Non-conventional Reaction Research Articles

Biocatalysis in Non-Conventional Media: Unlocking the Potential for Sustainable Chiral Amine Synthesis.

The application of biocatalysis has become essential in both academic and industrial domains for the asymmetric synthesis of chiral amines, and it serves as an alternative tool to transition-metal catalysis and complements traditional chemical methods. It relies on the swift expansion of available processes, primarily as a result of advanced tools for enzyme discovery, combined with high-throughput laboratory evolution techniques for optimizing biocatalysts. This concept paper explores the utilization of non-conventional media such as ether-type solvents, deep eutectic solvents, and micellar catalysis to enhance biocatalytic reactions for chiral amine synthesis. Each section focuses on the unique properties of these media, including their ability to stabilize enzymes, alter substrate solubility, and modulate enzyme selectivity. The paper aims to provide insights into how these innovative media can overcome traditional limitations, offering new avenues for sustainable and efficient chiral amine production through biocatalytic processes.

Intensification of biocatalytic processes by using alternative reaction media

Abstract Performances of biocatalytic processes in industry are often limited by productivity, product concentration and biocatalyst stability. Reasons can be such as unfavourable reaction thermodynamics, low water solubility of the substrates or inhibition caused by high substrate or product concentrations. A way to overcome these limitations and to enhance economic competitiveness of the process can be process intensification (PI) using an alternative reaction medium. Very early in industrial biotransformation processes, it was shown that many interesting target products of organic synthesis are much more soluble and sometimes even more stable in non-conventional reaction media than in buffered aqueous solutions. Moreover, the absence of water is also generally desired to prevent side and degradation reactions as well as microbial contamination, which in turn eliminates the need to work under sterile conditions thereby reducing energy expenditure. In addition, it was also discovered early on that solvents can influence the activity and stability of enzymes quite differently depending on their water affinity and thus if they form rather monophasic or biphasic systems with the latter.

Suitability of non-conventional reaction medium for biocatalysis: From lipase activity to thermophysical characterization

This work is focused on the demonstration of the ability of DES composed of choline chloride (ChCl) as hydrogen bond acceptor (HBA) and urea and/or glycerol as hydrogen bond donors (HBD) to be employed as biocatalytic milieu in Candida antarctica lipase B (CALB)-catalysed biodiesel production. Not only, the biocatalytic activity was maintained in the presence of common acyl acceptors like alcohols (methanol, ethanol and 1-propanol), but also the use of a ternary DES (ChCl:urea:glycerol) entailed a drastic activation of the enzyme regarding the biocatalytic potential in water. The necessity of characterizing the DES became evident, so different physical properties like density, refractive indices, speed of sound and dynamic viscosity were determined at temperatures comprised between (298.15 and 343.15) K and 0,1 MPa. in order to unravel the possible chemical interactions of DES with enzymes. Besides, several derived magnitudes like the molar volume, isentropic compressibility, isobaric thermal expansion, intermolecular free length, molar refraction, free volume, and internal pressure were determined together with the critical volume, critical temperature, critical pressure, boiling point and acentric factor. It was concluded that some properties like density, refractive index and dynamic viscosity or derived magnitudes like the molar volume and the free volume were useful tools to rationalize the interaction of DES with lipases.

Splicing HAC1/XBP1 mRNAs in Cytoplasm: The Non-Conventional mRNA Splicing Reaction in the Unfolded Protein Response

The majority of the secretory and transmembrane proteins are folded in the endoplasmic reticulum (ER). When unfolded proteins accumulate in the ER, a collective of signalling pathways, termed the unfolded protein response (UPR), are activated to restore the ER protein folding homeostasis. The most evolutionarily conserved branch of UPR is mediated by the kinase/endoribonuclease Ire1. Ire1 mediates a cytosolic non-conventional mRNA splicing reaction of HAC1 mRNA in yeast and XBP1 mRNA in mammalian cells. The spliced HAC1/XBP1 mRNA is translated and produces a functional transcription factor, which initiates a transcriptional response to restore the protein folding homeostasis. The HAC1/XBP1 mRNA splicing reaction is biochemically distinct from the ones that are catalyzed by the spliceosome. Here, we review recent studies that provide a mechanistic understanding of the non-conventional mRNA splicing reaction.

