Reaction Setup Research Articles

Covalent-Bond Formation via On-Surface Chemistry.

In this Review article pioneering work and recent achievements in the emerging research area of on-surface chemistry is discussed. On-surface chemistry, sometimes also called two-dimensional chemistry, shows great potential for bottom-up preparation of defined nanostructures. In contrast to traditional organic synthesis, where reactions are generally conducted in well-defined reaction flasks in solution, on-surface chemistry is performed in the cavity of a scanning probe microscope on a metal crystal under ultrahigh vacuum conditions. The metal first acts as a platform for self-assembly of the organic building blocks and in many cases it also acts as a catalyst for the given chemical transformation. Products and hence success of the reaction are directly analyzed by scanning probe microscopy. This Review provides a general overview of this chemistry highlighting advantages and disadvantages as compared to traditional reaction setups. The second part of the Review then focuses on reactions that have been successfully conducted as on-surface processes. On-surface Ullmann and Glaser couplings are addressed. In addition, cyclodehydrogenation reactions and cycloadditions are discussed and reactions involving the carbonyl functionality are highlighted. Finally, the first examples of sequential on-surface chemistry are considered in which two different functionalities are chemoselectively addressed. The Review gives an overview for experts working in the area but also offers a starting point to non-experts to enter into this exciting new interdisciplinary research field.

Merging allylic C-H bond activation and C-C bond cleavage en route to the formation of a quaternary carbon stereocenter in acyclic systems.

This protocol describes a diastereoselective approach for the synthesis of complex molecular architectures containing two stereogenic centers in a 1,4 relationship, one of which being an all-carbon quaternary stereogenic center. Such molecules could be intermediates in the synthesis of steroids, for example. Conceived as a single-flask synthetic sequence from ω-ene cyclopropanes, the protocol involves a concerted allylic C-H and C-C bond activation promoted by the Negishi reagent (Cp2Zr(η2-butene)). This zirconium-promenade-based procedure affords bifunctionalized products in high diastereomeric ratios after reaction of ω-ene cyclopropanes with the Negishi complex, followed by a thermal treatment and sequential addition of two different electrophiles. The method proves to be particularly efficient when carbonyl compounds are used as first electrophiles and hydrogen or elemental halides are used as second electrophiles. In addition, it offers the opportunity to create new C-C bonds via remote functionalization of a (sp3)-C-H bond, a result of a copper or copper/palladium transmetalation step that extends the scope of the process to alkyl, acyl and aromatic halide compounds as second electrophiles. The typical described protocol allows the synthesis of the highly diastereo-enriched 2-((1R*,2S*)-2-butyl-2 propylcyclopropyl)ethanol and may provide a new entry to access complex molecular segments of natural products such as steroids or C30 botryococcene. It requires a simple reaction setup and takes ∼18.5 h to run the reaction and 2 h for isolation and purification.

Design, synthesis and molecular docking studies of some morpholine linked thiazolidinone hybrid molecules

A novel series of morpoline linked thiazolidione hybrid molecules targeting bacterial enoyl acyl carrier protein (Enoyl-ACP) reductase were designed and synthesized through a three step reaction protocol, which involves simple reaction setup and moderate reaction conditions. The synthesized molecules were characterized with FT-IR, 1 H NMR, 13 C NMR and HRMS techniques. In vitro susceptibility tests against some Gram positive ( Staphylococcus aureus and Bacillus subtilis ) and Gram negative bacteria ( Escherichia coli and Pseudomonas aeruginosa ) gave highly promising results. Most of the molecules were found to be active against the tested bacterial strains. The most potent molecule (S2B7) gave MIC value of 2.0 µg/mL against Escherichia coli that was better than the reference drug streptomycin. Structure activity relationship showed nitro and chloro groups are crucial for bioactivity if present at meta position of arylidene ring in designed molecules. Molecular docking simulations against multiple targets showed that the designed molecules have strong binding affinity towards Enoyl-ACP reductase. Binding affinity of -8.6 kcal/mol was predicted for S2B7. Van der Waals forces, hydrogen bonding and hydrophobic interactions were predicted as the main forces of interaction.

