Organic Synthesis Research Articles

Asymmetric Three-Component Radical Alkene Carboazidation by Direct Activation of Aliphatic C-H Bonds.

Azide compounds are widely present in natural products and drug molecules, and their easy-to-transform characteristics make them widely used in the field of organic synthesis. The merging of transition-metal catalysis with radical chemistry offers a versatile platform for radical carboazidation of alkenes, allowing the rapid assembly of highly functionalized organic azides. However, the direct use of readily available hydrocarbon feedstocks as sp3-hybridized carbon radical precursors to participate in catalytic enantioselective carboazidation of alkenes remains a significant challenge that has yet to be addressed. Herein, we describe an iron-catalyzed asymmetric three-component radical carboazidation of electron-deficient alkenes by direct activation of aliphatic C-H bonds. This approach involves intermolecular hydrogen atom transfer between a hydrocarbon and an alkoxy/aryl carboxyl radical, leading to the formation of a carbon-centered radical. The resulting radical then reacts with electron-deficient alkenes to generate a new radical species that undergoes chiral iron-complex-mediated C-N3 bond coupling. An array of valuable chiral azides bearing a quaternary stereocenter were directly accessed from widely available chemical feedstocks, and their synthetic potential is further demonstrated through more facile transformations to give other valuable enantioenriched building blocks.

Enantioselective Synthesis of Heteroatom-Linked Non-Biaryl Atropisomers.

Atropisomers hold significant fascination, not only for their prevalence in natural compounds but also for their biological importance and wide-ranging applications as chiral materials, ligands, and organocatalysts. While biaryl and heterobiaryl atropisomers are commonly studied, the enantioselective synthesis of less abundant heteroatom-linked non-biaryl atropisomers presents a formidable challenge in modern organic synthesis. Unlike classical atropisomers, these molecules allow rotation around two bonds, resulting in low barriers to enantiomerization through concerted bond rotations. In recent years the discovery of new configurationally stable rare non-biaryl scaffolds such as aryl amines, aryl ethers and aryl sulfones as well as innovative methodologies to control their configuration have been disclosed in the literature and constitute the topic of this minireview.

Factors that Impact Photochemical Cage Escape Yields.

The utilization of visible light to mediate chemical reactions in fluid solutions has applications that range from solar fuel production to medicine and organic synthesis. These reactions are typically initiated by electron transfer between a photoexcited dye molecule (a photosensitizer) and a redox-active quencher to yield radical pairs that are intimately associated within a solvent cage. Many of these radicals undergo rapid thermodynamically favored "geminate" recombination and do not diffuse out of the solvent cage that surrounds them. Those that do escape the cage are useful reagents that may undergo subsequent reactions important to the above-mentioned applications. The cage escape process and the factors that determine the yields remain poorly understood despite decades of research motivated by their practical and fundamental importance. Herein, state-of-the-art research on light-induced electron transfer and cage escape that has appeared since the seminal 1972 review by J. P. Lorand entitled "The Cage Effect" is reviewed. This review also provides some background for those new to the field and discusses the cage escape process of both homolytic bond photodissociation and bimolecular light induced electron transfer reactions. The review concludes with some key goals and directions for future research that promise to elevate this very vibrant field to even greater heights.

Copper-Nitroxyl-Catalyzed α-Oxygenation of Cyclic Secondary Amines Including Application to Late-Stage Functionalization.

Cyclic secondary amines are prominent subunits in pharmaceutical compounds. Methods for direct functionalization of N-unprotected/unsubstituted piperidines and related heterocycles have limited precedent despite their potential to impact medicinal chemistry and organic synthesis. Herein, we report a Cu/nitroxyl co-catalyzed method for direct conversion of cyclic secondary amines to the corresponding lactams via aerobic dehydrogenation and oxidative coupling with water. The mild reaction conditions tolerate diverse functional groups, enabling application to molecules that cover broad chemical space. The method is showcased in selective functionalization of building blocks and complex molecules, including late-stage functionalization of bromodomain inhibitors.

