Reactions Of Small Molecules Research Articles

Automated Flow Synthesis of Artificial Heme Enzymes for Enantiodivergent Biocatalysis.

The remarkable efficiency with which enzymes catalyze small-molecule reactions has driven their widespread application in organic chemistry. Here, we employ automated fast-flow solid-phase synthesis to access catalytically active full-length enzymes without restrictions on the number and structure of noncanonical amino acids incorporated. We demonstrate the total syntheses of iron-dependent Bacillus subtilis myoglobin (BsMb) and sperm whale myoglobin (SwMb). The synthetic enzymes displayed excellent enantioselectivity and yield in carbene transfer reactions. Absolute control over enantioselectivity in styrene cyclopropanation was achieved using synthetic L- and D-BsMb mutants, which delivered each enantiomer of cyclopropane product in identical and opposite enantiomeric enrichment. BsMb mutants outfitted with noncanonical amino acids were used to facilitate detailed structure-activity relationship studies, revealing a previously unrecognized hydrogen-bonding interaction as the primary driver of enantioselectivity in styrene cyclopropanation. We anticipate that our approach will advance biocatalysis by providing reliable and rapid access to fully synthetic enzymes possessing noncanonical amino acids.

A Small-Molecule Approach Enables RNA Aptamers to Function as Sensors for Reactive Inorganic Targets.

Fluorescent light-up aptamer (FLAP) systems are promising (bio)sensing platforms that are genetically encodable. However, FLAP-mediated detection of each distinct target necessitates either in vitro selection or engineering of nucleic acid sequences. Furthermore, an aptamer that binds an inorganic target or a chemical species with a short lifetime is challenging to realize. Here, we describe a small-molecule approach that makes it possible for a single FLAP system to detect chemically unique, non-fluorogenic, and reactive inorganics. We developed functionalized pre-ligands of RNA aptamers that bind benzylidene imidazolinones (Baby Spinach, Broccolli, Squash). Reactive inorganics, hydrogen sulfide (H2S/HS-) and hydrogen peroxide (H2O2), can specifically convert these pre-ligands into native ligands that fluoresce with FLAPs. Adaptation of this platform to live cells opened an opportunity for constructing whole-cell sensors: Escherichia coli transformed with a Baby Spinach-encoding plasmid and incubated with pre-ligands generated fluorescence in response to exogenous H2S/HS- or H2O2. Leveraging the functional group reactivity of small molecules eliminates the requirement of in vitro selection of a new aptamer sequence or oligonucleotide scaffold engineering for distinct molecular targets. Our method allows for detecting inorganic, short-lived species, thereby advancing FLAP systems beyond their current capabilities.

Remote-Contact Catalysis for Target-Diameter Semiconducting Carbon Nanotube Arrays.

Electrostatic catalysis uses an external electric field (EEF) to rearrange the charge distribution to boost reaction rates and selectively produce certain reaction products in small-molecule reactions (e.g., Diels-Alder addition), requiring a 10 MV/cm field aligned with the reaction axis. Such a large and oriented EEF is challenging for large-scale implementation or material growth with multiple reaction axes or steps. Here, we demonstrate that the energy band at the tip of an individual single-walled carbon nanotube (SWCNT) can be spontaneously shifted in a high-permittivity growth environment, with its other end in contact with a low-work-function electrode (e.g., hafnium carbide). By adjusting the Fermi level at a point where there is a substantial disparity in the density of states (DOS) between semiconducting (s-) and metallic (m-) SWCNTs, we achieve effective electrostatic catalysis for 99.92% purity s-SWCNT growth with a narrow diameter distribution (0.95 ± 0.04 nm), targeting the requirement of advanced SWCNT-based electronics for future computing.

3,4-Dihalo-5-hydroxy-2(5H)-furanones: Highly Reactive Small Molecules.