Continuous-Flow Electrophilic Amination of Arenes and Schmidt Reaction of Carboxylic Acids Utilizing the Superacidic Trimethylsilyl Azide/Triflic Acid Reagent System.

A continuous flow protocol for the direct stoichiometric electrophilic amination of aromatic hydrocarbons and the Schmidt reaction of aromatic carboxylic acids using the superacidic trimethylsilyl azide/triflic acid system is described. Optimization of reagent stoichiometry, solvent, reaction time, and temperature led to an intensified protocol at elevated temperatures that allows the direct amination of arenes to be completed within 3 min at 90 °C. In order to improve the selectivity and scope of this direct amination protocol, aromatic carboxylic acids were additionally chosen as substrates. Selected carboxylic acids could be converted to their corresponding amine counterparts in good to excellent yields (11 examples, 55-83%) via a Schmidt reaction employing similar flow reaction conditions (<5 min at 90 °C) and a similar reactor setup as for the amination. The safety issues derived from the explosive, toxic, and volatile hydrazoic acid intermediate, the corrosive nature of triflic acid, and the exothermic quenching were addressed by designing a suitable continuous flow reaction setup for both types of transformations.

Sapium sebiferum leaf extract mediated synthesis of palladium nanoparticles and in vitro investigation of their bacterial and photocatalytic activities

There is a growing need to introduce eco-friendly and sustainable procedures for the synthesis of metal nanoparticles that include a mild reaction conditions, simple reaction setup, use of nontoxic medium such as water and plant extract, cost effectiveness as well as greater efficiency for biomedical and catalytic applications. For this purpose, small and highly dispersed palladium nanoparticles (PdNPs) were prepared by eco-friendly and cost effective green method using water soluble leaf extract of Sapium sebiferum as a reducing and capping agent. The formation of PdNPs was optimized at various temperatures i.e. (30°C, 60°C and 90°C) and different leaves extract (5mL and 10mL) in order to control their size and shape. The results indicated that PdNPs synthesized at 10mL leaf extract concentration and 60°C temperature have small sized (5nm) and spherical shape. The nanoparticles formation, their dispersion, size and shape were confirmed by various characterization techniques i.e. UV–Vis spectroscopy, Fourier-transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), scanning electron microscopy (SEM), high resolution transmission electron microscopy (HRTEM), thermo gravimetric analysis (TGA) and Dynamic light scattering technique (DLS) analysis. The biologically synthesized PdNPs were tested for size dependent photo degradation of methylene blue and inactivation of bacteria. The PdNPs synthesized at optimized condition (10mL extract concentration and 60°C) have strong photo catalytic activity and reduced 90% methylene blue in 70min. The optimized PdNPs also showed strong bacterial inhibition against Staphylococcus aureus 29(±0.8mm), Bacillus subtilis 19(±0.6mm) and pseudomonas aeruginosa 11(±0.6mm). The results of this examination demonstrate effective applications of extremely active PdNPs.

The Evolution of Pd0/PdII-Catalyzed Aromatic Fluorination.

