Multigram Scale Research Articles

Recyclable Fluorine‐Free Water‐Borne Binders for High‐Energy Lithium‐Ion Battery Cathodes

AbstractThe rapidly increasing demand for lithium‐ion batteries and the fight against climate change call for novel materials that enhance performance, enable eco‐friendly processing, and are designed for efficient recycling. In lithium‐ion batteries, the binder polymer, used for cathode production, constitutes an integral but often overlooked component. The currently used polyvinylidene fluoride is processed with toxic organic solvents and has numerous other disadvantages concerning adhesion, conductivity, and recyclability. A change to aqueous processing using new, multi‐functional, purpose‐built materials that are soluble in water and fluorine‐free would thus constitute an important advance in the battery sector. Herein, four water‐soluble surfactant‐like polymers based on 11‐aminoundecanoic acid, that can be obtained in high purity and at a multigram scale are described. Free radical polymerization allows modification of the polymer with a wide variety of comonomers. The materials presented significantly enhance adhesion, are thermally stable at temperatures up to 350 °C, and are compatible with state‐of‐the‐art high‐energy LiNi0.6Mn0.2Co0.2O2 (NMC 622) cathode materials. It is also shown new recycling pathways made possible by the reversible pH‐dependent water‐solubility of the materials.

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.

N-(sulfonio)sulfilimine reagents: Non-oxidizing Sources of Electrophilic Nitrogen Atom for Skeletal Editing.

The one-pot synthesis of λ4-dibenzothiophen-5-imino-N-dibenzothiophenium triflate (1) in multigram scale is reported. This compound reacts with Rh2(esp)2 (esp = α,α,α',α'-tetramethyl-1,3-benzenedipropionic acid) generating a Rh-coordinated sulfonitrene species, which is able to transfer the electrophilic nitrene moiety to olefins. When indenes are used as substrates, isoquinolines are obtained in good yields. We assumed that after formation of the corresponding N-sulfonio aziridine, a ring expansion occurs via selective C-C bond cleavage and concomitant elimination of dibenzothiophene. Unexpectedly, a similar protocol transforms 1-arylcyclobutenes into 1-cyano-1-arylcyclopropanes. Our calculations indicate that aziridination is not favored in this case; instead, sulfilimine-substituted cyclobutyl carbocations are initially formed, and these evolve to the isolated cyclopropanes via ring contraction. Both procedures are operationally simple, tolerate a range of functional groups, including oxidation-sensitive alcohols and aldehydes, and enable the convenient preparation of valuable 15N-labelled products. These results demonstrate the potential of 1 to provide alternative pathways for the selective transfer of N-atoms in organic molecules.

N‐(sulfonio)sulfilimine reagents: Non‐oxidizing Sources of Electrophilic Nitrogen Atom for Skeletal Editing

The one‐pot synthesis of λ4‐dibenzothiophen‐5‐imino‐N‐dibenzothiophenium triflate (1) in multigram scale is reported. This compound reacts with Rh2(esp)2 (esp = α,α,α′,α′‐tetramethyl‐1,3‐benzenedipropionic acid) generating a Rh‐coordinated sulfonitrene species, which is able to transfer the electrophilic nitrene moiety to olefins. When indenes are used as substrates, isoquinolines are obtained in good yields. We assumed that after formation of the corresponding N‐sulfonio aziridine, a ring expansion occurs via selective C‐C bond cleavage and concomitant elimination of dibenzothiophene. Unexpectedly, a similar protocol transforms 1‐arylcyclobutenes into 1‐cyano‐1‐arylcyclopropanes. Our calculations indicate that aziridination is not favored in this case; instead, sulfilimine‐substituted cyclobutyl carbocations are initially formed, and these evolve to the isolated cyclopropanes via ring contraction. Both procedures are operationally simple, tolerate a range of functional groups, including oxidation‐sensitive alcohols and aldehydes, and enable the convenient preparation of valuable 15N‐labelled products. These results demonstrate the potential of 1 to provide alternative pathways for the selective transfer of N‐atoms in organic molecules.

Synthesis of Quillaic Acid through Sustainable C-H Bond Activations.

To meet the demand for quillaic acid, a multigram synthesis of quillaic acid was accomplished in 14 steps, starting from oleanolic acid, leading to an overall yield of 3.4%. Key features include C-H activation at C-16 and C-23. Through Pd-catalyzed C-H acetoxylation, the oxidation at C-23 was observed as the major product, as opposed to at C-24. A copper-mediated C-H hydroxylation using O2 successfully afforded the single isomer, 16β-ol triterpenoid, followed by configuration inversion to the desired 16α-ol compound. In summary, with steps optimized and conducted on a multigram scale, quillaic acid could be feasibly acquired through C-H activation with inexpensive copper catalysts, promoting a more sustainable approach.

