Heterogeneous Reaction Mixture Research Articles

Solvent Effects on the Chemo- and Site-Selectivity of Transition Metal-Catalyzed Nitrene Transfer Reactions: Alternatives to Chlorinated Solvents.

Transition metal-catalyzed, non-enzymatic nitrene transfer (NT) reactions to selectively transform C-H and C=C bonds to new C-N bonds are a powerful strategy to streamline the preparation of valuable amine building blocks. However, many catalysts for these reactions use environmentally unfriendly solvents that include dichloromethane, chloroform, 1,2-dichloroethane and benzene. We developed a high-throughput experimentation (HTE) protocol for heterogeneous NT reaction mixtures to enable rapid screening of a broad range of solvents for this chemistry. Coupled with the American Chemical Society Pharmaceutical Roundtable (ACSPR) solvent tool, we identified several attractive replacements for chlorinated solvents. Selected catalysts for NT were compared and contrasted using our HTE protocol, including silver supported by N-dentate ligands, dinuclear Rh complexes and Fe/Mn phthalocyanine catalysts.

Various methods for enhancement in heterogeneous catalysed biodiesel production reaction rate

The biodiesel can be produced by transesterification and esterification reaction with edible and non-edible oil respectively. These reactions are catalysed by both homogeneous and heterogenous catalyst. The transesterification reactions for heterogeneous catalysts proceed at a relatively slow rate. The heterogeneous reaction mixture constitutes a three-phase system, oil/alcohol/catalyst therefore the mass transfer limitation controls the reaction rate. In the present study Tetra-hydrofuran, Hexane and Heptane as co-solvent have been tested for the transesterification and esterification reaction. Tetra-hydrofuran, assists in decreasing the mass transfer between the oil and methanol phases. Tetra-hydrofuran was found to be the best co-solvent. It also represents that the presence of Tetra-hydrofuran only enhance the solubility of phases not final equilibrium yield. Results are compared with homogeneous and heterogeneous catalysed reaction. Ultrasonic irradiation influenced the mixing of the reaction mixture and resulted in higher yields, for each co-solvent case.

Metal-Organic Materials (MOMs) Enhance Proteolytic Selectivity, Efficiency, and Reusability of Trypsin: A Time-Resolved Study on Proteolysis.

Proteases are involved in essential biological functions in nature and have become drug targets recently. In spite of the promising progress, two challenges, (i) the intrinsic instability and (ii) the difficulty in monitoring the catalytic process in real time, still hinder the further understanding and engineering of protease functionalities. These challenges are caused by the lack of proper materials/approaches to stabilize proteases and monitor proteolytic products (truncated polypeptides) in real time in a highly heterogeneous reaction mixture. This work combines metal-organic materials (MOMs), site-directed spin labeling-electron paramagnetic resonance (SDSL-EPR) spectroscopy, and mass spectrometry (MS) to overcome both barriers. A model protease, trypsin, which cleaves the peptide bonds at lysine or arginine residues, was immobilized on a Ca-MOM via aqueous-phase, one-pot cocrystallization, which allows for trypsin protection and ease of separation from its proteolytic products. Time-resolved EPR and MS were employed to monitor the populations, rotational motion, and sequences of the cleaved peptide truncations of a model protein substrate as the reaction proceeded. Our data suggest a significant (at least 5-10 times) enhancement in the catalytic efficiency (kcat/km) of trypsin@Ca-MOM and excellent reusability as compared to free trypsin in solution. Surprisingly, entrapping trypsin in Ca-MOMs results in cleavage site/region selectivity against the protein substrate, as compared to the near nonselective cleavage of all lysine and arginine residues of the substrate in solution. Remarkably, immobilizing trypsin allows for the separation and, thus, MS study on the sequences of truncated peptides in real time, leading to a time-resolved "movie" of trypsin proteolysis. This work demonstrates the use of MOMs and cocrystallization to enhance the selectivity, catalytic efficiency, and stability of trypsin, suggesting the possibility of tuning the catalytic performance of a general protease using MOMs.

