Origin of Chemoselectivity of Halohydrin Dehalogenase-Catalyzed Epoxide Ring-Opening Reactions.

By performing molecular dynamics (MD), quantum mechanical/molecular mechanical (QM/MM) calculations, and QM cluster calculations, the origin of chemoselectivity of halohydrin dehalogenase (HHDH)-catalyzed ring-opening reactions of epoxide with the nucleophilic reagent NO2- has been explored. Four possible chemoselective pathways were considered, and the computed results indicate that the pathway associated with the nucleophilic attack on the Cα position of epoxide by NO2- is most energetically favorable and has an energy barrier of 12.9 kcal/mol, which is close to 14.1 kcal/mol derived from experimental kinetic data. A hydrogen bonding network formed by residues Ser140, Tyr153, and Arg157 can strengthen the electrophilicity of the active site of the epoxide substrate to affect chemoselectivity. To predict the energy barrier trends of the chemoselective transition states, multiple analyses including distortion analysis and electrophilic Parr function (Pk+) analysis were carried out with or without an enzyme environment. The obtained insights should be valuable for the rational design of enzyme-catalyzed and biomimetic organocatalytic epoxide ring-opening reactions with special chemoselectivity.

Research Progresses and Applications of Knowledge Graph Embedding Technique in Chemistry.

A knowledge graph (KG) is a technique for modeling entities and their interrelations. Knowledge graph embedding (KGE) translates these entities and relationships into a continuous vector space to facilitate dense and efficient representations. In the domain of chemistry, applying KG and KGE techniques integrates heterogeneous chemical information into a coherent and user-friendly framework, enhances the representation of chemical data features, and is beneficial for downstream tasks, such as chemical property prediction. This paper begins with a comprehensive review of classical and contemporary KGE methodologies, including distance-based models, semantic matching models, and neural network-based approaches. We then catalogue the primary databases employed in chemistry and biochemistry that furnish the KGs with essential chemical data. Subsequently, we explore the latest applications of KG and KGE in chemistry, focusing on risk assessment, property prediction, and drug discovery. Finally, we discuss the current challenges to KG and KGE techniques and provide a perspective on their potential future developments.

Dynamic Kinetic Resolution of ß-Substituted α-Diketones via Asymmetric Transfer Hydrogenation.

Developing innovative dynamic kinetic resolution (DKR) modes and achieving the highly regio- and enantioselective semihydrogenation of unsymmetrical α-diketones are two formidable challenges in the field of contemporary asymmetric (transfer) hydrogenation. In this work, we report the highly regio- and stereoselective asymmetric semi-transfer hydrogenation of unsymmetrical α-diketones through a unique DKR mode, which features the reduction of the carbonyl group distal from the labile stereocenter, while the proximal carbonyl remains untouched. Moreover, the protocol affords a variety of enantioenriched acyclic ketones with α-hydroxy-α'-C(sp2)-functional groups, which represent a new product class that has not been furnished in known arts. The utilities of the products have been demonstrated in a series of further transformations including the rapid synthesis of drug molecules. Density functional theory calculations and plenty of control experiments have also been conducted to gain more mechanistic insights into the highly selective semihydrogenation.

Stretched Central Double Bonds in Dialumene and Disilene by Amino Substituents: A Case of Lone Pair Repulsion.

There have been remarkable advances in the syntheses and applications of groups 13 and 14 homonuclear ethene analogues. However, successes are largely limited to aryl- and/or silyl-substituted species. Analogues bearing two or more heteroatoms are still scarce. In this work, the block-localized wavefunction (BLW) method at the density functional theory (DFT) level was employed to study dialumene and disilene bearing two amino substituents whose optimal geometries exhibit significantly stretched central M=M (M=Al or Si) double bonds compared with aryl- and/or silyl-substituted species. Computational analyses showed that the repulsion between the lone electron pairs of amino substituents and M=M π bond plays a critical role in the elongation of the M=M bonds. Evidently, replacing the substituent groups -NH2 with -BH2 can enhance the planarity and shorten the central double bonds due to the absence of lone pair electrons in BH2 .

Captodative Effect Facilitates the Excitation in Diboron Molecule (CAAC)2 B2 (SH)2.

