bluuebunny/crossref_metadata_2025 huggingface dataset:
A Machine Learning Approach to Calculate Electronic Couplings between Quasi-Diabatic Molecular Orbitals: The Case of DNA
Authors: Bai Xin , Guo Xin , Wang Linjun
Published: February 2022

Diabatization of one-electron states in flexible molecular aggregates is a great challenge due to the presence of surface crossings between molecular orbital (MO) levels and the complex interaction between MOs of neighboring molecules. In this work, we present an efficient machine learning approach to calculate electronic couplings between quasi-diabatic MOs without the need of nonadiabatic coupling calculations. Using MOs of rigid molecules as references, the MOs that can be directly regarded to be quasi-diabatic in molecular dynamics are selected out, state tracked, and phase corrected. On the basis of this information, artificial neural networks are trained to characterize the structure-dependent onsite energies of quasi-diabatic MOs and the inter-molecular electronic couplings. A representative sequence of DNA is systematically studied as an illustration. Smooth time evolution of electronic couplings in all base pairs is obtained with quasi-diabatic MOs. Especially, our method can calculate electronic couplings between different quasi-diabatic MOs independently, and thus possesses unique advantages in many applications.
Model agnostic generation of counterfactual explanations for molecules
Authors: Wellawatte Geemi P , Seshadri Aditi , White Andrew D
Published: February 2022

An outstanding challenge in deep learning is its lack of interpretability. The inability of both designers and users of neural networks to explain why a prediction is made is a major drawback. This not only dissuades chemists from using deep learning predictions, but also has led to neural networks learning spurious correlations that are difficult to notice. Counterfactuals are a category of prediction explanations that provide a rationale behind the prediction value. Counterfactuals have satisfying properties like being in the same space as the features and require no deep learning expertise to understand. Counterfactuals are generated via optimization, which makes them complex to use when the features are chemical structures. Here we present an algorithm built on the "Superfast Traversal, Optimization, Novelty, Exploration and Discovery" method (Nigam et. al, 2021) that is efficient and model-agnostic for generating counterfactuals. We show this method is applicable in random forest models, sequence models, and graph neural networks in both classification and regression. Our method requires no additional training, data, or model gradients.
Quicksilver and Quick-thinking: Insight into the Alchemy of Mercury A new interdisciplinary research to discover the chemical reality of ancient alchemical recipes
Authors: Maini Lucia , Marchini Marianna , Gandolfi Massimo , Raggetti Lucia , Martelli Matteo
Published: February 2022

Ancient alchemical recipes represent an invaluable source to understand how our ancestors described and conceptualised nature. Such recipes were often dismissed as nonsense, or even interpreted as mere allegories for spiritual practices of self-purification. Our research adopts a totally new interdisciplinary outlook through collaboration between chemists and historians of science, to investigate one of the most intriguing of elements, that is mercury. A corpus of ancient sources —in Greek, Latin and Syriac—was scoured in search of information on the extraction of mercury from cinnabar. Following the sources, we replicated the recipes and explored the viability and feasibility of the reactions, as well as the technical underpinnings of the texts, in order to disclose the practical dimensions of ancient alchemy and an unexpected variety of reactions.
Nickel-Catalyzed Decarboxylative Coupling of Redox-Active Esters with Aliphatic Aldehydes
Authors: Xiao Jichao , Li Zhenning , Montgomery John
Published: February 2022

The addition of alkyl fragments to aliphatic aldehydes is a highly desirable transformation for fragment couplings, yet existing methods come with operational challenges related to the basicity and instability of the nucleophilic reagents commonly employed. We report herein that nickel catalysis using a readily available bioxazoline (BiOx) ligand can catalyze the reductive coupling of redox-active esters with aliphatic aldehydes using zinc metal as the reducing agent to deliver silyl-protected secondary alcohols. This protocol is operationally simple, proceeds under mild conditions, and tolerates a variety of functional groups. Initial mechanistic studies suggest a radical chain pathway. Additionally, alkyl tosylates and epoxides are suitable alkyl precursors to this transformation providing a versatile suite of catalytic reactions for the functionalization of aliphatic aldehydes.
Revisiting the structure of calcined and hydrated AlPO-11 with DFT-based molecular dynamics simulations
Authors: Fischer Michael
Published: February 2022

Published crystal structures of the AEL-type aluminophosphate AlPO-11 in its calcined form (space group Ima2) show some peculiar features, such as unusually short Al−O and P−O bonds and near-linear Al−O−P angles. Although experimental evidence for the presence of dynamic disorder was presented, the nature of the associated distortions remained unresolved. In this study, ab initio molecular dynamics (AIMD) calculations in the framework of density functional theory (DFT) were employed to study the dynamic behaviour of this zeotype. At 100 K, static local distortions that break the Ima2 symmetry are present in the time-averaged structures computed from the AIMD trajectories. At 300 and 500 K, the time-averaged structures approach Ima2 symmetry. Although shortened Al−O and P−O bonds and near-linear Al−O−P angles were found in the average structures, an analysis of radial and angular distribution functions confirmed their absence in the instantaneous structures. This deviation is due to a precession-like motion of some oxygen atoms around the Al−P connection line, which moves their time-averaged positions closer to the connection line. In hydrated AlPO-11, some of the water molecules are coordinated to framework Al atoms, leading to an octahedral coordination of 1/5 of the Al sites. DFT optimisations and AIMD simulations on partially hydrated models delivered evidence for an adsorption at the Al1 site. No dynamic disorder was observed for the hydrated form.
Breaking the aristotype: featurisation of polyhedral distortions in perovskite crystals
Authors: Morita Kazuki , Davies Daniel , Butler Keith , Walsh Aron
Published: February 2022