Recent Progress of Cu-Catalyzed Azide-Alkyne Cycloaddition Reactions (CuAAC) in Sustainable Solvents: Glycerol, Deep Eutectic Solvents, and Aqueous Media.

This mini-review presents a general overview of the progress achieved during the last decade on the amalgamation of CuAAC processes (copper-catalyzed azide-alkyne cycloaddition) with the employment of sustainable solvents as reaction media. In most of the presented examples, the use of water, glycerol (Gly), or deep eutectic solvents (DESs) as non-conventional reaction media allowed not only to recycle the catalytic system (thus reducing the amount of the copper catalyst needed per mole of substrate), but also to achieve higher conversions and selectivities when compared with the reaction promoted in hazardous and volatile organic solvents (VOCs). Moreover, the use of the aforementioned green solvents also permits the improvement of the overall sustainability of the Cu-catalyzed 1,3-dipolar cycloaddition process, thus fulfilling several important principles of green chemistry.

Biotransformation of cladribine by a magnetic immobilizated biocatalyst of Lactobacillus animalis

A stable biocatalyst with magnetic properties based on immobilized Lactobacillus animalis ATCC 35,046 to obtain 2-chloroadenine-2'-deoxyriboside, known as cladribine, is reported for the first time. This nucleoside analogue is an antitumor agent used in the treatment of a wide variety of types of leukemia. In this study, an eco-compatible and alternative bioprocess to obtain cladribine was developed. Product conversion was close to 90% at 2h in optimized nonconventional reaction media. The microscale biosynthesis of the compound of interest afforded a total productivity close to 370mg/L/h in the presence of DMSO, and it was stable at least for 30days in storage conditions.

Modeling Alcohol Dehydrogenase Catalysis in Deep Eutectic Solvent/Water Mixtures.

The use of oxidoreductases (EC1) in non‐conventional reaction media has been increasingly explored. In particular, deep eutectic solvents (DESs) have emerged as a novel class of solvents. Herein, an in‐depth study of bioreduction with an alcohol dehydrogenase (ADH) in the DES glyceline is presented. The activity and stability of ADH in mixtures of glyceline/water with varying water contents were measured. Furthermore, the thermodynamic water activity and viscosity of mixtures of glyceline/water have been determined. For a better understanding of the observations, molecular dynamics simulations were performed to quantify the molecular flexibility, hydration layer, and intraprotein hydrogen bonds of ADH. The behavior of the enzyme in DESs follows the classic dependence of water activity (a W) in non‐conventional media. At low a W values (<0.2), ADH does not show any activity; at higher a W values, the activity was still lower than that in pure water due to the high viscosities of the DES. These findings could be further explained by increased enzyme flexibility with increasing water content.

Miniemulsion in biocatalysis, a new approach employing a solid reagent and an easy protocol for product isolation applied to the aldol reaction by Rhizopus niveus lipase

Miniemulsion systems presented a great potential for biocatalytic reactions. However, different limitations jeopardized the applications of this non-conventional medium. In this work, miniemulsion systems (emulsion reactors) were applied for the first time to the aldol reaction between cyclohexanone and 4-nitrobenzaldehyde by Rhizopus niveus lipase allowing a decrease in the catalyst concentration from 20 mg mL−1 to 6 mg mL−1 in comparison with organic solvents. Moreover, the yield increased from ~25% to ~65% for 48 h reactions and the enantiomeric excess increased from ~10% to ~30% for (R,S)-anti-aldol product, showing the potentiality of this non-conventional reaction medium. The advances reported in this work expands the possibilities of the miniemulsion reaction medium to a whole new level, increasing the scope to solid reagents and products, and also different reactions (biocatalytic or not) that requires pH control by buffers with a simple product isolation procedure, enabling future applications of this poorly studied reaction medium.

