Recent Advancements in the Utilization of s-Block Organometallic Reagents in Organic Synthesis with Sustainable Solvents.

This mini-review offers a comprehensive overview of the advancements made over the last three years in utilizing highly polar s-block organometallic reagents (specifically, RLi, RNa and RMgX compounds) in organic synthesis run under bench-type reaction conditions. These conditions involve exposure to air/moisture and are carried out at room temperature, with the use of sustainable solvents as reaction media. In the examples provided, the adoption of Deep Eutectic Solvents (DESs) or even water as non-conventional and protic reaction media has not only replicated the traditional chemistry of these organometallic reagents in conventional and toxic volatile organic compounds under Schlenk-type reaction conditions (typically involving low temperatures of -78 °C to 0 °C and a protective atmosphere of N2 or Ar), but has also resulted in higher conversions and selectivities within remarkably short reaction times (measured in s/min). Furthermore, the application of the aforementioned polar organometallics under bench-type reaction conditions (at room temperature/under air) has been extended to other environmentally responsible reaction media, such as more sustainable ethereal solvents (e.g., CPME or 2-MeTHF). Notably, this innovative approach contributes to enhancing the overall sustainability of s-block-metal-mediated organic processes, thereby aligning with several key principles of Green Chemistry.

A Sustainable Synthetic Approach to Tacrine and Cholinesterase Inhibitors in Deep Eutectic Solvents under Aerobic Conditions.

An enhanced, sustainable, and efficient method for synthesizing tacrine, achieving a 98% yield, has been developed by replacing volatile organic compounds with more eco-friendly solvents such as deep eutectic solvent (DESs). The optimized protocol scales easily to 3 g of substrate without yield loss and extends successfully to tacrine derivatives with reduced hepatotoxicity. Particularly notable is the synthesis of novel triazole-based derivatives, yielding 90-95%, by integrating an in situ preparation of aryl azides in DESs with N-propargyl-substituted tacrine derivatives. Quantitative metrics validate the green aspects of the reported drug development processes.

An enhanced stereoselective synthesis of α,ß-unsaturated esters through the Horner-Wadsworth-Emmons reaction in deep eutectic solvents.

A new scalable synthesis of (E)-α,ß-unsaturated esters has been developed using protic, non-toxic, and biodegradable deep eutectic solvents through the Horner-Wadsworth-Emmons reaction between triethyl phosphonates and (hetero)aromatic carbonyl compounds, encompassing electron-withdrawing and electron-donating groups. Stereoselective preparation of disubstituted or trisubstituted ethyl cinnamate derivatives is achieved in the presence of LiOH, K2CO3, or DBU as bases, at room temperature and under air. Demonstrated with the synthesis of (E)-ethyl 3-(4-bromophenyl)acrylate, the same eutectic mixture (choline chloride/urea) proved to be reusable for three consecutive runs. Gram-scale reactions (10 mmol) can be carried out without the formation of side products, thereby ensuring high atom economy and an EcoScale score of 71.

Unveiling the Influence of Hydrated Deep Eutectic Solvents on the Dynamics of Water-Soluble Proteins.

Deep eutectic solvents (DESs) are mixtures of two or more pure compounds (e.g., Lewis or Brønsted acids and bases, anionic and/or cationic species) in a well-defined stoichiometric proportion, with a melting point lower to that of an ideal liquid mixture. These neoteric solvents are highly tunable through varying the structure or relative ratio of parent components and have been evaluated as solvents able to improve biomolecules' performance, specifically their stability and biocatalytic properties. Inspired by a recent crystallographic study, we have explored through molecular dynamics (MD) simulations the dynamic properties of two different proteins (hen egg-white lysozyme and the human VH antibody fragment HEL4) in a (20% w/w) hydrated solution of choline chloride-glycerol (1:2). We have developed proper force fields to account for DES, protein, and DES-protein interactions, which have been calibrated using pair distribution function measurements of pure DES solutions. MD results show that the presence of DES quenches the protein motion, increasing the rigidity of the overall protein structure. Specific interactions among DES components and protein residues, such as those between choline ions and two Tryptophan residues of lysozyme, may amplify the protein-DES interactions and lead to protein crystallization in the presence of hydrated DES. These findings open new horizons to improve or achieve control on protein properties by a proper choice of hydrated DESs used as solvents.

Introducing Water and Deep Eutectic Solvents in Organosodium Chemistry: Chemoselective Nucleophilic Functionalizations in Air.