Non-innocent electrophiles unlock exogenous base-free coupling reactions

Numerous important transition metal-catalysed reactions rely on stoichiometric quantities of an exogenous base to enable catalytic turnover. Despite playing a fundamental role, the base poses major challenges, such as restricting the accessible chemical space or causing heterogeneous reaction mixtures. Here we introduce a unifying strategy that eliminates the need for an exogenous base through the use of non-innocent electrophiles (NIE), which are equipped with a masked base that is released in a controlled fashion during the reaction. The universal applicability of this concept was demonstrated by turning multiple, traditionally base-dependent, catalytic reactions into exogenous base-free homogeneous processes. Furthermore, the advantageous features of NIEs were demonstrated in multiple applications, such as in a micromole-scale fluorescence-based assay. This led to the discovery of a Ni-catalysed deoxygenation reaction of aryl carbamates using isopropanol as a benign reductant. In a broader context, this work provides a conceptual blueprint for the strategic utilization of NIEs in catalysis. Bases play a fundamental role in several iconic coupling reactions in organic chemistry but are simultaneously responsible for limitations, such as functional group tolerance. Now, a broadly applicable solution is presented that uses non-innocent electrophiles equipped with an encrypted base.

Facile Method to Determine the Molecular Weight of Polymer Grafts Grown from Cellulose Nanocrystals.

One of the main challenges associated with the modification of cellulose nanocrystals (CNCs) with polymers by surface-initiated polymerization is the characterization of the resulting products, notably the molecular weight of the grafts. The solid nature of the (modified) CNC nanoparticles limits the possibility to apply solution-based characterization techniques, and the cleavage of the macromolecules from the surface of the CNCs to enable their characterization using solution-based techniques is intricate. Here, we report that 1H NMR spectroscopy of the supernatant of the heterogeneous reaction mixture can be used to approximate the molecular weight of poly(hexyl methacrylate) grafts grown from the surface of CNCs via surface-initiated atom transfer radical polymerization. This was achieved using 1H NMR spectra to determine the monomer conversion from the change of the relative ratio of monomer and solvent signals in the 1H NMR spectra, which in turn allowed determining the weight of PHMA produced. The number-average molecular weight of the grafted polymer was then estimated by assuming that standard atom transfer radical polymerization kinetics are at play and using the initiator concentration on the CNC surface determined by elemental analysis. The method was validated by comparing the results with the gravimetric data and the data of free polymers that were synthesized with a sacrificial initiator.

Photochemistry at Scale: Wireless Light Emitters Drive Sustainability in Process Research & Development

AbstractCarbon−carbon bond formation by dual Iridium‐Nickel photoredox catalysis has gained a lot of attention for late‐stage cross‐couplings of alkyls with aryls. However, the scalability of such reactions is greatly impeded by the poor light penetration depth into the strongly absorbing reaction media. Wireless internal illumination is a novel technique which circumvents the light penetration issue efficiently and therefore allows to scale photon‐driven reactions by conventional methods. Here we demonstrate that industrially relevant photoredox C−C couplings can be scaled seamlessly to different volumes, achieving qualitatively and quantitatively the same results at all scales. The use of conventional reactor types allows stirred, bubble column or fixed‐bed operation mode and is fully compatible with heterogeneous reaction mixtures. By minimizing reflection losses, we could also show a significant advantage in the reaction rate over an externally illuminated setup at the same light intensity.

Fabrication of magnetically recoverable BiVO4/NiFe2O4 composites for the photocatalytic degradation of methylene blue

