Herein, we report the catalytic activity of a series of platinum(II) pre-catalysts, bearing N-heterocyclic carbene (NHC) ligands, in the alkene hydrosilylation reaction. Their structural and electronic properties are fully investigated using X-ray diffraction analysis and nuclear magnetic resonance spectroscopy (NMR). Next, our study presents a structure-activity relationship within this group of pre-catalysts and gives mechanistic insights into the catalyst activation step. An exceptional catalytic performance of one of the complexes is observed, reaching a turnover number (TON) of 970 000 and a turnover frequency (TOF) of 40 417 h(-1) at 1 ppm catalyst loading. Finally, an attractive solvent-free and open-to-air alkene hydrosilylation protocol, featuring efficient platinum removal (reduction of residual Pt from 582 ppm to 5.8 ppm), is disclosed.

The integration of a membrane separation protocol with the platinum-catalyzed hydrosilylation of olefins was investigated. The catalytic reaction was first optimized in batch where [Pt(IPr*)(DMS)Cl 2 ] (IPr* =  1,3-bis[2,6-bis(diphenylmethyl)-4-methylphenyl]imidazol- 2-ylidene , DMS = dimethyl sulfide) demonstrated superior activity compared to the less sterically encumbered [Pt(SIPr)(DMS)Cl 2 ] (SIPr =  1,3-bis(2,6-diisopropyl-phenyl)imidazolidine ) congener. Filtration conditions were identified in membrane screening experiments. Hydrosilylation of 1-octene catalyzed by  Pt-II  was conducted in continuous mode and the platinum catalyst was separated efficiently over the commercially available Borsig  oNF-2  membrane, all under solvent free conditions. An advantage of this process is that both reaction and separation are coupled in a single step. Moreover, at the end of the process the intact catalyst was recovered in 80% yield as an off-white solid without any further purification.

BACKGROUND Transition metal catalysis has, over recent decades, developed into one of the most important methods of constructing molecules. However, although efficient in the construction of complex molecules, these catalysts can be expensive as they are often based upon second- and third-row transition metals which have, for the most part, low terrestrial abundance. Present removal and recovery techniques for homogeneous catalysts tend, at best, to focus on recovering the metal center and to consider ligands as single-use components. Recovery of the whole catalyst would be more beneficial from economic and environmental points of view. RESULTS The integration of a membrane separation protocol with gold-catalyzed carboxylative cyclization of propargylamine was investigated. Filtration conditions were identified in membrane screening experiments with the dinuclear catalyst [Au2Cl2(L)] (Au-1) and the mononuclear catalyst [Au(IPr)Cl] (Au-2). Recovery of the whole catalyst was then investigated. Catalyst Au-1 proved unstable and led to metal recovery for reprocessing upon completion of the process. However, the membrane methodology does allow recovery of the catalyst within the reaction mixture which increases its efficiency. On the other hand, catalyst Au-2 proved more stable and can be recovered along with its ancillary ligands. CONCLUSIONS For both catalysts a membrane-based recovery protocol was successfully demonstrated. This protocol was either internal or external in that the Au complex along with its ligands can be recovered after reaction. This initial work shows the possibility that ligands do not always need to be considered as single-use components. (c) 2021 Society of Chemical Industry (SCI).

BACKGROUND Amine transaminases have been extensively used for synthesizing various pharmaceutically relevant compounds, mainly in aqueous media. However, their applications are often limited by poor substrate solubility, low productivity and difficult product separation. This paper reports the use of Jeffamine (R) ED-600, a novel polyether amine donor, for the transaminase-catalyzed synthesis of 4-phenyl-2-butylamine in non-aqueous media. RESULTS Enzymatic transamination was performed in the presence of a non-polar organic solvent (n-heptane), in which the selected amine donor is not soluble, thus a two-liquid-phase system was achieved. Coupling the reaction system with membrane-assisted extraction resulted in simultaneous recovery of product, without any consistent contamination of the unreacted substrates. Moreover, a product yield of 60% was reached, compared with 15% without product extraction. The reaction was also successfully conducted without addition of any organic solvent, thus providing the first example of a solvent-free transamination system. In the presence of only enzyme and substrates, up to 6-fold higher product concentrations were achieved compared with the reaction performed in organic solvent. CONCLUSION The use of the Jeffamine (R) ED-600 in non-aqueous media resulted beneficial for 4-phenyl-2-butylamine synthesis. Enzymatic transamination in organic solvent with membrane-assisted product extraction enabled shifting of the equilibrium and selective product extraction. Solvent-free transamination minimized the required volume of the reactor and minimized the environmental impact. Extension to other substrate/enzyme solvent-free systems could open new possibilities and perspectives in transaminase-catalyzed chiral amine synthesis. (c) 2019 Society of Chemical Industry