While traditional crystallographic representations of structure play an important role in materials science, they are unsuitable for efficient machine learning. A range of effective numerical descriptors have been developed for molecular and crystal structures. We are interested in a special case, where distortions emerge relative to an ideal high-symmetry parent structure. We demonstrate that irreducible representations form an efficient basis for the featurisation of polyhedral deformations with respect to such an aristotype. Applied to dataset of 552 octahedra in ABO3 perovskite-type materials, we use unsupervised machine learning with irreducible representation descriptors to identify four distinct classes of behaviour, associated with predominately corner, edge, face, and mixed connectivity between neighbouring octahedral units. Through this analysis, we identify SrCrO3 as a material with tuneable multiferroic behaviour. We further show, through supervised machine learning, that thermally activated structural distortions of CsPbI3 are well described by this approach.
Absolute Configuration of Bromofluoroiodomethane after Preparative Gas Chromatographic Separation
Authors: Spenger Benjamin , Näf Stefan , Manov Stole , Stohner Jürgen
Published: February 2022

The enantiomers of bromofluoroiodomethane (CHBrFI) were separated on a preparative scale using gas chromatography (GC). The collected single enantiomers were analysed by vibrational circular dichroism spectroscopy and polarimetry in combination with ab initio calculations to determine the respective absolute configuration.
Tracking the Catalyst Layer Depth-Dependent Electrochemical Degradation of a Bimodal Pt/C Fuel Cell Catalyst: A Combined Operando Small- and Wide-Angle X-Ray Scattering Study
Authors: Schröder Johanna , Pittkowski Rebecca K. , Martens Isaac , Chattot Raphaël , Drnec Jakub , Quinson Jonathan , Kirkensgaard Jacob J. K. , Arenz Matthias
Published: February 2022

The combination of operando small- and wide-angle X-ray scattering (SAXS, WAXS) in grazing incidence configuration is presented as a new approach to provide depth-dependent insights into the changes in mean particle sizes and phase fractions occurring for fuel cell catalysts during accelerated stress tests (ASTs). As fuel cell catalyst, a bimodal Pt/C catalyst was chosen that consists of two distinguishable particle size populations. The presence of the two different sizes should favor and uncover electrochemical Ostwald ripening as the major degradation mechanism, i.e., it is expected that the size of the larger particles in the Pt/C catalyst grows at the expense of the smaller particles. The grazing incidence mode performed at the European Synchrotron Radiation Facility (ESRF) at the ID31 beamline revealed an intertwinement of the depth dependent degradation. While the larger particles show the same particle size changes close to the electrolyte-catalyst interface and within the catalyst layer, for the smaller Pt nanoparticles a different degradation scenario is observed. At the electrolyte-catalyst interface, the smaller particles increase in size while their phase fraction decreases during the AST. However, in the inner catalyst layer the phase fraction of smaller particles increases instead of decreases. The results of a depth-dependent degradation strongly suggest to employ a depth-dependent catalyst design for future improvement of the catalyst stability.
Tracking the Catalyst Layer Depth-Dependent Electrochemical Degradation of a Bimodal Pt/C Fuel Cell Catalyst: A Combined Operando Small- and Wide-Angle X-Ray Scattering Study
Authors: Schröder Johanna , Pittkowski Rebecca K. , Martens Isaac , Chattot Raphaël , Drnec Jakub , Quinson Jonathan , Kirkensgaard Jacob J. K. , Arenz Matthias
Published: February 2022

The combination of operando small- and wide-angle X-ray scattering (SAXS, WAXS) is here presented to provide insights into the changes in mean particle sizes and phase fractions in fuel cell catalyst layers during accelerated stress tests (ASTs). As fuel cell catalyst, a bimodal Pt/C catalyst was chosen that consists of two distinguishable particle size populations. The presence of the two different sizes should favor and uncover electrochemical Ostwald ripening as degradation mechanism, i.e., the growth of larger particles in the Pt/C catalyst at the expense of the smaller particles via the formation of ionic metal species. However, instead of electrochemical Ostwald ripening, the results point toward classical Ostwald ripening via the local diffusion of metal atoms on the support. Furthermore, the grazing incidence mode provides insights into the catalyst layer depth-dependent degradation. While the larger particles show the same particle size changes close to the electrolyte-catalyst interface and within the catalyst layer, the smaller Pt nanoparticles exhibit a slightly decreased size at the electrolyte-catalyst interface. During the AST, both size populations increase in size, independent of the depth. Their phase fraction, i.e., the ratio of smaller to larger size population, however, exhibits a depth-dependent behavior. While at the electrolyte-catalyst interface the phase fraction of the smaller size population decreases, it increases in the inner catalyst layer. The results of a depth-dependent degradation suggest that employing a depth-dependent catalyst design can be used for future improvement of catalyst stability.
Catalytic Enantioselective Nucleophilic Desymmetrisation of Phosphonate Esters
Authors: Formica Michele , Rogova Tatiana , Shi Heyao , Sahara Naoto , Farley Alistair J. M. , Christensen Kirsten E. , Duarte Fernanda , Dixon Darren J.
Published: February 2022

