Unlocking the Potential of Deep Eutectic Solvents and Ligand-to-Metal Charge Transfer Processes: A Reusable Iron-and-UV-Based System for Sustainable C-C Bond Formation.

Catalytic C-H functionalization has provided new opportunities to access novel organic molecules more sustainably and efficiently. However, these procedures typically rely on precious metals or complex organic catalysts as well as on hazardous solvents or reaction conditions. Herein, a pioneering methodology for direct C-C bond formation enabled by Ligand-to-Metal Charge Transfer (LMCT) and mediated by UV irradiation has been developed using Deep Eutectic Solvents (DESs) as sustainable reaction media. This direct C-H bond functionalization via a radical addition to electrophiles was successfully confirmed over a broad scope of substrates. More importantly, this is the first example of photocatalytic C-C bond formation in DESs. An inexpensive and abundant iron catalyst (FeCl3) was used under air and mild conditions. Different functional groups were well tolerated obtaining promising results that were comparable to those reported in the literature. Additionally, the reaction medium along with the catalyst could be reused for up to 5 consecutive cycles without a significant loss in the reaction outcome. Several green metrics were calculated and compared to those of conventional procedures, revealing the advantages of using DESs.

5-(Trifluorovinyl)dibenzothiophenium Triflate: Introducing the 1,1,2-Trifluoroethylene Tether in Drug-Like Structures.

This manuscript reports the synthesis and structure of an unprecedented sulfonium salt, 5-(trifluorovinyl)dibenzothiophenium triflate, and its use as a versatile reagent for the introduction of the bioisosteric 1,1,2-trifluoroethylene linker in drug-like structures. The protocol developed consists of the reaction of this compound with alcohols and phenols to deliver a complete set of 1,2,2-trifluoro-2-(alkoxy-/aryloxy)ethyl sulfonium salts, which have been purified by column chromatography and fully characterized. Subsequent single electron reduction under mild photochemical conditions efficiently affords the corresponding fluoroalkyl radicals that are trapped either intra- or intermolecularly through their reaction with (hetero)arenes. Theoretical calculations are used to evaluate the conformational consequences derived from the presence of the CF2 -CHF tether.

Enantioselective Catalytic Aldol Reactions in the Presence of Knoevenagel Nucleophiles: A Chemoselective Switch Optimized in Deep Eutectic Solvents Using Mechanochemistry.

In the presence of different nucleophilic Knoevenagel competitors, cyclic and acyclic ketones have been shown to undergo highly chemoselective aldol reactions with aldehydes. In doing so, the substrate breadth for this emerging methodology has been significantly broadened. The method is also no longer beholden to proline-based catalyst templates, e.g., commercially available O-t-Bu-L-threonine is advantageous for acyclic ketones. The key insight was to exploit water-based mediums under conventional (in-water) and non-conventional (deep eutectic solvents) conditions. With few exceptions, high aldol-to-Knoevenagel chemoselectivity (>10:1) and good product profiles (yield, dr, and ee) were observed, but only in DESs (deep eutectic solvents) in conjunction with ball milling did short reaction times occur.

Deep Eutectic Solvents as à-la-Carte Medium for Transition-Metal-Catalyzed Organic Processes.

Our society is facing a tremendous challenge to become more sustainable in every sphere of life. Regarding the chemical industry, one of the most significant issues to be addressed is the use of volatile organic compounds (VOCs) as solvents because they are petrol-derived and most of them are toxic and flammable. Among the possible solutions, deep eutectic solvents (DESs) have emerged as sustainable alternatives to VOCs in organic catalyzed transformations and other fields. The advantages of these new reaction media are not only related to their more benign physical and chemical properties and, for most of them, their renewable sources but also due to the possibility of being recycled after their use, increasing the sustainability of the catalyzed process in which they are involved. However, their use as media in catalytic transformations introduces new challenges regarding the compatibility and activity of known catalysts. Therefore, designed catalysts and "à-la-carte" DESs systems have been developed to overcome this problem, to maximize the reaction outcomes and to allow the recyclability of the catalyst/media system. Over the last decade, the popularity of these solvents has steadily increased, with several examples of efficient metal-catalyzed organic transformations, showing the efficiency of the catalysts/DES system, compared to the related transformations carried out in VOCs. Additionally, due to the inherent properties of the DES, unknown transformations can be carried out using the appropriated catalyst/DES system. All these examples of sustainable catalytic processes are compiled in this review.

Palladium-catalysed Csp3-H functionalisation of unactivated 8-aminoquinoline amides in deep eutectic solvents.

