Reaction Setup Research Articles

High-Energy Ball Milling Enables an Ultra-Fast Wittig Olefination Under Ambient and Solvent-free Conditions.

30 Seconds to success!-The Wittig reaction, a fundamental and extensively utilized reaction in organic chemistry, enables the efficient conversion of carbonyl compounds to olefins using phosphonium salts. Traditionally, meticulous reaction setup, including the pre-formation of a reactive ylide species via deprotonation of a phosphonium salt, is crucial for achieving high-yielding reactions under classical solution-based conditions. In this report, we present an unprecedented protocol for an ultra-fast mechanically induced Wittig reaction under solvent-free and ambient conditions, often eliminating the need for tedious ylide pre-formation under strict air and moisture exclusion. A range of aldehydes and ketones were reacted with diverse phosphonium salts under high-energy ball milling conditions, frequently giving access to the respective olefins in only 30 seconds.

Conditions for enhancement of gas phase chemical reactions inside a dark microwave cavity

The ability to slow down or enhance chemical reactions, by a seemingly simple setup of reactions inside a cavity made of two parallel mirrors is fascinating. Unfortunately, currently, theory and experiment have not yet fully converged. Since theory and experiment perfectly match for atom/molecular collisions in gas phase the enhancing chemical reactions in gas phase through its coupling to quantized electromagnetic modes in a dark cavity is investigated. Here the conditions and guidelines for selecting the proper type of reactions that can be enhanced by a dark cavity are provided. Showing that the asymmetric reaction rates of O + D2 → [ODD]# → OD + D and H + ArCl → [ArHCl]# → H + Ar + Cl can be enhanced by a dark cavity. On the other hand, an effect of the dark cavity on the symmetric reaction of hydrogen exchange in methane is predicted to be negligible. Notice that the theory is not limited to microwave cavities only.

Catalytic Deoxygenative Transformation of Ketoacids/Esters for the Synthesis of Coumarin, Benzofuranone, and Dihydrobenzo[b]oxepin‐2(3H)‐one Derivatives

AbstractWe disclose herein a triflic acid and silane‐promoted reductive deoxygenative transformation of ketoacid/esters for the divergent synthesis of different‐sized lactones, which hold substantial significance in pharmaceutical and natural product chemistry. Owing to the simple reaction conditions and setup, this protocol features broad substrate generality, scalability, and good functional group tolerance, including late‐stage functionalization of pharmaceutical compounds and natural products. The control experiments and detailed NMR study provide insight into the reaction mechanism.

Photochemical oxidative coupling of thiols to disulfides using Bi quantum dots: Mild and efficient catalysis

Herein, we present an efficient synthesis method utilizing Bi quantum dots (QDs) as catalysts for the photochemical oxidative coupling of thiols to disulfides under mild conditions. The protocol offers low catalyst loading, simplicity in reaction setup as well as high efficiency. Aromatic thiols and aliphatic thiols are successfully transformed into disulfides with good to quantitative yields, demonstrating tolerance to various substituents and heterocycles. Additionally, the protocol extends to the synthesis of asymmetric disulfides and allows for gram-scale synthesis.

Synthesis of N-heterocycles through alcohol dehydrogenative coupling.