Advancing the development of perfecting the use of polar organometallics in bio-inspired solvents, we report on the effective generation in batch of organosodium compounds, by the oxidative addition of a C-Cl bond to sodium, a halogen/sodium exchange, or by direct sodiation, when using sodium bricks or neopentylsodium in hexane as sodium sources. C(sp3 )-, C(sp2 )-, and C(sp)-hybridized alkyl and (hetero)aryl sodiated species have been chemoselectively trapped (in competition with protonolysis), with a variety of electrophiles when working "on water", or in biodegradable choline chloride/urea or L-proline/glycerol eutectic mixtures, under hydrous conditions and at room temperature. Additional benefits include a very short reaction time (20 s), a wide substrate scope, and good to excellent yields (up to 98 %) of the desired adducts. The practicality of the proposed protocol was demonstrated by setting up a sodium-mediated multigram-scale synthesis of the anticholinergic drug orphenadrine.

From oximes to tertiary alcohols in water, at room temperature and under air: a hybrid one-pot tandem assembly of enzymatic deoximation and RLi/RMgX reagents.

The highly efficient biodeoximation of aromatic ketoximes, promoted by the enzymatic oxidative system laccase/TEMPO/O2, has been successfully assembled with the fast and chemoselective addition of highly-polar s-block organometallic reagents (RLi/RMgX) en route to highly-substituted tertiary alcohols. By using this hybrid one-pot tandem protocol, tertiary alcohols have been selectively synthesized in good yields and under mild and bench-type reaction conditions (room temperature, the absence of a protecting atmosphere and aqueous media, which are non-typical conditions for polar organometallic reagents). The overall hybrid one-pot tandem transformation amalgamates two distant organic synthetic tools (RLi/RMgX reagents and enzymes) without the need for any tedious and energy/time-consuming intermediate isolation/purification steps.

Regio- and stereoselective biocatalytic hydration of fatty acids from waste cooking oils en route to hydroxy fatty acids and bio-based polyesters.

The development of biorefinery approaches is of great relevance for the sustainable production of valuable compounds. In accordance with circular economy principles, waste cooking oils (WCOs) are renewable resources and biorefinery feedstocks, which contribute to a reduced impact on the environment. Frequently, this waste is wrongly disposed of into municipal sewage systems, thereby creating problems for the environment and increasing treatment costs in wastewater treatment plants. In this study, regenerated WCOs, which were intended for the production of biofuels, were transformed through a chemo-enzymatic approach to produce hydroxy fatty acids, which were further used in polycondensation reaction for polyester production. Escherichia coli whole cell biocatalyst containing the recombinantly produced Elizabethkingia meningoseptica Oleate hydratase (Em_OhyA) was used for the biocatalytic hydration of crude WCOs-derived unsaturated free fatty acids for the production of hydroxy fatty acids. Further hydrogenation reaction and methylation of the crude mixture allowed the production of (R)- 10-hydroxystearic acid methyl ester that was further purified with a high purity (> 90%), at gram scale. The purified (R)- 10-hydroxystearic acid methyl ester was polymerized through a polycondensation reaction to produce the corresponding polyester. This work highlights the potential of waste products to obtain bio-based hydroxy fatty acids and polyesters through a biorefinery approach.

Green Solvents for Eco-Friendly Synthesis of Dimethindene: A Forward-Looking Approach.

Dimethindene is a selective histamine H1 antagonist and is commercially available as a racemate. Upon analyzing the synthetic pathways currently available for the industrial preparation of dimethindene, we set up a sustainable approach for the synthesis of this drug, switching from petroleum-based volatile organic compounds (VOCs) to eco-friendly solvents, such as 2-methyltetrahydrofuran (2-MeTHF) and cyclopentyl methyl ether (CPME) belonging to classes 3 and 2, respectively. Beyond decreasing the environmental impact of the synthesis (E-factor: 24.1-54.9 with VOCs; 12.2-22.1 with 2-MeTHF or CPME), this switch also improved the overall yield of the process (from 10% with VOCs to 21-22% with 2-MeTHF or CPME) and remarkably simplified the manual operations, working under milder conditions. Typical metrics applied at the first and second pass, according to the CHEM21 metrics toolkit, were also calculated for the whole synthetic procedure of dimethindene, and the results were compared with those of the classical procedure.

Selective Aerobic Oxidation of Alcohols in Low Melting Mixtures and Water and Use for Telescoped One-Pot Hybrid Reactions.

An efficient, selective and sustainable protocol was developed for the CuCl2 /TEMPO/TMEDA-catalyzed aerobic oxidation of activated alcohols to the corresponding carbonyl compounds using water or the environmentally friendly low melting mixture (LMM) d-fructose-urea as the reaction medium. Such oxidation reactions proceed under mild (room temperature or 40 °C) and aerobic conditions, with the carbonyl derivatives isolated in up to 98 % yield and within 4 h reaction time when using the above-mentioned LMM. The potential application of this methodology is demonstrated by setting up useful telescoped, one-pot two-step hybrid transformations for the direct conversion of primary alcohols either into secondary alcohols or into valuable nitroalkenes, by combining oxidation processes with nucleophilic additions promoted by highly polarized organometallic compounds (Grignard and organolithium reagents) or with nitroaldol (Henry) reactions, respectively.