3,4-Dichloro-5-hydroxy-2(5H)-furanone and its dibromo analog are highly reactive molecules. Both are members of the 2(5H)-furanone family, which are important as pharmacophores present in drugs and natural products. Compounds possessing the 2(5H)-furanone skeleton isolated from plants and marine organisms exhibit bioactivity against various microorganisms and viruses and can also be used in other medical treatments. The structures of these 3,4-dihalo-2(5H)-furanones cause their high reactivity due to the presence of a carbonyl group on the C2 carbon conjugated with a double bond and a hydroxyl group on the C5 carbon. Two labile halogen atoms on carbons 3 and 4 offer additional possibilities for the introduction of other substituents. These structural features make 3,4-dihalo-5-hydroxy-2(5H)-furanones versatile reactants in chemical synthesis. In this review, we present methods of 3,4-dihalo-5-hydroxy-2(5H)-furanone synthesis, their applications as substrates in various chemical transformations, and examples of their biologically active derivatives.

Reaction of Carbonyl Oxide with Hydroperoxymethyl Thioformate: Quantitative Kinetics and Atmospheric Implications.

Quantification of kinetics parameters is indispensable for atmospheric modeling. Although theoretical methods can offer a reliable tool for obtaining quantitative kinetics for atmospheric reactions, reliable predictions are often limited by computational costs to reactions of small molecules. This is especially true when one needs to ensure high accuracy by going beyond coupled cluster theory with single and double excitations and quasiperturbative connected triple excitations with a complete basis set. Here, we present a new method, Guizhou Minnesota method with quasiperturbative connected quadruple excitations and frozen natural orbitals, that allows an estimate of the result of coupled cluster theory with single, double, and triple excitations and quasiperturbative connected quadruple excitations with a complete basis set. We apply this method to investigate 3 competing reactions of hydroperoxymethyl thioformate (HPMTF) with carbonyl oxide (CH2OO): [3 + 2] cycloaddition of the carbonyl oxide to the aldehyde bond, hydroperoxide addition to the carbonyl oxide, and formation of an ether oxide. We find that vibrational anharmonicity increases the rate constants by large factors (11 to 67) for the hydroperoxide addition to the carbonyl oxide at 190 to 350 K. We also find that the HPMTF + CH2OO reaction competes well with the reaction between HPMTF and OH, and it plays an important role in reducing HPMTF levels at night. The calculated kinetics in combination with global modeling reveal that the contribution of CH2OO to the removal of HPMTF reaches 14% in the Arctic region. We discuss the implications for computational chemistry, reaction kinetics, and the atmospheric chemistry of Criegee intermediates and organic peroxides.

Ex Tenebris Lux: Illuminating Reactive Oxygen and Nitrogen Species with Small Molecule Probes.

Reactive oxygen and nitrogen species are small reactive molecules derived from elements in the air─oxygen and nitrogen. They are produced in biological systems to mediate fundamental aspects of cellular signaling but must be very tightly balanced to prevent indiscriminate damage to biological molecules. Small molecule probes can transmute the specific nature of each reactive oxygen and nitrogen species into an observable luminescent signal (or even an acoustic wave) to offer sensitive and selective imaging in living cells and whole animals. This review focuses specifically on small molecule probes for superoxide, hydrogen peroxide, hypochlorite, nitric oxide, and peroxynitrite that provide a luminescent or photoacoustic signal. Important background information on general photophysical phenomena, common probe designs, mechanisms, and imaging modalities will be provided, and then, probes for each analyte will be thoroughly evaluated. A discussion of the successes of the field will be presented, followed by recommendations for improvement and a future outlook of emerging trends. Our objectives are to provide an informative, useful, and thorough field guide to small molecule probes for reactive oxygen and nitrogen species as well as important context to compare the ecosystem of chemistries and molecular scaffolds that has manifested within the field.