Nitrogen heterocycles are found in the structures of many biologically important compounds, as well as materials used in the synthesis of fine chemicals. Notably, ~59% of US Food and Drug Administration-approved small-molecule drugs contain nitrogen heterocycles. It is therefore meaningful to explore greener or more sustainable methods for their synthesis. The use of alcohols as reagents is attractive as they can be readily obtained from biomass derived natural resources. In the last two decades, alcohol dehydrogenative coupling reaction to synthesize various heterocycles were extensively explored which furnished hydrogen (H2) and water (H2O) as the two greener byproducts. In this protocol, we describe several efficient catalytic transformations to synthesize quinolines, 1,8-naphthyridines, quinoxalines, quinazolines, pyrimidines, benzimidazoles, pyrroles and pyridines, using alcohol as starting materials. We also describe the synthesis of several homogeneous iridium/ruthenium catalysts and heterogeneous cobalt/copper catalysts that can be used in these transformations. The reaction setup is simple; in a Schlenk/reaction tube with magnetic stir-bar, alcohol, corresponding coupling reagents (nucleophiles), catalyst, base and solvent (water or organic solvent such as toluene, dioxane or p-xylene) are added. The reaction mixture is refluxed at the specified temperature (110-150 °C)-either in air or under argon-to furnish these heterocycles. Synthesis of the catalysts takes 3-5 h and the coupling reactions take 4-5 h depending on the target product. The cobalt- and copper-based heterogeneous catalytic systems displayed an good catalyst recyclability.

C-H activation under visible light using DDQ organo-photocatalyst: Practical, tunable and additive free

Here we present a practical, mild, selective, eco-friendly, metal-free, cost-effective, and tunable method for the photoactivation of C-H compounds using an organo photocatalyst without any additives. For this purpose, the organo photocatalyst DDQ was employed as a versatile and highly efficient catalyst for C-H bond functionalization under visible light irradiation in a straightforward reaction setup, free from additives and co-catalysts. Notably, under appropriate solvent conditions, the photooxidation of alkylarenes produced ketones, aldehydes, and carboxylic acids from corresponding starting materials. In CH3CN solvent, carboxylic acids were obtained. Interestingly over oxidation to carboxylic acid is avoided and aldehydes were produced from methyl arenes via acetal formation in CH3CN:MeOH. Furthermore, our results demonstrated that the photooxidation of 4-methoxytoluene was more efficient than that of 4-methoxybenzylalcohol. The proposed mechanism for this reaction involved the formation of a charge transfer complex between the starting material and DDQ, as indicated by UV–Vis and fluorescence spectra. Also, this method exhibited promising scalability, with 30 mmol of 4-methoxytoluene being converted to 4-methoxybenzoic acid with a yield of 92 % (TON: 345).

Improving the Phosphatase-Catalyzed Synthesis of 5′-Nucleotides: A Reaction Engineering Approach

5′-Phosphorylation of nucleosides is a reaction as important in nature and in industry as it is cumbersome to be performed. Whilst chemical phosphorylation relies on the use of harsh reagents, solvents, and conditions, as well as on the need for protection–deprotection steps, biocatalysis can be a tool to achieve one-step phosphorylation reactions, which are selective, protecting group-free, and occurring under mild and sustainable conditions. In this work, the wild-type non-specific acid phosphatase from Morganella morganii (PhoC-Mm) was expressed, purified, and used for the synthesis of inosine 5′-monophosphate (IMP), an important food additive, by using pyrophosphate (PPi) as an inexpensive phosphate donor in a fully aqueous medium at 30 °C. Via the fine-tuning of the reaction set-up taking into account the type of buffer, amount of PPi, mode/time of PPi addition, and enzyme and substrate concentration, PhoC-Mm could be used for catalyzing the phosphorylation of inosine (I) to IMP in a good yield and high purity (62% yield). The catalysis of the hydrolytic reaction direction, which is the primary function of phosphatases in nature, was here reversed to a certain extent by a reaction engineering approach, without the need for protein engineering strategies.

High-Entropy Design for 2D Halide Perovskite.