CO2 photoreduction integrated with oxidative coupling of amines over WO3/Cu(BTC) nanocomposite

Here, we report an efficient integrated CO2 photoreduction to methanol accompanied with the simultaneous oxidation of benzyl amines to corresponding imines using quadrangular WO3 nanoplates grafted with Cu(BTC) as a photocatalyst under visible light, enabling to provide efficient use of the photogenerated electrons and holes. Under the optimized reaction conditions, the maximum yield of methanol and N-(4-methoxybenzyl)-1-(4-methoxyphenyl)methanimine was found to be 642 μmol-g−1 and 98 %, respectively. The developed integrated dual functional system comprising CO2 reduction coupled with the oxidative organic synthesis opens a new window for value chain up gradation at both ends using sustainable solar energy.

Transcriptome analysis reveals the role of Long noncoding RNAs (lncRNA) in specific deposition of inosine monphosphate in Jingyuan chickens.

Inosine monphosphate (IMP) is one of the important indicators for evaluating meat flavor, and long noncoding RNAs (lncRNAs) play an important role in its transcription and post-transcriptional regulation. Currently, there is little information about how lncRNA regulates the specific deposition of IMP in chicken muscle. In this study, we used transcriptome sequencing to analyze the lncRNAs of the breast and leg muscles of the Jingyuan chicken and identified a total of 357 differentially expressed lncRNAs (DELs), of which 158 were up-regulated and 199 were down-regulated. There were 2,203 and 7,377 cis- and trans-regulated target genes of lncRNAs, respectively, and we identified the lncRNA target genes that are involved in NEGF signaling pathway, glycolysis/ glucoseogenesis and biosynthesis of amino acids pathways. Meanwhile, 621 pairs of lncRNA-miRNA-mRNA interaction networks were constructed with target genes involved in purine metabolism, fatty acid metabolism, and biosynthesis of amino acids. Next, three interacting meso-networks gga-miR-1603-LNC_000324-PGM1, gga-miR-1768-LNC_000324-PGM1 and gga-miR-21-LNC_011339- AMPD1 were identified as closely associated with IMP-specific deposition. Both differentially expressed genes (DEGs) PGM1 and AMPD1 were significantly enriched in IMP synthesis and metabolism-related pathways, and participated in the anabolic process of IMP in the form of organic matter synthesis and energy metabolism. This study obtained lncRNAs and target genes affecting IMP-specific deposition in Jingyuan chickens based on transcriptome analysis, which deepened our insight into the role for lncRNAs in chicken meat quality.

Application of DNA‐Conjugated Aryl Diazonium Intermediates in DNA‐Encoded Libraries

AbstractAryl diazonium intermediates have emerged as highly versatile intermediates in modern organic synthesis and chemical biology, demonstrating remarkable reactivity under mild reaction conditions. Their significance has extended to DNA‐encoded libraries (DELs), where they serve as valuable alternatives to traditional aryl halide‐based cross‐coupling reactions. Aryl diazonium intermediates as N2‐annulation synthons can efficiently transform into benzotriazinone core on DNA besides C−C coupling. This concept paper illuminates recent advances in this field, emphasizing their applications and potential across various facets of DELs, off‐DNA chemistry, DELs selection, and DNA‐based probes. It is anticipated that these developments will propel the broader utilization of DNA‐conjugated aryl diazonium salt intermediates in DELs, protein labeling, hit discovery, and other interdisciplinary fields.

An interactive approach to the notion of chemical substance and the case of water

AbstractFrom organic synthesis to quantum chemical calculation, chemists interact with chemical substances in a wide variety of ways. But what even is a chemical substance? My aim is to propose a notion of chemical substance that is consistent with the way in which chemical substances are individuated in chemistry, addressing gaps in previous conceptions of chemical substance. Water is employed as a case study to develop the account, not only because it is a familiar example of a chemical substance, but also because its structural peculiarities make it an ideal test case for drawing out potential issues and limitations. Examining four distinct views of chemical substance—the microstructural, thermodynamic, purification, and a functional/relational account—I conclude that each has considerable drawbacks when used as a standalone concept. However, these accounts are not rendered obsolete, but are combined into a semi-pluralist conceptual patchwork. My interactive account of chemical substance is consistent with existing substance descriptions and chemical practice.

