Highly Selective On-Surface Ring-Opening of Aromatic Azulene Moiety.

Controllable ring-opening of polycyclic aromatic hydrocarbons plays a crucial role in various chemical and biological processes. However, breaking down aromatic covalent C-C bonds is exceptionally challenging due to their high stability and strong aromaticity. This study presents a seminal report on the precise and highly selective on-surface ring-opening of the seven-membered ring within the aromatic azulene moieties under mild conditions. The chemical structures of the resulting products were identified using bond-resolved scanning probe microscopy. Furthermore, through density functional theory calculations, we uncovered the mechanism behind the ring-opening process and elucidated its chemical driving force. The key to achieving this ring-opening process lies in manipulating the local aromaticity of the aromatic azulene moiety through strain-induced internal ring rearrangement and cyclodehydrogenation. By precisely controlling these factors, we successfully triggered the desired ring-opening reaction. Our findings not only provide valuable insights into the ring-opening process of polycyclic aromatic hydrocarbons but also open up new possibilities for the manipulation and reconstruction of these important chemical structures.

Enhancing silicon-nitride formation through ammonolysis of silanes with pseudo-halide substituents.

Considering the challenges in reactivity, potential contamination, and substrate selectivity, the ammonolysis of traditional halosilanes in silicon nitride (SiN) thin film processing motivates the exploration of alternative precursors. In this pioneering study, we employed density functional theory calculations at the M06-2X/6-311++G(3df,2p) level to comprehensively screen potential pseudo-halide substituents on silane compounds as substitutes for conventional halosilanes. Initially, we investigated the ammonolysis mechanism of halosilanes, exploring factors influencing activation barriers, with the aid of frontier molecular orbital and charge density analyses. Subsequently, a systematic screening of silane substituents from group 14 to group 16 was conducted to identify pseudo-halides with low reaction barriers. Additionally, we examined the inductive effects on pseudohalide substituents. Using cluster models to represent the silicon surface validates the realistic prediction of ammonolysis barriers with a simplified model. Our findings indicate that pseudo-halide substituents from group 16, particularly those with electron-withdrawing groups, present as practical alternatives to traditional halosilanes in SiN thin film processing, including applications such as low-temperature atomic layer deposition (ALD) techniques.

Targeting Pathogenic Formate-Dependent Bacteria with a Bioinspired Metallo-Nitroreductase Complex.

Nitroreductases (NTRs) constitute an important class of oxidoreductase enzymes that have evolved to metabolize nitro-containing compounds. Their unique characteristics have spurred an array of potential uses in medicinal chemistry, chemical biology, and bioengineering toward harnessing nitro caging groups and constructing NTR variants for niche applications. Inspired by how they carry out enzymatic reduction via a cascade of hydride transfer reactions, we sought to develop a synthetic small-molecule NTR system based on transfer hydrogenation mediated by transition metal complexes harnessing native cofactors. We report the first water-stable Ru-arene complex capable of selectively and fully reducing nitroaromatics into anilines in a biocompatible buffered aqueous environment using formate as the hydride source. We further demonstrated its application to activate nitro-caged sulfanilamide prodrug in formate-abundant bacteria, specifically pathogenic methicillin-resistant Staphylococcus aureus. This proof of concept paves the way for a new targeted antibacterial chemotherapeutic approach leveraging on redox-active metal complexes for prodrug activation via bioinspired nitroreduction.

Hybrid Electrolyte Design for High-Performance Zinc-Sulfur Battery.