Hybrid halide perovskites are good candidates for a range of functional materials such as optical electronic and photovoltaic devices due to their tunable band gaps, long carrier diffusion lengths, and solution processability. However, the instability in moisture/air, the toxicity of lead, and rigorous reaction setup or complex postprocessing have long been the bottlenecks for practical application. Herein, we present a simultaneous configurational entropy design at A-sites, B-sites, and X-sites in the typical (CHA)2PbBr4 two-dimensional (2D) hybrid perovskite. Our results demonstrate that the high-entropy effect favors the stabilization of the hybrid perovskite phase and facilitates a simple crystallization process without precise control of the cooling rate to prepare regular crystals. Moreover, high-entropy 2D perovskite crystals exhibit tunable energy band gaps, broadband emission, and a long carrier lifetime. Meanwhile, the high-entropy composition almost maintains the initial crystal structure in deionized water for 18 h while the original (CHA)2PbBr4 crystal mostly decomposes, suggesting obviously improved humidity stability. This work offers a facile approach to synthesize humidity-stable hybrid perovskites under mild conditions, accelerating relevant preparation of optoelectronics and light-emitting devices and facilitating the ultimate commercialization of halide perovskite.

One-Pot Synthesis of Vinylogous Cyano Aminoaryls (VinCAs) as Benzenic Fluorophores: Tailoring Diverse Emission Colors for White Light Emitting Materials and Cell Imaging.

Donor-acceptor-based organic small molecules with an electronic push-pull effect can demonstrate intramolecular charge transfer to show interesting photoluminescence properties. This is an essential criterion for designing fluorogenic probes for cell imaging studies and the development of organic light-emitting diodes. Now, to design such optical materials sometimes it is necessary to tune the band gap by controlling the energies of the highest occupied molecular orbital and lowest unoccupied molecular orbital. Typically, the band gaps could be modulated by installing unsaturated handles between electron-rich donors and electron-deficient acceptors. However, these methods are often synthetically and economically challenging due to the involvement of expensive catalysts and difficult reaction setups. In our present study, we show a straightforward, cost-effective method for obtaining a series of donor-acceptor-type Vinylogous Cyano Aminoaryls (VinCAs) with diverse emission colors. Further studies reveal that these VinCAs can serve as effective cell imaging agents, showcasing potential use in chemical biology. Additionally, these molecules could be further used to generate white light emission (WLE), showing their potential utility in advanced lighting technologies.

Photo-Induced Generation of Oxygenated Quaternary Centers via EnT Enabled Singlet O2 Addition to C3-Maleimidated Quinoxaline: A Reagent-Less Approach.

Demonstrated here is an external photo-sensitizer-free (auto-sensitized) singlet oxygen-enabled solvent-dependent tertiary hydroxylation and aryl-alkyl spiro-etherification of C3-maleimidated quinoxalines. Such "reagent-less" photo-oxygenation at Csp3-H and etherification involving Csp3-H/Csp2-H are unparalleled. Possibly, the highly π-conjugated N-H tautomer allows the substrate to get excited by irradiation, and subsequently, it attains the triplet state via ISC. This excited triplet-state sensitized molecule then transfers its energy to a triplet-state oxygen (3O2) generating reactive singlet oxygen (1O2) for hydroxylation and spirocyclization depending on the solvent used. In HFIP, the generated alkoxy radical accepts a proton via HAT giving hydroxylated product. In contrast, in an aprotic PhCl it underwent a radical addition at the ortho-position of the C2 aryl to provide spiro-ether. An unprecedented orthogonal spiro-etherification was observed via the displacement of o-substitutents for ortho (-OEt, -OMe, -F, -Cl, -Br) substituted substrates. The order of ipso substitution follows the trend -OMe>-OEt>-F>-H>-Cl>-Br. Both these oxygenation reactions can be carried out with nearly equal ease using direct sunlight without the requirement of any elaborate reaction setup. Demonstration of large-scale synthesis and a few interesting transformations have also been realized. Furthermore, several insightful control experiments and quantum chemical computations were performed to unravel the mechanism.