Compounds containing one or more stereogenic phosphorous atoms in the P(V) oxidation state are important to chemistry, biology and medicine. These include marketed antiviral drugs such as Tenofovir alafenamide and Remdesivir, an effective treatment for Ebola which has also recently been approved for use against SARS-CoV-2 in the US. Existing approaches for the stereoselective synthesis of P-stereogenic centers, while elegant, remain mostly diastereoselective, with catalytic enantioselective approaches being limited in application. Accordingly, conceptually novel, broad-scope, catalytic strategies for the efficient stereoselective synthesis of diverse stereogenic P(V) containing compounds remain essential. To this end, we describe a novel enantioselective two-stage strategy, exploiting a catalytic and highly enantioselective desymmetrisation of phosphonate esters. Pivoting on the first stereocontrolled, sequential nucleophilic substitution of enantiotopic leaving groups from readily accessible pro-chiral P(V) precursors, a bifunctional iminophosphorane (BIMP) superbase catalyst was found to be essential in delivering reactive desymmetrised intermediates capable of downstream enantiospecific substitution. This uniquely modular, catalytic platform allows broad-scope, stereoselective access to a diverse library of chiral P(V) compounds including those with O, N and S-linkages.
Insights into Ionic Liquid Electrolyte Transport and Structure via Operando Raman Microspectroscopy
Authors: Fawdon Jack , Rees Gregory , La Mantia Fabio , Pasta Mauro
Published: February 2022

Ionic liquid electrolytes (ILEs) have become popular in various advanced Li-ion battery chemistries because of their high electrochemical and thermal stability, and low volatility. However, due to their relatively high viscosity and poor Li+ diffusion, it is thought large concentration gradients form, reducing their rate capability. Here, we utilised operando Raman microspectroscopy to visualise ILE concentration gradients for the first time. Specifically, using lithium bis(fluorosulfonyl)imide (LiFSI) in N-propyl- N-methylpyrrolidinium FSI, its "apparent" diffusion coefficient, lithium transference number, thermodynamic factor, ionic conductivity and resistance of charge-transfer against lithium metal, were isolated. Furthermore, the analysis of these concentration gradients led to insights into the bulk structure of ILEs, which we propose is composed of large, ordered aggregates.
Electric field orientations in solution and enzyme active site revealed by a two-directional vibrational probe
Authors: Zheng Chu , Mao Yuezhi , Kozuch Jacek , Atsango Austin , Ji Zhe , Markland Thomas , Boxer Steven
Published: February 2022

The catalytic power of an electric field depends on its magnitude and orientation with respect to the reactive chemical species. Understanding and designing new catalysts for electrostatic catalysis thus requires methods to measure the electric field orientation and magnitude at the molecular scale. We demonstrate that electric field orientations can be extracted using a two-directional vibrational probe by exploiting the vibrational Stark effect of both the C=O and C-D stretches of a deuterated aldehyde. Combining spectroscopy with molecular dynamics and electronic structure partitioning methods, we demonstrate that despite distinct polarities, solvents act similarly in their preference for electrostatically stabilizing large bond dipoles at the expense of destabilizing small ones. In contrast, we find that for an active site aldehyde inhibitor of liver alcohol dehydrogenase, the electric field orientation deviates markedly from that found in solvents, providing direct evidence for the fundamental difference between the electrostatic environments of solvents and a preorganized enzyme active site.
Lib-INVENT: Reaction Based Generative Scaffold Decoration for in silico Library Design
Authors: Fialkova Vendy , Zhao Jiaxi , Papadopoulos Kostas , Engkvist Ola , Bjerrum Esben Jannik , Kogej Thierry , Patronov Atanas
Published: February 2022

Due to the strong relationship between desired molecular activity to its structural core, screening of focused, core sharing chemical libraries is a key step in lead optimisation. Despite the plethora of current research focused on in silico methods for molecule generation, to our knowledge, no tool capable of designing such libraries has been proposed. In this work, we present a novel tool for de novo drug design called Lib-INVENT. This is capable of rapidly proposing chemical libraries of compounds sharing the same core while maximising a range of desirable properties. To further help the process of designing focused libraries, the user can list specific chemical reactions that can be used for the library creation. Lib-INVENT is therefore a flexible tool for generating virtual chemical libraries for lead optimisation in a broad range of scenarios. Additionally, the shared core ensures that the compounds in the library are similar, possessing desirable properties and can be also synthesized under the same or similar conditions.
Highly Twisted α-Diketone-Based Thermally Activated Delayed Fluorescence Emitters and their use in Organic Light-Emitting Diodes
Authors: Kumar Gupta Abhishek , Matulaitis Tomas , Cordes David , Slawin Alexandra , Samuel Ifor , Zysman-Colman Eli
Published: February 2022

We have designed a highly twisted small TADF emitter PXZ-α-DK based on an -diketone (α-DK) as a strong acceptor and phenoxazine (PXZ) as a strong donor to obtain red-shifted emission in comparison to the equivalent -diketone linked to 9,9-dimethyl-9,10-dihydroacridine (DMAC). The PXZ-α-DK shows emission at 586 nm and DMAC-α-DK shows emission at 548 nm in 1,3-bis(N-carbazolyl)benzene (mCP) host at 1.5 wt% doping of the emitter, with short-delayed lifetimes of 6.9 μs for PXZ-α-DK and 7.6 μs for DMAC-α-DK. OLEDs fabricated using these emitters show green electroluminescence at 555 nm for DMAC-α-DK, with a maximum external quantum efficiency, EQEmax, of 6.3%, and orange electroluminescence at 585 nm for PXZ-α-DK, with an EQEmax of 0.8%. We corroborate the optoelectronic properties of these emitters with DFT calculations.
Impact of warhead modulations on the covalent inhibition of SARS-CoV-2 Mpro explored by QM/MM simulations
Authors: Marti Sergio , Arafet Kemel , Lodola Alessio , Mulholland Adrian , Swiderek Katarzyna , Moliner Vicent
Published: February 2022

The COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus-2, SARS-CoV-2, shows the need for effective antiviral treatments. Here, we present a simulation study of the inhibition of the SARS-CoV-2 main protease (Mpro), a cysteine hydrolase essential for the life cycle of the virus. The free energy landscape for the mechanism of the inhibition process is explored by QM/MM umbrella sampling and free energy perturbation simulations at the M06-2X/MM level of theory for two proposed peptidyl covalent inhibitors sharing the same recognition motif while featuring distinct cysteine-targeting warheads. Regardless of intrinsic reactivity of the modelled inhibitors, namely a Michael acceptor and a hydroxymethylketone activated carbonyl, our results confirm that the inhibitory process takes place by means of a two-step mechanism, in which the formation of an ion pair C145/H41 dyad precedes the protein-inhibitor covalent bond formation, in both cases. The nature of this second step appears to be strongly dependent on the functional groups introduced in the warhead: in the present study, while the nucleophilic attack of the C145 sulfur atom on the C of the double bond of the Michael acceptor takes place concertedly to the proton transfer from H41 to C, in the compound with an activated carbonyl the sulfur attacks the carbonyl carbon concomitant to the proton transfer from H41 to the carbonyl oxygen through the hydroxyl group. Analysis of the free energy profiles, structures along the reaction path, and interactions between the inhibitors and the different pockets of the active site on the protein shows a measurable impact of the warhead on the kinetics and thermodynamics of the process. The present results can be used as a guide to select warheads to design efficient irreversible and reversible inhibitors of SARS-CoV-2 Mpro.
Seasonal lead release to drinking water and the effect of aluminum
Authors: Trueman Benjamin F , Bleasedale-Pollowy Aaron , Locsin Javier A , Bennett Jessica L , Krkošek Wendy H , Gagnon Graham A
Published: February 2022

Lead is a neurotoxin and an environmental contaminant. Many jurisdictions require that it be monitored in drinking water, especially where lead plumbing remains in use. But seasonal variation in lead concentrations can bias monitoring programs if it is not understood and accounted for. Here, we describe an unexpected pattern in lead release to drinking water, identified through point-of-use sampling. The median lead concentration representing paired first-draw water samples—collected in multiple years—was 46% lower in October compared to February. Seasonal variation in orthophosphate, pH, and alkalinity accounted for at least some of this pattern and predicted lead solubility in October was 76% of that in February. But seasonally varying aluminum may also have been a factor; as a supplement to the field study, we evaluated the effects of aluminum residual, temperature, and orthophosphate concentration on lead release from lead coupons. Increasing the orthophosphate concentration from 0–1 mg/L decreased lead release by 34%, and increasing water temperature from 4–21˚C increased lead release by 120%. Increasing the aluminum concentration from 20–500 µg/L increased lead release by 41% and modified the effect of orthophosphate, rendering it less effective in controlling lead release. We attributed this to a decrease in the concentration of soluble (<0.45 µm) phosphorus with increasing aluminum and an accompanying increase in particulate lead and phosphorus (>0.45 µm). These data suggest that residual aluminum from coagulation may interfere with orthophosphate corrosion control, especially when the treatment process does not allow the pH of minimum aluminum hydroxide solubility to be targeted.
Seasonal lead release to drinking water and the effect of aluminum
Authors: Trueman Benjamin F , Bleasdale-Pollowy Aaron , Locsin Javier A , Bennett Jessica L , Krkošek Wendy H , Gagnon Graham A
Published: February 2022

Lead is a neurotoxin and an environmental contaminant. Many jurisdictions require that it be monitored in drinking water, especially where lead plumbing remains in use. But seasonal variation in lead concentrations can bias monitoring programs if it is not understood and accounted for. Here, we describe an unexpected pattern in lead release to drinking water, identified through point-of-use sampling. The median lead concentration representing paired first-draw water samples—collected in multiple years—was 46% lower in October compared to February. Seasonal variation in orthophosphate, pH, and alkalinity accounted for at least some of this pattern and predicted lead solubility in October was 76% of that in February. But seasonally varying aluminum may also have been a factor; as a supplement to the field study, we evaluated the effects of aluminum residual, temperature, and orthophosphate concentration on lead release from lead coupons. Increasing the orthophosphate concentration from 0–1 mg/L decreased lead release by 34%, and increasing water temperature from 4–21˚C increased lead release by 120%. Increasing the aluminum concentration from 20–500 µg/L increased lead release by 41% and modified the effect of orthophosphate, rendering it less effective in controlling lead release. We attributed this to a decrease in the concentration of soluble (<0.45 µm) phosphorus with increasing aluminum and an accompanying increase in particulate lead and phosphorus (>0.45 µm). These data suggest that residual aluminum from coagulation may interfere with orthophosphate corrosion control, especially when the treatment process does not allow the pH of minimum aluminum hydroxide solubility to be targeted.
NHCs and Visible Light Co-catalyzed 1,4-Sulfonylacylation of 1,3-Enynes for Tetrasubstituted Allenyl Ketones
Authors: Wang Lihong , Ma Ruiyang , Sun Jiaqiong , Zheng Guangfan , Zhang Qian
Published: February 2022