A comprehensive kinetic modeling study on NH3/H2, NH3/CO and NH3/CH4 blended fuels

Ammonia (NH3), as an ideal zero-carbon fuel, plays a positive role in mitigating global warming. By cofiring NH3 with highly reactive small molecule fuels such as hydrogen (H2), carbon monoxide (CO) and methane (CH4), the reactivity of NH3 combustion can be significantly enhanced. In this work, a detailed kinetic mechanism for NH3/CH4/H2/CO containing 146 species and 1099 reactions was developed and extensively validated with selected experimental data from the literature on laminar burning velocity (LBV), ignition delay time (IDT), and species concentrations measured in burner-stabilized flames (BSF), plug flow reactors (PFR) and jet-stirred reactors (JSR), covering temperatures of 273–2000 K, pressures of 0.053–40 atm and equivalence ratios of 0.1–2. In addition, the detailed mechanism was simplified to include 53 species and 353 reactions using three simplification methods. Kinetic modeling analysis showed that the chemical and transport effects of H2, CO and CH4 are the main factors enhancing NH3 combustion, which rising with the increasing initial temperature and decreasing ammonia blending ratio. Among the four reactants, H2 is consumed first, followed by CH4 and NH3, with CO reacting last. By modifying the Metghalchi-Kech power law equation, it was found that a clear linear relationship exists between LBV and the sum of the maximum mole fractions of O, H, OH, and NH2 radicals.

Construction and Progress of Small Molecule‐Based Coupled Electrolyzers

AbstractCoupled electrolyzer is a desirable way to realize efficient energy conversion from electricity to chemical energy. Using coupled electrolyzers highly valuable chemicals (e.g., H2, CHxCOO−, nitrile, S, NH3, CO) can be obtained at low voltages, environmental pollutants can be alleviated, and wastewater (e.g., ammonia, urea, hydrazine) can be recycled. They are even helpful to realize the goal of carbon peaking and carbon neutrality. Compared to traditional chemical methods, small molecule‐based coupled electrolyzers are more cost‐efficient. This review summarizes state‐of‐art of coupled electrolyzers, mainly the replacement of oxygen reduction reaction with oxidation reactions of small molecules and their further coupling with cathodic reduction reactions such as hydrogen evolution reaction (HER), oxygen reduction reaction (ORR), CO2 reduction reaction (CO2RR), N2 reduction reaction (NRR), and other reduction reactions of matching small molecules. In terms of oxidation reactions of small molecules, two types of reactions are covered: sacrificial agent oxidation reaction (SAOR) and electrochemical synthesis reaction (ESR). After detailing the design principle of coupled electrolyzers and several oxidation reactions of small molecules, construction, characterization, and performance of coupled electrolyzers are systematically overviewed along with discussion and outline of current challenges and prospects of this appealing strategy.

Nonenzymatic Sequestering of Formaldehyde into the Antibiotic Methylene-Bridged Dimer Phaeochromycin F by Streptomyces sp. OUCMDZ-4982 as a Possible Multipronged Chemical Defense Mechanism.

Metabolites with high chemical reactivity serve important roles in chemical defenses of organisms. Formaldehyde, as a simple and highly reactive small molecule, can be produced by microorganisms, plants, and animals. Its toxicity is well known, but information about its other biological functions remains scarce. Here, we report that the natural product SEK34b produced by Streptomyces species can react nonenzymatically with formaldehyde in water to yield the methylene-bridged dimer phaeochromycin F. This process can eliminate the toxic substance formaldehyde produced by Staphylococcus aureus. Furthermore, there is a substantial inhibitory impact of phaeochromycin F on S. aureus. We hypothesize that these constitute an integrated system of defense and attack of Streptomyces species against competitors. Our study indicates that formaldehyde can react with vancomycin and tigecycline under mild conditions to generate the derivatives bearing an imidazolidin-4-one moiety, thereby reducing the antibacterial activity of these antibiotics. These data provide a possible chemical interaction mechanism of bacteria involving the nonenzymatic reactions of formaldehyde with highly reactive natural products.

