Singly-reduced iridium chromophores: synthesis, photophysics, and photochemistry
One-electron reduced photosensitizers have been invoked as key intermediates for photoredox catalysis including multi-photon excitation and electrophotocatalytic processes. To the best of our knowledge, however, such a mono-reduced photocatalyst has not been isolated across any class of photoredox catalysts. Thus, focusing on some of the most widely employed photosensitizers –iridium(III) chromophores, we aimed to investigate their corresponding one-electron reduced species. Specifically, we sought to identify their (1) structural identities, (2) ground state electronic configurations, (3) photophysical properties, and (4) involvement in multi-photon excitation processes. Towards this end, a family of mono-reduced heteroleptic iridium chromophores were crystallographically and spectroscopically characterized to reveal a ligand-centered reduction as their ground states. Furthermore, an unexpected long-lived excited state was observed via transient absorption spectroscopy suggesting that both the conventional iridium photocatalyst and its singly-reduced form can participate in a photoinduced bimolecular electron transfer. These studies demonstrate the first characterization of thus far elusive reduced iridium chromophores, providing opportunities to revisit a commonly invoked mechanism for photoredox catalysis.
Pablo Garrido Barros
California Institute of Technology (Caltech)
Orchestrating protons and electrons for selective electrocatalytic reductions
Electrocatalytic reduction of organic and small molecule substrates offers a promising approach to utilize renewably-sourced energy for sustainable synthetic schemes. However, at the harsh potentials required to promote these transformations, side reactivity often becomes dominant. Concerted proton-electron transfers (CPET) are an exciting opportunity to both operate at milder conditions and by pass high energy intermediates otherwise generated via stepwise electron and proton transfers, opening up new reaction pathways. While such approaches have been successfully applied in the context of chemical and photocatalytic reactions, adaption to electrochemical contexts has proven challenging; an inherent barrier is the thermodynamically favorable and kinetically facile hydrogen evolution reaction mediated by the electrode under the conditions required to form the reactive targeted bonds. This talk describes the design of a molecular CPET mediator via synthetic integration of a redox mediator and a Brønsted base, and its application towards the electrocatalytic reduction of unsaturated organic substrates and dinitrogen.
Amymarie K. Bartholomew
Design and synthesis of 2D van der Waals materials from superatomic building blocks
The evolving field of 2D van der Waals (vdW) materials presents innumerable opportunities for fundamental materials property research and diverse technological applications. Atomically precise nanoscale clusters (“superatoms”) are ideal candidates for the bottom-up synthesis of novel and tunable 2D materials, since their properties can be controlled via their constituent atoms, oxidation state, and ligand periphery. In the pursuit of superatom-derived vdW materials we have synthesized versatile trans-Co6Se8(CO)2(PPh3)4, which can selectively undergo both thermal exchange of PPh3 and photolytic exchange of CO. This allowed us to isolate the equatorially cyanide-ligated clusters [trans-Co6Se8(CO)2(CN)4]n–(n = 3, 4). Treatment of [trans-Co6Se8(CO)2(CN)4]3–with CoBr2 and pyridine in water formed square, plate-like crystals of [Co(py)4]2[trans-Co6Se8(CO)2(CN)4]. This 2D cyanometalate coordination polymer consists of porous sheets that can be mechanically exfoliated down to a thickness of 1.8 nm, corresponding to the height of a bilayer. Furthermore, the nature of the superatoms embedded in the materials should allow for post-synthetic tuning of the material properties –efforts are currently underway to oxidatively intercalate the crystals as well as to functionalize the exfoliated 2D sheets via photolytic ligand exchange at the carbonyl positions.
University of Michigan
Structural analysis of Legionella pneumophila Dot/Icm type IV secretion system core complex
One important way bacterial pathogens establish infections is by transporting effector proteins into a host cell across multiple membranes. Bacteria have evolved elaborate strategies to accomplish this, including the Type IV Secretion System (T4SS). The Legionella pneumophila Dot/Icm T4SS translocates hundreds of effector proteins and is essential for pathogenesis, leading to the potentially fatal pneumonia Legionnaires’ Disease. The components used by bacteria to move virulence factors across membrane have been thoroughly catalogued, but our mechanistic understanding of how these components fit together and move substrate lags behind. Using biochemistry, genetics, and cryo-electron microscopy, I have isolated the Dot/Icm T4SS core complex and determined its macromolecular structure, revealing distinctive structural characteristics and previously unknown components.