Core–Shell catalyst particles for tandem catalysis: An experimental/numerical approach towards optimal design

Tandem catalysis is a promising approach to intensify chemical processes and increase their efficiency. On the other hand, the design of efficient, optimal and targeted tailored tandem catalysts is yet so challenging as the optimal catalyst loading is difficult to assess a priori. In this article, we present a concise route towards the design of optimal core–shell tandem catalyst particles on the example of coupled RWGS and FTS reactions for any specific spherical morphology. The route features five consecutive steps including: tandem system identification, catalyst synthesis, i.e. mono- and tandem-functional, catalyst characterization and initial performance test, kinetic modeling with parameter estimation if necessary, and optimal design of catalysts. The initial step features thermodynamic equilibrium calculations for RWGS and FTS showing a common operational window. Then, Pt and Co are selected as active metals and the formulation of the tandem catalyst is designed. For the second step, the synthesis route for the tandem catalyst Pt,CeO2@SiO2-Co, and the mono-functional catalysts, Pt@SiO2 and CeO2@SiO2-Co are presented. For the third step, all catalysts were tested for CO2 hydrogenation as an exemplary tandem process. A reduced transport model from literature was adjusted for RWGS and FTS reactions with kinetic expression from literature to enable numerical optimization. The kinetic parameters are estimated based on the performance tests of the mono-functional reference materials, i.e. Pt@SiO2 for RWGS and CeO2@SiO2-Co for FTS. The model is validated by cross comparison to the data from the tandem reaction setup. In the fifth step, the model was used for the numerical optimization of the catalyst loading on core and shell leading to the identification of the optimal design, resulting in a significant increase of C2+ Yield.

Biocatalytic stereocontrolled head-to-tail cyclizations of unbiased terpenes as a tool in chemoenzymatic synthesis

Terpene synthesis stands at the forefront of modern synthetic chemistry and represents the state-of-the-art in the chemist’s toolbox. Notwithstanding, these endeavors are inherently tied to the current availability of natural cyclic building blocks. Addressing this limitation, the stereocontrolled cyclization of abundant unbiased linear terpenes emerges as a valuable tool, which is still difficult to achieve with chemical catalysts. In this study, we showcase the remarkable capabilities of squalene-hopene cyclases (SHCs) in the chemoenzymatic synthesis of head-to-tail-fused terpenes. By combining engineered SHCs and a practical reaction setup, we generate ten chiral scaffolds with >99% ee and de, at up to decagram scale. Our mechanistic insights suggest how cyclodextrin encapsulation of terpenes may influence the performance of the membrane-bound enzyme. Moreover, we transform the chiral templates to valuable (mero)-terpenes using interdisciplinary synthetic methods, including a catalytic ring-contraction of enol-ethers facilitated by cooperative iodine/lipase catalysis.

Organic Electrosynthesis: A Promising Green Tool in Solving Key Steps for the Total Synthesis of Complex Natural Products

Abstract: Electro-organic synthesis, an atom-efficient, sustainable, mild process, permits an ecofriendly and elegant green path to synthesize structurally complex, still valuable molecules, avoiding the use of conventional harsh oxidizing and reducing agents and long-route reaction protocols. Being one of the oldest forms of reaction setups in a laboratory, it deals with fundamental redox chemistry through the direct application of electrical potential. Here flow of electrons acts as an oxidizing agent at the anode at the same time reducing agent at the cathode, depending upon the requirement of the reaction. Simultaneously, it minimizes the generation of reagent waste during the reaction. However, electrifying organic synthesis plays more than preventing the waste footprint. This technology provides an alternative roadmap through nonclassical bond disconnections to access desired target molecules by cutting down a number of steps with the formation of apparently looking difficult bonds with excellent regio-, chemo-and stereoselectivity. Hence, it emerges as an alternative and attractive technique for the contemporary synthetic communities. Consequently, in recent years, multiple milestones have been achieved in the electro-organic synthesis of fascinating natural products through oxidative C-C bond formation, C-H/N-H functionalization, very rare oxidative N-N dimerization, RCDA dimerization, etc. Thus, synthesis of extremely complex natural products through finding new electro-synthetic route as a key methodology have become one of the alluring synthetic targets to synthetic chemists because of their versatile utilities in medicine, agriculture, food, and cosmetic industry. This review presents advances in electrochemistry in the total synthesis of 20 complex natural products reported since 2013. Enabling synthetic steps are analyzed alongside innate advantages as well as future prospects are speculated.