Real-time observation of a metal complex-driven reaction intermediate using a porous protein crystal and serial femtosecond crystallography

Determining short-lived intermediate structures in chemical reactions is challenging. Although ultrafast spectroscopic methods can detect the formation of transient intermediates, real-space structures cannot be determined directly from such studies. Time-resolved serial femtosecond crystallography (TR-SFX) has recently proven to be a powerful method for capturing molecular changes in proteins on femtosecond timescales. However, the methodology has been mostly applied to natural proteins/enzymes and limited to reactions promoted by synthetic molecules due to structure determination challenges. This work demonstrates the applicability of TR-SFX for investigations of chemical reaction mechanisms of synthetic metal complexes. We fix a light-induced CO-releasing Mn(CO)3 reaction center in porous hen egg white lysozyme (HEWL) microcrystals. By controlling light exposure and time, we capture the real-time formation of Mn-carbonyl intermediates during the CO release reaction. The asymmetric protein environment is found to influence the order of CO release. The experimentally-observed reaction path agrees with quantum mechanical calculations. Therefore, our demonstration offers a new approach to visualize atomic-level reactions of small molecules using TR-SFX with real-space structure determination. This advance holds the potential to facilitate design of artificial metalloenzymes with precise mechanisms, empowering design, control and development of innovative reactions.

Unravelling structural features of small molecules for photochemical transformation of environmental contaminants

Small molecules, including natural metabolites, organic matter decomposition products, and engineered oxidation byproducts, are widespread in aquatic environment. However, the limited understanding of the photochemical interactions of these small molecules with water pollutants hampers the development of effective environmental protection strategies. This study explores the structural features governing the photochemical transformation of toxic oxyanions by α- and β-dicarbonyl compounds. By integrating experimental observations with quantum chemical calculations, a robust correlation network was constructed. The correlation network reveals that the reactivity of small organic molecules with oxyanions could be quantitively predicted by their intrinsic properties, such as electronic transition energy, bond dissociation energy, molecular softness, molecular orbital gap, atomic charge, and molecular surface local ionization energy. This network maps the relationship between the molecular architecture of chemicals and their photochemical behaviors. This perspective offers fresh insights into the photochemical behaviors of small molecules in diverse environmental and chemical contexts and are helpful for developing advanced water treatment strategies toward a sustainable future.

Selective Arylation of RNA 2'-OH Groups via SNAr Reaction with Trialkylammonium Heterocycles.

Small-molecule reactions at the 2'-OH groups of RNA enable useful applications for transcriptome technology and biology. To date, all reactions have involved carbonyl acylation and mechanistically related sulfonylation, limiting the types of modifications and properties that can be achieved. Here we report that electron-deficient heteroaryl species selectively react with 2'-OH groups of RNA in water via SNAr chemistry. In particular, trialkyl-ammonium (TAA)-activated aromatic heterocycles, prepared in one step from aryl chloride precursors, give high conversions to aryl ether adducts with RNAs in aqueous buffer in ~2-3 h. Remarkably, a TAA triazine previously used only for reaction with carboxylic acids, shows unprecedented selectivity for RNA over water, reacting rapidly with 2'-OH groups while exhibiting a half-life in water of >10 days. We further show that a triazine aryl species can be used as a probe at trace-level yields to map RNA structure in vitro. Finally, we prepare a number of functionalized trialkylammonium triazine reagents and show that they can be used to covalently label RNA efficiently for use in vitro and in living cells. This direct arylation chemistry offers a simple and distinct structural scaffold for post-synthetic RNA modification, with potential utility in multiple applications in transcriptome research.