Given the extraordinary versatility in chemical reactions and applications, boron compounds have gained increasing attentions in the past two decades. One of the remarkable advances is the unprecedented preparation of unsaturated boron species. Notably, Braunschweig et al. found that the cyclic (alkyl)(amino) carbenes (CAACs) stabilized diboron molecules (CAAC)2 B2 (SR)2 host unpaired electrons and exist in the 90°-twisted diradical form, while other analogues, such as N-heterocyclic carbenes (NHCs), stabilized diboron molecules prefer a conventional B=B double bond. Since previous studies recognized the differences in the steric effect between CAAC and NHC carbenes, here we focused on the role of thiol substituents in (CAAC)2 B2 (SR)2 by gradually localizing involved electrons. The co-planarity of the thiol groups and the consequent captodative effect were found to be the culprit for the 90°-twisted diradical form of (CAAC)2 B2 (SR)2 . Computational analyses identified two forces contributing to the π electron movements. One is the "push" effect of lone pairs on the sulfur atoms which boosts the π electron delocalization between the BB center and CAACs. The other is the π electron delocalization within each (CAAC)B(SR) fragment where the pull effect originates from the π electron withdrawal by CAACs. There are two such independent and orthogonal push-pull channels which function mainly in individual (CAAC)B(SR) fragments. This enhanced π push-pull effect in the triplet state facilitates the electronic excitation in (CAAC)2 B2 (SR)2 by reducing the singlet-triplet gap.

New insights into the proton pumping mechanism of ba3 cytochrome c oxidase: the functions of key residues and water.

As the terminal oxidase of cell respiration in mitochondria and aerobic bacteria, the proton pumping mechanism of ba3-type cytochrome c oxidase (CcO) of Thermus thermophiles is still not fully understood. Especially, the functions of key residues which were considered as the possible proton loading sites (PLSs) above the catalytic center, as well as water located above and within the catalytic center, remain unclear. In this work, molecular dynamic simulations were performed on a set of designed mutants of key residues (Asp287, Asp372, His376, and Glu126II). The results showed that Asp287 may not be a PLS, but it could modulate the ability of the proton transfer pathway to transfer protons through its salt bridge with Arg225. Maintaining the closed state of the water pool above the catalytic center is necessary for the participation of inside water molecules in proton transfer. Water molecules inside the water pool can form hydrogen bond chains with PLS to facilitate proton transfer. Additional quantum cluster models of the Fe-Cu metal catalytic center are established, indicating that when the proton is transferred from Tyr237, it is more likely to reach the OCu atom directly through only one water molecule. This work provides a more profound understanding of the functions of important residues and specific water molecules in the proton pumping mechanism of CcO.

Unraveling the Pivotal Roles of Various Metal Ion Centers in the Catalysis of Quercetin 2,4-Dioxygenases.

Quercetin 2,4-dioxygenase (QueD) with various transition metal ion co-factors shows great differences, but the internal reasons have not been illustrated in detail. In order to explore the effects of metal ion centers on the catalytic reactivity of QueD, we calculated and compared the minimum energy crossing point (MECP) of dioxygen from the relatively stable triplet state to the active singlet state under different conditions by using the DFT method. It was found that the metal ions play a more important role in the activation of dioxygen compared with the substrate and the protein environment. Simultaneously, the catalytic reactions of the bacterial QueDs containing six different transition metal ions were studied by the QM/MM approach, and we finally obtained the reactivity sequence of metal ions, Ni2+ > Co2+ > Zn2+ > Mn2+ > Fe2+ > Cu2+, which is basically consistent with the previous experimental results. Our calculation results indicate that metal ions act as Lewis acids in the reaction to stabilize the substrate anion and the subsequent superoxo and peroxo species in the reaction, and promote the proton coupled electron transfer (PCET) process. Furthermore, the coordination tendencies of transition metal ion centers also have important effects on the catalytic cycle. These findings have general implications on metalloenzymes, which can expand our understanding on how various metal ions play their key role in modulating catalytic reactivity.

Organoelectrocatalysis Enables Direct Cyclopropanation of Methylene Compounds.