Polyvinyl Alcohol/Zr-based Metal Organic Framework Mixed-matrix Membranes Synthesis and Application for Hydrogen Separation

AbstractMembrane gas separation is an environmentally friendly and economical method used to separate valuable gases, industrial process gas wastes, and carbon dioxide from mixed gases. The most important part of this method is the membranes. Gas separation membranes are expected to have high separation and permeability performance, high mechanical strength, easy and fast production capability, and low prices. Polymer-based membranes are mostly preferred depending on the ease of modification capability. In this study, a zirconium-based metal organic framework (Zr-MOF, MIL-140 A) was synthesized and used as a filler within polyvinyl alcohol (PVA) matrix for the selective separation of hydrogen (H2) from carbon dioxide (CO2). The effect of MIL-140 A addition on the mechanical, structural, and morphological properties of PVA was evaluated. The MIL-140 A significantly improved the mechanical strength of the membrane. According to the gas separation results, the increasing concentration of MIL-140 A increased the selective separation performance of the nanocomposite membrane. The highest mechanical strength (43.1 MPa) and best film-forming ability were obtained with 3 wt% MIL-140 A loaded membrane. The ideal H2/CO2 selectivity and hydrogen permeability were obtained as 5.6 and 944 Barrer, respectively at 2 bar feed pressure and room temperature. The highest ideal H2/CO2 selectivity was obtained as 6.3 with the H2 permeability of 959 Barrer when the MIL-140 A ratio was 4 wt%.

In-silico green toxicology approach toward discovering safer ligands for development of safe-by-design metal organic frameworks

: A vast variety of chemical compounds have been fabricated and commercialized, they not only result in industrial exposure during manufacturing and usage, but also have environmental impacts throughout their whole life cycle. Consequently, attempts to assess the risk of chemicals in terms of toxicology have never ceased. In-silico toxicology, also known as predictive toxicology, has advanced significantly over the last decade as a result of the drawbacks of experimental investigations. In this study, ProTox-III was applied to predict the toxicity of the ligands used for metal organic framework design and synthesis. Initially, 35 ligands, that have been frequently utilized for MOF synthesis and fabrication, were selected. Subsequently, canonical SMILES of ligands were extracted from the PUBCHEM database and inserted into the ProTox-III online server. Ultimately, webserver outputs including LD50 and the probability of toxicological endpoints (cytotoxicity, carcinogenicity, mutagenicity, immunotoxicity and ecotoxicity) were obtained and organized. According to retrieved LD50 data, the safest ligand was 5-hydroxyisophthalic. In contrast, the most hazardous ligand was 5-chlorobenzimidazole, with an LD50 of 8 mg/kg. Among evaluated endpoints, ecotoxicity was the most active and was detected in several imidazolate ligands. This data can open new horizons in design and development of green MOFs.

Path toward “Net Zero Organic Synthesis”

Path toward “Net Zero Organic Synthesis”

Augmenting large language models with chemistry tools

AbstractLarge language models (LLMs) have shown strong performance in tasks across domains but struggle with chemistry-related problems. These models also lack access to external knowledge sources, limiting their usefulness in scientific applications. We introduce ChemCrow, an LLM chemistry agent designed to accomplish tasks across organic synthesis, drug discovery and materials design. By integrating 18 expert-designed tools and using GPT-4 as the LLM, ChemCrow augments the LLM performance in chemistry, and new capabilities emerge. Our agent autonomously planned and executed the syntheses of an insect repellent and three organocatalysts and guided the discovery of a novel chromophore. Our evaluation, including both LLM and expert assessments, demonstrates ChemCrow’s effectiveness in automating a diverse set of chemical tasks. Our work not only aids expert chemists and lowers barriers for non-experts but also fosters scientific advancement by bridging the gap between experimental and computational chemistry.