A Facile Method for Multigram Scale Light-Induced Synthesis of 4′-(Bromomethyl)-2-cyanobiphenyl

A Facile Method for Multigram Scale Light-Induced Synthesis of 4′-(Bromomethyl)-2-cyanobiphenyl

In situ Diazonium Salt Formation and Photochemical Aryl-Aryl Coupling in Continuous Flow Monitored by Inline NMR Spectroscopy.

A novel class of diazonium salts is introduced for the photochemical aryl-aryl coupling to produce (substituted) biphenyls. As common diazonium tetrafluoroborate salts fail, soluble and safe aryl diazonium trifluoroacetates are applied. In this mild synthesis route no catalysts are required to generate an aryl-radical by irradiation with UV-A light (365 nm). This reactive species undergoes direct C-H arylation at an arene, forming the product in reasonable reaction times. With the implementation of a continuous flow setup in a capillary photoreactor 13 different biphenyl derivatives are successfully synthesized. By integrating an inline 19F-NMR benchtop spectrometer, samples are reliably quantified as the fluorine-substituents act as a probe. Here, real-time NMR spectroscopy is a perfect tool to monitor the continuously operated system, which produces fine chemicals of industrial relevance even in a multigram scale.

Synthesis and Reactivity of the [NCCCO]- Cyanoketenate Anion.

Cyanoketene is a fundamental molecule that is actively being searched for in the interstellar medium. Its deprotonated form (cyanoketenate) is a heterocumulene that is isoelectronic to carbon suboxide whose structure has been the subject of debate. However, the investigation of cyanoketene and its derivatives is hampered by the lack of practical synthetic routes to these compounds. We report the first synthesis of the cyanoketenate anion in [K(18-crown-6)][NCCCO] (1) as a stable molecule on a multigram scale in excellent yields (>90%). The structure of this molecule is probed crystallographically and computationally. We also explore the protonation of 1, and its reaction with triphenylsilylchloride and carbon dioxide. In all cases, anionic dimers are formed. The cyanoketene could be synthesized and crystallographically characterized when stabilized by a N-heterocyclic carbene. The cyanoketenate is a very useful unsaturated building block containing N, C and O atoms that can now be explored with relative ease and will undoubtedly unlock more interesting reactivity.

Synthesis and Reactivity of the [NCCCO]– Cyanoketenate Anion

Cyanoketene is a fundamental molecule that is actively being searched for in the interstellar medium. Its deprotonated form (cyanoketenate) is a heterocumulene that is isoelectronic to carbon suboxide whose structure has been the subject of debate. However, the investigation of cyanoketene and its derivatives is hampered by the lack of practical synthetic routes to these compounds. We report the first synthesis of the cyanoketenate anion in [K(18‐crown‐6)][NCCCO] (1) as a stable molecule on a multigram scale in excellent yields (>90%). The structure of this molecule is probed crystallographically and computationally. We also explore the protonation of 1, and its reaction with triphenylsilylchloride and carbon dioxide. In all cases, anionic dimers are formed. The cyanoketene could be synthesized and crystallographically characterized when stabilized by a N‐heterocyclic carbene. The cyanoketenate is a very useful unsaturated building block containing N, C and O atoms that can now be explored with relative ease and will undoubtedly unlock more interesting reactivity.

Galvinol as ratiometric naked-eye colorimetric moisture sensor: Synthesis process development, applications and mechanistic studies

Moisture detection through a simple colorimetric approach using molecular materials has been a cost-effective and user-friendly technology of choice as high moisture and humidity conditions lead to serious issues across various fields. However, the poor availability of such efficient molecular systems is a serious concern, and hence the need is quite evident. In this regard, the galvinol (GALH) molecule has been explored as a highly responsive colorimetric moisture-sensing in liquid and gaseous systems. Notably, it has been synthesized in a multigram scale via an unexplored demethylative C-C coupling of butylated hydroxyl toluene (BHT). The deprotonated form of GALH (GAL-) has been investigated as a reversible colorimetric moisture sensing platform with limits of detection (LOD) for water (H2O) in acetonitrile and tetrahydrofuran solvents as 0.0022 and 0.0031% v/v, respectively. The moisture sensing mechanism is based upon the competitive ion pairing of GALH with tetra-n-butylammonium fluoride and H2O during the protonation/deprotonation process. The developed moisture sensing probe has shown its universal applicability during the fabrication of polystyrene resin anchored solid medium device for relative humidity detection, color indicating moisture absorbing silica gel preparation, paper strip-based moisture detection in organic solvents and soil as real sample analysis, moisture erasable inkjet-printing and inkless writing.

