Synthesis Reaction Research Articles

Exploration and Reflection on the Reform of the "Open Book Exam" in Organic Reactions for Drug Synthesis

Objective: In the era of big data, the traditional “memorization - repetition” learning method is inadequate for addressing the vast and ever - evolving knowledge in courses such as “Organic Reactions for Drug Synthesis”. This article aims to explore how to shift students from “memorization - repetition” to “understanding - application” through educational reform and changes in assessment mechanisms, enabling them to adapt to a rapidly changing knowledge system. Methods: The study analyzed examination data from 9 classes over three consecutive years to assess the impact of implementing “open - book exams” in the “Organic Reactions for Drug Synthesis” course. In the first and third years, a closed - book examination was employed, which is a traditional method that tests studentsʼ ability to recall and apply knowledge without external resources. The second year introduced an open - book examination, the exam allow students to consult materials, promoting a deeper understanding of concepts and the flexible application of knowledge to solve practical problems. Results: The analysis revealed that open - book exams positively influenced studentsʼ ability to understand and apply concepts, fostering greater learning autonomy and creativity. However, issues such as over - reliance on materials and insufficient mastery of basic knowledge were also identified. Conclusion: By examining the “successes” and “failures”, this article offers valuable insights for reforming assessment methods in courses like “Organic Reactions for Drug Synthesis”. Continuous exploration and practice can help educators develop teaching and assessment approaches better suited to the current era, ultimately enhancing studentsʼ comprehensive skills and innovative abilities.

Metal-Based Oxygen Reduction Electrocatalysts for Efficient Hydrogen Peroxide Production.

Hydrogen peroxide (H2O2) is a high-value chemical widely used in electronics, textiles, paper bleaching, medical disinfection, and wastewater treatment. Traditional production methods, such as the anthraquinone oxidation process and direct synthesis, require high energy consumption, and involve risks from toxic substances and explosions. Researchers are now exploring photochemical, electrochemical, and photoelectrochemical synthesis methods to reduce energy use and pollution. This review focuses on the 2-electron oxygen reduction reaction (2e- ORR) for the electrochemical synthesis of H2O2, and discusses how catalyst active sites influence O2 adsorption. Strategies to enhance H2O2 selectivity by regulating these sites are presented. Catalysts require strong O2 adsorption to initiate reactions and weak *OOH adsorption to promote H2O2 formation. The review also covers advances in single-atom catalysts (SACs), multi-metal-based catalysts, and highlights non-noble metal oxides, especially perovskite oxides, for their versatile structures and potential in 2e- ORR. The potential of localized surface plasmon resonance (LSPR) effects to enhance catalyst performance is also discussed. In conclusion, emphasis is placed on optimizing catalyst structures through theoretical and experimental methods to achieve efficient and selective H2O2 production, aiming for sustainable and commercial applications.

Study of Phase Separation and Reversibility in CO2-Responsive Superamphiphile Microemulsions.

Phase separation of microemulsions occupies a key position in many applications, such as oil recovery, nanomaterial synthesis, and chemical reactions. Achieving an intelligent response is crucial to microemulsion development and application. For this reason, in this study, CO2-responsive superamphiphilic molecules were developed as rapidly switchable oil-in-water microemulsions. These superhydrophilic molecules with linear structures were produced by electrostatic interaction of stearic acid and aminotrimethyltriazine COSM-1 in a 1:1 molar ratio. The introduction of n-butanol as a cosurfactant in the CO2-responsive microemulsion system resulted in the spontaneous formation of stable microemulsions. The effect of the addition of n-butanol on the carbon dioxide-responsive microemulsion system was investigated, and the optimum amount of n-butanol was determined by optimization. After exposure to CO2 for 30 s, the superhydrophilic molecules decomposed into inactive components at the interface, leading to a complete phase separation of the microemulsion into oil and water phases. The system was purged with N2 at 60 °C for 10 min to remove the CO2, and the phase separation system was transformed into a clear microemulsion, which was then evaluated for its properties. The rapid response and complete demulsification of these surface CNFS superamphiphiles to CO2 suggest that they have promising applications in product separation, microemulsion recovery, and enhanced crude oil recovery.