The Csp3-H activation of aliphatic amides is described for the first time in deep eutectic solvents (DESs) without the need for Ag salts. The use of eutectic mixtures improves the yields obtained with volatile organic solvents, and allows for the reuse of the catalyst. Post-synthetic modifications can also be performed in DESs, increasing the sustainability of the process and the value of the products obtained.

Two-Step Synthesis of Heptacyclo[6.6.0.02,6 .03,13 .04,11 .05,9 .010,14 ] tetradecane from Norbornadiene: Mechanism of the Cage Assembly and Post-synthetic Functionalization.

A selective and scalable two-step approach to the dimerization of norbornadiene (NBD) into its thermodynamically most stable dimer, heptacyclo[6.6.0.02,6 .03,13 .04,11 .05,9 .010,14 ] tetradecane, (HCTD) is reported. Calculations indicate that the reaction starts with the Rh-catalyzed stepwise homo Diels-Alder cyclisation of NBD into its exo-cis-endo dimer. Treatment of this compound with acid promotes its evolution to HCTD via a [1,2]-sigmatropic rearrangement. The assemblies of 7,12-disubstituted cages from 7-(alkyl/aryl) NBDs, as well as the selective post-synthetic C-H functionalization of the core HCTD scaffold at position C1, or positions C1 and C4 are described.

New guidelines for testing "Deep eutectic solvents" toxicity and their effects on the environment and living beings.

Deep eutectic solvents (DESs) were described at the beginning of this century as an alternative to ionic liquids (ILs) in green chemistry. Despite their obvious sustainable advantages as reaction media, there is still controversy about their potential toxicity. Most of the ecotoxicity assays done up to now involving DESs are based on antibiograms. This is not a good approach due to the high density and viscosity of most DESs already described. Additionally, antibiograms do not allow continuous monitoring of neither cellular growth nor changes on physicochemical parameters like culture acidification due to cellular growth or DESs metabolization. This work starts by displaying advantages and disadvantages of the DESs toxicity assays already reported. Then, using a new DES recently described and Escherichia coli as a model microorganism, liquid cultures with continuous monitoring of pH, temperature, shaking and optical density have been used, for the first time, to quantify potential toxicity of the DES as well as the degree of the cellular tolerance (in preadapted and non-preadapted cells). The results obtained show that this new DES is not toxic for E. coli at concentrations up to 300 mM and cellular preadaptation was crucial for the cells to grow. At concentrations between 300 mM and 450 mM, cells can tolerate this DES. Above 600 mM, the DES is toxic causing complete inhibition of growth. This toxicity is not only due to the chemical composition of the DES, but also due to the high acidification of the media caused by the DES hydrolysis during cellular growth. The consequences of sterilization procedures on the DES stability are also analysed into detail, finding that sterilization by autoclave promotes DES hydrolysis. From these results, new guidelines are proposed for furthers studies aiming to characterize and quantify DESs toxicity.

Palladium Mesoionic Carbene Pre-catalyst for General Cross-Coupling Transformations in Deep Eutectic Solvents.

A strong σ-donor mesoionic carbene ligand has been synthesized and applied to four different palladium-catalyzed cross-coupling transformations, proving the catalyst/medium compatibility and the increased activity of this system over previous reports in Deep Eutectic Solvent medium. Some cross-coupling processes could be carried out at room temperature and using aryl chlorides as starting materials. The possible implementation of multistep synthesis in eutectic mixtures has also been explored. The presence of palladium nanoparticles in the reaction media has been evaluated and correlated to the observed activity.

Deep Eutectic Solvents as Reaction Media for the Palladium-Catalysed C-S Bond Formation: Scope and Mechanistic Studies.

A unique jigsaw catalytic system based on deep eutectic solvents and palladium nanoparticles where C-S bonds are formed from aryl boronic acids and sodium metabisulfite, is introduced. The functionalization step is compatible with a broad spectrum of reagents such as nucleophiles, electrophiles or radical scavengers. This versatile approach allows the formation of different types of products in an environmentally friendly medium by selecting the components of the reaction, which engage one with another as pieces in a jigsaw. This simple procedure avoids the use of toxic volatile organic solvents allowing the formation of complex molecules in a one-pot reaction under mild conditions. Despite the fact that only 1 mol % of metal loading is used, the recyclability of the catalytic system is possible. Kinetic experiments were performed and the reaction order for all reagents, catalyst and ligand was determined. The obtained results were compared to palladium nanocrystals of different known shapes in order to shed some light on the properties of the catalyst.