National Institute of Standards and Technology Center for Neutron Research
Dynamics of Hydroxyl Anions in Antiperovskite Li2OHCl Promotes Lithium Ion Conduction
Lithium-ion batteries have revolutionized many aspects of modern life by enabling the development of countless portable electronic devices and the proliferation of electric vehicles. Though impressive, these devices face many drawbacks in safety and performance due to their dependence on liquid electrolytes, which are highly flammable, prone to degradation at high voltages, and incompatibility with some chemistries. In this regard, solid-state batteries, and in turn, the solid electrolytes that make the devices possible, have received much attention for their promise to improve upon these concerns. Li2OHCl is one such solid electrolyte material and is a defective antiperovskite (A3BX) for which high performance has been reported but where the atomic-level mechanism of ion migration is unclear. The stable phase is both crystallographically defective, having ≈1/3 of the Li sites vacant, and disordered, where dynamic OH–anions “tumble” within a large crystallographic void space. This presentation will discuss how the analysis of X-ray total scattering, X-ray and neutron diffraction data, quasielastic neutron scattering (QENS), as well as theoretical calculations show conclusively that the high lithium ion conductivity seen in cubic Li2OHCl is correlated to the “paddlewheel” rotation of the OH–anions. From this work, it is suggested that in antiperovskites and derivative compounds yet explored, a high cation vacancy concentration combined with dynamic molecular anions can facilitate high cation mobility for future solid-state ionic conductors.
University of California San Diego
Spectral Signatures and Spatial Coherence of Polarons in Organic Materials
Polarons play a central role in the electronic and optical properties of organic materials and are among the cross disciplinary research topics in chemistry, physics, and materials science. The spectral line shape of the mid-infrared (IR) absorption spectrum provides valuable information about the “hole” polaron delocalization lengths in conjugated homopolymers and copolymers. A theory describing the spatial coherence length of polarons in disordered organic materials is presented, revealing a simple relationship between the oscillator strength of the mid IR absorption band and the polaron coherence function. The Hamiltonian, represented in a multiparticle basis set, has been successful in quantitatively reproducing several recently measured spectra recorded in doped and undoped polymer films, confirming the association of an enhanced peak ratio (A/B) with extended polaron coherence. Emphasis is placed on the fundamental nature and origin of the components polarized along the intra and interchain directions and their dependence on the spatial distribution of disorder as well as the position of the dopant counter anion relative to the polymer 𝜋-stack. It is shown how simple optical probe like steady state absorption can be efficiently used to extract important information about the polaron coherence lengths, quantities which are crucial for our detailed understanding of energy and charge transport processes in these materials. The model has been further adapted to treat chemically induced polarons in covalent organic frameworks (COFs) and our analysis provides conclusive evidence of why iodine doped COFs have so far shown lower bulk conductivity compared to polythiophenes.
University of Pittsburgh
Development of non-RBD targeting inhibitors of SARS-CoV2 Spike protein
The Spike protein of SARS-CoV2, is a highly glycosylated trimer that interacts with the ACE2 receptor on host cells via the receptor binding domain (RBD) to facilitate viral entry. As such, the Spike trimer has become the target for a majority of approved therapeutics and vaccines used to treat or prevent SARS-CoV2. The function of the spike protein relies on the ability of the RBD to transition from a solvent excluded down state, to a solvent exposed up state where the RBD can bind the ACE2 receptor. The majority of neutralizing antibodies in convalescent plasma generated from infection or vaccination target the RBD, creating a selective pressure for evolution. As variants of concern emerge, mutations associated with immune escape accumulate on the RBD, and thus neutralization efficiency of antibodies decreases. Thus developing spike inhibitors that target other features of Spike is highly attractive. Here we developed two inhibitors of SARS-CoV2 viral entry that inhibit the function of spike and characterized them using biophysical and virological assays. Both molecules demonstrated the ability to inhibit SARS-CoV2 viral entry at low nanomolar concentrations, and demonstrated colocalization with Spike via fluorescence microscopy. Subsequently, we characterized interactions of both inhibitors with spike using analytical SEC, fluorescence binding experiments, and electron microscopy.