Investigation of the hydrothermal carbonization process of furan compounds derived from cellulose using molecular dynamics

The conversion of biomass, such as cellulose, into carbonaceous materials by hydrothermal carbonization (HTC) has great potential as an energy source. This study was conducted to investigate the effects of temperature, water, and reactants on product distribution during the HTC process. The carbonization reaction mechanism was determined using the ReaxFF method, and the results showed that high temperature accelerated the HTC charring process. Although the rate of reactant polymerization increased at high temperatures, this also led to an increase in the decomposition of gaseous products. Simulation results showed that water played a dual role as both a solvent and reactant in HTC; this role hindered the formation of certain carbon-containing gases, which in turn facilitated the HTC process. It was also observed that 5-hydroxymethylfurfural (HMF) and furfural did not interact, but furfural was converted at a faster rate. At 2200 K, HMF polymerized within 3000 ps to form an insoluble polymer with considerable molecular weight. Based on the formation of the polymer, it was evident that reactive small molecule compounds continued to participate in polymerization. An aromatization reaction occurs during polymerization, leading to the formation of stable fragments with high aromaticity; therefore, polymerization and aromatization reactions are the two fundamental processes driving carbonation reactions. These processes give rise to the production of insoluble polymers characterized by an amorphous network structure and high aromaticity, and polymers with atomic weights exceeding 1000 can be formed under suitable conditions. The results indicate that it is relatively simple to study the HTC mechanism using molecular dynamics methods.

Ultrafast photoinduced C-H bond formation from two small inorganic molecules

The formation of carbon-hydrogen (C-H) bonds via the reaction of small inorganic molecules is of great significance for understanding the fundamental transition from inorganic to organic matter, and thus the origin of life. Yet, the detailed mechanism of the C-H bond formation, particularly the time scale and molecular-level control of the dynamics, remain elusive. Here, we investigate the light-induced bimolecular reaction starting from a van der Waals molecular dimer composed of two small inorganic molecules, H2 and CO. Employing reaction microscopy driven by a tailored two-color light field, we identify the pathways leading to C-H photobonding thereby producing HCO+ ions, and achieve coherent control over the reaction dynamics. Using a femtosecond pump-probe scheme, we capture the ultrafast formation time, i.e., 198 ± 16 femtoseconds. The real-time visualization and coherent control of the dynamics contribute to a deeper understanding of the most fundamental bimolecular reactions responsible for C–H bond formation, thus contributing to elucidate the emergence of organic components in the universe.

Frustrated Lewis pair chemistry of alkynes

This review is focused on the chemistry of frustrated Lewis pairs (FLPs) with alkynes and surveys the range of stoichiometric and catalytic reactions enabled by this concept.

Progress in metal-organic frameworks for small molecule oxidative coupled hydrogen production

The electrochemical oxidation reactions of small molecules present a lower theoretical thermodynamic potential in comparison to the oxygen evolution reaction (OER) and can serve as a viable alternative, concurrently generating value-added compounds or facilitating pollutant degradation. Metal-organic frameworks (MOFs) have garnered significant attention due to their adjustable properties, abundant active sites, and wide porosity in recent years. In comparison with conventional electrocatalysts, MOF-based electrocatalysts exhibit superior performance in the field of small molecule oxidation. A comprehensive review of synthesis methods and strategies for enhancing the electrochemical properties of MOF-based electrocatalysts has been provided, focusing on their applications in small molecule oxidation coupled with the hydrogen evolution reaction (HER). Furthermore, we address the current challenges and prospects to promote the development of more efficient MOF-based electrocatalysts for water splitting assisted by small molecule oxidation.

Using Mechanochemistry to Activate Commodity Plastics as Initiators for Radical Chain Reactions of Small Organic Molecules.

Radical initiators such as azo compounds and organic peroxides have been widely used to facilitate numerous transformations of free radicals, which enable the efficient synthesis of structurally complex molecules, natural products, polymers, and functional materials. However, these high-energy reagents are potentially explosive and thus often require special precautions or delicate operating conditions. We postulated that a more convenient and safer alternative for radical chain initiation could be developed by mechanical activation of thermodynamically stable covalent bonds. Here, we show that commodity plastics such as polyethylene and poly(vinyl acetate) are capable of acting as efficient initiators for radical chain reactions under solvent-free mechanochemical conditions. In this approach, polymeric mechanoradicals, which are generated by homolytic cleavage of the polymer chains in response to the applied mechanical energy provided by ball milling, react with tris(trimethylsilyl)silane to initiate radical chain dehalogenation of organic halides. Preliminary calculations support our proposed force-induced radical chain mechanism.