Eight new dinuclear gold(I) complexes, [Au-2(L)X-2] (1-8), were synthesized using a straightforward synthetic procedure under very mild conditions. The complexes have been characterized by NMR spectroscopy, elemental analysis, and single-crystal X-ray structure analysis. Their catalytic activity was investigated in the carboxylative cyclization of propargylamine (PPA). A superior performance in comparison to [Au(IPr)Cl] (9) was obtained for complexes 1 and 2 having an eight-methylene bridge connecting two NHCs with an arene bearing an isopropyl substituent for X = Cl, Br. This prompted more detailed kinetic and mechanistic studies by FTIR comparing dinuclear complex 2 of X = Cl to complex 9. Fortuitously the FTIR studies allowed monitoring of the formation of the products carbamic acid (CA) and carbamate salt (CS), as well as a key cyclized intermediate first discovered by Ikariya. These data allow additional insight into the mechanism as well as the central role which may be played by Au(I) carbamate formation as a higher energy resting state present in the catalytic cycle. The crystal structures of four of the new complexes and a detailed computational study relevant to the role of carbamic acid (CA) and carbamates in the catalytic cycle are also reported.

In this report, we investigate the integration of a membrane separation protocol in line with the gold-catalyzed hydration of alkynes. The catalytic reaction is optimised towards that end and subsequently merged with membrane technology via the development of an organic solvent nanofiltration (OSN) procedure. The protocol is investigated over both ceramic and polymeric membranes. Several gold catalysts were screened in the hydration of diphenylacetylene 1, and high rejection was observed in all cases using Borsig-type polymeric membranes. Catalyst recycling was also achieved up to 4 times using [Au(OTf)(IPr)] (3). In addition, the retained catalyst in the last catalytic cycle was analyzed and readily converted into [Au(Cl)(IPr)] (synthetic precursor to 3), using a straightforward treatment. The sustainability of the process was improved by using a green solvent, 2-methyltetrahydrofuran (Me-THF), and by reducing the amount of solvent used via the implementation of a second membrane.

The immense potential of transaminase-catalyzed reactions for chiral amine synthesis is often hampered by unfavorable thermodynamic equilibrium positions and product inhibition issues. In the here presented proof of concept, we demonstrate a membrane assisted strategy for addressing these challenges. It involves a separation based on differently sized amine donor and amine product molecules. Novel High Molecular Weight (HMW) amine donors, provided in excess for thermodynamic equilibrium shifting, are successfully employed in transaminase-catalyzed reactions and are effectively retained by commercial nanofiltration membranes by a size exclusion mechanism. Retention of HMW amine donors combined with selective product removal, in batch mode, shifted the equilibrium enhancing substrate conversion by an additional 25% compared to the control reaction. Along with the potential of this approach, certain limitations were also revealed in this study. Only few of the investigated enzymes accepted the HMW donor molecules, and along with very efficient amine product removal, there was undesirable loss of ketone substrate. Therefore, a broader enzyme screening, and the selection of a selective and solvent stable membrane, is essential for better and broader applicability of the concept.

BACKGROUND Ring-closing metathesis (RCM) for the synthesis of macrocycles has been used more and more often over recent years, including some interesting applications on industrial scale. However, like all macrocyclization strategies RCM is plagued by the traditional issue of low volume efficiency. To-date this is typically addressed in a molecule specific manner with varying degrees of success. Here we report a process intensification method of metathesis macrocyclization that reduces the solvent load required for the reaction significantly. RESULTS Metathesis macrocylizations were successfully carried out in a solvent volume of upto 82% lower than an equivalent batch reaction, with only minimal impact upon the reaction outcome. A switch of reaction solvent to ethyl acetate renders the process more benign and applicable to large scale. CONCLUSION A membrane-assisted processing method that relies upon organic solvent nanofiltration permitting an internal solvent recycling and concumittent in situ product removal. The method is also designed to be applicable to a wide range of metathesis cyclizations. (c) 2019 Society of Chemical Industry