The modulation of selectivity of highly reactive carbon radical cross-coupling for the construction of C-C bonds represents a challenging task in organic chemistry. N-Heterocyclic carbenes (NHCs) catalyzed radical transformations opened a new avenue for acyl radical cross-coupling chemistry. With this method, highly selective cross-coupling of acyl radical with alkyl radical for efficient construction of C-C bonds were succussfully realized. However, the cross-coupling reaction of acyl radical with vinyl radicals represents an uncharted domain. We herein describe NHCs and photocatalysis co-catalyzed radical 1,4-sulfonylacylation of 1,3-enynes, providing structurally diversified valuable tetrasubstituted allenyl ketones. Mechanistic studies indicated that ketyl radicals are formed from aroyl fluorides via oxidative quenching process of excited photocatalysis, allenyl radicals are generated from chemo specific sulfonyl radical addition to the 1,3-enynes, finally, unprecedented key allenyl and ketyl radical cross-coupling provides tetrasubstituted allenyl ketones.
Palladium-Catalyzed intramolecular Cyclization of ‘2-bromo-1,5- di-ene-7-yne’System: A Versatile Route to the Poly-ene Substituted Cyclohexenols
Authors: Ray Jayanta Kumar , Paul Sunanda , Singha Raju
Published: February 2022

A general and efficient methodology has been developed for the synthesis of substituted cyclohexenol system with conjugated bis-exocyclic diene via Pd-catalyzed intramolecular 6-exo-dig cyclization of ‘ene-yne’ moiety. This method is straight forward and high yielding.
Oxygen Vacancy Modulated MnO2 Bi-Electrode System for Attomole-Level Pathogen Nucleic Acid Sequence Detection
Authors: Agarkar Tanvi , Nair Vandana Kuttappan , Tripathy Sayantan , Chawla Vipin , Ghosh Souradyuti , Kumar Ashvani
Published: February 2022

DNA amplification detection is typically a lengthy and sophisticated procedure involving high-end instrumentation. Electrochemical detection has recently opened a relatively low budget, a straightforward and speedy method for detection with the aid of an electrochemically active redox probe. However, electrochemical sensors of nucleic acid amplification characteristically employ a tri-electrode geometry involving standard reference electrode usually made up of a noble metal that adds up the cost of detection. This work proposes a sensitive and rapid approach for detecting the endpoint of nucleic acid amplification test using a novel bi-electrode sensing geometry. The sensing layer of the electrode was comprised of a transition metal oxide to tune its electronic state for regulating its electrochemical response. The fabricated device was then used to detect dengue virus sequence DNA (using rolling circle amplification) and Staphylococcus aureus genomic DNA (using polymerase chain reaction) with the limit of detection in the order of 103 target DNA copies.
Carbon-Negative Cement Manufacturing from Seawater-Derived Magnesium Feedstocks
Authors: Badjatya Palash , Akca Abdullah , Fraga Alvarez Daniela , Chang Baoqi , Ma Siwei , Pang Xueqi , Wang Emily , van Hinsberg Quinten , Esposito Daniel , Kawashima Shiho
Published: February 2022

This study describes and demonstrates a carbon-negative process for manufacturing cement from widely abundant seawater-derived magnesium (Mg) feedstocks. In contrast to conventional Portland cement, which starts with carbon-containing limestone as the source material, the proposed process uses membrane-free electrolyzers to facilitate the conversion of carbon-free magnesium ions (Mg2+) in seawater into magnesium hydroxide (Mg(OH)2) precursors for the production of Mg-based cement. After a low-temperature carbonation curing step converts Mg(OH)2 into magnesium carbonates through reaction with carbon dioxide (CO2), the resulting Mg-based binders can exhibit compressive strength comparable to that achieved by Portland cement after curing for only two days. Although the proposed “cement-from-seawater” process requires similar energy use per ton of cement as existing processes, its potential to achieve a carbon-negative footprint makes it highly attractive to decarbonize one of the most carbon intensive industries.
Computer Quiz Games in General Chemistry for Engineering Majors in an English as a Second Language Environment
Authors: Ling Szu Szu , Saffre Fabrice , Gater Deborah L. , Halim Lilia , Isakovic Abdel F.
Published: February 2022

Computer quiz games are introduced to improve teaching and learning in a freshman engineering chemistry course in an English-as-a-Second-Language (ESL) environment. These quiz games are developed and implemented as a supplemental and augmentative tool to enhance traditionally delivered lectures. The paper shows an increase in students’ motivation and compare the performance between students who participated in computer quiz games, a paper-based quiz or neither activity. Assessment of the effectiveness of quiz games in learning is conducted via a proposed novel chemistry achievement test, Freshman Engineering Chemistry Aptitude Test and an attitude questionnaire. The findings contribute to our understanding of the role of game-based learning in students’ achievement in chemistry and their motivation and attitudes towards learning general chemistry at a university within an ESL environment, while the computer games developed are useful in all English based Chemistry classes.
Assembly of pH-Responsive Antibody-Inspired Protein-Drug Conjugates
Authors: Raabe Marco , Heck Astrid , Pieszka Michaela , Wang Tao , Zegota Maksymilian Marek , Nuhn Lutz , Ng David Y. W. , Kuan Seah Ling , Weil Tanja
Published: February 2022

