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Mechanistic Exploration of N-Heterocyclic Carbene Boranes as the Hydrogen Atom Transfer Reagent in Selective Hydro-defluorination Reactions
No full textIn the modern era of organic synthesis, mechanisms centering on radical intermediates have become increasingly impact-ful in unlocking novel reactivity. Among all, hydrogen atom transfer (HAT) represents one of the most fundamental chemical reaction steps and has found applications in designing practical transformations. Herein, we present a detailed case study on selective hydrodefluorination of trifluoromethylarenes utilizing N-heterocyclic carbene boranes (NHC-boranes) as the HAT donor. Under the optimal conditions featuring an acridine-based photocatalyst, complete selectivity for mono-hydrodefluorination was achieved across a wide array of substrates. Comprehensive mechanistic studies com-bining experimental and computational approaches disproved a chain process involving a fluorine atom transfer but ra-ther pointed to a HAT non-chain mechanism, where the key step involves the difluorobenzylic radical abstracting a hy-drogen atom from the NHC-borane to generate a boryl radical in a polarity-matched fashion. Evaluation of a selection of Lewis base-ligated boranes revealed molecular descriptors critical to the outcomes of this reaction, and a classification model is built to explain the structure-reactivity relationship and how various elementary steps can be influenced. These results collectively provide valuable information for future reaction design to elevate the utility of boranes in organic radical chemistry
Efficient Method for Twist-Averaged Coupled Cluster Calculation of Gap Energy: Bulk Study of Stannic Oxide
No full textWe study the gap energy of the semiconducting oxide SnO2 through ab-initio calculations including both DFT and coupled cluster methods. The effectiveness of twist-averaging in reducing finite-size errors is evaluated across different functionals. We report an overestimation of gap energy when applying finite-size scaling at the thermodynamic limit in equation-of-motion (EOM) CCSD calculations. To mitigate one-body and many-body errors, we integrate twist averaging with a post-processing correction mechanism, comparing finite-size and infinite-size DFT calculations using hybrid functionals. While inspired by the Kwee, Zhang, and Krakauer (KZK) approach, our method is tailored to hybrid functionals for a more accurate treatment of exchange-correlation effects. Our approach ensures that the many-body interactions are accurately reflected in the estimated gap for an infinite system. We introduce unique single twist angles that yield cost- effective and accurate energies, in comparison to full twist averaging in the EOM-CCSD calculations. Applying this approach to SnO2, we calculate a fundamental gap of 3.46 eV, closely matching the 3.59 eV gap obtained from two-photon spectroscopy experiments, thereby demonstrating the accuracy of this method
Iterative, Programmable, and Controllable De Novo Synthesis of Fully Heteroleptic All-Carbon Substituted Silanes from Four Different Organometallic Reagents
No full textAll-carbon substituted silanes are a class of unnatural yet important compounds. To access them from SiCl4 or Si(OR)4 and organometallic reagents is intuitively the most straightforward de novo approach, which unfortunately is only applicable to homoleptic but not heteroleptic ones. Thus, alternative silyl precursors and techniques to enable controllable substitutions at silicon are highly desirable. Herein, we targeted the structurally most complicated and synthetically most challenging fully heteroleptic all-carbon substituted silanes and developed Ph3SiCl and Ph2Si(OMe)2 as the synthetic equivalent of SiCl4 or Si(OR)4 for the de novo synthesis of them. Mono-selective dephenylative etherifications of triphenyl-substituted silanes as well as diphenyl-substituted ones were key to success. Within 5-7 steps, four different carbon units from organometallic reagents could be ligated to one silicon center in a controllable, programmable, and iterative fashion. Meanwhile, unique reactivities of hexafluoroisopropoxysilanes and silanes with hemicrown ether auxiliaries in organometallic substitution reactions were disclosed
A minimally instrumented method for the detection of rifampicin resistance-causing mutations in Mycobacterium tuberculosis utilizing lateral flow readout
No full textGenotypic methods for the determination of antimicrobial resistance in Mycobacterium tuberculosis (M.tb) require expensive instruments, which limits their availability in peripheral locations. We present a minimally instrumented method for the detection of the four most common mutations associated with rifampicin resistance in M.tb: S531L, H526Y, H526D, and D516V. The detection is based on the oligonucleotide ligation assay, coupled with lateral flow readout. The assay can detect wild-type and mutant DNA from as few as 10 and 100 gene copies per reaction, respectively. In heterozygous samples, the assay can detect < 3% mutant DNA for all 4 mutations. Preliminary validation of the assay was carried out using genomic DNA extracted from 29 M.tb isolates being cultured at the ICMR-National Institute for Research in Tuberculosis in Chennai, India. The assay achieved a sensitivity and specificity of 100% for the detection of M.tb, and 90.90% and 100% respectively, for the detection of rifampicin resistance. The assay is simple to extend to other resistance-causing mutations and may aid in the reduction of instrumentation associated with current TB genotypic AMR detection
Amine Carboxyborane: A Versatile Ligated Boryl Radical Precursor
No full textAmine carboxyborane has been demonstrated as a novel precursor for amine-ligated boryl radicals. The anion of amine carboxyborane was effectively oxidized using a 5CzBN photocatalyst under blue LED light, with subsequent decarboxylation facilitating the generation of ligated boryl radicals. This process enabled an efficient halogen atom transfer (XAT) with alkyl bromides, resulting in Giese addition products with various electron-deficient double bonds. Moreover, direct addition of several boryl radicals was also possible using ligated carboxyboranes
Exploration of Chemical Space through Automated Reasoning