ConspectusAromatic fluorides are prevalent in both agrochemical and pharmaceutical agents. However, methods for their rapid and general preparation from widely available starting materials are limited. Traditional approaches such as the Balz–Schiemann and Halex reactions require harsh conditions that limit functional group tolerance and substrate scope. The use of transition metals to affect C–F bond formation has provided some useful alternatives, but a broadly applicable method remains elusive. In contrast to the widespread use of Pd0/PdII catalysis for aryl–Z bond formation (Z = C, N, O), the analogous C–F cross-coupling process was unknown until fairly recently. In large part, this is due to the challenging Ar–F reductive elimination from Pd(II) intermediates. We have discovered that certain biaryl monophosphine ligands are uniquely capable of promoting this transformation. In this Account, we describe the discovery and development of a Pd-catalyzed C–F cross-coupling process and the systematic developments that made this once hypothetical reaction possible.Key to these developments was the discovery of an unusual in situ ligand modification process in which a molecule of substrate is incorporated into the ligand scaffold and the identity of the modifying group is crucial to the outcome of the reaction. This prompted the synthesis of a variety of “premodified” ligands and the identification of one that led to an expanded substrate scope, including (hetero)aryl triflates and bromides. Contemporaneously, a new Pd(0) precatalyst was also discovered that avoids the need to reduce Pd(II) in situ, a process that was often inefficient and led to the formation of byproducts.The use of inexpensive but hygroscopic sources of fluoride necessitates a reaction setup inside of a N2-filled glovebox, limiting the practicality of the method. Thus, a preformed wax capsule was designed to isolate the catalyst and reagents from the atmosphere and permit benchtop storage and setup. This new technology thus removes the requirement to employ a glovebox for the aromatic fluorination process and other air-sensitive protocols.In every catalyst system that we have studied to date, we observed the formation of regioisomeric fluoride side products. Through deuterium labeling studies it was found that they likely arise from a deprotonation event resulting in the formation of HF and a Pd–benzyne intermediate. Through an investigation of the mechanism of this undesired pathway, a new ligand was designed that substantially reduces the formation of the aryl fluoride regioisomer and even allows room-temperature Ar–F reductive elimination from a Pd(II) intermediate.

Daniel Fitzpatrick: Reaction Hacker

Some of the best ideas are born out of boredom or frustration. When Daniel Fitzpatrick started his graduate work in Steven Ley’s lab at the University of Cambridge, he was assigned a chemical synthesis project. Fitzpatrick, who had just moved halfway around the world from his native New Zealand, found much of the work repetitive and dull. Setting up numerous reactions for optimization and then working each one up “was taking a huge amount of time, but it didn’t require any sort of intellectual thought on my part,” he recalls. He thought, “In other areas these sorts of repetitive tasks have been relegated to machines, so I’m sure it could happen in this case too.” Within a year of joining the lab, Fitzpatrick built a reaction setup that could be monitored remotely, and then he connected the hardware to an internet-powered control system. He was now free to monitor his

Application of a new micro-reactor 1H NMR probe head for quantitative analysis of fast esterification reactions

A fully liquid-thermostatted micro-reactor probe head for 1H NMR spectroscopic studies of fast reaction kinetics, which was recently developed, is tested in the present work by studying fast esterification kinetics in the stopped flow mode. It is shown that reliable kinetic data can be obtained using this set-up for reactions with time constants down to a few seconds. The two test systems are the formation of methyl acetate (MA) and methyl formate (MF). Both are homogeneously catalyzed by sulfuric acid, which is added to the educts in different amounts. The temperatures of the kinetic studies are chosen between 303 and 333K. The reaction kinetic data for both systems is correlated by activity-based kinetic models. For the MA formation, reference data from the literature is available, however only for regimes with time constants of minutes to hours. That data fits well to the results of the present study. The MF formation was studied here at conditions in which the time constants are of the order of seconds and therefore no reference data is available. The new probe head substantially extends the range in which NMR spectroscopy can be used for studies of fast reaction kinetics.

Direct trans-Selective Ruthenium-Catalyzed Reduction of Alkynes in Two-Chamber Reactors and Continuous Flow

An efficient trans-selective hydrogenation of alkynes under low hydrogen pressure and low reaction temperatures is reported, applying a commercially available ruthenium hydride complex. The developed reaction conditions, which tolerate a variety of functional groups, are carried out in a two-chamber setup with ex situ generated hydrogen. The reaction setup is highly suitable for deuterium labeling. The trans-selective hydrogenation was extrapolated to a transfer hydrogenation protocol, employing a packed bed immobilized ruthenium hydride catalyst in continuous flow with a retention time of only 10 min.

Flash Latex Production in a Continuous Helical Photoreactor: Releasing the Brake Pedal on Acrylate Chain Radical Polymerization

The continuous photopolymerization of acrylate and methacrylate monomer miniemulsions (25% solids content) is investigated at room temperature in a compact helix minireactor. Using n-butyl acrylate, the process yields 95% conversion after only 27 s residence time, and gel-free high-molecular-weight products. Under optimized conditions, a 25-fold increase in efficiency is obtained when compared to a batch photopolymerization. The reaction set-up offers a frugal process because of moderate irradiance (2.6 mW cm−2), photoinitiator concentration (0.75 wt%), and low-power UV-A fluorescent lamp.