A device for the transaminase-catalysed synthesis combined with continuous recovery of chiral amines was designed. The system enabled the separation of the reaction components in three liquid phases: a reaction phase, an organic solvent phase (where the poorly water soluble ketone substrate was supplied), and an aqueous extraction phase for continuous product recovery. The transaminase-mediated asymmetric synthesis of (S)-1-methyl-3-phenylpropylamine was employed as model reaction. Factors influencing the performance of the system, such as reactor geometry, working volumes and operating parameters, were investigated. Specifically, reaction yield and product recovery were enhanced by i) reducing the thickness of the reaction phase, while continuously stirring and ii) reducing the volume of the extraction phase. Under the optimal condition tested, 85 % of the product formed was extracted and a product concentration value of 9 g/L was reached. However, co-extraction of the unreacted amine donor (17 %) was observed. Advantages and drawbacks of this process compared to existing technologies, as well as possible optimization strategies are discussed.

Homogeneous catalysis has proved to be a reliable method for preparing numerous molecular entities, but catalysts can be expensive and difficult to remove. Because of this, industry targets catalysts that are easily separated and recovered and feature increased turnover numbers. The ongoing shift from multipurpose batch reactors toward continuous manufacturing in fine chemicals synthesis results in a new set of catalyst requirements. This paper reports the design and use of Pd complexes suitable for a semicontinuous Suzuki cross-coupling reaction based on a membrane-assisted reactor. These Pd complexes contain tailed N-heterocyclic carbene (NHC) ligands, allowing internal catalyst recovery by organic solvent nanofiltration with top-layer-modified ceramic membranes. These membranes give selective nanofiltration of the catalyst based on a combination of size exclusion and affinity separation (solvent–solute–membrane interactions). The semicontinuous system developed led to significantly improved turnover numbers, simplified product isolation, and consequently reduced mass intensity by simply adding more of the reactants and reagents to the reaction vessel.

Within practically all multistep synthetic sequences used to prepare molecular entities, a step can be found in which a change of solvent is required. Presently this is nearly always carried out by distillation process. Alternatives to distillation do, however, exist such as the nonthermal membrane based solvent exchange. Although highly efficient and useful in several circumstances, this technique is seldom carried out within an industrial setting, possibly due to some uncertainty as to the issues to be confronted. By making use of a practical example in which the Refametnib intermediate DIM-DAB (2) undergoes a solvent exchange from the reaction solvent THF to its crystallization solvent ethanol, these issues are illustrated and explained. Furthermore, the at first sight seemingly arbitrary rejection profile of DIM-DAB (2) over various membranes is explained by applying Spiegler–Kedem theory. Use of this modeling leads to a more targeted membrane screening phase, in which solute rejection is determined in a particular solvent over a number of membranes. Moreover, this model can also be used to simulate membrane performance in a solvent exchange without necessarily requiring the experimental demonstration. The simulation increases the efficiency of the experimental work by allowing a more comprehensive view of membrane performance. This in turn leads to more informed decisions of which membrane is the most suited to the requirements of the process.

Valorization of biomass calls for development of new and/or optimized process technologies. Cost-effective separation processes are of utmost importance to separate biomass components on an industrial scale. Also the complexity of biomass depolymerization/hydrolysis processes increases even further the need for efficient separation processes. Within this study, the use of commercial nanofiltration membranes and in-house developed Grignard-functionalized ceramic membranes has been investigated for the fractionation of a mixture of lignin derivatives, obtained from the depolymerization of Organosolv lignin according to the derivatization followed by reductive cleavage (DFRC) approach. Gas chromatography coupled with mass spectrometry, liquid chromatography-high resolution-mass spectrometry and gel permeation chromatography have been intensively used for the characterization of the depolymerization mixture before and after membrane separation. Higher permeation fluxes are observed with the modified ceramic membranes (25-30 L m(-2) h(-1)) exhibiting amphiphilic surface properties. Separation of lignin derivatives by molecular weight based on size-exclusion has been observed with the polyamide Desal-5DK membrane, while a separation governed by solute-membrane interactions appears to be possible with the functionalized ceramic membranes, where retentions for individual solutes are highly dependent on the chemistry of the grafted groups. For instance, it has been observed that aromatics such as 2,6-dimethoxy-4-propenylphenol are either rejected by or preferentially transported across the membrane, depending on the chosen membrane functionalization. This offers perspectives towards the development of membrane processes for fine separation of small lignols and to enable the use of these molecules in chemical and materials applications. (C) 2017 Elsevier B.V. All rights reserved.