Bismuth vanadate (BiVO4) and nickel ferrite (NiFe2O4) nanoceramics were successfully synthesized using hydrothermal and sol-gel methods, respectively. Three different composites between magnetic NiFe2O4 and non-magnetic BiVO4 phases (25 wt% BiVO4 + 75 wt% NiFe2O4, 50 wt% BiVO4 + 50 wt% NiFe2O4 and 75 wt% BiVO4 + 25 wt% NiFe2O4) were prepared and characterized by powder X-ray diffraction (PXRD), scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS) and UV–Visible spectroscopy. The PXRD analysis indicated the formation of well-defined composites between the two phases. All three composites were found to be magnetic in nature as confirmed from magnetic measurements carried out using vibrating sample magnetometer (VSM). The saturation magnetization (Ms) values found to be decreased almost linearly with increasing BiVO4 content in the composite, due to magnetic dilution induced in the composites by the non-magnetic BiVO4 phase. Band gaps of all the as-synthesized compounds were determined using diffuse reflectance spectroscopy (DRS) and are found to be in the visible region which makes them suitable for the photocatalytic dye degradation application. Among all the prepared magnetic composites, the composite with 50 wt% BiVO4 + 50 wt% NiFe2O4 exhibited the highest photocatalytic activity towards the degradation of 10 ppm methylene blue solution. Further enhancement of photocatalytic efficiency was achieved by the addition of a known volume of H2O2. Overall, 80% dye degradation efficiency was achieved using the composite of 50 wt% BiVO4 + 50 wt% NiFe2O4 under sunlight. Since the composites are magnetic in nature they can be easily separated from the heterogeneous reaction mixture using a laboratory magnet, after the photocatalytic treatment.

Fabrication of magnetically recoverable and reusable MgFe2O4/Ag3PO4 composite for catalytic reduction of 4-Nitrophenol

In recent years, an immense interest has been focused on to develop high-performance magnetic based nanocatalysts as they can be easily separated from the heterogeneous reaction mixture, without filtration/centrifugation process. Herein, a novel magnetically recoverable and reusable MgFe2O4/Ag3PO4 composite has been fabricated via a hydrothermal route to carry out 4-nitrophenol (4-NP) reduction reaction in aqueous medium. X-ray diffraction (XRD) patterns and Fourier transform infrared (FTIR) spectral analyses revealed the formation of a well-defined composite between magnetic (MgFe2O4) and non-magnetic (Ag3PO4) phases. The band gap of Ag3PO4 decreased from 2.31 eV to 1.71 eV after making composite with MgFe2O4. The fabricated composite is magnetic in nature with saturation magnetization (MS) of 15 emu/g. The prepared materials have been employed as catalysts to drive 4-NP reduction using the mild reducing agent sodium borohydride (NaBH4) and the progress of the catalytic reaction was ascertained using UV–visible spectrophotometry. Results show that the fabricated MgFe2O4/Ag3PO4 composite demonstrated superior catalytic performance over the individual components (MgFe2O4 and Ag3PO4) of the composite. Moreover, the composite completed the 4-nitrophenol reduction reaction in 1 min whereas the Ag3PO4 achieved the same reduction reaction in 15 min, despite all the catalytic reduction reactions were performed under the identical conditions. Enhanced catalytic performance of the MgFe2O4/Ag3PO4 magnetic composite can be attributed to strong electronic coupling between MgFe2O4 and Ag3PO4 that facilitates the electrons transfer from borohydride to nitrophenol and thereby catalytic reduction reaction occurs. Furthermore, the composite catalyst was found to be phase stable even after 5 consecutive recycles.

Enhanced catalyst performance through compartmentalization exemplified by colloidal l-proline modified microgel catalysts

Exploring and controlling chemical reactions in compartments opens new platforms for designing bioinspired catalysts and energy-autonomous systems. Aqueous polymer networks or hydrogels serve as a perfect model for biological tissues, allowing systematic investigations of chemical transformations in compartments. Herein, we report the synthesis of a versatile, colloidal microgel catalyst containing covalently bound l-proline as an organocatalyst. The key finding of our work is that the catalytic activity can be tuned by adjusting the distribution of the organocatalyst in the microgel network as well as the properties of the solvent. We demonstrate that l-proline groups integrated into microgels enable the reaction of 4-nitrobenzaldehyde and cyclohexanone in a heterogeneous reaction mixture in which free l-proline is not active. By controlling the localization of the l-proline groups within the microgel network (core or corona), the rate of the aldol reaction in homogenous and heterogeneous reaction mixtures can be modulated. Furthermore, microgels with covalently attached catalysts can be recycled and reused in sequential catalytic runs without deterioration of the catalyst performance in terms of activity and selectivity. The internal structure of the microgel in heterogeneous reaction mixtures was studied by computer simulations.