Interfacing High-Throughput Electrosynthesis and Mass Spectrometric Analysis of Azines.

Combinatorial electrochemistry has great promise for accelerated reaction screening, organic synthesis, and catalysis. Recently, we described a new high-throughput electrochemistry platform, colloquially named "Legion". Legion fits the footprint of a 96-well microtiter plate with simultaneous individual control over all 96 electrochemical cells. Here, we demonstrate the versatility of Legion when coupled with high-throughput mass spectrometry (MS) for electrosynthetic product screening and quantitation. Electrosynthesis of benzophenone azine was selected as a model reaction and was arrayed and optimized using a combination of Legion and nanoelectrospray ionization MS. The combination of high-throughput synthesis with Legion and analysis via MS proves a compelling strategy for accelerating reaction discovery and optimization in electro-organic synthesis.

Heterogeneous Organocatalysts for Light-Driven Reactions in Continuous Flow

Within the realm of organic synthesis, photocatalysis has blossomed since the beginning of the last decade. A plethora of classical reactivities, such as selective oxidation of alcohol and amines, redox radical formation of reactive species in situ, and indirect activation of an organic substrate for cycloaddition by EnT, have been revised in a milder and more sustainable fashion via photocatalysis. However, even though the spark of creativity leads scientists to explore new reactions and reactivities, the urgency of replacing the toxic and critical metals that are involved as catalysts has encouraged chemists to find alternatives in the branch of science called organocatalysis. Unfortunately, replacing metal catalysts with organic analogues can be too expensive sometimes; however, this drawback can be solved by the reutilization of the catalyst if it is heterogeneous. The aim of this review is to present the recent works in the field of heterogeneous photocatalysis, applied to organic synthesis, enabled by continuous flow. In detail, among the heterogeneous catalysts, g-CN, polymeric photoactive materials, and supported molecular catalysts have been discussed within their specific sections, rather than focusing on the types of reactions.

One pot conversion of phenols and anilines to aldehydes and ketones exploiting α gem boryl carbanions

Functional group interconversion is an important asset in organic synthesis. Phenols/anilines being naturally abundant and the carbonyl being the most common in a wide range of bioactive molecules, an efficient conversion is of prime interest. The reported methods require transition metal catalyzed cross coupling which limits its applicability. Here we have described a method for synthesizing various aldehydes and ketones, starting from phenol and protected anilines via Csp2-O/N bond cleavage in a one-pot/stepwise manner. Our synthetic method is found to be compatible with a diverse range of phenols and anilines carrying sensitive functional groups including halides, esters, ketal, hydroxyl, alkenes, and terminal alkynes as well as the substitution on the aryl cores. A short-step synthesis of bioactive molecules and their functionalization have been executed. Starting from BINOL, a photocatalyst has been designed. Here, we have developed a transition metal-free protocol for the conversion of phenols and anilines to aldehydes and ketones.

(E)-1-(5-(Hydroxymethyl) furan-2-yl)-4,4-dimethylpent-1-en-3-one

This study presents a novel approach in the realm of catalytic organic synthesis by integrating biomass catalytic conversion with organic synthesis techniques. Utilizing N-acetylglucosamine as the primary feedstock, the first phase of the research involves its catalytic transformation into 5-hydroxymethylfurfural (HMF). The subsequent phase employs a condensation reaction between HMF and 3,3-Dimethyl-2-butanone to synthesize a new compound, (E)-1-(5-(hydroxymethyl) furan-2-yl)-4,4-dimethylpent-1-en-3-one. This two-step process not only demonstrates the feasibility of converting biomass into valuable chemical precursors but also exemplifies the synthesis of novel compounds through green chemistry principles. The successful execution of this methodology offers fresh insights and opens new avenues for advancements in catalytic organic synthesis, emphasizing sustainability and efficiency.