Rechargeable aqueous Zn/S batteries exhibit high capacity and energy density. However, the long-term battery performance is bottlenecked by the sulfur side reactions and serious Zn anode dendritic growth in the aqueous electrolyte medium. This work addresses the problem of sulfur side reactions and zinc dendrite growth simultaneously by developing a unique hybrid aqueous electrolyte using ethylene glycol as a co-solvent. The designed hybrid electrolyte enables the fabricated Zn/S battery to deliver an unprecedented capacity of 1435 mAh g-1 and an excellent energy density of 730 Wh kg-1 at 0.1 Ag-1 . In addition, the battery exhibits capacity retention of 70% after 250 cycles even at 3 Ag-1 . Moreover, the cathode charge-discharge mechanism studies demonstrate a multi-step conversion reaction. During discharge, the elemental sulfur is sequentially reduced by Zn to S2- ( S 8 → S x 2 - → S 2 2 - + S 2 - ) ${{\rm{S}}_8}{\bm{ \to }}{\rm{S}}_{\rm{x}}^{2{\bm{ - }}}{\bm{ \to }}{\rm{S}}_2^{2{\bm{ - }}}{\bm{ + }}{{\rm{S}}^{2{\bm{ - }}}})$ , forming ZnS. On charging, the ZnS and short-chain polysulfides will oxidize back to elemental sulfur. This electrolyte design strategy and unique multi-step electrochemistry of the Zn/S system provide a new pathway in tackling both key issues of Zn dendritic growth and sulfur side reactions, and also in designing better Zn/S batteries in the future.

Dispersion-Corrected DFT-D4 Study of the Adsorption of Halobenzenes and 1,3,5-Trihalobenzenes on the Cu(111) Surface─Effect of Sigma Hole Properties.

Halogen bonds, characterized by directionality, tunability, hydrophobicity, and variable sizes, are ideal noncovalent interactions to design and control the formation of self-assembled nanostructures. The specific self-assembly cases formed by the halogen-bonding interaction have been well studied by scanning tunneling microscopy (STM) experiments and density functional theory (DFT) calculations. However, there is a lack of systematic theoretical adsorption studies on halogenated molecules. In this work, the adsorption of halobenzenes and 1,3,5-trihalobenzenes on the Cu(111) surface was examined by dispersion-corrected DFT methods. The adsorption geometries, noncovalent molecule-surface interactions, electronic densities, and electrostatic potential maps were examined for their most stable adsorption sites using the DFT-D4 method. Our calculations revealed that the iodo compounds favor a different adsorption geometry from aryl chlorides and bromides. Down the halogen group (Cl to I), the adsorption energy increases and the distance between the halogen atom and Cu surface decreases, which indicates stronger molecule-surface interactions. This is supported by the changes in the density of states upon adsorption. Noncovalent interaction analysis was also employed to further understand the nature and relative strength of the molecule-surface interactions. Electrostatic potential maps revealed that the positive character of the halogen sigma hole becomes stronger upon adsorption. Thus, surface adsorption of the halogenated molecule will enhance the formation of intermolecular halogen bonds. The present theoretical findings are expected to contribute toward a more comprehensive understanding of halogen bonding on the Cu(111) surface.

A Computational Study on the Reaction Mechanism of Stereocontrolled Synthesis of ß-Lactam within [2]Rotaxane.

The macrocycle effect of [2]rotaxane on the highly trans-stereoselective cyclization reaction of N-benzylfumaramide was extensively investigated by various computational methods, including DFT and high-level DLPNO-CCSD(T) methods. Our computational results suggest that the most favorable mechanism of the CsOH-promoted cyclization of the fumaramide into trans-ß-lactam within [2]rotaxane initiates with deprotonation of a N-benzyl group of the interlocked fumaramide substrate by CsOH, followed by the trans-selective C-C bond formation and protonation by one amide functional group of the macrocycle. Our distortion/interaction analysis further shows that the uncommon trans-stereoselective cyclization forming ß-lactam within the rotaxane may be attributed to a higher distortion energy (mainly from the distortion of the twisted cis-fumaramide conformation enforced by the rotaxane). Our systematic study should give deeper mechanistic insight into the reaction mechanism influenced by a supramolecular host.

Halogen Bonding in Haspin-Halogenated Tubercidin Complexes: Molecular Dynamics and Quantum Chemical Calculations.