With the advent of chemical strategies that allow the design of smart bioconjugates, peptide- and protein-drug conjugates are emerging as highly efficient therapeutics to overcome limitations of conventional treatment, as exemplified by antibody-drug conjugates. While targeting peptides serve similar roles as antibodies to recognize overexpressed receptors on diseased cell surfaces, peptide-drug conjugates suffer from poor stability and bioavailability due to their low molecular weights. Through a combination of a supramolecular protein-based assembly platform and a pH-responsive dynamic covalent linker, we devise herein the convenient assembly of a trivalent protein-drug conjugate. The conjugate mimics key features of antibody-drug conjugates such as (1) a multipartite structure, (2) peptide recognition sites arranged at distinct locations and at defined distances, (3) a high molecular weight protein scaffold, and (4) an attached drug molecule. These antibody-inspired protein-drug conjugates target cancer cells that overexpress somatostatin receptors, enable controlled release in the microenvironment of cancer cells through an entirely new dynamic covalent biotin linker and exhibit stability in biological media.
DiSCoVeR: a Materials Discovery Screening Tool for High Performance, Unique Chemical Compositions
Authors: Baird Sterling , Diep Tran , Sparks Taylor
Published: February 2022

We present Descending from Stochastic Clustering Variance Regression (DiSCoVeR), a Python tool for identifying high-performing, chemically unique compositions relative to existing compounds using a combination of a chemical distance metric, density-aware dimensionality reduction, and clustering. We introduce several new metrics for materials discovery and validate DiSCoVeR on Materials Project bulk moduli using compound-wise and cluster-wise validation methods. We visualize these via multiobjective Pareto front plots and assign a weighted score to each composition where this score encompasses the trade-off between performance and density-based chemical uniqueness. We explore an additional uniqueness proxy related to property gradients in chemical space. We demonstrate that DiSCoVeR can successfully screen materials for both performance and uniqueness in order to extrapolate to new chemical spaces.
Revealing the contest between triplet-triplet exchange and triplet-triplet energy transfer coupling in correlated triplet pair states in singlet fission
Authors: Abraham Vibin , Mayhall Nicholas
Published: February 2022

Understanding the separation of the correlated triplet pair state 1(TT) intermediate is critical for leveraging singlet fission to improve solar cell efficiency. This separation mechanism is dominated by two key interactions: (i) the exchange interaction (K) between the triplets which leads to the spin splitting of the biexciton state into 1(TT),3(TT) and 5(TT) states, and (ii) the triplet-triplet energy transfer integral (t) which enables the formation of the spatially separated (but still spin entangled) state 1(T...T). We develop a simple ab initio technique to compute both the biexciton exchange (K) and biexciton transfer coupling. Our key findings reveal new conditions for successful correlated triplet pair state dissociation. The biexciton exchange interaction needs to be ferromagnetic or negligible to the triplet energy transfer for favourable dissociation. We also explore the effect of chromophore packing to reveal geometries where these conditions are achieved for tetracene.
Study on the structure vs activity of designed non-precious metal electrocatalysts for CO2 conversion
Authors: Rao Tingke , Yuan Wangchao , Jeyachandran Nivetha , Nabi Azeem Ghulam , Di Tommaso Devis , Giordano Cristina
Published: February 2022

The rising level of carbon dioxide (CO2), mainly a consequence of human activities, it is leading to devastating consequences to our environment and has raised concerns to the public opinion. To face this issue, governments are working to reduce the level of CO2 emissions, whilst the scientific community is focusing to implement the electro-chemical conversion of the emitted CO2 (CO2RR) as source of added value chemicals. Due to the high stability of the CO2 molecule, to make its conversion practical, the process requires a suitable electro-catalyst. With the aim to understand the mechanism toward specific CO2RR product and thus increase selectivity, in this contribution, we have explored copper nanoparticles (Cu NPs), as one of the most promising catalyst for CO2 conversion, and investigated the reactivity as a function of selected experimental parameters. The results were rationalized via theoretical investigation, also discussed in the paper, to understand the mechanism behind their activity but, most importantly, to relate structure to selectivity. The Cu NPs, prepared via an unconventional sol-gel process, were shown to be pure, with homogeneous size and morphology, and were tested toward CO2RRs showing a total FE above 90%. The higher FE toward the production of C2H4 (up to 33% at an applied potential of -1.0 V) is one of the highest FE reported so far for Cu, without using expensive support. The final products were characterized using X-ray diffraction (XRD) and scanning electron microscopy (SEM).
JAEGER – Hunting for Antimalarials with Generative Chemistry
Authors: Godinez William , Ma Eric , Chao Alexander , Pei Luying , Skewes-Cox Peter , Canham Stephen , Jenkins Jeremy , Young Joseph , Martin Eric , Guiguemde Armand
Published: February 2022

Recent advances in generative modeling allow designing novel compounds through deep neural networks. One such neural network model, the Junction Tree Variational Auto- Encoder (JT-VAE), excels at proposing chemically valid structures. Based on JT-VAE, we built a generative modeling approach (JAEGER) for finding novel chemical matter with desired bioactivity. Using JAEGER, we designed compounds to inhibit malaria. To prioritize the compounds for synthesis, we used the in-house Profile-QSAR (pQSAR) program, a massively-multitask bioactivity model based on 12,000 Novartis assays. Based on the pQSAR activity predictions, we selected, synthesized, and experimentally profiled two compounds. Both compounds exhibited low nanomolar activity in a malaria proliferation assay as well as a biochemical assay measuring activity against PI(4)K, which is an essential kinase that regulates intracellular development in malaria. The compounds also showed low activity in a cytotoxicity assay. Our findings show that JAEGER is a viable approach for finding novel active compounds for drug discovery.
Graph-Based Approaches for Predicting Solvation Energy in Multiple Solvents: Open Datasets and Machine Learning Models
Authors: Ward Logan , Dandu Naveen , Blaiszik Ben , Narayanan Badri , Assary Rajeev S. , Redfern Paul C. , Foster Ian , Curtiss Larry A.
Published: February 2022