Mild and efficient catalyst for nitrodopamine synthesis: from milligram to multi-gram scales

Sodium hydrogen sulfate is proposed as a mild acidic catalyst for the dopamine nitration with sodium nitrite. This reagent system gives nitrodopamine in high yield and excellent purity and is suitable for routine synthesis from milligram to multi-gram scale.

Scaling up the advanced dry reforming of methane (DRM) reactor system for multi-walled carbon nanotubes and syngas production: An experimental and modeling study

Dry reforming of methane (DRM) offers an avenue for converting carbon dioxide (CO2) and methane (CH4)—the two major greenhouse gases—into syngas, a vital chemical precursor. However, DRM is constrained by high energy demands, catalyst deactivation, and an unfavorable H2/CO ratio. Previously, a unique dual-reactor system that produces multi-walled carbon nanotubes (MWCNTs) and syngas as products was proposed. This system offers at least 65 % CO2 conversion at 50 % of the energy demands of DRM. The present study experimentally proves and scales the concept from the milligram scale to the multi-gram scale and, ultimately to the multi-kilogram scale of MWCNT production. This study also introduces and experimentally validates a lumped Langmuir-Hinshelwood-Haugen-Watson (LHHW) kinetics model capturing a network of nine primary reactions involving CO, O2, H2, CH4, CO2, H2O, and solid carbon. The model performs within a 5 % error margin at the milligram scale for the carbon formation rate at 550 °C. The model is validated at 500 °C, 550 °C, and 600 °C on a multi-gram scale to capture the temperature effect. The CH4-conversion and CO2-conversion predictabilities at this scale are within 8 % and 30 % error margins, respectively. At a multi-kilogram scale, the model predicts the carbon formation rate within a 21 % error margin at 550 °C. Finally, characterization of the MWCNTs using Raman, SEM, TEM, STEM, and TGA-DTA confirms MWCNT quality consistency at all scales. This study, in summary, provides valuable experimental scale-up data and a kinetics model that can serve as a foundation for the development of future commercial-scale reaction systems.

Synthesis of gem-Difluorinated 2,3-Dihydrobenzofurans Using Freon-22 via [4 + 1] Annulation of Difluorocarbene and Antitumor Activity Evaluation.

As an inexpensive industrial chemical, chlorodifluoromethane (Freon-22), despite its relatively low reactivity, can serve as a practical CF2 source for the construction of gem-difluorinated ring structures. Here, we develop a protocol for the efficient assembly of valuable fluorinated 2,3-dihydrobenzofurans from the [4 + 1] annulation in good yields under basic conditions. The reliable practicability and scalability of the process have also been demonstrated by preparation at the multigram scale, late-stage modifications of pharmaceutical molecules, and potential antitumor potency.

Electrochemical Hofmann rearrangement at high current densities in a simple flow setup

A reliable electrochemical version for the Hofmann rearrangement has been established, which can be performed at high current density in simple, commercial flow electrolysis cells. The protocols have been optimized towards both aromatic and aliphatic substrates, yielding good to excellent yields across a broad substrate scope. The method can also easily be performed at multi-gram scale.

Electrochemical Benzylic C(sp3)-H Direct Amidation.

Amide bonds are ubiquitous and found in a myriad of functional molecules. Although formed in a reliable and robust fashion, alternative amide bond disconnections provide flexibility and synthetic control. Herein we describe an electrochemical method to form the non-amide C-N bond from direct benzylic C(sp3)-H amidation. Our approach is applied toward the synthesis of secondary amides by coupling secondary benzylic substrates with substituted primary benzamides. The reaction has been scaled up to a multigram scale in flow.

Chiral NHC Ligands for Enantioselective Gold(I) Catalysis Under Aerobic Conditions: the Importance of Conformational Flexibility and Steric Hindrance of NHC Ligand on Reactivity.

Gold(I) catalysis has been recognized as a valuable tool for the unique transformation of multiple carbon-carbon bonds. Enantioselective π-catalysis based on gold(I) complexes is, however, still underdeveloped due to lack of privileged ligands. Herein, we present an accessible method to a new family of stable yet catalytically active chiral NHC-Au(I)-Cl complexes. The key to preserving a simultaneous fine balance between reactivity and stability in this newly developed family appears to be sterically hindered, but conformationally flexible NHC ligands. These could be easily accessed on a multigram scale by merging sterically hindered anilines with commercially available amino alcohols and amines via a four-steps synthetic sequence without the need for chromatographic purification. Further investigations of the catalytic activity of NHC-Au-Cl complexes identified the OH functionality incorporated into the NHC core as crucial for the level of enantioselectivity as well as the TsO- anion responsible for the activation of NHC-Au(I)-Cl. Finally, NMR studies and X-ray investigations revealed for the first time that the widely accepted ion metathesis (NHC-Au-Cl to NHC-Au-OSO2 R) responsible for the activation of NHC-Au-Cl complexes does not take place (or it is very slow) in commonly used MeNO2 in contrast to DCM.