University of California‐San Francisco
De Novo Designed Proton Channels Unveil Key Functions of Transient Water Wires in Proton Selectivity and Conductivity
The precise movement of protons across cellular membranes is critical for many bioenergetic and biocatalytic processes. To achieve these biological functions, natural proton channel proteins have developed fine-tuned mechanisms for the selective translocation of protons. One such mechanism, involves the instantaneous formation and dissipation of linear chains of water within an otherwise apolar region of the channel lumen. This experimentally-elusive transient water wire hypothesis supposes that these water wires are crucial to defining the selectivity of these channels for protons over all other ions: these water wires form fast enough for the rapid diffusion of protons along the length of the hydrogen-bonded water network, but do not allow for the de-solvation and diffusion of other cations. To experimentally test this hypothesis for the first time, we turn to de novo protein design where we successfully designed and characterized several proton-selective channels. In this work, we introduced polar Gln mutants to key positions in the apolar pore of a non-conductive pentameric helical bundle, creating several channels with varying apolar lengths. Molecular dynamics simulations of the six channels using their X-ray crystallographic structures indicate that the introduction of the polar Gln mutants lowered the energy barrier for water penetration into the pore, enabling formation of transient water networks that can allow for proton conduction within the channel lumen. Results from liposomal flux assays and single-channel electrophysiology suggest that our designed channels are extremely selective for protons over all other ions, including K+ and Na+. Moreover, our findings indicate that the positions and locations of the polar mutations within the pore are critical to the rates of conduction that we observe. Our work demonstrates for the first time that these transient water wires define proton channel selectivity and conductivity: these short-lived networks allow for the movement of protons across membranes with high precision and fidelity.
University of California, Berkeley
Organometallic Gold(III)Reagents for Cysteine Arylation and Protein-Polymer Conjugation
Cysteine arylation facilitated by organometallic reagents has emerged as a powerful tool that allows for the introduction of a diverse array of substrates to biomolecules through the formation of robust covalent linkages. We reported on a series of organometallic gold(III) complexes that serve as efficient and versatile reagents for chemoselective cysteine arylation of peptides and proteins. The gold(III) organometallic reagents we have studied mediate the conjugation of small molecule and oligomer substrates to cysteine amino acid residues on biomolecules rapidly, with high efficiency, and in a broad pH range. This talk aims to discuss our prior work while also covering ongoing research using gold(III) reagents to access protein-polymer conjugates.
Gabriel dos Passos Gomes
University of Toronto
kraken: A full-scale discovery platform for the chemical space of organophosphorus ligands for catalysis
The ability to forge difficult chemical bonds through catalysis has transformed society on all fronts, from feeding our ever-growing populations to increasing our life expectancies by synthesizing new drugs. Not only has the rise in popularity of metal-catalyzed cross-coupling reactions enabled us to make existing processes more efficient, but it also has allowed us to synthesize novel and unexplored molecules and materials, unlocking the technologies of the future. In metal catalysis, ligand’s choice often leads to the most significant impact on the reaction outcomes, such as yield or product selectivity. Identifying optimal metal-ligand combinations can be a laborious experimental process. This practice is often held back by the difficulty of meaningfully comparing results with different ligands. I will introduce our efforts to develop a platform for inverse design of catalysts utilizing high-throughput virtual screening (HTVS) and machine learning (ML), coupled with an extensive ligands database. Advances in cheminformatics have led to the emergence of a vast diversity of calculated molecular descriptors of varying sophistication, allowing one to simulate properties that are difficult to quantify experimentally. Such workflows have been employed by theoreticians and experimentalists alike, becoming particularly powerful when embedded within large databases that map the accessible compound space. Such a library could enable predictive models for catalyst performance and serve as a blueprint for novel designs. We have developed kraken, a full-scale discovery platform for the chemical space of organophosphorus ligands for catalysis. At the center of this strategy lies an open database of 190 descriptors for 183 million organophosphorus ligands encompassing features that are most important for catalysis, including conformational flexibility and the ability for both coordinative and non-covalent bonding. I will demonstrate kraken’s application to challenging transformations, by exploiting the chemical space of organophosphorus compounds and exploring new ligands.
Core/Shell Magic-Sized Nanocrystals
Magic-sized nanocrystals (MSNCs) are a class of nanocrystals (NC) that grow via discrete jumps in size, in contrast to conventional quantum dots that grow through the continuous addition of monomers. Discrete growth limits size dispersity and inhomogeneity in the optoelectronic properties of semiconductor NCs. Despite this, MSNCs are limited in their study and application due to their poor stability and undesirable photoluminescence, which is dominated by low-energy trap emission. In this talk, I will present our efforts to synthesize core/shell NCs based on CdSe MSNC cores. Thin CdS shells lead to dramatic improvements in the emissive properties of the MSNCs, while thicker CdS shells yield particles with low photoluminescence quantum yields (PLQYs). We then synthesized MSNCs with thick CdxZn1-xS shells that maintain high PLQY and have a clear tetrahedral shape. These results show MSNCs can compete with other state-of-the-art NCs. Furthermore, these core/shell structures will allow us to elucidate the structure-property relationships that underpin MSNCs.