Deep eutectic ionic liquids based on DABCO-derived quaternary ammonium salts: A promising reaction medium in gaining access to terpyridines

Owing to the directional H-bonding, coordination and π-stacking abilities, terpyridines have been widely used as supramolecular tectons in molecular architectures, skeletons in molecular devices and metallopolymers, and are gaining importance in medicinal chemistry. In this paper, we have synthesized, characterized and applied deep eutectic ionic liquids (DEILs) based on 1,4-diazabicyclo[2.2.2]octane; triethylenediamine (DABCO)-derived quaternary ammonium salts for the preparation of terpyridines. These DEILs were synthesized through N-alkylation of DABCO with haloalkanes (1-bromopentane or 1-bromoheptane) followed by mixing and heating with methanol or polyethylene glycol as a hydrogen bond donor. The synthesized DEILs were structurally characterized by IR and NMR. The formation of deep eutectic solvent was confirmed by freezing point depression, it composition was investigated through phase diagram, and its thermal stability was determined through differential scanning calorimetry, derivative thermogravimetry and thermal gravimetric analysis studies. Further, these DEILs were investigated for their effectiveness towards synthesis of 2,2′:6′,2″-terpyridine, 3,2′:6′,3″-terpyridineand 4,2′:6′,4″-terpyridine derivatives through Krohnke reaction. The results show that these three types of terpyridines can be obtained in reasonable yields (80%–97%) by the one-pot reaction of 2-, 3- or 4-acetylpyridine with a variety of aromatic aldehydes in the presence of DEIL as a reaction medium, sodium hydroxide as a base and ammonium acetate as a cyclizing agent. This methodology is highly efficient and cost-effective for synthesis of symmetrical as well as unsymmetrical terpyridines. Importantly, these DEILs can be reused several times without an obvious loss of activity and are non-toxic, low-volatile, biodegradable and highly thermally stable. Therefore, these DEILs as a non-conventional reaction medium for the synthesis of terpyridines provides appealing opportunities to be investigated in the domain of green synthesis.

The Prospect of Photochemical Reactions in Confined Gel Media.

Nature is intrinsically able to control kinetics, conversion, and selectivity of biochemical processes by means of confined reaction environments such as enzyme pockets, bilayer membranes, micelles, vesicles, cells, or bioorganic frameworks. The main reason for this fact is the optimal molecular alignment and restricted motion of reactant molecules compared to those found in bulk solution. Under this inspiration, a number of synthetic photo-nanoreactors based on supramolecular self-assembled systems have been developed during the last decades, including mesoporous inorganic materials, microemulsions, micelles, vesicles, lipid bilayer foams, polyelectrolyte nanoparticles, etc. In a broader sense, nanoreactor technology constitutes nowadays a promising tool to enhance organic synthesis under sustainable reaction conditions. In general, nanoreactors change the essential properties of the molecules within them, thus affecting their chemical reactivity. Among the nanoreactor-like systems described in the literature to facilitate photochemical processes, the more recent use of viscoelastic supramolecular gels, typically made of low-molecular-weight (LMW) compounds self-assembled through noncovalent interactions, as compartmentalized reaction media is particularly appealing due to the versatility of these materials in terms of fabrication, properties, and processability. Furthermore, the high specific surface areas found in supramolecular gels, their stimuli-responsive reversibility, good diffusion properties enhancing the interactions between reactants and the three-dimensional (3D) porous network, functional tunability, and blocking effect of external oxygen are some of the most important features that can benefit photoinduced processes carried out in confined gel media. Not surprisingly, the efficiency of photochemical processes inside gel media is largely dependent on the type of reaction, characteristics of the gel network, solvent nature, reactant properties, and reaction conditions. Thus, the main focus of this Account is to provide a concise overview of the most relevant examples reported by us and others in order to illustrate the main advantages associated with the emerging use of gel-based materials as nonconventional reaction media to facilitate and control photochemical reactions. In particular, photodimerization, triplet-triplet annihilation upconversion (TTA-UC) coupled to single electron transfer (SET), photooxidation, photoreduction, and trifluoromethylation reactions will be illustrated during the discussion. These examples suggest that gel-based media can provide a versatile platform for the discovery of new reaction pathways and facilitate the way that photochemical reactions are traditionally carried out in academia and industry in terms of reaction conditions and required infrastructure. In addition, the use of physical or chemical gels as reaction systems may also accelerate high-throughput screening of photocatalysts. Overall, a judicious choice of gelators, reactants, solvent, and reaction conditions for the assembly of these gelators is crucial for controlling conversion, kinetics, and selectivity of intragel photoinduced processes.

Ionic Liquid Gels: Supramolecular Reaction Media for the Alcoholysis of Anhydrides.