AUTOMATION IN ANALYTICAL CHEMISTRY: THE ROLE OF AI IN CHROMATOGRAPHY

Artificial Intelligence (AI) has facilitated significant breakthroughs in drug discovery, the design of materials, and organic synthesis. The advancements in the latter group are especially remarkable due to the abilities of the latest computational methods (molecular design algorithms) that enable the exploration of extensive chemical spaces and enhance research in fields such as predicting molecule properties, designing molecules, retrosynthesis, predicting reaction conditions, and predicting reaction outcomes. A literary review was conducted following PRISMA guidelines. This study aimed to review existing data on the application of AI in separation chromatography. The evolution and utilization of AI in the pharmaceutical industry and its future aspects were articulated in this study. The utilization of AI can completely transform the field of chromatography analysis by facilitating expedited, more precise, and more effective data processing. By automating chromatography analysis, AI can enhance efficiency and minimize the potential for human mistakes. This advancement enables scientists to dedicate their efforts towards addressing intricate and demanding analytical issues. With the evolution of technology and the increasing adoption, we can anticipate more progress in chromatography analysis and analytical chemistry.

Tungsten Oxide Dispersed on Silica as Robust and Readily Available Oxo/Imido Heterometathesis Catalyst.

Continuing our investigation of catalytic oxo/imido heterometathesis as novel water-free method for C=N bond construction, we report here the application of classical transition metal oxides dispersed on silica (MOx/SiO2, M=V, Mo, W) as cheap, robust and readily available alternative to the catalysts prepared via Surface Organometallic Chemistry (SOMC). The oxide materials demonstrated activity in heterometathetical imidation of ketones, WO3/SiO2 being the most efficient. We also describe a new well-defined supported W imido complex (≡SiO)W(=NMes)2(Me2Pyr) (Mes=2,4,6-Me3C6H2, Me2Pyr=2,5-dimethylpyrrolyl) and characterize it with SOMC protocols, which allowed us to identify the position of W on the oxo/imido heterometathesis activity scale (Mo<W<Ta) and showed that W in fact provides an optimal balance between activity and stability. Noteworthy, the performance of WO3/SiO2 was only slightly inferior to that of the SOMC analog enabling the efficient synthesis of a broad range of ketimines hardly accessible by classical methods, in most cases W being a competitive and robust alternative to the most active albeit highly sensitive Ti imido systems. Combined with the availability of the catalyst, this facilitates a more widespread application of heterometathesis methodology in organic synthesis including potential larger scale applications.

Microwave‐Assisted Catalyst‐Free Conjugate Addition of Amines to Maleimide

AbstractA catalyst‐free approach has been introduced for the conjugate addition of aromatic amine nucleophiles to α, β‐unsaturated N‐methyl maleimide under microwave irradiation by utilizing water as a promoter. Catalyst‐free, environmentally friendly, short‐reaction time, green solvent, and mild reaction conditions are the advantages of this protocol. This reaction provided good to excellent yields with aromatic anilines as nucleophiles. The benefits of this reaction align with the principles of green and sustainable synthetic chemistry, making it widely applicable in organic synthesis and pharmaceutical chemistry.

Indium Triflate's Transformative Role in Modern Organic Synthesis: A Five‐Year Survey of Functionalization, Cyclization, and Multicomponent Reactions

AbstractIndium triflate (In(OTf)3) has proven to be a powerful and sustainable catalyst in the synthesis of modern organic compounds, enabling a variety of transformations such as functionalization, cyclization, and multicomponent reactions. To provide insight into the most recent methods and applications, this study attempts to provide a comprehensive and up‐to‐date summary of these advances in the application of indium triflate as a catalyst in organic synthesis, focusing on the last five years of literature. The application of indium triflate as opposed to alternative indium(III) catalysts in organic transformations will be the main emphasis of this review, which will cover recent developments through research articles and reviews published between 2019 and 2023. This minireview will make a significant contribution to the existing literature by consolidating recent advancements in the use of indium triflate in modern organic synthesis.