Cyclopropane is a prevalent structural unit in natural products and bioactive compounds. While the transition metal-catalyzed alkene cyclopropanation of functionalized compounds such as α-diazocarbonyl derivatives has been well established and provides straightforward access to cyclopropanes, cyclopropanation directly from the more stable and simpler methylene compounds has remained an unsolved challenge despite the highly desirable benefits of minimal prefunctionalization and increased operational safety. Herein we report an electrocatalytic strategy for the cyclopropanation of active methylene compounds, employing an organic catalyst. The method shows a broad substrate scope and excellent scalability, requires no metal catalyst or external chemical oxidant, and provides convenient access to several types of cyclopropane-fused heterocyclic and carbocyclic compounds. Mechanistic investigations suggest that the reactions proceed through a radical-polar crossover process to form the two new carbon-carbon bonds in the nascent cyclopropane ring.

Photoelectrochemical Asymmetric Catalysis Enables Direct and Enantioselective Decarboxylative Cyanation.

The development of efficient and sustainable methods for decarboxylative transformations is of great importance due to the ease of availability and nontoxicity of carboxylic acids. Despite tremendous efforts in this area, it remains challenging to develop enantioselective transformations direct from carboxylic acids. Herein we disclose a photoelectrocatalytic method for the direct and enantioselective decarboxylative cyanation. The photoelectrochemical reactions convert carboxylic acids to enantioenriched nitriles by employing cerium/copper relay catalysis with a cerium salt for catalytic decarboxylation and a chiral copper complex for stereoselective C-CN formation.

Diradical Generation via Relayed Proton-Coupled Electron Transfer.

Diradical generation followed by radical-radical cross-coupling is a powerful synthetic tool, but its detailed mechanism has yet to be established. Herein, we proposed and confirmed a new model named relayed proton-coupled electron transfer (relayed-PCET) for diradical generation, which could open a door for new radical-radical cross-coupling reactions. Quantum mechanics calculations were performed on a selected carbene-mediated diradical cross-coupling reaction model and a designed model, and the exact electronic structural changes during the radical processes have been observed for the first time.

N-Body Reduced Density Matrix-Based Valence Bond Theory and Its Applications in Diabatic Electronic-Structure Computations.

Valence bond (VB) theory, as a helpful complement to the more popular molecular orbital theory, is a fundamental electronic-structure theory that aims at interpreting molecular structure and chemical reactions in a lucid way. Both theoretical and experimental chemists have shown great interest in VB theory because of its capability of providing intuitive insight into the nature of chemical bonding and the mechanism of chemical reaction in a clear and comprehensible language rooted in Lewis structure. Therefore, there is a great call for the renaissance of VB theory. Nevertheless, this is possible only after a series of methods and algorithms were developed and efficiently implemented in user-friendly programs so as to serve computational chemists for general applications. In the past three decades, we have devoted a great amount of scientific enthusiasm toward this goal. In this Account, we will concisely summarize and briefly but insightfully discuss recent developments in ab initio VB theory, especially the N-body reduced density matrices (RDM)-based approach and its applications in diabatic electronic-structure computations, which is very useful for the vivid interpretation of many fundamental chemical processes such as electron and energy transfers. Furthermore, because of the fundamentally important role that the diabatic state plays in electron and energy transfers, which are two frontier research topics in both molecular and biochemical sciences, there are a broad range of applications that VB theory can handle.We start by briefly reviewing the general feature of ab initio VB wave functions. In particular, we focus on the multistructural ab initio VB theory that uses strictly localized orbitals, including the fundamental VB self-consistent field (VBSCF) and two post-SCF methods, VBCI and VBPT2, that use the VBSCF wave function as reference. We then allot a section to describing the recent developments of the RDM-based VB approach in the second quantization language. In this section, the enhanced Wick theorem is first outlined, followed by a brief discussion of its applications in evaluating VBSCF energy gradients and a Hessian with respect to the orbital expansion coefficients, together with a short review of the implementation of an automatic formula and code generator (AFCG) designed for many-body methods with nonorthogonal orbitals. Then, we introduce the application of the RDM-based approach in implementing the post-SCF method that addresses dynamic electronic correlation via perturbation theory, viz., the icVBPT2 method that adopts an internal contraction technique naturally. We finish this section by incorporating VB theory with the concept of seniority number, in which the tensor analysis technique is carefully exploited with the RDM-based approach, resulting in significant improvements in both the number of the active electrons/orbitals and in the speedup of the computational efficiency, thus pushing VB theory to its new limit. With these achievements available, we present the applications of VB theory in diabatic electronic-structure computations by using the intuitive insight rendered by VB theory. Therefore, we believe that there is a bright future in VB theory with true opportunities and new challenges coexisting both for theoretical developments and computational applications.