Persistent organonickel complexes as general platforms for Csp2-Csp3 coupling reactions.

The importance of constructing Csp2-Csp3 bonds has motivated the development of electrochemical, photochemical and thermal activation methods to reductively couple abundant aryl and alkyl electrophiles. However, these methodologies are limited to couplings of very specific substrate classes and require specialized sets of catalysts and reaction set-ups. Here we show a consolidation of these myriad strategies into a single set of conditions that enable reliable alkyl-aryl couplings, including those that were previously unknown. These reactions rely on the discovery of unusually persistent organonickel complexes that serve as stoichiometric platforms for C(sp2)-C(sp3) coupling. Aryl, heteroaryl or vinyl complexes of Ni can be inexpensively prepared on a multigram scale by mild electroreduction from the corresponding C(sp2) electrophile. Organonickel complexes can be isolated and stored or telescoped directly to reliably diversify drug-like molecules. Finally, the procedure was miniaturized to micromole scales by integrating soluble battery chemistries as redox initiators, enabling a high-throughput exploration of substrate diversity.

Multifunctional Deep Eutectic Solvent-Catalyzed Synthesis of Dihydropyrimidinethiones: A Sustainable Approach for Green and Efficient Reactions

Background: This study investigates the synthesis of dihydropyrimidinethiones using a multifunctional deep eutectic solvent (DES) composed of Choline chloride (ChCl) and ammonium thiocyanate. This DES serves as a catalyst, solvent, and reagent, providing a simple, highyielding, and environmentally friendly method for dihydropyrimidinethione synthesis. The use of DES in this capacity offers several advantages, including reduced environmental impact, high efficiency, and ease of use, highlighting its potential as a sustainable alternative in organic synthesis. Objective: The objective of this study is to investigate the application of a deep eutectic solvent (DES) composed of ChCl and ammonium thiocyanate as a catalytic solvent and reagent system for synthesizing dihydropyrimidinethiones. The aim is to simplify the reaction setup, improve yields, and enhance the green metrics of the process. Methods: ChCl and ammonium thiocyanate were combined to form a DES catalyst-solvent system. Dihydropyrimidinethiones were synthesized in one-pot reactions at ambient temperature. Green metrics and DES recovery were evaluated. Comparative analysis with traditional methods was conducted. Results: The DES efficiently catalyzed dihydropyrimidinethione synthesis with high yields. Simplified reaction setup, safe solvent properties, and favorable green metrics. DES was recoverable and reusable, outperforming traditional methods in efficiency and eco-friendliness. Conclusion: The ChCl and ammonium thiocyanate DES demonstrated remarkable efficiency and eco-friendliness in dihydropyrimidinethione synthesis. The toxicity-free, multifunctional roles of the DES, serving as a catalyst, solvent, and reagent, highlight its novelty and potential as a sustainable alternative in organic chemistry. This study simplifies the synthesis process and improves yields and green metrics, showcasing the DES as a promising candidate for future research and industrial applications.

Development of High-Throughput Experimentation Approaches for Rapid Radiochemical Exploration.

Positron emission tomography is a widely used imaging platform for studying physiological processes. Despite the proliferation of modern synthetic methodologies for radiolabeling, the optimization of these reactions still primarily relies on inefficient one-factor-at-a-time approaches. High-throughput experimentation (HTE) has proven to be a powerful approach for optimizing reactions in many areas of chemical synthesis. However, to date, HTE has rarely been applied to radiochemistry. This is largely because of the short lifetime of common radioisotopes, which presents major challenges for efficient parallel reaction setup and analysis using standard equipment and workflows. Herein, we demonstrate an effective HTE workflow and apply it to the optimization of copper-mediated radiofluorination of pharmaceutically relevant boronate ester substrates. The workflow utilizes commercial equipment and allows for rapid analysis of reactions for optimizing reactions, exploring chemical space using pharmaceutically relevant aryl boronates for radiofluorinations, and constructing large radiochemistry data sets.