University of Minnesota, Twin Cities
Additive manufacturing of dynamic boronate-ester networks
Additive manufacturing (AM), or 3D printing, is a rapidly expanding field, with the growth in demand driving innovation towards increasing complexity in both form and function. Of particular interest is the manufacture of parts that are able to be modified post-printing. To that end, we present the development of an AM strategy for the 3D printing of dynamic polymer networks, in which the incorporation of a boronate ester monomer results in parts that undergo dynamic covalent exchange. The rapidity of boronate transesterification necessitates the dilution with a static comonomer, but the ease of exchange allows for mild processing conditions. This transesterification is harnessed to modify parts both mechanically, via welding of discrete parts into a larger assembly, and chemically, through the introduction of functionality via exchange with fluorescent boronic acid. Additionally, the ability of boronate esters to hydrolyze is leveraged to trigger a decrease in crosslinking density, allowing for swelling that can be tuned via choice of formulation
University of Toronto
Punching the Ticket to More Efficient Materials Development
To solve the urgent technological challenges that humanity faces, researchers across many areas of chemistry search for new molecules with useful properties. However, finding the best molecules for a particular application is incredibly challenging because this requires exploring extremely large chemical spaces. Self-driving labs that close the chemical discovery “loop” could be a powerful new tool for exploring chemical space. Integrating property prediction, synthesis and characterization, autonomous robotic systems guided by machine learning can perform experiments more efficiently and require much less human labor. Automated synthesis platforms are key to independent self-driving labs. Unfortunately, they are currently limited to only a small subset of the reactions available to human chemists. To efficiently utilize the current generation of self-driving labs, we must understand what areas of chemical space can and cannot be reached by automated synthesis. We have developed a framework where in human chemists and automated synthesis platforms combine their strengths–greater synthetic scope and higher throughput, respectively –to maximize the accessible chemical space. To demonstrate this framework, we simulate a self-driving lab performing a multi-objective inverse design campaign targeting fluorescence wavelength, synthetic cost, spectral overlap and fluorescence rate on a space of ca. 3,500 possible organic laser molecules.
University of California, San Diego
Spatiotemporal regulation of AMPK illuminated by a sensitive kinase activity reporter
AMP activated protein kinase (AMPK) is a heterotrimeric kinase essential for maintaining cellular energy homeostasis in response to energy insult and calcium signaling. How AMPK achieves signaling specificity over a variety of downstream targets throughout the cell has remained unclear. To monitors patially distinct AMPK activity, we developed a single-fluorophore excitation-ratiometric AMPK activity reporter (ExRai AMPKAR) which exhibits an excitation wavelength change upon phosphorylation by AMPK, providing a specific readout of AMPK activity in living cells. Using subcellularly localized ExRai AMPKAR, we identified the spatial specificity of upstream kinases of AMPK at the lysosome, mitochondria, and cytoplasm. While AMPK subunits have been reported to be localized to the nucleus, and several nuclear targets of AMPK have been identified, it remains unclear whether AMPK is active in the nucleus. Owing to its ultrasensitivity, ExRai AMPKAR unveiled robust AMPK activity in the nucleus following metabolic stress and calcium increase, resolving a controversy in the field. We discovered that nuclear AMPK activity results from cytosolic activation of AMPK and subsequent shuttling into the nucleus. Thus AMPK is distinctly regulated within subcellular locations, as revealed by a live biochemistry approach using ExRai AMPKAR.
Physikalische Chemie, Ruhr-Universität Bochum
From Ultrafast to Ultraslow: Mapping Multiple Steps in Photoredox Reactions using Ultrafast Laser Spectroscopies
In the past decade, photoredox catalysis has emerged as a favourite among synthetic organic chemists given its ability to transform synthetic methodologies. Recent advances in this field have been in the direction of replacing traditionally used transition metal catalysts with organic catalysts, which provide access to newer forms of chemistry and also do not suffer from the problems of toxicity and scarcity. However, while new synthetic methodologies and applications for these organo-catalysts are emerging fast, quantitative understanding of their mechanistic underpinnings remains scarce. In this talk, I will be presenting our studies on the kinetic and mechanistic details of organocatalyzed atom transfer radical polymerization (O-ATRP) reactions using ultrafast transient electronic and vibrational absorption spectroscopies. O-ATRP operates through a multistep photoredox catalytic cycle and while the complete process can take anywhere from micro to milliseconds, the individual steps occur over a wide range of timescales from femtosecond (fs) upwards. Using a custom build laser system at Rutherford Appleton laboratory which enables access to timescales from 100 fs to 1 ms in a single continuous measurement, we have directly observed multiple steps of the OATRP catalytic cycle. By studying nine photocatalysts(PC)with phenoxazine, phenothiazine and dihydrophenazine6, 7cores in toluene, dichloromethane and N, N dimethylformamide, we have explored the effects of structural modifications and solvent polarity on the excited state lifetimes of these PCs as well as on the subsequent steps of the cycle. Our observations challenge previously proposed mechanisms and offer new insights about the structure-function-dynamic relationship of these PCs.