Haspin, an atypical serine/threonine protein kinase, is a potential target for cancer therapy. 5-iodotubercidin (5-iTU), an adenosine derivative, has been identified as a potent Haspin inhibitor in vitro. In this paper, quantum chemical calculations and molecular dynamics (MD) simulations were employed to identify and quantitatively confirm the presence of halogen bonding (XB), specifically halogen∙∙∙π (aromatic) interaction between halogenated tubercidin ligands with Haspin. Consistent with previous theoretical finding, the site specificity of the XB binding over the ortho-carbon is identified in all cases. A systematic increase of the interaction energy down Group 17, based on both quantum chemical and MD results, supports the important role of halogen bonding in this series of inhibitors. The observed trend is consistent with the experimental observation of the trend of activity within the halogenated tubercidin ligands (F < Cl < Br < I). Furthermore, non-covalent interaction (NCI) plots show that cooperative non-covalent interactions, namely, hydrogen and halogen bonds, contribute to the binding of tubercidin ligands toward Haspin. The understanding of the role of halogen bonding interaction in the ligand-protein complexes may shed light on rational design of potent ligands in the future.

Asymmetric Nucleophilic Allylation of α-Chloro Glycinate via Squaramide Anion-Abstraction Catalysis: SN1 or SN2 Mechanism, or Both?

The nucleophilic substitution mechanism of enantioselective allylation of α-chloro glycinate catalyzed by squaramide organocatalysts was studied using density functional theory. Based on a comprehensive study of SN1 and SN2 pathways of a catalyst-free reaction, we found that the catalytic reaction slightly favors the SN1 mechanism, instead of the previously proposed SN2 mechanism. Further investigation of different leaving groups and nucleophiles revealed that this is not limited to the present reaction, and the SN1 mechanism might have been generally overlooked. For the squaramide-catalyzed reactions, the SN1 mechanism was predicted to be preferred. However, the rate-determining step of the SN1 pathway has changed from the chloride-leaving step to the C-C bond-formation step. Therefore, a first-order dependence on both substrates was predicted, in agreement with the observed second-order kinetics. Intriguingly, the lowest-energy enantioselective transition states (TSs) originate from different pathways; R-inducing TS corresponds to the SN1 pathway, while S-inducing TS corresponds to SN2. The calculated enantiomeric excesses of two squaramide catalysts agree well with the experimental values. Given the ubiquity of nucleophilic substitution reactions in chemistry and biology, we believe that our finding will inspire more studies that will lead to an improved mechanistic understanding of important chemical reactions, and it may even lead to better catalysts.

In silico characterization and prediction of thiourea-like neutral bidentate halogen bond catalysts.

Preorganization is a common strategy to align halogen bond (XB) donors to form two or more halogen bonds simultaneously. Previous approaches have utilized various non-covalent interactions such as steric interactions, ππ stacking, and hydrogen bond interactions. However, some of the introduced aligning interactions may compete with halogen bond interactions if the donors are employed in catalysis. To achieve thiourea-like properties, we have designed in silico several neutral bidentate halogen bond donors in whose structures the donor moieties are connected via covalent bonds. Compared to previous XB catalyst designs, the new design does not involve other potentially competitive non-covalent interactions such as hydrogen bonds. One of the designed XB donors can deliver strong halogen bonds, with a O-I distance as short as 2.64 Å. Density functional theory (DFT) calculations predicted that our designed catalysts may catalyze important organic reactions on their own, particularly for those reactions that involve (developing) soft anions such as thiolates.

Column Characterization and Selection Systems in Reversed-Phase High-Performance Liquid Chromatography.