The solvation properties of molecules, often estimated using quantum chemical simulations, are important in the synthesis of energy storage materials, drugs, and industrial chemicals. Here, we develop machine learning models of solvation energies to replace expensive quantum chemistry calculations with inexpensive-to-compute message-passing neural network models that require only the molecular graph as inputs. Our models are trained on a new database of solvation energies for 130,258 molecules taken from the QM9 dataset computed in five solvents (acetone, ethanol, acetonitrile, dimethyl sulfoxide, and water) via an implicit solvent model. Our best model achieves a mean absolute error of 0.5 kcal/mol for molecules with nine or fewer non-hydrogen atoms and 1 kcal/mol for molecules with between 10 and 14 non-hydrogen atoms. We make the entire dataset of 651,290 computed entries openly available and provide simple web and programmatic interfaces to enable others to run our solvation energy model on new molecules. This model calculates the solvation energies for molecules using only the SMILES string and also provides an estimate of whether each molecule is within the domain of applicability of our model. We envision that the dataset and models will provide the functionality needed for the rapid screening of large chemical spaces to discover improved molecules for many applications.
Design, Synthesis and Biological Evaluation of Novel SARS-CoV-2 3CLpro Covalent Inhibitors
Authors: Stille Julia , Tjutrins Jevgenijs , Wang Guanyu , Venegas Felipe A. , Hennecker Christopher , Rueda Andres Mauricio , Sharon Itai , Blaine Nicole , Miron Caitlin E. , Pinus Sharon , Labarre Anne , Plescia Jessica , Patrascu Mihai Burai , Zhang Xiaocong , Wahba Alexander S. , Vlaho Danielle , Huot Mitchell , Schmeing T. Martin , Mittermaier Anthony K , Moitessier Nicolas
Published: February 2022

Severe diseases such as the ongoing COVID-19 pandemic, as well as the previous SARS and MERS outbreaks, are the result of coronavirus infections and have demonstrated the urgent need for antiviral drugs to combat these deadly viruses. Due to its essential role in viral replication and function, 3CLpro> has been identified as a promising target for the development of antiviral drugs. Previously reported SARS-CoV 3CLpro non-covalent inhibitors were used as a starting point for the development of covalent inhibitors of SARS-CoV-2 3CLpro. We report herein our efforts in design and synthesis which led to submicromolar covalent inhibitors when the enzymatic activity of the viral protease was used as a screening platform.
Caught in the act: Observation of the solvent response triggered by excited-state proton transfer in real time
Authors: Hoberg Claudius , Ockelmann Thorsten , Shee James , Balzerowski Patrick , DasMahanta Debasish , Novelli Fabio , Head-Gordon Martin , Havenith Martina
Published: February 2022

Real-time observation of the solvent response following Excited State Proton Transfer (ESPT) of the photoacid HPTS into water using Optical Pump THz Probe (OPTP) spectroscopy from 0.1 ps up to 300 ps is reported. Subsequent to an instantaneous (< 0.2 ps) electronic response of the solute to photoexcitation, an oscillation with a period of 4 ps involving an intermolecular H (pyranine) - O (water) mode is observed. While for the methylated derivative, MPTS, and the deprotonated photoacid this oscillation relaxes on a time scale of 1.5 – 2 ps, for HPTS the oscillation decays more rapidly within 0.4 ps, which marks the onset of proton transfer. Energy transfer from the excited solute to the solvent takes place on a time scale of 120 ps and is proportional to the Stokes shift associated with energetic relaxation from the Franck-Condon region to the ground state of the photoexcited HPTS.
How Stable Are 2H-MoS2 Edges Under Hydrogen Evolution Reaction Conditions?
Authors: Abidi Nawras , Bonduelle-Skrzypczak Audrey , Steinmann Stephan
Published: February 2022

MoS2, have emerged as a promising class of electrocatalysts for the production of H2 via the hydrogen evolution reaction (HER) in acidic conditions.The edges of MoS2 are known for their HER activity, but their precise atomistic nature and stability under HER conditions is not yet known. In contrast to other typical uses of MoS2 as a catalyst, under HER there is no external source of sulfur. Therefore, the sulfidation of the edges can only decrease under operating conditions and the thermodynamics of the process are somewhat ill-defined. Our results suggest that the 50%S S-edge may be active for HER via the Volmer-Tafel mechanism and is, despite a high H coverage, stable with respect to H2S release. At the 50%S Mo-edge, the adsorbed hydrogen opens the way for H2S release, leading to the 0%S Mo-edge, which was previously investigated and found to be HER active. HER being a water-based process, we also considered the effect of the presence of H2O and the in-situ formation of OH. For the 50%S Mo-edge, H2O is only very weakly adsorbed and OH formation is unfavorable. Nevertheless, OH assists the loss of sulfur coverage, leading to OH-based HER active sites. In contrast, OH is strongly adsorbed on the 50%S S-edge. By explicitly considering the electrochemical potential using grand-canonical density functional theory, we unveil that the Volmer-Heyrovsky mechanism on sulfur sites is still accessible in the presence of surface OH at the 50%S S-edge. However, the 50%S S-edge is found to be mildly unstable with respect to H2S in the presence of water/OH. Hence, we suggest that the 50%S S-edge evolves over time towards a 0%S S-edge, covered by surface OH that will block permanently the active sites.
The catalytic mechanism of the Suzuki-Miyaura reaction
Authors: macharia Juliet , Joshi Chetan , Izzo Joseph , Wambua Victor , Kim Sungjin , Hirschi Jennifer , Vetticatt Mathew
Published: February 2022