Electroactivity of weak electricigen Bacillus subtilis biofilms in solution containing deep eutectic solvent components.

Bacillus subtilis is a Gram-positive, spore-forming bacterium with a versatile and adaptable metabolism, which makes it a viable cell factory for microbial production. Electroactivity has recently been identified as a cellular characteristic linked with the metabolic activity of B. subtilis. The enhancement of B. subtilis electroactivity can positively enhance bioproduction of high-added value metabolites under electrofermentative conditions. Here, we explored the use of deep eutectic solvents (DESs) and DES components as biocompatible nutrient additives for enhancing electroactivity of B. subtilis. The strongest electroactivity was obtained in an aqueous choline chloride: glycerol (1:2 mol mol-1) eutectic mixture. At low concentration (50-500 mM), this mixture induced a pseudo-diauxic increase in planktonic growth and increased biofilm formation, likely due to a nutritional and osmoprotectant effect. Similarities in electroactivity enhancements of choline chloride-based eutectic mixtures and quinone redox metabolism in B. subtilis were detected using high performance liquid chromatography and differential pulse voltammetry. Results show that choline chloride-based aqueous eutectic mixtures can enhance biomass and productivity in biofilm-based electrofermentation. However, the specific mechanism needs to be fully elucidated.

Deep Eutectic Solvents in Solar Energy Technologies.

Deep Eutectic Solvents (DESs) have been widely used in many fields to exploit their ecofriendly characteristics, from green synthetic procedures to environmentally benign industrial methods. In contrast, their application in emerging solar technologies, where the abundant and clean solar energy is used to properly respond to most important societal needs, is still relatively scarce. This represents a strong limitation since many solar devices make use of polluting or toxic components, thus seriously hampering their eco-friendly nature. Herein, we review the literature, mainly published in the last few years, on the use of DESs in representative solar technologies, from solar plants to last generation photovoltaics, featuring not only their passive role as green solvents, but also their active behavior arising from their peculiar chemical nature. This collection highlights the increasing and valuable role played by DESs in solar technologies, in the fulfillment of green chemistry requirements and for performance enhancement, in particular in terms of long-term temporal stability.

Ligand-Free Copper-Catalyzed Ullmann-Type C-O Bond Formation in Non-Innocent Deep Eutectic Solvents under Aerobic Conditions.

An efficient and novel protocol was developed for a Cu-catalyzed Ullmann-type aryl alkyl ether synthesis by reacting various (hetero)aryl halides (Cl, Br, I) with alcohols as active components of environmentally benign choline chloride-based eutectic mixtures. Under optimized conditions, the reaction proceeded under mild conditions (80 °C) in air, in the absence of additional ligands, with a catalyst [CuI or CuII species] loading up to 5 mol% and K2 CO3 as the base, providing the desired aryloxy derivatives in up to 98 % yield. The potential application of the methodology was demonstrated in the valorization of cheap, easily available, and naturally occurring polyols (e. g., glycerol) for the synthesis of some pharmacologically active aryloxypropanediols (Guaiphenesin, Mephenesin, and Chlorphenesin) on a 2 g scale in 70-96 % yield. Catalyst, base, and deep eutectic solvent could easily and successfully be recycled up to seven times with an E-factor as low as 5.76.

A one-pot two-step synthesis of tertiary alcohols combining the biocatalytic laccase/TEMPO oxidation system with organolithium reagents in aerobic aqueous media at room temperature.

The one-pot/two-step combination of enzymes and polar organometallic chemistry in aqueous media is for the first time presented as a proof-of-concept study. The unprecedented combination of the catalytic oxidation of secondary alcohols by the system laccase/TEMPO with the ultrafast addition (3 s reaction time) of polar organometallic reagents (RLi/RMgX) to the in situ formed ketones, run under air at room temperature, allows the straightforward and chemoselective synthesis of tertiary alcohols with broad substrate scope and excellent conversions (up to 96%).

Copper-catalyzed Goldberg-type C-N coupling in deep eutectic solvents (DESs) and water under aerobic conditions.

An efficient and selective N-functionalization of amides is first reported via a CuI-catalyzed Goldberg-type C-N coupling reaction between aryl iodides and primary/secondary amides run either in Deep Eutectic Solvents (DESs) or water as sustainable reaction media, under mild and bench-type reaction conditions (absence of protecting atmosphere). Higher activities were observed in an aqueous medium, though the employment of DESs expanded and improved the scope of the reaction to include also aliphatic amides. Additional valuable features of the reported protocol include: (i) the possibility to scale up the reaction without any erosion of the yield/reaction time; (ii) the recyclability of both the catalyst and the eutectic solvent up to 4 consecutive runs; and (iii) the feasibility of the proposed catalytic system for the synthesis of biologically active molecules.