Successful chemical production of molecules while simultaneously reducing the environmental impact of the process relies not only on more efficient reactions but also on developments in reactor and separation technology. Recent decades have also witnessed a significant growth in industrial interest in solvent-based separations using membranes stable to organic solvents. The incorporation of membranes into a chemical process can be via a simple downstream processing method or an integrated reaction membrane method. This paper deals with homogeneous organometallic catalyzed reactions and probes the separation of a number of readily available palladium complexes from reaction mixtures with highly stable ceramic membranes. A number of different processing methods, namely, online, at-line, and off-line are compared and contrasted. A high rejection of Palladium species and consequently very low palladium contamination of reaction products with a single organic solvent nanofiltration (OSN) step has been demonstrated.

A new generation of membranes modified by using Grignard reactions was recently introduced. These alkyl modified membranes have an enhanced hydrophobicity, and a potential for organic solvent nanofiltration (OSN). In this work, the solvent filtration performance and application potential of these Grignard functionalized membranes were further explored. To this purpose, the retention of model solutes using a variety of grafted and ungrafted membranes was investigated in 5 different solvent/solute test mixtures. Experiments were performed with two different solvents, acetone with intermediate polarity and toluene as an apolar solvent, and 3 different solute classes, namely polyethylene glycol, polystyrene and a well-known catalyst ligand. The varying retention behavior can be explained by the changing affinity of solvents and solutes for the modified and unmodified membrane surfaces. Results of sorption tests confirm this conclusion. Subsequently, filtration of a phosphine mixture in isopropanol containing different solutes with similar size but varying polarity, showed the clear potential of affinity-based separations with Grignard modified membranes. A filtration test during four days revealed that the grafted groups are sufficiently stable. As a conclusion, Grignard functionalization of ceramic membranes allows to tune solvent-membrane-solute interactions in OSN in a controlled way for specific separations, without the extra complexity of swelling. (C) 2015 Elsevier B.V. All rights reserved.

Cyclic peptides have found numerous and wide ranging applications that include drug molecules, nanomaterials, and chiral chromatography stationary phases. However, in the crucial cyclization step, high dilution conditions are often required, resulting in large volumes of solvent being consumed to prepare relatively small quantities of product. This paper demonstrates the synthesis of a cyclic nonapeptide with in-line solvent recycling via organic solvent nanofiltration (OSN) resulting in a significant reduction in the solvent load of the reaction and concomitant improvement in process mass intensification (PMI). The membrane was used to remove the reaction product from the reaction vessel, as the cyclic peptide product shows limited stability in the presence of an excess of reaction reagent. In comparison to the standard batch reaction, no loss in yield or product purity was observed for the OSN process tested. The proof-of-concept study outlined in this paper was performed on a real active pharmaceutical ingredient (API), and the technique used is widely applicable and flexible.

The attention for microreactors for organic synthesis reactions, in both academia and industry, has considerably increased over the past few years, as indicated by the progressively growing number of publications. A review of articles on liquid-phase organic syntheses in microreactors in 2011-2012 is presented in this contribution. The main topics discussed in this review are noncatalytic and homogeneously catalyzed reactions, multistep syntheses, heterogeneously catalyzed reactions, microwave-assisted reactions, and photocatalytic reactions. A number of important publications from the period 2008-2010 are also mentioned to complete the overview. The goal of the present review is to illustrate the important topics of the publications during the past few years on organic synthesis in microreactors.

Organic solvent nanofiltration (OSN), a relatively new low energy separation technology, has been used to reduce metal contamination of ring closing metathesis reaction products. The catalysts used were readily available commercial Hoveyda-Grubbs and Umicore M series catalysts. These reactions were performed in a flow reactor with in-line membrane separation, and high catalyst retention can be achieved. In the flow reactor set up a beneficial effect on catalyst life-time on changing from solvents such as dichloromethane to environmentally more benign acetone, which reduces initiation rates, was demonstrated.

A large-scale mobile pilot installation for organic solvent nanofiltration has been designed to facilitate the transfer of this new promising technology for process intensification to industry. The installation, suitable for all requirements ranging from proof of principle testing to pilot scale production, is mobile and can be equipped both with ceramic and polymeric membranes. The pilot is full ATEX, meets the regulatory requirements of pharmaceutical and fine chemical manufacturing and is available to customers on a rental basis. In this paper, the technical specifications of the pilot unit, possible applications and some successful case studies are presented.