Study on the Thermal Safety of 3,7‐Dinitro‐1,3,5,7‐Tetraazabicyclo[3.3.1]nonane Synthesized by Nitrolysis of Hexamine

AbstractThe thermal flow curves of the nitrolysis for the synthesis of 3,7‐dinitro‐1,3,5,7‐tetraazabicyclo[3.3.1]nonane (DPT) from hexamine in the presence of different amounts of acetic anhydride were obtained using reaction calorimetry. The maximum heat release rates during the feeding process, the corresponding maximum adiabatic temperature rises, and the Maximum Temperature of the Synthesis Reaction (MTSR) were determined, respectively. The thermal stability of the reaction product DPT and the reaction mixture was analyzed, and data on their thermal decomposition characteristics were obtained. The thermal decomposition kinetic model was utilized to simulate the stability under adiabatic conditions. TD24 (The temperature corresponding to the time required to reach the maximum reaction rate under adiabatic conditions for 24 hours) of the reaction mixture was calculated as 69.65°C. According to the thermal hazard parameters of the reaction, the process's hazard level under various acetic anhydride addition conditions was determined to be level 5 using the cooling failure scenario method.

Assessing electronic structure modulation strategies toward the development of low‐cost oxygen evolution reaction catalysts

AbstractOxygen evolution reactions (OER) are critical to electrochemical synthesis reactions, including hydrogen production and organic hydrogenation. However, the high cost of existing OER catalysts (primarily Ir/Ru and its derived oxides) limits their practical application for electrochemical synthesis. To develop a low‐cost, high‐efficiency alternative, we need a deeper understanding of both the mechanisms that drive OER and the relationship between the catalyst's electronic structure and active sites. Here, we summarized recent developments of catalysts, especially focusing on the electronic structure modulation strategies and their subsequent activity enhancement. Most importantly, we pointed out the study directions for further work.

Position-specific kinetic isotope effects for nitrous oxide: a new expansion of the Rayleigh model

Abstract. Nitrous oxide (N2O) is a potent greenhouse gas and the most significant anthropogenic ozone-depleting substance currently being emitted. A major source of anthropogenic N2O emissions is the microbial conversion of fixed nitrogen species from fertilizers in agricultural soils. Thus, understanding the enzymatic mechanisms by which microbes produce N2O has environmental significance. Measurement of the 15N / 14N isotope ratios of N2O produced by purified enzymes or axenic microbial cultures is a promising technique for studying N2O biosynthesis. Typically, N2O-producing enzymes combine nitrogen atoms from two identical substrate molecules (NO or NH2OH). Position-specific isotope analysis of the central (Nα) and outer (Nβ) nitrogen atoms in N2O enables the determination of the individual kinetic isotope effects (KIEs) for Nα and Nβ, providing mechanistic insight into the incorporation of each nitrogen atom. Previously, position-specific KIEs (and fractionation factors) were quantified using the Rayleigh distillation equation, i.e., via linear regression of δ15Nα or δ15Nβ against [-fln⁡f/(1-f)], where f is the fraction of substrate remaining in a closed system. This approach, however, is inaccurate for Nα and Nβ because it does not account for fractionation at Nα affecting the isotopic composition of substrate available for incorporation into the β position (and vice versa). Therefore, we developed a new expansion of the Rayleigh model that includes specific terms for fractionation at the individual N2O nitrogen atoms. By applying this Expanded Rayleigh model to a variety of simulated N2O synthesis reactions with different combinations of normal, inverse, and/or no KIEs at Nα and Nβ, we demonstrate that our new model is both accurate and robust. We also applied this new model to two previously published datasets describing N2O production from NH2OH oxidation in a methanotroph culture (Methylosinus trichosporium) and N2O production from NO by a purified Histoplasma capsulatum (fungal) P450 NOR, demonstrating that the Expanded Rayleigh model is a useful tool in calculating position-specific fractionation for N2O synthesis.

Applications of Clauson-Kaas Reaction in Organic Synthesis.

Pyrrole-embedded organic molecules received a considerable importance due to their numerous biological and material applications. Hence, several synthetic strategies have been devised for the construction of diverse pyrrole analogues over the years. Among these, the Clauson-Kaas reaction is one of the most widely used protocols for the synthesis of various N-substituted pyrroles. This review briefly describes the Clauson-Kaas reaction along with modifications and a detailed account on its applications in the various sectors of organic synthesis.