Direct Heterocycle C-H Alkenylation via Dual Catalysis Using a Palladacycle Precatalyst: Multifactor Optimization and Scope Exploration Enabled by High-Throughput Experimentation.

One of the major challenges in developing catalytic methods for C-C bond formation is the identification of generally applicable reaction conditions, particularly if multiple substrate structural classes are involved. Pd-catalyzed direct arylation reactions are powerful transformations that enable direct functionalization of C-H bonds; however, the corresponding direct alkenylation reactions, using vinyl (pseudo) halide electrophiles, are less well developed. Inspired by process development efforts toward GSK3368715, an investigational active pharmaceutical ingredient, we report that a Pd(II) palladacycle derived from tri-tert-butylphosphine and Pd(OAc)2 is an effective single-component precatalyst for a variety of direct alkenylation reactions. High-throughput experimentation identified optimal solvent/base combinations for a variety of HetAr-H substrate classes undergoing C-H activation without the need for cocatalysts or stoichiometric silver bases (e.g., Ag2CO3). We propose this reaction proceeds via a dual cooperative catalytic mechanism, where in situ-generated Pd(0) supports a canonical Pd(0)/(II) cross-coupling cycle and the palladacycle effects C-H activation via CMD in a redox-neutral cycle. In all, 192 substrate combinations were tested with a hit rate of approximately 40% and 24 isolated examples. Importantly, this method was applied to prepare a key intermediate in the synthesis of GSK3368715 on multigram scale.

Direct Electrochemical Reductive Synthesis - a Tool for Novel Classes of N-Oxy Heterocycles

Nitrogen containing heterocycles represent an important and common structural motif in natural products and blockbuster pharmaceuticals. Thus, their synthesis plays a crucial role in the chemical industry. The N-oxy motif is commonly found as major metabolites for such nitrogen containing heterocycles. As an innovative tool, electrochemistry enables direct access to N-oxy heterocycles via direct reduction of easily accessible nitro arenes. By using electrical current from renewable resources as an inherently safe and inexpensive reagent, electrochemistry contributes to an increased sustainability of chemical processes.[1,2] A simple galvanostatic set-up in an undivided beaker-type cell with inexpensive electrolytes was used to access a broad variety of quinoline N-oxides and 1-oxy quinazolin-4-ones in up to a multi-gram scale. This toolset offers an innovative synthetic protocol for synthesizing this novel class of compounds by only using sustainable chemicals and electricity as an inherently safe reagent.[3,4]

Direct Synthesis of 8‐Fluorocaffeine and Its Transformation to 8‐Substituted Caffeine

AbstractCaffeine is a naturally occurring central nervous system (CNS) stimulant found in many drinks and foods. Many interesting biological activities of caffeine, and some of its derivatives, have been reported. Therefore, this study aims to conduct chemical transformations of caffeine. The method used is direct fluorination of caffeine using Selectfluor® in acetonitrile at room temperature, followed by purification to obtain 8‐fluorocaffeine. This reaction can be done on a multigram scale. Subsequently, 8‐fluorocaffeine was further modified by a nucleophilic substitution reaction with amines and alcohols as the nucleophiles under reflux conditions in an appropriate solvent to form fifteen 8‐substituted caffeine derivatives, with yields ranging from moderate to high. Of these derivatives, four are novel compounds, which are 8‐(3‐chloro‐4‐fluorophenyl)aminocaffeine, 8‐(3‐aminophenyl)amino‐caffeine, 8‐(azetidin‐1‐yl)‐caffeine, and 8‐(tetrahydrofuran‐3‐yl)oxycaffeine.

Nature-Inspired Tetrahydropentalene Building Blocks: Scalable Synthesis for Medicinal Chemistry Needs

Inspired by the bioactivity of natural compounds with a bicyclo[3.3.0]octane core, the study focuses on developing tetrahydropentalene-2,5-dione (2,5-THP-dione) derivatives as potential building blocks for the use in medicinal chemistry. Using the commercially available 2,5-THP-dione, a number of alkylated derivatives and a monofunctional ketone were synthesized. Using optimized protocols for synthesis, target compounds were obtained with high yields on a multigram scale. These compounds are promising derivatives for further chemical derivatization and therapeutic use, and thus highlight the value of 2,5-THP-dione in creating complex molecular structures for drug discovery, as well as the importance of tetrahydropentalene derivatives as valuable building blocks in synthetic chemistry.