University of Wisconsin−Madison
Carotenoid-mediated light-harvesting in plants uncovered by ultrabroadband two-dimensional electronic spectroscopy
Plants absorb across the visible solar spectrum and rapidly funnel the energy downhill to power growth. In excess sunlight, they dissipate harmful energy as heat to protect against photodamage. Previous measurements have been limited to the two lowest-energy, exclusively chlorophyll transitions of their light-harvesting machinery, leaving the carotenoid-mediated pathways unexplored. I will discuss the development of an ultrabroadband two-dimensional(2D)electronic spectrometer that enables mapping of the energy flow in the major light-harvesting protein of plants, LHCII, across the visible range. I will then discuss two previously inaccessible pathways of light harvesting as well as dissipation in LHCII, both mediated by carotenoids, uncovered by this apparatus. By analyzing the vibrational wave packets in the 2D spectra, I identified a debated dark state (SX) specific to a single carotenoid, lutein 2, that serves as a key mediator for efficient light harvesting. On a second carotenoid, lutein 1, I resolved a dissipative energy transfer from the chlorophyll to its dark S1state. The distinct photophysics revealed for these two chemically identical pigments highlight the capability of the protein binding pocket to control the electronic structure, and in turn, function of carotenoids in photosynthesis.
Nucleophilic C(sp3)–H Fluorination Enabled by Photoredox Catalysis
The direct, intermolecular functionalization of C(sp3)–H bonds represents a longstanding challenge in synthetic organic chemistry. C(sp3)–H fluorination is consistently difficult to achieve through nucleophilic functionalization, in part due to the attenuated nucleophilicity of fluoride and the prevalence of atom transfer focused methods. C–H fluorination methodologies are in high demand in order to facilitate the synthesis and derivatization of pharmaceuticals, agrochemicals, and materials. The unique appeal of C–F bond formation in molecular design is largely attributed to the role of fluorine as a versatile bioisostere, its ability to influence pharmacokinetic and pharmacodynamic properties, and the utility of 18F radiolabeling for positron emission tomography (PET) imaging. Here we describe a strategy that transforms C(sp3)–H bonds into carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar crossover, effecting formal hydride abstraction in the absence of a strong Lewis acid or strong oxidant. The resulting carbocation can be functionalized by a variety of nucleophiles—including halides, water, alcohols, thiols, an electron-rich arene, and an azide—to affect diverse bond formations. Reaction development is demonstrated in the context of nucleophilic fluorination of secondary and tertiary benzylic and allylic C(sp3)–H bonds and is applicable to late-stage diversification of bioactive molecules. Mechanistic studies indicate that HAT is mediated by methyl radical, a previously unexplored HAT agent with complementary polarity to those commonly used in photoredox catalysis. Accordingly, this method can deliver unique site-selectivity for late-stage C(sp3)–H functionalization
Center for Computational Quantum Physics, Flatiron Institute, Simons Foundation
Ab Initio Quantum Chemistry for Periodic Solids: From Hartree-Fock to Coupled-Cluster Theory
Wavefunction-based quantum chemistry methods, such as Hartree-Fock (HF), second-order Møller-Plesset perturbation theory (MP2), and coupled-cluster theory with single and double excitations (CCSD), are most widely used for the study of molecular systems. However, highly accurate ab initioquantum chemical description of solid-state properties remains a theoretical and computational challenge. In this talk, I will present our recent development of wave function-based techniques that incorporate periodic boundary conditions, as well as their applications to electronic structure problems of crystalline solids. First, I will briefly introduce the basics of periodic ab initio quantum chemistry methods, including HF, CCSD, and its equation-of-motion counterpart (EOM-CCSD).Then, I will describe a development towards fast evaluation of exact exchange in periodic HF using concentric atomic density fitting, providing 10x speed up relative to traditional implementations. Going beyond HF, I will present an EOM-CCSD study on electronically excited states of solids. In particular, I will show how periodic EOM-CCSD can be used to accurately predict a wide range of exciton properties, including optical gaps, exciton dispersion, and absorption spectra, for insulators and semiconductors.