Abstract: Experimental and theoretical 13C kinetic isotope effects are utilized to obtain atomistic insight into the catalytic mechanism of the Pd(PPh3)4 catalyzed Suzuki-Miyaura reaction of aryl halides and aryl boronic acids. Under catalytic conditions, we establish that oxidative addition of aryl bromides occurs to a 12-electron monoligated palladium complex (Pd(PPh3)). For aryl iodides, the first irreversible step in the catalytic cycle precedes oxidative addition and is shown to be binding of the iodoarene to Pd(PPh3). Our results suggest that the commonly proposed oxidative addition to the 14-electron Pd(PPh3)2 complex can occur only in the presence of excess added ligand or under stoichiometric conditions. The transmetalation step, under catalytic conditions, is shown to proceed via a tetracoordinate boronate (8B4) intermediate with a Pd-O-B linkage.
Exploring Electrochemical C(sp3)–H Oxidation for the Late-Stage Methylation of Complex Molecules
Authors: Lin Song , Novaes Luiz , Ho Justin , Mao Kaining , Liu Kaida , Tanwar Mayank , Neurock Matthew , Villemure Elisia , Terrett Jack
Published: February 2022

The “magic methyl” effect – a dramatic boost in the potency of biologically active compounds from the incorporation of a single methyl group – provides a simple yet powerful strategy employed by medicinal chemists in the drug discovery process. Despite significant advances, methodologies that enable the selective C(sp3)–H methylation of structurally complex medicinal agents remain very limited. In this work, we disclose a modular, efficient, and selective strategy for the α-methylation of protected amines (i.e., amides, carbamates, and sulfonamides) by means of electrochemical oxidation. Mechanistic analysis guided our development of an improved electrochemical protocol on the basis of the classic Shono oxidation reaction, which features broad reaction scope, high functional group compatibility, and operational simplicity. Importantly, this reaction system is amenable to the late-stage functionalization of complex targets containing basic nitrogen groups that are prevalent in medicinally active agents. When combined with organozinc-mediated C–C bond formation, our protocol enabled the direct methylation of a myriad of amine derivatives including those that have previously been explored for the “magic methyl” effect. This synthetic strategy thus circumvents multistep de novo synthesis that is currently necessary to access such compounds and has the potential to accelerate drug discovery efforts.
Mechanistic insights of key host proteins and potential repurposed inhibitors regulating SARS-CoV-2 pathway
Authors: Pramanik Debabrata , Pawar Aiswarya , Roy Sudip , Singh Jayant K
Published: February 2022

The emergence of pandemic situations originated from SARS-CoV-2 and its new variants created worldwide medical emergencies. Due to the non-availability of efficient drugs and vaccines, hundreds of thousands of people succumbed to death intoxicated by this virus. At these emergency hours, repurposing existing drugs can effectively treat patients critically infected by SARS-CoV-2. Using a high-throughput screening approach, we validated a list of potential repurposed drugs, like Nafamostat, Camostat, Silmitasertib, Valproic acid, Zotatifin, and essential host target proteins HDAC2, eIF4E2, CSK22, that are essential for viral mechanism. We determined multiple dissociation pathways of repurposed drugs, suggesting the availability of sub pockets within the host target proteins. We showed the preferential residues involved in the (un)binding kinetics of the ligands correlated to the underlying mechanism of the host protein activity. Interestingly, the residues we obtained for HDAC2 and CSK22 target proteins, which we highlighted, are also involved in the catalytic activity. The mechanistic insight presented in this work is envisaged to help use these key host proteins and potential repurposed drugs as a treatment for the SARS-CoV-2 virus.
Identifying Nonadditive Contributions to the Hydrophobicity of Chemically Heterogeneous Surfaces via Dual-Loop Active Learning
Authors: Kelkar Atharva , Dallin Bradley , Van Lehn Reid
Published: February 2022

Hydrophobic interactions drive numerous phenomena involving surfaces that are chemically heterogeneous at the nanoscale. Nonadditive contributions to the hydrophobicity of such surfaces depend on the chemical identities and spatial patterns of polar and nonpolar groups in ways that remain poorly understood. Here, we develop an active learning framework that utilizes molecular dynamics (MD) simulations, enhanced sampling, and a convolutional neural network to predict the hydration free energy (a thermodynamic descriptor of hydrophobicity) for nearly 200,000 chemically heterogeneous self-assembled monolayers (SAMs). Analysis of this data set reveals that SAMs with distinct polar groups exhibit substantial variations in hydrophobicity as a function of their composition and patterning, but the clustering of nonpolar groups is a common signature of highly hydrophobic patterns. Further MD analysis relates such clustering to the perturbation of interfacial water structure. These results provide new insight into the influence of chemical heterogeneity on hydrophobicity via quantitative analysis of a large set of surfaces, enabled by the active learning approach.