP) was inserted into T7RdhA at a site of high variability and surface accessibility, it was determined that while there is a change in fluorescent signals, there is no clear gradient that directly correlates increasing PFAS concentrations to a gradient change in fluorescence. Overall, these results provide foundational preliminary work in studying how T7RdhA can serve as both a detector and remediator of PFAS through real-time biosensing.

Degradable plastics are vital for the shift to a circular materials economy. The insertion of ketones, a known photodegradable functional group, into polymer backbones is one strategy to synthesize thermoplastic polymers with inherent degradability. This strategy is however limited in the literature to metal-mediated methods or those that rely on carbon monoxide monomer. This work develops a metal-free, controlled, light-initiated RAFT polymerization to synthesize copolymers of poly(methyl acrylate) with low amounts of randomly incorporated tert-butyl vinyl ether. This novel polymer microstructure is shown to undergo hydrolysis, affording poly(methyl acrylate-co-hydroxyl). Oxidizing the hydroxyl groups gives rise to the poly(ketone); however, full conversion to ketone was not observed via the oxidation methods tested. However, this work explores two additional degradation pathways starting from poly(MA-co-OH). The hydrolyzed copolymer readily degraded via photooxidative methods, and further work is ongoing to probe proton-coupled electron transfer (PCET) reactivity to cleave the backbone of poly(MA-co-OH). Overall, this light-driven approach offers versatile polymer microstructures that can degrade, thus paving the way for the development of sustainable materials in our economy.

Total synthesis has emerged as a leading strategy to access medicinally-relevant natural products minimally available by isolation. Among natural product classes, steroids stand out for their variety of therapeutic effects. Recent studies have elucidated the structure of “taccalonolides,” a family of heavily functionalized, complex steroids with intriguing chemotherapeutic activity. The Sorensen group is interested in becoming the first to synthesize a taccalonolide in full. This thesis aims to employ principles of Diversity-Oriented Synthesis to produce a steroid with powerful functional group handles that permit access to bioactive taccalonolide-like derivatives. We envision a Michael Addition cascade with a previously unreported epoxide-opening terminating step could establish the taccalonolide-like trans-hydrindane system while building much of the steroid’s complexity. This strategy features the use of biocatalysis, organometallic substitution, and materials from the chiral pool to ensure enantiomeric control. So far, results have produced and isolated a cyclopentene precursor to the desired epoxide-containing fragment with two critical stereocenters set, ensuring stereocontrol in future steps.

Inspired by the prevalence of secondary coordination sphere interactions in nature, prior work in the Roque group has developed a Ni(II) bis(trifluoromethyl) complex with an appended photosensitizer in the secondary coordination sphere. The secondary coordination sphere photosensitizer has been shown to unlock new photophysical pathways which facilitate an unprecedented light-driven Ni-CF3 bond homolysis. This work further studies this complex by probing the effects of appending electron-donating and withdrawing groups on both the photosensitizer and the ligand backbone. These studies provide further support for the proposed photophysical mechanism and demonstrate that ligand derivatization can have noticeable impacts on the solubility, reactivity, and photophysics of the complex. The insight from this work helps to inform key design principles for future iterations of this concept. Additionally, work towards developing substrate scope for the migratory arylation of alcohols is presented.

Lenacapavir, a novel drug for HIV, is administered as only a twice-yearly injectable, and it has shown to be 100% effective in clinical trials. However, its reliance on palladium catalysts to synthesize key fragments of lenacapavir contribute to its immense cost, thus presenting a significant barrier to accessing advanced HIV treatments. Expanding global access to lenacapavir has motivated replacement of palladium conditions with more sustainable and affordable earth-abundant transition metal catalysts such as nickel to substantially decrease the cost of synthesis. In particular, this thesis targets the Sonogashira C(sp)–C(sp2) coupling to synthesize Fragment A. Previous studies have shown bidentate N-donor ligands such as bipyridine to be effective in nickel-catalyzed Sonogashira cross-couplings; interest has thus been drawn to α-diimine (DI) ligands, due to their affordable synthesis and high modularity. This work explores the use of substituted DI ligands and well-defined nickel complexes for catalyzing a regioselective Sonogashira coupling on model bromopyridine substrates relevant to Fragment A. Well-defined nickel complexes — including bis ligand complexes, (MesDI)NiMe2, and (MesDI)Ni(η2-alkyne) complexes — were all synthesized and demonstrated catalytic competence, suggesting the presence of several potential pathways for entering the catalytic cycle. DI ligands therefore proved to be effective alternatives for nickel-catalyzed, regioselective Sonogashira couplings of model substrates applicable to improving the synthesis of lenacapavir.