A highly efficient CuI nanoparticles-catalyzed synthesis of tetrahydrochromenediones and dihydropyrano[c]chromenediones under grinding

Abstract A concise and CuI nanoparticle-catalyzed synthesis of tetrahydrochromenediones and dihydropyrano[c]chromenediones under solvent-free grinding conditions via the three-component condensation reaction of Meldrum’s acid, an aromatic aldehyde, and an active methylene compound, including dimedone or 4-hydroxycoumarin, was developed. This new method gives desirable advantages such as simple reaction setup, very mild reaction conditions, production of the desired products in high yields without by-products, recyclability of the catalyst, and environmentally benign procedure.

Secondary Alkyl Groups in Palladium-Catalyzed Cross-Coupling Reactions

Important classes of cross-coupling reactions are those leading to the incorporation of secondary alkyl groups. While early work in cross-coupling focused mainly on primary alkyl groups, the past decade has seen significant advances in introducing secondary and tertiary groups. This review will focus on the advances made in recent years referencing landmark publications where necessary. Expansion of scope, ease of reaction setup, and mechanistic considerations will be stressed. Applications of methodologies towards complex scaffolds and natural products will be also be evaluated. 1 Introduction 2.1 Suzuki Coupling 2.2 Mizoroki–Heck Coupling 2.3 Stille Coupling 2.4 Sonagashira Coupling 2.5 Kumada Coupling 2.6 Negishi Coupling 2.7 Hiyama Coupling 2.8 Lithium Coupling 2.9 Titanium Coupling 2.10 C–H Activation 3 Conclusion

Harnessing the Versatility of Continuous-Flow Processes: Selective and Efficient Reactions.

There is a great need for effective transformations and a broad range of novel chemical entities. Continuous-flow (CF) approaches are of considerable current interest: highly efficient and selective reactions can be performed in CF reactors. The reaction setup of CF reactors offers a wide variety of possible points where versatility can be introduced. This article presents a number of selective and highly efficient gas-liquid-solid and liquid-solid reactions involving a range of reagents and immobilized catalysts. Enantioselective transformations through catalytic hydrogenation and organocatalytic reactions are included, and isotopically labelled compounds and pharmaceutically relevant 1,2,3-triazoles are synthesized in CF reactors. Importantly, the catalyst bed can be changed to a solid-phase peptide synthesis resin, with which peptide synthesis can be performed with the utilization of only 1.5 equivalents of the amino acid.

Miniature high-throughput chemosensing of yield, ee, and absolute configuration from crude reaction mixtures.

High-throughput experimentation (HTE) has emerged as a widely used technology that accelerates discovery and optimization processes with parallel small-scale reaction setups. A high-throughput screening (HTS) method capable of comprehensive analysis of crude asymmetric reaction mixtures (eliminating product derivatization or isolation) would provide transformative impact by matching the pace of HTE. We report how spontaneous in situ construction of stereodynamic metal probes from readily available, inexpensive starting materials can be applied to chiroptical chemosensing of the total amount, enantiomeric excess (ee), and absolute configuration of a wide variety of amines, diamines, amino alcohols, amino acids, carboxylic acids, α-hydroxy acids, and diols. This advance and HTS potential are highlighted with the analysis of 1 mg of crude reaction mixtures of a catalytic asymmetric reaction. This operationally simple assay uses a robust mix-and-measure protocol, is amenable to microscale platforms and automation, and provides critical time efficiency and sustainability advantages over traditional serial methods.

Restabilization of Acrylic Acid in Isoperibolic Reactors

AbstractThe spontaneous polymerization, i.e, runaway, of acrylic acid during storage is a serious problem which may endanger life and facilities. In respond to a starting polymerization, effective emergency measures are necessary. For these investigations, a polytropic reactor setup, namely, an isoperibolic reactor is introduced to offer a rational access to restabilization studies. Furthermore, safety diagrams are created where the used amount of stabilizer is plotted against the polymerization progress in terms of the rising temperature. Such diagrams display the minimum required amount of the shortstopper (RESTAB™) for terminating a runaway polymerization. The suitability of the reaction setup is investigated using unstabilized acrylic acid.