Coupled fermentation-bioconversion process for production of chiral α-chlorohydrin with recombinant ketoreductase

Abstract Enzymatic production of chemicals typically includes fermentation of engineered bacteria, preparation of enzymes, and bioconversion processes. Here coupled fermentation-bioconversion process for production of chiral atazanavir intermediate α-chlorohydrin was established. In the fermentation step, the ketoreductase was released from recombinant E. coli cells into medium after high-temperature induction, and the enzyme activity reached 5960 U/mL in the fermentation supernatant. In the bioconversion step, the fermentation supernatant was used directly for conversion of 200 g/L α-chloroketone in heterogeneous reaction mixture, and the residual amount of chloroketone reached less than 0.1% after 24 h of reaction. After filtration and drying, powder α-chlorohydrin was obtained with total yield of 95.7%. Finally, the filtrate of the reaction mixture was used for 2nd batch conversion, and powder α-chlorohydrin was obtained with yield of 95.6%. The above coupled process simplified enzyme preparation procedure, allowed the bioproduction of α-chlorohydrin to be carried out smoothly with reduced waste water discharge, and was advantageous for industrial scale-up.

Evaluation of Just-Suspended Speed Correlations in Lab-Scale Tanks with Varying Baffle Configurations

Suspension of insoluble solids in stirred tanks is important for many operations in the pharmaceutical and specialty chemical industries. A common goal in solid suspension is to achieve the just-suspended speed, Njs, where all of the particles are suspended off the tank bottom. Operating at Njs results in high mass transfer between the solid and liquid phases, which is important because many solid–liquid operations rely on adequate mass transfer to achieve the goals of the operation (e.g., reaction completion in a heterogeneous reaction mixture). Njs can be predicted on the basis of physical properties and tank geometry, often through the use of the Zwietering and Grenville–Mak–Brown (GMB) correlations. These correlations use impeller- and tank-geometry-specific constants (S for Zwietering and Z for GMB) that typically have been obtained in larger-scale tanks with four flat baffles. Glass-lined tanks commonly used in the pharmaceutical and specialty chemical industries often have reduced baffling. This wo...

Online Measurement of Oxygen-Dependent Enzyme Reaction Kinetics.

As the application of biocatalysis to complement conventional chemical and catalytic approaches continues to expand, an increasing number of reactions involve poorly water-soluble substrates. At required industrial concentrations necessary for industrial implementation, this frequently leads to heterogeneous reaction mixtures composed of multiple phases. Such systems are challenging to sample, and therefore, it is problematic to measure representative component concentrations. Herein, an online method for following the progress of oxygen-dependent reactions through accurate measurement of the oxygen mass balance in the gas phase of a reactor is demonstrated and validated. The method was successfully validated and demonstrated by using two model reactions: firstly, the oxidation of glucose by glucose oxidase and, secondly, the Baeyer-Villiger oxidation of macrocyclic ketones to lactones. Initial reaction rate constants and time-course progressions calculated from the oxygen mass balance were validated against conventional online methods of dissolved oxygen tension and pH titration measurements. A feasible operating window and the sensitivity to dynamic changes of reaction rates were established by controlling oxygen transfer through the operating parameters of the reactor. Such kinetic data forms the basis for reaction characterisation, from which bottlenecks may be made evident and directed improvement strategies can be identified and implemented.

The Evolution of Chemical High-Throughput Experimentation To Address Challenging Problems in Pharmaceutical Synthesis.