The search of new enantioselective catalysts, able to promote synthetically useful organic reactions with high levels of asymmetric induction, should be associated with the attention to the suitable reaction medium able to achieve the best efficiency in chemical processes. We have investigated the enantioselective desymmetrization of cyclic meso-anhydrides in nonconventional reaction media such as ionic liquids and supramolecular gels. With this aim, we examined several variables in the reacting system: the nature of ionic liquid used as the reaction medium, the gelation solvent, the structure of the anhydrides, the structure of alcohols, the chiral catalysts, and the reaction conditions, i.e., temperature and time. The different components of the system differently influence the reaction outcome, and to understand the interactions existing among them, 1H NMR investigation was carried out. In general, the nonconventional reaction media demonstrated better performance than conventional ones, applying only a small amount of solvent. Good results in terms of yield and enantiomeric excess have been obtained in ionic liquid gels that seem promising media in the catalytic field. Furthermore, to the best of our knowledge, this is one of the first examples for the study of asymmetric alcoholysis of anhydrides in ionic liquid solution and gel phase.

Ionic Liquids for Clean Biocatalytic Processes

Background: Biocatalysis has many attractive features in the context of green chemistry, due to the high efficiency of chemical transformations and the renewable character of the enzymes used. Since the beginning of this century, ILs have emerged as exceptionally interesting non-aqueous reaction media for biotransformations because of their unique solvent properties, headed by their negligible vapour pressure and their exceptional ability to maintain enzymes in active and stable conformations. However, the goal of green chemistry is much more than simply replacing hazardous solvents with environmentally benign ones, and it is necessary to devise new clean methodologies that will fulfil the sustainable requirements for efficient transformations of substrates, product recovery and the reuse of all the elements of the reaction system. Results: The use biocatalyst in IL/scCO2 biphasic systems was the first approach forward to develop integral green chemical processes in non-aqueous environments. The combination of these sustainable tools provides synergies in both biocatalyst performance (i.e. improved activity and enantioselectivity, enhanced stability, etc.), and the genuine separation technologies of nearly pure products. Sponge-Like Ionic Liquids (SLILs) were recently reported as a new platform for green biocatalytic chemical processes using straightforward technologies. These SLILs are a new class of hydrophobic ILs based on cations with long alkyl side-chains (e.g. 1-octadecyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide, ([C18mim][NTf2], etc.), which behaves as a sponge-like system by switching from liquid to solid phase as the temperature changes. Thus, such ILs are able to dissolve (“soak up”) hydrophobic compounds as a liquid phase, and products can then be “wrung out” by centrifugation of the resulting solid phase after cooling. Based on this property, clean biocatalytic processes for the production of nearly pure compounds of high added value (e.g. geranyl acetate, anisyl acetate, biodiesel, monolaurin, etc.) can be easily designed by the coupling of both biotransformation and separation steps, in a sustainable approach of high potential for practical applications at industrial level. Conclusions: The use of biocatalytic approaches in green non-conventional reaction media holds much promise for the development of a sustainable chemical manufacturing industry. The combination of enzymes with multiphase neoteric systems (SLILs, ILs and/or scCO2) should be explored in the near future, as a clear strategy for developing integral new green multi-catalytic synthetic processes of industrial interest (e.g. pharmaceutical drugs). Keywords: Biocatalysis, clean processes, ionic liquids, sponge-like ionic liquids, green chemistry, terpene, biodiesel, anisyl acetate, lipases.

The Great Chemistry Race

The Great Chemistry Race

Synthesis of Organochalcogen Compounds using Non-Conventional Reaction Media

Organochalcogen compounds (containing S, Se and Te) are interesting either for use as an intermediate in the synthesis of complex molecules or for the exploitation of their biological properties. The growing in the number of papers on the synthesis and application of organochalcogen compounds has been accompanied by a concern about how they are prepared. Here, we provide a comprehensive and updated review on recent synthetic methods available for their synthesis using alternative solvents or solvent-free conditions and non-classical energy sources (microwaves irradiation, sonochemistry and mechanochemistry). Organized in fourteen sections, this review brings the more than one hundred alternative methods described so far to access organic compounds containing selenium, tellurium and sulfur.

ChemInform Abstract: Recent Advances in Biocatalytic Promiscuity: Hydrolase‐Catalyzed Reactions for Nonconventional Transformations

AbstractReview: [102 refs.

Recent Advances in Biocatalytic Promiscuity: Hydrolase-Catalyzed Reactions for Nonconventional Transformations.