Computation‐Guided Scope Exploration of a Conjugate Addition/Truce‐Smiles Cascade Reaction for Scaffold Diversification

Based on the successful application of a nitroaryl transfer cascade reaction in the total synthesis of various monoterpene indole alkaloids proceeding via fused bicyclic intermediate, we investigated analogous cascade reactions involving spiro, bridged, and alternatively fused bicyclic intermediates. Unfortunately, none of these was found to afford the desired nitroaryl transfer product. DFT studies of the original cascade process revealed that the Truce‐Smiles rearrangement is the rate‐determining step. In addition, we found that the subsequent SO2 extrusion is accompanied by retro‐Mannich ring opening, resulting in a stabilized enolate that only recyclizes after activation of the cyclic imine moiety. Computation of the reaction profiles of the proposed alternative cascade reactions showed that the barrier for the Truce‐Smiles rearrangement is unreasonably high for the bridged and alternatively fused systems, but only moderately higher for the five‐membered spiro system. Reasoning that even more electron‐deficient arenesulfonamides should have a lower barrier for the Truce‐Smiles rearrangement, we synthesized the corresponding 2,4‐dinitrobenzenesulfonamide precursor and found that it indeed smoothly undergoes the nitroaryl transfer cascade at room temperature. In this case, however, the cascade reaction produces a cyclic imine product, as the intermediate 2,4‐dinitrophenyl‐substituted enolate is insufficiently nucleophilic to undergo the Mannich cyclization.

Modeling compound lipid homeostasis using stable isotope tracing.

Lipids represent the most diverse pool of metabolites found in cells, facilitating compartmentation, signaling, and other functions. Dysregulation of lipid metabolism is linked to disease states such as cancer and neurodegeneration. However, limited tools are available for quantifying metabolic fluxes across the lipidome. To directly measure reaction fluxes encompassing compound lipid homeostasis, we applied stable isotope tracing, high-resolution mass spectrometry, and network-based isotopologue modeling to non-small cell lung cancer (NSCLC) models. Compound lipid metabolic flux analysis (CL-MFA) enables the concurrent quantitation of fatty acid synthesis, elongation, headgroup assembly, and salvage reactions within virtually any biological system. Here, we resolve liver kinase B1 (LKB1)-mediated regulation of sphingolipid recycling in NSCLC cells and precision-cut lung slice cultures. We also demonstrate that widely used tissue culture conditions drive cells to upregulate fatty acid synthase flux to supraphysiological levels. Finally, we identify previously uncharacterized isozyme specificity of ceramide synthase inhibitors, highlighting the molecular detail revealed by CL-MFA.

Hydrogenation‐Driven Metal Dispersion and Catalytic Enhancement of Borophane‐Supported Single‐Atom Catalysts for Electrochemical Nitrogen Reduction

AbstractThe present study delves into electrochemical nitrogen reduction reaction (NRR) for ammonia synthesis using borophane‐supported single‐atom catalysts (SACs) through density functional theory (DFT) calculations. In comparison to previously reported borophene, which serves as a potential substrate for SACs in NRR, hydrogenated borophane, especially borophane‐2H(B5H2), not only prevents metal aggregation, resulting in stable atomically dispersed metal centers, but also enhances catalytic activity by modulating the metal's charge state. Among all candidates, atomic tungsten anchored on W1/borophane‐2H(B5H2) displays the most favorable NRR activity and product selectivity.

Impact of C-H Cross-Coupling Reactions in the One-Step Retrosynthesis of Drug Molecules.

Pharmaceutical synthesis requires a diversity of chemical reactions. The discovery of new reactions enable novel retrosynthetic disconnections, potentially expediting access to complex molecules. This Synopsis demonstrates the use of enumerative combinatorics to find impactful underdeveloped reactions for drug synthesis. By mapping pharmaceutical target molecules onto available building blocks using just one retrosynthetic disconnection even if the requisite reaction is not yet known, we highlight the importance of site-selective C-H cross-coupling methods. This cheminformatics-driven retrosynthetic analysis identifies novel reaction methods of value to the synthesis toolbox.