Reversed-phase high-performance liquid chromatography (RP-HPLC) is the most popular chromatographic mode, accounting for more than 90% of all separations. HPLC itself owes its immense popularity to it being relatively simple and inexpensive, with the equipment being reliable and easy to operate. Due to extensive automation, it can be run virtually unattended with multiple samples at various separation conditions, even by relatively low-skilled personnel. Currently, there are >600 RP-HPLC columns available to end users for purchase, some of which exhibit very large differences in selectivity and production quality. Often, two similar RP-HPLC columns are not equally suitable for the requisite separation, and to date, there is no universal RP-HPLC column covering a variety of analytes. This forces analytical laboratories to keep a multitude of diverse columns. Therefore, column selection is a crucial segment of RP-HPLC method development, especially since sample complexity is constantly increasing. Rationally choosing an appropriate column is complicated. In addition to the differences in the primary intermolecular interactions with analytes of the dispersive (London) type, individual columns can also exhibit a unique character owing to specific polar, hydrogen bond, and electron pair donor-acceptor interactions. They can also vary depending on the type of packing, amount and type of residual silanols, "end-capping", bonding density of ligands, and pore size, among others. Consequently, the chromatographic performance of RP-HPLC systems is often considerably altered depending on the selected column. Although a wide spectrum of knowledge is available on this important subject, there is still a lack of a comprehensive review for an objective comparison and/or selection of chromatographic columns. We aim for this review to be a comprehensive, authoritative, critical, and easily readable monograph of the most relevant publications regarding column selection and characterization in RP-HPLC covering the past four decades. Future perspectives, which involve the integration of state-of-the-art molecular simulations (molecular dynamics or Monte Carlo) with minimal experiments, aimed at nearly "experiment-free" column selection methodology, are proposed.

Tailoring long-range superlattice chirality in molecular self-assemblies via weak fluorine-mediated interactions.

Controllable fabrication of enantiospecific molecular superlattices is a matter of imminent scientific and technological interest. Herein, we demonstrate that long-range superlattice chirality in molecular self-assemblies can be tailored by tuning the interplay of weak intermolecular non-covalent interactions between hexaphenylbenzene-based enantiomers. By means of high-resolution scanning tunneling microscopy measurements, we demonstrate that the functionalization of a hexaphenylbenzene-based molecule with fluorine (F) atoms leads to the formation of molecular self-assemblies with distinct long-range chiral recognition patterns. We employed density functional theory calculations to quantify F-mediated lone pair F⋯π, C-H⋯F, and F⋯F interactions attributed to the distinct enantiospecific molecular self-organizations. Our findings underpin a viable route to fabricate long-range chiral recognition patterns in supramolecular assemblies by engineering the weak non-covalent intermolecular interactions.

Anion Texturing Towards Dendrite-Free Zn Anode for Aqueous Rechargeable Batteries.

The reversibility of metal anode is a fundamental challenge to the lifetime of rechargeable batteries. Though being widely employed in aqueous energy storage systems, metallic zinc suffers from dendrite formation that severely hinders its applications. Here we report texturing Zn as an effective way to address the issue of zinc dendrite. An in-plane oriented Zn texture with preferentially exposed (002) basal plane is demonstrated via a sulfonate anion-induced electrodeposition, noting no solid report on (002) textured Zn till now. Anion-induced reconstruction of zinc coordination is revealed to be responsible for the texture formation. Benchmarking against its (101) textured-counterpart by the conventional sulphate-based electrolyte, the Zn (002) texture enables highly reversible stripping/plating at a high current density of 10 mA cm-2 , showing its dendrite-free characteristics. The Zn (002) texture-based aqueous zinc battery exhibits excellent cycling stability. The developed anion texturing approach provides a pathway towards exploring zinc chemistry and prospering aqueous rechargeable batteries.

Bicyclic Guanidine-Catalyzed Asymmetric Cycloaddition Reaction of Anthrones-Bifunctional Binding Modes and Origin of Stereoselectivity.

We report a computational analysis of the [5,5] bicyclic guanidine-catalyzed asymmetric cycloaddition reaction of anthrones. Based on extensive conformational search of key intermediates and transition states on the potential energy surface and density functional theory calculations, we studied five plausible binding modes between the guanidine catalyst and substrates for this reaction. Our results indicate that the most favorable pathway is a stepwise conjugate addition-Aldol sequence via the dual hydrogen-bond binding mode. The predicted level of enantioselectivity is in good agreement with experimental values. Trends in variation of substrates and catalysts have also been reproduced by our calculations. Decomposition analysis revealed the significance of aromatic interactions in stabilizing the key enantioselectivity-determining transition state structures.