Scalable Negishi Coupling between Organozinc Compounds and (Hetero)Aryl Bromides under Aerobic Conditions when using Bulk Water or Deep Eutectic Solvents with no Additional Ligands.

Pd-catalyzed Negishi cross-coupling reactions between organozinc compounds and (hetero)aryl bromides have been reported when using bulk water as the reaction medium in the presence of NaCl or the biodegradable choline chloride/urea eutectic mixture. Both C(sp3 )-C(sp2 ) and C(sp2 )-C(sp2 ) couplings have been found to proceed smoothly, with high chemoselectivity, under mild conditions (room temperature or 60 °C) in air, and in competition with protonolysis. Additional benefits include very short reaction times (20 s), good to excellent yields (up to 98 %), wide substrate scope, and the tolerance of a variety of functional groups. The proposed novel protocol is scalable, and the practicability of the method is further highlighted by an easy recycling of both the catalyst and the eutectic mixture or water.

Advances in deep eutectic solvents and water: applications in metal- and biocatalyzed processes, in the synthesis of APIs, and other biologically active compounds.

Owing to a growing awareness towards environmental impact, the search for "greener", safer, and cost-effective solvents able to replace petroleum-derived solvents has never been greater today. In this context, the use of environmentally responsible solvents like water and the so-called deep eutectic solvents (DESs), constructed from bio-based compounds, has recently experienced important growth in several fields of sciences. This short review highlights the key features of the chemistry of water and (hydrated) DESs when applied to metal- and biocatalyzed transformations as well as to the synthesis of active pharmaceutical ingredients (APIs) and other biologically relevant compounds by providing, through discussion of all relevant literature over the past five years, a comparison of the outcomes of the reactions when carried out in one or the other solvent.

A Fast and General Route to Ketones from Amides and Organolithium Compounds under Aerobic Conditions: Synthetic and Mechanistic Aspects.

We report that the nucleophilic acyl substitution reaction of aliphatic and (hetero)aromatic amides by organolithium reagents proceeds quickly (20 s reaction time), efficiently, and chemoselectively with a broad substrate scope in the environmentally responsible cyclopentyl methyl ether, at ambient temperature and under air, to provide ketones in up to 93 % yield with an effective suppression of the notorious over-addition reaction. Detailed DFT calculations and NMR investigations support the experimental results. The described methodology was proven to be amenable to scale-up and recyclability protocols. Contrasting classical procedures carried out under inert atmospheres, this work lays the foundation for a profound paradigm shift of the reactivity of carboxylic acid amides with organolithiums, with ketones being straightforwardly obtained by simply combining the reagents under aerobic conditions and with no need of using previously modified or pre-activated amides, as recommended.

Deep eutectic solvent-catalyzed Meyer-Schuster rearrangement of propargylic alcohols under mild and bench reaction conditions.

The Meyer-Schuster rearrangement of propargylic alcohols into α,ß-unsaturated carbonyl compounds has been revisited by setting up an atom-economic process catalyzed by a deep eutectic solvent FeCl3·6H2O/glycerol. Isomerizations take place smoothly, at room temperature, under air and with short reaction times. The unique solubilizing properties of the eutectic mixture enabled the use of a substrate concentration up to 1.0 M with the medium being recycled up to ten runs without any loss of catalytic activity.

Regiodivergent synthesis of functionalized pyrimidines and imidazoles through phenacyl azides in deep eutectic solvents.

We report that phenacyl azides are key compounds for a regiodivergent synthesis of valuable, functionalized imidazole (32-98% yield) and pyrimidine derivatives (45-88% yield), with a broad substrate scope, when using deep eutectic solvents [choline chloride (ChCl)/glycerol (1:2 mol/mol) and ChCl/urea (1:2 mol/mol)] as environmentally benign and non-innocent reaction media, by modulating the temperature (25 or 80 °C) in the presence or absence of bases (Et3N).

Fast and Chemoselective Addition of Highly Polarized Lithium Phosphides Generated in Deep Eutectic Solvents to Aldehydes and Epoxides.

Highly polarized lithium phosphides (LiPR2 ) were synthesized, for the first time, in deep eutectic solvents as sustainable reaction media, at room temperature and in the absence of protecting atmosphere, through direct deprotonation of both aliphatic and aromatic secondary phosphines (HPR2 ) by n-BuLi. The subsequent addition of in-situ generated LiPR2 to aldehydes or epoxides proceeded quickly and chemoselectively, thereby allowing the straightforward access to the corresponding α- or ß-hydroxy phosphine oxides, respectively, under air and at room temperature (bench conditions), which are traditionally considered as textbook-prohibited conditions in the field of polar organometallic chemistry of s-block elements.