Enhanced CO2 hydrogenation reaction by Tuning interfacial Cu/ZnOx through synergistic interactions in the precursors

The Cu/ZnO/Al2O3 is a typical industrial catalyst for water–gas-shift reaction and methanol synthesis, and is also gaining momentum in CO2 hydrogenation reaction. The dynamic evolution of the phases and microstructures of the precursor of this catalyst leads to a notable synergistic effect that defines its overall catalytic function and performance. To gain insights into the role and interaction between the relevant precursors, we compared Cu/ZnO/Al2O3 catalysts using a conventional co-precipitation and a fractional precipitation method, where the latter one shows an enhanced Cu/ZnOx interface due to a thorough and strong interaction between two components in the precursor. The ZnOx decoration on Cu with unsaturated Znδ+ species boosted the methanol formation to a rate of 508 gCH3OH‧kgcat−1‧h−1 with 58 % selectivity at 513 K and 3 MPa. This work provides mechanistic insights into the synergistic interplay between the involved phases in the Cu/ZnO/Al2O3 catalyst.

Lying or Standing of Thiophene on a Surface Determines the Reaction Difference.

Adsorption configurations of molecules on a surface play an important role in the on-surface reaction. In the on-surface synthesis reaction, most of the molecules prefer the lying adsorption configuration to maximize the interaction between the molecule and substrate. In this work, we report an on-surface study of 2,3,4,5-tetrabromothiophene by scanning tunneling microscopy, density functional theory, and X-ray photoelectron spectroscopy. Due to different interactions between thiophene and metal surfaces, lying or standing configurations of 2,3,4,5-tetrabromothiophene can be selected by the choice of metal substrates. Moreover, a catalytic role of the metal substrate in the molecular reaction with lying and standing adsorption configurations is demonstrated at the molecular level. This work broadens the understanding of thiophene's configurations in surface reactions and the product diversity driven by adsorption configurations. It also offers a guiding framework for synthesizing multifunctional materials by thiophene derivatives.

Organocatalyzed Enantioselective [3+2] Cycloaddition Reactions for Synthesis of Dispiro[benzothiophenone-indandione-pyrrolidine] Derivatives

An organocatalytic enantioselective [3+2] cycloaddition reaction involving 2-arylidene-1,3-indandiones and N-2,2-difluoroethylbenzothiophenone imines was developed. This approach efficiently afforded dispiro[benzothiophenone-indandione-pyrrolidine]s, featuring three stereocenters, in 84–98% yields with 3–93% ee and 9:1–>20:1 dr. Notably, the method maintained its yield and enantioselectivity integrity even in a gram-scale amplification experiment. For example, the product with substituents on aromatics were obtained in 90% yield with 91% ee and >20:1 dr. Its absolute configuration was established through X-ray single-crystal diffraction analysis, and a plausible reaction mechanism was proposed.

Evaluation of Processing Parameters in the Solvothermal Synthesis of Cu-Rich Tetrahedrites for Potential Application as Thermoelectric Materials

The major issue associated with thermoelectric performance is the low efficiency of power conversion. The main challenge is achieving a combination of high Seebeck coefficient, high electrical conductivity, and low thermal conductivity for a significantly improved figure of merit (ZT). Developing strategies include the production of tetrahedrites with an intrinsically low thermal conductivity through the solvothermal method, using a low reaction time and processing temperature. Here, we report on the preparation of Cu-rich tetrahedrites through the solvothermal technique at low temperature, providing a promising strategy for the preparation of materials with potential applications in thermoelectricity. The influence of synthesis reaction time and temperature on the morphological, structural, and thermoelectrical properties of the samples was investigated through different characterization techniques. Tetrahedrite synthesized at 180 °C for 19 h yielded a favorable ZT value of >0.43 and a thermal conductivity of 0.2 Wm−1 K−1 (423 K), related to the Sb3+/Sb5+ and Cu+/Cu2+ ratio, as was observed by XPS. The cubic tetrahedrite phase attributed to the (222) plane was confirmed by XRD and TEM and the intense Raman mode observed at 351 cm−1. SEM images revealed that nanotetrahedral Cu-rich tetrahedrites efficiently assemble into spherical structures, resulting in an improvement in the Seebeck coefficient (437 µVK−1) and electrical conductivity.

Human selenocysteine synthase, SEPSECS, has evolved to optimize binding of a tRNA-based substrate.