Enzymes have emerged in recent decades as ideal catalysts for synthetic transformations under mild reaction conditions. Their capacity to accelerate a myriad of biotransformations with high levels of selectivity and broad substrate specificity including excellent atom economy has led to a current full recognition. The six classes of enzymes (oxidoreductases, transferases, hydrolases, lyases, isomerases and ligases) possess outstanding abilities to perform specific modifications in target molecules. Nevertheless, in the last fifteen years, novel examples have appeared related to nonconventional processes catalyzed by various classes of biocatalysts. Amongst these, hydrolases have received special attention since they display remarkable activities in initially unexpected reactions such as carbon-carbon and carbon-heteroatom bond-formation reactions, oxidative processes and novel hydrolytic transformations. In this review, the main findings in this area will be disclosed, highlighting the catalytic properties of hydrolases not only to catalyze single processes but also multicomponent and tandem nonconventional reactions.

Biokatalyse in unkonventionellen Reaktionsmedien

Biocatalysis in organic media enables higher concentrations of mostly hydrophobic reagents compared to traditional aqueous reaction systems. The resulting economic and ecologic advantages call for more intensive research efforts to attain deeper understanding of the behaviour of biocatalysts under non-conventional reaction conditions.

Computational approaches to homogeneous gold catalysis.

Homogenous gold catalysis has been exploding for the last decade at an outstanding pace. The best described reactivity of Au(I) and Au(III) species is based on gold's properties as a soft Lewis acid, but new reactivity patterns have recently emerged which further expand the range of transformations achievable using gold catalysis, with examples of dual gold activation, hydrogenation reactions, or Au(I)/Au(III) catalytic cycles.In this scenario, to develop fully all these new possibilities, the use of computational tools to understand at an atomistic level of detail the complete role of gold as a catalyst is unavoidable. In this work we aim to provide a comprehensive review of the available benchmark works on methodological options to study homogenous gold catalysis in the hope that this effort can help guide the choice of method in future mechanistic studies involving gold complexes. This is relevant because a representative number of current mechanistic studies still use methods which have been reported as inappropriate and dangerously inaccurate for this chemistry.Together with this, we describe a number of recent mechanistic studies where computational chemistry has provided relevant insights into non-conventional reaction paths, unexpected selectivities or novel reactivity, which illustrate the complexity behind gold-mediated organic chemistry.

Redox Isomerization of Allylic Alcohols to Carbonyl Compounds Catalyzed by Ruthenium(IV) Complexes Containing N-Heterocyclic Ligands in Ionic Liquids

Bis-allyl ruthenium(IV) complexes containing N-heterocyclic ligands [Ru(η3:η3-C10H16)Cl2(κ1-N-L)] (L = pyrazole (1a), benzimidazole (1b)) are active catalysts in the redox isomerization of allylic alcohols into saturated carbonyl compounds using the ionic liquid [BMIM][BF4] (BMIM = 1-butyl-3-methylimidazolium) as a non-conventional reaction media in the absence of additional base. Complex 1b has been found to be the most efficient catalyst for the isomerization of a series of primary and secondary allylic alcohols (9 substrates). In addition, we have studied the effect of the counter anion in the ionic liquid finding that non coordinating anions (BF4-, PF6- and SbF6-) led to the best reactions times and conversion, when compared with the coordinating chloride anion (Cl-). It is important to note that the catalytic system could be recovered through seven catalytic cycles with only partial loss of the initial activity in the first five cycles. Since this catalytic system: i) shows high efficiency and selectivity, ii) involves no presence of phosphines or any base as co-catalyst, iii) proceeds without the formation of by-products (atom economy), and iii) is readily recovered, it can be considered as a genuine example of a Green chemical process. Keywords: Allylic alcohols, ionic liquids, recovery, redox isomerizations, ruthenium catalyst.

Mechanochemical reactions and syntheses of oxides

Technological and scientific challenges coupled with environmental considerations have prompted a search for simple and energy-efficient syntheses and processing routes of materials. This tutorial review provides an overview of recent research efforts in non-conventional reactions and syntheses of oxides induced by mechanical action. It starts with a brief account of the history of mechanochemistry. Ensuing discussions will review the progress in homogeneous and heterogeneous mechanochemical reactions in oxides of various structures. The review demonstrates that the event of mechanically induced reactions provides novel opportunities for the non-thermal manipulation of materials and for the tailoring of their properties.