Optimization of potential non-covalent inhibitors for the SARS-CoV-2 main protease inspected by a descriptor of the subpocket occupancy.

The main protease is regarded as an essential drug target for treating Coronavirus Disease 2019. In the present study, 13 marketed drugs were investigated to explore the possible binding mechanism, utilizing molecular docking, molecular dynamics simulation, and MM-PB(GB)SA binding energy calculations. Our results suggest that fusidic acid, polydatin, SEN-1269, AZD6482, and UNC-2327 have high binding affinities of more than 23 kcal mol-1. A descriptor was defined for the energetic occupancy of the subpocket, and it was found that S4 had a low occupancy of less than 10% on average. The molecular optimization of ADZ6482 via reinforcement learning algorithms was carried out to screen out three lead compounds, in which slight structural changes give more considerable binding energies and an occupancy of the S4 subpocket of up to 43%. The energetic occupancy could be a useful descriptor for evaluating the local binding affinity for drug design.

Electrocatalytic Allylic C-H Alkylation Enabled by a Dual-Function Cobalt Catalyst.

The direct functionalization of allylic C-H bonds with nucleophiles minimizes pre-functionalization and converts inexpensive, abundantly available materials to value-added alkenyl-substituted products but remains challenging. Here we report an electrocatalytic allylic C-H alkylation reaction with carbon nucleophiles employing an easily available cobalt-salen complex as the molecular catalyst. These C(sp3 )-H/C(sp3 )-H cross-coupling reactions proceed through H2 evolution and require no external chemical oxidants. Importantly, the mild conditions and unique electrocatalytic radical process ensure excellent functional group tolerance and substrate compatibility with both linear and branched terminal alkenes. The synthetic utility of the electrochemical method is highlighted by its scalability (up to 200 mmol scale) under low loading of electrolyte (down to 0.05 equiv) and its successful application in the late-stage functionalization of complex structures.

Radical Hydro-Fluorosulfonylation of Unactivated Alkenes and Alkynes.

Recently, radical fluorosulfonylation is emerging as an appealing approach for the synthesis of sulfonyl fluorides, which are highly in demand in various disciplines, particularly in chemical biology and drug discovery. Here, we report the first establishment of radical hydro-fluorosulfonylation of alkenes, which is enabled by using 1-fluorosulfonyl 2-aryl benzoimidazolium (FABI) as an effective redox-active radical precursor. This method provides a new and facile approach for the synthesis of aliphatic sulfonyl fluorides from unactivated alkenes, and can be further applied to the late-stage modifications of natural products and peptides, as well as ligation of drugs in combination with click chemistry. Remarkably, this system could enable the radical hydro-fluorosulfonylation of alkynes, affording valuable alkenylsulfonyl fluoride products with a rare, high Z-selectivity, which are normally less stable and more challenging to synthesize in comparison with the E-configured products.

Electrocatalytic Dehydrogenative Cyclization of 2-Vinylanilides for the Synthesis of Indoles.

Indole is prevalent in bioactive compounds and natural products. The development of efficient and sustainable methods to access this privileged structural scaffold has been a long-standing interest of synthetic chemists. Herein, we report an electrocatalytic method for the synthesis of indoles through dehydrogenative cyclization of 2-vinylanilides. The reactions employ an organic redox catalyst and do not require any external chemical oxidant, providing speedy and efficient access to 3-substituted and 2,3-disubstituted indoles.

Catalyst- and Reagent-Free Formal Aza-Wacker Cyclizations Enabled by Continuous-Flow Electrochemistry.

The development of efficient and sustainable methods to access saturated N-heterocycles is of great importance because of the prevalence of these structures in natural products and bioactive compounds. Pd-catalyzed aza-Wacker type cyclization is a powerful method and provides access to N-heterocycles bearing an alkene moiety available for further synthetic manipulations from readily available materials. Herein we disclose a catalyst- and reagent-free formal aza-Wacker type cyclization reaction for the synthesis of functionalized saturated N-heterocycles. Key to the success is to conduct the reactions in a continuous-flow electrochemical reactor without adding supporting electrolyte or additives. The reactions are characterized by broad tolerance of di-, tri- and tetrasubstituted alkenes.