The evolution of the genetic code to incorporate selenocysteine (Sec) enabled the development of a selenoproteome in all domains of life. O-phosphoseryl-tRNASec selenium transferase (SepSecS) catalyzes the terminal reaction of Sec synthesis on tRNASec in archaea and eukaryotes. Despite harboring four equivalent active sites, human SEPSECS binds no more than two tRNASec molecules. Though, the basis for this asymmetry remains poorly understood. In humans, an acidic, C-terminal, α-helical extension precludes additional tRNA-binding events in two of the enzyme monomers, stabilizing the SEPSECS•tRNASec complex. However, the existence of a helix exclusively in vertebrates raised questions about the evolution of the tRNA-binding mechanism in SEPSECS and the origin of its C-terminal extension. Herein, using a comparative structural and phylogenetic analysis, we show that the tRNA-binding motifs in SEPSECS are poorly conserved across species. Consequently, in contrast to mammalian SEPSECS, the archaeal ortholog cannot bind unacylated tRNASec and requires an aminoacyl group. Moreover, the C-terminal α-helix 16 is a mammalian innovation, and its absence causes aggregation of the SEPSECS•tRNASec complex at low tRNA concentrations. Altogether, we propose SEPSECS evolved a tRNASec binding mechanism as a crucial functional and structural feature, allowing for additional levels of regulation of Sec and selenoprotein synthesis.

Modulating Near-Infrared Persistent Luminescence via Diverse Preparation Approaches.

Near-infrared (NIR) persistent luminescence (PersL) materials have attracted extensive attention due to their great promise in medical diagnostics, bio-imaging, night vision surveillance, multi-level anticounterfeiting, and information encryption. To achieve NIR PersL (micro/nano-) materials with the desired properties, a variety of synthesis methods have been employed, including solid-phase reaction and liquid-phase synthesis. Different synthesis methods have different but important effects on the micro/nano-structure, luminescence, and PersL properties of the materials. Moreover, the influence of various synthesis methods on the properties of NIR PersL materials determines the selection of preparation approaches for other new material systems. Taking the representative NIR PersL ZnGa2O4:Cr3+ material as an example, four synthesis procedures are applied, namely, high-temperature solid-state reaction (SSR), high-temperature molten salt method (MSM), hydrothermal method (HM), and microwave-assisted solid-state (MASS) method. The structural and luminescent properties of samples made by SSR, MSM, HM, and MASS are compared. Notably, it is revealed that the MASS method can create additional trapping energy levels, which is of great significance for emerging applications. This work demonstrates the different effects of synthesis methods on PersL performance and provides a good guideline for the rapid and reasonable selection of preparation methods for diverse applications.

Principles of designing electrocatalysts to boost C–N coupling reactions for urea synthesis

AbstractThe electrocatalytic C–N coupling reaction can achieve green and sustainable urea synthesis as well as CO2 conversion and nitrogen fixation. However, the electrocatalytic C–N coupling reaction still faces challenges such as difficult adsorption and activation of reactive species, a large number of reactive intermediates, high reaction energy barriers, and inert reactive kinetics, resulting in the low urea yielding rate and Faradic efficiency. The development of efficient catalysts is key to improve the urea yielding rate and Faradic efficiency. This review covers the development history and basic principles of electrocatalytic C–N coupling for urea production, analyzes the nanostructure–catalytic activity relationship as well as the electronic structure–catalytic activity relationship, and discusses the main reaction mechanism of electrocatalytic C–N coupling for urea production. Based on these analyses, the concept of designing efficient C–N coupling catalysts is derived. Finally, the research status of electrocatalytic C–N coupling for urea synthesis is summarized, and the prospect for developing efficient electrocatalysts and C–N coupling mechanism are proposed.

Carbon nanotubes as heterogeneous catalysts for the multicomponent reaction synthesis of heterocycles

Carbon nanotubes as heterogeneous catalysts for the multicomponent reaction synthesis of heterocycles

Palladium-Catalyzed [3 + 2] Cycloaddition of 4-Vinyl-4-Butyrolactones with Alkenes: Synthesis of Spirocyclopentane Compounds.

A palladium-catalyzed [3 + 2] cycloaddition of 4-vinyl-4-butyrolactones (VBLs) with alkenes has been developed to afford various spirocyclopentane products in high yields with excellent diastereoselectivities. The scale-up reaction and further derivations of the product worked well, demonstrating the potential application of the current reaction in organic synthesis.