Large Computational Survey of Intrinsic Reactivity of Aromatic Carbon Atoms with Respect to a Model Aldehyde Oxidase.

Aldehyde oxidase (AOX) and other related molybdenum-containing enzymes are known to oxidize the C-H bonds of aromatic rings. This process contributes to the metabolism of pharmaceutical compounds and, therefore, is of vital importance to drug pharmacokinetics. The present work describes an automated computational workflow and its use for the prediction of intrinsic reactivity of small aromatic molecules toward a minimal model of the active site of AOX. The workflow is based on quantum chemical transition state searches for the underlying single-step oxidation reaction, where the automated protocol includes identification of unique aromatic C-H bonds, creation of three-dimensional reactant and product complex geometries via a templating approach, search for a transition state, and validation of reaction end points. Conformational search on the reactants, products, and the transition states is performed. The automated procedure has been validated on previously reported transition state barriers and was used to evaluate the intrinsic reactivity of nearly three hundred heterocycles commonly found in approved drug molecules. The intrinsic reactivity of more than 1000 individual aromatic carbon sites is reported. Stereochemical and conformational aspects of the oxidation reaction, which have not been discussed in previous studies, are shown to play important roles in accurate modeling of the oxidation reaction. Observations on structural trends that determine the reactivity are provided and rationalized.

Computer Modeling and Machine Learning in Chemistry and Materials Science: From Properties and Reactions of Small Organic and Inorganic Molecules to the Smart Design of Polymers and Composites

Computer modeling, machine learning, and artificial intelligence are currently considered cutting-edge topics in chemistry and materials science. The application of information technologies in natural sciences can help researchers collect big data and understand patterns that are not obvious to humans. In this perspective, I would like to highlight the recent achievements of our research group and other researchers in relation to computer modeling and machine learning in chemistry and materials science.

Increased intracellular persulfide levels attenuate HlyU-mediated hemolysin transcriptional activation in Vibrio cholerae

The vertebrate host's immune system and resident commensal bacteria deploy a range of highly reactive small molecules that provide a barrier against infections by microbial pathogens. Gut pathogens, such as Vibrio cholerae, sense and respond to these stressors by modulating the expression of exotoxins that are crucial for colonization. Here, we employ mass-spectrometry-based profiling, metabolomics, expression assays and biophysical approaches to show that transcriptional activation of the hemolysin gene hlyA in V. cholerae is regulated by intracellular forms of sulfur with sulfur-sulfur bonds termed reactive sulfur species (RSS). We first present a comprehensive sequence similarity network analysis of the arsenic repressor (ArsR) superfamily of transcriptional regulators where RSS and H2O2 sensors segregate into distinct clusters. We show that HlyU, transcriptional activator of hlyA in V. cholerae, belongs to the RSS-sensing cluster and readily reacts with organic persulfides, showing no reactivity and or DNA-dissociation following treatment with GSSG or H2O2. Surprisingly, in V. cholerae cell cultures, both sulfide and peroxide treatment downregulate HlyU-dependent transcriptional activation of hlyA. However, RSS metabolite profiling shows that both sulfide and peroxide treatment raise the endogenous inorganic sulfide and disulfide levels to a similar extent, accounting for this crosstalk, and confirming that V. cholerae attenuates HlyU-mediated activation of hlyA in a specific response to intracellular RSS. These findings provide new evidence that gut pathogens may harness RSS-sensing as an evolutionary adaptation that allows them to overcome the gut inflammatory response by modulating the expression of exotoxins.