No full textThe vast size of composition space poses a significant challenge for materials chemistry: exhaustive enumeration of potentially interesting compositions is typically infeasible, hindering assessment of important criteria ranging from novelty and stability to cost and performance. We report a tool, Comgen, for the efficient exploration of composition space, which makes use of logical methods from computer science used for proving theorems. We demonstrate how these techniques, which have not previously been applied to materials discovery, can enable reasoning about scientific domain knowledge provided by human experts. Comgen accepts a variety of user-specified criteria, converts these into an abstract form, and utilises a powerful automated reasoning algorithm to identify compositions that satisfy these user requirements, or prove that the requirements cannot be simultaneously satisfied. In contrast to machine learning techniques, explicitly reasoning about domain knowledge, rather than making inferences from data, ensures that Comgen’s outputs are fully interpretable and provably correct. Users interact with Comgen through a high-level Python interface. We illustrate use of the tool with several case studies focused on the search for new ionic conductors. Further, we demonstrate the integration of Comgen into an end-to-end automated workflow to propose and evaluate candidate compositions quantitatively, prior to experimental investigation. This highlights the potential of automated formal reasoning in materials chemistry
Reference-Free Thio-Succinimide Isomerization Characterization by Electron-Activated Dissociation
No full textRationale
Isomerism can be an important aspect in pharmaceutical drug development. Identification of isomers can provide insights into drug pharmacology and contribute to better design of drug molecules. The general approaches to differentiate isomers include Fourier-transform infrared spectroscopy (FTIR), nuclear magnetic resonance (NMR), and circular dichroism. Although proven effective, a commonly used method to differentiate isomers is chromatography coupled with mass spectrometry (MS). Notably, MS is routinely applied in leucine and isoleucine differentiation to facilitate protein sequencing. This work focuses on isomer differentiation of widely applied thio-succinimide structure bridging the antibody backbone and linker-payload of antibody-drug conjugates (ADCs). The hydrolysis of thio-succinimide stabilizes the payload-protein structure while generating a pair of constitutional isomers: thio-aspartyl and thio-isoaspartyl.
Methods
This paper introduces a hybrid method using ligand binding assay (LBA) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) to reveal isomerization details of thio-succinimide hydrolysis over time in plasma samples incubated with ADC. By applying two orthogonal dissociation methods, collision-induced dissociation (CID) and electron-activated dissociation (EAD), this pair of isomers showed different MS/MS spectra. This observation enables a unique approach in distinguishing thio-succinimide hydrolysis isomers.
Results
We observed signature [R1+Thio+57+H]+, [R2+Succ+H2O-57+H]+ and [R2+Succ+H2O-44+2H]2+ product ions that differentiated thio-aspartyl and thio-isoaspartyl isomers using EAD. A newly discovered [R2+ThioSucc+H2O-44+2H]2+ ion also served as additional evidence that further supported our findings.
Conclusions
This study is a first-to-date identification of thio-succinimide hydrolysis isomers without using synthesized reference materials. This approach should be applicable to all thio-succinimide-linked molecules. Correct identification of thio-succinimide hydrolysis isomers may eventually benefit the development of ADCs in the future
Kinetic Trapping of Rylene Diimide Covalent Organic Cages
No full textFormation of imine organic cages relies on error-correction of dynamic covalent chemistry. Here, we demonstrate kinetically-trapped rylene diimide cages formed in high yields and we investigate the effect of substituents on their formation kinetics and stability. Thereby, we identified that alkoxy groups in triformylbenzene, used to stabilize covalent organic cages or COFs, act as stereoelectronic chameleons. We underscore critical factors governing the chemistry of kinetically-trapped imine assemblies like sterics, electronics, catalysis, and water concentration
Multi-scale Measurements of Greenhouse Gas Emissions at U.S. Natural Gas Liquefaction Terminals
No full textAddressing methane emissions across the liquefied natural gas (LNG) supply chain is key to reducing climate impacts of LNG. Actions to address methane emissions have emphasized the importance of the use of measurement-informed emissions inventories, given the systematic underestimation in official GHG emission inventories. Despite significant progress in field measurements of GHG emissions across the natural gas supply chain, no detailed measurements at US liquefaction terminals are publicly available. In this work, we conduct multiscale, periodic measurements of methane and carbon dioxide emissions at two US LNG terminals over a 16-month campaign. We find that methane emissions intensity varied from 0.007% to 0.045%, normalized to LNG production. Carbon dioxide emissions accounted for over 95% of total GHG emissions using 100-year global warming potential for methane. Thus, contrary to observations across other natural gas supply chain segments, we find that reported GHG emissions intensity closely matches measurement informed GHG emissions intensity of 0.24 – 0.27 kg CO2e/kg CH4. In the context of developing LNG supply chain emissions intensity, we conclude that the use of Greenhouse Gas Reporting Program emissions intensity provides reasonably accurate estimates of total GHG emissions at LNG terminals
Orthogonal Phase Transfer of Oppositely Charged FeII4L6 Cages
No full textCoordination cages and their encapsulated cargo can be manoeuvred between immiscible liquid layers in a process referred to as phase transfer. Among the stimuli reported to drive phase transfer, counterion exchange is the most widespread. This method exploits the principle that counterions contribute strongly to the solubility preferences of coordination cages, and involves exchanging hydrophilic and hydrophobic counterions. Nevertheless, phase transfer of anionic cages remains relatively unexplored, as does selective phase transfer of individual cages from mixtures. Here we compare the phase transfer behaviour of two FeII4L6 cages with the same size and geometry, but with opposite charges. As such, this study presents a rare example wherein an anionic cage undergoes phase transfer upon countercation exchange. We then combine these two cages, and demonstrate that their quantitative separation can be achieved by inducing selective phase transfer of either cage. These results represent unprecedented control over the movement of coordination cages between different physical compartments, and are anticipated to inform the development of next-generation supramolecular systems