Mechanistic Chromatographic Column Characterization for the Analysis of Flavonoids Using Quantitative Structure-Retention Relationships Based on Density Functional Theory.

This work aimed to unravel the retention mechanisms of 30 structurally different flavonoids separated on three chromatographic columns: conventional Kinetex C18 (K-C18), Kinetex F5 (K-F5), and IAM.PC.DD2. Interactions between analytes and chromatographic phases governing the retention were analyzed and mechanistically interpreted via quantum chemical descriptors as compared to the typical 'black box' approach. Statistically significant consensus genetic algorithm-partial least squares (GA-PLS) quantitative structure retention relationship (QSRR) models were built and comprehensively validated. Results showed that for the K-C18 column, hydrophobicity and solvent effects were dominating, whereas electrostatic interactions were less pronounced. Similarly, for the K-F5 column, hydrophobicity, dispersion effects, and electrostatic interactions were found to be governing the retention of flavonoids. Conversely, besides hydrophobic forces and dispersion effects, electrostatic interactions were found to be dominating the IAM.PC.DD2 retention mechanism. As such, the developed approach has a great potential for gaining insights into biological activity upon analysis of interactions between analytes and stationary phases imitating molecular targets, giving rise to an exceptional alternative to existing methods lacking exhaustive interpretations.

Application of Halogen Bonding to Organocatalysis: A Theoretical Perspective.

The strong, specific, and directional halogen bond (XB) is an ideal supramolecular synthon in crystal engineering, as well as rational catalyst and drug design. These attributes attracted strong growing interest in halogen bonding in the past decade and led to a wide range of applications in materials, biological, and catalysis applications. Recently, various research groups exploited the XB mode of activation in designing halogen-based Lewis acids in effecting organic transformation, and there is continual growth in this promising area. In addition to the rapid advancements in methodology development, computational investigations are well suited for mechanistic understanding, rational XB catalyst design, and the study of intermediates that are unstable when observed experimentally. In this review, we highlight recent computational studies of XB organocatalytic reactions, which provide valuable insights into the XB mode of activation, competing reaction pathways, effects of solvent and counterions, and design of novel XB catalysts.

Prediction of Chromatographic Elution Order of Analytical Mixtures Based on Quantitative Structure-Retention Relationships and Multi-Objective Optimization.

Prediction of the retention time from the molecular structure using quantitative structure-retention relationships is a powerful tool for the development of methods in reversed-phase HPLC. However, its fundamental limitation lies in the fact that low error in the prediction of the retention time does not necessarily guarantee a prediction of the elution order. Here, we propose a new method for the prediction of the elution order from quantitative structure-retention relationships using multi-objective optimization. Two case studies were evaluated: (i) separation of organic molecules in a Supelcosil LC-18 column, and (ii) separation of peptides in seven columns under varying conditions. Results have shown that, when compared to predictions based on the conventional model, the relative root mean square error of the elution order decreases by 48.84%, while the relative root mean square error of the retention time increases by 4.22% on average across both case studies. The predictive ability in terms of both retention time and elution order and the corresponding applicability domains were defined. The models were deemed stable and robust with few to no structural outliers.

Affinity of Antifungal Isoxazolo[3,4-b]pyridine-3(1H)-Ones to Phospholipids in Immobilized Artificial Membrane (IAM) Chromatography.

Currently, rapid evaluation of the physicochemical parameters of drug candidates, such as lipophilicity, is in high demand owing to it enabling the approximation of the processes of absorption, distribution, metabolism, and elimination. Although the lipophilicity of drug candidates is determined using the shake flash method (n-octanol/water system) or reversed phase liquid chromatography (RP-LC), more biosimilar alternatives to classical lipophilicity measurement are currently available. One of the alternatives is immobilized artificial membrane (IAM) chromatography. The present study is a continuation of our research focused on physiochemical characterization of biologically active derivatives of isoxazolo[3,4-b]pyridine-3(1H)-ones. The main goal of this study was to assess the affinity of isoxazolones to phospholipids using IAM chromatography and compare it with the lipophilicity parameters established by reversed phase chromatography. Quantitative structure-retention relationship (QSRR) modeling of IAM retention using differential evolution coupled with partial least squares (DE-PLS) regression was performed. The results indicate that in the studied group of structurally related isoxazolone derivatives, discrepancies occur between the retention under IAM and RP-LC conditions. Although some correlation between these two chromatographic methods can be found, lipophilicity does not fully explain the affinities of the investigated molecules to phospholipids. QSRR analysis also shows common factors that contribute to retention under IAM and RP-LC conditions. In this context, the significant influences of WHIM and GETAWAY descriptors in all the obtained models should be highlighted.