Catalytic 2-Ethylhexanoic Acid Promotes Mild Miyaura Borylations.

The Miyaura borylation of aryl and heteroaryl chlorides and bromides using a combination of potassium carbonate and 5 mol % 2-ethylhexanoic acid at 25 °C is reported. The in situ generation of a catalytic amount of potassium 2-ethylhexanoate under these conditions avoids the need for special handling of stoichiometric quantities of hygroscopic potassium 2-ethylhexanoate during the reaction setup as well as difficulties in removing the resulting carboxylic acid during product isolation.

Palladium-charcoal Catalyzed Direct Esterification of Aldehydes to Esters by NaIO4

Abstract:: An efficient direct oxidation method was developed to oxidize some aromatic and aliphatic aldehydes to esters by the dual utilization of NaIO4 and Pd-C. At ambient conditions, various aldehydes were employed in a clean esterification reaction to afford numerous esters in good to excellent yields. By this adopted method, some multifunctional aldehydes, high-energy-containing aromatic and unsaturated aldehydes, were advantageously oxidized to esters without noticeable difficulties. Moreover, no over-oxidation occurred to alcohols, and mostly by products were not formed during this oxidation process. Conventional and some modern methods lag behind owing to their easier operability and easy work-up process. This investigation has proven that the required oxidant (NaIO4) or catalyst (Pd-C) is useless to employ in excess, although some current methods utilize hugely expensive reagents for such conversions. Mundane reaction set-up, easy product recovery technique, nontoxic catalyst, and cheap and available starting materials are the noteworthy advantages of this method.

Highly efficient and air-tolerant calcium-based Birch reduction using mechanochemistry

Abstract In this study, we report a mechanochemical protocol for highly efficient and air-tolerant calcium-based Birch reduction. The developed mechanochemical approach allows the use of readily available calcium metal as a safer-to-handle reductant for Birch reduction of various aromatic compounds. The reaction was rapid and the desired dearomatization products were obtained in good yields within 15 min at ambient temperature. Notably, all synthetic operations can be performed under ambient conditions without a complicated reaction setup involving inert gases. The feasibility of the gram-scale synthesis was demonstrated, further highlighting the practical utility of this protocol.

Strongly reducing NaHS regenerates Fe(II)EDTA for efficient NO removal with high cycling performance under high oxygen conditions

Fe(II)EDTA can remove NO efficiently, but it has not been industrially applied. This is because the oxygen present in the flue gas will oxidize Fe(II)EDTA and Fe(II)EDTA-NO to Fe(III)EDTA and deactivate them. In order to solve this problem, this paper innovatively proposes to use NaHS to reduce Fe(III) EDTA, because NaHS has high reducing ability and low price. Therefore, a series of experimental conditions were explored in order to obtain the best reaction setup. The results indicate that increasing the concentrations of NaHS, temperature, and pH enhances the rate of NaHS reduction. The mechanism of the increase in reduction rate was studied in depth using potentiometric titration. It was found that an increase in OH- concentration will generate S8 precipitate, which is beneficial to the forward progress of the reaction and promotes the large-scale production of the active component Fe2+. Oxygen is an inevitable factor in actual flue gas, so this study innovatively proposed a kinetic model under aerobic conditions and used this model to predict the trend of Fe(III)EDTA reduction by NaHS. On this basis, NO removal experiments were conducted under high oxygen conditions. After 15 cycles, the reduction performance of NaHS was still very high, and the NO removal rate was higher than 70%. The reason for this phenomenon is that the stabilizer exists in a form that is conducive to the removal of NO by the active component Fe2+. Therefore, this study provides theoretical guidance for promoting the industrial application of Fe(II) EDTA technology for NO removal.