Biomolecular condensates are stabilized by the collective action of short, low-affinity interactions distributed across intrinsically disordered protein sequences, precisely the interaction grammar that short peptides are chemically designed to engage. This conceptual alignment makes tetrapeptides and other minimal sequence fragments natural candidates for condensate modulation: they are readily synthesized, chemically tunable across a vast combinatorial space, and small enough to partition into the dense phase without the steric constraints that limit larger molecules. Yet whether short peptides act as passive occupants of the condensate milieu or as active, sequence-specific perturbants of its internal architecture remains an open question. Here, we use Mpipi coarse-grained molecular dynamics simulations to characterize how a combinatorial library of tetrapeptides drawn from a low-dimensional sequence space actively perturbs two prototypical LCD condensates: hnRNPA1-LCD and FUS-LCD. We find that tetrapeptide partitioning into the condensate is governed primarily by aromatic hydrophobicity, which drives exponential increases in uptake, while charge plays a more delicate secondary role. Also, the spatial mode of perturbation is controlled not by peptide composition alone but by the host protein’s aromatic sequence architecture: the same tetrapeptides produce discrete, hotspot-concentrated disruptions in A1-LCD where charged and aromatic residues are clustered, and diffuse, sequence-wide perturbations in FUS-LCD where aromatics are regularly spaced. This architectural dependence is confirmed by binding–disruption alignment analysis, where spatial coupling between peptide binding and contact remodeling is strong in A1-LCD and collapses in FUS-LCD. Despite this local remodeling, the condensates’ hub–clique network topology remains invariant across all conditions, indicating it is an emergent collective property of the condensed state rather than a tunable structural feature.

Suzuki-Miyaura cross-coupling is one of the most important named chemical reactions used in industrial synthesis. Although palladium catalysts are most often used for these reactions, catalysts that instead use first-row metals are of interest in part because they may offer complementary reactivity to the shortcomings of palladium catalysts, in addition to being more sustainable, lower cost, and usually less toxic. This work highlights nickel catalysts bearing phenoxyimine (FI) and phenoxythiazoline (FTz) ligands for C(sp$2$)–C(sp$3$) cross-coupling reactions, specifically expanding the scope of the Chirik group’s previously reported nickel-catalyzed Suzuki-Miyaura cross-coupling method from boronic acids and boronic neopentyl glycol esters to boronic pinacol esters. These substrates are of particular interest given their ease of installment on highly functionalized scaffolds via Miyaura borylation. Reaction conditions are optimized for this specific type of reaction, the reactivity of FI and FTz ligands are compared, and the expanded nucleophile scope is briefly investigated. The results herein demonstrate the applications these nickel complexes have toward C(sp$2$)–C(sp$3$) Suzuki-Miyaura cross-coupling and establish a method that can be used to cross-couple boronic pinacol esters.

Modified nucleotides in tRNA are diverse and abundant, and aberrations are implicated in several human diseases. However, the physiological role of these modified nucleotides remains poorly understood. Previous studies have shown that S. cerevisiae strains containing multiple knockouts of tRNA modifying enzymes display temperature sensitive growth due to degradation of hypomodified tRNAs through the rapid tRNA decay (RTD) pathway. Based on high throughput screens indicating negative genetic interactions, five single knockout and five double knockout strains were generated. Single knockout strains pus1-Δ, trm1-Δ, tan1-Δ, trm8-Δ, and maf1-Δ and double knockout strains pus1-Δ dus3-Δ and trm1-Δ dus2-Δ did not exhibit temperature sensitive growth. In contrast, double knockout strains, trm8-Δ dus3-Δ, tan1-Δ dus2-Δ, and maf1-Δ dus2-Δ exhibited temperature sensitive growth. tRNA sequencing was used to determine tRNA abundances to assess whether tRNA stability was affected in the tan1-Δ dus2-Δ strain. While sequencing results were largely inconclusive, this work provides a characterization of several knockout strains and a basis for further investigation into the tan1-Δ dus2-Δ strain.