An effective modular process for biodiesel manufacturing using heterogeneous catalysis

We present an innovative reaction set-up and process for biodiesel manufacturing by heterogeneous catalysis.

Formation of 2-nitrophenol from salicylaldehyde as a suitable test for low peroxynitrite fluxes

There has been some dispute regarding reaction products formed at physiological peroxynitrite fluxes in the nanomolar range with phenolic molecules, when used to predict the behavior of protein-bound aromatic amino acids like tyrosine. Previous data showed that at nanomolar fluxes of peroxynitrite, nitration of these phenolic compounds was outcompeted by dimerization (e.g. biphenols or dityrosine). Using 3-morpholino sydnonimine (Sin-1), we created low fluxes of peroxynitrite in our reaction set-up to demonstrate that salicylaldehyde displays unique features in the detection of physiological fluxes of peroxynitrite, yielding detectable nitration but only minor dimerization products.By means of HPLC analysis and detection at 380nm we could identify the expected nitration products 3- and 5-nitrosalicylaldehyde, but also novel nitrated products. Using mass spectrometry, we also identified 2-nitrophenol and a not fully characterized nitrated dimerization product. The formation of 2-nitrophenol could proceed either by primary generation of a phenoxy radical, followed by addition of the NO2-radical to the various resonance structures, or by addition of the peroxynitrite anion to the polarized carbonyl group with subsequent fragmentation of the adduct (as seen with carbon dioxide). Interestingly, we observed almost no 3- and 5-nitrosalicylic acid products and only minor dimerization reaction.Our results disagree with the previous general assumption that nitration of low molecular weight phenolic compounds is always outcompeted by dimerization at nanomolar peroxynitrite fluxes and highlight unique features of salicylaldehyde as a probe for physiological concentrations of peroxynitrite.

ChemInform Abstract: Nucleophilic Nitrenoids Through π‐Acid Catalysis: Providing a Common Basis for Rapid Access into Diverse Nitrogen Heterocycles

AbstractReview: [48 refs.

Nucleophilic Nitrenoids Through π‐Acid Catalysis: Providing a Common Basis for Rapid Access into Diverse Nitrogen Heterocycles

AbstractNitrogen heterocycles are some of the most important and sought‐after structural motifs in synthetic chemistry. General methods that can be applied towards a structurally diverse range of different scaffolds are rare. This Focus Review discusses an emerging area with the field of π‐acid catalysis based on the activation of carbon‐carbon triple bonds in conjunction with nucleophilic nitrenoids. The resulting approach provides ready access into α‐imino metal carbene reactivity patterns that can be employed in a number of quenching processes to realize a variety of powerful new transformations. The resulting methods are characterized by high efficiency, simple and straightforward reaction set ups, mild conditions, and excellent functional group tolerance. In this Focus Review the different nucleophilic nitrenoid types are explored showing how they can be used across a range of (poly)cyclization and formal cycloaddition processes to provide an alternative and direct disconnection pathway in the generation of N‐heterocyclic motifs.

Stabilization of single speciesSynechocystisbiofilms by cultivation under segmented flow

The application of segmented flow on a Synechocystis sp. PCC 6803 biofilm prevented excessive biomass formation and clogging by fundamentally changing the structure of the microbial community. It was possible to continuously operate a capillary microreactor for 5 weeks, before the experiment was actively terminated. The biofilm developed up to a thickness of 70-120 µm. Surprisingly, the biofilm stopped growing at this thickness and stayed constant without any detachment events occurring afterwards. The substrates CO2 and light were supplied in a counter-current fashion. Confocal microscopy revealed a throughout photosynthetically active biofilm, indicated by the red fluorescence of photo pigments. This control concept and biofilm reaction setup may enable continuous light driven synthesis of value added compounds in future.