Site-Selective Electrochemical Benzylic C-H Amination.

C-H/N-H cross-coupling is an ideal strategy to synthesize various amines but remains challenging owing to the requirement for sacrificial chemical oxidants and the difficulty in controlling the regio- and chemo-selectivity. Herein we report a site-selective electrochemical amination reaction that can convert benzylic C-H bonds into C-N linkages via H2 evolution without need for external oxidants or metal catalysts. The synthetic strategy involves anodic cleavage of benzylic C-H to form a carbocation intermediate, which is then trapped with an amine nucleophile leading to C-N bond formation. Key to the success is to include HFIP as a co-solvent to modulate the oxidation potentials of the alkylbenzene substrate and the aminated product to avoid overoxidation of the latter.

Radical Fluorosulfonylation: Accessing Alkenyl Sulfonyl Fluorides from Alkenes.

Sulfonyl fluorides have widespread applications in many fields. In particular, their unique biological activity has drawn considerable research interest in the context of chemical biology and drug discovery in the past years. Therefore, new and efficient methods for the synthesis of sulfonyl fluorides are highly in demand. In contrast to extensive studies on FSO2+ -type reagents, a radical fluorosulfonylation reaction with a fluorosulfonyl radical (FSO2. ) remains elusive so far, probably owing to its instability and difficulty in generation. Herein, the development of the first radical fluorosulfonylation of alkenes based on FSO2 radicals generated under photoredox conditions is reported. This radical approach provides a new and general access to alkenyl sulfonyl fluorides, including structures that would otherwise be challenging to synthesize with previously established cross-coupling methods. Moreover, extension to the late-stage fluorosulfonylation of natural products is also demonstrated.

Electrophotocatalytic Decarboxylative C-H Functionalization of Heteroarenes.

Decarboxylative C-H functionalization reactions are highly attractive methods for forging carbon-carbon bonds considering their inherent step- and atom-economical features and the pervasiveness of carboxylic acids and C-H bonds. An ideal approach to achieve these dehydrogenative transformations is through hydrogen evolution without using any chemical oxidants. However, effective couplings by decarboxylative carbon-carbon bond formation with proton reduction remain an unsolved challenge. Herein, we report an electrophotocatalytic approach that merges organic electrochemistry with photocatalysis to achieve the efficient direct decarboxylative C-H alkylation and carbamoylation of heteroaromatic compounds through hydrogen evolution. This electrophotocatalytic method, which combines the high efficiency and selectivity of photocatalysis in promoting decarboxylation with the superiority of electrochemistry in effecting proton reduction, enables the efficient coupling of a wide range of heteroaromatic bases with a variety of carboxylic acids and oxamic acids. Advantageously, this method is scalable to decagram amounts, and applicable to the late-stage functionalization of drug molecules.

Fenton-Derived OH Radicals Enable the MPnS Enzyme to Convert 2-Hydroxyethylphosphonate to Methylphosphonate: Insights from Ab Initio QM/MM MD Simulations.

The mechanism for dioxygen activation represents one of the core issues in metalloenzymes. In most cases, the activation of the O2 molecule requires additional electrons from an external reducant. However, nonheme hydroxyethylphosphonate dioxygenase (HEPD) and methylphosphonate synthase (MPnS) are exceptional C-H oxygenases. Both enzymes do not utilize reductants, rather they employ directly iron(III)-superoxide species to initiate H-abstraction reactions and lead thereby to catalysis of the C-C cleavage in 2-hydroxyethylphosphonate (2-HEP). Using the recently characterized MPnS structure and QM(B3LYP)/MM-based metadynamics simulations, we deciphered the chemical mechanism for MPnS. Our simulations demonstrate O2 activation in MPnS is mediated by an adjacent Lysine residue (Lys28) in the active site, leading to an unusual H 2 O 2 intermediate in the reductant-independent nonheme MPnS enzyme. Furthermore, the so-generated H 2 O 2 intermediate is subsequently employed in a Fenton-type reaction, leading to a locked •OH radical that spontaneously attaches to the substrate carbonyl group. Meanwhile, the proton from the Fe(III)-OH is shuttled back to the deprotonated Lys28, affording the Fe(IV)-oxo species that is identified by experiment in HEPD. Thus, our calculations demonstrate an unusual proton-shuttle mechanism for O 2 activation in metalloenzymes.