The structural complexity of pharmaceuticals presents a significant challenge to modern catalysis. Many published methods that work well on simple substrates often fail when attempts are made to apply them to complex drug intermediates. The use of high-throughput experimentation (HTE) techniques offers a means to overcome this fundamental challenge by facilitating the rational exploration of large arrays of catalysts and reaction conditions in a time- and material-efficient manner. Initial forays into the use of HTE in our laboratories for solving chemistry problems centered around screening of chiral precious-metal catalysts for homogeneous asymmetric hydrogenation. The success of these early efforts in developing efficient catalytic steps for late-stage development programs motivated the desire to increase the scope of this approach to encompass other high-value catalytic chemistries. Doing so, however, required significant advances in reactor and workflow design and automation to enable the effective assembly and agitation of arrays of heterogeneous reaction mixtures and retention of volatile solvents under a wide range of temperatures. Associated innovations in high-throughput analytical chemistry techniques greatly increased the efficiency and reliability of these methods. These evolved HTE techniques have been utilized extensively to develop highly innovative catalysis solutions to the most challenging problems in large-scale pharmaceutical synthesis. Starting with Pd- and Cu-catalyzed cross-coupling chemistry, subsequent efforts expanded to other valuable modern synthetic transformations such as chiral phase-transfer catalysis, photoredox catalysis, and C-H functionalization. As our experience and confidence in HTE techniques matured, we envisioned their application beyond problems in process chemistry to address the needs of medicinal chemists. Here the problem of reaction generality is felt most acutely, and HTE approaches should prove broadly enabling. However, the quantities of both time and starting materials available for chemistry troubleshooting in this space generally are severely limited. Adapting to these needs led us to invest in smaller predefined arrays of transformation-specific screening "kits" and push the boundaries of miniaturization in chemistry screening, culminating in the development of "nanoscale" reaction screening carried out in 1536-well plates. Grappling with the problem of generality also inspired the exploration of cheminformatics-driven HTE approaches such as the Chemistry Informer Libraries. These next-generation HTE methods promise to empower chemists to run orders of magnitude more experiments and enable "big data" informatics approaches to reaction design and troubleshooting. With these advances, HTE is poised to revolutionize how chemists across both industry and academia discover new synthetic methods, develop them into tools of broad utility, and apply them to problems of practical significance.

ChemInform Abstract: Synthesis and Reactions of Five‐Membered Heterocycles Using Phase Transfer Catalyst (PTC) Techniques

AbstractReview: 113 refs.

Mechanistic studies of two-dimensional covalent organic frameworks rapidly polymerized from initially homogenous conditions.

Covalent organic frameworks (COFs) are periodic two- and three-dimensional (2D and 3D) polymer networks with high surface areas, low densities, and designed structures. Despite intense interest in framework materials, the nucleation and growth processes of COFs, and even of more established metal-organic frameworks (MOFs), are poorly understood. The kinetics of COF growth under varied reaction conditions provides mechanistic insight needed to improve their crystallinity and rationally synthesize new materials. Such kinetic measurements are unprecedented and difficult to perform on typical heterogeneous COF reaction mixtures. Here we synthesize 2D boronate ester-linked COF-5 under conditions in which the monomers are fully soluble. These homogeneous growth conditions provide equal or better material quality compared to any previous report and enable the first rigorous studies of the early stages of COF growth. COF-5 forms within minutes, and the precipitation rate is readily quantified from optical turbidity measurements. COF-5 formation follows an Arrhenius temperature dependence between 60-90 °C with an activation energy of 22-27 kcal/mol. The measured rate law includes a second order in both boronic acid and catechol moieties, and inverse second order in MeOH concentration. A competitive monofunctional catechol slows COF-5 formation but does not redissolve already precipitated COF, indicating both dynamic covalent bond formation and irreversible precipitation. Finally, stoichiometric H2O provides a 4-fold increase in crystallite domain areas, representing the first rational link between reaction conditions and material quality.

{Mo132} Nanoball as an Efficient and Cost-Effective Catalyst for Sustainable Oxidation of Sulfides and Olefins with Hydrogen Peroxide

Atom-efficient and selective oxidation of sulfides to sulfoxides and sulfones in water and epoxidation of olefins in ethanol with hydrogen peroxide catalyzed by Keplerate nanoball polyoxomolybdate {Mo132} under heterogeneous conditions are reported. The reaction yield and selectivity was affected crucially by catalyst concentration. A structurally diverse set of sulfides and olefins were transformed into desired oxidation products regardless of the electronic nature of the substituents. In spite of the heterogeneous reaction mixtures throughout the work, no difficulties with reaction progress were noted. Products were isolated easily from green media, and the catalyst could be reused several times without any appreciable decrease in catalytic activity and selectivity. Accelerated reactions under ultrasonic irradiation did not change the selectivity of the oxidation products.