Diastereo- and Atroposelective Synthesis of Bridged Biaryls Bearing an Eight-Membered Lactone through an Organocatalytic Cascade.

We present herein an unprecedented stereoselective synthesis of bridged biaryls with defined axial and central chirality from readily available starting materials. This N-heterocyclic carbene-catalyzed method proceeds through propargylic substitution of azolium enolates followed by two-directional cyclization, as supported by DFT calculation. A range of benzofuran/indole-derived bridged biaryls bearing an eight-membered lactone are accessed with uniformly high stereoselectivity (>98:2 dr, mostly >98% ee).

Modeling halogen bonding with planewave density functional theory: Accuracy and challenges.

Inspired by the recent interest of halogen bonding (XB) in the solid state, we detail a comprehensive benchmark study of planewave DFT geometry and interaction energy of lone-pair (LP) type and aromatic (AR) type halogen bonded complexes, using PAW and USPP pseudopotentials. For LP-type XB dimers, PBE-PAW generally agrees with PBE/aug-cc-pVQZ(-pp) geometries but significantly overbinds compared to CCSD(T)/aug-cc-pVQZ(-pp). Grimme's D3 dispersion corrections to PBE-PAW gives better agreement to the MP2/cc-pVTZ(-pp) results for AR-type dimers. For interaction energies, PBE-PAW may overbind or underbind for weaker XBs but clearly overbinds for stronger XBs. D3 dispersion corrections exacerbate the overbinding problem for LP-type complexes but significantly improves agreement for AR-type complexes compared to CCSD(T)/CBS. Finally, for periodic XB crystals, planewave PBE methods slightly underestimate the XB lengths by 0.03 to 0.05 Å. © 2019 Wiley Periodicals, Inc.

Iodoimidazolinium-Catalyzed Reduction of Quinoline by Hantzsch Ester: Halogen Bond or Brønsted Acid Catalysis.

Halogen-bond (XB) catalyzed reactions could also be catalyzed by Brønsted acids, which may complicate the picture of the true activation pathway for these reactions. Herein, we report the first density functional theory study of the mechanistic pathways for the uncatalyzed, iodoimidazolinium halogen bond catalyzed, and a competitive Brønsted acid-catalyzed reduction of quinoline by Hantzsch ester. The uncatalyzed reaction was found to proceed via stepwise pathways. In the lowest energy pathway, proton transfer from Hantzsch ester, a weak Brønsted acid, to quinoline prior to hydride reduction was identified as the key to the lowered energy barriers compared to other reaction pathways. The same reaction steps are involved in the XB-catalyzed pathway, but with substantially lowered reaction barriers, particularly for the hydride-transfer steps. In contrast to the general belief that halogen bond catalysts bind to the electrophile quinoline and activate it by lowering its LUMO energy, we discovered that it is preferable to lower the LUMO energy of quinoline through protonation by Hantzsch ester as a Brønsted acid and stabilize the conjugate anion of Hantzsch ester via halogen bond. Finally, our calculations reveal that the iodoimidazolinium type of catalyst is prone to reduction by Hantzsch ester, generating a Brønsted acid as product. The Brønsted acid catalyzed pathway was calculated to be competitive with the halogen bond catalyzed pathway. Our theoretical findings highlight the need to be cautious when applying iodoimidazolinium catalysts in organocatalysis, and we hope it will aid the design of new halogen bond catalysts that could avoid undesirable Brønsted acid catalysis.