Dual-sulfonated dipyridinium phosphotungstate catalyst for liquid-phase Beckmann rearrangement of cyclohexanone oxime

The heteropolyanion (HPA)-based ionic liquid (IL) hybrid was prepared by pairing Keggin-structured HPA of the phosphotungstate anion PW12O403− (PW) with dual-sulfonated 4,4′-dipyridinium IL-cation [DPySO3H]2+. The obtained powdered IL–HPA hybrid material [DPySO3H]1.5PW was characterized and catalytically assessed in Beckmann rearrangement of cyclohexanone-oxime to e-caprolactam. Under the optimized reaction conditions: 10 mol% catalyst, 130 °C, 2 h, benzonitrile as the solvent, and without the environmentally harmful cocatalyst ZnCl2, [DPySO3H]1.5PW exhibits 100% conversion and 73.0% selectivity, remarkably higher than control catalysts involving other HPA-anions or the partially proton-substituted IL-cation. Moreover, the catalyst [DPySO3H]1.5PW can be isolated and reused via filtration from the liquid–solid heterogeneous reaction mixture demonstrated by the four-run recycling test.

Synthesis and Reactions of Five-Membered Heterocycles Using Phase Transfer Catalyst (PTC) Techniques

Phase transfer catalysts (PTCs) have been widely used for the synthesis of organic compounds particularly in both liquid-liquid and solid-liquid heterogeneous reaction mixtures. They are known to accelerate reaction rates by facilitating formation of interphase transfer of species and making reactions between reagents in two immiscible phases possible. Application of PTC instead of traditional technologies for industrial processes of organic synthesis provides substantial benefits for the environment. On the basis of numerous reports it is evident that phase-transfer catalysis is the most efficient way for generation and reactions of many active intermediates. In this review we report various uses of PTC in syntheses and reactions of five-membered heterocycles compounds and their multifused rings.

RUTHENIUM DOPED ZnO SEMICONDUCTOR: SYNTHESIS, CHARACTERIZATION AND PHOTODEGRADATION OF AZO DYE

Ruthenium doped zinc oxide was synthesized by a simple sol–gel method via ultrasonication. The samples were characterized by X-ray diffraction, high resolution scanning electron microscopy (HR-SEM), high resolution transmission electron microscope (HR-TEM), energy dispersive spectroscopy (EDS) and UV-visible spectroscopy techniques and tested for the feasibility as a heterogeneous photocatalyst. The photocatalytic activity of Ru doped ZnO was tested using an azo dye, congo red (CR) in an aqueous solution, as a model compound. For comparison, the photocatalytic activity of pure ZnO was also performed. The parameters studied include the effect of initial CR concentration, photocatalyst weight and charge transfer phenomenon. The observed reaction mechanism was rationalized based on the elementary chemical reaction occurring in the irradiated heterogeneous reaction mixture. Total mineralization of CR was observed for both pure and Ru doped ZnO system. However, the photocatalytic activity of Ru doped ZnO was found to be higher than that of a pure ZnO .

ChemInform Abstract: Highly Atom‐Economic, Catalyst‐ and Solvent‐Free Oxidation of Sulfides into Sulfones Using 30% Aqueous H2O2.

Highly atom-efficient oxidation of sulfides into sulfones under solvent- and catalyst-free reaction conditions using a 30% aqueous solution of H2O2 at 75 °C is reported. A structurally diverse set of phenyl alkyl-, phenyl benzyl-, benzyl alkyl-, dialkyl-, heteroaryl alkyl- and cyclic sulfides were transformed into sulfones regardless of the aggregate state and electronic nature of the substituents. In spite of the heterogeneous reaction mixtures throughout the work, no difficulties with stirring and reaction progress were noted. In numerous cases, only 10 mol% excess of H2O2 was used, thus contributing considerably to the high atom economy of the process. Some solid substrates required a variable excess of hydrogen peroxide; however, the reactions were performed strictly without organic solvents. The transformation was demonstrated to be amenable for scale-up with both liquid and solid sulfides. In addition, isolation and purification of the crude products can be simply done with only filtration and crystallization.